Principles and Practice of Geriatric Medicine

Principles and Practice of Geriatric Medicine Fourth Edition Volume 1 Editors M.S. John Pathy University of Wales, Car...

Author: M.S. John Pathy | Alan J. Sinclair | Professor John E. Morley

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Principles and Practice of

Geriatric Medicine Fourth Edition Volume 1 Editors

M.S. John Pathy University of Wales, Cardiff, UK

Alan J. Sinclair University of Warwick, Coventry, UK

John E. Morley Saint Louis University School of Medicine and Saint Louis Veterans’ Affairs Medical Center, St Louis, MO, USA


Geriatric Medicine Fourth Edition

In memory of my wife, Norma Mary, for her enduring support and encouragement and to my children, Aidan, Anne, Sarah, Helen and Damian for graciously accepting the limitations of my time. - M.S. John Pathy In loving memory of my parents, to whom I owe so much, and to my wife, Caroline, for her unflinching support throughout these last two years during the preparation of this textbook. - Alan J. Sinclair To all my older friends and patients who have taught me geriatrics, to my wife Pat and my children Robert, Sue and Jacqueline who have supported me throughout my career and to my grandchildren Amanda, Conor, Katelyn, Nicole and Paige who are my eternal joy and my hope for the future of elder care. - John E. Morley


Geriatric Medicine Fourth Edition

Editors

M.S. John Pathy University of Wales, Cardiff, UK

Alan J. Sinclair University of Warwick, Coventry, UK

John E. Morley Saint Louis University School of Medicine and Saint Louis Veterans’ Affairs Medical Center, St Louis, MO, USA

Copyright  2006 John Wiley & Sons Ltd, The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, England Telephone: (+44) 1243 779777 Email (for orders and customer service enquiries): [email protected] Visit our Home Page on www.wiley.com All Rights Reserved. No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, scanning or otherwise, except under the terms of the Copyright, Designs and Patents Act 1988 or under the terms of a licence issued by the Copyright Licensing Agency Ltd, 90 Tottenham Court Road, London W1T 4LP, UK, without the permission in writing of the Publisher. Requests to the Publisher should be addressed to the Permissions Department, John Wiley & Sons Ltd, The Atrium, Southern Gate, Chichester, West Sussex PO19 8SQ, England, or emailed to [email protected], or faxed to (+44) 1243 770620. This publication is designed to provide accurate and authoritative information in regard to the subject matter covered. It is sold on the understanding that the Publisher is not engaged in rendering professional services. If professional advice or other expert assistance is required, the services of a competent professional should be sought.

Other Wiley Editorial Offices John Wiley & Sons Inc., 111 River Street, Hoboken, NJ 07030, USA Jossey-Bass, 989 Market Street, San Francisco, CA 94103-1741, USA Wiley-VCH Verlag GmbH, Boschstr. 12, D-69469 Weinheim, Germany John Wiley & Sons Australia Ltd, 42 McDougall Street, Milton, Queensland 4064, Australia John Wiley & Sons (Asia) Pte Ltd, 2 Clementi Loop #02-01, Jin Xing Distripark, Singapore 129809 John Wiley & Sons Canada Ltd, 5353 Dundas Street West, Suite 400, Etobicoke, Ontario, Canada M9B 6HB Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic books.

British Library Cataloguing in Publication Data A catalogue record for this book is available from the British Library

ISBN-13 978-0-470-09055-8 ISBN-10 0-470-09055-3 Typeset in 10 / 11.5 pt Times Roman by Laserwords Private Limited, Chennai, India. Printed and bound by Grafos SA, Barcelona, Spain. This book is printed on acid-free paper responsibly manufactured from sustainable forestry in which at least two trees are planted for each one used for paper production.

Contents of Volume 1 List of Contributors . . . . . . . . . . . . . . . . . . . xiii Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . xxiii Preface to Third Edition . . . . . . . . . . . . . . . xxv Preface to Second Edition . . . . . . . . . . . . . xxvi Preface to First Edition . . . . . . . . . . . . . . . xxvii 1 Historical Perspectives . . . . . . . . . . . . . . 1 Michael J. Denham

Part I Human Aging: A Biological Perspective 2 A Biological Perspective on Aging . . . . 13 Thomas B.L. Kirkwood

3 Immunity and Aging . . . . . . . . . . . . . . . 19 Katsuiku Hirokawa, Masanori Utsuyama and Takashi Makinodan

4 Physiology of Aging . . . . . . . . . . . . . . . 37 Rafi Kevorkian

5 Aging of the Brain . . . . . . . . . . . . . . . . 47 Charles Mobbs

6 Psychological Aspects of Aging . . . . . . 53 Peggy A. Szwabo

7 Neurochemistry of Aging . . . . . . . . . . . 59

10 Social and Community Aspects of Aging . . . . . . . . . . . . . . . . . . . . . . . . . 101 Rodney M. Coe, John E. Morley and Nina Tumosa

11 Sexuality and Aging . . . . . . . . . . . . . . 115 John E. Morley

12 Physical Fitness and Exercise . . . . . . 123 Maria A. Fiatarone Singh

13 Transportation, Driving, and Older Adults . . . . . . . . . . . . . . . . . . . . . . . . 141 Desmond O’Neill and David Carr

14 Smoking in the Elderly . . . . . . . . . . . . 151 Norman J. Vetter

15 Alcohol Use and Abuse . . . . . . . . . . . . 157 Mary C. Dufour

16 On the Evolution of All-cause and Cause-specific Mortality in the Age Class 75–84 years: a Worldwide Overview . . . . . . . . . . . . . . . . . . . . . . 169 Hugo E. Kesteloot

17 Elder Abuse . . . . . . . . . . . . . . . . . . . . . 181 Jed Rowe

18 Smart Homes . . . . . . . . . . . . . . . . . . . . 189 Roger D. Orpwood

Alan M. Palmer and Paul T. Francis

8 Neuropathology of Aging . . . . . . . . . . . 69 Seth Love

Part III

Medicine in Old Age

19 Preventive Geriatrics . . . . . . . . . . . . . 201

Part II Human Aging: Social and Community Perspectives 9 The Demography of Aging . . . . . . . . . . 87 Kenneth G. Manton

Joseph H. Flaherty and Antony J. Bayer

20 Polypharmacy, is this Another Disease? . . . . . . . . . . . . . . . . . . . . . . 215 Oscar A. Cepeda and John E. Morley

vi

CONTENTS OF VOLUME 1

21 The Problem-Orientated Approach to Geriatric Medicine . . . . . . . . . . . . . . 223

36 Diseases of the Pancreas . . . . . . . . . . . 417 John S. Morris

Cameron G. Swift

Section 3 Hematological Disorders Section 1 Eating Disorders and Nutritional Health 22 Oral Health . . . . . . . . . . . . . . . . . . . . . 239 Janet E. Griffiths

23 Oral Disease . . . . . . . . . . . . . . . . . . . . 261 Donald Murray Walker

24 Epidemiology of Nutrition and Aging 279 Wija A. van Staveren and Lisette C.P.G.M de Groot

25 Absorption of Nutrients . . . . . . . . . . . 291 Akeeb Adedokun

26 The Anorexia of Aging . . . . . . . . . . . . 297 Ian M. Chapman

27 Weight Loss in Older Adults . . . . . . . 309 David R. Thomas and Bruno Vellas

37 Anemia in Older Persons . . . . . . . . . . 427 David R. Thomas

38 Disorders of Hemostasis . . . . . . . . . . . 437 Kingsley K. Hampton

39 Disseminated Intravascular Coagulation . . . . . . . . . . . . . . . . . . . 445 Kingsley K. Hampton

40 Anticoagulants in the Elderly . . . . . . 449 Hamsaraj G.M. Shetty and Philip A. Routledge

41 Myelodysplasia . . . . . . . . . . . . . . . . . . 455 Martha Wadleigh, David S. Rosenthal and Richard M. Stone

42 Management of Leukemia in the Elderly . . . . . . . . . . . . . . . . . . . . . . . 465 Hussain Saba and Lodovico Balducci

28 Dehydration . . . . . . . . . . . . . . . . . . . . . 321 Margaret-Mary G. Wilson

29 Vitamins and Minerals in the Elderly 329 Seema Joshi and John E. Morley

30 Obesity in the Elderly . . . . . . . . . . . . . 347 Richard Y.T. Chen and Gary A. Wittert

Section 4 Cardiovascular Disease and Health 43 Epidemiology of Heart Disease . . . . . 475 Chris MacKnight and Colin Powell

44 Cardiac Aging and Systemic Disorders . . . . . . . . . . . . . . . . . . . . . 487 David J. Stott and Arun K. Singh

Section 2 Gastro Disorders 31 Changes in Gastrointestinal Motor and Sensory Function Associated with Aging . . . . . . . . . . . . . . . . . . . . . . . . . 357 Christopher K. Rayner and Michael Horowitz

32 Gastrointestinal Bleeding . . . . . . . . . . 371 Syed H. Tariq

33 Liver and Gall Bladder . . . . . . . . . . . 381 Margaret-Mary G. Wilson

34 Sphincter Function . . . . . . . . . . . . . . . 395 Syed H. Tariq

35 Constipation . . . . . . . . . . . . . . . . . . . . 407 Charlene M. Prather

45 Arrhythmias in the Elderly . . . . . . . . 493 A. John Camm and Laurence Nunn

46 Ischemic Heart Disease in Elderly Persons . . . . . . . . . . . . . . . . . . . . . . . 515 Wilbert S. Aronow

47 Valvular Disease in the Elderly . . . . . 529 Jeffrey S. Borer

48 Hypertension . . . . . . . . . . . . . . . . . . . . 541 Ramzi R. Hajjar

49 Mechanisms of Heart Failure . . . . . . 555 Michael P. Frenneaux and Lynne K. Williams

50 Heart Failure in the Elderly . . . . . . . 567 Michael W. Rich


51 Management of Acute Cardiac Emergencies and Cardiac Surgery . 585 Wilbert S. Aronow

52 Cardiac Surgery in the Elderly . . . . . 593 Ulrich O. von Oppell and Adam Szafranek

53 Pathogenesis of Atherosclerosis . . . . . 611 Andrew C. Newby

54 Peripheral Vascular Disease in Elderly Persons . . . . . . . . . . . . . . . . . . . . . . . 623 Wilbert S. Aronow

55 Venous Thromboembolism . . . . . . . . . 633 Gordon D.O. Lowe

56 Cardiac Cachexia . . . . . . . . . . . . . . . . 639 Gerhard-Paul Diller and Stefan D. Anker

57 Cardiac Rehabilitation in Older People . . . . . . . . . . . . . . . . . . . . . . . . 647 Niccolò Marchionni, Francesco Fattirolli, Lucio A. Rinaldi and Giulio Masotti

Section 5 Respiratory Diseases 58 Epidemiology of Respiratory Infection . . . . . . . . . . . . . . . . . . . . . . 665 Joseph M. Mylotte

59 The Effect of Aging on the Respiratory Skeletal Muscles . . . . . . . . . . . . . . . . 671 Meme Wijesinghe and Lindsey Dow

60 Aspiration Pneumonia . . . . . . . . . . . . 685 Takashi Ohrui and Hidetada Sasaki

61 Respiratory Disease in the Elderly . . 693 Martin J. Connolly

62 Pulmonary Rehabilitation . . . . . . . . . 727 Peter Spiegler and Jonathan S. Ilowite

63 Sleep Disorders in Elderly People . . . 733 Paul Montgomery

vii

66 Parkinson’s Disease and Parkinsonism in the Elderly . . . . . . . . . . . . . . . . . . . . 765 Jeremy R. Playfer

67 Non Parkinsonian Movement Disorders in the Elderly . . . . . . . . . . . . . . . . . . 777 Katie Kompoliti and Cynthia L. Comella

68 Normal Pressure Hydrocephalus . . . . 787 Dennis S. Oh and Peter McL. Black

69 Epidemiology of Stroke . . . . . . . . . . . 795 Mitchell T. Wallin and John F. Kurtzke

70 Management of Carotid Artery Stenosis . . . . . . . . . . . . . . . . . . . . . . . 805 Lucy J. Coward and Martin M. Brown

71 Acute Stroke . . . . . . . . . . . . . . . . . . . . 815 Peter Crome and Elliot F. Epstein

72 Secondary Stroke . . . . . . . . . . . . . . . . 827 Helen Rodgers

73 Communication Disorders and Dysphagia . . . . . . . . . . . . . . . . . . . . . 841 Pamela M. Enderby

74 Stroke Rehabilitation . . . . . . . . . . . . . 849 Lalit Kalra

75 Clinical Psychology in Physical Rehabilitation . . . . . . . . . . . . . . . . . . 859 Julie R. Wilcox and Janice Rees

76 Epilepsy . . . . . . . . . . . . . . . . . . . . . . . . 869 Pamela M. Crawford

77 Syncope and Nonepileptic Attacks . . 879 Richard C. Roberts

78 Peripheral Neuropathy . . . . . . . . . . . . 889 Bakri H. Elsheikh Mohamed and Miriam L. Freimer

79 Disorders of the Neuromuscular Junction . . . . . . . . . . . . . . . . . . . . . . 899 Ian K. Hart

Section 6 CNS Disorders 64 Neurological Signs of Aging . . . . . . . . 743 Andrew J. Larner

65 Headache in the Elderly . . . . . . . . . . . 751 Stephen D. Silberstein and William B. Young

80 Sarcopenia and Sarcopenic-Obesity . 909 Richard N. Baumgartner and Debra L. Waters

81 Muscle Disorders . . . . . . . . . . . . . . . . . 935 David Hilton-Jones

82 Motor Neurone Disease . . . . . . . . . . . 949 Hardev S. Pall

viii


83 Abnormalities of the Autonomic Nervous System . . . . . . . . . . . . . . . . . . . . . . . . 969 Kenneth J. Collins

84 Control of Chronic Pain . . . . . . . . . . . 981 Robert D. Helme and Benny Katz

85 Cervical and Lumbar Spinal Canal Stenosis . . . . . . . . . . . . . . . . . . . . . . . 991 M.S. John Pathy

86 Spinovascular Insufficiency . . . . . . . 1001 M.S. John Pathy

87 Subarachnoid Hemorrhage . . . . . . . 1015 Jan van Gijn and Gabriel J.E. Rinkel

88 Acute and Chronic Subdural Hematoma . . . . . . . . . . . . . . . . . . . 1027 Jonathan A. Vafidis

Appendix: Conversion of SI Units to Standard Units . . . . . . . . . . . . . . . . . . . i Index . . . . . . . . . . . . . . . . . . . . . . . . . . . iii

Contents of Volume 2 List of Contributors . . . . . . . . . . . . . . . . . . . xiii Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . xxiii Preface to Third Edition . . . . . . . . . . . . . . . xxv Preface to Second Edition . . . . . . . . . . . . . xxvi Preface to First Edition . . . . . . . . . . . . . . . xxvii

Section 7 Dementia Disorders

and

Cognitive

89 Communication Disorders in Dementia . . . . . . . . . . . . . . . . . . . . . 1037

99 Organization of Services in Geriatric Psychiatry . . . . . . . . . . . . . . . . . . . . 1163 Susan M. Benbow and David Jolley

100 Depression in Late Life: Etiology, Diagnosis and Treatment . . . . . . . . 1173 Natalie Sachs-Ericsson and Dan G. Blazer

101 The Older Patient with Down’s Syndrome . . . . . . . . . . . . . . . . . . . . 1185 John E. Morley

102 Drug Misuse and the Older Person: A Contradiction in Terms? . . . . . . . . 1191 Ilana B. Crome

Jennie A. Powell

90 Delirium . . . . . . . . . . . . . . . . . . . . . . . 1047 Joseph H. Flaherty

91 Memory Clinics . . . . . . . . . . . . . . . . . 1061 Antony J. Bayer

92 Cellular Changes in Alzheimer’s Disease . . . . . . . . . . . . . . . . . . . . . . 1073 Jean-Pierre Brion

93 Clinical Aspects of Alzheimer’s Disease . . . . . . . . . . . . . . . . . . . . . . 1083 Fatemeh Nourhashémi, Alan J. Sinclair and Bruno Vellas

94 Mild Cognitive Impairment . . . . . . . 1095 Pieter Jelle Visser

95 Vascular Dementia . . . . . . . . . . . . . . 1103

Section 8 Special Senses 103 Disorders of the Eye . . . . . . . . . . . . . 1205 Nina Tumosa

104 The Epidemiology of Hearing in Aging Population . . . . . . . . . . . . . . . . . . . 1211 Adrian C. Davis and Padma Moorjani

105 Auditory System . . . . . . . . . . . . . . . . 1219 R. Gareth Williams

106 Disorders of the Vestibular System . 1235 ˚ Linda M. Luxon and Charlotte Agrup

107 Smell and Taste . . . . . . . . . . . . . . . . . 1249 Richard L. Doty

Ingmar Skoog

96 Other Dementias . . . . . . . . . . . . . . . . 1111 Wee Shiong Lim and William A. Banks

97 Treatment of Behavioral Disorders . 1135 Ladislav Volicer

98 Geriatric Psychiatry . . . . . . . . . . . . . 1149 Abhilash K. Desai and George T. Grossberg

Section 9 Bone and Joint Health 108 Age-related Changes in Calcium Homeostasis and Bone Loss . . . . . 1261 Harvey James Armbrecht

109 Paget’s Disease of Bone . . . . . . . . . . 1269 Sanjay Sharma and Kenneth W. Lyles

x


110 Epidemiology of Osteoporosis . . . . . 1281 Horace M. Perry

111 Osteoporosis and its Consequences: a Major Threat to the Quality of Life in the Elderly . . . . . . . . . . . . . . . . . 1285 René Rizzoli

112 Gait, Balance, and Falls . . . . . . . . . . 1299 Peter W. Overstall and Thorsten Nikolaus

113 Foot Problems in the Elderly . . . . . . 1311 Arthur E. Helfand and Donald F. Jessett

114 Hip Fracture and Orthogeriatrics . . 1329 Antony Johansen and Martyn Parker

115 Diseases of the Joints . . . . . . . . . . . . 1347 Terry L. Moore

116 Back Pain . . . . . . . . . . . . . . . . . . . . . . 1355

125 Prostate Diseases . . . . . . . . . . . . . . . . 1469 Timothy D. Moon and Jennifer L. Maskel

126 Urinary Incontinence . . . . . . . . . . . . 1485 Margaret-Mary G. Wilson

127 Renal Diseases . . . . . . . . . . . . . . . . . . 1495 Carlos G. Musso and Juan F. Mac´ıas-Núnez

Section 12 Cancer 128 Cancer and Aging . . . . . . . . . . . . . . . 1509 Claudia Beghe and Lodovico Balducci

129 Oncological Emergencies and Urgencies . . . . . . . . . . . . . . . . . . . . 1519 Samuel Spence McCachren

130 Breast Cancer in the Elderly . . . . . . 1531 R.E. Mansel and A. Srivastava

John V. Butler

Section 10 Endocrine and Metabolic Disorders 117 Water and Electrolyte Balance in Health and Disease . . . . . . . . . . . . . . . . . . . 1369 Allen I. Arieff

118 Endocrinology of Aging . . . . . . . . . . 1389 John E. Morley and Moon J. Kim

119 The Pituitary Gland . . . . . . . . . . . . . 1397 James F. Lamb and John E. Morley

120 Thyroid Disorders . . . . . . . . . . . . . . . 1405 Rachel F. Oiknine and Arshag D. Mooradian

121 Ovarian and Testicular Function . . . 1415 Syed H. Tariq

122 Type 2 Diabetes Mellitus in Senior Citizens . . . . . . . . . . . . . . . . . . . . . . 1431 Alan J. Sinclair and Graydon S. Meneilly

Section 11 Urogenital Disorders 123 Gynecology and the Older Patient . 1449 Radha Indusekhar, F. O’Mahony and P.M.S. O’Brien

124 The Aging Bladder . . . . . . . . . . . . . . 1459 James M. Cummings and Kimberly C. Berni

Section 13 Functional Disorders and Rehabilitation 131 Multidimensional Geriatric Assessment . . . . . . . . . . . . . . . . . . . 1543 Laurence Z. Rubenstein and Andreas E. Stuck

132 Function Assessment Scales . . . . . . . 1553 Fredric D. Wolinsky

133 Frailty . . . . . . . . . . . . . . . . . . . . . . . . 1565 John E. Morley

134 Rehabilitation . . . . . . . . . . . . . . . . . . 1571 Paul M. Finucane and Philip J. Henschke

Section 14 Special Issues 135 Skin Disorders in the Elderly . . . . . 1589 Daniel S. Loo, Mina Yaar and Barbara A. Gilchrest

136 Pressure Ulceration . . . . . . . . . . . . . . 1605 Joseph E. Grey and Keith G. Harding

137 Perioperative and Postoperative Medical Assessment . . . . . . . . . . . . . . . . . . . 1631 D. Gwyn Seymour

138 Anesthesia in Older People . . . . . . . 1647 Suzanne Crowe

139 Health Issues in the Aging Female . 1659 Carolyn Philpot


140 Antiaging . . . . . . . . . . . . . . . . . . . . . . 1665 Alfred L. Fisher

141 Ethical Issues . . . . . . . . . . . . . . . . . . . 1681 Maureen Junker-Kenny and Davis Coakley

142 Restraints and Immobility . . . . . . . . 1689 Elizabeth A. Capezuti and Laura M. Wagner

143 Centenarians . . . . . . . . . . . . . . . . . . . 1701 Thomas T. Perls and Dellara F. Terry

Section 15 Diagnostic Interventions 144 Diagnostic Imaging and Interventional Radiology . . . . . . . . . . . . . . . . . . . . 1711 J. Richard Harding

Section 16 Infectious Disorders 145 Infectious Diseases . . . . . . . . . . . . . . 1725 Ann R. Falsey

146 Tuberculosis . . . . . . . . . . . . . . . . . . . . 1739 Shobita Rajagopalan and Thomas T. Yoshikawa

147 Infective Endocarditis in the Elderly 1749 Philippe Moreillon, Alain Bizzini and Yok Ai Que

148 Infections of the Central Nervous System . . . . . . . . . . . . . . . . . . . . . . . 1763 Michael Blank and Allan R. Tunkel

xi

153 Nursing Home Care . . . . . . . . . . . . . 1817 David R. Thomas and John E. Morley

154 Clinical Audit of Health Care . . . . . 1827 Jonathan M. Potter and Michael G. Pearson

155 Improving Quality of Care . . . . . . . . 1837 Julie K. Gammack and Carolyn D. Philpot

156 Resident Assessment Instrument/ Minimum Data Set . . . . . . . . . . . . 1855 Brant E. Fries, Catherine Hawes, John N. Morris and Roberto Bernabei

157 Nursing (UK) . . . . . . . . . . . . . . . . . . . 1867 Nicky Hayes

158 Geriatric Occupational Therapy: Focus on Participation in Meaningful Daily Living . . . . . . . . . . . . . . . . . . . . . . . 1879 Karen F. Barney

159 Systems of Health Care: the United Kingdom, the United States, and Australia . . . . . . . . . . . . . . . . . . . . . 1889 Julie K. Gammack, Gideon A. Caplan and Krishnendu Ghosh

160 Geriatric Day Hospitals . . . . . . . . . . 1907 Neil D. Gillespie and Irene D. Turpie

161 Health and Care for Older People in the United Kingdom . . . . . . . . . . . . . . . 1915 Clive Bowman and Catherine Dixon

162 Geriatrics in the United States . . . . 1923

Part IV

Health Care Systems

149 Geriatric Medicine Education in Europe . . . . . . . . . . . . . . . . . . . . . . 1783 Antonio Cherubini, Philippe Huber and Jean-Pierre Michel

150 Education in Geriatric Medicine in the United Kingdom . . . . . . . . . . . . . . . 1789 Robert W. Stout

151 The Contribution of Family Doctors to the Primary Care of Older People: Lessons from the British Experience . . . . . . . . . . . . . . . . . . . 1799 Steve Iliffe

152 Carers and the Role of the Family . 1809 Jo Moriarty

John E. Morley and Julie K. Gammack

163 Geriatrics and Gerontology in Japan 1935 Yuko Suda and Ryutaro Takahashi

164 Care of the Elderly in Israel: Old Age in a Young Land . . . . . . . . . . . . . . . . . 1947 A. Mark Clarfield, Jenny Brodsky and Arthur Leibovitz

165 Geriatric Medicine in China . . . . . . 1953 Leung-Wing Chu

166 Aging in Developing Countries . . . . 1965 Luis M. Gutiérrez-Robledo

167 Geriatrics from the European Union Perspective . . . . . . . . . . . . . . . . . . . 1977 Alfonso J. Cruz-Jentoft and Paul V. Knight

xii


168 Delivery of Health Care in India . . . 1983 Om Prakash Sharma

169 Geriatrics in Latin America . . . . . . . 1993 Fernando Morales-Mart´ınez and Martha Pelaez

170 Management of the Dying Patient . . 2001 Ilora G. Finlay and Saskie Dorman

Appendix: Conversion of SI Units to Standard Units . . . . . . . . . . . . . . . . . . . i Index . . . . . . . . . . . . . . . . . . . . . . . . . . . iii

Contributors AKEEB ADEDOKUN Saint Louis University, St Louis, MO, USA ˚ GRUP CHARLOTTE A University College of London Hospitals NHS Trust, London, UK STEFAN D. ANKER Applied Cachexia Research Unit, Charite, Campus Virchow – Klinikum, Berlin, Germany ALLEN I. ARIEFF University of California, San Francisco, CA, USA HARVEY JAMES ARMBRECHT Saint Louis University Health Sciences Center and Saint Louis Veterans’ Affairs Medical Center, St Louis, MO, USA WILBERT S. ARONOW Westchester Medical Center/New York Medical College, Valhalla, NY, USA, and Mount Sinai School of Medicine, New York, NY, USA LODOVICO BALDUCCI University of South Florida College of Medicine, Tampa, FL, USA and H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA

CLAUDIA BEGHE University of South Florida College of Medicine, Tampa, FL, USA and James A. Haley Veterans’ Hospital, Tampa, FL, USA SUSAN M. BENBOW University of Staffordshire, Staffordshire, UK ROBERTO BERNABEI Hebrew Rehabilitation Center for Aged, Boston, MA, USA and Università Cattolica del Sacro Cuore, Rome, Italy KIMBERLY C. BERNI Saint Louis University, St Louis, MO, USA ALAIN BIZZINI University of Lausanne, Lausanne, Switzerland PETER McL. BLACK Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA MICHAEL BLANK Drexel University College of Medicine, Philadelphia, PA, USA DAN G. BLAZER Duke University Medical Center, Durham, NC, USA

WILLIAM A. BANKS Saint Louis University School of Medicine and Saint Louis Veterans’ Affairs Medical Center, St Louis, MO, USA

JEFFREY S. BORER Weill Medical College of Cornell University, New York, NY, USA

KAREN F. BARNEY Saint Louis University, St Louis, MO, USA

CLIVE BOWMAN BUPA Care Services, Leeds, UK

RICHARD N. BAUMGARTNER University of Louisville, Louisville, KY, USA

JEAN-PIERRE BRION Université Libre de Bruxelles, Brussels, Belgium

ANTONY J. BAYER Cardiff University, Cardiff, UK

JENNY BRODSKY JDC-Brookdale Institute, Jerusalem, Israel

xiv

CONTRIBUTORS

MARTIN M. BROWN The National Hospital for Neurology and Neurosurgery, London, UK, and University College London, London, UK JOHN V. BUTLER Caerphilly District Miners Hospital, Caerphilly, UK A. JOHN CAMM St George’s Hospital Medical School, London, UK ELIZABETH A. CAPEZUTI New York University, New York, NY, USA GIDEON A. CAPLAN Prince of Wales Hospital, Randwick, New South Wales, Australia DAVID CARR Division of Geriatrics and Nutritional Science, Park Provence, St Louis, MO, USA

KENNETH J. COLLINS St Pancras and University College Hospitals, London, UK CYNTHIA L. COMELLA Rush University Medical Center, Chicago, IL, USA MARTIN J. CONNOLLY University of Manchester & Manchester Royal Infirmary, Manchester, UK LUCY J. COWARD The National Hospital for Neurology and Neurosurgery, London, UK, and University College London, London, UK PAMELA M. CRAWFORD York Hospital, York, UK ILANA B. CROME Keele University Medical School, Keele, UK

OSCAR A. CEPEDA Saint Louis University School of Medicine, St Louis, MO, USA

PETER CROME Keele University Medical School, Keele, UK

IAN M. CHAPMAN University of Adelaide, Royal Adelaide Hospital, Adelaide, South Australia, Australia

SUZANNE CROWE Adelaide & Meath Hospital incorporating the National Children’s Hospital, Dublin, Ireland

RICHARD Y.T. CHEN University of Adelaide, Royal Adelaide Hospital, Adelaide, South Australia, Australia

ALFONSO J. CRUZ-JENTOFT Hospital Ramón y Cajal, Madrid, Spain

ANTONIO CHERUBINI Perugia University Medical School, Perugia, Italy LEUNG-WING CHU University of Hong Kong and Hong Kong West Cluster Geriatrics Service, Queen Mary Hospital, Fung Yiu King Hospital, Tung Wah Hospital and Grantham Hospital, Hong Kong

JAMES M. CUMMINGS Saint Louis University, St Louis, MO, USA ADRIAN C. DAVIS University of Manchester, Manchester, UK LISETTE C.P.G.M. DE GROOT Wageningen University, Wageningen, The Netherlands

A. MARK CLARFIELD Ben Gurion University of the Negev, Beer Sheva, Israel, and McGill University, Montreal, QC, Canada

MICHAEL J. DENHAM Wellcome Trust Centre for the History of Medicine at UCL, London, UK

DAVIS COAKLEY Trinity College, Dublin, Ireland

ABHILASH K. DESAI Saint Louis University Health Sciences Center, St Louis, MO, USA

RODNEY M. COE Saint Louis University Health Sciences Center, St Louis, MO, USA

GERHARD-PAUL DILLER National Heart and Lung Institute, London, UK

CONTRIBUTORS

CATHERINE DIXON BUPA Care Services, Leeds, UK

PAUL T. FRANCIS King’s College London, London, UK

SASKIE DORMAN Velindre Cancer Centre, Cardiff, UK

MIRIAM L. FREIMER Ohio State University College of Medicine, Columbus, OH, USA

RICHARD L. DOTY University of Pennsylvania, Philadelphia, PA, USA LINDSEY DOW Royal United Hospital NHS Trust, Bath, UK MARY C. DUFOUR CSR Incorporated, Arlington, VA, USA BAKRI H. ELSHEIKH MOHAMED Ohio State University College of Medicine, Columbus, OH, USA PAMELA M. ENDERBY University of Sheffield, Sheffield, UK ELLIOT F. EPSTEIN Walsall Manor Hospital, Walsall, UK ANN R. FALSEY University of Rochester School of Medicine and Dentistry, Rochester, NY, USA FRANCESCO FATTIROLLI University of Florence and Azienda Ospedaliero Universitaria Careggi, Florence, Italy MARIA A. FIATARONE SINGH University of Sydney, New South Wales, Australia, Hebrew Rehabilitation Center for Aged, Roslindale, MA, USA, and Tufts University, Boston, MA, USA ILORA G. FINLAY Cardiff University, Cardiff, UK PAUL M. FINUCANE University of Limerick, Limerick, Ireland ALFRED L. FISHER University of California, San Francisco, CA, USA JOSEPH H. FLAHERTY Saint Louis University School of Medicine and Saint Louis Veterans’ Affairs Medical Center, St Louis, MO, USA

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MICHAEL P. FRENNEAUX University of Birmingham, Birmingham, UK BRANT E. FRIES University of Michigan and Ann Arbor Veterans’ Affairs Medical Center, Ann Arbor, MI, USA JULIE K. GAMMACK Saint Louis University School of Medicine, St Louis, MO, USA, and Geriatric Research Education and Clinical Center, St Louis, MO, USA KRISHNENDU GHOSH University Hospital, Coventry, UK BARBARA A. GILCHREST Boston University School of Medicine, Boston, MA, USA NEIL D. GILLESPIE University of Dundee, Dundee, UK D. GRAMMATOPOULOS University of Warwick, Warwick, UK JOSEPH E. GREY University of Wales College of Medicine, Cardiff, UK JANET E. GRIFFITHS University Dental Hospital, Cardiff, UK GEORGE T. GROSSBERG Saint Louis University Health Sciences Center, St Louis, MO, USA ´ LUIS M. GUTIERREZ -ROBLEDO Instituto Nacional de Ciencias Médicas y Nutrición “Salvador Zubirán”, México D.F., Mexico

RAMZI R. HAJJAR Saint Louis University Health Sciences Center, St Louis, MO, USA, and Saint Louis Veterans’ Affairs Medical Center, St Louis, MO, USA KINGSLEY K. HAMPTON Royal Hallamshire Hospital, Sheffield, UK

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CONTRIBUTORS

J. RICHARD HARDING St Woolos and Royal Gwent Hospitals, Newport, UK KEITH G. HARDING University of Wales College of Medicine, Cardiff, UK IAN K. HART Walton Centre for Neurology and Neurosurgery, Liverpool, UK CATHERINE HAWES Texas A&M University System Health Science Center, College Station, TX, USA NICKY HAYES King’s College Hospital NHS Trust, London, UK ARTHUR E. HELFAND Temple University, Philadelphia, PA, USA, and Thomas Jefferson University, Philadelphia, PA, USA ROBERT D. HELME Barbara Walker Centre for Pain Management, Fitzroy, Victoria, Australia PHILIP J. HENSCHKE Repatriation General Hospital, Daw Park, South Australia, Australia DAVID HILTON-JONES Radcliffe Infirmary NHS Trust, Oxford, UK, Milton Keynes Hospital NHS Trust, Buckinghamshire, UK, and Myasthenia Gravis Association Myasthenia Centre, Oxford, UK KATSUIKU HIROKAWA Tokyo Medical & Dental University, Tokyo, Japan MICHAEL HOROWITZ University of Adelaide, Adelaide, South Australia, Australia PHILIPPE HUBER University Hospital of Geneva, Geneva, Switzerland STEVE ILIFFE Royal Free & UCL Medical School, London, UK JONATHAN S. ILOWITE Winthrop University Hospital, New York, NY, USA

RADHA INDUSEKHAR University Hospital of North Staffordshire, Stoke-on-Trent, UK DONALD F. JESSETT Formerly of University of Wales, Cardiff, UK ANTONY JOHANSEN University Hospital of Wales, Cardiff, UK DAVID JOLLEY University of Staffordshire, Staffordshire, UK SEEMA JOSHI Saint Louis University Health Sciences Center, St Louis, MO, USA MAUREEN JUNKER-KENNY Trinity College, Dublin, Ireland LALIT KALRA King’s College London, London, UK BENNY KATZ Pain Management Clinic for the Elderly, Victoria, Australia HUGO E. KESTELOOT Katholieke Universiteit Leuven, Leuven, Belgium RAFI KEVORKIAN Saint Louis University, St Louis, MO, USA MOON J. KIM Saint Louis University School of Medicine and Saint Louis Veterans’ Affairs Medical Center, St Louis, MO, USA THOMAS B.L. KIRKWOOD University of Newcastle, Newcastle-upon-Tyne, UK PAUL V. KNIGHT Royal Infirmary, Glasgow, UK KATIE KOMPOLITI Rush University Medical Center, Chicago, IL, USA JOHN F. KURTZKE Veterans’ Affairs Medical Center and Georgetown University, Washington, DC, USA

CONTRIBUTORS

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JAMES F. LAMB Ohio State University College of Medicine and Public Health, Columbus, OH, USA

JENNIFER L. MASKEL University of Wisconsin and Veterans’ Affairs Medical Center, Madison, WI, USA

ANDREW J. LARNER Walton Centre for Neurology and Neurosurgery, Liverpool, UK

GIULIO MASOTTI University of Florence and Azienda Ospedaliero Universitaria Careggi, Florence, Italy

ARTHUR LEIBOVITZ Shmuel Harofeh Medical Centre, Beer Yaacov, Israel

SAMUEL SPENCE McCACHREN Thompson Cancer Survival Center, Knoxville, TN, USA

WEE SHIONG LIM Tan Tock Seng Hospital, Singapore DANIEL S. LOO Boston University School of Medicine, Boston, MA, USA SETH LOVE University of Bristol, Bristol, UK GORDON D.O. LOWE University of Glasgow, Glasgow, UK, and Glasgow Royal Infirmary, Glasgow, UK LINDA M. LUXON University College of London Hospitals NHS Trust, London, UK, and University College London, London, UK KENNETH W. LYLES Veterans’ Affairs Medical Center, Duke University Medical Center, Durham, NC, USA

GRAYDON S. MENEILLY University of British Columbia, Vancouver, BC, Canada JEAN-PIERRE MICHEL University Hospital of Geneva, Geneva, Switzerland CHARLES MOBBS Mount Sinai School of Medicine, New York, NY, USA PAUL MONTGOMERY University of Oxford, Oxford, UK TIMOTHY D. MOON University of Wisconsin and Veterans’ Affairs Medical Center, Madison, WI, USA ARSHAG D. MOORADIAN Saint Louis University, St Louis, MO, USA

´ -NUNEZ ´ JUAN F. MACIAS University Hospital of Salamanca, Salamanca, Spain

TERRY L. MOORE Saint Louis University Health Sciences Center, St Louis, MO, USA

CHRIS MACKNIGHT Dalhousie University, Halifax, NS, Canada

PADMA MOORJANI University of Manchester, Manchester, UK

TAKASHI MAKINODAN University of California at Los Angeles School of Medicine, Los Angeles, CA, USA

´ FERNANDO MORALES-MARTINEZ University of Costa Rica, San José, Costa Rica

ROBERT E. MANSEL Wales College of Medicine, Cardiff University, Cardiff, UK KENNETH G. MANTON Duke University, Durham, NC, USA NICCOLO` MARCHIONNI University of Florence and Azienda Ospedaliero Universitaria Careggi, Florence, Italy

PHILIPPE MOREILLON University of Lausanne, Lausanne, Switzerland JO MORIARTY King’s College London, London, UK JOHN E. MORLEY Saint Louis University School of Medicine and Saint Louis Veterans’ Affairs Medical Center, St Louis, MO, USA

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CONTRIBUTORS

JOHN N. MORRIS Hebrew Rehabilitation Center for Aged, Boston, MA, USA

PETER W. OVERSTALL County Hospital, Hereford, UK

JOHN S. MORRIS Princess of Wales Hospital, Bridgend, UK

HARDEV S. PALL University of Birmingham, Birmingham, UK, and University Hospital Birmingham Foundation Trust, Birmingham, UK

CARLOS G. MUSSO Hospital Italiano de Buenos Aires, Buenos Aires, Argentina

ALAN M. PALMER Pharmidex, London, UK

JOSEPH M. MYLOTTE University at Buffalo, Buffalo, NY, USA ANDREW C. NEWBY University of Bristol, Bristol, UK THORSTEN NIKOLAUS University of Ulm, Ulm, Germany

MARTYN PARKER University Hospital of Wales, Cardiff, UK M.S. JOHN PATHY University of Wales, Cardiff, UK MICHAEL G. PEARSON Royal College of Physicians, London, UK

´ FATEMEH NOURHASHEMI Toulouse University Hospital, Toulouse, France

MARTHA PELAEZ Pan American Health Organization, World Health Organization, Washington, DC, USA

LAURENCE NUNN St George’s Hospital Medical School, London, UK

THOMAS T. PERLS Boston University School of Medicine, Boston, MA, USA

P.M.S. O’BRIEN University Hospital of North Staffordshire, Stoke-on-Trent, UK

HORACE M. PERRY Saint Louis University, St Louis, MO, USA

DENNIS S. OH Tufts University School of Medicine, Springfield, MA, USA TAKASHI OHRUI Tohoku University School of Medicine, Sendai, Japan RACHEL F. OIKNINE Saint Louis University, St Louis, MO, USA F. O’MAHONY University Hospital of North Staffordshire, Stoke-on-Trent, UK DESMOND O’NEILL Adelaide & Meath Hospital incorporating the National Children’s Hospital, Dublin, Ireland ROGER D. ORPWOOD University of Bath, Bath, UK

CAROLYN D. PHILPOT Saint Louis University School of Medicine, St Louis, MO, USA JEREMY R. PLAYFER Royal Liverpool University Hospital, Liverpool, UK JONATHAN M. POTTER Royal College of Physicians, London, UK COLIN POWELL Dalhousie University, Halifax, NS, Canada JENNIE A. POWELL Llandough Hospital, Cardiff, UK CHARLENE M. PRATHER Saint Louis University, St Louis, MO, USA YOK AI QUE Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland

CONTRIBUTORS

SHOBITA RAJAGOPALAN Charles R. Drew University of Medicine and Science, Los Angeles, CA, USA CHRISTOPHER K. RAYNER University of Adelaide, Adelaide, South Australia, Australia JANICE REES St Woolos Hospital, Newport, UK MICHAEL W. RICH Washington University School of Medicine, St Louis, MO, USA LUCIO A. RINALDI University of Florence and Azienda Ospedaliero Universitaria Careggi, Florence, Italy GABRIEL J.E. RINKEL University Medical Centre, Utrecht, The Netherlands RENE´ RIZZOLI University Hospitals, Geneva, Switzerland RICHARD C. ROBERTS University of Dundee, Dundee, UK HELEN RODGERS University of Newcastle, Newcastle-upon-Tyne, UK DAVID S. ROSENTHAL Dana-Farber Cancer Institute, Boston, MA, USA PHILIP A. ROUTLEDGE Cardiff University, Cardiff, UK JED ROWE Moseley Hall Hospital, Birmingham, UK LAURENCE Z. RUBENSTEIN Geriatric Research Education and Clinical Center, UCLA – Greater Los Angeles Veterans’ Affairs Medical Center, CA, USA

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HIDETADA SASAKI Tohoku University School of Medicine, Sendai, Japan D. GWYN SEYMOUR University of Aberdeen, Aberdeen, UK OM PRAKASH SHARMA Geriatric Society of India, New Delhi, India SANJAY SHARMA Veterans’ Affairs Medical Center, Duke University Medical Center, Durham, NC, USA HAMSARAJ G.M. SHETTY University Hospital of Wales, Cardiff, UK STEPHEN D. SILBERSTEIN Thomas Jefferson University, Philadelphia, PA, USA ALAN J. SINCLAIR University of Warwick, Coventry, UK ARUN K. SINGH Glasgow Royal Infirmary, Glasgow, UK INGMAR SKOOG University of Gothenburg, Gothenburg, Sweden PETER SPIEGLER Winthrop University Hospital, New York, NY, USA ANURAG SRIVASTAVA Wales College of Medicine, Cardiff University, Cardiff, UK RICHARD M. STONE Dana-Farber Cancer Institute, Boston, MA, USA DAVID J. STOTT Glasgow Royal Infirmary, Glasgow, UK ROBERT W. STOUT Queen’s University Belfast, Belfast, UK

HUSSAIN SABA University of South Florida College of Medicine, Tampa, FL, USA, and James A. Haley Veterans’ Hospital, Tampa, FL, USA

ANDREAS E. STUCK Department of Geriatric Medicine, Spital Bern Ziegler, Bern, Switzerland

NATALIE SACHS-ERICSSON Florida State University, Tallahassee, FL, USA

YUKO SUDA Toyo University, Tokyo, Japan

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CONTRIBUTORS

CAMERON G. SWIFT King’s College London, London, UK

NORMAN J. VETTER University of Wales College of Medicine, Cardiff, UK

ADAM SZAFRANEK University Hospital of Wales, Cardiff, UK

PIETER JELLE VISSER University of Maastricht, Maastricht, The Netherlands, and VU Medical Center, Amsterdam, The Netherlands

PEGGY A. SZWABO Saint Louis University School of Medicine, St Louis, MO, USA

LADISLAV VOLICER University of South Florida, Tampa, FL, USA

RYUTARO TAKAHASHI Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan

ULRICH O. VON OPPELL University Hospital of Wales, Cardiff, UK

SYED H. TARIQ Saint Louis University School of Medicine, St Louis, MO, USA DELLARA F. TERRY Boston University School of Medicine, Boston, MA, USA DAVID R. THOMAS Saint Louis University Health Sciences Center and Saint Louis Veterans’ Affairs Medical Center, St Louis, MO, USA NINA TUMOSA Saint Louis University School of Medicine and Saint Louis Veterans’ Affairs Medical Center, St Louis, MO, USA ALLAN R. TUNKEL Drexel University College of Medicine, Philadelphia, PA, USA IRENE D. TURPIE McMaster University, Hamilton, ON, Canada MASANORI UTSUYAMA Tokyo Medical & Dental University, Tokyo, Japan JONATHAN A. VAFIDIS University Hospital of Wales, Cardiff, UK JAN VAN GIJN University Medical Centre, Utrecht, The Netherlands WIJA A. VAN STAVEREN Wageningen University, Wageningen, The Netherlands BRUNO VELLAS Toulouse University Hospital, Toulouse, France

MARTHA WADLEIGH Dana-Farber Cancer Institute, Boston, MA, USA LAURA M. WAGNER Baycrest Centre for Geriatric Care, Toronto, ON, Canada DONALD MURRAY WALKER University of Sydney, Westmead, New South Wales, Australia MITCHELL T. WALLIN Veterans’ Affairs Medical Center and Georgetown University, Washington, DC, USA DEBRA L. WATERS University of Otago, Dunedin, New Zealand MEME WIJESINGHE Royal United Hospital NHS Trust, Bath, UK JULIE R. WILCOX Cardiff Royal Infirmary, Cardiff, UK LYNNE K. WILLIAMS University of Birmingham, Birmingham, UK R. GARETH WILLIAMS University Hospital of Wales, Cardiff, UK MARGARET-MARY G. WILSON Saint Louis University Health Sciences Center and Veterans’ Affairs Medical Center, St Louis, MO, USA GARY A. WITTERT University of Adelaide, Royal Adelaide Hospital, Adelaide, South Australia, Australia

CONTRIBUTORS

FREDRIC D. WOLINSKY University of Iowa, Iowa City, IA, USA, and Center for Research in the Implementation of Innovative Strategies and Practices, Iowa City Veterans’ Affairs Medical Center, Iowa City, IA, USA MINA YAAR Boston University School of Medicine, Boston, MA, USA

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THOMAS T. YOSHIKAWA Charles R. Drew University of Medicine and Science, Los Angeles, CA, USA WILLIAM B. YOUNG Thomas Jefferson University, Philadelphia, PA, USA

Preface “I offer no apology for the publication of this volume. The subject is one of the highest importance, and yet it has been strangely overlooked during the last half-century by the physicians of all countries.” -George Edward Day (1815 – 1872)

George Day’s introduction to his textbook Disease of Advanced Life, published in 1848, regrettably remains appropriate for textbooks published over 150 years later. Modern physicians can still fail to recognize the differences in disease presentation and management between middle-aged and older adults. It is our hope that this Fourth Edition of “Principles and Practice of Geriatric Medicine” will help increase the awareness of geriatric principles and improve the treatment of older individuals. John Pathy’s original vision for the first edition was to provide, in a single volume, a comprehensive reference source for all those involved in the medicine of old age. We have endeavored to adhere to this vision, but inevitably the size of the textbook has grown. While in any text of this size some overlap with general texts of medicine will occur, the emphasis is on those assessments and disorders that are particularly of relevance to older persons. Over the seven years since the last edition of this text was published, there have been dramatic advances in our understanding of the pathophysiology of disease as it interacts with the physiological processes of aging. There has been a continuing validation of assessment tools for older persons and the development of some new ones. Large-scale studies of the efficacy of various geriatric systems such as Acute Care for the Elderly Units, Geriatric Evaluation and Management Units, and Home Care Systems have been carried out. All of these have demonstrated the value and cost-effectiveness of the geriatric specialist approach to managing older people. In comparison, most studies assessing Coronary Care Units and Intensive Care Units have failed to come close to demonstrating the effectiveness that has been shown for geriatric units. Despite this, all major hospitals have highly expensive critical care units, while fewer have developed geriatric units. The last decade has also seen an increased awareness of the need to enhance the quality of long-term care. This increase in geriatric knowledge has been recognized by the addition of nearly 40 new chapters in this edition. In addition, many of the previous chapters have been totally rewritten to allow the recognition of the changes that have occurred in our understanding of the care of older persons.

Previous editions of this textbook were edited by a single person, John Pathy. With the rapid increase in geriatric knowledge and John’s desire for the Fourth Edition to reflect the input of other academic minds, he has added two new editors to share the burden with him, namely, Alan Sinclair and John Morley. This has allowed a more even distribution of the editing tasks, though John Pathy has continued to carry the lion’s share. In recognition of the globalization of the world, in general, and geriatrics, in particular, one of the new editors, John Morley, is from the United States, while Alan Sinclair draws on his European experiences. In addition, a major effort has been made at the end of the text to recognize the differences (as well as the similarities) of geriatrics as it is practiced around the world. The enormous good fortune the editors had in recruiting a stellar class of contributors from around the world has, we hope, allowed this text to be truly representative of a global view of geriatric medicine. From the beginning, John Pathy has made this a goal of his text, and the editors feel that this edition has truly achieved an international view of old-age medicine as originally developed by Marjorie Warren and her colleagues in the United Kingdom. The general outline of the text still follows that of the first edition. The first sections provide a general perspective of old age, the processes of aging, and social and community perspectives. The chapter on preventive medicine now focuses on issues of particular importance to older persons. In Part III “Medicine in Old Age”, the section “Eating Disorders and Nutritional Health” has been increased to recognize the increased importance and understanding of nutrition in old age. Chapters on frailty, sarcopenia, palliative care, and women’s health have been added to recognize the increasing importance of these issues in older persons. The final part on “Health Care Systems” focuses first on the emergence of continuous quality improvement, geriatric systems and evidence-based medicine as the foundation of high-quality geriatric medicine. The development of novel education systems is discussed. Finally, unique aspects of geriatric care around the world are examined. In an attempt to improve the readability of the text, we have asked the authors to make liberal use of tables and figures, and key points have been added at the end of each chapter. References have been limited, and at the beginning of the reference list, authors identify a few key references to allow for further reading. The new editors have tried to keep the easy reading style of the previous editions, but, as can be

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PREFACE

imagined, this has been a difficult task as we have increased the number of contributors from around the world. Overall, we hope our readers enjoy and learn from this textbook; for the three of us, it has been a true labor of love. We particularly would like to thank our contributors for the excellent job they have done. We would also like to thank Layla Paggetti from John Wiley & Sons for her tireless

efforts in making sure this book came to fruition. Finally, we would like to thank our families for their forbearance. This book is dedicated to all those who care for older persons. M.S. John Pathy, Alan J. Sinclair, John E. Morley December 2005

Preface to the Third Edition With an increasingly aging population in both the industrialized and developing world, the health care needs of older people can no longer be dismissed by society. A national provision for geriatric medical services was initially a British phenomenon that was later adopted by other European nations. On the other hand, the USA has long been at the forefront of much gerontological research. During the past decade, however, clinical practice and teaching in geriatric medicine has also moved forward at a phenomenal pace. The balance in this new edition reflects and emphasizes these changes. Those familiar with the previous editions will note that this edition has been published as a two volume set. This has been necessitated by the addition of 27 new chapters and the reorganization of and increase in the number of

clinical chapters. The original objective of providing an authoritative text on the medicine of old age has been maintained thanks to the distinguished panel of nearly 200 international contributors. It is with deepest regret that I record the deaths of Professor Verna Wright and Professor Frank Benson. Dr John Morris, Dr Arup Banergee and Dr Brian Williams have generously provided editorial advice on the gastroenterology, haematology and cardiology sections respectively. The sustained support of Michael Osuch and Lewis Derrick of John Wiley & Sons is gratefully acknowledged. It is hoped that these two volumes will encourage and inform all those whose clinical practice brings them into contact with elderly patients.

Preface to the Second Edition In this new edition my priority was not only to revise and update, but to reorganize and restructure to make the information as accessible and useful to the reader as possible. The result is that not only have we included some 45 distinguished new contributors, and indeed several entirely new topics, but about 50% of the book has been rewritten almost from scratch, with the remainder heavily revised and updated, and the entire content radically reorganized into what I believe is a more practical and logical format. New subjects now considered to be at the forefront of practice, and some published here for the first time, are covered, and I am delighted to welcome the following group of new authors: Professor D. Armstrong, Dr C.A. Bar, Dr W.H. Barker, Dr A.J. Bayer, Professor M. Bergman, Dr E.T. Bloom, Dr D.G. Clements, Dr K.J. Collins, Dr I.G. Finlay, Dr P. Finucane, Dr C. Freer, Dr S.R. Gambert, Professor A.M. Gelb, Ms J.E. Griffiths, Dr J.T. Hartford, Ms A.E. Helfand, Dr S.J. James, Mr D.F. Jessett, Dr R.A. Kane, Professor H. Katsunuma, Professor H. Kesteloot, Dr J. Lubinski, Dr L.M. Luxon, Professor W.J. Maclennan, Dr S.S. McCachren, Professor J.F. Macias-Nunez, Dr S.E.

Mathers, Dr K. Morgan, Dr J.G. O’Brien, Dr M.E. Piper, Dr J. Powell, Ms H.G. Prince, Dr T. Pullar, Dr D.S. Rosenthal, Dr H.R. Silberman, Dr I.C. Stewart, Dr R. Strong, Professor M. Swash, Professor C.G. Swift, Professor W.A. Wallace, Dr M.F. Wilkins, Dr W.G. Wood, Dr A.M. Woods, Professor V. Wright. It is with deepest regret, however, that I must record the death of three contributors: Professor A.N. Exton-Smith, Dr R.A. Griffiths and Sir Alan Parks. I express my sincere appreciation to Dr A.J. Bayer for his invaluable assistance with some of the chapters, to my secretary, Mrs Shirley Green, for her meticulous typing, checking of references and collating material, and to the Department of Medical Illustration, University of Wales College of Medicine, for undertaking the additional illustrations for the revised chapter on rehabilitation in the elderly. It is a pleasure to acknowledge the high standard of general editorial services provided by Dr Lewis Derrick, Desk Editor, and the continuing support of Mrs Verity Waite, Publishing Editor in Medicine, John Wiley & Sons.

Preface to the First Edition In some parts of the world, notably Europe, North America and Japan, the impact of an expanding elderly population resulting from an era of unprecedented reduction in the diseases of early life has already had a dramatic effect on the epidemiology of disease. Within the foreseeable future no nation will escape a similar increase in the number of its elderly citizens with similar changes in the disease profile of its society. In the developed industrial nations Governments and medical schools, recognizing this phenomenon, are increasingly encouraging teaching and research in the medicine of later life. The objective of this textbook, written by authors of international repute, is to provide in a single volume a comprehensive reference source for all who are involved in the medicine of old age. Some overlap with textbooks of general medicine is inevitable but appropriate emphasis and attention is given to those disorders which are of particular relevance to the elderly. Whilst this is primarily a clinical textbook, an account is given of the fundamental changes associated with aging which are so inextricably interlinked with diseases that their study is essential to our understanding and management of elderly sick and disabled people. Equally important for those treating and caring for the old is an understanding of the influence, for good or ill, of the

social environment within which the elderly have to function and its effect on their health. Knowledge of programmes aimed at the promotion and maintenance of health, early detection of its impending breakdown and the organization and provision of services for health care are additional essential components of a complete account of the medicine of old age. The early chapters of the book provide a general perspective of old age and the process of aging. Preventive aspects together with accounts of nutrition and sleep in the elderly and the interpretation of biochemical data in older patients, precede the main clinical section which occupies the greater part of the text. The later chapters cover rehabilitation, the management of the dying patient and aspects of the delivery of health care. I acknowledge with gratitude the willing help of my colleagues, Dr Deirdre Hine and Dr D. Gwyn Seymour who read through much of the text and provided valuable criticisms and suggestions; and to my secretaries Mrs Lorraine Spriggs who did much of the typing and the arduous task of checking references, and Mrs Sylvia Bevan. I am indebted to Dr Ralph Marshall and his team in the Department of Medical Illustration at the University Hospital of Wales for preparing a number of figures and photographs.

1

Historical Perspectives Michael J. Denham Wellcome Trust Centre for the History of Medicine at UCL, London, UK

INTRODUCTION The broad subject of old age has attracted the attention of writers and philosophers for many centuries. It contains the interrelated topics of the theories of aging, of how to increase longevity, and the medical management of sick elderly people. Initially, the first two themes attracted most attention. It was not until the twentieth century that literature relating to medical care came to the fore. This chapter concentrates on the twentieth-century developments in medical care of the elderly (geriatric medicine), mainly from a British perspective since much of the pioneering work was carried out in the United Kingdom.

THE EARLIER WRITERS ON OLD AGE Early writers such as Hippocrates, Cicero, Galen, Roger Bacon, and Francis Bacon discussed old age in general terms pointing to features such as skin changes, reduction in physical strength, and deteriorating memory, sight, and hearing. None were sure of the cause(s) of old age. Theories ranged from incorrect diet, loss of heat to loss of moisture. Although the basis of growing old was unclear, several philosophers thought that a healthy old age could be promoted by keeping active, eating sensibly, and exercising regularly. Later, British writers of the eighteenth and nineteenth centuries, such as Sir John Floyer, Sir John Hill, Sir Anthony Carlisle, Professor George Day, and Sir John Sinclair, wrote about old age and how life might be prolonged, but devoted limited attention to medical management of disease in older people. They generally considered it impossible to turn an elderly man into a young person, but agreed that much could be done to make later life healthy. Lifestyle was important. They recommended wise eating of easily digestible foods taken at regular intervals, exercising regularly, ensuring good sleep, keeping clean, wearing warm clothing, and avoiding constipation. In 1863, Dr Daniel Maclachlan, medical

superintendent at the Royal Hospital Chelsea, criticized the lack of English literature relating to old age and pointed out that precise diagnosis could be difficult in older people because several diseases could exist simultaneously. In 1882, the English translation of Jean Martin Charcot’s Clinical Lectures of the Diseases of Old Age was published, which described an extensive range of subjects including the overt signs of old age, rheumatism, gout, arthritis, fever and its feeble response in older people, respiratory infections, cerebral hemorrhage, and cerebral softening. However, his contribution to treatment and management was limited. The early twentieth-century English writers such as Sir Henry Weber, Dr Robert Saundby, G. Stanley Hall and Sir Humphry Rolleston continued to describe old age, but again medical management received little attention. Maurice Ernest’s writing in 1938 pointed out that until the nineteenth century only superficial knowledge existed of how the body worked.

THE BIRTH OF MODERN GERIATRIC MEDICINE Modern geriatric medicine commenced in the United States. Although American writers in the nineteenth century, such as Dr Benjamin Rush, had published on the subject of old age, the real impetus for advance came later when a young medical student, Ignatz Nascher (1863–1944), an immigrant to America from Vienna, was taken to an almshouse to see some interesting cases. An old woman hobbled up to the medical teacher with a complaint. The class was told that she was suffering from old age and that nothing can be done for her. This remark impressed him so strongly that after qualification he took up the study of the diseases of old age. His lifetime work on the subject resulted in his becoming known as the “father of geriatric medicine”. His publication of Geriatrics in 1916 was followed by others including Dr Malford Thewlis, who published the first edition of his book, Geriatrics, in 1919; Dr Edmund Cowdry’s whose Problems of Aging appeared in 1939; and

Principles and Practice of Geriatric Medicine, 4th Edition. Edited by M.S. John Pathy, Alan J. Sinclair and John E. Morley.  2006 John Wiley & Sons, Ltd.

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Dr Alfred Worcester who published a series of lectures in 1940 called The Care of the Aged, the Dying, and the Dead. Dr Nathaniel Shock, in 1951, published the first edition of his classification of geriatrics and gerontology but pointed to the scarcity of material. In 1942 the American Geriatrics Society was formed with a membership of physicians, while in 1945 the Gerontological Society of America was created with a multidisciplinary membership. Each of the societies produced its own journal in 1946. Unfortunately, this momentum for change was not sustained, partly because physicians saw little attraction in the subject. Interest was not reignited until the 1960s when Medicare and Medicaid were introduced. Thus it was that leadership and instruction in modern geriatric medicine in the postwar era passed to the United Kingdom (UK), where the achievements of a handful of pioneers were becoming known.

BRITISH DEVELOPMENTS Health care in the United Kingdom goes back to that provided by the monasteries until they were dissolved in 1536. After the dissolution many of the aged and infirm, who could not be managed at home with the help of family members, were left uncared for. The Poor Law Relief Act of 1601 attempted to remedy these problems. Parishes levied a rate on all occupiers of property to provide work for the unemployed and accommodation for the lame, old, and blind. Workhouses were built for these purposes, but were made as unpleasant as possible to discourage people from entering them. Infirmaries were established to look after sick inmates of the workhouses. Outdoor relief was available for the poor but this was curtailed in 1832. Hospitals did not become central to health care until the nineteenth–twentieth centuries, by which time two different types of hospitals were evolving: the voluntary hospitals and the workhouse/municipal infirmaries (AbelSmith, 1964). Voluntary hospitals, some of which dated back to the tenth century, were financed from endowments, subscriptions, fees, and fund raising. They had a high reputation with good nursing and medical staff, and acted as a base for clinical teaching of medical students. They were reluctant to admit the chronic sick fearing that their beds could become blocked because these patients were slower in improving and there could be social problems preventing their discharge. An important consequence was that medical students rarely saw them and, therefore, were not taught about the diseases of old age or how to manage the mixture of medical and social problems they would meet after qualification. Workhouse infirmaries were funded by local rates. They gradually became long-stay institutions for the chronic sick. Examples of unsatisfactory conditions and poor care in workhouses and infirmaries surfaced in the 1860s and resulted in visits by the Lancet commissioners and the inspectors of the Poor Law Board. The 1869 report of the Lancet Sanitary Commission was damning, stating “The fate of the “infirm” inmates of crowded workhouses is

lamentable in the extreme; they lead a life which would be like that of a vegetable, were it not that it preserves the doubtful privilege of sensibility to pain and mental misery” (Anonymous, 1869). In 1929 the Local Government Act came into force, which aimed to correct the existing bipartite system of health care of “one part for the pauper and the other part for the nonpauper”. However, Charles Webster concluded that health services between the two world wars were ramshackle and uncoordinated, with hostility between sections of the service, increasingly chaotic funding, and with a hospital service which was unevenly distributed and limited in rural areas (Webster, 1993). Further reform came in 1948 with the creation of the National Health Service (NHS) which rearranged British health care into a tripartite system. First, there was the hospital service which was formed by the nationalization of 1143 voluntary and 1545 municipal hospitals. It became the dominant partner in the Service. Second, there were the general practitioner and the ophthalmic, pharmaceutical, and dental services. The third arm, which was managed by the local authorities, included health centers, health visitors, and ambulance services. Their immensely valuable home help and meals-on-wheel services did not really “take off” until some years later. Importantly, health care for all became free of charge. Voluntary and charitable organizations made important contributions to the care of the older person and research into old age. In 1943 the Nuffield Foundation was created, one of whose objectives was the care of the aged and the poor. This support led to the formation of the National Corporation for the Care of Old People in 1947. The Foundation also stimulated major research into the causes of old age (Gerontology). These moves to assist older people became increasingly important as the proportion of older people in the population steadily increased. In 1841, the over65-year-old people comprised 4.5% of the population, which rose to 4.7% in 1901, 7.8% by 1921, 9.6% by 1931 and reached 10.5% in 1947.

AN OVERVIEW OF EARLY GERIATRIC MEDICINE IN THE UNITED KINGDOM Modern geriatric medicine in the United Kingdom dates from 1926 when Dr Marjory Warren was appointed to the West Middlesex Hospital, where her interests were initially surgical. However, in 1935 the Hospital took over control of the adjacent old Poor Law institution and Warren was put in charge of 874 patients. The situation she found was described in the first of her many articles on the modern treatment of the chronic sick (Warren, 1943). At about the same time, three other British doctors were also keen to improve the medical care of the elderly: Dr Eric Brooke, Mr Lionel Cosin, and Dr Trevor Howell. Like her, they, too, applied classification, diagnosis, and treatment to their elderly patients, which had been previously missing. After the war, a further wave of

HISTORICAL PERSPECTIVES

enthusiasts, such as Lord Amulree, Drs John Agate, Charles Andrews, Ferguson Anderson (later Professor), Bill Davison, Hugo Droller, Norman Exton-Smith (later Professor), Tom Wilson, and Lyn Woodford-Williams, began to make their mark with many publications. These newly appointed postwar consultants in geriatric medicine had to embark on a steep learning curve. In the early days, they had the responsibility for very large numbers of inpatients, sometimes many hundreds, who were often kept in bed for no discernable medical reason, which could ultimately lead to a totally bedridden state. Generally there was a massive waiting list for admission, often precipitated by the death or illness of the carer or the person’s inability to prepare meals for him/herself. These new consultants learnt that illness and the presentation of disease in the older person differed from that of younger people, that more time was required to recover, that prescribing drug therapy required great care, that extensive teamwork was needed for successful rehabilitation, and that local social service support was usually essential to provide alternative accommodation or domiciliary support services. They had to provide a service although they lacked adequate resources and staffs, had poor ward accommodation, inadequate investigative/treatment facilities, and were not always based on the main hospital site. They had to fight antagonism and resistance from their fellow consultants and some hospital management committees. One chairman of such a committee refused a consultant geriatrician the use of empty beds in general medical wards: “Over my dead body”, he said. When he died the geriatrician got the beds. Another consultant had to fight for proper washing facilities in the wards and for curtains to be placed around the beds of elderly patients. Yet others had to struggle to get heating installed in the wards and repairs made to the leaking ward roofs. Important studies of the elderly living at home or in residential homes appeared shortly after the war. Dr Joseph Sheldon, a general physician, published The Social Medicine of Old Age in 1948, which was the result of his research into the health of the elderly living in the community in Wolverhampton. In 1955, Professor William Hobson and Dr John Pemberton published The Health of the Elderly at Home, which was a study of older people living at home in Sheffield. In 1962, Professor Peter Townsend published The Last Refuge, a seminal study of old people living in residential homes. The British Ministry of Health, which was created in 1919, and its medical officers supported the newly emerging style of medical care of the sick elderly patient with official circulars, memoranda, meetings, and documents. These highlighted its firm belief in modern management of elderly patients and the drive to establish a geriatric unit in every health district. The ministry organized surveys of hospitals in England and Wales, which were to be the basis of the forthcoming NHS. The reports, published in 1945, were generally very critical of services and accommodation for the chronic sick. “The worst and oldest buildings were set aside for the chronic sick” (Jones et al., 1945). “The buildings are old, dark, devoid of modern sanitary conveniences, death

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traps in the case of “fire”, and unfit for the nursing of the chronic sick” (Bevers et al., 1945). “The first essential is that every patient should be thoroughly examined and treated with a view to restoring a maximum degree of activity” (Gray and Topping, 1945). Later, Lord Amulree and Dr Edwin Sturdee, both medical officers of the Ministry, presented a paper on the care of the chronic sick to the Parliamentary Medical Committee in 1946 (Amulree and Sturdee, 1946). In it they stated, “not only is the problem of the treatment of the chronic sick not being met, but also most people do not realize there is a problem”. In 1957, Dr Christopher Boucher, a Principal Medical Officer at the Ministry, published the result of an important survey of services available to the chronic sick and elderly (Boucher, 1957). However, the ministry realized that it could not force change, but could only use persuasion to improve proper medical services for older people (Godber, 1991). Perhaps this was why that, even in 1978, 42 health districts in England still lacked geriatric beds in general hospitals. The British Medical Association played its part in planning the medical care of older people with a series of very specific reports. A coordinated geriatric service was recommended to the newly created Regional Health Authorities, supported by a wide range of domiciliary services, which would be needed by the infirm elderly to enable them to stay at home for as long as possible (British Medical Association, 1947, 1948, 1955). However, commentators looked back to the old Poor Law and the new NHS with mixed feelings (Webster 1988, 1991; Thane 1993, 2000). They pointed out that while the old Poor Law system had given a coordinated personal service to its clients, the tripartite structure of the NHS service led to lack of cooperation and coordination between the arms of the service. Chronic and mental services received a smaller share of capital and revenue, and clear guidelines for the treatment of old people were lacking. The political will to produce a nationwide effective geriatric service was lacking. On the other hand, the new service did provide the less well off with forms of care to which previously they had only limited entrée, and the elderly now had access to consultant services.

THE EARLY PIONEERS IN GERIATRIC MEDICINE In 1935, Dr Marjory Winsome Warren, CBE, MB (1897–1960), was placed in charge of 874 patients from the adjacent Public Assistance Institution. These included 16 maternity patients and about 144 “mental observation” patients, who were subsequently transferred to their appropriate departments. She assessed and examined the remainder. She described the situation as follows: Having lost all hope of recovery, with the knowledge that independence has gone, and with a feeling of helplessness and frustration, the patient rapidly loses morale and self respect and develops an apathetic. . .temperament, which leads to laziness and faulty habits, with or without incontinence. Lack of interest in the surroundings,

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confinement to bed. . .soon produces pressure sores. . .inevitable loss of muscle tone make for a completely bedridden state. . .[leading to] disuse atrophy of the lower limbs, with postural deformities, stiffness of joints, and contractures. . .in this miserable state, dull, apathetic, helpless, and hopeless, life lingers on, sometimes for years. (Warren, 1946)

She criticized the medical profession: “It is surprising that [it] has been so long awakening to its responsibilities towards the chronic sick and aged, and that the country at large should have been content to do so little for this section of the community” (Warren, 1946). She recognized the importance of the environment in helping patients recover. She improved ward lighting, arranged repainting of the wards from the previous drab color to cream, replaced old-fashioned beds, provided modern bedside lockers, bed tables, and headphones, as well as bright red top blankets, light colored bedspreads, and patterned screen curtains. Wards were equipped with handrails attached to the walls, and suitable armchairs provided. Floors were no longer highly polished and steps were avoided. Special chairs and walking sticks and frames were provided for arthritic and heart patients. Some equipment she designed herself is still used today. She was the first British geriatrician to publish admission, death, and discharge data. By 1948, Warren reported that the general medical staff acknowledged that their “chronic” elderly patients actually did better in the geriatric unit than in their own wards. Mr Lionel Zelick Cosin, FRCS (1910–1993), came from a surgical background to the care of the elderly chronic sick (Cosin, 1991). At the outbreak of war, he was drafted to Orsett Lodge Hospital in Essex, which had been upgraded to an Emergency Medical Service Hospital in 1939. He became responsible for 300 chronic sick patients in addition to his surgical commitments. He found that they were fed and kept clean but no other treatment was given. When ordinary admissions restarted in 1944, he admitted elderly women with fractured femurs, successfully operated on them, gave them rehabilitation, and discharged them home. In 1950, he was invited to establish a geriatric unit at Cowley Road Hospital in Oxford, where he became its first clinical director and established the first day hospital in the United Kingdom. He classified, diagnosed, and treated his elderly patients. He reorganized inpatient accommodation, creating an acute geriatric ward for investigation, treatment, and physiotherapy as well as a long-stay annex ward for the permanently bedfast, long-stay wards for the frail ambulant, and “residential home” type of accommodation for the more robust patients. These methods resulted in the average length of stay falling from 286 days to 51 days. The proportion remaining in hospital longer than 180 days declined from 20 to 7%. Admissions increased from 200 a year to 1200 through the same number of beds. The average age of the patients increased from 68 to 75 years. Approximately 10% of his patients became permanent bedfast (Cosin, 1956). Dr Eric Barrington Brooke, FRCP (1896–1957), became the first medical superintendent of newly built, 800 bedded,

St Helier Hospital in Carshalton. The building was hit several times by enemy bombs, his superintendent’s house was destroyed by a flying bomb in 1944, and he was severely wounded and lost an eye but he returned to duty in due course. In 1953, he was appointed consultant physician to the Southampton group of hospitals. His approach to his long waiting list for admissions was different from others because he had few hospital beds. He devised a scheme of managing patients at home with a domiciliary “inpatient service” supplemented by increased use of the outpatient department. The process began with a home visit made by a member of the hospital-based geriatric team. These revealed that only one in three of the patients on the list required admission on a short-term basis for investigation and treatment, terminal care, or to provide holiday relief for caring relatives. Where appropriate, he arranged for a coordinated home-based service with district nurses, home helps, domiciliary occupational therapists, a laundry service, and the Red Cross library. The local Women’s Voluntary Service set up a hot “meals-on-wheels” domiciliary service. He viewed the general practitioner as the key member of the whole support scheme. Dr Trevor Henry Howell, FRCP Ed. (1909–1988), first encountered elderly patients when he was a general practitioner before the war. What puzzled him was what represented “normal” for age and what represented disease. After his war service, he established a geriatric research unit at Battersea Hospital in London before becoming medical superintendent at Queen’s Hospital, Croydon. He kept meticulous records of his patients, which formed the basis of over 300 papers and four books that he wrote. He kept a handwritten record of every book he read, every patient he saw, and every postmortem held on his patients. Like his colleagues, he firmly supported teaching medical students. He and Sturdee were the driving force behind the creation in 1948 of the Medical Society for the Care of the Elderly, which later became the British Geriatrics Society. Howell was its secretary for many years.

THE SECOND WAVE OF GERIATRICIANS These were led by Lord Amulree, KBE, MD, FRCP (1900–1983), who, prior to his appointment as geriatric physician to University College Hospital and St Pancras Hospital in London in 1949, had worked at the Ministry of Health on aspects of care of the older person. This had brought him in touch with all the early pioneers. His appointment in geriatric medicine was, for a long time, the only one at a London teaching hospital. He and his staff classified, diagnosed, and treated elderly inpatients. Assessment visits were made to old people who were on the waiting list for admission. This ensured either appropriate placement of patients in hospital or that the necessary home support was arranged to enable the person to continue to stay at home. The result was a considerable shortening in the average inpatient length of stay, increased patient/bed turnover, and a reduced the waiting list.


Amulree was unique amongst geriatricians in having a “wide-angled” view of the care of elderly people. This resulted from his experience as a clinician, as a medical officer of the Ministry of Health and a Liberal peer in the House of Lords, where he spoke on matters relevant to the care of the elderly. He wrote extensively and his work included one of the first comprehensive articles on care of the elderly (Amulree, 1951). He is possibly best remembered for his maxim “Adding Life to Years”, as well as his stature, wisdom, and willingness to help colleagues. He was President of the British Geriatrics Society for 25 years. When all his achievements are taken into account, there is a case for calling him “the father of British geriatric medicine”. Professor Norman Exton-Smith, CBE, FRCP (1920–1990), was based at the Withington Hospital in London, before moving to University College Hospital and St Pancras Hospital when Lord Amulree retired. Like others he made detailed assessment of his clinical management of sick elderly people. His style of medical management of inpatient care increased patient turnover and reduced their length of stay. He adapted progressive patient care to fit the needs of geriatric medicine. He led and/or encouraged research work, imbuing enthusiasm in his research team, registrars, and colleagues. He established a research unit at St Pancras Hospital and supported work in subjects such as thermoregulation, control of the autonomic nervous system, falls, osteoporosis, osteomalacia, fractures of the femur, nursing of the elderly patient, pressure sores, nutrition of the older person, meals on wheels, terminal care, predicting mortality, and cognitive assessment. He wrote many papers, a substantive textbook on geriatric medicine, and coauthored several books. Exton-Smith considered the components of an effective geriatric department that included having a sufficient number of beds, both in total and in the District General Hospital; practicing progressive patient care; having adequate medical and nurse staffing; consulting with other consultant colleagues; making home visits; having a day hospital; and having good coordination with primary care and local authority services to produce a successful planned discharge. He thought that approximately half to two-thirds of all geriatric beds should be in the main hospital where the main diagnostic and treatment facilities were based, while the remainder should be in smaller units near the patients’ home. Professor Sir William Ferguson Anderson, OBE, FRCP (Glasgow, Edinburgh, and London), (1914–2001), was a strong advocate on behalf of older people. In 1965, he was appointed David Cargill Professor of Geriatric Medicine in the University of Glasgow. He firmly believed in the speciality as an academic discipline and the need to teach medical students about old age. He took geriatric medicine into the community, notably in Rutherglen, where he established health centers for the elderly. He wrote extensively, and his textbook Practical Management of the Elderly went into five editions. He lectured in many countries spreading the message of the achievements of British geriatric medicine, was a visiting professor to many countries, a major advisor to several medical charities for the elderly, and a superb charismatic ambassador for the speciality.

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GERIATRIC MEDICINE IN THE HOSPITAL Home visits were considered essential in the early days of the speciality. They were initiated by the geriatrician to assess patients on the waiting lists from a medical and social point of view, to gauge priority for admission, to ensure that right patients were admitted to the right bed, to reduce misplacement of elderly patients in inappropriate wards or local authority accommodation and help some patients remain at home with local authority domiciliary support. Knowledge gained at visits was often useful when planning discharge, and often assisted rapport with both patient and relatives. These visits revealed that the true list was often substantially shorter than the “paper” list because some patients had died, moved, recovered, or had been admitted elsewhere since being placed on the list. As waiting lists decreased, so the need for home visits began to disappear. However, domiciliary visits, made by the consultants at the request of the general practitioner, continued. Progressive patient care was widely practiced throughout the United Kingdom. It was a concept first developed in America in an attempt to overcome a shortage of skilled nurses. It involved moving patients from ward to ward, or sometimes within wards, as they improved or required further treatment. Most were admitted first to the initial treatment ward. From there patients could be discharged home, or moved to the continuation care wards, where they would be divided further into two groups: continued rehabilitation or continued nursing care. From those wards the patients could be discharged, moved to a halfway house to await a place in a welfare home, or returned home. The disadvantage of the system was that beds were not always used to maximum efficiency and nursing continuity was lost as patients moved from ward to ward. On the other hand, it was argued that it helped patients’ morale to be moved on as they improved. A consultative service provided by geriatricians to consultant colleagues was another important feature of the new style geriatric service. An excellent example of such collaboration, involving the general and geriatric physicians, resulted in a reduction in mean and median durations of stay in general medical wards (Burley et al., 1979). The mean stay for females over 65 years in general wards was reduced from 25 to 16 days and for the over 85s from 50 to 19 days. These changes were not due to increased transfers to the geriatric wards. Collaboration was particularly important for the orthopedic surgeons to assist the rehabilitation of elderly women after operations for a fractured neck of the femur. A thriving example, which achieved wide recognition, was created in Hastings by Dr Robert Irvine and Mr Michael Devas. Day hospitals were one of the major innovations in modern geriatric medicine and are viewed by many geriatricians as an essential part of their service. These facilities provided rehabilitation, physical maintenance, follow-up care after discharge from hospital, and allowed minor medical procedures to be undertaken without the need for inpatient admission. The Department of Health and Social Services recommended 2 places/1000 for those over 65 years with the usual size of

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a day hospital being 20–40 places per day (Department of Health and Social Security, 1971). They are generally open 5 days a week and require one session of consultant time, two sessions of junior doctor time, ten whole-time equivalent nurses and a rehabilitation team to provide a service for 30-day patients. Transport has been a major limiting factor in day hospital efficiency. One psychogeriatrician with a large rural area thought patients spent almost as long in the ambulance as at the hospital and wondered if a new form of psychiatric day care should be created called transport therapy: “the patient is jogged along the countryside for several hours. . .the hospital became irrelevant and to travel happily becomes more important than to arrive. Meals can be taken at a friendly transport cafe, always provided there is a greater-than-average provision of functioning lavatories” (Arie, 1975). Other delays can result from the considerable time taken to use the tail lift to “load” patients into the ambulance, and the diversion of day hospital ambulance to other duties. The efficiency and effectiveness of day hospitals has been much debated with criticism targeted at inadequate audit of their function, poor working policies and insufficient consultant input. Unfortunately, reliable data is difficult to obtain. Simple attendance rates are difficult to assess, since they depend on the size of the unit, the availability of transport, public holidays, and staff shortages. Properly designed trials are bedeviled by methodological limitations of the studies. Patients usually attend for different reasons and the number attending individual day hospitals may be small. Day units have different roles in different localities, and there can be difficulties in defining the control groups. The Royal College of Physicians of London reviewed 13 research studies including 6 randomized controlled trials, only two of which were based in the United Kingdom (Research Unit of the Royal College of Physicians, 1994). Unfortunately, they tended to give contradictory results depending on the nature of the treatment received by the control groups. Long-stay care, for those geriatric patients who fail to recover, has its own special requirements (A Better Home Life, 1996). The pace of life is slower but the patients need to be kept as mentally and physically active as possible to prevent institutionalization. Different nursing skills are required. The accommodation needs to be designed to take account of the fact that it is likely to be the patient’s home for several years and, therefore, it needs to be appropriately designed. Within the last 20 years or so, much of the longstay care, which used to be part of the NHS, has been transferred into the private/voluntary sector.

GERIATRIC MEDICINE IN THE COMMUNITY General practitioners have a pivotal role in elderly care. They provide free medical service for all those on their list of patients and act as first line of referral when the

person becomes ill. They can obtain medical support from the geriatric service or the local social service department. Regular review of their patients over the age of 75 years has been promoted. However, older people may not consult their general practitioner about their symptoms because they may feel that little could be done for them. Case-finding programs, which involve a search for untreated disability, have been revealing. Programs in Scotland found that general practitioners were largely aware of the major disorders affecting the elderly at home but were much less aware of minor disorders such as problems with sight, hearing, and care of toenails, which can have a major impact on quality of life and for which treatment can produce benefit (Williamson et al., 1964). Another major Scottish innovation was the creation of successful health centers to provide a “walk-in” medical assessment and treatment for elderly people (Anderson and Cowan, 1955). An effective social service department is an essential component of any geriatric service, since it can provide an extensive range of domiciliary care, such as home helps, meals on wheels, occupational therapy, appliances, and visits from the local social worker. Many provide residential homes for those who cannot manage at home even with maximum support and day centers for those who require diversional activities. The local social service departments liaise with voluntary organizations such as Age Concern, old people’s clubs, and church organizations. However, many of these services were inadequate in the early days of the NHS and took time to develop.

TEACHING GERIATRIC MEDICINE The teaching of medical students about the medical care of sick elderly people had long been recommended, but it was not until 1949 that Lord Amulree was appointed to University College Hospital, a London teaching hospital. Further advance had to wait until 1965 when Sir Ferguson Anderson became the first UK Professor of Geriatric Medicine. After this, progress was slow but by 1998 almost all the London teaching hospitals had a professorial chair in the speciality, and increasing numbers of chairs in geriatric medicine have been made in the country as a whole. These academic departments were usually based on an active geriatric unit with good community links. The curricula vary but could include biological and sociological gerontology as well as clinical geriatric medicine. Postgraduate research courses leading to the degrees of M.Sc. and Ph.D. have been set up. Some universities have a cluster of associated chairs, as the University of Manchester with two chairs in geriatric medicine, one each in cognitive gerontology, old-age psychiatry, gerodontology, biological gerontology, and social gerontology. However, research of attitudes of medical students toward the elderly has shown that they tend to lose their initial


interest and empathy for older people as they train and qualify. A survey of their attitudes before qualification showed that they had empathy for, and a “bedside interest in”, the elderly, which disappeared after graduation when the doctors considered their career prospects (Gale and Livesley, 1974). Parkhouse and McLaughlin (1976) found that no doctor, who had graduated in 1974, wished to enter geriatric medicine. Lambert et al. (1996) showed that little had changed in a review of career preferences among newly qualified doctors: preferences for geriatric medicine remained very low at 0.9%, well below general medicine and surgery, although above genetics. Factors blamed included the prejudice of medical teachers against geriatric medicine; poor image/role of the geriatrician, and mediocre working conditions. As a result, recruitment of medical staff into the speciality was poor. The Royal College of Physicians responded in 1972 and 1977 with a range of recommendations, including integration of geriatric medicine with general medicine, appointment of consultant physicians with a special interest in geriatric medicine, and rotation of junior training posts between the two specialties (Royal College of Physicians of London, 1972, 1977). The College also introduced the Diploma of Geriatric Medicine in 1986 to encourage general practitioners to gain interest in the care of older people.

ACHIEVEMENTS OF GERIATRIC MEDICINE As the new style treatment methods were applied to the previously neglected chronic sick, clear evidence emerged of its effectiveness, particularly in hospitals. Official health data sources, such as Hospital In Patient Enquiry (HIPE) data collection, the Office of Health Economics, and Health and Personal Social Services Statistics for England, showed that the number of deaths and discharges of elderly people, and patient turnover from geriatric wards, steadily increased while the average and median lengths of stay decreased. In 1980, the Chief Medical Officer for England and Wales was able to report “the average length of stay for patients in hospital departments of geriatric medicine is steadily diminishing – more so than in any other hospital speciality. Only 10% remain in hospital for more than 6 months; the median length of stay is only 21.7 days” (Department of Health and Social Security, 1980). Progress was such that in 1984 the Nuffield Provincial Hospital Trust was able to comment “It [geriatric medicine] has established its expertise and has had notable success in developing and raising the standards of services for the old” (Batchelor, 1984). Concomitant with these developments, individual geriatricians began to create differing styles of practice: while some did not take emergency admissions, others took increasing numbers of acutely ill patients, and still others reintegrated with general medicine, taking part in unselected acute medical take and joint ward rounds with their general physician colleagues.

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GERONTOLOGY: THE SCIENCE OF THE AGING PROCESS Interest in gerontology in the United Kingdom was stimulated by the support of charitable foundations and the enthusiasm of a few individuals. The Nuffield Foundation created a medical and biological Research Committee, which gave grants to Howell for his research, to Dr Alex Comfort to work with Sir Peter Medawar at Birmingham and later at University College London, and to Professor Sir Frederick Bartlett at the University of Cambridge to establish a research unit to investigate the psychological aspects of aging. The Nuffield and the Ciba Foundations supported Vladimir Korenchevsky (1880–1959), a Russian biologist, who had studied under Pavlov and Metchnikoff. His enthusiasm for the science of aging culminated in his becoming director of the Oxford Gerontological Institute. He was a driving force behind the creation of the International Association of Gerontology (IAG). The Ciba Foundation supported the IAG, which held its first meeting in 1950 in Liege, Belgium. The first meeting of the clinical section of the IAG was held in Sunderland in the United Kingdom in 1958 and was chaired by Dr Oscar Olbrich. A later meeting was held in Manchester in 1974, which was organized by Professor Brocklehurst. The Ciba Foundation maintained its interest in old age by establishing a series of special colloquia in London, which were attended by many international experts on aging, and supported the British Society for the Research in Ageing, which was founded by Korenchevsky.

PROBLEM AREAS The birth of geriatric medicine in the United Kingdom was hampered by the indifference of the medical profession to elderly patients for many reasons. The care of the aged and infirm lacked the dramatic appeal of acute illness in the young. Physicians questioned why elderly people should be put through extensive rehabilitation when they had only a few years to live. Complete recovery was rarely possible and the result was often disproportionate to the effort required. Chronic sick patients were often accommodated in poorly equipped and staffed hospitals. General physicians feared “bed blocking” if they admitted elderly patients, appeared uninterested in deciding what was normal or abnormal in this age-group, in learning what treatment could achieve, were displeased at the diversion of resources from general medicine to geriatric medicine, and were unenthusiastic about the considerable social/nonmedical components of geriatric medicine. Geriatricians were viewed as “secondrate” physicians. Another concern was the quality of care given to the elderly in hospital. This culminated in the publication in 1967 of Sans Everything: a Case to Answer, which alleged inappropriate care in hospitals for the elderly and mentally ill. Official investigations found that the complaints were inaccurate, vague, lacking in substance, misinterpretations,

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or overemotional (Martin, 1984). Following yet another allegation of improper care in a unit for the mentally subnormal in 1967, the Secretary of state for Health created the Hospital Advisory Service (HAS) in 1969, which was to act as his “eyes and ears”. It was to be responsible only to him and was to be independent of the Department of Health. Visits to hospitals for the elderly and mentally ill started in 1970 and were carried out by teams of “inpost” professionals: consultant geriatricians or psychiatrists, senior nurses, paramedical staff, administrators, and later social workers. It is best considered as a form of “peer review”. Later its remit was extended to cover community services, at which time it was renamed the Health Advisory Service. The development of specialist service for the elderly mentally ill lagged behind that of the physically ill. Not infrequently, these patients were inappropriately admitted to geriatric wards, where staff had limited experience in managing them. Sometimes they were admitted to large general mental hospitals where the general psychiatrists did not welcome them. The ministry was aware of the problems presented by these patients and published advisory documents (e.g. Ministry of Health, 1950; Department of Health and Social Security, 1972). Eventually, guidelines were introduced to ensure admission to an appropriate ward: assessment by a multidisciplinary team was recommended. Joint assessment units with input from the local authority, psychiatrists, and the geriatrician were set up, although they tended to silt up owing to the failure to move the patients on to suitable ward or accommodation. Psychogeriatric day hospitals were opened, which provided a useful community function. Local authority residential homes were encouraged to take more mentally ill patients. However, it was not until the 1970s that consultant psychogeriatricians were appointed. Another source of debate was the term geriatrics and its allied words. The word gerocomy, attributed to Galen, was used for the medical care of the elderly and was adapted to geroncology for their sociological aspects. In 1903, Metchnikoff invented the word gerontology for the biological study of the aging process. Nascher is generally credited with coining the word geriatrics (Nascher, 1916). “The term was. . . derived from the Greek, geron, old man and iatrikos, medical treatment. The etymological construction is faulty but euphony and mnemonic expediency were considered of more importance than correct grammatical construction”. Howell pointed out at least one author who had confused gerontology (the science of old age) and geriatrics (the care of the aged). The word gerontology has been attacked as a barbarous misspelling and the word geratology, the study of old age, has been suggested instead. The founders of the Medical Society for the Care of the Elderly did not use the word geriatrics since it was, in 1940s, almost unknown. Many UK hospital geriatric units, aware of the public’s perception of geriatrics as being apparently synonymous with senility, now call themselves “Department for the Medical Care of the Elderly” or “Care of the Elderly Department”.

KEY POINTS • In spite of interest in old age, enlightened medical treatment of the elderly sick patient did not start until the twentieth century. • Classification of patients and modern treatment methods showed that the majority of those admitted to elderly care wards could be discharged. • Community studies found unreported minor illness in older people, which could have a major impact on the quality of life if left untreated. • University authorities were slow to implement the education of medical students about the medical and social aspects of illness in the older person. • Powerful charitable foundations supported research into the causes of aging.

KEY REFERENCES • Abel-Smith B. The Hospitals 1800 – 1948 1964; Heinemann, London. • Boucher CA. Survey of Services Available to the Chronic Sick and Elderly 1954 – 1955 Reports on Public Health and Medical Subjects No. 98, 1957; Ministry of Health. • Thane P. Geriatrics. In WF Bynum & R Porter (eds) Companion Encyclopaedia of the History of Medicine 1993, pp 1092 – 118; Routledge, London and New York. • Thane P. Inventing geriatric medicine. Old Age in English History 2000, pp 436 – 57; Oxford University Press, Oxford and London. • Warren MW. Care of the chronic aged sick. Lancet 1946; 1:841 – 3. • Webster C. The Health Services Since the War. Volume 1 Problems of Health Care. The National Health Service Before 1957 1988; HMSO, London. • Webster C. The elderly and the early National Health Service. In M Pelling & RM Smith (eds) Life, Death and the Elderly 1991, pp 165 – 93; Routledge, London.

REFERENCES Abel-Smith B. The Hospitals 1800 – 1948 1964; Heinemann, London. A Better Home Life 1996; Centre for Policy on Ageing, London. Amulree L. Adding Life to Years 1951; The National Council of Social Service (Incorporated), London. Amulree L & Sturdee EL. Care of the chronic sick and of the aged. British Medical Journal 1946; 1:617 – 8. Anderson WF & Cowan NR. A consultative health centre for older people. Lancet 1955; 2:239 – 40. Anonymous. The Lancet Sanitary Commission 1869; Lancet, London. Arie T. Day care in geriatric psychiatry. Gerontologia Clinica 1975; 17:31 – 9. Batchelor I. Policies for a Crisis 1984; Nuffield Provincial Hospital Trust, London. Bevers EC, Gask GE & Parry RH. Ministry of Health: Hospital Survey – the Hospital Services of Berkshire, Buckinghamshire, and Oxfordshire 1945; HMSO, London. Boucher CA. Survey of Services Available to the Chronic Sick and Elderly 1954 – 1955 Reports on Public Health and Medical Subjects No. 98, 1957; Ministry of Health.

HISTORICAL PERSPECTIVES British Medical Association. Report of the committee on the care and treatment of the elderly and infirm. British Medical Journal: Supplement 1947; 1:133 – 40. British Medical Association. The right patient in the right bed. British Medical Journal (Supplement) 1948; 2:71 – 2. British Medical Association. Appendix IX: Report of the geriatrics joint subcommittee of the British Medical Association. British Medical Journal (Supplement) 1955; 1:181 – 90. Burley LE, Currie CT, Smith RG & Williamson J. Contribution from geriatric medicine within acute medical wards. British Medical Journal 1979; 2:90 – 2. Cosin L. A new approach to the problems of geriatric care. Kaiser Foundation Medical Bulletin 1956; 4:321 – 8. Cosin L. Geriatrics as a Speciality 1991; The British Library, National Sound Archive, London. Department of Health and Social Security. Hospital Geriatric Services Appendix A and B: DS 329/71 1971; Department of Health and Social Security, London. Department of Health and Social Security. Services for Mental Illness Related to Old Age 1972; HMSO, London. Department of Health and Social Security. On the State of the Public Health: the Annual Report of the Chief Medical Officer of the Department of Health and Social Security for the Year 1979 1980; HMSO, London. Gale J & Livesley B. Attitudes towards geriatrics: a report of the King’s survey. Age Ageing 1974; 3:49 – 53. Godber G. Geriatrics as a Speciality 1991; The British Library, National Sound Archive, London. Gray AMH & Topping A. Ministry of Health: Hospital Survey – the Hospital Services of London and the Surrounding Area 1945; HMSO, London. Jones AT, Nixon JA & Picken RMF. Welsh Board of Health: Hospital Surveys – the Hospital Services of South Wales and Monmouthshire 1945; HMSO, London.

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Lambert T, Goldacre M & Parkhouse J. Career preferences and their variation by medical school among newly qualified doctors. Health Trends 1996; 28:135 – 44. Martin JP. Hospitals in Trouble 1984; Basil Blackwell, Oxford. Ministry of Health. Care of the Aged Suffering from Mental Infirmity, R.H.B. (50) 26, H.M.C. (50) 25 1950; National Health Service, London. Nascher IL. Geriatrics 1916; Kegan Paul, French, Truber, London. Parkhouse J & McLaughlin C. Career preferences of doctors graduating in 1974. British Medical Journal 1976; 2:620 – 32. Research Unit of the Royal College of Physicians. Geriatric Day Hospitals 1994; Royal College of Physicians of London. Royal College of Physicians of London. Report of the Royal College of Physicians of London on Geriatric Medicine 1972; Royal College of Physicians of London. Royal College of Physicians of London. Medical care of the elderly: report of the working party of the royal college of physicians of London. Lancet 1977; 1:1092 – 5. Thane P. Geriatrics. In WF Bynum & R Porter (eds) Companion Encyclopaedia of the History of Medicine 1993, pp 1092 – 118; Routledge, London and New York. Thane P. Inventing geriatric medicine. Old Age in English History 2000, pp 436 – 57; Oxford University Press, Oxford and London. Warren MW. Care of chronic sick. British Medical Journal 1943; 2:822 – 3. Warren MW. Care of the chronic aged sick. Lancet 1946; 1:841 – 3. Webster C. The Health Services Since the War. Volume 1 Problems of Health Care. The National Health Service Before 1957 1988; HMSO, London. Webster C. The elderly and the early National Health Service. In M Pelling & RM Smith (eds) Life, Death and the Elderly 1991, pp 165 – 93; Routledge, London. Webster C. Caring for Health: History and Diversity 1993; Open University, UK. Williamson J, Stokoe IH, Gray S et al. Old people at home: their unreported needs. Lancet 1964; 1:1117 – 20.

PART I

Human Aging: A Biological Perspective

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A Biological Perspective on Aging Thomas B.L. Kirkwood University of Newcastle, Newcastle-upon-Tyne, UK

INTRODUCTION The biological perspective on aging is important for what it tells us about why and how the body becomes progressively more vulnerable to disability and disease as we grow older. Although there is significant variability in how aging affects individuals, certain underlying processes appear to follow a fairly common course. Furthermore, humans share features of aging with a wide range of other animal species. Thus, research that is being done on factors that influence aging in these species may throw light on at least some aspects of human senescence.

WHY AGING OCCURS One of the questions of greatest interest for biological gerontologists is the nature of the genetic contribution to longevity. How do genes act on the aging process? How did the relevant genes evolve? It is clear on several grounds that aging and longevity are influenced by genes (Finch and Tanzi, 1997). Firstly, the life spans of human monozygotic twin pairs are statistically more similar than life spans of dizygotic twins, pointing clearly to a role for genetics. Secondly, there are significant differences in life span between different genetically inbred strains of any given laboratory animal, such as the mouse. Third, studies of simple organisms like fruit flies, nematode worms, and yeast have identified gene mutations that affect duration of life. However, although genes influence longevity, it has also been shown that genes account for only about 25% of the variance in human life span (Finch and Tanzi, 1997; Cournil and Kirkwood, 2001). The nature of the genetic contribution to the aging process has received much attention, both from the perspective of evolutionary theory and through experimentation. The evolutionary angle is valuable because it can tell us a great deal about the kinds of genes that are likely to underlie

the aging process (Kirkwood and Austad, 2000). Although it is widely supposed that aging evolved as some kind of evolutionary necessity – to clear older generations out of the way as a form of inbuilt population control – there is in fact scant evidence that aging plays such a role in nature, or that such an evolutionary pressure could have worked. The reason is simple: animals in nature die young. Only rarely do they survive long enough to reveal significant aging. Out of a population of newborn wild mice, for example, nine out of ten of them will be dead before 10 months even though half of the same animals reared in captivity would still be alive at 2 years (Austad, 1997). Thus, aging in mice is seen only in protected environments, and a similar statement would have applied to primitive human populations, before the advent of civilization. The fact that aging is rarely seen in natural animal populations speaks tellingly against any suggestion that aging evolved as a genetically programmed means to limit population size and avoid overcrowding. Instead of being programmed to die, organisms are genetically programmed to survive. However, in spite of a formidable array of survival mechanisms, most species appear not to be programmed well enough to last indefinitely. The key to understanding why this should be so, and what governs how long a survival period should be catered for, comes from looking once more at the data from survival patterns in wild populations. If 90% of wild mice are dead by 10 months, any investment in programming for survival much beyond this point can benefit at most 10% of the population. This immediately suggests that there will be little evolutionary advantage in programming long-term survival capacity into a mouse. The argument is further strengthened when we observe that nearly all of the survival mechanisms required by the mouse to combat intrinsic deterioration (DNA damage, protein oxidation, etc.) require metabolic resources. Metabolic resources are scarce, as is evidenced by the fact that the major cause of mortality for wild mice is cold, due to insufficient energy to maintain body temperature. From a Darwinian point of view, the mouse will benefit more from investing any spare


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HUMAN AGING: A BIOLOGICAL PERSPECTIVE

resource into thermogenesis or reproduction than into better DNA repair capacity that it needs. This concept, with its explicit focus on evolution of optimal levels of cell maintenance, is termed the disposable soma theory (Kirkwood, 1977, 1997). In essence, the investments in durability and maintenance of somatic (nonreproductive) tissues are predicted to be sufficient to keep the body in good repair through the normal expectation of life in the wild environment, with some measure of reserve capacity. Thus, it makes sense that mice (with 90% mortality by 10 months) have intrinsic life spans of around 3 years, while humans (who probably experienced something like 90% mortality by age 50 in our ancestral environment) have intrinsic life spans limited to about 100 years. The distinction between somatic and reproductive tissues is important because the reproductive cell lineage, or germ line, must be maintained at a level that preserves viability across the generations, whereas the soma needs only to support the survival of a single generation. As far as is known, all species that have a clear distinction between soma and germ line undergo somatic senescence, while animals that do not show senescence, such as the freshwater Hydra, have germ cells distributed throughout their structure. The above argument clearly identifies the level of extrinsic mortality as the principal driver in the evolution of longevity. If the level of extrinsic mortality is high, the average survival period is short and there is little selection for a high level of maintenance. Any spare resources should go instead towards reproduction. Consequently, the organism is not long-lived even in a protected environment. Conversely, if the level of extrinsic mortality is low, selection is likely to direct a higher investment in building and maintaining a durable soma. Studies comparing the biochemistry of cellular repair among long- and short-lived species bear this prediction out. Cells from long-lived organisms exhibit greater capacity to repair molecular damage and withstand biochemical stresses than cells from short-lived species (Kapahi et al., 1999; Ogburn et al., 2001). The disposable soma theory provides a bridge between understanding not only why aging occurs but also how aging is caused in molecular and cellular terms. It thus extended earlier considerations by Medawar (1952), who suggested that because organisms die young there is little force of selection to oppose the accumulation within the genome of mutations with late-acting deleterious effects, and by Williams (1957) who suggested that genes with beneficial effects would be favored by selection even if these genes had adverse effects at later ages. This is known as the theory of antagonistic pleiotropy, the term pleiotropy meaning that the same gene can have different effects in different circumstances. By combining the insights from the mutation accumulation, antagonistic pleiotropy, and disposable soma theories, evolutionary biology has established a solid basis to explain why aging occurs. The four cornerstones of this basis are: (i) there are no specific genes for aging; (ii) genes of particular importance for aging and longevity are those governing durability and maintenance of the soma; (iii) there may

exist other genetically determined trade-offs between benefits to young organisms and their viability at older ages; and (iv) there may exist a variety of gene mutations with late deleterious effects that contribute to the senescent phenotype. It is clear that multiple genes probably contribute to the aging phenotype and a major challenge is therefore to identify how many of each category exist, and which are the most important.

HOW AGING AFFECTS TISSUES The evolutionary explanation of aging, as summarized above, leads to a number of clear predictions about the nature of the underlying mechanisms that lead eventually to agerelated frailty, disability, and disease (and eventually to increasing mortality). In its essence, aging is neither more nor less than the progressive accumulation through life of a variety of random molecular defects that build up within cells and tissues. These defects start arising very early in life, probably even in utero, but in the early years both the fraction of affected cells and the average burden of damage per affected cell are low. However, over time, the faults increase, resulting eventually in age-related functional impairment of tissues and organs. This view of the aging process makes clear the life-course nature of the underlying mechanisms. Aging is a continuous process, starting early and developing gradually, instead of being a distinct phase that begins in middle to late life. The view also helps us reexamine the sometimes controversial relationship between “normal aging” and age-related disease. In an extreme version of this view, the term “normal aging” is reserved for individuals in whom identifiable pathology is absent, whereas specific age-related diseases, such as Alzheimer’s disease, are seen as distinct entities. An obvious difficulty that arises, however, when any attempt is made to draw a line between normal aging and age-related disease is that as a cohort ages, the fraction of individuals who can be said to be aging “normally” declines to very low levels. Whether the word “normal” can usefully be applied to such an atypical subset is debatable. In a clinical context, it often makes sense to try and draw a distinction between normal aging and disease, since this may have implications for treatment. However, if our aim is to understand the mechanisms responsible for agerelated conditions, such a distinction can obscure what is really going on and impede progress toward developing novel interventions that are targeted at “upstream” processes. The majority of chronic, degenerative conditions, such as dementia, osteoporosis, and osteoarthritis, involve the progressive accumulation of specific types of cellular and molecular lesions. Since the aging process, as we have seen, is caused by the general accumulation of such lesions, there may be a much greater overlap between the causative pathways leading to normal aging and age-related diseases than has hitherto been recognized. In the case of osteoporosis, for example, progressive bone loss from the late 20s onwards

A BIOLOGICAL PERSPECTIVE ON AGING

is the norm. Whether an individual reaches a critically low bone density, making him or her highly susceptible to fracture is governed by how much bone mass they had to start with and by their individual rate of bone loss. The process that leads eventually to osteoporosis is thus entirely “normal”, but what distinguishes whether or not this process results in an overtly pathological outcome is a range of moderating factors. In the case of Alzheimer’s disease, most people above age 70 have extensive cortical amyloid plaques and neurofibrillary tangles (the so-called “hallmarks” of classic Alzheimer’s disease) even though they may show no evidence of major cognitive decline (Esiri et al., 2001). In this instance, what determines whether or not the diagnosis of Alzheimer’s disease is called for may be not so much the presence of lesions as which specific targets are affected.

MECHANISMS OF CELLULAR DAMAGE Aging is highly complex, involving multiple mechanisms at different levels. Much recent evidence suggests that an important theme linking several different kinds of damage is the action of reactive oxygen species (ROS; also known as “free radicals”) which are produced as by-products of the body’s essential use of oxygen to produce cellular energy (Martin et al., 1996; von Zglinicki et al., 2001). Of particular significance are the contributions of ROS-induced damage to cellular DNA through (1) damage to the chromosomal DNA of the cell nucleus resulting in impaired gene function, (2) damage to telomeres – the protective DNA structures that appear to “cap” the ends of chromosomes (analogous to the plastic tips of shoelaces), and (3) damage to the DNA that exists within the cell’s energy-generating organelles, the mitochondria, resulting in impaired energy production.

DNA Damage and Repair Damage to DNA is particularly likely to play a role in the life-long accumulation of molecular damage within cells, since damage to DNA can readily result in permanent alteration of the cell’s DNA sequence. Cells are subject to mutation all the time, both through errors that may become fixed when cells divide and as a result of ROS-induced damage which can occur at any time. Numerous studies have reported age-related increases in somatic mutation and other forms of DNA damage, and have suggested that an important determinant of the rate of aging at the cell and molecular level is the capacity for DNA repair (Promislow, 1994; Burkle et al., 2002). Although DNA damage may take many forms, it is estimated that oxidative damage is among the most important, accounting for large numbers of oxidative hits per cell per day. A key player in the immediate cellular response to ROS-induced DNA damage is the enzyme poly(ADP-ribose) polymerase (PARP). Grube and Bürkle (1992) discovered a strong, positive correlation of PARP activity with the species

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life span, cells from long-lived species having higher levels of PARP activity than cells from short-lived species. In a similar vein, it was found that human centenarians, who have often maintained remarkably good general health, have a significantly greater poly(ADP-ribosyl)ation capacity than the general population (Muiras et al., 1998).

Telomeres In many human somatic tissues a decline in cellular division capacity with age appears to be linked to the fact that the telomeres, which protect the ends of chromosomes, get progressively shorter as cells divide (Kim et al., 2002). This is due to the absence of the enzyme telomerase, which is normally expressed only in germ cells (in testis and ovary) and in certain adult stem cells. Some have suggested that in dividing somatic cells, telomeres act as an intrinsic “division counter”, perhaps to protect us against runaway cell division as happens in cancer but causing aging as the price for this protection (Campisi, 1997). Erosion of telomere length below a critical length appears to trigger activation of the same kinds of cell cycle checkpoint, especially the p53/p21/pRb system, as are involved in the more general cellular response to DNA damage. While the loss of telomeric DNA is often attributed mainly to the so-called “end-replication” problem – the inability of the normal DNA-copying machinery to copy right to the very end of the strand in the absence of telomerase – it has been found that stress, especially oxidative stress, has an even bigger effect on the rate of telomere loss (von Zglinicki, 2002). Telomere shortening is greatly accelerated (or slowed) in cells with increased (or reduced) levels of stress. The clinical relevance of understanding telomere maintenance and its interaction with stress is considerable. A growing body of evidence suggests that telomere length is linked with aging and mortality (e.g. Cawthon et al., 2003). Not only do telomeres shorten with normal aging in several tissues (e.g. lymphocytes, vascular endothelial cells, kidney, liver), but also their reduction is more marked in certain disease states. For example, there appears to be a 100-fold higher incidence of vascular dementia in people with prematurely short telomeres (von Zglinicki et al., 2000). Viewed together with the observation that oxidative stress accelerates telomere loss, the intriguing possibility arises that prematurely short telomeres in vivo are an indicator of previous exposure to stress and may therefore serve as a prognostic indicator for disease conditions in which oxidative stress plays a causative role (von Zglinicki, 2002).

Mitochondria An important connection between oxidative stress and aging is suggested by the accumulation of mitochondrial DNA (mtDNA) deletions and point mutations with age (Wallace, 1992). Mitochondria are intracellular organelles, each carrying its own small DNA genome, which are responsible for

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generating cellular energy. As a by-product of energy generation, mitochondria are also the major source of ROS within the cell, and they are therefore both responsible for, and a major target of, oxidative stress. Any age-related increase in mutation of mtDNA is likely to contribute to a progressive decline in the cell and tissue capacity for energy production. Age-related increases in frequency of cytochrome c oxidase (COX)-deficient cells have been reported in human muscle (Müller-Höcker, 1989; Müller-Höcker et al., 1993; Brierley et al., 1998) and brain (Cottrell et al., 2000), associated with increased frequency of mutated mtDNA. Until recently, the evidence for age-related accumulation of mtDNA mutations came mainly from tissues such as brain and muscle where cell division in the adult, if it occurs at all, is rare. This led to the idea that accumulation of mtDNA mutation was driven mainly by the dynamics of mitochondrial multiplication and turnover within nondividing cells (Kowald and Kirkwood, 2000). However, recent work has revealed a strongly age-dependent accumulation of mtDNA mutations in human gut epithelium, which has the highest cell division rate of any tissue in the body (Taylor et al., 2003). Thus, it appears that mtDNA mutation accumulation may be a widespread phenomenon.

Proteins So far, we have concentrated on damage to DNA. However, damage can also affect any of the macromolecules that make up the cell, as well as those that form extracellular structures such as cartilage and bone. In particular, damage to protein molecules occurs to a considerable extent, and accumulation of faulty proteins contributes to important agerelated disorders such as cataract, Parkinson’s disease, and Alzheimer’s disease. In some ways, the accumulation of defective proteins is harder to explain than the accumulation of DNA damage, since individual protein molecules are subject to a continual cycle of synthesis and breakdown. Thus, damage to any individual protein molecule should be cleared as soon as that molecule is degraded. The exceptions occur when the defective protein molecules become resistant to breakdown, for example, because they form aggregates large enough to withstand the normal removal systems. It is the buildup of such aggregates that is commonly linked with cell and tissue pathology.

Interactions between Mechanisms We have so far considered a number of distinct mechanisms that can contribute to cellular aging. For each of these, there is evidence supporting the hypothesis that it is indeed an agent of senescence. However, the extent of the contribution to senescence almost invariably appears too small for the mechanism to be a sufficient explanation of age-related degeneration. The obvious solution to this “conundrum” is that cellular aging is multicausal and that the various

mechanisms all play their part. For example, a buildup of mtDNA mutations will lead to a decline in the cell’s energy production, and this will reduce the capacity to carry out energy-dependent protein clearance. In recent years, novel methods based on computer modeling of interactions and synergism between different aging mechanisms have begun to build a better integrated picture of how cells breakdown with age (Kirkwood et al., 2003).

METABOLIC FACTORS INFLUENCING AGING Numerous opportunities exist to test the evolutionary prediction that in safe environments (those with low extrinsic mortality) aging will evolve to be retarded, whereas aging should evolve to be more rapid in hazardous environments. Field observations comparing a mainland population of opossums subject to significant predation by mammals, with an island population not subject to mammalian predation, found the predicted slower aging in the island population (Austad, 1993). What is interesting from the metabolic perspective is to understand how these ecologically driven effects are mediated at the level of cellular and molecular mechanisms. The disposable soma theory predicts that the proportional effort devoted to cellular maintenance and repair processes will vary directly with longevity. For instance, the long-lived rodent species Peromyscus leucopus exhibits lower generation of ROS, higher cellular concentrations of some antioxidant enzymes, and overall lower levels of protein oxidative damage than the shorter-lived species Mus musculus (Sohal et al., 1993). A direct relation between species longevity and rate of mitochondrial ROS production in captive mammals has also been found (Ku et al., 1993; Barja and Herrero, 2000), as has a similar relationship between mammals and similar-sized but much longer-lived birds (Herrero and Barja, 1999). Markers of glycoxidation, the nonenzymatic modification of reducing sugars, are also found to accumulate more slowly in long-lived, as opposed to short-lived, mammals (Sell et al., 1996). Of particular significance in terms of metabolic factors influencing aging rates has been the discovery that insulin signaling pathways appear to have effects on aging that may be strongly conserved across the species range (Gems and Partridge, 2001). Insulin signaling regulates responses to varying nutrient levels and so the discovery of the major role for these pathways in aging fits well with the central concept of the disposable soma theory, namely, that aging results from and is controlled by the metabolic allocation of the organism’s metabolic resources to maintenance and repair. One of the clearest examples of how metabolic signaling affects aging and longevity comes from a study on genes of the insulin signaling pathway in Caenorhabditis elegans (Murphy et al., 2003). When threatened with overcrowding, which the larval worm detects by the increasing concentration of a pheromone, it diverts its development from the normal succession of larval molts into a long-lived, dispersal

A BIOLOGICAL PERSPECTIVE ON AGING

form called the dauer larva (Larsen et al., 1995). Dauers show increased resistance to stress and can survive very much longer than the normal form, reverting to complete their development into adults should more favorable conditions be detected. An insulin/IGF-1-like gene, daf-2, heads the gene regulatory pathway that controls the switch into the dauer form, and mutations in daf-2 produce animals that develop into adults with substantially increased lifespans (Kenyon et al., 1993). In common with other members of the evolutionarily conserved insulin/IGF1 signaling pathway, daf-2 also regulates lipid metabolism and reproduction. The daf-2 gene product exerts its effects by influencing “downstream” gene expression, in particular via the actions of another gene belonging to the dauer-formation gene family, daf-16, which it inhibits (Kimura et al., 1997). It was shown by Murphy et al. (2003) that more than 300 genes appeared to have their expression levels altered by daf-16 regulation. This large number suggests that, as predicted by the evolutionary theory, many genes are involved in determining longevity. The genes modulated by daf-16 turned out to be a heterogeneous group although several broad categories could be discerned. The first category comprised a variety of stress-response genes, including players like antioxidant enzymes. A second group of genes encoded antimicrobial proteins, which are important for survival in this organism because its death is commonly caused by proliferation of bacteria in the gut. A miscellaneous third group included genes involved in protein turnover, which is an important cellular maintenance system. Thus, the metabolic regulation of the rate of aging in C. elegans is mediated through genetic effects on a diverse array of survival mechanisms, exactly as the disposable soma theory predicted. By this point, it will be seen that, from a range of studies at the genetic, cellular, and molecular levels, both in humans and a variety of other organisms, a picture is clearly emerging of the main elements of the biological science of human aging (Figure 1). These elements are the result of the relentless role of biochemical stresses, such as exposure to ROS, driving a gradual but progressive accumulation of damage to cells, tissues, and organs. The process is not entirely passive, since the rate of accumulation is strongly resisted by maintenance and repair processes, which are controlled by genes. Furthermore, the regulation of these genes may, at least in some organisms, be influenced by metabolic factors, for example, responding to levels of nutrition. This picture is one that readily accommodates the role of at least five major elements contributing to the individuality of the human aging process: genes, nutrition, lifestyle (e.g. exercise), environment, and chance. The recognition of this interplay of factors is likely to be crucial for integrating biological, clinical, and social gerontology. For example, environment is often defined by social factors such as housing, transport, and income. Poor environments may adversely affect an individual’s opportunities to do the optimal things for healthy aging in terms of nutrition, lifestyle, and so on. In particular, a poor environment can reinforce a tendency for the older person to suffer social isolation, which in turn can exacerbate psychological and physical deterioration. On the positive side, the

17 The aging process

Age-related frailty, disability, and disease Anti-inflammation

Inflammation

Accumulation of cellular defects Good lifestyle

Healthy food Random molecular damage

Stress

Environment

Poor food

Figure 1 The aging process is driven by a life-long accumulation of molecular damage, resulting in gradual increase in the fraction of cells carrying defects. After sufficient time has passed, the increasing levels of these defects interfere with both the performance and functional reserves of tissues and organs, resulting in age-related frailty, disability, and disease. Stress, adverse environment, and poor nutrition can increase the rate at which molecular damage arises. Molecular damage is partially countered by cellular maintenance and repair systems (dashed arrows). Accumulation of cellular damage can cause inflammation, which can exacerbate the development of overt age-related frailty, disability, and disease. This may be countered by anti-inflammatory factors (dotted arrow)

understanding that we now have of the biological science of human aging supports the idea that the aging process is much more malleable than has hitherto been recognized. This opens the way to a range of interventions that may improve health in old age and extend quality life.

KEY POINTS • There is no biological program specifically to cause aging. • The body is programmed for survival but our survival mechanisms, which evolved to cater for the typical longevity of our evolutionary ancestors, are insufficient to prevent damage from accumulating. • Aging is caused by the life-long accumulation of subtle molecular and cellular faults, a process that probably begins in utero. • Multiple mechanisms contribute to the buildup of damage that causes aging, and there are multiple maintenance and repair systems working to combat this buildup of damage. It is the genetic setting of these maintenance and repair systems that explains the genetic contribution to human longevity (which explains about 25% of the variation in human life span). • The rate at which damage accumulates, and thus the aging process itself, is malleable through the actions of factors such as nutrition, lifestyle, and environment.

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KEY REFERENCES • Kapahi P, Boulton ME & Kirkwood TBL. Positive correlation between mammalian life span and cellular resistance to stress. Free Radical Biology and Medicine 1999; 26:495 – 500. • Kirkwood TBL. The origins of human ageing. Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences 1997; 352:1765 – 72. • Kirkwood TBL & Austad SN. Why do we age? Nature 2000; 408:233 – 8. • Murphy CT, McCarroll SA, Bargmann CI et al. Genes that act downstream of DAF-16 to influence the lifespan of Caenorhabditis elegans. Nature 2003; 424:277 – 84. • von Zglinicki T. Oxidative stress shortens telomeres. Trends in Biochemical Sciences 2002; 27:339 – 44.

REFERENCES Austad SN. Retarded senescence in an insular population of opossums. Journal of Zoology 1993; 229:695 – 708. Austad SN. Comparative aging and life histories in mammals. Experimental Gerontology 1997; 32:23 – 38. Barja G & Herrero A. Oxidative damage to mitochondrial DNA is inversely related to maximum life span in the heart and brain of mammals. FASEB Journal 2000; 14:312 – 8. Brierley EJ, Johnson MA, Lightowlers RN et al. Role of mitochondrial DNA mutations in human aging: implications for the central nervous system and muscle. Annals of Neurology 1998; 43:217 – 23. Burkle A, Beneke S, Brabeck C et al. Poly(ADP-ribose) polymerase-1, DNA repair and mammalian longevity. Experimental Gerontology 2002; 37:1203 – 5. Campisi J. Aging and cancer: the double-edged sword of replicative senescence. Journal of the American Geriatrics Society 1997; 45:482 – 8. Cawthon RM, Smith KR, O’Brien E et al. Association between telomere length in blood and mortality in people aged 60 years or older. Lancet 2003; 361:393 – 5. Cottrell DA, Blakely EL, Johnson MA et al. Cytochrome c oxidase deficient cells accumulate in the hippocampus and choroid plexus with age. Neurobiology of Aging 2000; 22:265 – 72. Cournil A & Kirkwood TBL. If you would live long, choose your parents well. Trends in Genetics 2001; 17:233 – 5. Esiri MM, Matthews F, Brayne C et al. Pathological correlates of late-onset dementia in a multicentre, community-based population in England and Wales. Lancet 2001; 357:169 – 75. Finch CE & Tanzi R. The genetics of aging. Science 1997; 278:407 – 11. Gems D & Partridge L. Insulin/IGF signalling and ageing: seeing the bigger picture. Current Opinion in Genetics & Development 2001; 11:287 – 92. Grube K & Bürkle A. Poly(ADP-ribose) polymerase activity in mononuclear leukocytes of 13 mammalian species correlates with speciesspecific life span. Proceedings of the National Academy of Sciences of the United States of America 1992; 89:11759 – 63. Herrero A & Barja G. 8-oxo-deoxyguanosine levels in heart and brain mitochondrial and nuclear DNA of two mammals and three birds in relation to their different rates of aging. Aging Clinical and Experimental Research 1999; 11:294 – 300. Kapahi P, Boulton ME & Kirkwood TBL. Positive correlation between mammalian life span and cellular resistance to stress. Free Radical Biology and Medicine 1999; 26:495 – 500. Kenyon C, Chang J, Gensch E et al. A C. elegans mutant that lives twice as long as wild-type. Nature 1993; 366:461 – 4. Kim S, Kaminker P & Campisi J. Telomeres, aging and cancer: in search of a happy ending. Oncogene 2002; 21:503 – 11.

Kimura KD, Tissenbaum HA, Liu YX & Ruvkun G. daf-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans. Science 1997; 277:942 – 6. Kirkwood TBL. Evolution of ageing. Nature 1977; 270:301 – 4. Kirkwood TBL. The origins of human ageing. Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences 1997; 352:1765 – 72. Kirkwood TBL & Austad SN. Why do we age? Nature 2000; 408:233 – 8. Kirkwood TBL, Boys RJ, Gillespie CS et al. Towards an e-biology of ageing: integrating theory and data. Nature Reviews. Molecular Cell Biology 2003; 4:243 – 9. Kowald A & Kirkwood TBL. Accumulation of defective mitochondria through delayed degradation of damaged organelles and its possible role in the ageing of post-mitotic and dividing cells. Journal of Theoretical Biology 2000; 202:145 – 60. Ku H-H, Brunk UT & Sohal RS. Relationship between mitochondrial superoxide and hydrogen-peroxide production and longevity of mammalian-species. Free Radical Biology and Medicine 1993; 15:621 – 7. Larsen PL, Albert P & Riddle DL. Genes that regulate both development and longevity in Caenorhabditis elegans. Genetics 1995; 139:1567 – 83. Martin GM, Austad SN & Johnson TE. Genetic analysis of ageing: role of oxidative damage and environmental stresses. Nature Genetics 1996; 13:25 – 34. Medawar PB. An Unsolved Problem of Biology 1952; Lewis, London. Muiras M-L, Müller M, Schächter F & Bürkle A. Increased poly(ADPribose) polymerase activity in lymphoblastoid cell lines from centenarians. Journal of Molecular Medicine 1998; 76:346 – 54. Müller-Höcker J. Cytochrome-c-oxidase deficient cardiomyocytes in the human heart – an age-related phenomenon. A histochemical ultracytochemical study. American Journal of Pathology 1989; 134:1167 – 73. Müller-Höcker J, Seibel P, Schneiderbanger K & Kadenbach B. Different in situ hybridization patterns of mitochondrial DNA in cytochrome c oxidase-deficient extraocular muscle fibres in the elderly. Virchows Archives A 1993; 422:7 – 15. Murphy CT, McCarroll SA, Bargmann CI et al. Genes that act downstream of DAF-16 to influence the lifespan of Caenorhabditis elegans. Nature 2003; 424:277 – 84. Ogburn CE, Carlberg K, Ottinger MA et al. Exceptional cellular resistance to oxidative damage in long-lived birds requires active gene expression. The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences 2001; 56:B468 – 74. Promislow DEL. DNA-repair and the evolution of longevity – a critical analysis. Journal of Theoretical Biology 1994; 170:291 – 300. Sell DR, Lane MA, Johnson WA et al. Longevity and the genetic determination of collagen glycoxidation kinetics in mammalian senescence. Proceedings of the National Academy of Sciences of the United States of America 1996; 93:485 – 90. Sohal RS, Ku H-H & Agarwal S. Biochemical correlates of longevity in two closely-related rodent species. Biochemical and Biophysical Research Communications 1993; 196:7 – 11. Taylor RW, Barron MJ, Borthwick GM et al. Mitochondrial DNA mutations in human colonic crypt stem cells. Journal of Clinical Investigation 2003; 112:1351 – 60. von Zglinicki T. Oxidative stress shortens telomeres. Trends in Biochemical Sciences 2002; 27:339 – 44. von Zglinicki T, Bürkle A & Kirkwood TBL. Stress, DNA damage and ageing – an integrative approach. Experimental Gerontology 2001; 36:1049 – 62. von Zglinicki T, Serra V, Lorenz M et al. Short telomeres in patients with vascular dementia: an indicator of low antioxidative capacity and a possible prognostic factor? Laboratory Investigation 2000; 80:1739 – 47. Wallace DC. Mitochondrial genetics: a paradigm for aging and degenerative diseases? Science 1992; 256:628 – 32. Williams GC. Pleiotropy, natural selection and the evolution of senescence. Evolution 1957; 11:398 – 411.

3

Immunity and Aging Katsuiku Hirokawa1 , Masanori Utsuyama1 and Takashi Makinodan2 1

Tokyo Medical & Dental University, Tokyo, Japan, and 2 University of California at Los Angeles School of Medicine, Los Angeles, CA, USA.

INTRODUCTION Protozoa floating in the Cambrian sea many billion years ago could have been the first cell-like living organisms on earth resembling today’s Amoeba. From such unicellular organisms, it took billions of years for the evolution of a wide variety of multicellular organisms. One necessary condition for the survival of these organisms, including Protozoa, is that each one must be able to maintain its identity by discriminating itself from many others in the same environment. It is interesting to note that this ability to discriminate “self” from “non-self” is the basic function of the immune system. Leukocytes in higher vertebrates as mammals are quite similar to Cambrian Protozoa in terms of appearance and function and constitute a major component of the immune system. In a broad sense, they can be categorized into granulocytes, macrophage (monocytes), and lymphocytes. Animals are equipped with three types of defense systems against invading pathogenic microbes. One is a physical barrier composed of skin and mucosal surface of gastrointestinal and respiratory tract. This barrier is reinforced by humoral substances containing lysozymes or acid. Second is a natural (innate) immune system composed of granulocytes, macrophages, dendritic cells, and natural killer (NK) cells. Granulocytes and macrophages can nonspecifically ingest and kill microbes by lytic enzymes in lysozymes. NK cells can nonspecifically kill tumor cells and virus-infected cells. The importance of granulocytes is illustrated by the fact that people suffering from drug-induced hypo- or agranulocytosis occasionally die within a week after the onset of the disease. Third is an acquired (specific) immune system. Its major component is lymphocytes, but many of their functions are helped by macrophages, dendritic cells, and NK cells. Unlike natural immune system, killing of microbes by acquired immune system is specific to a certain type of microbe (a specific antigen); therefore, there are countless numbers of clones of lymphocytes corresponding to the countless

numbers of antigens in the environment and each clone of lymphocytes can specifically react to a corresponding antigen, resulting in proliferation of specific effector cells or production of specific antibody. Moreover, the immune reaction retains memory analogous to that of the nervous system, and the sequence of generation of effector cells and antibody production occurs very quickly upon subsequent infections by the same microbes. However, immunological functions are known to decline with age in many mammals, including humans (Makinodan and Kay, 1980; Hirokawa, 1992; Linton and Dorshkind, 2004), and the decline occurs more in the acquired immune system than in the natural immune system. It is of clinical importance that with a decrease of immunologic vigor, the incidence of various age-associated diseases such as infections, cancers, and vascular diseases increases. Table 1(a) shows causes of death observed in 3000 autopsy cases in geriatric institutions in Geneva, Switzerland (Mac Gee, 1993). The most prevalent fatal condition was bronchopneumonia. The same observation was also seen in Tokyo Metropolitan Geriatric Hospital, Japan (Table 1b). Infections such as bronchopneumonia compose almost 40% of the direct causes of death in autopsy cases over 60 years of age, although a variety of antibiotics are available. The occurrence of severe acute respiratory syndrome (SARS) in the winter of 2003 clearly indicated the immune deficient state of the elderly. Fatality rate increased with age in SARS (Hong Kong, China), occurring in more than 50% in people 65 years and over (Table 1c). These results suggest that elderly people whose immune functions are at an exceptionally high level can live longer and become centenarians. They also underscore the importance of age-related decline of immune functions. Regarding infection, there is a hypothesis that chronic antigenic stimulation could lead to an increasing prevalence of senescent, dysfunctional T cells, and therefore contributes to more general alterations in the immune system (Pawelec et al., 2004). A related serious problem of our society is acquired immune deficiency syndrome (AIDS), and AIDS is due


20

HUMAN AGING: A BIOLOGICAL PERSPECTIVE Table 1a Causes of death in a hospitalized geriatric population: An autopsy study of 3000 patients

42.9% 28.1% 21.2% 19.6% 12.3% 6.5% 5.5% 3.3%

The data, based on 3000 consecutive autopsies (1758 females/ 1242 males: mean age 80.3 years) performed from 1972 to 1992 in Geneva Geriatric Instutitions (Mac Gee W).

100 Relative activity (%)

Bronchopneumonia Malignant neoplasms Pulmonary thromboembolism Acute myocardial infarction Urinary tract infection Acute cerebrovascular disease Internal hemorrhage Congestive cardiac failure

Age change of immune system in C57BL/6 mice Auto-Ab

80

LPS

60

NK

40

0 0

Table 1b Major causes of death in autopsy cases of elderly persons at Tokyo Metropolitan Geriatric Hospital

Infections Vascular diseases in brain and heart Malignancies Others

People over 60 years (%)

People over 70 years (%)

39.2 29.7

27.6 43.1

18.7 12.4%

22.4 6.9%

The data, based on 923 autopsy cases (570 females/353 males) over 60 years of age.

Table 1c Fatality rate of SARS increased with age in Hong Kong

Age 24 years and under 25 – 44 years 45 – 64 years 65 years and over Total

Fatality rate (%) 0 6 15 52 14 – 15

Source: WHO report. Consensus document on the epidemiology of severe acute respiratory syndrome (SARS). 17 October 2003 http://www.who.int/csr/sars/guidelines/en/. Reproduced by permission of the World Health Organization.

to insufficiency of CD4+ helper T cells caused by HIV infection. With most elderly people, a much wider range of nonspecific immunological deficiency occurs. This chapter will outline how the immune functions decline with age in humans and animal models.

SENESCENCE OF IMMUNE SYSTEM 1. T cell-dependent immune system is most susceptible to aging The natural immune system is already functioning at the time of birth and does not show a pronounced age-related change during the course of life in healthy individuals. On the other hand, the acquired immune system is immature and does not function well in the early stage after birth. Its activity develops quickly by exposure to innumerable

Anti-SRBC Killer-T PHA

Thymus

20

3

6

15 9 12 Age (months)

18

21

24

Figure 1 Age-related changes in the immune functions of C57BL/6 mice. Age-related decline is seen in three kinds of T cell-dependent immune functions: mitogenic response of spleen cells to phytohemagglutinin (PHA, closed triangle), cytolytic T cell activity (killer T, open squares), and anti-SRBC antibody response (anti-SRBC, open circles). Thymic involution (open diamonds) precedes the decline of these T cell-dependent immune functions. Proliferative activity of B cells (LPS, closed triangles) declines very slightly with age. Activity of natural killer (NK) cells (closed squares) declines moderately. Production of autoantibody (auto-Ab, closed circles) increases with age (Reprinted from Archives of Gerontology and Geriatrics, 19: 171, Hirokawa et al., Copyright 1994, with permission from Elsevier)

antigens, including microbes in the environment, peaks at puberty, and starts to gradually decline thereafter. Studies in several long-lived mouse strains and humans performed in several laboratories, including ours (Makinodan and Kay, 1980; Hirokawa, 1992; Linton and Dorshkind, 2004; Deng et al., 2004), indicate that: (a) decline primarily occurs in T cell-dependent immune functions such as T cell-dependent antibody formation, cytolytic T cell activity, T cell proliferative response to various mitogens and tuberculin skin test; (b) all these changes are preceded by thymic involution; (c) activity of NK cells also declines with age, but the magnitude of the decline is less than that of T cells; (d) there is a marginal decline in B cell mitogenic response to lipopolysaccharide (Figure 1); and (e) transition of pro-B cells into pre-B cells and migration of newly made B cells to the spleen from bone marrow are reduced in old individuals. Considering the fact that T cells are mainly produced in the thymus, a causal relationship appears to exist between thymic involution and subsequent age-related decline in T cell functions. Physiologically, the major reason why T cells are more susceptible to aging than other immune cells is that the recruitment of T cells is quite limited, as the thymic capacity to provide T cells to peripheral lymphoid tissues declines quickly after puberty. The situation is quite different in B cells, dendritic cells, and macrophages, which are constantly replenished by the bone marrow throughout life. 2. Lymphoid and hemopoietic tissues As cells composing the acquired immune system are mainly located in lymphoid tissues, we will see how lymphoid tissues change with age.

IMMUNITY AND AGING

(a)

21

(b)

Figure 2 Histology of the thymus from newborn (a) and 28-years-old male (b) The thymus from newborn maintains the basic structure of thymus, composed of cortex and medulla. By contrast, the thymus from a young adult male is composed of a large amount of fatty tissue and fragments of thymic tissues

(a) Thymus The Thymus is the key organ for the development of T cells. Thymic involution is generally known to occur after puberty. However, an early sign of involution such as fatty infiltration could be observed as early as 5 years of age, and the number of thymic epithelial cells starts to decline shortly after birth. Normal thymic architecture of cortex and medulla, as seen in the newborn stage, completely disappears in the thymus of people over 20 years of age due to extensive fatty infiltration (Figure 2). In a normal mouse strain (mean life span about 2 years), the thymic size peaks at 4–6 weeks and gradually declines, but without fatty infiltration. As will be seen in the later section, the thymic capacity to provide T cells to the periphery is high in the newborn stage and quickly declines thereafter. Nevertheless, Douek et al. (1998) reported that thymocytes were still proliferating in the thymus of human adults and newly generated T cells were being exported to peripheral lymphoid tissues. From a structural viewpoint, thymic fragments of human adults are composed of cortical and medullary portions and they provide T cells to the periphery, although very low in number (Shiraishi et al., 2003) and less functional. This will be discussed later. (b) Spleen Splenic weight decreases in elderly people, but unlike the thymus, the onset of the decrease is at about the seventh decade, far later than that of thymus. It is composed of red pulp and white pulp. The latter portion occupies about 20% of total spleen and is mainly responsible for

immune reactions. Germinal centers are well developed in white pulp of the young spleen, but rarely seen in that of the old spleen (Figure 3). (c) Lymph node The size of the lymph node is most prominent in the first decade in humans, as with the case of the thymus. Thereafter, lymph nodes are less conspicuous or not palpable in healthy individuals. Lymph nodes become swollen at the time of infection, but the magnitude of swelling is less prominent in elderly people than in the young. As is seen in the spleen, there is a profound reduction of the germinal center reaction in the lymphoid tissues of the aged. As the germinal center is necessary for generation of high affinity antibodies, the absence of germinal center is considered a cause for the compromised humoral responses in aging (Zheng et al., 1997). (d) Mucosal lymphoid tissue The intestine contains a considerable amount of lymphoid tissue, produces a large amount of immunoglobulin (Ig) A, and plays a major role in the protection against infectious diseases of the intestinal tract. There are accumulating data showing that deficits are found in the intestinal mucosal immune responses of elderly humans and old animals (Schmucker, 2002). Nasalassociated lymphoid tissue is important for the protection of respiratory infections, and its function is also impaired with the advancement of age. It is important to note that the production of IgA antibody in nasal mucosa is efficiently enhanced by local administration of antigen, not by systemic injection of antigen

22


(b)

(a)

Figure 3 Histology of white pulp of spleen from 36-year-old male (a) and 83-year-old male (b). Formation of germinal center is observed in (a), but not in (b)

Table 2 Concentration of IgA antibody in the nasal mucosa is efficiently increased by intranasal immunization of antigen, not by other routes

Immunization route Age of mice Ig A levels in nasal mucosa Ig G levels in serum

in → in

iv → ip

3m

18 m

3m

18 m

172 ± 17 30364 ± 2370

54 ± 20 11230 ± 4584

2 ± 0.8 162481 ± 14322

2 ± 0.8 111903 ± 7488

Levels of antibodies, ng/mouse. in, intranasal immunization; iv, intravenous immunization; ip, intraperitoneal immunization. in → in, antigen was first intranasally given and a booster 3 weeks later by the same route; iv → ip, antigen was first intravenously given and a booster 3 weeks later by ip. Antigen; Influenza virus vaccine (A/PR/8/34) mixed with cholera toxin B. Asanuma et al. (2001).

(Table 2). Thus, efficient protection against influenza could be accomplished by intranasal local administration of vaccine. (e) Bone marrow The Bone marrow is a primary source of hematopoietic and lymphoid cells. An apparent age-related decrease of red bone marrow is observed in humans and rats, but not in mice. Proliferative activity assessed by Ki-67positive cells was high in the middle-aged group and declined slightly in the elderly group. Apoptosis was relatively low in the young and middle-aged group, but significantly increased in the elderly group (Figure 4). These data suggest that hypocellularity in the bone marrow of elderly people could be ascribed partly to the increase in apoptosis and decrease of proliferative

capacity. Interestingly, plasma cells, or IgA, and IgG containing cells increase in human bone marrow, with a concomitant increase of these immunoglobulins in serum. In aged mice, bone marrow, and not spleen, becomes the major site of immunoglobulin production. 3. Serum immunoglobulins Despite age-related atrophy of lymphoid tissues, such as spleen, lymphoid tissues, and thymus, the level of serum IgA and IgG gradually increases with age, but that of IgM does not change. Increased level of serum immunoglobulin is consistent with an increase in immunoglobulin synthesizing plasma cells in lymphoid tissues and bone marrow, and with a decrease in the rate of degradation. Although serum immunoglobulin level increases with age, immunoglobulins

IMMUNITY AND AGING 50

Percentage

40

and B cells generally declines with age in association with altered composition of their subsets (Utsuyama et al., 1992; Cossarizza et al., 1996; Fagnoni et al., 2000). It should be stressed that the decline starts during childhood or after puberty (Utsuyama et al., 1992). This section will present an overview of changes of various immune cells at the cellular level.

Apoptosis Ki–67

30 20 10 0

Young

Middle

Old

Figure 4 The percentage of apoptotic cells and proliferating cells in human bone marrow of 3 different age-groups. The percentage of apoptotic cells was determined by the terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) method. The Ki-67+ cells indicate cells in the proliferating phase. Vertical bars indicate SEM. Young, subjects less than 20 years old. Middle, subjects between 50 and 59 years old. Old, subjects between 80 and 100 years old

Age-change in serum level of total IgG, anti-flagellin and autoantibody 120 Total IgG

Relative values (%)

100 80

Auto–Ab(%)

60 40 20

Anti–flagellin 0 20

30

23

40

50

60

70

80

Age (years) Figure 5 Age-related changes of total IgG (closed circles), relative values of anti-Flagellin (open circles) and incidence of autoantibody (auto-Ab, open triangles) in human serum (the highest level, 100%). Modified from Rowley et al. (1968) and Suzuki et al. (1984)

produced in old mice are less protective because of their low titer and affinity. The production of specific antibodies decreases with age with an increased production of autoantibodies (Figure 5), which will be discussed later. Interestingly, frequency of benign monoclonal gammopathy increases with age.

CELLS OF THE IMMUNE SYSTEM Much information is available regarding cells in the peripheral blood, but little about cells making up the microenvironment of various lymphoid tissues, except for thymus, whose role in the aging of immune system will be discussed in the next section. Absolute number of lymphocytes, T cells,

1. Hematopoietic stem cells (HSCs) The number of hematopoietic stem cells (HSCs) in the bone marrow does not change greatly with age, when assessed by the number of colonies formed in the spleen of lethally irradiated mice (CFU-s). However, when the number of cells per colony is counted, the cell counts in colonies derived from young bone marrow are apparently higher than those from old bone marrow, indicating that proliferative activity of old bone marrow cells declines with age (Albright and Makinodan, 1976). A recent review paper relates agerelated functional activity of HSCs with age-related decline in replicative activity of HSCs in both murine models and human, and concludes that age-related functional decline in adult tissue HSCs limits longevity in mammals (Geiger and Van Zant, 2002). The ability of HSCs to differentiate into mature B cells also declines, and IL-7 plays an important role in the expansion of B cell precursors in bone marrow. An apparent decrease in the number of IL-7 responsive B220+ B cell precursors was observed in old mice when compared with young mice (Jonsson and Phillips, 1993). Progenitors of T cells also decrease with age, when assessed by the ability of bone marrow from young and old donors to repopulate the thymus and spleen of lethally irradiated mice. However, alteration of the thymic microenvironment is much more responsible for the thymic involution than alteration of progenitors of T cells, as the size of thymus restored by bone marrow transplantation is apparently smaller in Y → O than in O → Y bone marrow chimera (Table 3). 2. T cells T cells play a pivotal role in the acquired immune system and are most profoundly affected by aging. The magnitude of decrease in T cell functions in vivo between young and old individuals is sometimes more than 10-fold, and generally greater than the decrease observed in B cells or NK cells. Age-related changes of T cells can be ascribed to the following three types: (a) quantitative change, (b) a change in the proportion of T cell subsets, (c) a qualitative change, such as proliferative response and cytokine production. (a) Quantitative change The number of T cells in human peripheral blood is high in infants and young adults before 20 years of age, and a significant decrease is observed between the second and third decade. The number stays at almost the same level through the sixth decade and declines after the seventh decade (Table 4) (Figure 6) (Utsuyama et al., 1992). Such a decline in T cell numbers appears to be associated with the acceleration of thymic involution. Some investigators have proposed that the thymus plays

24

HUMAN AGING: A BIOLOGICAL PERSPECTIVE Table 3 Comparison of regeneration of thymus, splenic T cells, and their subset among four combinations of bone marrow chimera mice constructed between young and old mice

Types of radiation bone marrow chimeras (donors → recipients) Y→Y O→Y Y→O O→O

Thymic weight (mg)

Splenic T cells (×106 )

CD4:CD8 (ratio)

Na¨ıve T: memory T (ratio)

43.9 44.4 14.2 13.6

21.1 24.3 9.9 8.4

6.5 6.1 8.9 7.9

0.91 0.33 0.16 0.13

Numbers indicate levels 8 weeks after the construction of bone marrow chimera mice: bone marrow cells from donor mice were grafted to sublethally irradiated mice. Y, Young mice; O, Old mice.

Table 4 Age-related changes in cells in peripheral blood

Age 1 – 19 20 – 29 30 – 39 40 – 49 50 – 59 60 – 69 70 – 79 80 – 89 90 –

WBC

Lymphocytes

T cells

CD4/8 ratio

B cells

NK cells

Monocytes

6.8 ± 0.5 6.3 ± 0.3 6.6 ± 0.4 7.0 ± 0.6 6.6 ± 0.4 6.5 ± 0.4 5.8 ± 0.4 6.1 ± 0.3 6.1 ± 0.4

2.7 ± 0.4 2.2 ± 0.2 2.2 ± 0.2 2.3 ± 0.2 2.5 ± 0.2 2.2 ± 0.2 2.0 ± 0.2 1.8 ± 0.1 1.7 ± 0.2

1.7 ± 0.2 1.4 ± 0.1 1.3 ± 0.1 1.4 ± 0.1 1.5 ± 0.1 1.3 ± 0.1 1.1 ± 0.1 1.1 ± 0.1 0.9 ± 0.1

1.56 ± 0.09 1.67 ± 0.10 1.56 ± 0.10 2.31 ± 0.21 1.98 ± 0.13 2.49 ± 0.25 2.91 ± 0.70 2.13 ± 0.18 2.21 ± 0.39

0.27 ± 0.06 0.16 ± 0.02 0.15 ± 0.02 0.15 ± 0.02 0.16 ± 0.02 0.17 ± 0.03 0.13 ± 0.02 0.11 ± 0.01 0.08 ± 0.02

0.38 ± 0.05 0.38 ± 0.06 0.38 ± 0.06 0.42 ± 0.05 0.42 ± 0.05 0.52 ± 0.05 0.57 ± 0.12 0.45 ± 0.04 0.41 ± 0.06

0.33 ± 0.04 0.18 ± 0.02 0.23 ± 0.03 0.22 ± 0.02 0.23 ± 0.02 0.31 ± 0.03 0.39 ± 0.04 0.29 ± 0.02 0.41 ± 0.06

Values ×103 indicate cell counts per mm3 in the peripheral blood, except for CD4/8 ratio. Cell counts of WBC (white blood cells), lymphocytes, and monocytes were obtained by routine blood cell count. Cell counts of T cells, B cells, and NK (natural killer) cells were obtained by flow cytometric method.

1000

Male Female 3500

y = − 7.8x + 1653.9 (r2 = 0.114) 800

3000 CD4+ T cells mm−3

3 years old

2500

2000

600 23 years old 400

1500 200 1000 0 500

−3

0

3

6

9

12

15

Months after intensive chemotherapy 0

Figure 6 Number of T cells (per mm3 ) in peripheral blood of male (closed circles) and female (open circles), ranging in age from 6 to 97 years. The line indicates regression

Figure 7 Regeneration of CD4+ T cells in peripheral blood in patients following intensive chemotherapy. Number of CD4+ T cells drastically declined after chemotherapy. In a 3-year-old patient, the number recovered nearly to the previous level in 9 months. In a 23-year-old patient, however, recovery of the number of CD4+ Ta cells was significantly delayed. Modified from Mackall et al. (1995)

a time-keeper’s role or acts as an ‘aging clock’. The level of T cell numbers is easily influenced by exogenous factors, such as infection and stress, and the individual variation increases with advancing age. In this regard,

the most important point is that the recovery in the T cell number after exposure to stress or drug treatment is reduced in old individuals as compared with younger ones (Mackall et al., 1995; (Figure 7)).

0

10

20

30

40

50

60

70

80

90

100 110

IMMUNITY AND AGING

(b) Change in T cell subsets CD4 + :CD8 + T cell ratio In long-lived C57BL/6 mice, the percentage of splenic T cells gradually increases after birth, peaks at around 3 months of age, stays at a constant level until 12 months of age, and then gradually declines thereafter. The number of CD4+ T cells stays relatively constant in the adult and senescent stages, while that of CD8+ T cells gradually declines with age. Thus, the ratio of CD4+ :CD8+ T cell subset rises after 3 months of age. Of clinical importance is that a similar age change is observed in human peripheral blood. Thus, the ratio of CD4+ /CD8+ T cells is low in infants and young adults, increases in middle-aged people, and again decreases in old people over 80 years of age (Table 4) (Utsuyama et al., 1992). In a Swedish longitudinal Octogenarians (OCTO)-immune study, a combination of decreased CD4+ :CD8+ T cell ratio and poor T cell proliferation was associated with higher mortality in a subgroup of very old Swedish individuals (Wikby et al., 1998). In this respect, it is interesting to note that the number of CD8+ T cells carrying receptors for viral epitope (cytomegalovirus (CMV) or Epstein–Barr virus (EBV)) increases with age in some cohorts (Ouyang et al., 2002), which could contribute to the decrease of CD4+ :CD8+ T cell ratio. Na¨ıve and memory helper T cell subsets Human CD4+ and CD8+ T cells can be divided into two subsets based on the expression of two markers: CD45RA and CD45RO that seem to differentiate the so-called na¨ıve and memory T cells. At birth, most of the T cells

25

are of na¨ıve type and the number decreases thereafter with reciprocal increase in the number of memory type T cells (Cossarizza et al., 1996). Figure 8 shows age-related changes of na¨ıve and memory T cells in human and C57BL/6 mice (Utsuyama et al., 1992). In mouse T cells, CD4+ CD45RBhigh CD44low and CD4+ CD45RBlow CD44high are referred to as na¨ıve and memory T cells, respectively (Mossmann and Coffman, 1987). The age-related reciprocal change in the ratio between na¨ıve and memory T cell subsets in mice (Figure 8b) is much more clear-cut than in humans (Figure 8a). In young mice, na¨ıve and memory T cells are almost comparable to the proinflammatory Th1 and anti-inflammatory Th2 T cell ratio, in terms of cytokine production. However, the situation changes in old mice; that is, na¨ıve T cells produce more IL-4 than IL-2 and memory T cells produce more IL-2 than IL-4. Other T cell subsets CD28 is a costimulatory molecule that is required for optimal activation and proliferation by antigenic stimulation of T cells. T cells expressing CD28 decrease with age in vivo, and progressive loss of CD28 is observed in long-term T cell culture (Effros et al., 1994). Thus, expansion of CD28− T cells may be one of the hallmarks of immunosenescence. CD95 is a surface molecule mediating apoptotic signal and plays an important role in immunological regulation. T cells expressing CD95 decrease with age, especially within the CD8+ T cell subset (Fagnoni et al., 2000).

Naive T cells Memory T cells 80

Percentage in CD4+ T cell

Cell number (⫻100 mm−3)

4

2

0

6−19

30−39 50−59 70−79 90− 20−29 40−49 60−69 80−89 Age (years)

(a) Human PBL

60

40

20

0

NB

2w

3m

12 m 18 m

24 m

Age (b) Mouse spleen

Figure 8 Age-related decrease of na¨ıve T cells (open columns) is seen with a concomitant increase of memory T cells (cross-hatched columns) in human peripheral blood (a) and mouse spleen (b). After Utsuyama et al. (1992) (Reprinted from Mechanisms of Age and Development, vol 63, Utsuyama M et al., pp 57 – 66, Copyright 1992, with permission from Elsevier)

26


Naturally arising CD25+ CD4+ regulatory T cells contribute to the maintenance of immunologic self-tolerance and negative control of various immune responses (Sakaguchi, 2004). Suppressive activity of human CD4+ CD25+ T cells is reported to decline with age (Tsaknaridis et al., 2003). (c) Qualitative change Qualitative changes in T cells are observed by their ability to proliferate and produce various cytokines following antigenic or mitogenic stimulation (Douziech et al., 2002; Utsuyama et al., 1993). Antigenic stimulation is received by the T cell antigen receptor (TCR), and the signal is transmitted through CD3 molecules to activate various signal transduction molecules, eventually giving rise to proliferation and cytokine production. Aging definitely influences signal transduction and cytokine production, which will be discussed later. T cells from aged humans appear to be more sensitive to TNF-α-induced apoptosis (Salvioli et al., 2003).

donors in response to IL-2 is decreased as compared to those from young donors (Borrego et al., 1999). 5. NKT cells NKT cells represent a unique subset of T cells sharing some characteristics with NK cells and are found at high frequency in the liver. The number of liver NKT cells decreases in old humans and mice (DelaRosa et al., 2002; Tsukahara et al., 1997), in association with impaired cytotoxicity and cytokine production. It is interesting to note that liver NKT cells bearing TCRαβ decrease in number with age, but those bearing TCRγ δ are functionally increased in very old mice (Mocchegiani and Malavolta, 2004).

3. B cells B cells play an important role in the production of antibody. Quantitatively, the number of B cells in human peripheral blood decreases with age (Table 4) (Utsuyama et al., 1992; Huppert et al., 1998). Antibody forming capacity is known to decrease with age in humans and animals, and the decline is due to insufficiency of helper T cells, intrinsic changes in B cells, or both. For example, immunization with tetanus toxoid (TT) results in a significant increase in serum titers in young adults for up to 1 year, but the serum TT titers falls off to baseline by 6 months in old adults (Burns et al., 1993). Stem cells in the bone marrow differentiate to pro-B cells, then to pre-B cells, and finally to B cells with sIgM. It is well known that frequencies of pre-B cells are diminished in aged mice. Age-related decrease was also observed in the number of both pro-B cells and very early B-lineage progenitors in mouse bone marrow (Miller and Allman, 2003). Qualitatively, various age changes appear to occur in B cells. An intrinsic molecular change may occur in the aging B cells, as utilization of VH and VL genes in antibodies to a bacterial epitope (e.g. phosphorylcholine hapten) differs between young and old mice. Old mice express less diversified antibody repertoires, possibly as a consequence of reduction in the number of antibody precursors and increased peripheral selection that may be responsible for the progressive establishment of immunodeficiency.

6. Macrophages Macrophages are one of the prototype cells of the innate immune system. Conflicting results are reported on functions of macrophages and monocytes. Phagocytosis and lysosomal enzyme activity do not change with age; however, the ability of macrophages to present antigen declines with aging. Lectin-induced proliferation of T cells is inhibited by prostaglandin (PG) E2, hydrogen peroxide (H2 O2 ), and transforming growth factor (TGF) β2, which are produced by macrophages. The inhibitory effect is significantly greater when macrophages are derived from aged rats. The production of H2 O2 and nitric oxide (NO) in peritoneal macrophages is reduced in old mice when compared to that of young mice (Ding et al., 1994). Antitumor activity of peritoneal macrophages declines with age, together with the reduced capacity to produce IL-1 and NO. Adherence of macrophages to fibronectin (FN) and type 1 collagen increases during aging, and this may be related to atherogenesis of the aorta during aging. Age-related increases in the number of monocyte/macrophage/osteoclast precursor cells could explain the increased resorptive activity seen in the elderly. Tumor necrosis factor (TNF) production by alveolar macrophages and spleen cells in response to a Streptococcus-derived factor (OK-4323) increases with age in mice (Han et al., 1995). Both splenic and activated peritoneal macrophages from aged mice express significantly lower levels of all Toll-like receptors (TLRs). Secretion of IL-6 and TNF-α is decreased when stimulated with known ligands for TLRs (Renshaw et al., 2002). Lipopolysaccharide (LPS) stimulated macrophages from aged animals have significantly higher levels of the inducible cycloxygenase 2 enzyme, leading to increased production of PGE2 , which is known to inhibit T cell function (Hayek et al., 1997), as mentioned above.

4. NK cells NK cells are a critical component of the innate immune response against various infections and tumors. The number of NK cells increases with age in humans after a certain point in old age, but contrarily, it decreases in mice (Utsuyama et al., 1992; Mariani et al., 1994). Despite discrepancy in the number of NK cells between humans and mice, the killer cell activity declines both in humans and mice (Mariani et al., 1994). Proliferation of purified NK cells from healthy elderly

7. Granulocytes Granulocytes are a major component of natural immunity and operate as the front line of defense against various infectious agents. In healthy subjects, most functions of granulocytes do not change or even increase compared with young control. However, age-related impairment or alteration of various magnitude was detected including phagocytosis, intracellular killing, chemotaxis, proliferative response to GM-CSF, expression of CD16, production of superoxide

IMMUNITY AND AGING

anion, mobilization of intracellular free calcium, apoptosis, and antibody-dependent cell-mediated cytotoxicity (ADCC) activity (Seres et al., 1993; Fulop et al., 1997; Schroeder and Rink, 2003; Plackett et al., 2004). 8. Antigen presenting cells (APC) Macrophages, B cells, and dendritic cells play an important role in presenting antigen to T cells. In senescent accelerated mice (SAMP1), B cells and dendritic cells express low level of Major Histocompatibility Complex MHC-II and intercellular adhesion molecule 1 (ICAM-1) and show a decrease in antigen presenting cells (APC) function. A decrease is also observed in accessory function of human monocytes, which is essential for T cells to proliferate in response to phytohemagglutinin (PHA) stimulation. The type of MHC should be the same between APC and T cells; however, T cells from aged, but not young, humans can be stimulated with influenza vaccine presented by allogeneic APC (Schwab et al., 1992). Dendritic cells (DC) are “professional” APC, for they are most efficient in presenting antigens to T cells. Since maturation of DC subsets is suppressed by IL-10, age-related increase of IL-10 could negatively influence the maturation of DC in the elderly (Uyemura et al., 2002). The number of DC is decreased in skin (Langerhans’ cells) of aged mice and peripheral blood of elderly people (Shodell and Siegal, 2003). 9. Extrathymic T cells It is established that T cells of various types could be developed outside of the thymus, although the number is smaller than those derived from the thymus. T cells of extrathymic origin have either αβ or γ δ type TCR, and are found in the liver and within epithelial cells of the digestive tract. With the age-related decline of thymic function to provide T cells to the periphery, extrathymic T cells generally increase in number. They probably play a role in the local defense against pathogenic microbes as well as in the maintenance of mucosal epithelium.

ROLE OF THYMUS IN AGING OF THE IMMUNE SYSTEM The immunological function of the thymus was first revealed by the famous brief report of Miller (Miller, 1961), indicating that neonatal but not adult thymectomy brought about immune deficiency in mice. This suggests that the thymus starts to lose its function to provide T cells to the periphery shortly after the birth. Table 5 summarizes the rate of decline in various thymic functions in longlived mice: (a) immigration of pre-T cells into the thymus; (b) proliferative activity of thymocytes; (c) emigration of T cells to the spleen; (d) the thymic function to provide helper T cells; and (e) killer T cells (Hirokawa et al., 1994). The results clearly indicate that most thymic functions decline very rapidly; that is, within 4 weeks after birth. In this respect,

27

Table 5 Age-related changes in thymic function in mice

Experiments Experiment 1 Immigration of pre-T cells Into thymus Experiment 2 1. Rate of proliferation of thymocytes 2. Rate of emigration of T cells to spleen Experiment 3 1. Rate of proliferation of thymocytes 2. Activity of helper T cells 3. Activity of killer T cells

1d

1w

2w

4w

17 m

24 m

100

NT

NT

7

3

3

100

45

15

NT

17

NT

100

25

15

NT

1

NT

100

73

71

85

NT

65

100

62

41

40

NT

10

100

125

55

25

3

0.5

The numbers are percentages as compared with the value at 1-day-old mice (100%) and average of 3 mice. NT, not tested; d, days; w, weeks; m, months. Experiment 1: Bone marrow cells from young B10.Thy-1.1 mice were injected i.v. into congeneic C57BL/6.Thy-1.2 mice at various ages from day 1 to 24 months old, and the number of donor-type thymocytes was counted 4 weeks later. Experiment 2: Bone marrow cells from young B10.Thy-1.1 mice were directly injected into thymus of congeneic C57BL/6 mice at various ages from day 1 to 24 months old, and the numbers of donortype T cells in thymus (1) and spleen (2) were counted 4 weeks later. Experiment 3: Thymus from C57BL/6 mice at various ages from 1 day to 24 months old was implanted into congenic nude mice at 6 weeks of age. Twelve weeks later, number of thymocytes (1), activity of helper T cells (2), and killer T cells (3) in spleen were assessed.

repopulation of CD4+ T cells after their elimination with anti-CD4 antibody (GK1.5) is 5 times less in aged than in young mice, and there is no repopulation in thymectomized mice (Rice and Bucy, 1995). In humans, Mackall et al. (1995) reported that regeneration of CD4+ T cells after intensive chemotherapy was seen within 6 months in a 3-yearold infant, but was significantly retarded in a young adult 23 years of age (Figure 7). Such thymic changes, which start in the early phase of life, could be determined by assessing age-related changes occurring in either pre-T cells in the bone marrow or the thymic microenvironment, or both. To address this issue, four combinations of bone marrow chimeric mice were constructed by transplantation of bone marrow cells from young (3 months old) or old (24 months old) donors into young or old irradiated recipient mice (Y → Y, Y → O, O → Y, O → O). It was shown that the thymic weight was almost comparable for those chimeric mice when the recipients are young, regardless of the age of bone marrow donors, but was distinctly reduced when the recipients are old, regardless of the age of bone marrow donors. In other words, the magnitude of in vivo proliferative capacity of the thymocytes was mainly dependent upon the age of thymic microenvironment (Table 3). In the experiment of intrathymic injection of bone marrow cells in mice, it was shown that the rate of emigration of T cells from the thymus greatly decreased between birth and 1 month of age (Table 5) (Hirokawa et al., 1988). These findings, taken together, indicate that the

28


age-related alteration of thymic microenvironment is more responsible for the physiologic impairment in generating new T cells than that caused by intrinsic changes in progenitors (pre-T cells) in bone marrow (Hirokawa et al., 1988). As already described in the preceding sections, the impairment of T cell functions in the aged individuals is partly ascribed to a change in composition of T cell subsets. Such age-related change in T cell subsets can also be due to alteration in the ability of thymus to provide T cells to the periphery. It was shown that the thymus of young mice, as compared with that of old mice, produces more CD4+ than CD8+ splenic T cells. In case of CD4+ T cell subsets, the thymus of young mice produces more na¨ıve T cells than memory T cells, while the thymus of old mice does the opposite (Table 3). These findings are consistent with the facts that CD8+ T cells are more susceptible to aging than CD4+ T cells, and na¨ıve T cells decrease with age as memory T cells increase (Utsuyama et al., 1992).

CAUSES OF AGE-RELATED DECLINE IN THYMIC FUNCTION Physiological thymic involution is considered to be under the control of both extrathymic and intrathymic factors. Since thymic involution is accelerated after puberty, sex hormone could be a possible candidate influencing thymic function. In practice, thymic involution can be delayed or reversed by castration regardless of age. Thymic hypoplasia with T cell-dependent immunodeficiencies was observed in congenitally hypopituitary Snell dwarf mice (Dorshkind et al., 2003) and in rats that had undergone hypophysectomy. Conversely, thymic hyperplasia could be induced in rats by the destruction of the anterior portion of hypothalamus (AHTL, Anterior Hypothalamus Lesioning) (Utsuyama et al., 1997a). AHTL gives rise to decreased secretion of somatostatin (SST) and relative increase in growth hormone releasing hormone (GHRH) in the hypothalamus. This leads to increased secretion of growth hormone (GH), causing thymic hyperplasia. As compared with young adult, high level of GH (>10 folds) is detected in the serum of newborn mice or rats, or rats treated with AHTL. In other words, size and function of thymus are partly dependent on the serum level of GH, which, in turn, is regulated by the balance between SST and GHRH in the hypothalamus (Figure 9) (Hirokawa et al., 2001). Regarding intrathymic factors influencing thymic size, most important is the thymic microenvironment composed mainly of epithelial cells. As shown in the experiment of bone marrow chimeras constructed with tissues from young and old donor mice (Table 3), the age of thymic microenvironment is crucial for the magnitude of thymopoiesis. Thus, it is important to search for genes or factors that are expressed at high level in the newborn stage and progressively decline thereafter. It has been recently reported that stromal cells expressing Notch ligand Delta-like-1 acquire the capacity to induce the differentiation of hematopoietic progenitors into CD4 CD8 double- and single-positive T cells (Schmitt

Newborn

Adult

Hypothalamus

Hypothalamus

SST

GHRH

SST

GHRH

Pituitary gland

Pituitary gland

GH

GH

Thymus

Aging

Thymus

Figure 9 Control of thymic function by hypothalamus-pituitary axis. In newborn animals, positive signal of growth hormone releasing hormone (GHRH) is superior to negative signal of somatostatin (SST) in hypothalamus, leading to high secretion of growth hormone (GH). In young adult animals, negative signal (SST) exceeds positive one (GHRH) leading to a decrease in secretion of GH. A decrease in the serum level of GH in the young adult gives rise to thymic involution

and Zuniga-Pflucker, 2002). A decline in IL-7 production is another factor that is responsible for thymic involution (Andrew and Aspinall, 2002). The mRNA expression of Notch ligand Delta-like-1 and IL-7 is very high at birth and quickly declines thereafter (Hirokawa and Utsuyama, 2004). In addition, there are many other genes that are expressed at high level in the thymic stromal cells at birth and quickly decline thereafter (Hirokawa and Utsuyama, 2004). Many of them seem to participate in the process of physiological thymic involution.

CYTOKINE PRODUCTION Among many cytokines, two types of cytokines, Th1 and Th2, are recognized. Th1 types are IL-2, IFNγ , and TNFβ, mainly responsible for cell-mediated immunity and suppressing antibody formation. Th2 types are IL-4, IL-5, IL-6, IL-10, and IL-13, responsible for antibody formation and suppressing cell-mediated immunity. It is generally accepted that production of Th1 type cytokines decreases with age, with a reciprocal increase of Th2 type cytokines, although there are some conflicting reports (Deng et al., 2004; Glaser et al., 2001; Neuber et al., 2003). For instance, production of IL-2 and INFγ was reported to decline with age (Deng et al., 2004), and such a decline is considered to be responsible for the impaired proliferation of old T cells upon antigenic stimulation. In contrast, production of IL-4, IL-5, IL-6, and 1L-10 by T cells increases with age (Castle et al., 1997; Neuber et al., 2003). Although INFγ belongs

IMMUNITY AND AGING

T cell clone 40000

Anti-CD3

30000

20000

*

10000

0 Splenic T cells

(a)

Anti-CD3 40000

20000

*

0 (b)

Old

10000

Old

Cells of the immune system are generally activated by stimuli such as antigens or cytokines through various receptors on the membrane. The stimulation through a receptor induces a cascade of intracellular signal transduction eventually reaching the nuclei and leading to DNA replication or generation of mRNA of some proteins. Important receptors of T cells are TCR, costimulatory receptors, and cytokine receptors. The level of TCR expression does not change with age or, at best, only slightly (Fulop et al., 1999). TCR/CD3 complex on T cells are internalized after mitogenic stimulation and reexpressed in certain interval. The level of reexpression is significantly retarded in T cells from old, as compared with young mice (Wakikawa et al., 1997). CD28 is an important costimulatory receptor and the expression is known to decrease in humans (Effros et al., 1994). Information is limited about the age-related change in the expression level of cytokine receptors. The expression level of IL-2R is decreased in the elderly. An increase of IL-2R after mitogenic stimulation is retarded in T cells from old mice. Intracellular signal transduction is apparently different between cells derived from young and old individuals (Pawelec et al., 2001). Pantel and Miller (Pantel and Miller, 1992) reported that quantitative and qualitative changes were observed in the pattern of protein phosphorylation between young and old T cells stimulated with mitogens. The activity of phospholipase C (PLC) acts on the phosphatidy-4,5 bisphosphate (PIP2) for liberation of inositoltrisphosphate (IP3) and diacylglycerol (DAG). The amount of PLC and PIP2 proteins extracted from T cells are comparable between young and old mice. However, phosphorylation of PLC was significantly impaired in old T cells as compared with young ones, when assessed in vivo after stimulation with anti-CD3 antibody (Utsuyama et al., 1993). Phosphorylation of PLC is dependent upon protein tyrosine kinase (PTK) associated with CD3 molecules. Our laboratory found that

PMA + INM *

30000

Young

SIGNAL TRANSDUCTION

PMA + INM

Young

to Th1 type cytokines, there are many reports indicating age-related increase in production of IFNγ or number of IFNγ + cells (Castle et al., 1997; Neuber et al., 2003; McNerlan et al., 2002; Pietschmann et al., 2003). The decrease in Th1 cytokines could explain a decrease in delayed type response to tuberculosis in the elderly, and increased production of Th2 cytokines would be consistent with increased frequency of autoimmune phenomena in the elderly population. IFNγ has a double edge effect in the immune system: one is antiviral effect and the other is suppressive effect on T cell function. With respect to the latter, production of TNF-α (Han et al., 1995) and TGF-β also increases with age. These cytokines are known to contribute to age-related decline in immune functions. In any event, age-related change in the composition of T cell subsets is associated with an altered balance in cytokine production, and, together, they contribute to the impaired immune response capacity of old individuals.

29

Figure 10 The proliferative response of T cell clones and splenic T cells after stimulation with anti-CD3mAb or PMA + INM. (a): [3 H]thymidine uptake of T cell clones established from young and old mice after stimulation with anti-CD3mAb or PMA + INM. (b): [3 H]thymidine uptake of splenic T cells prepared from young and old mice after stimulation with anti-CD3mAb or PMA + INM. ∗ indicates a significant difference between young and old mice (P < 0.001). anti-CD3mAb: anti-CD3 monoclonal antibody (2.5µg/ml). PMA: phorbol myristate acetate (100 ng ml−1 ). INM: ionomycin (20 ng ml−1 )

phosphorylation of PTK such as lck, fyn, and ZAP-70 is impaired in old T cells as compared with young ones (Utsuyama et al., 1997b). These findings collectively suggested that the decline in the proliferative response of old T cells could be partly ascribed to the impairment of intracellular signal transduction. Impaired phosphorylation of PTK and PLCγ 1 in an old T cell clone is associated with LPS messengers and low influx of Ca2+ . An old T cell clone can be fully activated to the level of a young one by stimulation with phorbol myristate acetate (PMA) plus ionomycin (INM) that bypass receptor activation and directly stimulate Protein kinase C (PKC) and induce influx of Ca2+ (Utsuyama et al., 1997b). However, when using splenic cells freshly prepared from young and old mice, the proliferative response of T cells of old mice to PMA plus INM is still lower than that of the young one (Figure 10) (Utsuyama et al., 1997b). These results indicate that age changes of signal transduction

30


appear to be present in multiple sites within cells. The JakStat pathway is one of the main signal routes under the IL-2R of T cells and is altered with age (Pawelec et al., 2001). An age-related increase is observed in proportion of CD3ζ chains, associated with a FC-epsilon R instead of forming the usual ζ /ζ -homodimer in mice (Tamura et al., 2000). In humans, T cells showed selective reduction in an isoform of PKC. Such a change in molecules may affect T cell function. As regards B cells, a decreased sensitivity to the growthpromoting effects of IL-4 may be one of the mechanisms underlying defective specific antibody synthesis in aging. Such an age-related change of B cells might be related to decreased activity of PTK/PKC in human. A significant decrease of IP3 formation in granulocytes from elderly subjects was also reported. These results suggest that alterations in signal transduction pathways occur with age in probably all cells of the immune system.

of thymulin section is detected in aging rats by administration of growth hormone and thyroxine. Autonomic nerves may have influence on thymic function. An age-related decrease in noradrenergic nerves (Bellinger et al., 1992) as well as dopamine-D1 like receptors (Ricci et al., 1995) in the thymus may be responsible for reduced thymic mass with age. The hypothalamus plays an important role in the control of both endocrine functions and autonomic nerves; therefore, it also could be a control center regulating the rate of immunological aging. Inducing a lesion in the anterior portion of hypothalamus brings about either atrophy or hypertrophy of the thymus, depending upon the specific area of destruction (Utsuyama et al., 1997a). As mentioned in the previous section, thymic function and size are partly under the control of hypothalamus (Hirokawa et al., 2001). Lymphocytes can produce various hormones and neurotransmitters and express receptors for them. Figure 11 shows the expression of receptors for hormones and neurotransmitter in lymphocytes, revealed by RT-PCR. Changes of the expression level with age are variable; that is, an increase, or a decrease, or

NEUROENDOCRINE-IMMUNE NETWORK The immune system is closely related with the neuroendocrine system. Thymic involution accelerates in association with rise of sex steroids after puberty. In fact, restoration of thymic mass as well as certain immune functions is observed in the aged animals after gonadectomy. An increase

Stress

Hypothalamus CRF

0

Old/Young ratio 1 2 3

Pituitary gland

4

Glucocorticoid-R TRH-R

Cytokines

ACTH

Adrenal gland

ANS

ACTH-R Glucocorticoid

NOR

Prolactin-R Oxytocin-R Immune system

TSH-R Acethylcolin-R GAPDH Young

Old

Splenic T cells Figure 11 mRNA expression of various receptors (R) to hormones and neurotransmitters of T cells from young and old mice. Columns indicate ratio of old: young. mRNA expression of TRH-R, ACTH-R, and Acetylcholine-R are shown to increase with age

Infection

Figure 12 Stress-induced activation model of the neuroendocrine-immune network. Various types of stress from the external environment are received by the nervous system, and some signals eventually stimulate the hypothalamus to secrete Corticotropin releasing factor (CRF). CRF then stimulates the pituitary gland to secrete ACTH, which, in turn, stimulates the adrenal cortex to secrete glucocorticoid. At the same time, other stress-induced signals trigger the hypothalamus to stimulate the autonomic nervous system (ANS), eventually leading to the secretion of noradrenalin (NOR) by the adrenal medulla. Both glucocorticoid and NOR also suppress immune functions. Independently, infection stimulates the immune system to produce various types of cytokines, most of which enter the brain and stimulate the hypothalamus that eventually results in the secretion of both glucocorticoid and NOR

IMMUNITY AND AGING

no change. Furthermore, cells of the nervous system can produce various cytokines and cytokine receptors. Age-related changes were reported in the levels of cytokines and their receptors in normal or pathological conditions (Utsuyama and Hirokawa, 2002; Godbout and Johnson, 2004). Another possible center for regulating immunological aging is the pineal gland, which produces melatonin for circadian rhythm. It is interesting to note that grafting of pineal gland in aged mice produces a remarkable restoration of thymic structure and cellularity. There is a growing belief that direct innervation or hardwiring of peripheral immune effector sites monitors and modulates immune homeostasis, together with the cytokine network (Downing and Miyan, 2000). More physiological studies in vivo are needed to further understand the significance of the neuroendocrine-immune network in aging. The data thus obtained would be helpful in understanding various diseases that are associated with immune dysfunction in the elderly population. As seen in Figure 12, the neuroendocrine-immune network acts as an integral system to combat various types of stress, including infection. As the network’s function declines with age, its capacity to cope with stress declines. Thus, one physiologic characteristic of aging is the decrease in physiologic capacity of the neuroendocrine-immune network to cope with stress from the external environment.

IMMUNE RISK PHENOTYPES As already mentioned, elderly people with elevated level of immune functions can live longer and become centenarians. Thus, the level of immune functions may predict the life span of individuals. In this respect, the longitudinal study in Baltimore (Shock et al., 1984) suggests that the number

31

of lymphocytes in the peripheral blood appeared to be a simple predictor of mortality; that is, individuals with a significant drop in the number of lymphocytes show higher rate of mortality within the next couple of years. In similar longitudinal studies of OCTO and Nonagenarian (NONA) on naturally aging population in Sweden, the concept of immune risk phenotype (IRP) was presented (Ferguson et al., 1995). Parameters included in the high IRP phenotype were high CD8, low CD4, and poor T cell proliferative response that could predict two-year mortality of persons 80 years of age or older (Ferguson et al., 1995). Further studies are required for the confirmation of the concept of IRP that would be helpful in understanding the importance of immune functions in morbidity and mortality of the elderly.

AUTOIMMUNE PHENOMENA INCREASING WITH AGE Some autoimmune diseases are known to occur in young adults rather than in the elderly. For example, systemic lupus erythematosus (SLE) is an autoimmune disease that generally occurs in young females over 20 years of age. From the viewpoint of T cell immunity, however, people over 20 years of age are already in the early phase of the age-related decline of immune functions. As peak incidence of SLE, rheumatoid arthritis, and Hashimoto’s thyroiditis are observed at the third, fifth, and sixth decade respectively (Figure 13), one could speculate that autoimmune diseases occur in the people whose immune functions are in the declining phase. These autoimmune diseases occur in a limited number of persons with distinct genetic background, as well as other factors such as aging of the immune system. It is important to

Autoimmune diseases and age Immunity

SLE

RA

Thyroiditis

Relative frequency in each decade

100

SS

80

60

40

20

0

0–9

10 –19

20–29

30 – 39

40 – 49 Age

50 – 59

60 – 69

70 – 79

80 –

Figure 13 Age-related change of immune response and incidence of four autoimmune diseases in humans. SLE: systemic lupus erythematosus. RA: rheumatoid arthritis. Thyroiditis: Hashimoto’s thyroiditis. SS: Sjögren’s syndrome. Ordinate indicates relative values or frequencies, as compared with the peak level

32


note that autoimmune phenomena occur in most of the aged people, and they are called age-associated autoimmune phenomena rather than autoimmune disease, as they are generally not associated with clinical manifestations. On the other hand, the range of autoimmune disease is expanding. For instance, atherosclerosis might be an autoimmune disease due to an immune reaction against heat shock protein 60 (Wick, 2000). Age-associated autoimmune phenomena are composed of two types of autoimmunity: one is the production of autoantibody and the other the generation of autoreactive T cells. 1. Autoantibodies Accumulating data show that various kinds of autoantibodies are detectable in the sera of the elderly individuals. Both the frequency and the concentration of autoantibodies also increase with age and with a concomitant decrease of normal immune functions (Figures 1 and 5). 2. Auto-reactive T cells It is very common to find focal lesions of lymphocytic infiltration in many organs of elderly autopsy cases, and most of these lymphocytes are revealed to be CD4+ T cells when examined immunohistologically. The composition of the infiltrating lymphocytes in these lesions of submandibular glands was quite similar to those seen in Sjogren’s disease. Focal lesions of T cell infiltration were also found in the thyroid, adrenal glands, liver, and kidney of the elderly autopsy cases as well as in aging mice. The incidence of focal T cell infiltration apparently increases with advancement in age, although the onset, incidence, and severity are different, depending on tissues and organs. In NFS/sld mouse, an animal model of human Sjogren’s syndrome, α fodrin, a cytoskeletal protein, was identified as an autoantigen causing autoimmune disease (Haneji et al., 1997). Interestingly, the lesion in NFS/sld mouse starts to appear as early as 1 month of age and becomes more pronounced and aggravated with age, and similar lesions develop in other sites (Kobayashi et al., 2004).

RESTORATION OF IMMUNE FUNCTIONS The development of methods to restore impaired immune functions of elderly people is urgently needed (Hirokawa and Utsuyama, 2002). Most of the methods reported are still at the level of animal models. Broadly speaking, there are two ways for immunological restoration: one is activation or functional enhancement of existing immune cells in individuals, and the other is transplantation or infusion of active or functional immune cells from young donors. 1. Enhancement of immune cell functions (a) Caloric restriction The effects of caloric restriction (CR) in rodents are pronounced in terms of elongation of life span and

restoration of immunological functions (MaCay et al., 1935). There has been accumulating evidence that similar observations are found not only in rodents but also in many other animal species, and CR influences various physiological systems, including the immune system (Longo and Finch, 2003; Heilbronn and Ravussin 2003; Pahlavani, 2004). Two important outcomes of CR are reduction of oxidative stress and improved glucoregulation. Studies are now ongoing to see the effect of CR on various physiological parameters in monkeys (Roth et al., 2002), and they suggest several beneficial effects. Although data are limited, CR in humans could bring about similar physiological changes resembling those of rodents and monkeys. Thus, for example, there is a study reporting that long-term calorie restriction is highly effective in reducing the risk of atherosclerosis in humans (Fontana et al., 2004). Animals under CR have decreased fat mass and alterations in insulin/insulin-like growth factor 1 (IGF-1). Mice with a fat-specific insulin receptor knockout (FIRKO) have reduced fat mass and show an increase in mean life span, although intake of calorie is normal (Blüher et al., 2003). (b) Antioxidants Harman (Harman, 1969) hypothesized that degenerative changes associated with aging could be produced by the accumulation of deleterious side reactions of free radicals produced during cellular metabolism. Free radicals or reactive oxygen species (ROS) are harmful to immune cells, gradually attenuating their activities with increase in age. For instance, oxidative inactivation of CD45 protein tyrosine phosphatase may contribute to T lymphocyte dysfunction in the elderly (Rider et al., 2003). Thus, vitamin E and other dietary antioxidants may play an important role in reducing ROS-initiated decline of immune functions with age. In animal models, vitamin E supplementation has been shown to increase immunological function and enhance survival against infection (Adolfsson et al., 2001). Dietary supplementation with thioproline, a free radical scavenger, can significantly increase phagocytosis, NK activity, and proliferative response of lymphocytes in old mice (De La Fuente et al., 2002). In humans, restoration of immune functions has been observed in some, but not all individuals (Ravaglia et al., 2000; Gardner et al., 2000). It is interesting to note that age-related physiological zinc deficiency induces deleterious changes in thymus structure and function, which can be partially corrected by a mild oral zinc supplementation (Mocchegiani and Muzzioli, 2000). (c) Endocrine hormones Age-related changes in the production of several hormones may be closely related with immunosenescence (Arlt et al., 2002). Sex steroid hormones are inhibitory for lymphoid cells. Therefore, their withdrawal generally gives rise to enhanced immunological functions, as already described in gonadectomy. In contrast,

IMMUNITY AND AGING

pituitary hormones, such as growth hormone and thyroid stimulating hormone, are stimulatory for the thymus and T cells. Concentration of dehyroepiandrosteron (DHEA) declines with age in humans. In vivo treatment of old rats with DHEA results in the restoration of age-associated defects in the protein kinase C signal transduction pathway with enhancement of mitogenic response of spleen cells (Corsini et al., 2002). Melatonin is a hormone secreted by the pineal gland, and it plays an important role in the regulation of circadian rhythm. Melatonin was shown to act as a free radical scavenger; therefore, it could chemically correct immunodeficiencies of the elderly (Pierpaloi et al., 1994). However, data reported on its effect on immunity are conflicting; some are positive (Atre and Blumenthal, 1998) and others are negative (Pahlavani et al., 2002). (d) Thymic peptides Peptides isolated from the thymus are thymosin, thymic humoral factor (THF), thymopoietin, and FTS or thymulin, and they used to be called thymic hormones, but not any more. It is now generally accepted that they are not directly involved in T cell differentiation. Both successful and unsuccessful restoration of T cell function by thymic peptides, based on in vivo and in vitro experiments, have been reported by many investigators. 2. Grafting of cells and tissues In animal experiments, transfusion of T and B cells from young mice into old mice did not give rise to a significant effect, probably due to inhibitory effects of preexisting cells in old individuals (Makinodan and Kay, 1980). In humans, the treatment of AIDS patients by transfusion of autologous T cells, expanded ex vivo in large scale, has been successful; that is, T cells were expanded 100–1000-fold by ex vivo culture for 2 weeks with recombinant interleukin2 and immobilized monoclonal antibody to CD3 (Shimizu et al., 2000). This model of large scale ex vivo expansion of T cells could be applied for the restoration of immune functions of the elderly. The level of immune functions of aged mice can be restored to a level approaching that of young adult mice by grafting both newborn thymus and bone marrow cells of young donor animals (Hirokawa and Utsuyama, 2002). The results suggest that intrinsic cellular change of the immune system is more responsible for immune deficiencies of aged individuals than the environmental or structural tissue change, including connective tissues and humoral factors. Table 6 shows relative levels of anti-SRBC antibody response in eight combinations of chimeras, constructed by young or old recipients, young or old bone marrow cells, and newborn or old thymus. The relative magnitude of antibody response is always high or medium, regardless of the age of recipients and bone marrow cell donors. Thymic stromal tissues, rather than bone marrow cells, are important for restoration of the T celldependent immune system. In practice, aged mice treated

33

Table 6 Eight combinations of chimeras constructed by young/old recipients, young/old bone marrow, and newborn/old thymus

Recipients

Bone marrow

Thymus

anti-SRBC antibody response

Young Young Young Young Old Old Old Old

Young Young Old Old Young Young Old Old

Newborn Old Newborn Old Newborn Old Newborn Old

High Low High Low High Low Medium Low

Young (2 months) and old (23 months) C57BL/6 male mice were irradiated (8.5Gy) and transplanted with bone marrow cells (5 × 105 ) from young (3 months) or old (24 months) C57BL/6 male mice. One month later, thymus from newborn or old (24 months) mice was transplanted under kidney capsule of recipient mice. One month after the last treatment, anti-SRBC antibody response was assessed.

with multiple newborn thymus grafting can survive significantly longer than control mice (Hirokawa and Utsuyama, 2002). For human application, MHC type should be the same or very close between donors and recipients. Therefore, a new method needs to be developed for the reconstruction of the thymic microenvironment using appropriate cells and genes of the individual (Hirokawa and Utsuyama, 2004).

CONCLUDING REMARKS The immune system not only functions as the body’s defense system against infections from the external environment but also as the body’s regulatory system, maintaining homeostasis of the internal environment. In the latter case, the immune system operates together with the endocrine and nervous systems using many common mediators among themselves. In other words, the neuroendocrine-immune network combats various kinds of stresses from the outer environment, and its age-related decline in functional capacity is causally related to the increase in occurrence of various age-associated diseases and decline in quality of life (QOL) in the elderly population. Thus, the restoration of immune capacity is necessary not only for protection against infection but also for the improvement of QOL in the elderly. Age-related functional decline is observed in many kinds of cells and tissues composing the immune system, but the most pronounced decline occurs in those involved in T celldependent immune functions that are due mainly to thymic involution starting in the early phase of life. Accordingly, the restoration of T cell-dependent immune functions is becoming an important issue in combating infectious diseases and improving the QOL of the elderly population. Various methods to restore T cell-dependent immune functions in the frail elderly population are now under investigation in many laboratories. Among them, the reconstruction of thymic microenvironment using modern tissue and gene technology appears to be one of the most exciting and challenging tasks.

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KEY POINTS • Infection, a major cause of death in the elderly population, is primarily due to age-related decline in T cell-dependent immune functions. • Age-related decline of T cell-dependent immune functions, caused by thymic involution that occurs early in life, is manifested quantitatively by a decrease in the number of T cells and a shift in the proportion of T cell subsets, and qualitatively by changes in proliferative activity and cytokine production that are caused by alteration of molecules involved in intracellular signal transduction. • The immune system collaborates with the neuroendocrine system, and the neuroendocrine-immune network combats various kinds of environmental stress, including infections. • Age-related decline in immune functions is causally related to increase in occurrence of various ageassociated diseases, including infections, autoimmune diseases, and autoimmune phenomena against internal antigens, and, as a consequence, to decrease in quality of life (QOL). • Restoration of impaired immunological functions in the elderly is an urgent need, and therefore, various restorative methods are discussed, including caloric restriction, antioxidant dietary supplements, hormone supplement, and grafting of limiting immune cells and tissues.

KEY REFERENCES • Hirokawa K & Utsuyama M. Animal models and possible human application of immunological restoration in the elderly. Mechanisms of Ageing and Development 2002; 123:1055 – 63. • Hirokawa K, Utsuyama M, Kasai M et al. Understanding the mechanism of the age change of thymic function to promote T cell differentiation. Immunology Letters 1994; 40:269 – 77. • Linton PJ & Dorshkind K. Age-related changes in lymphocytes development and function. Nature Immunology 2004; 5:133 – 9. • Makinodan T & Kay MMB. Age influence on the immune system. Advances in Immunology 1980; 29:287 – 330. • Utsuyama M, Wakikawa A, Tamura T et al. Impairment of signal transduction in T cells from old mice. Mechanisms of Ageing and Development 1997b; 93:131 – 44.

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Mackall C, Fleisher TA, Brown MK et al. Age, thymopoiesis, and CD4+ T lymphocytes regeneration after intensive chemotherapy. The New England Journal of Medicine 1995; 332:143 – 9. Makinodan T & Kay MMB. Age influence on the immune system. Advances in Immunology 1980; 29:287 – 330. Mariani E, Monaco MC, Cattini L et al. Distribution and lytic activity of NK cell subsets in the elderly. Mechanisms of Ageing and Development 1994; 76:177 – 87. McNerlan SE, Rea IM & Alexander HD. A whole blood method for measurement of intracellular TNF alpha, IFN-gamma and IL-2 expression in stimulated CD3 lymphocytes: difference between young and elderly subjects. Experimental Gerontology 2002; 37:227 – 34. Miller JFAP. Immunological function of thymus. Lancet 1961; ii:748 – 9. Miller JP & Allman D. The decline in B lymphopoiesis in aged mice reflects loss of very early B-lineage precursors. Journal of Immunology 2003; 171:2326 – 30. Mocchegiani E & Malavolta M. NK and NKT cell functions in immunosenescence. Aging Cell 2004; 3:177 – 84. Mocchegiani E & Muzzioli M. Giacconi R: zinc and immunoresistance to infection in aging: new biological tools. Trends in Pharmacological Sciences 2000; 21:205 – 8. Mossmann TR & Coffman RL. Two types of helper T cell clone: implication for immune regulation. Immunology Today 1987; 8:223 – 7. Neuber K, Schmidt S & Mensch A. Telomere length measurement and determination of immunosenescence-related markers (CD28, CD45RO, CD45RA, interferon-gamma and interleukin 4) in skin homing T cells expressing the cutaneous lymphocyte antigen: indication of a non-ageing T cell subset. Immunology 2003; 109:24 – 31. Ouyang Q, Wagner WM, Walter S et al. An age-related increase in the number of CD8+ T cells carrying receptors for an immunodominant EBV epitope is counteracted by a decreased frequency of their antigen specific responsiveness. Mechanisms of Ageing and Development 2002; 124:477 – 85. Pahlavani MA, Vargas DA, Evans TR et al. Melatonin fails to modulate immune parameters influenced by calorie restriction in aging Fischer 344 rats. Experimental Biology and Medicine 2002; 227:201 – 7. Pantel HR & Miller RA. Age-associated changes in mitogen-induced protein phosphorylation in murine T lymphocytes. European Journal of Immunology 1992; 22:253 – 60. Pawelec G, Akbar A, Caruso C et al. Is immunosenescence infectious? Trends in Immunology 2004; 25:406 – 10. Pawelec G, Hirokawa K & Fulop T. Altered T cell signaling in ageing. Mechanisms of Ageing and Development 2001; 122:1613 – 37. Pahlavani MA. Influence of caloric restriction on aging immune system. The Journal of Nutrition, Health & Aging 2004; 8:38 – 47. Pierpaloi W, Regelson W & Fabris N. The aging clock. Annals of the New York Academy of Sciences 1994; 719:1 – 588. Pietschmann P, Gollob E, Brosch S et al. The effect of age and gender on cytokine production by human peripheral blood mononuclear cells and markers of bone metabolism. Experimental Gerontology 2003; 38:1119 – 27. Plackett TP, Boehmer ED, Faunce DE et al. Aging and innate immune cells. Journal of Leukocyte Biology 2004; 76:291 – 9. Ravaglia G, Forti P, Maioli F et al. Effect of micronutrient status on natural killer cell immune function in healthy free-living subjects aged >/=90 y. The American Journal of Clinical Nutrition 2000; 71:590 – 8. Renshaw m, Tockwell J, Engelman C et al. Impaired Toll-like receptor expression and function in aging. Journal of Immunology 2002; 169:4697 – 701. Ricci A, Vega JA, Zaccheo D et al. Dopamine D1-like receptors in the thymus of aged rats: a radioligand binding and autoradiographic study. Journal of Neuroimmunology 1995; 56:155 – 60. Rice JC & Bucy RP. Differences in the degree of depletion, rate of recovery, and the preferential elimination of naive CD4+ T cells by antiCD4 monoclonal antibody (GK1.5) in young and aged mice. Journal of Immunology 1995; 154:6644 – 54. Rider DA, Sinclair AJ & Young SP. Oxidative inactivation of CD45 protein tyrosine phosphatase may contribute to T lymphocyte dysfunction in the elderly. Mechanisms of Ageing and Development 2003; 124:191 – 8.

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Roth GS, Lane MA, Ingram DK et al. Biomarkers of caloric restriction may predict longevity in humans. Science 2002; 297:811. Rowley MJ, Buchanan H & Mackay IR. Reciprocal change with age in antibody to extrinsic and intrinsic antigens. Lancet 1968; 2:24 – 6. Sakaguchi S. Naturally arising CD4+ regulatory T cells for immunologic self-tolerance and negative control of immune responses. Annual Review of Immunology 2004; 22:531 – 62. Salvioli S, Capri M, Scarcella E et al. Age-dependent changes in the susceptibility to apoptosis of peripheral blood CD4+ and CD8+ T lymphocytes with virgin or memory phenotype. Mechanisms of Ageing and Development 2003; 124:409 – 18. Schmitt TM & Zuniga-Pflucker JC. Induction of T cell development from hematopoietic progenitor cells by delta-like-1 in vitro. Immunity 2002; 17:689 – 92. Schmucker DL. Intestinal mucosal immunosenescence in rats. Experimental Gerontology 2002; 37:197 – 203. Schroeder AK & Rink L. Neutrophil immunity of the elderly. Mechanisms of Ageing and Development 2003; 124:419 – 25. Schwab R, Russo C & Weksler ME. Altered major histocompatibility complex-restricted antigen recognition by T cells from elderly humans. European Journal of Immunology 1992; 22:2989 – 93. Seres I, Csongor J, Mohacsi A et al. Age-dependent alterations of human recombinant GM-CSF effects on human granulocytes. Mechanisms of Ageing and Development 1993; 71:143 – 54. Shimizu N, Sekine T, Itoh K et al. Large scale ex vivo expansion of primary T lymphocytes in late-stage AIDS patients. AIDS Research and Human Retroviruses 2000; 10:611 – 2. Shiraishi J, Utsuyama M, Seki S et al. Essential microenvironment for thymopoiesis is preserved in human adult and aged thymus. Clinical & Developmental Immunology 2003; 10:53 – 9. Shock NW, Greulick RG, Andres RA et al. Normal Human Aging: The Baltimore Longitudinal Study on Aging 1984; US Governmental Printing Office, Washington. Shodell M & Siegal FP. Circulating interferon-producing plasmacytoid dendritic cells decline during human ageing. Scandinavian Journal of Immunology 2003; 56:519 – 21. Suzuki K, Hirokawa K & Hayakeyama S. Age-related change of distribution of immunoglobulin containing cells in human bone marrow. Changes in patients with benign monoclonal gammopathy and multiple myeloma. Virchows Arch A Pathol Anat Histopathol 1984; 404:243 – 51. Tamura T, Kunimatsu T, Yee ST et al. Molecular mechanism of the impairment in activation signal transduction in CD4+ T cells from old mice. International Immunology 2000; 12:1205 – 15. Tsaknaridis L, Spencer L, Culbertson N et al. Functional assay for human CD4+ CD25+ Treg cells reveals an age-dependent loss of activity. Journal of Neuroscience Research 2003; 74:296 – 308.

Tsukahara A, Seki S, Iiai T et al. Mouse liver T cells: their change with aging and in comparison with peripheral T cells. Hepatology 1997; 26:301 – 9. Utsuyama M & Hirokawa K. Differential expression of various cytokine receptors in the brain after stimulation with LPS in young and old mice. Experimental Gerontology 2002; 37:411 – 20. Utsuyama M, Hirokawa K, Kurashima C et al. Differential age-change of CD4+ CD45RA+ and CD4+ CD29+ T cell subsets in human peripheral blood. Mechanisms of Ageing and Development 1992; 63:57 – 66. Utsuyama M, Kobayashi S & Hirokawa K. Induction of thymic hyperplasia and suppression of splenic T cells by lesioning of the anterior hypothalamus in aging Wistar rats. Journal of Neuroimmunology 1997a; 77:174 – 80. Utsuyama M, Wakikawa A, Tamura T et al. Impairment of signal transduction in T cells from old mice. Mechanisms of Ageing and Development 1997b; 93:131 – 44. Utsuyama M, Varga Z, Fukami K et al. Influence of age on the signal transduction of T cells in mice. International Immunology 1993; 5:1177 – 82. Uyemura K, Castle SC & Makinodan T. The frail elderly; role of dentritic cells in the susceptibility of infection. Mechanisms of Ageing and Development 2002; 123:955 – 62. Wakikawa A, Utsuyama M & Hirokawa K. Altered expression of various receptors on T cells in young and old mice after mitogenic stimulation. A flow cytometric analysis. Mechanisms of Ageing and Development 1997; 94:113 – 2. Wick G. Atherosclerosis – an autoimmune disease due to an immune reaction against heat shock protein 60. Herz 2000; 25:87 – 90. Wikby A, Maxson P, Olsson J et al. Changes in CD8 and CD4 lymphocyte subsets, T cell proliferation responses and non-survival in the very old: the Swedish longitudinal OCTO-immune study. Mechanisms of Ageing and Development 1998; 102:187 – 98. Zheng B, Han S, Takahashi Y & Kelsoe G. Immunosenescence and germinal center reaction. Immunological Reviews 1997; 160:63 – 77.

FURTHER READING Whisler RL, Newhouse YG, Grants IS et al. Differential expression of the alpha- and beta-isoforms of protein kinase C in peripheral blood T and B cells from young and elderly adults. Mechanisms of Ageing and Development 1995; 77:197 – 211.

4

Physiology of Aging Rafi Kevorkian Saint Louis University, St Louis, MO, USA

THE HUMAN BODY EVOLVING, CHANGING, AND AGING In the last century, we have seen a near doubling of life expectancy in humans. Modern medicine has left us with a vast knowledge of information toward the aging process. A multitude of changes have been known to occur consistently in humans. This chapter will examine and focus on these changes. The organ systems will be highlighted with a brief synopsis of each and how they age. The aging process affects all organ systems and, as such, understanding these changes will allow us to better understand the functional impact they have on the aged individual. A multitude of changes occur in each organ. These changes are irrespective of diseases modifying aging. The rate of age-related decline in organ function varies greatly. Aging has been defined as a failure to maintain homeostasis under conditions of physiological stress. All species show aging. Within a normal cell, oxidative stress (free radical theory of aging) chronically leads to changes in gene expression. This leads to alteration in the phenotype and aging of tissue. In a different model, “wear and tear” (somatic mutation, error catastrophe, protein glycosylation) of cells leads to necrosis or apoptosis. This leads to an increase in cell turnover causing an alteration in the phenotype leading to an aged cell. Senescence is defined as the permanent exit from the cell cycle of cells that would normally be able to undertake division. This may also lead to aging because it leads to a decline in the growth potential of cell populations, which have undergone turnover. These cells display biochemical features that are distinct from their growing counterparts. The expression of some genes (intrinsic mutagenesis, programmed death) goes up, while others go down or are unaffected. Olovnikov proposed that cells might count divisions through the progressive shortening of chromosome ends (telomeres). Telomerases are enzymes that prevent shortening of telomeres. The consequence of this is that a small amount of terminal DNA is not replicated with repeated cell divisions. This may contribute to senescence. It has been shown by Zglinicki that

mild oxidative stress may increase the rate of telomere shortening. DNA helicases unwind damaged DNA to allow for repair. Organisms that have greater resistance to DNA damage have conferred longevity (Von Zglinki et al., 2000). The neuroendocrine theory of aging stresses the need to regulate the biological clock to maintain homeostasis. The hypothalamo–pituitary–adrenal axis acts as the master regulator to adjust to the physiological needs of the organism during stress. The neuroendocrine-immuno theory of aging stresses the relation of the endocrine system as it regulates the immune system to fight off infection. As the immune system wanes, the organism becomes susceptible to death due to higher chance for infection. Aging then would result from a “decreasing ability to survive stress”. Thus, a multitude of factors can lead to aging.

AGING OF ORGANS Aging of the Skin The skin is the largest organ of the body. It has many important functions. It functions as a mechanical barrier, regulates temperature, initiates immunological functions, communicates external stimuli to the body, and protects against the effects of ultraviolet light. The skin is composed of three major layers. The outermost layer is the epidermis, followed by the dermis, which leads to the hypodermis. In the epidermis, a multitude of cells exist such as keratinocytes, melanocytes, Langerhans cells, and Merkel cells. The basement membrane separates the epidermis from the dermis. The dermis is composed of connective tissue, consisting mainly of collagen fibers, and elastin. The fibroblasts are the major cell type. The hypodermis is composed of the adipocytes, as well as the intravascular bundle. The typical signs of aging include wrinkling and sagging of the skin. Extrinsic aging is more prominent in the hands, neck, and the face and is attributed to sun exposure (Gilchrest, 1989).


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Intrinsically aged skin is thin, pale, and finely wrinkled. Histological staining shows flattening of the dermo-epidermal junction. This form of aging is felt to be secondary to superoxide free radical formation. Aged skin demonstrates a reduced keratinocyte proliferative capacity. The number of epidermal cell layers remains unaltered during aging (Table 1). A decrease in melanocytes contributes to the paling of the skin. The dermo-epidermal junction flattens with age due to the retraction of the epidermal papillae (Table 2). This leads to a skin structural unit, which is less resistant to shear forces than younger skin is. Skin thickness tends to decrease after the seventh decade (de Rigal et al., 1989). Within aging skin, increased vasoconstrictor responses and decreases in both vasodilators and vasoprotective agents have been demonstrated. Atrophy and hypertrophy of the subcutaneous tissue are common in aged individuals. The repair of physical damage is an essential day-today function of skin. Alteration in wound healing may lead Table 1 General effects of aging on the cell types resident within the skin

Cell type

Effect of aging

Keratinocytes Melanocytes

↓ proliferation, ↓ differentiation ↓ density, ↓ proliferation, ↓ biochemical activity ↓ antigen presentation, ↓ response to activating factors ↓ proliferation, ↓ ECM production, ↑ ECM turnover ↓ proliferation, ↓ response to vasodilators ↓ proliferation, ↓ response to mitogens

Epidermal lymphocytes Fibroblasts Endothelial cells Inflammatory cells ECM, extracellular matrix

Table 2 General effects of aging on the function of individual components of the skin

Skin structure

General effects of aging

Epidermis Basement membrane Dermis Vasculature Sebaceous glands Hypodermis Hair Nails

Little change in overall structure and function Flattening (loss of rete ridges) ↓ thickness, ↑ stiffness ↓ number of blood vessels, ↓ blood flow ↓ secretion of sebum in women ↓ or ↑ dependent on body location Graying, hair loss ↓ growth and change in appearance

Table 3 Summary of age-associated changes in skin function

Skin function Wound healing a. Inflammatory response b. Re-epithelialization c. Dermal repair d. Angiogensis Immunoregulation Thermoregulation Barrier function

General effects of aging Dysfunctional and protracted Slowed and sometimes inhibited Impaired granulation tissue formation Reduced Dysfunctional and impaired leading to neoplasm Impaired ability to perceive the cold, decreased sweat response Decreased with respect to UV protection

to chronic ulceration and nonhealing. The dysfunction of dendritic cells leads to the formation of skin neoplasms. The decrease in the protective effect of the skin leads to further loss of protection from UV light. Sunlight is also felt to lead to the generation of oxygen radicals leading to aging. It has been shown in vitro that Keratinocytes and dermal fibroblasts from habitual sun exposed sites have shorter life spans (Glichrest, 1979; Gilchrest, 1980; Gilchrest et al., 1983). In summary, the skin is the major barrier for our body to protect us within the environment (Table 3). As the aging process ensues, cellular functions are altered leading to problems with wound healing, immunosurveillance, temperature regulation, and general barrier functions.

Skeletal Muscle Aging Skeletal muscle comprises 40–50% of the human body. It is composed of muscle tissue, nerve tissue, blood vessels, and connective tissue. Myoblasts are precursor cells, which fuse together forming bundles of muscle fibers. There are two types of individual muscle fibers: type I or slow twitch and type II or fast twitch. Type two has two components: type A are called fast-oxidative fibers, and type B are known as fast-glycolytic fibers. There are several types of muscle contractions: shortening contractions, isometric contractions, and lengthening contractions. Skeletal muscles have developed adaptive responses to the generation of reactive oxygen species to protect themselves from oxidative damage. These age-related changes in muscle mass are termed sarcopenia (see Chapter 80, Sarcopenia and SarcopenicObesity). This leads to an age-related decrease in muscle strength and power. The basal metabolic rate of muscle decreases by 4% per year after the age of 50. The synthesis of myosin heavy chains declines with age, whereas the sarcoplasmic protein pool is unchanged (Balagopal et al., 1997; Rooyackers et al., 1996; Welle et al., 1993; Short et al., 1999). The regenerative potential of skeletal muscle, and overall muscle mass, declines with age. Several cytokines (Cannon, 1998), including Interleukin-1, tumor necrosis factor (TNF), Interleukin-15, ciliary neurotrophic factor, as well as growth hormone and insulin-like growth factor-I (IGF-I) (Welle, 1998) have strong influence on the balance between muscle protein synthesis and breakdown. Glucocorticoids have catabolic effects, reducing protein synthesis and stimulating protein degradation in muscle. In older rats, muscle wasting occurred more rapidly and the recovery of muscle mass was impaired (Dardevet et al., 1995). Testosterone declines with age in men and a concomitant change in body composition occurs with a lower percentage of muscle mass and a redistribution of body fat (Baumgartner et al., 1995). Thyroid hormone (T3) acts on nuclear receptor proteins, which, in skeletal muscle cells, regulate the gene expression of myofibrillar protein isoforms (Yu et al., 1999). As circulating T3 levels decrease with aging, there is an associated fiber shift from fast to slow (Sonntag, 1987). Insulin-mediated skeletal muscle cell glucose uptake declines with advancing age (Paolisso et al., 1995; Ferrannin et al., 1996).

PHYSIOLOGY OF AGING

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Table 4 Summary of changes in muscle

Table 5 Changes in vision with aging

Age-related changes of muscle

Vision

Reduction in muscle mass (30 – 40%) Decreased myosin heavy chain synthesis Decrease in force Infiltration of fat into muscle tissue Increased fatigability Decrease in basal metabolic rate Decreased innervations Increased number of myofibril per motor unit Loss or reduced proliferation of satellite cells

Impaired dark adaptation Yellowing of lens Inability to focus on near items (presbyopia) Decreased contrast sensitivity Decreased lacrimation Minimal decrease in static acuity Profound decrease in dynamic acuity (moving target)

During senescence, there is a loss of motor neurons and muscle fibers. The loss of motor neurons is of primary importance because it is likely to be the main reason for loss of muscle fibers. Electrophysiological studies have demonstrated a reduced number of motor units in old muscle (Dohert and Brown, 1993). The size of the average motor unit increases with age. The loss of strength does not result from failure of the central nervous system to activate motor nerves. However, a reduced rate of firing of motor nerves during maximal voluntary contraction in older subjects may limit the maximal force production in some muscles (Kamen et al., 1995). During a sustained contraction, central fatigue may be more common in older adults than in younger persons. Age-related fiber atrophy generally is restricted to type II fibers, at least in the muscles of the leg. This selective atrophy is important functionally because type II fibers can generate more power than type I fibers. It is unclear whether there is impairment in the release of calcium affecting the rate of relaxation and contraction. Welle et al. have shown that older human muscle has reduced expression of several mRNA’s encoding proteins involved in mitochondrial electron transport and ATP synthesis (Welle et al., 2000). An accumulation of DNA deletions is seen in mitochondria of skeletal muscle with age (De flora et al., 1996). In summary, a multitude of changes occur with skeletal muscle and aging, affecting size, strength, endurance, and functionality in the elderly (Table 4).

the lens continues to grow throughout life. It has defense mechanisms from reducing compounds that can cause damage. Aggregation of proteins are thought to be responsible for the yellowing of the lens as well as the increase in light scattering. Glutathione, a key-protecting molecule in the lens, tends to decrease with aging. Crystallins are proteins that provide the high refractive index of the lens. Alterations in structure and increased aggregation of these proteins are noted with aging. Cataract formation increases with aging. A multitude of enzymes have lowered activity in a cataract. The retina is the light-responsive part of the eye. It is highly vascular unlike the lens, and it has 6 neural cell types organized in 10 layers. The photoreceptor cells (rods and cones), and the retinal pigment epithelium (RPE) are most affected with aging. Photoreceptor density decreases with aging. There is also loss of ganglion cells and RPE. Lipofuscin is a protein that is formed through many mechanisms. Its accumulation can cause cell death in cell culture (Davies et al., 2001; Shamsi and boulton, 2001). Age-related macular degeneration (AMD) is the major cause of nonpreventable blindness in Western countries. Prevalence increases with aging. The molecular pathway leading to AMD has not been elucidated yet. There are also age-related changes to the sclera where it is thinner, yellower, and less elastic. Light scattering appears to increase through the cornea with aging. The vitreous body tends to liquefy with age, and collagen fibers concentrate. In summary, a multitude of changes occur with aging affecting the functionality and cognitive capabilities of elders (Table 5).

The Aging Eye The Aging Cardiovascular System Multiple population-based studies have shown a significant increase in the prevalence of impaired vision with advancing age (Tielsh et al., 1990; Klaver et al., 1998; Klein et al., 1991; Attebo et al., 1996). As such, visual impairment is negatively associated with the independence and functional status of elderly people (Wang et al., 1999; Klein et al., 1998). In addition, impaired vision may negatively affect cognitive functions among the elderly (Uhlmann et al., 1991; Lin denberger and Baltes, 1994). The eye suffers age-related disease and is affected by many systemic illnesses (see Chapter 103, Disorders of the Eye). The eye consists of the retina, lens, cornea, and a neurovasculature. The lens is a transparent, avascular tissue contained within a capsule. The lens cells divide, but are not shed. As a result,

Aging is associated with complex and diversified changes of cardiovascular structure and function. Changes occur at the structural/functional levels, as well as the molecular/cellular level. The heart becomes slightly hypertrophic and hyperesponsive to sympathetic (but not parasympathetic) stimuli, so that the exercise induced increases in heart rate and myocardial contractility are blunted in older hearts. The aorta and major elastic arteries become elongated and stiffer, with increased pulse wave velocity, evidence of endothelial dysfunction, and biochemical patterns resembling atherosclerosis. The arterial baroreflex is altered in aging, with the baroreceptor of the heart showing greater impairment than the baroreceptor control of peripheral vascular resistance. No

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Table 6 Effects of normal aging on the cardiovascular system

Structural/functional level Systolic function 1. No change in maximum capacity of the coronary flow bed 2. Moderate left ventricular hypertrophy 3. Maintenance of ability to generate wall tension 4. Decreased velocity of myocardial shortening 5. Increased myocardial stiffness 6. Prolonged duration of (systolic) contraction 7. Increased left ventricular cavity diameter 8. No change in stroke volumes, heart rate, cardiac output, or ejection fraction at rest 9. Greater use of the Frank – Starling mechanism 10. Decline in maximum heart rate and maximum oxygen uptake with exercise 11. Increased ventricular stiffness 12. Decreased ventricular relaxation Diastolic function 1. Delayed relaxation 2. Diastolic peak filling rate deceases with age 3. Decreased peak velocity of early filling while atrial fraction increase with age 4. Ratio of early peak to atrial peak (E/A ratio) flow velocity decrease with age Arterial function 1. Increased arterial stiffness 2. Decreased endothelial function 3. Increased blood pressure Molecular/cellular level 1. Increased catecholamine levels 2. Decrease in β-adrenoceptor-mediated responses 3. Preservation of β-adrenoceptor number/density but decreased sensitivity 4. Maintenance of peak amplitude of force generation 5. Increased duration of the myoplasmic calcium transient during excitation-contraction coupling (in rats) 6. Prolongation of the ventricular transmembrane action potential (in rats) 7. Cell dropout and compensatory cellular hypertrophy

conclusive evidence has been shown that alterations in afferent, central neural, efferent, and effector organ portions of the reflex arch are altered with aging. Reflexes arising from cardiopulmonary vagal afferents are blunted in aged individuals. In summary, a multitude of changes occur in the aged heart (Table 6). It is important to clarify that all these changes in cardiovascular function do not imply failure of the system, and in the absence of overt cardiovascular disease, do not result in symptoms.

The Aging Immune System The function of the immune system declines with age (Table 7). This leads to an increased frequency of infections, increased prevalence of neoplasms, and autoimmune disorders. Thymic involution is a hallmark of aging although there are thymic independent pathways for the development of the immune system. Response to vaccines is also decreased. The ability of hematopoetic stem cells to replicate decrease with aging (Geiger and Van Zant, 2002).

There is an age-dependent alteration to antigen presenting cells. Certain cytokines increase with aging such as: (1) interferon γ , (2) TGF-β, (3) TNF, (4) IL-6, and (5) IL-1, which can lead to dysregulation of hematopoiesis. Most tests of T-cell function is depressed in elderly individuals (Thoman and Weigle, 1989). They tend to secrete less IL-2 after being stimulated by antigen presenting cells. Several studies have suggested a positive association between good T-cell function in vitro and individual longevity (Roberts-Thomson et al., 1974; Murasko et al., 1988; Wayne et al., 1990), and between absolute lymphocyte counts and longevity (Bender et al., 1986). A high proportion of centenarians have relatively well preserved immune functions compared to the less elderly (Franceschi et al., 1995). Monocytes have also been shown to have decreased function with aging (Table 8, 9). Natural killer cells have been shown not to have altered function with aging (Kutza et al., 1991). Table 7 Changes in immune system function

Immune system 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12.

Decreased cell-mediated immunity Lower affinity antibody production Increased autoantibodies Decreased delayed-type hypersensitivity Decreased cell proliferative response to mitogens Atrophy of thymus and loss of thymic hormones Increased interleukin IL-6 Decreased IL-2 and IL-2 responsiveness Decreased production of B cells by bone marrow Accumulation of memory T cells (CD-45) Impaired macrophage function Facilitated production of anti-idiotype antibodies

Table 8 Changes in T cells with age

Decreased

Increased

Number of reactive T cells Number of mitogen-responsive cells

Number of memory cells T-cell help for nonspecific-antibody production

Proliferative response Expression of early activation genes Sensitivity to activating signals Cytotoxic cell target T-cell help for specific antibody production Help for generation of cytotoxic cells

Table 9 B cell changes with aging

B cells ↓ ↓ ↓ ↓ ↓ ↓

surface MHC class II molecule expression proportion of cells capable of clonal expansion number of bone marrow precursors number of T cell-dependent antibody-forming cells potency antibody efficacy

MHC, major compatibility complex

PHYSIOLOGY OF AGING

In summary, a multitude of changes occur in the immune system that affects function and survival in the elderly.

The Aging Pulmonary System The aging lung mimics closely changes in lung tissue that are associated with disease process such as emphysema. There is stiffening of the chest wall, loss of respiratory muscle strength, a decrease in intervertebral spaces and a decrease in elastic recoil of the lung tissue. These changes result in age-related declines in the lung volumes and flow rates affecting the forced expiratory volume (FEV1) and the forced vital capacity (FVC) (Johnson and Dempsey, 1991). The PaO2 decreases progressively and linearly, falling from approximately 95 Torr at age 20 to about 75 torr at age 70 (Sorbini et al., 1968). The alveolar dead space increases while the pulmonary diffusing capacity decreases progressively and linearly with age, falling approximately 20% over the course of adult life. The ventilatory responses to both hypoxia and hypercapnia have also been shown to decrease with age. The ability to exercise, as indicated by the maximal oxygen uptake (Vo2 max) also decreases linearly and progressively, falling about 35% between the ages of 20 and 70. The alveolar ducts also enlarge resulting in decreased surface area. In summary, a multitude of changes occur in the lung with aging that affect the exercise potential of the aged (Table 10).

The Aging Nervous System The nervous system is composed of a multitude of cells, and layers which control many aspects of function such as memory, speech, verbal, and visual function, as well as sensory and motor functions. There is great variation between individuals (Table 11). Both normal senescent age-related changes and late onset diseases of the brain produce decline in performance. The number of contacts and the total surface area of the synapses decrease significantly and their average synaptic size increases at a different extent according to the brain area Table 10 Changes with aging of the lung

Pulmonary system 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11.

Decreased FEV1 and FVC Increased residual volume Cough less effective Ciliary action less effective Ventilation – perfusion mismatching causes PaO2 to decrease with age Trachea and central airways increase in diameter Decreased lung mass Decreased respiratory muscle strength Diffusion of carbon monoxide decreased Maximal inspiratory and expiratory pressures decrease Chest wall stiffens

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Table 11 Changes in the aging nervous system

Central nervous system 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11.

Small decrease in brain mass Decreased brain flow and impaired autoregulation of perfusion Proliferation of astrocytes Decreased density of dendritic connections Increased numbers of scattered senile plaques and neurofibrillary tangles Decreased myelin and total brain lipid Altered neurotransmitters including dopamine and serotonin Nonrandom loss of neurons to modest extent Increased monoamine oxidase activity Decrease in hippocampal glucocorticoids receptors Slowed central processing and reaction time (Belli and Wilber, 2001)

Table 12 Age-related changes in the pre- and postsynaptic markers of the striatal dopamine synapse (Agnati et al., 1990)

Presynaptic markers Tyrosine hyrdroxylase - IR TH-activity Dopamine DA turnover Cold stress-induced DA turnover increase Reserpine-induced DA turnover increase DA turnover increase induced by training in reaction time

↓ ↓ →/↓ →/↑ ↓ ↓ ↓

Postsynaptic markers D1 receptor levels D2 receptor levels D1 receptor turnover D2 receptor turnover Adenylate cyclase activity cAMP-induced phosphorylation DA/cholecystokinin receptor interaction D2 denervation supersensitivity

↓/→ ↓ ↓ ↓ ↓ ↓ ↓ ↓

TH, tyrosine hyrdroxylase; DA, dopamine; IR, immunoreactive.

taken into account. Pre- and postsynaptic elements thicken with age, while vesicle size decreases (Table 12). There is failure of the chemical transmission process with aging (Agnati et al., 1990). The regulation of calcium influx is essential to presynaptic and postsynaptic events. Tannaka et al. (1996) showed that reduced calcium influx with aging might cause the reduced acetylcholine release by aged synapses. Brain aging is also associated with oxidative damage and low energy metabolism (Cotman and Su, 1990), and nitric oxide has cytotoxic action on neurons (Nomura, 1996). Adrenal glucocorticoids have been shown to accelerate age-related damage in the hippocampus, because of their ability to compromise energy metabolism and make neurons more vulnerable to glutamate excitoxicity (Maines et al., 1998). Autonomic dysfunction increases with aging. Age-associated changes have been reported in some, but not all regions of the autonomic nervous system. There is greater age-related changes in the sympathetic system than in the parasympathetic system.

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Table 13 Age-related changes in the Peripheral Nervous System

Table 15 Changes of aging in the GI tract

Peripheral nervous system

System

Change

1. 2. 3. 4. 5. 6.

General

Reduced total body mass Reduced basal metabolic rate Reduced proportion of body fat

Gastrointestinal

Increased gastric acid production Reduced gastric emptying rate Reduced gut motility Reduced gut blood flow Reduced absorption surface Decrease in gut-associated lymphoid tissue

Hepatic – biliary

Reduced liver mass Reduced liver blood flow Reduced albumin synthesis Impaired clearance of drugs that – require phase I metabolism

Loss of spinal motor neurons Decreased vibratory sensation, especially in feet Decreased thermal sensitivity Decreased sensory nerve action potential amplitude Decreased size of large myelinated fibers Increased heterogeneity of axon myelin sheaths

In summary, the aging nervous system has many features that affect individuals in a wide variety of ways (Table 13).

The Aging Skeleton Almost everyone loses bone with aging (Table 14). Women have acceleration of bone loss with onset of menopause. Men lose bone more slowly, and lose cortical bone only as they lose tissue in general, not preferentially, as is the case in women. Both men and women lose trabecular and cortical bone. Osteoporosis is a systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue. This increases the susceptibility to fracture. Remodeling of both cortical and trabecular bone takes place through sequences of activation, resorption (by osteoclasts), and formation (by osteoblasts). A multitude of hormones regulate bone remodeling; (a) calcitriol, (b) parathyroid hormone (PTH), (c) sex steroids, (d) calcitonin, (e) Insulin-like growth factors (IGF-1, IGF-2). Vitamin D and PTH maintain serum calcium. Serum calcium levels do not change with age, but the way in which they are maintained changes dramatically. With increasing age, serum calcium levels are increasingly maintained by resorption of calcium from bone rather than resorption from the diet. The decreased sensitivity of the parathyroids to calcium, decreased responsiveness of the kidney to PTH, and decreased responsiveness of the intestine to 1,25(OH)2 D all work together to increase serum PTH levels with age. Calcium supplementation is effective in lowering PTH levels and reducing bone loss in the elderly (Dawson-Hughes et al., 1990)

The Aging Gastrointestinal Tract The digestive tract maintains much of its normal physiological function during the aging process. There are a number of physiological changes that occur with aging that have the Table 14 Changes in calcium homeostasis with age

Parameter

Age-related change

Serum calcium Intestinal calcium absorption Serum parathyroid hormone Serum 1,25(OH)2 D Resorption of calcium from bone Net calcium balance

No change ↓ ↑ ↓ or no change ↑ ↓

potential to influence drug deposition and metabolism, and may influence gastrointestinal (GI) function. Pharyngoesophageal function changes with age, but the clinical significance is unclear. In elderly individuals, a decrease in the number of myenteric ganglion cells per unit area along with a thickening of the smooth muscle layer has been described. In a study by Sonies (1992), age had no effect on peristaltic velocity, basal lower esophageal sphincter (LES) pressures, or frequency of “abnormal” double and triple peaked waveforms. Moore et al. (1983) and Horowitz et al. (1984) have both shown that gastric emptying is reduced in the elderly. Goldschmiedt et al. (1991) showed that gastric acid levels are increased with aging. The incidence of peptic ulcer disease is known to increase with age. Gastroduodenal mucosal prostaglandin levels have been shown to decline in aging (Cryer et al., 1992). Changes in small bowel motor patterns are described with aging. This includes relatively minor effects on small bowel manometric patterns with decreased frequency of contractions after eating, reduction in the frequency of the migrating motor complex, and reduced frequency of propagated clustered contractions (Anuras and Sutherland, 1984). The physiologic and clinical consequences of these changes are uncertain. The absorption of nutrients by the intestinal tract depends on a multitude of factors. Highly lipid soluble compounds such as vitamin A show increased absorption whereas vitamin D is decreased. Fat absorption is decreased whereas cholesterol is increased. Carbohydrate absorption has been shown to decrease in rats. Numerous studies have assessed sigmoid functioning and colonic transit, and there is little evidence of any alteration in these measures in older adults (Orr and Chen, 2002). In summary, physiologic changes of the GI tract are primarily preserved although changes do occur that have clinical consequences (Table 15).

The Aging Kidney The aging kidney maintains its ability to regulate body fluid homeostasis under general conditions (Table 16). It becomes progressively limited in its ability to respond to stresses.

PHYSIOLOGY OF AGING Table 16 Changes in the renal system with aging

Renal system 1. Decreased creatinine clearance and GFR 10 ml/decade (Hoolensberg et al., 1974) 2. Decrease of 25% in renal mass 3. Decrease in sodium and potassium excretion and conservation 4. Decreased concentrating and diluting capacity 5. Decreased serum renin and aldosterone 6. Accentuated ADH release in response to dehydration 7. Decreased nitric oxide production 8. Increased dependence of renal prostaglandins to maintain perfusion 9. Decreased vitamin D activation 10. Impaired secretion of acid load GFR, glomelular filtration rate; ADH, antidiuretic hormone.

Table 17 Morphologic changes in aged kidneys

Morphologic changes

Reduced size and weight Relative cortical atrophy

Vascular changes

Hyalinosis of arterial walls

Glomerular changes

Increased number of sclerosed glomeruli Hypertrophy of the remnant glomeruli Increased thickness of basal membrane Mesangial matrix expansion Irregular fusion of foot processes

Tubular changes

Reduction in the number of tubules Atrophy of the tubular epithelium Increased thickness of basal membrane

Interstitial changes

Interstitial fibrosis

These changes result from anatomic changes as well as from alterations in tubular cell function and responsiveness to hormonal and hemodynamic factors. The loss of renal mass is mainly due to progressive atrophy of the renal cortex, with relative sparing of the medulla. By age 80, between 10 and 30% of the glomeruli are completely sclerosed. The glomeruli of the outer cortex are affected the most (Table 17). There are also functional changes in aged kidneys. Renal blood flow decreases about 10% per decade after a peak in young adulthood, and the renal plasma flow is reduced by 50%. The cause of age-related changes in the kidney remain unknown (Viig and Wie, 1995). One hypothesis, the hyperfiltration theory due to reduced nephron mass, proposes that a kidney with reduced number of glomeruli, has increased capillary blood flow through each Glomerular bed and a corresponding high intracapillary pressure (Neuringer, 1993). This high pressure results in local endothelial damage, platelet aggregation, and thrombin production. This leads to the release of growth factors from platelets such as (1) platelet-derived growth factor, (2) epidermal growth factor, (3) fibroblast growth factor, and (4) tumor necrosis factor α (Neuringer, 1993; Hostetter et al., 1981; Brenner, 1985). These factors increase fibroblast collagen production and mesangial cell sclerosis (Wardle, 1992). Angiotensin II secretion is then increased due to the disruption of vascular hemodynamics. As glomeruli become sclerosed, the amount of blood flow to each remaining nephron increases, further

43

potentiating the damage. The other hypothesis describes an imbalance between synthesis and degradation of matrix proteins leading to glomerulosclerosis. There is limited data for this hypothesis. In summary, a multitude of functional and morphologic changes occur in the aged that affect homeostasis (Table 18).

The Aging of the Endocrine System Aging is associated with hormonal changes. Aging is associated with anatomic changes of the endocrine glands as a result of programmed cell death, autoimmune destruction of the gland, or neoplastic transformation of glandular tissue. Age-related changes could also occur in hormonal secretion secondary to physiologic changes due to circadian and seasonal rhythm, or in frequency or height of hormonal pulses. Other changes with aging include (1) altered bioactivity of hormones, (2) altered transport of hormones to binding receptor sites, (3) altered hormone –receptor interactions, or (4) postreceptor changes. Aging is associated with alterations in plasma membrane properties and intrinsic changes in cellular enzyme activity, and changes in calcium mobilization and gene expression. Aging is associated with important structural changes (Table 19). Changes in hormone secretion are noted with aging. They are related to altered endocrine cell physiology than cellular Table 18 Functional changes in aged kidneys

Renal blood flow

Decreased Relative increase of medullary blood flow

Glomerulus

Decreased glomelular filtration rate Increased filtration fraction Increased permeability to macromolecules

Tubule

Impaired ability for sodium and potassium handling Deranged tubular transport Impaired concentration and dilution Impaired acidification

Other

Decreased synthesis of rennin Decreased 1-α-hydroxylase activity

Table 19 Anatomic changes of endocrine glands with aging

Endocrine gland

Structural changes

Pituitary

Increased occurrence of adenomas and empty sellae, proportional decrease in eosinophil cells, increased nonparenchymal cells Lymphocytic and plasma cell infiltration, fibrosis, and increased nodularity Increase in oxyphil cells, large oxyphil nodules Fibrotic changes in cortex, accumulation of lipofuscin, mitochondrial fragmentation, increased adenomas and vascular hemorrhage, cellular depletion of zona reticularis Germ cell arrest, thinning of germinal epithelium Depletion of oocytes, papilomatous outgrowths, sclerosis of medulla Loss of compact structure of islet cells, amyloid deposition

Thyroid Parathyroid Adrenal glands

Testis Ovary Pancreas

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Table 20 Age-related changes in the degradation of hormones

Increased

Decreased

Probably no change

Epinephrine PTH Cortisol

Aldosterone Testosterone Dihydrotestosterone Estradiol Noradrenaline Insulin GH

FSH, LH GnRH in rats ACTH AVP Glucagon Calcitriol T4, T3 TSH

FSH, follicle stimulating hormone; LH, luteinizing hormone; PTH, parathyroid hormone; GnRH, gonadotropin-releasing hormone; ACTH, adenocorticotropic hormone; AVP, arginine vasopressin; GH, growth hormone; TSH, thyroid stimulating hormone.

depletion. Age-related changes in the pituitary gland are attributed to altered pulsatile pattern of hormone secretion. Desynchronization of various biological rhythms occurs with aging. Glandular sensitivity to secretagogs are also affected with some glands having reduced, increased, inhibited, or no alteration in response. Finally, clearance of hormones is also altered with aging. In summary, a multitude of changes occur in the aged endocrine glands affecting homeostasis greatly (Table 20).

Aging of Other Systems A multitude of changes occur in other systems of the body (Table 21). The dysregulation of these systems affect homeostasis in a multitude of ways. In summary, the aged body, complex yet intricate, adaptive yet reactive, has shown a resolute progression and preservation of function. Although many changes occur leading to decreased reserves, the successful aging process that some seniors possess proves the will of humanity to strive for longevity. Table 21 Changes of organ systems with aging

System

Change

Hematopoeisis

Decreased bone marrow reserves in response to high demand Impaired shivering Decreased cutaneous vasoconstriction and vasodilatation Increased core temperature to start sweating Detection decreased by 50% Decreased thirst drive Reduced number of organ of Corti hair cells Increased threshold vestibular responses Bilateral loss of high-frequency tones Central processing deficit Decrease in expression and activity of lipoprotein lipase Decreased leptin levels in females and increased in males Incomplete bladder emptying and increased residuals Reduced intensity for orgasm for men and women Prolonged refractory period for erections for men

Temperature Regulation

Smell Thirst Balance Audition Adipose

Genitourinary

KEY POINTS • A multitude of theories have been proposed to explain how the body ages. • Cytokines play a major role in the aging process. • Modulation of cytokines can slow the aging process. • The aging of certain organ systems compound the aging affects of other organs. • The rate of decline among organs varies greatly.

KEY REFERENCES • Balagopal P, Rooyackers OE, Adey DB et al. Effects of aging on in vivo synthesis of skeletal muscle myosin heavy chain and sarcoplasmic proteins in humans. American Journal of Physiology 1997; 273:E790 – 800. • Baumgartner RN, Stauber PM, McClugh D et al. Cross sectional age differences in body composition in persons 60+ years of age. The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences 1995; 50:M307 – 16. • Cannon JG. Intrinsic and extrinsic factors in muscle aging. Annals of the New York Academy of Sciences 1998; 854:72 – 7. • Franceschi C, Monti D, Sansoni P & Cossarizzi A. The immunology of exceptional individuals: the lesson of centenarians. Immunology Today 1995; 16:12 – 6. • Geiger H & Van Zant G. The aging of lymph-hematopoietic stem cells. Nature Immunology 2002; 3:329 – 33.

REFERENCES Agnati L, Zolim F, Grlimadi R et al. Cellular and synaptic alterations in the aging brain. Aging 1990; 2:5 – 25. Anuras S & Sutherland J. Small intestine manometry in healthy elderly subjects. Journal of the American Geriatrics Society 1984; 32:581 – 3. Attebo K, Mitchell P & Smith W. Visual acuity and the causes of visual loss in Australia. The Blue Mountains Eye Study. Opthalmology 1996; 103:357 – 64. Balagopal P, Rooyackers OE, Adey DB et al. Effects of aging on in vivo synthesis of skeletal muscle myosin heavy chain and sarcoplasmic proteins in humans. American Journal of Physiology 1997; 273:E790 – 800. Baumgartner RN, Stauber PM, McClugh D et al. Cross sectional age differences in body composition in persons 60+ years of age. The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences 1995; 50:M307 – 16. Belli TJ & Wilber LA. Effects of aging and gender on interhemispheric function. Journal of Speech, Language and Hearing Research 2001; 44:246 – 63. Bender BS, Nagel JE, Adler WH & Andres R. Absolute peripheral blood lymphocyte count and subsequent mortality of elderly men. The Baltimore Longitudinal study of aging. Journal of the American Geriatrics Society 1986; 34:649 – 54. Brenner BM. Nephron adaptation to renal injury or ablation. American Journal of Physiology 1985; 249:F324 – 37. Cannon JG. Intrinsic and extrinsic factors in muscle aging. Annals of the New York Academy of Sciences 1998; 854:72 – 7. Cotman CW & Su JH. Mechanisms of neuronal death in Alzheimer’s disease. Brain Pathology 1990; 6:493 – 506.

PHYSIOLOGY OF AGING Cryer B, Redfern JS, Goldschmiedt M et al. Effect of aging in gastric and duodenal mucosal prostaglandin concentrations in humans. Gastroenterology 1992; 102:1118 – 23. Dardevet D, Sorret C, Taillandier D et al. Sensitivity and protein turnover response to glucocorticoids are different in skeletal muscle mass from adult and old rats. Lack of regulation of the ubiquitin-proteosome proteolytic pathway in aging. Journal of Clinical Investigation 1995; 96:2113 – 9. Davies S, Elliott MH, Floor E et al. Photoxicity of lipofuscin in retinal pigment epithelial cells. Free Radical Biology and Medicine 2001; 31:256 – 65. Dawson-Hughes B, Dalla GE, Krall EA et al. A controlled trial of the effect of calcium supplementation on bone density in postmenopausal women. New England Journal of Medicine 1990; 323:878 – 83. De flora S, Izzotti A, Randerath K et al. DNA adducts and chronic degenerative disease. Pathogenetic relevance and implications in preventitive medicine. Mutation Research 1996; 366:197 – 238. de Rigal J, Escoffier C, Querleux B et al. Assessment of aging of the human skin by in vivo ultrasonic imaging. Trends in Biotechnology 1989; 93:621 – 5. Dohert TJ & Brown WF. The estimated numbers and relative sizes of the thenar motor units as selected by multiple point stimulation in young and older adults. Muscle & Nerve 1993; 16:355 – 66. Ferrannin E, Vichi S & Becknielsen H. Insulin sensitivity and age. Diabetes 1996; 45:947 – 56. Franceschi C, Monti D, Sansoni P & Cossarizzi A. The immunology of exceptional individuals: the lesson of centenarians. Immunology Today 1995; 16:12 – 6. Geiger H & Van Zant G. The aging of lymph-hematopoietic stem cells. Nature Immunology 2002; 3:329 – 33. Glichrest BA. Relationship between actinic damage and chronologic aging in keratinocyte cultures in human skin. Journal of Investigative Dermatology 1979; 72:219 – 23. Gilchrest BA. Prior chronic sun exposure decreases life span of human skin fibroblasts in vitro. Journal of Gerontology 1980; 35:537 – 41. Gilchrest BA. Skin aging and photoaging: an overview. Journal of the American Academy of Dermatology 1989; 21:610 – 3. Gilchrest BA, Szabo G, Flynn E & Goldwyn RM. Chronologic and actinically induced aging in human facial skin. Journal of Investigative Dermatology 1983; 80:81S – 85S. Goldschmiedt M, Barnett CC, Schwarz BE et al. Effect of age on gastric acid concentrations in healthy men and women. Gastroenterology 1991; 101:977 – 90. Hoolensberg NK, Adams DF & Solomon HS. Senescence and the renal vasculature in normal man. Circulation Research 1974; 34:309 – 16. Horowitz M, Maddern GJ, Chatterton BE et al. Change in gastric emptying rates with age. Clinical Science 1984; 67:213 – 8. Hostetter TH, Olson JL, Renke HG et al. Hyperinflation in remnant nephrons: apotentially advers response to renal ablation. American Journal of Physiology 1981; 241:F85 – 93. Johnson BD & Dempsey JA. Demand vs. capacity in the aging pulmonary system. Exercise and Sport Sciences Reviews 1991; 19:171 – 210. Kamen G, Sison SL, Duke Du CC & Patten C. Motor unit discharge behaviour in older adults during maximal effort contractions. Journal of Applied Physiology 1995; 79:1908 – 13. Klaver CC, Wolfs RC, Vingerling JR et al. Age specific prevalence and causes of blindness and visual impairment in an older population. The Rotterdam study. Archives of Ophthalmology 1998; 116:653 – 8. Klein BE, Klein R, Lee KE & Cruickshanns KJ. Performance based and self assessed measures of visual function related to history of falls, hip fractures, and measured gait time. The Beaver Dam Eye Study. Opthalmology 1998; 105:160 – 4. Klein R, Klein BE, Linton KL & Demets DL. The Beaver Dam Eye Study: visual acuity. Opthalmology 1991; 98:1310 – 5. Kutza J, Kaye D & Murasko DM. Basal natural killer cell activity of young versus elderly humans. Journals of Gerontology 1991; 50A:b110 – 6. Lin denberger U & Baltes PB. Sensory functioning and intelligence in old age: a strong connection. Psychology and Aging 1994; 9:339 – 55.

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Maines LW, Keck BJ, Dager A & Lakoski JM. Age-dependent loss of corticosterone modulation of central serotonin 5-HT1A receptor binding sites. Journal of Neuroscience Research 1998; 53:86 – 98. Moore JG, Tweedy C, Christian PE & Datz FL. Effect of age on gastric emptying of liquid-solid meals in man. Digestive Diseases and Sciences 1983; 28:340 – 4. Murasko DM, Weiner P & Kaye D. Association of lack of mitogen induced lymphocyte proliferation with increased mortality in the elderly. Aging: Immunology and Infectious Disease 1988; 1:1 – 239. Neuringer JR. Brebber Bm. Haemodynamic theory of progressive renal disease: a 10 year update in brief review. American Journal of Kidney Diseases 1993; 22:98 – 104. Nomura Y. Neurochemical aspect of brain aging, neuronal death, and decreased synaptic functions. Hokkaido Igaku Zasshi 1996; 71:309 – 14. Orr WC & Chen CC. Aging and neuronal control of the GI tract IV. Clinical and physiological aspects of gastrointestinal motility and aging. American Journal of Physiology: Gastrointestinal and Liver Physiology 2002; 283:G1226 – 31. Paolisso G, Scheen A & Lefebvre P. Glucose handling, diabetes, and aging. Hormone Research 1995; 43:52 – 7. Roberts-Thomson IC, Whittingham S, Youngchaiyud U & Mackay IR. Ageing, immune response and mortality. Lancet 1974; 2:368 – 70. Rooyackers OE, Adey PA, Ades DB & Nair KS. Effect of age on in vivo rates of mitochondrial protein synthesis in human skeletal muscle. Proceedings of the National Academy of Sciences of the United States of America 1996; 93:15364 – 9. Shamsi FA & boulton M. Inhibition of RPE lysosomal and antioxidant activity by the age pigment lipofuscin. Investigative Ophthalmology & Visual Science 2001; 42:3041 – 6. Short KR, Barazzoni R & Nair KS. Age effects on mitochondrial protein synthesis in skeletal muscle, liver and heart. FASEB Journal 1999; 13:A909. Sonies BC. Oropharynegeal dysphagia in the elderly. Clinics in Geriatric Medicine 1992; 8:569 – 77. Sonntag WE. Hormone secretion and action in aging animals. Review Biological Research and Aging. 1987; 3:299 – 335. Sorbini CA, Grassi V, Solinas E & Muiesan G. Arterial oxygen tension in relation to age in healthy subjects. Respiration 1968; 25:3 – 13. Tannaka Y, Hasegama A & Ando S. Impaired synaptic function with aging as characterized by decreased calcium influx and acetylcholine release. Journal of Neuroscience Research 1996; 43:63 – 76. Thoman ML & Weigle WO. The cellular and subcellular bases of immunosencense. Advances in Immunology 1989; 46:221 – 62. Tielsh JM, Sommer A, Witt K et al. Blindness and visual impairment in an American urban population. The Baltimore Eye Survey. Archives of Ophthalmology 1990; 108:286 – 90. Uhlmann RF, larson EB, Koepsell TD et al. Visual impairment and cognitive dysfunction in Alzheimer’s disease. Journal of General Internal Medicine 1991; 6:126 – 32. Viig J & Wie JY. Understanding the biology of aging: the key to prevention therapy. Journal of the American Geriatrics Society 1995; 43:426 – 34. Von Zglinki T, Serra V, Lorenz M et al. Short telomeres in patients with vascular dementia: an indicator of low antioxidative capacity and a possible risk factor? Lab Investigation 2000; 80(11):1739 – 47. Wang JJ, Mitchell P, Smith W et al. Impact of visual impairment on use of community support service by elderly persons: The Blue Mountain Eye Study. Investigative Ophthalmology & Visual Science 1999; 40:12 – 9. Wardle En. Cellular biology of glomerulosclerosis. Nephron 1992; 61:125 – 8. Wayne SJ, Rhyne RL, Garry PJ & Goodwin JS. Cell-mediated immunity as a predictor of morbidity and mortality in subjects over 60. Journals of Gerontology 1990; 45:45 – 8. Welle S. Growth hormone and insulin like growth factor I as anabolic agents. Current Opinion in Clinical Nutrition and Metabolic Care 1998; 1:257 – 62. Welle S, Bhatt K & Thornton CA. High abundance mRNA’s in human muscle; comparison between young and old. Journal of Applied Physiology 2000; 89:297 – 304.

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Welle S, Thornton C, Jozefowicz R & Statt M. Myofibrillar protein synthesis in young and old men. American Journal of Physiology 1993; 264:E693 – 8. Yu F, Degens H & Larsson L. The influence of thyroid hormone on myosin isoform composition and shortening velocity of single skeletal muscle fibres with special reference to ageing and gender. Acta Physiologica Scandinavica 1999; 167:313 – 6.

FURTHER READING Muiesan G, Sorbini CA & Grassi V. Respiratory function in the aged. Bulletin De Physio-Pathologie Respiratoire 1971; 7:973 – 1009.

5

Aging of the Brain Charles Mobbs Mount Sinai School of Medicine, New York, NY, USA

In a single review, it is obviously impossible to comprehensively address the neurobiology of aging. One book on the subject (Hof and Mobbs, 2001) is almost 1000 pages long but is still not comprehensive. Numerous reviews examining various specific aspects of brain aging have also been published (Grady and Craik, 2000; Toescu et al., 2000; Barnes, 2001; Brandt, 2001; Farkas and Luiten, 2001; Mattson et al., 2001; Finch, 2003). Therefore, the present review focuses on two major functions, motor systems and cognitive systems, that are most susceptible to age-related pathologies.

MOTOR SYSTEMS Motor functions are among the most vulnerable to age-related disease. These impairments in humans may be associated with the development of several age-related diseases of motor systems (including Huntington’s disease and Parkinson’s disease) superimposed on universal but gradual impairments in neuromuscular functions, especially due largely to decrease in muscle mass. The incidence of each disease peaks at a characteristic age (for Huntington’s disease around age 40, for Parkinson’s disease around age 70), then begins to decline, but the relative contribution of the universal age-related declines in neuromuscular function continues to increase with age. As the incidence of disease increases, the contribution of disease to individual variation in motor function also increases, and to the extent that risk of disease is primarily genetic, genotype contributes substantially to phenotype during this time. However, as the incidence of motor diseases decreases (after about age 70) there is also a decline in the relative contribution of motor disease genes to agerelated impairments in motor function.

Huntington’s Disease Huntingtons’ disease is an autosomal dominant neurodegenerative disease associated with profound movement disorders

whose age-specific incidence peaks around the age of 40 (Greenamyre and Shoulson, 1994). Monozygotic twins are essentially 100% concordant in the development of Huntington’s disease, demonstrating the primary contribution of genotype to the risk of developing Huntington’s disease (Sudarsky et al., 1983). Huntington’s disease is caused by a variable expansion of a CAG repeat producing a polyglutamine stretch in the gene product, huntingtin (Lunkes et al., 1998). Using this genetic marker, Kremer et al., (1994) demonstrated that by late middle age the concordance between genotype and Huntington’s phenotype is essentially 100%. Nevertheless, at relatively young ages (under 20), there is little concordance between genotype and Huntington’s phenotype, since at these young ages only about 10% of individuals who express CAG repeats in the huntingtin gene exhibit Huntington’s phenotype. Therefore, with respect to incidence, Huntington’s disease represents an extreme coupling between genotype and age-related phenotype, in which the coupling increases from very low (below the age of 20, where a great majority of individuals bearing the CAG repeat do not exhibit the Huntington phenotype) to essentially 100% concordance by age 70 (at which age almost every individual who bears the CAG repeat would have developed the disease). By the same token, however, the relative contribution of the CAG repeat to phenotypic variation in the whole population increases with age as the incidence of the disease peaks at about 40 years of age, but then begins to decline as the incidence of Huntington’s disease decreases.

Parkinson’s Disease Parkinson’s disease is about 10-fold more prevalent than Huntington’s disease, and the incidence rate of Parkinson’s disease peaks later than that of Huntington’s disease, at about 75 years of age, after which incidence rate begins


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to decline (Martilla, 1987). In contrast to the perfect concordance for Huntington’s disease in identical twins, several studies have failed to observe any concordance for Parkinson’s disease in identical twins (Lilienfeld, 1994). This observation demonstrates a much lower overall contribution of genotype to Parkinson’s phenotype than for Huntington’s phenotype. On the other hand, several families have been studied where Parkinson’s disease follows an autosomal dominant pattern of inheritance (Golbe et al., 1996), and in several different families this led to the identification of an allele of α-synuclein as the genetic basis of the disease in these families. (Polymeropoulos et al., 1997). In another group of families where Parkinson’s disease is inherited in an autosomal recessive pattern, mutations in the gene coding for parkin account for the appearance of the Parkinson’s phenotype (Hattori et al., 1998; Kitada et al., 1998). Nevertheless, mutations in α-synuclein and parkin only account for a small subset of all cases of familial Parkinson’s disease (Vaughan et al., 1998), and thus, of an even smaller subset of all cases of Parkinson’s disease. These observations demonstrate that the coupling of genotype to phenotype is much lower, and the genetic basis much more complex in Parkinson’s disease, than in Huntington’s disease. On the other hand, Parkinson’s disease is not only much more common than Huntington’s disease, it is a much more heterogeneous syndrome, and thus plausibly involves a more heterogeneous set of pathophysiological processes. Thus, for those forms of Parkinson’s disease for which a single gene defect has been defined, the coupling between genotype and phenotype behaves as it does in Huntington’s. Thus, within kindreds in whom α-synuclein mutations are common, at young ages, there is no concordance between mutations in α-synuclein and Parkinson’s phenotype, whereas by age 70, there is a very high concordance between genotype and phenotype. On the other hand, in the population as a whole, this relationship is less evident since α-synuclein mutations only account for a small proportion of all cases of Parkinson’s disease, in contrast to Huntington’s disease, where all cases are accounted for by mutations in a single gene. It should be noted that the incidence rate of familial forms of Parkinson’s disease peaks earlier than nonfamilial forms than in sporadic or nonfamilial forms. Thus, mutations in parkin lead to juvenile-onset Parkinson’s disease, whose incidence peaks at around 20 years of age and the incidence of Parkinson’s disease due to mutations in α-synuclein peaks at around 50 years of age. In contrast, the incidence rate of Parkinson’s disease in the population as a whole peaks around 70 years. Since twin studies indicated that genotype makes little contribution to the late-onset (and most common) form of the disease, taken together, these data imply that the contribution of genotype to Parkinson’s phenotype increases with age until about age 50, then begins to decline, such that, by age 70 and over, there is little contribution of genotype to phenotype (Langston, 1998).

Nonpathological Age-related Changes in Motor Function For age-related diseases, the effect of genotype generally increases with age until about age 70 (in humans), then begins to decline as the incidence of age-related diseases declines. However, as the incidence of disease decreases in later life, relative contribution of disease to the variance in age-related phenotype also begins to decline. Thus, a major question is the extent to which genotype accounts for nondisease phenotype during aging. While it might be assumed that the effect of life-long environmental effects would increasingly dominate genetic effects, there is little evidence to support this as a general phenomenon. For example, twin studies have indicated that although psychomotor speed declines with age, the effect of genotype and possibly early environment continues to dominate this phenotype during aging (at least until age 67), whereas in contrast, effects of exercise were minimal (Simonen et al., 1998).

COGNITIVE FUNCTION Although genetic effects on motor diseases increase with age before they decrease, it might be hypothesized that cognitive functions are more likely to reflect cumulative experience during aging, and thus the contribution of genotype might be less for cognitive functions. However, as described below, effects of genotype are probably at least as great on cognitive functions during aging as for motor functions.

Alzheimer’s Disease Twin studies have demonstrated a much greater significant genetic contribution to the risk of developing Alzheimer’s disease than for Parkinson’s disease, with most studies indicating that about 50% of the variance in vulnerability to Alzheimer’s disease is genetic (Pedersen et al., 2004). Conclusions from twin studies have been corroborated by family studies. For example, offspring whose parents had both been diagnosed with Alzheimer’s disease had a 47% chance of developing Alzheimer’s disease by age 65, far higher than the risk of the general population at that age (Bird et al., 1993). Similarly, analysis of 70 families with evidence of the hereditary forms of Alzheimer’s disease indicated that offspring whose parents had Alzheimer’s disease had a lifetime risk of developing the disease (by age 87) of 64% (compared to a risk of less than 10% in the general population by that age). Interestingly, the risk for offspring in families with early-onset Alzheimer’s disease was only 53%, compared to 86% for offspring in families with lateonset Alzheimer’s disease (Farrer et al., 1990). Thus, at least within these families, there is evidence of increased penetrance of genotype during aging. On the other hand, the incidence rate of Alzheimer’s disease appears to decrease

AGING OF THE BRAIN

after age 90 (Lautenschlager et al., 1996). Because of the relatively small number of individuals alive at these very advanced ages, it is not yet known if the effect of genotype on the risk of Alzheimer’s disease may decline after age 90. Allelic variations in several specific genes (presenilin 1, presenilin 2, β-amyloid precursor, and Apolipoprotein E (ApoE)) have been implicated in the etiology of Alzheimer’s disease (Cruts and Van Broeckhoven, 1998). How aging influences the penetrance of these genes is of great interest. Campion et al., (1999) addressed this question in a study which examined the genetic basis of early-onset autosomal dominant Alzheimer’s disease in the whole population of a single city in France. In this study, early-onset autosomal dominant Alzheimer’s disease was defined by the occurrence of Alzheimer’s disease before the age of 61 in three generations of a family. Thirty-four such families were observed in the city examined, with a population of almost 5 00 000. In 56% of such families, allelic variations in presenilin 1 were observed, and in 15% of such families, allelic variations of the β-amyloid precursor were observed. In contrast, in nine families which did not exhibit an earlyonset form of the Alzheimer’s disease, such allelic variations were not observed. These data suggest that the penetrance of presenilin 1 and β-amyloid precursor mutations reaches 100% at relatively young ages (around age 60). However, since the incidence of Alzheimer’s disease before the age of 60 is less than 5% of the incidence at age 80–90, this demonstrates that the coupling between presenilin 1 (or β-amyloid precursor) and Alzheimer’s disease phenotype peaks at around age 60, then returns to being negligible by age 80. In contrast to the (eventual) complete penetrance of the presenilin and β-amyloid alleles, alleles of the ApoE gene are never completely penetrant, but nevertheless account for a much larger proportion (possibly 20%) of cases of Alzheimer’s disease (Slooter et al., 1998). Nevertheless, the effect of ApoE genotype peaks at around age 70, then declines (but is significant even at 90 years of age) (Farrer et al., 1997; Slooter et al., 1998). Thus, taken together, the evidence indicates that the coupling between genotype and Alzheimer’s disease phenotype peaks at about 70 years of age, then, as with other age-related diseases, the role of genotype begins to decline.

Nonpathological Age-related Impairments in Cognitive Functions Several studies have examined the effects of aging and genotype on performance in standardized intelligence tests (Swan et al., 1992; Plomin et al., 1994; Finkel et al., 1995; McClearn et al., 1997; Emery et al., 1998; Finkel et al., 1998). For example, Plomin et al., (1994), as part of the Swedish Adoption/Twin Study of Aging examined cognitive functions in 112 pairs of twins (both monozygotic and dizygotic) reared apart and in 111 matched pairs of twins reared together. The age of the twins was 64.1 ± 7.5 (mean ± SD) years. At this age, the average heritability

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of general cognitive function (a composite of spatial, verbal, memory, and speed of processing performances, after removal of effects of age and gender) was 80%. In a review of studies from both the Swedish Adoption/Twin Study of Aging and the Minnesota Twin Study of Adult Development and Aging, Finkel et al., (1995) concluded that both sets of studies suggested that heritability of general cognitive function is about 80% throughout adulthood (though this estimate is higher than has been observed in other studies), but evidence suggested a possible decrease in heritability after age 70. A further analysis of the Swedish Twin study appeared to corroborate this result, since in Swedish twins over the age of 80, heritability of general cognitive function was estimated to be about 62% (McClearn et al., 1997). Although direct comparisons are not conclusive, other studies have suggested that heritability of general cognitive function increases from about 50% in childhood and adolescence to about 80% in adulthood (McCartney et al., 1990; MaGue et al., 1993). Although aging influences the heritability of general cognitive function, the effect of age on cognitive function itself is more specific to certain subsystems. In general, functions reflecting knowledge improve with age, whereas functions reflecting speed of processing and memory are impaired with age. Thus, aspects of cognition reflected by the Wechsler subscales of Information, Vocabulary, and Comprehension are relatively unimpaired or even improve with age in nondemented individuals, whereas cognitive functions reflected by the subscales of Block Design, Picture Arrangement, and Digit Symbol, tend to deteriorate robustly with age (Botwinick, 1978). Interestingly, the heritability of general cognitive function during aging is greater than the heritability of any of the functions reflected by subscales, which has been interpreted to indicate that the “nature of the genetic influence in the cognitive domain appears to be more general than specific” (Plomin et al., 1994). Thus, in contrast to the effect of age on the heritability of general cognitive function, heritability on memory function alone appears to be stable with age (Finkel and McGue, 1998). Since cognitive function is defined by experience, it may seem surprising that heritability of cognitive function can increase with age at all (although decreasing after the age of 70). One resolution of this apparent paradox is that the influence of experience may greatly depend on genotype; that is, the effect of experience may be enhanced by genotype. For example, in a twin study examining the effect of genotype on the acquisition of a motor skill, Fox et al., (1996) reported that while genotype influenced the initial performance of the skill, the effect of genotype on the enhancement of the skill by practice was even greater. These investigators concluded that “the effect of practice is to decrease the effect of environmental variation (previous learning) and increase the relative strength of genetic influences on motor performance”. Similarly, it seems plausible that genotype may influence the cumulative effect of experience on general cognitive functions. On the other hand, after the age of 70, it appears that these genetic effects have reached their peak, and the effects of unique experiences come to dominate.

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KEY POINTS • Pathological and nonpathological age-related impairments are quantitatively and qualitatively distinct: pathological impairments involve substantial neuronal loss, whereas, nonpathological impairments do not involve such loss. • Pathological impairments in motor functions include Parkinson’s disease and Huntington’s disease, the former entailing very little genetic effects while the latter is almost entirely genetic. • Nonpathological impairments in motor functions include loss of muscle mass. • About half the vulnerability to Alzheimer’s disease is due to genetic effects. • The importance of heredity in determining agerelated impairments increases with age until about age 70, after which environmental influences become increasingly important.

KEY REFERENCES • Cruts M & Van Broeckhoven C. Molecular genetics of Alzheimer’s disease. Annals of Medicine 1998; 30(6):560 – 5. • Finch CE. Neurons, glia, and plasticity in normal brain aging. Neurobiology of Aging 2003; 24(suppl 1):S123 – 7; discussion S131. • Langston JW. Epidemiology versus genetics in Parkinson’s disease: progress in resolving an age-old debate. Annals of Neurology 1998; 44(3 suppl 1):S45 – 52. • Lunkes A, Trottier Y & Mandel JL. Pathological mechanisms in Huntington’s disease and other polyglutamine expansion diseases. Essays in Biochemistry 1998; 33:149 – 63. • Pedersen NL, Gatz M, Berg S & Johansson B. How heritable is Alzheimer’s disease late in life? Findings from Swedish twins. Annals of Neurology 2004; 55(2):180 – 5.

REFERENCES Barnes CA. Plasticity in the aging central nervous system. International Review of Neurobiology 2001; 45:339 – 54. Bird TD, Nemens EJ & Kukull WA. Conjugal Alzheimer’s disease: is there an increased risk in offspring? Annals of Neurology 1993; 34(3):396 – 9. Botwinick J. Aging and Behavior 1978; Springer, New York. Brandt J. Mild cognitive impairment in the elderly. American Family Physician 2001; 63(4):620, 622, 625 – 6. Campion D, Dumanchin C, Hannequin D et al. Early-onset autosomal dominant Alzheimer disease: prevalence, genetic heterogeneity, and mutation spectrum. American Journal of Human Genetics 1999; 65(3):664 – 70. Cruts M & Van Broeckhoven C. Molecular genetics of Alzheimer’s disease. Annals of Medicine 1998; 30(6):560 – 5. Emery CF, Pedersen NL, Svartengren M & McClearn GE. Longitudinal and genetic effects in the relationship between pulmonary

function and cognitive performance. The Journals of Gerontology. Series B, Psychological Sciences and Social Sciences 1998; 53(5):P311 – 7. Farkas E & Luiten PG. Cerebral microvascular pathology in aging and Alzheimer’s disease. Progress in Neurobiology 2001; 64(6):575 – 611. Farrer LA, Cupples LA, Haines JL et al. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. The Journal of the American Medical Association 1997; 278(16):1349 – 56. Farrer LA, Myers RH, Cupples LA et al. Transmission and age-at-onset patterns in familial Alzheimer’s disease: evidence for heterogeneity. Neurology 1990; 40(3 Pt 1):395 – 403. Finch CE. Neurons, glia, and plasticity in normal brain aging. Neurobiology of Aging 2003; 24(suppl 1):S123 – 7; discussion S131. Finkel D & McGue M. Age differences in the nature and origin of individual differences in memory: a behavior genetic analysis. International Journal of Aging & Human Development 1998; 47(3):217 – 39. Finkel D, Pedersen NL, McGue M & McClearn GE. Heritability of cognitive abilities in adult twins: comparison of Minnesota and Swedish data. Behavior Genetics 1995; 25(5):421 – 31. Finkel D, Pedersen NL, Plomin R & McClearn GE. Longitudinal and cross-sectional twin data on cognitive abilities in adulthood: the Swedish Adoption/Twin Study of Aging. Developmental Psychology 1998; 34(6):1400 – 13. Fox PW, Hershberger SL & Bouchard TJ. Genetic and environmental contributions to the acquisition of a motor skill. Nature 1996; 384:356 – 8. Golbe LI, Di Iorio G, Sanges G et al. Clinical genetic analysis of Parkinson’s disease in the Contursi kindred. Annals of Neurology 1996; 40(5):767 – 75. Grady CL & Craik FI. Changes in memory processing with age. Current Opinion in Neurobiology 2000; 10(2):224 – 31. Greenamyre JT & Shoulson I. Huntington’s disease. In DB Calne (ed) Neurodegenerative Diseases 1994, pp 685 – 704; W.B. Saunders, Philadelphia. Hattori N, Matsumine H, Asakawa S et al. Point mutations (Thr240Arg and Gln311Stop) in the Parkin gene. Biochemical and Biophysical Research Communications 1998; 249(3):754 – 8. Hof PR & Mobbs CV (eds). Functional Neurobiology of Aging 2001; Academic Press, San Diego. Kitada T, Asakawa S, Hattori N et al. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 1998; 392(6676):605 – 8. Kremer B, Goldberg P, Andrew SE et al. A worldwide study of the Huntington’s disease mutation. The sensitivity and specificity of measuring CAG repeats. The New England Journal of Medicine 1994; 330:1401 – 6. Langston JW. Epidemiology versus genetics in Parkinson’s disease: progress in resolving an age-old debate. Ann Neurol. 1998; 44(3 suppl 1):S45 – 52. Lautenschlager NT, Cupples LA, Rao VS et al. Risk of dementia among relatives of Alzheimer’s disease patients in the MIRAGE study: what is in store for the oldest old? Neurology 1996; 46(3):641 – 50. Lilienfeld DE. An epidemiological overview of amyotrophic lateral sclerosis, Parkinson’s disease, and dementia of the Alzheimer’s type. In DB Calne (ed) Neurodegenerative Diseases 1994, pp 399 – 425; W.B. Saunders, Philadelphia. Lunkes A, Trottier Y & Mandel JL. Pathological mechanisms in Huntington’s disease and other polyglutamine expansion diseases. Essays in Biochemistry 1998; 33:149 – 63. MaGue M, Bouchard TJ, Iaconon WG & Lykken DT. Behavioral genetics of cognitive ability: a life-span perspective. In R Plomin & GE McClearn (eds) Nature, Nurture, and Psychology 1993, pp 59 – 76, American Psychological Association, Washington. Martilla RJ. Epidemiology. In W Koller (ed) Handbook of Parkinson’s Disease 1987, pp 35 – 50; Marcel Dekker, New York. Mattson MP, Duan W, Lee J & Guo Z. Suppression of brain aging and neurodegenerative disorders by dietary restriction and environmental enrichment: molecular mechanisms. Mechanisms of Ageing and Development 2001; 122(7):757 – 78.

AGING OF THE BRAIN McCartney M, Harris MJ & Bernieri F. Growing up and growing apart: A developmental meta-analysis of twin studies. Psychological Bulletin 1990; 107:226 – 37. McClearn GE, Johansson B, Berg S et al. Substantial genetic influence on cognitive abilities in twins 80 or more years old. Science 1997; 276(5318):1560 – 3. Pedersen NL, Gatz M, Berg S & Johansson B. How heritable is Alzheimer’s disease late in life? Findings from Swedish twins. Annals of Neurology 2004; 55(2):180 – 5. Plomin R, Pedersen NL, Lichtenstein P & McClearn GE. Variability and stability in cognitive abilities are largely genetic later in life. Behavior Genetics 1994; 24(3):207 – 15. Polymeropoulos MH, Lavedan C, Leroy E et al. Mutation in the alphasynuclein gene identified in families with Parkinson’s disease. Science 1997; 276(5321):2045 – 7. Simonen RL, Videman T, Battie MC & Gibbons LE. Determinants of psychomotor speed among 61 pairs of adult male monozygotic twins. The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences 1998; 53(3):M228 – 34.

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Slooter AJ, Cruts M, Kalmijn S et al. Risk estimates of dementia by apolipoprotein E genotypes from a population-based incidence study: the Rotterdam Study. Archives of Neurology 1998; 55(7):964 – 8. Sudarsky L, Myers RH & Walsh TM. Huntington’s disease in monozygotic twins reared apart. Journal of Medical Genetics 1983; 20:408 – 11. Swan GE, LaRue A, Carmelli D et al. Decline in cognitive performance in aging twins. Heritability and biobehavioral predictors from the National Heart, Lung, and Blood Institute Twin Study. Archives of Neurology 1992; 49(5):476 – 81. Toescu EC, Myronova N & Verkhratsky A. Age-related structural and functional changes of brain mitochondria. Cell Calcium 2000; 28(5 – 6):329 – 38. Vaughan J, Durr A, Tassin J et al. The alpha-synuclein Ala53Thr mutation is not a common cause of familial Parkinson’s disease: a study of 230 European cases. European consortium on genetic susceptibility in Parkinson’s disease. Annals of Neurology 1998; 44(2):270 – 3.

6

Psychological Aspects of Aging Peggy A. Szwabo Saint Louis University School of Medicine, St Louis, MO, USA

INTRODUCTION This chapter will address how adults psychologically adapt as they age. Psychological theories of adult development have been extensively written about in the scientific literature. Several approaches addressing life stage perspective will be presented as it relates to mental vitality in late life. Psychology is the study of behavior and the facts and factors that influence behavior. Psychology of aging studies behavior that is organized or disorganized as the adult ages, that is, how the adult adapts or does not adapt to life stresses. These behaviors may be constant throughout life as the person experiences tasks and challenges. Generally, psychology is viewed as a broad field encompassing personality development, intelligence, memory, motivation, neuropsychological changes, creativity, and sensory and motor functioning. Important for the aging person are information processing, cognition, life satisfaction, and personal control. As with all fields, psychology of aging interrelates with the biological and social aspects of aging. Psychological processes are constantly intertwined with biological, social, and environmental factors. Understanding the psychology of aging helps the practitioner assess the person’s ability to adapt to change, understand, and cope with aging, illness, and loss. Furthermore, understanding the older adult’s previous or lack of coping and adaptive skills, the practitioner may be able to predict and understand potential problems. Successful psychological aging is dependent upon mental vitality. Mental vitality can be described as psychological or intellectual energy. That is, given life’s choices, how does the aging adult face the challenge? What is the individual’s mental vigor to cope with changing biopsychosocial changes? What has been their history of adapting and coping throughout life? Studies have found that ill health is related to problems with cognition, learning, and motivation, thus challenging the elder’s ability to cope (Havighurst, 1968; Botwinick, 1977). As Kermis (l986) so aptly put, aging is the greatest challenge.

Mental vitality encompasses present life-style choices, as well as one’s history of choices. These choices include reducing stress, establishing rest and relaxation, challenging the mind, cultivating satisfying relationships and activities, and avoiding known risk factors such as smoking, poor nutrition, weight problems, and excessive alcohol consumption. Equally important are the attitudes and beliefs that the older adult has about aging that reflect how successfully one ages. A mentally vigorous older adult with a positive attitude will be able to better cope with life’s challenges and make informed choices. While cognitive deficits have been extensively written about, it is the positive changes and adaptive abilities that may be more important in daily living skills.

LIFE STAGE PERSPECTIVE In this chapter, the focus will be on the emphasis of mental vitality as a life stage approach. This developmental-stage theory emphasizes integration of life experiences. The developmental theorists attempt to describe human development as a sequence of stages or steps. Developmental-stage models hold that changes in the adult personality are results of interaction of the social and biological environment. How the individual interacts with others and integrates that interaction into his/her personality is determined by the developmental tasks that the person performs. These tasks are markers of the individual’s movement through the life cycle. Each task combines some aspects of the person’s biological, psychological, and social functioning. Developmental tasks combine the drive toward growth of the person with the demands, constraints, and opportunities of the social environment. These tasks occur for all people in approximately the same sequence, which may overlap each other without a particular onset or termination. Failure and delay in resolving these tasks may affect how successful one will be in resolving future tasks, adjustment, and overall mental health. All of these tasks act to move the individual toward optimal psychological function and personal integrity if they are


54


successfully accomplished. Erikson (1963), the most familiar of the developmental-stage theorists, applied his approach to the aged. In his eight stages of development, the person has a conflict with two possible outcomes, adaptive or maladaptive solutions. If an early stage is resolved with a low degree of adaptation, resolving later stages will be more difficult. Erikson’s last two stages directly apply to adults and aging adults. These two stages are broad and cover many years, resulting in other theorists defining more definitive age-specific conflicts. Havighurst and Peck postulated theories that have particular significance for the elderly. Both authors elaborate on Erikson’s psychosocial tasks with consideration of tasks of the older adult (Havighurst, 1968; 1972; Peck, l968; Erikson, l963). Havighurst (1968) describes the six tasks of old age as follows: 1. adjusting to declining physical strength and health; 2. adjusting to retirement and its reduced income; 3. adjusting to changes in the health of one’s spouse or partner; 4. establishing an explicit affiliation with one’s age group; 5. adopting and adapting social roles in a flexible way; 6. establishing satisfactory physical living arrangements. Aging adults experience a variety of physical, social, and psychological losses. These losses can affect mobility both physically and socially, resulting in increasing isolation. There is a chance that the environment will continue to diminish unless the individual takes action. Havighurst’s (1968) focus is on reorganizing functions and expectations. For example, older adults who do not accept their changing physical and health limitations and adapt may become maladjusted. Partner roles may change if one partner becomes ill. The partner who nurtured may need nurturing care; the healthy partner may have to assume new roles of banker, handyman, and decision maker. Old age is a time of almost constant change. Older adults who do not adapt or adjust flexibly may find themselves increasingly stressed and maladjusted. According to Havighurst (1968), the continued refining roles and expectations to meet environmental demands accomplish the maintenance of identity. Peck’s (1968) tasks are summarized into three areas of conflict. The first is ego differentiation versus workrole preoccupation, and finding a way to identify and appreciate self without the job or one’s career as the marker of success. This includes satisfaction with retirement and children leaving home. The task is to find new ways, activities, and passions to define one’s self. The second is body transcendence versus body preoccupation, which is understanding the changes in the body and illnesses without being preoccupied with symptoms or illness concerns. The question is, can one live successfully despite age-related changes and disease states? Many older adults cope with illness and live successful lives despite pain or infirmity. Others are preoccupied with their illness, by constantly talking about their symptoms, medication requests, and frequent doctor appointments or “shopping”. Lastly, the

third area of conflict is ego transcendence versus ego preoccupation. This process is the coming to terms with the reality of death, putting closure on the past, ensuring the welfare of children and others, and leaving a legacy. There is a need to share one’s wisdom, knowledge, and experience. Conversely, if maladaptive, there is a tendency to treat the world as if it will end with their death. This person may not make wills or plans for the future, or for anything that would go on after their death (Peck, 1968). In summary, the personality is constantly changing in response to the individual’s adaptation throughout life. Life challenges can occur at any time in the life cycle, but older people are more likely to have to confront more challenges simultaneously. Losses, physical and functional changes, and cultural expectations stress older adults when their psychological reserves are low and their social supports are diminishing (Kermis, 1986).

WHAT DO WE KNOW? Aging is not uniform or static. There is differentiation among the aging commonly divided into four groupings of the young-old (60–70 years of age), the old (71–74 years of age), the old-old (75–84 years of age), and the frail-old (85 years of age and over) (Neugarten, 1977; Neugarten, 1979; Riley and Suzman, 1985). Each grouping has different tasks, abilities, and issues. For example, the 60–70-yearold groups may still be employed and more active. They may be dealing with retirement, considering housing options, developing leisure activities, and relationship issues. The 71–74-year-old group may be adjusting to retirement, loss or changes in work-role identity, income changes, friends moving or ill, widowhood, and readjusting time management. Neugarten (1974, 1979) noted that chronic illness and role losses were more characteristic of those over the age of 75. She, further, contended that the 55–74-year olds are more like the middle-aged with fairly good health and as active as they wish. Riley and Suzman (1985) further divided the old-old into the old-old and the frail-old. The old-old group may have more medical conditions, more medications on board, and may require more support services either by family or agencies or both. There are more losses, more issues with dependency and those related to assisted living situations. For couples, one partner may need more care and placement, resulting in the couple being separated. As a group, the frail elderly is growing the fastest, with estimates of over 3 million in the United States (Aging Demographics, NIA, 2004). Worldwide, the World Health Organization (WHO) estimates 4 million elders over the age of 85 (Aging Demographics, AAHSA, 2004). This group is primarily female, widowed, and more likely to face declining functional ability without a spousal caregiver. The old-old and particularly the frail-old group experience more physiological changes, more comorbid medical conditions, more

PSYCHOLOGICAL ASPECTS OF AGING

frailties, higher rates of dementia, and loss of connectedness. Connectedness is the desire to feel connected to others, their homes, and community. This sense of connectedness is threatened when there are limitations in functioning, necessitating moves to a more secure and assisted living environment, removing the elder form the security of their neighborhood, their home (Kropf, 1992). Overall, the frail elder is more likely to be in a supported living setting with more health problems, is more dependent upon others to meet their daily needs, and generally takes longer to recover from acute illnesses (Blazer, 1980; Beckett and Schneider, 1992). Many of this population, primarily women, may outlive their financial and health care resources (Beckett and Schneider, 1992; Mercer and Garner, 1989). With each group, there may be a wide range of health or illness states varying from healthy, chronic but stable, acute, and acute superimposed with chronic illnesses. Rather than relying totally on age categories alone, it is also important to address health status, adaptive abilities, and social characteristics.

AGE-RELATED PSYCHOLOGICAL CHANGES Intelligence Intelligence is composed of crystallized and fluid intelligence. Crystallized intelligence is the ability to apply past learning to new situations. Crystallized intelligence increases with age, experience and knowledge. Examples of crystallized intelligence are problem-solving activities, mechanical skills, word meanings, and understanding social relationships. Fluid intelligence is the ability to improve organization of information and to generate new hypotheses. Fluid intelligence decreases with age. Fluid intelligence consists of reasoning and abstraction, relationships between objects, acquiring new ideas, and adapting to change. IQ increases until the 20s, then levels off and generally remains stable throughout the life cycle. With aging, there is decreased speed on timed tests. Poor health represents an adverse factor in the older adult’s performance. If given more time, the older adult is as accurate as a younger adult is. In general, older adults perform better on everyday practical tasks over laboratory-based tests. Performance on Wechler Adult Intelligence Scale (WAIS) demonstrates that older adults have an increase in verbal skills, while there is a decrease in tests of performance. Results show that intelligence is stable until the 70 s, when there is a decrease in performance countered by an increase in verbal skills (Botwinick, 1977). These verbal skills reflect the knowledge and skills acquired over a lifetime. Aging does influence intellectual functioning. Changes in motor skills and slower decision-making time affect reaction time. Performance is also affected by changes in cerebral cortex functioning and cardiovascular deterioration. When decision making, older adults have been found to sacrifice

55

speed for accuracy and to reject quick, simplistic solutions to problems, preferring to work slowly and to examine issues from a variety of perspectives before responding. Older persons are more likely to make errors of omission rather than errors of commission, which suggests cautiousness, deliberateness, and anxiety (Poon, 1985). As a compensatory strategy and to avoid embarrassment, many older persons avoid unfamiliar activities and places. This cautiousness may be mistaken for resistance or obstreperousness. A word of caution is advised to many older adults who do not have the advantage of many years of formal education as compared to younger persons and have been many years away from the classroom environment (Botwinick, 1977). Deliberateness, slower response time, and time away from traditional school activities impact tests of intellectual abilities. Clinicians need to clearly evaluate the impact of physical infirmities, compensatory skills, and the older adult’s social environment before coming to any conclusions regarding intellectual decline. The impact of the living situation, lack of stimulation, and isolation may constrain intellectual functioning and should not be ignored (Botwinick, 1977). If healthy and fit, the older adult’s response time is no different from that of less healthy younger people.

MEMORY The capacity to learn continues throughout life. Optimal learning involves reading or following instructions on how to organize information, finding tasks meaningful and rewarding, and being able to link visual memory with auditory information. There are three phases of information processing – encoding, storage, and retrieval. With aging, more time and effort is required to encode information. Sensory changes can reduce memory efficiency. Because sensory memory lasts less than a second and with aging sensory changes, the older adult is less able to encode as well. Short-term memory lasts a few seconds and declines with age. Recall involves search and retrieval of information from storage. Recognition requires matching information in storage with information obtained in the environment. Recognition abilities remain stable over time (Poon, 1985). All ages do well in recognition tasks, but recall diminishes over time. It is easier for older adults to do tasks of recognition than recall information. Long-term memory includes storage of information, a fact learned earlier in life, and day-to-day experiences, and is relatively permanent. Long-term memory increases from age 20 to 50 and then is constant into the 70s. Older adults require more time to encode new information. This encoding process is affected not only by sensory losses but also by changes in the environment, such as moves and deaths. These events contribute to memory deficits. Many older adults adapt fairly well, and deficits may not be evident until a traumatic event occurs or is uncovered by a skilled clinician. Using compensatory strategies to augment

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memory, such as use of calendars and notes and taking time and practicing new material, is indicated. Structure and familiarity also help in improving memory and retention. With slowed recall and physical decline, there is a slower response, which can be misconstrued as more significant memory deficits or resistance. In summary, older adults do retain well-practiced and adaptive skills. Less-practiced tasks and recall requiring a timed response declines.

development of one’s life story and the filling in of gaps and discontinuities. This creative process, which is similar to Butler’s (1963) Life Review, is a positive therapeutic process. Adams-Price (1998) concludes that late-life creativity reflects aspects of late-life thinking: synthesis, reflection, and wisdom.

IMPLICATIONS FOR PRACTICE SENSORY The nervous system is important in receiving, processing, and storing information. The senses provide contact to the environment. Changes or decline in senses affects one’s participation in their environment and their quality of life. Losses or changes in vision, hearing, taste, smell, and touch influence the individual’s functioning, activities, stimuli response, and perceptions. Sensory losses can produce alterations in behavior, independence, confidence, and self-esteem. On the other hand, assumptions are made that sensory-impaired elders are senile, stubborn, or manipulative. Careful assessment of sensory loss is indicated before assumptions can be made concerning self-care and adaptive capabilities. Glasses and hearing aides help compensate for sensory losses and allow more independence.

CREATIVITY Even though creativity is generally not considered a component of psychological functioning, it is an area that is a part of mental vitality and quality of life. There have been many debates that creativity is limited to a few and it declines with age (Adams-Price, 1998). Research shows that creative thinking is a universal ability that helps adults manage satisfying lives. Creativity is a complex of traits, skills, and capacities, including the ability to work independently, curiosity, unconventional thinking, openness to experience, and tolerance of ambiguity (Adams-Price, 1998; Generations, 1991). Cognitive psychologists define creativity as a mental process like imagination and intuition. The newer definition is particularly apropos to the older adult. It is the integration of cognitive processes, knowledge, thinking style, personality, motivation, and environment over a lifetime. Creativity is a way to address and resolve dissatisfactions, improve quality of life, and can be a response to limits and an uncertain future (Generations, 1991; Adams-Price, 1998). Older adults do appear to experience a decrease in divergent thinking, the ability to generate novel ideas, but this is a qualitative change in the creative process. In contrast, there is an increase in crystallized intelligence and integrative or convergent thinking (Sasser-Coen, 1993). Later life may afford more time for reflection, life review, and creative pursuits aimed at the

Aging is an adaptive challenge. Mental vitality is the vigor needed to meet this task. As clinicians, continual evaluation of the older person’s understanding of the implication of agerelated changes and losses is required. Identifying coping skills and adaptive strategies is paramount as well to an effective relationship and treatment planning. To incorporate the aforementioned psychological changes into practice, recommendations are outlined. 1. Face-to-face education should occur, presenting the information in small increments and supplemented with one-page practical handouts to carry home. 2. Helpful teaching techniques include teaching time, with practice and episodic spot checks to reinforce or to correct, and phone number and contact person to call if they have questions or concerns. 3. Allow time to complete forms in a setting conducive to writing. 4. Printed materials need to be in larger boldface type and simplified to adjust for sensory changes. The guidelines of the Americans with Disabilities Act recommend that print be at least 18-point font. Signs should be in large print or symbols with contrasting background of eggshell, matte, or nonglare paper for easier reading and to clarify directions (ADA, 1990). 5. Observe accessibility and visibility issues in the physical environment. Are the directions and locations easy to follow? Lighting should be 100 to 300 lux to ensure adequate vision and easy reading (ADA, 1990). 6. Encourage the older person to take notes or write their concerns before their appointment. 7. If necessary or beneficial, suggest that the older person bring someone to assist or take notes. 8. Encourage the older adult’s participation in the treatment planning. 9. Allow the older person the opportunity to present concerns, fears, or objections to the plan. 10. Allow time to process information and study their options. 11. Ask how they are coping and what coping strategies they use. For example, “How do you handle this?” “You have a lot to deal with,” “How are you holding up?” or “What helps you?” 12. Encourage innovative or creative solutions. Ask how they would solve. 13. Referral to support group, if exists, for their medical condition.

PSYCHOLOGICAL ASPECTS OF AGING

14. Referral to geriatric/gerontology professional for counseling and environmental options.

CONCLUSION Not all cognitive changes are negative. The positive cognitive changes include greater experience-based knowledge, increased accuracy, better judgment concerning their abilities, and generally an improved ability to handle familiar tasks as compared to their younger counterparts. Aging presents psychological and cognitive challenges requiring mental vitality to adapt. An older person who ages “successfully” has been able to use their accumulated knowledge and wisdom to accomplish most day-to-day living activities well. Rigidity and exaggerated and maladaptive behaviors may represent psychological and neurological problems and are not normal aging, and a referral to a specialist is warranted. As with any treatment planning, the older adult’s problems may be obvious but treatment interventions are based upon what the person can do.

KEY POINTS • Mental vitality or energy is needed for older adults to cope with life changes. • Intelligence changes with age. Older persons have increased verbal skills and they demonstrate slowed performance skills. Life-long experience and knowledge is reflected in verbal skills. • Older adults tend to be more cautious in decisionmaking activities, pondering their options before responding. This deliberateness should not be mistaken for resistance. • Memory changes with age. Long-term memory remains fairly constant. It is easier to do tasks of recognition over recall activities. • Illness, social, and environmental changes affect learning, memory, and creativity. These changes need to be incorporated in treatment planning. • Creativity is a positive therapeutic process that encourages reflection and development of the older adult’s life story.

KEY REFERENCES • Mercer S & Garner J. An international overview of aged women. In J Garner & S Mercer (eds) Women as They Age Challenge, Opportunity, and Triumph 1989; The Haworth Press, Binghamton.

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• Peck R. Psychological developments in the second half of life. In B Neugarten (ed) Middle Age and Aging: A Reader in Social Psychology 1968; University of Chicago Press, Chicago. • Poon L. Differences in human memory with aging: nature, causes, and clinical implications. In J Birren & K Schaie (eds) Handbook of the Psychology of Aging 1985, 2nd edn Van Nostrand Reinhold, New York. • Sasser-Coen JR Qualitative changes in creativity in the second half of life. Journal of Creative Behavior 1993; 27(1):18 – 27.

REFERENCES Adams-Price CE. Creativity and Successful Aging 1998; Springer Press, New York. Aging Demographics, AAHSA web page, September 2004, www.AAHSA. com. Aging Demographics, National Institute of Aging, web page, 2004, www.nih.gov/nia. Americans with Disabilities Act of 1990, ADA Accessibility Guidelines for Buildings and Facilities. 28 CFR Ch 1. Sections 4.30.4, 703 & Advisory Appendix, www.usdoj.gov/crt/ada/pubs/ada.txt. Beckett J & Schneider R. Older women. In R Schneider & N Kropf (eds) Gerontological Social Work Knowledge, Service Settings, and Special Populations 1992; Nelson-Hall, Chicago. Blazer D. The epidemiology of mental illness in late life. In E Busse & D Blazer (eds) The Handbook of Geriatric Psychiatry l980; Van Nostrand Reinhold, New York. Botwinick J. Intellectual abilities. In J Birren & K Schaie (eds) Lifespan Developmental Psychology 1977; Academic Press, New York. Butler R. The life review: an interpretation of reminiscence in the aged. Psychiatry 1963; 26:65 – 76. Creativity in later life. Theme issue. Generations Spring, 1991; 15(2). Erikson E. Childhood and Society 1963; W.W. Norton, New York. Havighurst R. Personality and patterns of aging. The Gerontologist 1968; 8:20 – 3. Havighurst R. Developmental Task and Education 1972; Mckay, New York. Kermis M. Mental Health in Late Life the Adaptive Process 1986; Jones and Bartlett Publishers, Boston. Kropf N. Home health and community services. In R Schneider & N Kropf (eds) Gerontological Social Work Knowledge, Special Settings, and Special Populations 1992; Nelson-Hall, Chicago. Mercer S & Garner J. An international overview of aged women. In J Garner & S Mercer (eds) Women as They Age Challenge, Opportunity, and Triumph 1989; The Haworth Press, Binghamton. Neugarten B. Age groups in American society and the rise of the youngold. In F Eisele (ed) Political Consequences of Aging 1974; American Academy of Political and Social Sciences, Philadelphia. Neugarten B. Personality and aging. In J Birren & K Schaie (eds) Handbook of the Psychology of Aging and the Social Sciences 1977; Van Nostrand Reinhold, New York. Neugarten B. Time, age, & the life cycle. American Journal of Psychiatry 1979; 136(7):887 – 94. Peck R. Psychological developments in the second half of life. In B Neugarten (ed) Middle Age and Aging: A Reader in Social Psychology 1968; University of Chicago Press, Chicago. Poon L. Differences in human memory with aging: nature, causes, and clinical implications. In J Birren & K Schaie (eds) Handbook of the Psychology of Aging 1985, 2nd edn Van Nostrand Reinhold, New York. Riley M & Suzman R. Introducing the “oldest old”. Milbank Memorial Quarterly 1985; 63:177 – 86. Sasser-Coen JR Qualitative changes in creativity in the second half of life. Journal of Creative Behavior 1993; 27(1):18 – 27.

7

Neurochemistry of Aging Alan M. Palmer1 and Paul T. Francis2 1

Pharmidex, London, UK, and 2 King’s College London, London, UK

Based in part on the chapter ‘Neurochemistry’ by Alan M. Palmer and Steven T. DeKosky, which appeared in Principles and Practice of Geriatric Medicine, 3rd Edition.

INTRODUCTION The world’s population is getting older. During the first 50 years of this millennium, the worldwide population aged over 65 years is projected to increase from 6.9% of the total population to 15.9%, which constitutes an extra billion people (Table 1). This is attributable to a combination of a progressive increase in life expectancy (Table 1) and elevated fertility in many countries during the two decades after World War II (i.e. the “Baby Boom” effect; Figure 1) (see also Chapter 9, The Demography of Aging). This growing number of older adults increases demands on the public health system and on medical and social services, particularly for chronic neurological diseases such as stroke, Alzheimer’s disease (AD), and Parkinson’s disease (see Chapter 9, The Demography of Aging). Such disorders affect older adults disproportionately and contribute to disability, diminish quality of life, and increased healthcare costs. Thus, stroke afflicts 30% of persons aged over 65 years (fatally in 10%), and its incidence doubles during successive decades. AD affects 10% of the population aged over 65 years and is rising to 49% of those aged 80 years or more, and Parkinson’s disease affects 1% of persons aged 60 or older and 2.6% of those over the age of 85 years (Palmer and DeKosky, 1998). Both age-associated neurological deficits and the increased risk to ischemic stroke and neurodegenerative disease with advancing age can be attributed to neurobiological deterioration. In many cases, the changes in degenerative diseases are qualitatively the same, but quantitatively more severe, than those of normal aging. Aging itself causes more modest changes in overall function. Thus, there is a mild slowing of both motor speed and reaction time and a decline of complex cognitive skills, particularly memory. Memory is a complex function, encompassing the encoding, storage, and retrieval of diverse types

of information. There are multiple memory systems in the brain. For example, there are dissociable systems underlying such memory functions as new learning of verbal information, acquisition of a procedural skill, and retrieval of semantic knowledge from long-term storage. Age does not affect all domains of cognition equally. For some functions, such as speed of visual-motor processing, slight decline often can be detected as people enter their 40s and 50s. However, for most cognitive abilities, no measurable decline is evident until age 65 or older. For example, the average expected number of words recalled from a 15-word list after a 30-minute delay is approximately 10 for people aged 55–65, nine for those aged 66–70, and eight for those up to age 85. These changes, while noticeable, are not disabling. Furthermore, some aspects of cognition, such as an individual’s general fund of information, can actually continue to improve throughout their lifetime. There is considerable current interest in distinguishing age-related changes in cognition from “mild cognitive impairment” (MCI) (see also Chapter 94, Mild Cognitive Impairment), which may be a prodrome of various forms of dementia (Figure 2). Noncognitive changes in behavior are also important in aging since there is often an increase in psychiatric symptoms, including major depression, and a profound disruption of the sleep-wake cycle (see Chapter 63, Sleep Disorders in Elderly People; Chapter 98, Geriatric Psychiatry and Chapter 100, Depression in Late Life: Etiology, Diagnosis and Treatment). This chapter will consider the neurochemical pathology of aging and, where appropriate, relate this to the changes associated with stroke, vascular dementia, AD, and Parkinson’s disease (see also Chapter 66, Parkinson’s Disease and Parkinsonism in the Elderly; Chapter 71, Acute Stroke; Chapter 92, Cellular Changes in Alzheimer’s Disease and Chapter 95, Vascular Dementia).


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Table 1 Trends in world population

Year Total population (thousand persons) Population aged >65 (thousand persons) Percentage of those aged >65 Male life expectancy at birth (years) Female life expectancy at birth (years)

1950

2000

2050

2 518 629

6 070 581

8 918 724

130 865

419 197

1 418 742

5.2

6.9

15.9

45.2

63.3

72.0

47.9

67.6

76.7

Data derived from the 2002 revision of the UN “World Population Prospects” (www.un.org).

Proportion of US population over 65 years (% of total US population)

30

NEUROCHEMICAL CHANGES IN THE AGING BRAIN

25

Cholinergic Neurons

20

15

10

5

0 1960

1980

2000

2020

2040

Figure 1 The proportion of adults aged over 65 as a proportion of the total US population (Data from the US Census, Middle Series Projections)

Aging Cognitive function

and 90. In the older brain, tissue loss is most obvious on the surface and is seen as shrinkage of the brain gyri and sulci, which reflects a loss of neurons – from 10 to 60% – in different cortical areas. Neuronal loss is particularly evident in the hippocampus, but is also seen in the cerebellum, locus ceruleus, nucleus basalis of Meynert and the raphe nucleus. Besides neuronal loss, there also appears to be diminished dendritic arborization with age, although the number of synapses appears not to decline with age, which contrasts with AD, where there is clear evidence of synapse loss (Palmer and DeKosky, 1998) (see also Chapter 8, Neuropathology of Aging and Chapter 5, Aging of the Brain).

AD MCI

Mild Moderate Clinical AD

Severe

Time Figure 2 The decline in cognitive function in aging and Alzheimer’s disease (see also Chapter 93, Clinical Aspects of Alzheimer’s Disease and Chapter 95, Vascular Dementia)

THE AGING BRAIN Brain weight and volume decrease with age. On average, the brain loses 5–10% of its weight between the ages of 20

The cholinergic hypothesis of memory posits that the deterioration in cognitive function associated with age or AD is attributable to decreased cholinergic neurotransmission. The major success of this hypothesis is that it has led to the rational development of new medicines, principally acetylcholinesterase (AChE) inhibitors which inhibit ACh catabolism, together with numerous other cholinomimetics that are currently undergoing clinical development (Palmer, 2002; Wilkinson et al., 2004). Although the first AChE inhibitors (e.g. tacrine) were associated with significant side effects and short plasma half-lives, second-generation compounds (e.g. donepezil, rivastigmine, and galantamine) have superior safety and efficacy profiles. Other cholinomimetic approaches to therapy include selective muscarinic M1 receptor agonists, M2 receptor antagonists, and nicotinic receptor agonists. Despite the apparent clinical utility of cholinomimetic approaches to the treatment of cognitive dysfunction, the evidence to support this hypothesis does have a number of shortcomings. In addition, recent data suggest a greater role of cholinergic neurons in mediating some of the noncognitive behavioral symptoms associated with AD (Francis et al., 1999). The utility of AChE inhibitors in the treatment of MCI is currently under investigation, but clear efficacy has not yet been established.

Dopaminergic Neurons There is a steady decline in dopaminergic cells in the substantia nigra with age in humans. The number of dopaminergic neurons in each substantia nigra declines from 400 000 at birth to 250 000 at age 60. In Parkinson’s disease, cell counts range from 60 000 to 120 000. Dopaminergic cells in the substantia nigra innervate the neostriatum and corresponding changes in the concentration of dopamine in the neostriatum have also been observed (Table 2). It has been

NEUROCHEMISTRY OF AGING

Noradrenergic Neurons

Table 2 Summary of neurochemical changes in aging

Neuron type

Cortex

Hippocampus

Striatum

Cholinergic

Reduced in most studies

Noradrenergic

No change in most studies

Reduced in most studies No change

Serotonergic

No change in some studies but reductions in others No change

No change in most studies No change in most studies No change

No change

Reduced in all studies No change

Reduced in all studies No change

Dopaminergic

GABAergic EAAergic

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No change in most studies Reduced in most studies Reduced in one study No change

The table is largely derived from Palmer and DeKosky (1998).

suggested that Parkinson’s disease is related to a combination of environmentally induced subclinical damage to the substantia nigra pars compacta and the age-related loss of additional nigra neurons. Essential to this hypothesis is the existence of deteriorated function of the nigrostriatal pathway with advancing age. However, the hypothesis that Parkinson’s disease is simply the additive effects of aging and cumulative neurotoxicity has been challenged by data indicating that the pattern of striatal cell loss in normal aging differs substantially from the pattern typically observed in Parkinson’s disease. Nonetheless, before frank Parkinsonian symptoms emerge it is necessary that there is more than an 85% loss of dopamine from the striatum. The age-related loss of dopamine from the striatum therefore contributes to emergence of symptoms in Parkinson’s disease and to the shuffling gait and stooped posture often seen in the very elderly. Age-related changes in dopaminergic neurons were largely restricted to the neostriatum since neither the cerebral cortex nor the hippocampus displayed marked age-related changes (Palmer and DeKosky, 1998). The age-associated loss of nigrostriatal neurons may also underlie the striking increase in choreic symptoms seen midlife in patients with Huntington’s disease. In addition to changes in dopamine (DA), a number of studies have consistently demonstrated elevation in the activity of the DA catabolic enzyme monoamine oxidase-B (MAO-B). This may serve to reduce synaptic concentration of DA with age and this will exacerbate the functional consequences of age-related loss of DA neurons. In contrast to MAO-B, the activity of MAO-A is relatively spared in Parkinson’s (Palmer and DeKosky, 1998). Dopamine receptors have not yet been extensively studied in the aging human brain, but evidence indicates increased binding to D-1 receptors and reduced binding to D-2 receptors in the neostriatum. This age-related loss of D-2 receptors with age has been suggested to underlie the increasing incidence and severity of tardive dyskinesia with aging (Palmer and DeKosky, 1998).

Marked loss of locus ceruleus neurons has been reported, as a function of age, from approximately 19 000 cells in youth to about 10 000 cells for people in their ninth decade (Palmer and DeKosky, 1998). In contrast to morphometric studies, neurochemical studies have indicated a general sparing of noradrenergic indices in aging, with the possible exception of the hippocampus (Table 2). This is probably a reflection of the assessment in neurochemical studies of only transmitter and metabolite concentration and the postmortem instability, which in turn leads to increased variability, in these markers (Palmer and DeKosky, 1998). This is supported by studies of experimental animals, where postmortem influence is small and pronounced age-related reductions in noradrenergic activity have been reported, particularly in hypothalamic regions (Palmer and DeKosky, 1998). Noradrenaline is catabolized largely by MAO-A; about one-third is catabolized by MAO-B. Therefore, noradrenergic function may also be affected by the age-related increase in MAO activity, albeit to a lesser extent than dopamine. The two general types of adrenergic receptors, α and β, have been further subdivided into α1 and α2 and β1 and β2. β2 receptors have been found to decline with age in the cerebral cortex whereas, β1 receptors were unaffected (Palmer and DeKosky, 1998). Disturbances of the noradrenergic system are considered to play a role in depressive illness, so age-associated changes may contribute to the increased incidence in depression in the elderly. Reduced concentration of noradrenaline (NA) have generally been reported in postmortem AD brain together with marked atrophy and cell loss from the locus ceruleus. This has been corroborated by data obtained from tissue removed antemortem where both the concentration of noradrenaline was reduced in both temporal and frontal cortex. In addition, high affinity uptake of [3 H]noradrenaline was reduced in the temporal cortex (Palmer, 1996). Evidence suggests that these changes may contribute to some of the noncognitive changes in behavior associated with AD (Palmer, 2002).

Serotonergic Neurons There are reports indicating loss of 5-hydroxytryptamine (serotonin, 5-HT) nerve terminals in the cerebral cortex but not in the hippocampus or neostriatum (Table 2). 5-HT is principally catabolized by the MAO-A and so is not likely to be affected by the age-related increase in MAO-B activity. The 5-HT content in the neocortex from AD subjects has, in general, been found to be reduced. Neurofibrillary tangles and neuronal loss occur in the dorsal raphe nucleus, but it is unclear what proportion of cells are affected and whether the affected cells relate topographically to areas of pronounced neocortical damage (Palmer and DeKosky, 1998). Postmortem data indicating and serotonergic denervation has been corroborated by antemortem studies in which the release and uptake of 5-HT have been measured in addition to the

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concentration of both 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) (Palmer, 1996). Dysfunction of serotonergic (and noradrenergic) neurons probably relate more to noncognitive changes in behavior, such as aggression and depression that often accompany AD. In addition, the activity of serotonergic (and noradrenergic) neurons has been shown to closely reflect the state of behavioral arousal (maximal during periods of vigilance and absent during rapid-eye-movement sleep), so loss of these neurons may be responsible for the disturbance of sleep (and selective attention) associated with aging and AD (Palmer and DeKosky, 1998).

Cortical Interneurons γ -Aminobutyric acid (GABA) constitutes a major inhibitory transmitter system in the cortex, accounting for as many as 30% of all cortical neurons. A number of markers of GABA metabolism have been examined in human brain and all have been shown to decline with aging (Table 2). A large number of peptides have been described in the cerebral cortex that are localized to neurons and are released upon depolarization. These are believed to play a role in slow chemical signaling. It appears that virtually all such peptides are colocalized with GABA in a GABAergic interneurons. Although neuropeptides have not been extensively examined in the aging human brain, it can be expected that they will change in concert with GABAergic neurons (Palmer and DeKosky, 1998). In AD, reduced concentrations of both GABA and somatostatin-like immune reactivity have been reported. By contrast, studies of tissue obtained antemortem have indicated that the concentration of GABA and somatostatin-like immunoreactivity (SLIR), the potassium-evoked release of GABA and SLIR and glutamic acid decarboxylase (GAD) activity were unaltered in AD (Palmer, 1996). This suggests that GABAergic neurons are not affected until a relatively late stage of the disease. In such a case, it is likely that loss of cortical interneurons contributes to the final stages of the syndrome of dementia, but it is difficult to predict the consequences (if any) of the small losses associated with aging.

Excitatory Amino Acid–releasing Neurons Pyramidal cells are the largest and most abundant neuron type in the cerebral cortex and play a key role in all aspects of higher mental and sensorimotor function. The neurotransmitter(s) associated with these neurons is considered to be an excitatory amino acid (EAA), principally L-glutamate and L-aspartate (Francis, 2003). Age-related loss of pyramidal neurons from the hippocampus and cortex have been demonstrated (Morrison and Hoff, 1997). Corresponding neurochemical data to support these changes is equivocal (Palmer and DeKosky, 1998). In experimental animals, EAA neurotransmission is, in at least a functional sense, preserved with

normal aging since EAA uptake in cortex, hippocampus, and striatum and EAA release in cortex are preserved with age in a study using long-lived Fischer 344/Norwegian brown strain of rat aged 3, 12, 24, and 37 months (Palmer et al., 1994). This corresponds with data from most other studies. The exceptions (Segovia et al., 2001) may be attributable to comparisons between immature and mature animals since brain maturation may not be complete until 12 months. Thus “aging” changes may simply reflect changes occurring as a result of brain maturation rather than senescence. Other complicating factors include the common use of animals that do not achieve senescence (most inbred strains die before “old age” is achieved), along with the practice of comparing just two age points. Tissue from the same animals used in Palmer et al. (1994) was used in a detailed study of the integrity of N-methylD-aspartate (NMDA) receptors. Both coagonist sites (for glutamate and glycine) were examined along with polyamine and zinc modulatory sites (Palmer, 2000). No age-related changes were observed, which largely corresponds with data from other studies (Segovia et al., 2001), particularly if the caveats mentioned above are taken into account. Thus, it appears that both EAA terminals and NMDA receptors are preserved with aging; α-amino-3-hydroxy-5-methyl4-isoxazolepropionic acid (AMPA)/kainate receptors also appear to be unchanged with aging (Segovia et al., 2001). However, there may be losses in distinct brain regions. This is supported by an immuonhistochemical study showing an age-related loss of human AMPA receptors from cholinergic neurons in the basal forebrain. What’s more, since these alterations increase cation permeability, they may well contribute to the age-related loss of cholinergic neurons and contribute to the vulnerability of these neurons in AD (Ikonomovic et al., 2000). The relative preservation of EAA nerve terminals in aging contrast to the status of these neurons in AD (Francis, 2003). Some of the symptoms of AD, particularly aphasia, agnosia, and apraxia, are often similar to those associated with cortical disconnection syndromes (Pearson, 1996). This has led to the hypothesis that AD represents a global cortical disconnection syndrome in which each cortical region functions in isolation. Support has derived from correlations between the loss of pyramidal neurons from layers III and V of Alzheimer’s patients with the severity of dementia and scores on five psychometric tests (Mann, 1996).

STRUCTURAL MARKERS OF BRAIN MEMBRANES Markers of Neuronal Membrane and Connectivity Neuron membrane –specific protein and lipid membrane markers have been utilized in human as well as experimental animal studies to quantify “axodendritic expanse”, the amount of a neuronal (as opposed to glial) membrane present in a given volume of tissue (or expressed per mg wet weight


or per mg protein). Lipid sialoganglioside is enriched in neuronal membranes, and has been used as a neuronal marker. This relative stability is in contrast to the marked loss of gangliosides in AD, in which massive neuronal and axodendritic loss occurs (Palmer and DeKosky, 1998). A more specific marker of neuronal connections is synaptophysin, a protein present at the synapse itself. Increases in synaptophysin occur in animal brains during the period of developmental synaptogenesis. In respect to normal aging, little data is available but studies in monkeys show no reduction. This may reflect the fact that synapses take up a small proportion of the neuropil or that synapse loss occurs at a similar rate to brain atrophy (Geinisman et al., 1995). However, synaptophysin decreases in the target zone after lesion-induced denervation and increases with regeneration of synapses (Palmer and DeKosky, 1998). Therefore, as expected in AD, synaptophysin is decreased in areas of known synapse loss which are affected by the disease (cortex and hippocampus) but not in regions that are behaviorally or neuropathologically uninvolved, such as the cerebellum (Palmer and DeKosky, 1998). Actual synapse loss in AD compared to age equivalent controls has been shown in electron microscopic studies, which directly quantify synapses (Palmer and DeKosky, 1998). The severity of dementia of AD patients has been shown to correlate with synapse counts in biopsy tissue and synaptophysin concentration in postmortem tissue (Palmer and DeKosky, 1998).

White Matter White matter represents axons, their insulating sheath, and the supporting cell. Age-related white matter changes are a frequent finding in CT/MRI of older subjects. The evidence points toward an association between white matter changes and cognitive impairment, with speed of mental processes, attention, concentration, executive functions, and visual spatial skills being the cognitive domains more commonly affected (Ferro and Madureira, 2002).

PROTEIN SYNTHESIS AND GENE EXPRESSION Overall, the data suggest that there is a reduction in the capacity to synthesis proteins during aging, which is related to changes in the nucleus. Studies of the aging rodent brain indicate diminished rates of protein synthesis, but such studies have not been performed on the human brain, although the shrinkage of neurons and decreases in specific proteins (e.g. neurotransmitter receptor enzymes) may stem from such declines. In AD, the capacity for protein synthesis is reduced, which in pyramidal cells may be associated with the formation of neurofibrillary tangles. This, along with impaired cytoskeletal transport of proteins, will substantially disrupt normal function.

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POSSIBLE CAUSES OF AGE-ASSOCIATED NEURODEGENERATION The cause of age-associated neurodegeneration is not yet known. However, there are a number of mechanisms of neurodegeneration that may play a role in senescent brain dysfunction. These include the triumvirate of excitotoxicity, oxidative stress, and impaired energy metabolism, along with neurotrophic factors, and are considered below.

Excitotoxicity The excitotoxic hypothesis of brain injury posits that elevated interstitial concentrations of EAAs cause cell death by overactivation of EAA receptors. EAAs could accumulate because of a disruption of energy metabolism leading to increased EAA release or impairment or reversal of EAA uptake (or a combination of both). Another possibility is that the number of EAA receptors or their selectivity for particular ions change and thus cause cell death. For example, loss of basal forebrain cholinergic neurons in AD may be linked to the numbers of calcium-permeable AMPA/kainate receptors present on such cells. By whatever mechanism a major consequence of these changes is depolarization of the postsynaptic membrane, which removes the depolarization block to the NMDA receptor channel complex, thus permitting a large influx of Ca2+ ions over the period that it is in the open state. Toxicity is then determined by both the magnitude and duration of the rise in cytosolic Ca2+ concentrations. It is now well established that excitotoxic mechanism contribute to the neurodegenerative changes associated with stroke and motor neuron disease, while for AD the extent of such involvement remains to be established clearly. In aging, there is increased vulnerability of selected populations of neurons to excitotoxicity and oxidative stress. Environmental stress can also contribute to hippocampal cell death. These neurons have endogenous glucocorticoid receptors, which interact with glucocorticoids secreted from adrenal glands in response to stress reduce glucose uptake (Behl, 1998). This increases vulnerability to cell death and may provide the basis to stress-induced neurodegeneration, which has been observed in experimental animals. The hippocampus is particularly vulnerable to both age- and Alzheimer-associated degeneration and is selectively vulnerable to the effect of metabolic poisons (Palmer et al., 1994).

Oxidative Stress The brain is particularly vulnerable to free radical damage because of its high requirement for both energy and oxygen, along with particularly high concentrations of polyunsaturated fatty (which are major substrates for free radicals) acids and transition metals (which often catalyze radical-generating reactions). This situation is exacerbated by a lower antioxidant capacity than that in most other organs. Oxidative stress

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occurs when pro-oxidant activity exceeds the capacity of the tissue’s antioxidant capacity. Oxidative stress increases with age because of increased pro-oxidant activity rather than any diminution of antioxidant capacity (Palmer et al., 1994). This elevated pro-oxidant activity causes oxidative damage to DNA, protein, and lipids in the brain, which leads to neuronal dysfunction and ultimately to neuron loss. Nerve terminals are particularly vulnerable because of the high number of mitochondria, which is the source of most free radicals. This is supported by age-related increases in a marker of DNA damage (8-hydroxydeoxyguanosine concentration) and elevated lipid peroxidation in synaptosomes (pinched off nerve endings). The oxidative polymerization of lipids leads to the formation of lipofuscin and increases in a linear fashion with age in humans. Its formation occurs as a result of free radical formation, so accumulation with age may reflect the cumulative consequence of free radical reaction over the lifespan. Lipofuscin has been shown to accumulate in both the cholinergic nucleus basalis of Meynert and the serotonergic raphe nucleus and may therefore be associated with the age-associated loss of these cells. Similarly, neuromelanin accumulation, also thought to occur in response to free radical reactions, increases with aging in the noradrenergic locus coeruleus and the dopaminergic substantia nigra, and there is good evidence for free radical involvement in the etiology of Parkinson’s disease (Beal, 2003). In addition to oxidative damage to DNA and lipids, there is also evidence for an age-related increase of oxidized protein (assessed by measuring the concentration of protein carbonyls) in brain tissue from both humans and experimental animals. The full significance of oxidative stress increasing with age is not yet clear, but the fact that damage to DNA, lipids, and proteins is also evident in AD and Parkinson’s disease (Floyd, 1999) suggests that these age-related changes increase vulnerability to the pathogenic process associated with neurodegenerative diseases. There is evidence of free radical damage to all classes of macromolecules (protein, DNA, RNA, lipids, and sugars) in brains of patients with AD, although great care must be taken to control for the effects of postmortem delay and brain acidosis occurring as a consequence of terminal coma. Taking this into account, there is evidence of damage to specific proteins such as the glial glutamate transporter GLT-1, glutamine synthase and β-actin as well as the lipids arachidonic acid and docosahexaenoic acid (Butterfield et al., 2001). The oxidative damage to GLT-1 has been attributed to the action of an aldehydic product of lipid peroxidation, 4-Hydroxynonenal (Lauderback et al., 2001). The functional consequences of this modification are as yet unknown but may explain the functional reduction in glutamate uptake seen in AD (Procter, 1996) in the presence of stable amounts of GLT-1 protein (Beckstrom et al., 1999).

Reduced Energy Availability/Mitochondrial Function There remains some uncertainty as to whether the cerebral metabolic rate as determined by positron emission tomography (PET) declines with aging but the most closely controlled

studies indicate that at least some brain regions are affected. The complication is that brain atrophy as well as functional decline can both contribute to reductions. Only when studies using full coregistration of PET with MRI become more frequent will it be possible to resolve this issue. Cerebral metabolic rate for glucose and for oxygen and cerebral blood flow are all reduced in AD and the pattern of reductions tends to mirror neuropathology. Again the complication is atrophy and cell loss. However, evidence energy levels appear to be reduced in AD, probably because of impaired mitochondrial function (Beal, 1998; Francis et al., 1993). The likely cause is not known, but it may be related to reductions in the activity of key enzymes in the Kreb’s cycle. Thus, there have been consistent reports of reduced activity of pyruvate dehydrogenase α-ketoglutarate dehydrogenase and cytochrome oxidase (Blass, 2003). Other evidence points to the possibility of uncoupling of oxidative phosphorylation and oxidation (Francis et al., 1993), which would reduce energy availability; it is also likely to increase free radical production.

Neurotrophic Factors Over the past decade, there has been much interest in the possible role of neurotrophic factors in neurological disorders. In particular, nerve growth factor (NGF), the founding member of the neurotrophin family, has generated great interest in relation to AD. This interest is based on the observation that cholinergic basal forebrain are dependent upon NGF and its receptors for their survival. In fact, NGF transduces its effects by binding two classes of cell surface neurotrophin receptors: TrkA and p75, both of which are produced by cholinergic neurons. Recent findings indicate an early defect in NGF receptor expression in CBF neurons; therefore, treatments aimed at facilitating NGF actions may prove highly beneficial in counteracting the cholinergic dysfunction found in end-stage AD and attenuating the rate of degeneration of these cholinergic neurons (Lad et al., 2003). There are no quantitative data on changes in NGF receptor density over the lifespan or in aging.

Amyloid (Aβ) Aβ, a 40–42 amino acid peptide derived from amyloid precursor protein, is considered to play a central role in the pathophysiology of AD since it forms the core of senile plaques. In some cases, (autosomal dominant AD and Down’s syndrome (see Chapter 92, Cellular Changes in Alzheimer’s Disease and Chapter 101, The Older Patient with Down’s Syndrome)) this occurs because of increased production of Aβ, whereas in sporadic AD it may be linked to altered Aβ processing or impaired clearance of Aβ. Both Aβ deposition and plaque formation increase with aging, although the mechanism is not yet clear, it may be linked to oxidative stress since amyloidoisis is blocked by antioxidants.


APPROACHES TO THERAPY Aging is a highly complex multifactorial process characterized by the progressive loss of the ability of organs and cells to maintain normal function. Thus, there is no unitary neurochemistry of aging and age-associated brain dysfunction manifests in a variety of way and increases the likelihood of coincidence neurological disease. It is therefore unlikely that there will ever be a single pharmacotherapy for brain aging, but, rather, specific therapies will be used for particular symptoms, as is now being realized in neurological disorders such as AD (Palmer, 2002). Understanding the underlying neurochemistry thus provides an essential framework for rational therapy, which may be categorized as either neuroprotective or palliative (see also Chapter 97, Treatment of Behavioral Disorders).

Neuroprotective Therapy Antiexcitotoxic Agents

Excitotoxicity clearly plays an important role in mediating neurodegenerative changes in stroke, severe hypoglycemia, severe epilepsy, and severe head injury. Although the involvement of excitotoxic mechanism in chronic brain injury is less clear-cut, evidence is emerging for a critical role in mediating the neurodegenerative changes associated with motor neuron disease and AIDS. Excitotoxicity coupled with oxidative stress may also be central to the neuropathology associated with the diseases of Huntington, Parkinson, and Alzheimer. Since most of these diseases are age-related, disease-induced changes are probably potentiated by the neurodegeneration associated with normal aging, which itself may be caused by excitotoxic injury, probably in conjunction with oxidative stress (Palmer et al., 1994). Thus, there is great potential for drugs that block the cascade of destruction associated with excitotoxic injury. Preclinical studies have now established the utility of NMDA and AMPA/kainate receptor antagonists in the treatment of acute brain injury. However, none of these compounds showed clear efficacy in clinical trials (Dawson et al., 2001). However, one well tolerated NMDA receptor antagonist (memantine) has recently been launched as a palliative for AD (Palmer and Stephenson, 2005). Whether it is also able to alter the course of this disease remains to be established (Tariot et al., 2004). Antioxidants

The proposed involvement of oxidative damage in aging has prompted studies to examine the neuroprotective efficacy of various antioxidants. However, the results so far are encouraging but variable (Floyd, 1999). The nitrone-based free radical trap PBN (α-phenyl-N -tert-butyl nitrone) has been investigated extensively. Chronic low-level administration to old experimental animals appears to reverse their

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age-enhanced susceptibility to stroke. In addition to its radical scavenging activity, it has also been shown to block inflammation-induced neurodegeneration, suggesting there that the senescent brain may be an enhanced neuroinflammatory state as well as at an increased level of oxidative stress (Floyd and Hensley, 2000).

Palliative Therapy Of the behavioral changes seen in apparently normal elderly, relatively few have a significant impact on function. Those changes that affect function relate primarily to motor slowness, difficulty with complex cognitive complexity, visual and auditory alterations, depression, and sleep disturbance. The most successful example of palliative therapy is the use of levodopa to treat Parkinson’s disease. The effect of levodopa on age-associated motor dysfunction is not yet clearly established. The age-associated impairments in cognitive function may well respond to therapies aimed and improving cognitive function in Alzheimer patients. Some of the symptoms of AD, particularly aphasia, agnosia, and apraxia, are often similar to those associated with cortical disconnection syndromes. Quantitative data on the distribution of senile plaques and neurofibrillary tangles further suggest that corticocortical projection fibers are selectively affected within association areas of the cortex. This has led to the hypothesis that AD represents a global cortical disconnection syndrome in which each cortical region functions in isolation. Support for this hypothesis has come from an antemortem study of AD, in which loss of the perikarya of pyramidal neurons from layers III and V of the midtemporal gyrus of Alzheimer’s patients was found to correlate significantly with an assessment of the severity of dementia and scores on five psychometric tests (Mann, 1996). As pyramidal neurons use EAA as a neurotransmitter and receive prominent excitatory inputs, the cortical disconnection hypothesis of AD predicts that changes in EAA neurons and receptors make a substantial contribution to the progressive impairments of memory, personality, and intellect that characterize AD (Francis, 2003). Studies have demonstrated that the NMDA receptor antagonist Memantine improves global functioning and activities of daily living, cognitive function, and caregiver burden (Tariot et al., 2004). Another approach is to target 5-HT1A receptors, which in the cerebral cortex are entirely located on pyramidal cells. 5-HT1A receptor antagonists have been shown to increase EAA release; it has been suggested that such compound will be effective in the treatment of AD (Schechter et al., 2002). Cholinergic mechanisms have also been linked to memory dysfunction, although recent evidence suggests that the cholinergic system may play a greater role in attentional processing. There are a number of approaches to the treatment of the cholinergic deficit in AD, most of which have focused on ACh replacement with precursor (choline or lecithin) the AChE inhibitor physostigmine or the muscarinic agonist are coline. More recent studies have used M2 muscarinic antagonists, M1 muscarinic

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agonists, nicotinic agonist, or improved AChE inhibitors (Palmer, 2003). Again in AD, dysfunction of noradrenergic and serotonergic neurons probably relate more to noncognitive changes in behavior, such as aggression, depression, and sleep disturbances, that often accompany AD (Palmer and DeKosky, 1993; Procter, 1996). Thus, there is now a theoretical basis for treating subsets of elderly persons and patients with AD who display overt noncognitive changes in behavior with drugs that act upon noradrenergic and serotonergic systems (Palmer and DeKosky, 1998). Thus, for example, 20–30% of elderly persons with concurrent mental illness are depressed. Similarly, depression affects a similar proportion of Alzheimer patients and anti-antidepressant therapy appears to be effective, although there have been no double blind yet (Palmer and DeKosky, 1998).

CONCLUSIONS AND FUTURE DIRECTIONS Neurochemical changes in the aging brain are varied and for many markers they are qualitatively the same, but quantitatively less severe than those occurring in neurodegenerative disease. Impairments in dopamine transmission probably contribute to the gait and movement disorders in the elderly and contribute to the age-associated increase in the prevalence of Parkinson’s disease. Similarly, alterations in EAA and cholinergic transmission probably contribute to the impairments in cognition and attention seen in the elderly whereas the age-related decline in noradrenergic and serotonergic transmission are likely to contribute to the ageassociated changes in noncognitive behavior, such as depression, aggression, and sleep disturbance. This lays the conceptual framework for palliative therapy for the behavioral abnormalities associated with old age. Similarly, the development of preventative therapy depends on a clear understanding of the mechanisms responsible for age-associated neurodegeneration. The most plausible mechanism at present is that it occurs as a result of oxidative stress, which causes damage to DNA, lipid, and protein, which contribute to cell dysfunction. If this is sufficient to impair the production of ATP (which is required for neurons to maintain their high level of activity), then the membrane potential will not be maintained. This inability to maintain neuronal membrane potential (because of diminished activity of the Na+ /K+ ATPase) eases the Mg2+ blockade of the NMDA receptor and facilitates activation by EAAs, leading to increase influx of Ca2+ and, if sustained at a high level, will lead to cell death. Given the major implications of cognitive competency for personal independence and quality of life, together with growing evidence that how an individual lives in earlier stages of life affects cognitive aging, greater attention to memory and the aging brain is likely to have significant public health benefits. It is now clear that significant cognitive decline is not an inevitable consequence of advanced age. Furthermore, AD and related disorders, which in the past

have been approached with a sense of therapeutic nihilism, are increasingly being seen as targets for active intervention. But what of “age-associated memory impairment”? New research that offers to attain the ancient goal of improving our cognitive ability raises an important issue – the use, by healthy people, since aging is not considered a disease. There is a long history of “cognitive enhancers” but the effectiveness of such supposed “nootropics” is far from clear (Rose, 2002). Although pharmaceutical companies race to provide treatments for memory loss in AD, there is much less enthusiasm to treat “age-associated memory impairment”. Long term, however, it is clear that there is likely to be an increased need for drugs to improve cognitive function in both the demented and nondemented elderly. With the projected growth in the elderly (Figure 1), there will be a corresponding decline in the number of working taxpayers relative to the number of older persons. This means that there is likely to be inadequate public resources and fewer adults available to provide informal care to older, less able family members and friends. Having drugs available to improve brain function (for both cognitive and noncognitive aspects) would clearly be a positive contribution. However, CNS drug discovery is associated with significant challenges (Palmer and Stephenson, 2005) and the pharmacotherapy of aging remains an embryonic science.

KEY POINTS • The number of people in the world aged over 65 years is projected to increase sharply in the next 2–3 decades. • Aging is associated with loss of brain cells, but this loss is much less pronounced than that seen in neurodegenerative disorders such as Alzheimer’s dementia and Parkinson’s disease. • Aging is associated with modest changes in cognitive function and mild changes in noncognitive changes in behavior. • Aging is a major risk factor for neurodegenerative diseases and psychiatric disorders such as depression. • Our understanding of the neuronal basis of aging is becoming more sophisticated, but the pharmacotherapy aging remains an emerging science.

KEY REFERENCES • Geinisman Y, Detoledo-Morrell L, Morrell F & Heller RE. Hippocampal markers of age-related memory dysfunction: behavioral, electrophysiological and morphological perspectives. Progress in Neurobiology 1995; 45:223 – 52. • Morrison JH & Hoff PR. Life and death of neurons in the aging brain. Science 1997; 278:412 – 19.

NEUROCHEMISTRY OF AGING • Palmer AM. Pharmacotherapy for Alzheimer’s disease: progress and prospects. Trends in Pharmacological Sciences 2002; 23:426 – 33. • Palmer AM & DeKosky ST. The neurochemistry of ageing. In MSJ Pathy (ed) Principles and Practice of Geriatric Medicine 1998, 3rd edn, pp 65 – 76; John Wiley & Sons, Chichester. • Palmer AM, Robichaud PJ & Reiter CT. The release and uptake of excitatory amino acids in rat brain: effect of aging and oxidative stress. Neurobiology of Aging 1994; 15:103 – 11.

REFERENCES Beal MF. Mitochondrial dysfunction in neurodegenerative diseases. Biochimica Biophysica Acta 1998; 10:211 – 23. Beal MF. Mitochondria, oxidative damage, and inflammation in Parkinson’s disease. Annals of the New York Academy of Sciences 2003; 991:120 – 31. Beckstrom H, Julsrud L, Haugeto O et al. Interindividual differences in the levels of the glutamate transporters GLAST and GLT, but no clear correlation with Alzheimer’s disease. Journal of Neuroscience Research 1999; 55:218 – 29. Behl C. Effects of glucocorticoids on oxidative stress-induced hippocampal cell death: implications for the pathogenesis of Alzheimer’s disease. Experimental Gerontology 1998; 33:689 – 96. Blass JP. Cerebrometabolic abnormalities in Alzheimer’s disease. Neurological Research 2003; 25:556 – 66. Butterfield DA, Drake J, Pocernich C & Castegna A. Evidence of oxidative damage in Alzheimer’s disease brain: central role for amyloid betapeptide. Trends in Molecular Medicine 2001; 7:548 – 54. Dawson DA, Wadsworth G & Palmer AM. A Comparative assessment of the efficacy and side effect liability of neuroprotective compounds in experimental stroke. Brain Research 2001; 892:344 – 50. Ferro JM & Madureira S. Age-related white matter changes and cognitive impairment. Journal of the Neurological Sciences 2002; 15:221 – 5. Floyd RA. Antioxidants, oxidative stress, and degenerative neurological disorders. Proceedings of the Society for Experimental Biology and Medicine 1999; 222:236 – 45. Floyd RA & Hensley K. Nitrone inhibition of age-associated oxidative damage. Annals of the New York Academy of Sciences 2000; 899:222 – 37. Francis PT. Glutamatergic systems in Alzheimer’s disease. International Journal of Geriatric Psychiatry 2003; 18:S15 – S21. Francis PT, Palmer AM, Snape M & Wilcock GK. The cholinergic hypothesis of Alzheimer’s disease: a review of progress. Journal of Neurology, Neurosurgery, and Psychiatry 1999; 66:137 – 47. Francis PT, Sims NR, Procter AW, Bowen DM. Cortical pyramidal neurone loss may cause glutamatergic hypoactivity and cognitive impairment in Alzheimer’s disease: investigative and therapeutic perspectives. Journal of Neurochemistry 1993; 60:1589 – 604. Geinisman Y, Detoledo-Morrell L, Morrell F & Heller RE. Hippocampal markers of age-related memory dysfunction: behavioral, electrophysiological and morphological perspectives. Progress in Neurobiology 1995; 45:223 – 52.

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Ikonomovic MD, Nocera R, Mizukami K & Armstrong DM. Age-related loss of the AMPA receptor subunits GluR2/3 in the human nucleus basalis of Meynert. Experimental Neurology 2000; 166:363 – 75. Lad SP, Neet KE & Mufson EJ. Nerve growth factor: structure, function and therapeutic implications for Alzheimer’s disease. Current Drug Targets: CNS and Neurological Disorders 2003; 2:315 – 34. Lauderback CM, Hackett JM, Huang FF et al. The glial glutamate transporter, GLT-1, is oxidatively modified by 4[hydroxy-2-nonenal in the Alzheimer’s disease brain: the role of a beta 1 – 42. Journal of Neurochemistry 2001; 78:413 – 16. Mann DM. Pyramidal nerve cell loss in Alzheimer’s disease. Neurodegeneration 1996; 5:423 – 27. Morrison JH & Hoff PR. Life and death of neurons in the aging brain. Science 1997; 278:412 – 19. Palmer AM. Neurochemical studies of Alzheimer’s disease. Neurodegeneration 1996; 5:381 – 91. Palmer AM. Preservation of N-methyl-D-aspartate receptor binding sites with age in rat neocortex. The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences 2000; 55:B530 – 32. Palmer AM. Pharmacotherapy for Alzheimer’s disease: progress and prospects. Trends in Pharmacological Sciences 2002; 23:426 – 33. Palmer AM. Cholinergic therapies for Alzheimer’s disease: progress and prospects. Current Opinion in Investigational Drugs 2003; 4:833 – 40. Palmer AM & DeKosky ST. Monoamine neurons in aging and Alzheimer’s disease. Journal of Neural Transmission 1993; 91:135 – 59. Palmer AM & DeKosky ST. The neurochemistry of ageing. In MSJ Pathy (ed) Principles and Practice of Geriatric Medicine 1998, 3rd edn, pp 65 – 76; John Wiley & Sons, Chichester. Palmer AM, Robichaud PJ & Reiter CT. The release and uptake of excitatory amino acids in rat brain: effect of aging and oxidative stress. Neurobiology of Aging 1994; 15:103 – 11. Palmer AM & Stephenson FA. CNS drug discovery: challenges and solutions. Drugs News Perspectives 2005; 18:51 – 7. Pearson RC. Cortical connections and the pathology of Alzheimer’s disease. Neurodegeneration 1996; 5:429 – 34. Procter AW. Neurochemical correlates of dementia. Neurodegeneration 1996; 5:403 – 7. Rose SP. Smart drugs’: do they work? Are they ethical? Will they be legal?. Nature Reviews. Neuroscience 2002; 3:975 – 9. Schechter LE, Dawson LA & Harder JA. The potential utility of 5HT1A receptor antagonists in the treatment of cognitive dysfunction associated with Alzheimer’s disease. Current Pharmaceutical Design 2002; 8:139 – 45. Segovia G, Porras A, Del Arco A & Mora F. Glutamatergic neurotransmission in aging: a critical perspective. Mechanisms of Ageing and Development 2001; 122:1 – 29. Tariot PN, Farlow MR, Grossberg GT et al. Memantine Study Group. Memantine treatment in patients with moderate to severe Alzheimer disease already receiving donepezil: a randomized controlled trial. JAMA 2004; 291:317 – 24. Wilkinson DG, Francis PT, Schwam E & Payne-Parrish J. Cholinesterase inhibitors used in the treatment of Alzheimer’s disease: the relationship between pharmacological effects and clinical efficacy. Drugs & Aging 2004; 21:453 – 78.

8

Neuropathology of Aging Seth Love University of Bristol, Bristol, UK

INTRODUCTION The effects of age on the nervous system, and the nature of the association between senescence and senility have long exercised us and been subjected to detailed clinical, electrophysiological, biochemical, morphologic and molecular genetic study. This chapter includes a detailed description of the gross and microscopic alterations in the nervous system that occur with increasing age. Inevitably, this involves some consideration of the histological overlap between the alterations of “normal” aging and those due to degenerative neurological diseases, particularly Alzheimer’s disease. The pathological findings in Alzheimer’s disease and other neurological diseases are, however, described in more detail elsewhere in this book.

GROSS CHANGES

early as 30 years of age and affected the supratentorial and infratentorial parts of the brain proportionately. Hartmann et al. (1994) calculated that the weight of the brain decreases from mean values of 1336 g in young adult males and 1198 g in young adult females by about 2.7 g per year in males and 2.2 g per year in females. Similar figures can be derived from data based on magnetic resonance imaging (MRI). In the MRI series of Coffey et al. (1992), the volume of the cerebral hemispheres was found to fall by an average of 0.23% per year in healthy adults; the reduction in volume was greater than average in the frontal lobes (0.55% per year), the temporal lobes (0.28% per year) and the amygdala-hippocampal complex (0.30% per year). Resnick et al. (2003) reported that the mean annual rates of tissue loss in adults aged between 59 and 85 years were 5.4, 2.4, and 3.1 ml per year for total brain, gray, and white volumes, respectively. Thus, although there is some shrinkage of gray matter, the greater part of the reduction in brain weight is due to atrophy of the white matter.

External Appearance External examination is relatively insensitive to the effects of age on the adult brain but some changes are usually evident by about the 7th decade. The sulci are slightly wider and the gyri narrower than in younger individuals and there is often some thickening and opacity of the leptomeninges over the cerebral convexities, particularly toward the vertex. The dura mater may become firmly adherent to the skull vault.

Brain Weight Several studies have documented an approximately inverse linear relationship between age and brain weight in later years. In a series of over 7000 autopsies, Peress et al. (1973) found that a decline in brain weight was evident from as

Ventricular Size Not surprisingly, as brain weight declines, ventricular size tends to increase. The effects of aging on the volume of ventricular and sulcal cerebrospinal fluid (CSF) have been the subject of several CT and MRI studies. In an MRI study of 76 healthy adults, Coffey et al. (1992) found the volume of the lateral ventricles to increase by an average of 3.2% per year and of the third ventricle by 2.8% per year. Pfefferbaum et al. (1994) reported that the ventricular volume increased between 21 and 70 years by approximately 0.3 ml per year but the volume of sulcal CSF increased more rapidly, at 0.6 ml per year. Resnick et al. (2003) found mean ventricular volume to increase by 1.4 cm3 per year over a 4-year period in his cohort of normal 59–85 year olds.


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MICROSCOPIC CHANGES IN THE GRAY MATTER Neuronal Loss and Neuronal Shrinkage in Cerebral Cortex and Hippocampus There is marked regional variation in the pattern of neuronal loss in the central nervous system. Several studies have been made of the distribution and extent of neuronal loss in the neocortex. The earliest of these were based on relatively time-consuming manual counting methods and, of necessity therefore, included fewer cases and smaller samples of cortex than later studies in which counts were obtained by means of automated image-analyzers. Variations in the methodology and results of these studies were discussed in detail by Terry et al. (1987). Early studies (see Love, 1998) indicated a variable but substantial depletion of neurons from the cerebral cortex during adult life in many regions, amounting to 40–50%. In contrast, both Haug et al. (1984) and Terry et al. (1987) found no correlation between age and neuronal density in several regions of cerebral cortex, the “loss” of large neurons being largely attributable to shrinkage and associated, therefore, with an “increase” in the number of smaller neurons. Terry et al. (1987) suggested that the fully automated acquisition and analysis of some earlier morphometric data, with no manual editing of the digitized images, may have been inaccurate. It is worth noting that most of these investigators have found a two- to threefold variation between the numbers of neurons in any given region of cortex even in neurologically normal individuals of similar age, so that the relatively small early series should be interpreted with circumspection. Using stereological methods that avoid artifacts due to gray matter atrophy, processing, or sectioning, Pakkenberg et al. (2003) calculated that the number of neocortical neurons in women was 19.3 billion and in men, 22.8 billion, a difference of 16%. The number of neurons declined by less than 10% between 20 and 90 years. In summary, the evidence is of some, but only mild, loss of neurons from the neocortex of neurologically normal individuals during adult life, and shrinkage of many of the larger neurons that remain. The gender-related difference in the number of neocortical neurons probably exceeds the loss of neurons that is attributable to aging. Several recent studies have shown that neuronal populations in the entorhinal cortex of cognitively normal subjects remain stable well into old age (Trillo and Gonzalo, 1992; Lippa et al., 1992; Gómez-Isla et al., 1996). This contrasts with findings in Alzheimer’s disease, in which severe loss of neurons from laminae II and IV is an early manifestation (Lippa et al., 1992; Gómez-Isla et al., 1996). Studies differ as to the extent and distribution of neuronal loss from the aging hippocampus. Miller et al. (1984) recorded a loss of neurons from the CA1 field, of approximately 3.6% per decade. Devaney and Johnson (1984) made a rather confusing study of neuronal density in the hippocampus. They counted dispersed cells in a hemocytometer and related their numbers to the weight of the whole of the hippocampus. The density of neurons as determined in this way

increased slightly between 20 and 87 years but this is probably attributable to senescent shrinkage of the molecular layer of the dentate fascia and hippocampal white matter. Probably the most accurate quantification of neurons in different parts of the hippocampus has been that of West and colleagues (West, 1993; West et al., 1994) employing modern stereological methods. They found an age-related decline in the numbers of neurons in the subiculum and hilus of the dentate gyrus, at about 0.7% per annum and 0.4% per annum respectively, but no significant change in the number of neurons in the CA1 field (which shows most marked loss of neurons in Alzheimer’s disease). Although the number of CA1 neurons is probably well preserved during normal aging, Dickson et al. (1994) found hippocampal sclerosis, characterized by marked focal loss of neurons and gliosis predominantly involving the CA1 field, to be a surprisingly common finding in demented patients over 80 years of age, usually in the absence of other neurodegenerative diseases to account for the dementia.

Cholinergic and Peptidergic Input to Cerebral Cortex and Changes in the Nucleus Basalis of Meynert Most investigators have found that there is only mild or no reduction in the number of neurons in the nucleus basalis of Meynert complex, which provides the cholinergic input to the cerebral cortex (Chui et al., 1984; Mann et al., 1984; Bigl et al., 1987; Lowes-Hummel et al., 1989). However, substantial age-related reductions, of 50% or more, were reported by McGeer et al. (1984) and de Lacalle et al. (1991). These last authors found the neuronal loss to be greatest in the posterior subdivision (64.5% by 90 years), where there was also 10% shrinkage of the remaining neurons. The loss from the intermediate subdivision was 42% and no significant change in the number of neurons occurred in the anterior subdivision, where the cell size actually increased by an average of 15%. According to Baloyannis et al. (1994), it is principally the small spiny GABA-ergic neurons in the nucleus basalis that decrease in number in normal aging, the large cholinergic neurons being spared. In keeping with this observation, the density of cholinergic fibers in the neocortex, entorhinal cortex, and amygdaloid complex declines only slightly in normal aging, compared with the dramatic loss in Alzheimer’s disease (Geula and Mesulam, 1989; Benzing et al., 1993; Emre et al., 1993). The density of somatostatin-, neurotensin- and substance Pcontaining nerve fibers in the cerebral cortex, amygdaloid complex, and subcortical white matter seems to be preserved well into old age (Benzing et al., 1993; Emre et al., 1993; Ang and Shul, 1995).

Other Subcortical Nuclei The numbers of neurons in many of the subcortical nuclei that have been studied are relatively stable throughout adulthood. The density of neurons in the striatum remains constant

NEUROPATHOLOGY OF AGING

(Pesce and Reale, 1987), although there is some shrinkage of the large, strongly calbindin-positive neurons (Selden et al., 1994). No significant loss of neurons occurs from the supraoptic or paraventricular nuclei of the hypothalamus (Goudsmit et al., 1990; Wierda et al., 1991). There is loss of neurons from the suprachiasmatic nucleus, although less so than in Alzheimer’s disease (Swaab et al., 1993). Swaab et al. (1993) documented hypertrophy of neurons containing estrogen receptors in the infundibular/arcuate nucleus of the hypothalamus in postmenopausal women and speculated that this may be related to the development of hot flushes. Similar observations were made by Abel and Rance (2000). With increasing age, there is a mild loss of pigmented neurons from the substantia nigra and locus ceruleus (Perry et al., 1990; Fearnley and Lees, 1991). This loss is not related to coexistent Alzheimer-type or Lewy body pathology (Perry et al., 1990; Love et al., 1996) and has not been demonstrated in all series (Kubis et al., 2000). In the substantia nigra, the fallout of neurons with age is largely confined to the medial ventral and dorsal tiers of the pars compacta, whereas Parkinson’s disease affects the lateral ventral tier most severely (Fearnley and Lees, 1991). The number of neurons remains constant with age in the roof nuclei of the cerebellum (Heidary and Tomasch, 1969), the ventral cochlear nucleus (Konigsmark and Murphy, 1970), the nucleus of the facial nerve (van Busirk, 1945) and the inferior olivary complex (Moatamed, 1966). With aging, there is a significant decrease in the number of neurons in the vestibular nuclear complex (Tang et al., 2001). Alvarez et al. (2000) found that aging does not affect the size of the complex, and that the neuronal loss affects the descending, medial and lateral vestibular nuclei but not the superior nucleus. Tomlinson et al. (1981) counted neurons in the locus ceruleus in brains from 25 neurologically normal adults and noted that the counts gradually declined after middle age. The number of cholinergic neurons in the pedunculopontine nucleus was reported to decrease with age between the third and tenth decades (Ransmayr et al., 2000); however, four centenarians had neuronal cell counts comparable to those in much younger adults, leading the authors to speculate that centenarians may start out with greater numbers of neurons in the pedunculopontine nucleus or may experience slower loss of neurons with aging.

Dendritic Changes There is accumulating evidence that the dendrites in several regions of the adult brain are capable of considerable growth and plasticity, resulting in expansion of the dendritic tree. This may be a compensatory response to loss of adjacent neurons. This phenomenon is best documented for dendrites in the molecular layer of the hippocampal dentate gyrus (Flood et al., 1987; de Ruiter and Uylings, 1987) and in lamina II of the parahippocampal cortex (Buell and Coleman, 1979; Flood and Coleman, 1990). In contrast, the extent of the dendritic trees decreases in both of these regions in patients with Alzheimer’s disease. Whereas the expansion

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of the dendritic tree in the parahippocampal cortex seems to continue well into old age, that in the molecular layer of the dentate gyrus peaks in middle age and subsequently regresses (Flood et al., 1987). The dendritic trees of neurons in the subiculum (Flood, 1991) and the pyramidal cell layer of the hippocampus remain relatively constant during normal aging (Flood and Coleman, 1990; Hanks and Flood, 1991) but regress in Alzheimer’s disease. Outside of the hippocampus and parahippocampal gyrus, only relatively minor dendritic alterations have been observed in the cerebral cortex. Jacobs and Scheibel (1993) found that the number of dendritic segments in pyramidal cells in the superior temporal gyrus remained relatively stable with age although the length of the dendrites tended to decrease. A decrease in the number of basal dendrites with advancing age was noted by Nakamura et al. (1985) in pyramidal neurons in the motor cortex (Brodmann area 4). Limited information is available concerning changes to dendrites in the subcortical nuclei. Arendt et al. (1994) found that the dendritic field of neurons in the nucleus basalis increased in size during normal aging. In contrast, the growth of dendrites that occurred in Alzheimer’s disease tended to increase their density without enlarging the dendritic field. Significant loss of dendrites was observed in neurons in the substantia nigra of elderly subjects (Cruz-Sanchez et al., 1995)

Synaptic Density With increasing age, there is a mild decline in the density of synapses in the hippocampus and in parts of the cerebral neocortex, whether assessed by electron microscopy (Adams, 1987; Bertoni-Freddari et al., 1990) or synaptophysin immunohistochemistry (Masliah et al., 1993; Eastwood et al., 1994). A possible exception is the postcentral (primary somatosensory) cortex, in which Adams (1987) found the density of synapses to remain constant. Masliah et al. (1993) calculated that the density of synaptic terminals in the frontal cortex of subjects over 60 years was approximately 20% below that of younger subjects. The loss synapses in the hippocampus and at least some regions of the neocortex is probably accompanied by an increase in the mean area of contact at each synapse (Adams, 1987; Bertoni-Freddari et al., 1990). Love et al. (2005) found that the concentration of synaptic proteins in the superior temporal cortex was related to the apolipoprotein E (APOE ) genotype. In superior temporal cortex from normal brain, the concentration of the postsynaptic protein PSD95 (postsynaptic density-95) was significantly higher in cortex from people with than without an APOE ε2 allele. In contrast, possession of the APOE ε4 allele was associated with lower concentrations of two presynaptic proteins, synaptophysin and syntaxin. A positron emission tomographic investigation showed that people who possess an ε4 allele have lower rates of cerebral glucose metabolism in the posterior cingulate, parietal, temporal, and prefrontal cortex (Reiman et al., 2004), and in another study,

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morphometry revealed that neurons in nucleus basalis of Meynert from people with ε4 have smaller Golgi apparatus (Dubelaar et al., 2004), another measure of metabolic activity. These APOE-related premorbid differences in synapses and metabolic activity may influence the capacity of the brain to respond to injury and may thereby account for the association between APOE and clinical outcome in a range of neurological diseases, such as head injury (Chiang et al., 2003; Teasdale et al., 1997), hemorrhagic stroke (McCarron et al., 2003), and multiple sclerosis (Chapman et al., 2001; Fazekas et al., 2001).

Dystrophic Axons and Ubiquitinated Deposits During normal aging, axons in certain parts of the central nervous system tend to undergo dystrophic changes: they develop focal argyrophilic swellings within which lysosomes, mitochondria, membranous bodies, and neurofilaments accumulate. Sites of predilection include the gracile and cuneate nuclei, the substantia nigra, the globus pallidus, and the anterior horns of the spinal cord. These dystrophic axons react strongly with antibodies to ubiquitin, which also label smaller, dotlike structures in the white matter and cerebral cortex. Ubiquitin is an 8-kDa polypeptide involved in the degradation of many abnormal or short-lived proteins. The density of the dotlike structures increases with age and they are particularly prominent after about 60 years (Dickson et al., 1990). These small ubiquitinated bodies correspond to dystrophic neurites (Dickson et al., 1990; Dickson et al., 1992; Migheli et al., 1992; Yasuhara et al., 1994) and foci of granular degeneration of myelin sheaths in the white matter (Dickson et al., 1990, 1992; Migheli et al., 1992).

Lipofuscin Lipofuscin, a pigment produced by oxidation of lipids and lipoproteins, accumulates with age in the form of irregularly shaped, brown cytoplasmic granules that are acid-fast, sudanophilic, and autofluorescent under ultraviolet light. Electron microscopy shows the granules to contain both highly electron-dense, and homogeneous, moderately electron-lucent material, aggregated together within a unit membrane. Lipofuscin accumulates to a varying extent in most neurons and glia (Wisniewski and Wen, 1988). Neurons of the inferior olivary nuclei tend to amass large amounts of lipofuscin from early adulthood. With increasing age, relatively large amounts of lipofuscin also accumulate in the dentate nucleus of the cerebellum, pyramidal neurons in the cerebral cortex and hippocampus, large neurons in the amygdala, thalamus and hypothalamus, and motor neurons in brain stem and spinal cord.

Hirano Bodies Hirano bodies are brightly eosinophilic rod-shaped or oval cytoplasmic inclusions (Figure 1). They contain actin, actinassociated proteins, tau, low and middle molecular weight

Figure 1 Hirano bodies (arrows) in the pyramidal cell layer of the hippocampus

neurofilament subunits, and C-terminal β-amyloid precursor protein epitopes, and consist of a regular lattice of multiple layers of parallel 10–12-nm filaments, a 12-nm gap separating adjacent layers (Hirano, 1994). Filaments in one layer are transversely or diagonally orientated with respect to those in the adjacent layers. Hirano bodies are most numerous in the CA1 field of the hippocampus, particularly in the stratum lacunosum, but can occur elsewhere in the central nervous system (and are occasionally seen in Schwann cells in the peripheral nervous system). In the stratum lacunosum, their density increases until middle age and declines gradually thereafter. There is an increased density of Hirano bodies in the stratum lacunosum in chronic alcoholics (Laas and Hagel, 1994). In normal elderly subjects, Hirano bodies also occur in the stratum pyramidale, where their number continues to increase well into old age, but they are particularly numerous in this region in patients with Alzheimer’s disease.

Granulovacuolar Degeneration The term “granulovacuolar degeneration” describes the accumulation of small, round, dense bodies, more or less in the center of clear vacuoles, in the neuronal cytoplasm (Figure 2). The dense bodies are ubiquitinated (Love et al., 1988; Dickson et al., 1993) and react with antibodies to some, but not all, epitopes of the microtubule-associated protein, tau (Dickson et al., 1993). These data have been interpreted as suggesting that the dense bodies are a product of partial degradation of tau, which is the main constituent of neurofibrillary tangles. In the absence of Alzheimer’s disease, granulovacuolar degeneration rarely occurs to any noticeable extent before the 7th decade but becomes increasingly prominent thereafter (Peress et al., 1973; Xu et al., 1992). Neurons in the CA1 field are most severely affected and, in descending order of severity, those in the prosubiculum, CA2, CA3, and CA4 fields less so (Xu et al., 1992). In normal aging, granulovacuolar degeneration is virtually confined


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(a) Figure 2 Granulovacuolar generation of several neurons (arrows) in the CA1 field of the hippocampus

to the hippocampal formation. Granulovacuolar degeneration is more severe in patients with Alzheimer’s disease and may involve other neurons in a wide range of subcortical nuclei in addition to those in the hippocampus (Xu et al., 1992).

Plaques The nature and composition of plaques are considered in detail in Chapter 92, Cellular Changes in Alzheimer’s Disease. The plaques that develop during normal aging, after 55–60 years, are predominantly diffuse (nonneuritic) (Mann et al., 1990; Crystal et al., 1993). They consist largely of nonfibrillar extracellular Aβ peptide, predominantly Aβ1 – 42 . They are readily visualized by silver impregnation or immunohistochemistry for Aβ (Figure 3). Despite the absence or marked paucity of amyloid fibrils in these plaques, they are usually faintly autofluorescent under ultraviolet light in thioflavin-S preparations (although much less so than neuritic plaques). The diffuse plaques of aging resemble those of Alzheimer’s disease in both their chemical composition (see, for example, Fukumoto et al., 1996) and widespread neocortical distribution. They are usually much less abundant than in Alzheimer’s disease, but there is overlap in the density of diffuse plaques in patients and cognitively normal elderly people. In the latter group, the plaques rarely involve the striatum or cerebellum, which are often affected in Alzheimer’s disease, but plaques can occur in the lateral inferior pulvinar and superior colliculus (Leuba et al., 2001). Although diffuse plaques are a common finding in older age, their accumulation does not seem to be consistent or progressive (Crystal et al., 1993; Mackenzie, 1994). Delaere et al. (1993) reported that Aβ deposits were a constant finding in the brains of the “oldest old”, based on a study of 20 centenarians. However, even in very old subjects, diffuse plaques may be very scanty or even absent (e.g, Giannakopoulos et al., 1993; Morris et al., 1996).

(b) Figure 3 (a) Diffuse plaques in the superficial cortex (modified Bielschowsky silver impregnation). (b) Immunohistochemistry for Aβ reveals several diffuse plaques (toward right of figure) as well as some densely labeled neuritic plaques (arrows) and a blood vessel with changes of amyloid angiopathy (asterisk)

Neuritic plaques can also occur in cognitively normal elderly subjects, predominantly in the CA1 field, subiculum and entorhinal cortex, and also, in small numbers, in the neocortex. Neuritic plaques are usually much more numerous in the context of Alzheimer’s disease (see Chapter 92, Cellular Changes in Alzheimer’s Disease), but the distinction is not clear cut and reports differ as to the extent of overlap (Davis et al., 1999; Leuba et al., 2001; Neuropathology Group. MRC CFAS, 2001). Neuritic plaques contain extracellular Aβ in the form of amyloid fibrils, and irregularly swollen dystrophic neurites, which are strongly argyrophilic (Figure 4). Microglia and astrocyte processes may also be present. Within the dystrophic neurites are accumulations of lysosomes, degenerating mitochondria and membranous bodies. Some dystrophic neurites also contain paired helical filaments, composed of modified tau proteins (see Neurofibrillary tangles in following text). Neuritic

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(a)

(b) Figure 4 (a) Neuritic plaques and neurofibrillary tangles (arrows) in the temporal cortex (modified Bielschowsky silver impregnation). Note the swollen, darkly impregnated dystrophic neurites within the plaques (modified Bielschowsky silver impregnation). (b) Neurofibrillary tangles are strongly immunopositive for tau. In this section of hippocampus from a patient with Alzheimer’s disease, the antibody also labels many neuropil threads, nerve cell processes that contain abnormal filaments similar to those in the tangles

plaques in Alzheimer’s disease probably include at least two, usually distinct, types of dystrophic neurite: those containing tau proteins and those that contain the synaptic protein, chromogranin A (Yasuhara et al., 1994; Wang and Munoz, 1995). It has been reported that the tau-positive dystrophic neurites tend to be more elongated, less globular in shape, than those containing chromogranin A, but that the latter predominate in the neuritic plaques that may occur in cognitively normal subjects (Yasuhara et al., 1994).

Neurofibrillary Tangles Neurofibrillary tangles consist of hyperphosphorylated tau proteins that are variably ubiquitinated and glycated (Brion

et al., 1985; Mori et al., 1987; Love et al., 1988; Yan et al., 1995; Yen et al., 1995). These form filaments measuring up to 10 nm in diameter, paired in right-handed helices with a period of approximately 80 nm and a maximum width of approximately 20 nm (Terry, 1963; Kidd, 1964; Ruben et al., 1993). The filaments are aggregated together in the cytoplasm in looped or twisted skeins that are faintly basophilic, appear autofluorescent when stained with thioflavin-S and viewed under ultraviolet light, and can be impregnated with silver or immunostained for tau to facilitate their light microscopic detection (Figure 4). Although the frequency of neurofibrillary tangles tends to increase with age after 55–60 years (Tomlinson et al., 1968; Peress et al., 1973; Price et al., 1991; Arriagada et al., 1992; Hof et al., 1995; Davis et al., 1999), they are not a consistent feature of normal aging and are much more numerous and widely distributed in Alzheimer’s disease and certain other neurological disorders (e.g. Wisniewski et al., 1979; Love et al., 1995; Spillantini et al., 1999). When present in cognitively normal elderly individuals, tangles may be confined to the transentorhinal cortex or may also involve the subiculum and CA1 field of the hippocampus, lamina II and, to a lesser extent IV, of the entorhinal cortex (in the anterior part of the parahippocampal gyrus) and the anterior olfactory nucleus (Price et al., 1991; Braak and Braak, 1991; Arriagada et al., 1992; Hof et al., 1995; Braak and Braak, 1996). In the absence of dementia, the neocortex and subcortical nuclei contain few, if any, neurofibrillary tangles (although in one study, some degree of neocortical neurofibrillary pathology was found in as many as one-third of nondemented elderly individuals (Neuropathology Group, MRC CFAS, 2001)). The involvement of different populations of neurons by neurofibrillary tangles seems to follow a consistent, predictable topographic sequence during “normal” aging that is indistinguishable from the earliest, presymptomatic stages of Alzheimer’s disease (Braak and Braak, 1991; Arriagada et al., 1992; Braak and Braak, 1996). It is arguable that the asymptomatic accumulation of neurofibrillary tangles in the transentorhinal cortex and limbic region should be regarded as a preclinical manifestation of Alzheimer’s disease (for further discussion, see Braak and Braak (1996)).

Lewy Bodies The structure and patterns of distribution of these neuronal inclusions are described in the context of Parkinson’s disease and other Lewy body diseases in Chapter 66, Parkinson’s Disease and Parkinsonism in the Elderly and Chapter 96, Other Dementias. Lewy bodies are an incidental finding in the substantia nigra and locus ceruleus in a small proportion of neurologically normal adults. These Lewy bodies are of the classical (brain stem) type: usually roughly spherical, with an eosinophilic core surrounded by a paler “halo” (Figure 5). One or more Lewy bodies may be present in the cytoplasm of a single neuron. Electron microscopy shows the core to consist of amorphous, electron-dense material and the halo to comprise


(a)

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Lewy bodies occur in Parkinson’s disease, dementia with Lewy bodies, and other Lewy body diseases (see Chapter 96, Other Dementias (Lewy Body etc.)). The prevalence of brain stem Lewy bodies is much lower in adults who do not have neurological disease. Perry et al. (1990) observed Lewy bodies in 2.3% of 131 subjects between 51 and 100 years who had been screened to exclude neurological or psychiatric disorders. In a series of 273 brains from non-Parkinsonian patients, Gibb and Lees (1988) found the prevalence to increase from 3.8 to 12.8% between the sixth and ninth decades. A lower age-specific prevalence was reported by Wakabayashi et al. (1993): an increase from 0.7% to 6.5% over the same age span. It has been suggested that incidental Lewy bodies are a manifestation of preclinical Parkinson’s disease (Gibb and Lees, 1988; Wakabayashi et al., 1993).

CENTRAL WHITE MATTER

(b) Figure 5 (a) Incidental Lewy body (arrow) in the substantia nigra of an 84-year-old man who did not have clinical features of Parkinson’s disease. (b) The principal constituent of the Lewy body is α-synuclein, here demonstrated immunohistochemically in Lewy bodies in the cerebral cortex

radiating filaments between which are scattered granules of lipofuscin and neuromelanin, mitochondria, dense-core vesicles, and other organelles (Forno, 1996). The principal constituent of the Lewy body is α-synuclein (Spillantini et al., 1997; Wakabayashi et al., 1997), a protein that is normally associated with presynaptic vesicles (Iwai et al., 1995). Its functions are still unclear, but may include protection against oxidative stress, maintenance of the presynaptic vesicular pool, and a role in synaptic plasticity (Hashimoto et al., 2002; Kaplan et al., 2003; Murphy et al., 2000). Other constituents of the Lewy body include phosphorylated neurofilament subunits (Hill et al., 1991), ubiquitin (Love et al., 1988), epitopes of complement proteins (Yamada et al., 1992), multicatalytic proteinase (Masaki et al., 1994), cyclin-dependent kinase 5 (Brion and Couck, 1995), and several other proteins (for review, see Pollanen et al., 1993).

As noted earlier (see Brain weight), with increasing age, the white matter declines in volume to a greater extent than does the gray matter, although the two processes are obviously related since the degeneration of a nerve cell is accompanied by the loss of its myelinated axon, and the latter usually occupies a greater volume than the cell body and dendrites. In a morphometric comparison of three groups of neurologically normal adults, ≤50 years, 51–70 years, and 71–93 years, Meier-Ruge et al. (1992) found a 16–20% loss of white matter volume in the elderly compared with the young adults and a 10–15% loss of myelinated fibers. In a stereological study of changes in cranial white matter between 18 and 93 years, males were found to have a total myelinated fiber length of 176 000 km at 20 years and 97 200 km at the age of 80 (Marner et al., 2003). In females, the lengths were 149 000 km at 20 and 82 000 km at 80 years. These figures correspond to a decrease of 10% per decade, and a sex difference of 16%. The loss predominantly affects small caliber fibers. Other agerelated changes in the white matter include a tendency for axons in some regions to form dystrophic swellings, and an accumulation of ubiquitinated dotlike structures (see Dystrophic axons and ubiquitinated deposits, explained previously). In many neurologically normal, elderly subjects, scattered hyperintensities and more diffuse high signal regions are demonstrable in the cerebral white matter on T2-weighted MRI, particularly in the periventricular region. The histological correlates of these “lesions” are somewhat inconsistent. Some are probably infarcts; others are foci of rarefaction or gliosis, often perivascular. Correlations have been described with denudation of the ependymal lining of the lateral ventricles (Scheltens et al., 1995) and perivenous collagenous thickening (Moody et al., 1995). The substrate of some MRI hyperintensities may remain obscure despite careful histological examination (Grafton et al., 1991).

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SPINAL CORD AND NERVE ROOTS

CORPORA AMYLACEA

The degenerative changes of the spinal column, such as cervical spondylosis and intervertebral disk disease which become increasingly frequent and pronounced with age, are often associated with degenerative changes in the spinal cord. These include anteroposterior flattening of the lower cervical cord and various degrees of loss of neurons from the anterior horn (Wang et al., 1999). Degeneration of posterior column fibers, particularly in the cervical region, is common in the elderly (Ohnishi et al., 1976), and often accompanied by large numbers of copora amylacea (see following text). A morphometric study by Low et al. (1977) of the intermediolateral column of the spinal cord in adults, revealed a progressive loss of preganglionic sympathetic neurons with age, amounting to about 8% per decade. A similar rate of attrition of myelinated fibers was noted in the T6–8 rami communicantes, containing the preganglionic sympathetic nerve fibers (Low and Dyck, 1978). The authors suggested that this loss may account for the tendency to postural hypotension in the elderly. It should be noted, however, that there are also alterations in the paravertebral and prevertebral sympathetic ganglia of elderly subjects (see Sympathetic ganglia, in the following text). The population of motor neurons in the lumbosacral spinal cord declines slightly with age. Tomlinson and Irving (1977) found that the decline occurred only after 60 years of age but Kawamura et al. (1977a) recorded a gradual loss of motor neurons in the L3–5 segments from early adulthood onwards. Not surprisingly, the latter authors also found that there was a corresponding age-related loss of myelinated fibers from the L3–5 anterior spinal nerve roots (Kawamura et al., 1977b).

Corpora amylacea are spherical inclusions, predominantly located in astrocyte processes, although they can also occur within axons. They are composed largely of sulphated polysaccharides (polyglucosans) and stain deeply with hematoxylin, periodic acid-Schiff and methyl violet. Minor constituents include ubiquitin, heat-shock proteins (Martin et al., 1991; Cisse et al., 1993), tau (Loeffler et al., 1993; Singhrao et al., 1993), certain complement proteins (Singhrao et al., 1995), and oligodendrocyte proteins – myelin basic protein, proteolipid protein, galactocerebroside, and myelin oligodendrocyte protein (Singhrao et al., 1994). On electron microscopy, corpora amylacea appear as densely packed 6–7-nm filaments that are not bounded by a unit membrane (Ramsay, 1965). Toward the center of the inclusions, the filaments may be admixed with amorphous granular material. Corpora amylacea increase in number with normal aging, particularly in the subpial and subependymal regions of the brain (Figure 6), around blood vessels, and in the white matter of the spinal cord (Martin et al., 1991), although not to the extent that they do in Alzheimer’s disease and other neurodegenerative disorders. The subpial region of the inferomedial part of the temporal lobe is a site of predilection for accumulation of these bodies. Several hypotheses have been proposed to account for their formation and distribution. It was suggested by Tokutake et al. (1995) that they are involved in astrocytic absorption and accumulation of inorganic materials from the blood and cerebrospinal fluid, by Cisse and Schipper (1995) that they are a product of degeneration and autophagy of mitochondria, and by Singhrao et al. (1995) that they may shield immunogenic products of neuronal and oligodendroglial degeneration from lymphocytic recognition and autoimmune activation.

GLIOSIS The number of astrocytes and the extent of associated gliosis have generally been thought to increase with age in most parts of the central nervous system. Beach et al. (1989) assessed the severity of gliosis at different ages by immunostaining sections for glial fibrillary acidic protein (GFAP). They found that gliosis increased with age in the cerebral cortex, white matter, and subcortical nuclei, but that its severity and distribution were very variable. Whereas the white matter of young adults showed an even pattern of GFAP immunoreactivity, that in the elderly tended to be uneven. Gliosis was accentuated around blood vessels. Terry et al. (1987) reported that the increase in the number of glia in the elderly was more pronounced in the frontal and temporal cortices than in the parietal cortex. In contrast to these older studies, more recent stereological analysis of neocortical cells by Pakkenberg et al. (2003) revealed no significant difference when the number of neocortical glia in six elderly individuals, of mean age 89.2 years, was compared with that in six young adults with a mean age of 26.2 years.

BLOOD VESSELS AND AMYLOID ANGIOPATHY The development of atherosclerotic and hypertensive changes and their relationship to brain hemorrhages and infarcts

Figure 6 Numerous periventricular corpora amylacea in an 87 year old


(a)

(b)

Figure 7 (a) Degenerative change affecting arteries and arterioles in the cerebral white matter. The tunical media and adventitia have been replaced by a thick layer of hyaline collagenous connective tissue. There is also some fibrous thickening of the intima. (b) Severe CAA, in which Aβ-immunopositive amyloid has replaced the tunica media and adventitia of several blood vessels in the cerebral cortex, and in some cases has also infiltrated the adjacent brain parenchyma. Note the narrowed lumen of some of the affected blood vessels (arrows)

are considered in Chapter 71, Acute Stroke and Chapter 72, Secondary Stroke. In the elderly, mild loss of smooth muscle cells, medial fibrosis, and hyaline change are very common in parenchymal blood vessels in the brain and spinal cord, particularly in the basal ganglia and cerebral white matter (Hauw et al., 2002) (Figure 7a). Mineralization of vessel walls is also common, especially in the globus pallidus and deep cerebellar white matter. The smooth muscle degeneration and fibrosis are exacerbated in patients with hypertension (Masawa et al., 1994). A mild degree of cerebral atheroma is also common, even in the absence of hypertension and other specific risk factors such as cigarette smoking and diabetes mellitus (see Chapter 122, Type 2 Diabetes Mellitus in Senior Citizens;

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Chapter 48, Hypertension). These changes decrease the compliance of cerebral blood vessels and probably contribute to an increased tendency to tortuosity or “corkscrewing” (Fang, 1976) and an enlargement of the perivascular spaces. Many elderly people have patchy, segmental deposition of amyloid in the media and adventitia of blood vessels in the cerebral cortex and leptomeninges (Figures 3b and 7b). This abnormality is termed cerebral amyloid angiopathy (CAA), although it is not always confined to the cerebrum and may also involve the cerebellar cortex and leptomeninges, and rarely other parts of the central nervous system (CNS). CAA is present in about 30% of the normal elderly (Tomonaga, 1981; Esiri and Wilcock, 1986; Vinters and Gilbert, 1983; Love et al., 2003), and over 90% of patients with Alzheimer’s disease (Esiri and Wilcock, 1986; Ellis et al., 1996; Premkumar et al., 1996; Chalmers et al., 2003), in whom the CAA tends to also be more severe – involving a greater proportion of blood vessels, over a greater part of their circumference, and sometimes extending into the adjacent brain parenchyma (so-called dyshoric change). In contrast to the predominance of Aβ1 – 42 in plaques, Aβ1 – 40 predominates in CAA although Aβ1 – 42 is also present. Sporadic Aβ-related CAA is very rare before 60 years, but thereafter increases in prevalence with age (Love et al., 2003). The pathogenesis of CAA remains unclear. Some observations suggest that Aβ is deposited from interstitial fluid as it passes along perivascular drainage pathways toward the subarachnoid space (Weller et al., 2000; Weller and Nicoll, 2003); degenerative vascular changes that impede the flow of fluid along these pathways may partly account for the increased prevalence of CAA with age. However, it is likely that multiple factors contribute to development of CAA (Love, 2004). The deposition of amyloid progressively replaces, first the tunica media, and then the adventitia, with resulting loss of vascular compliance and contractility. In severe cases, the amyloid extends into the adjacent brain parenchyma (Figure 7b). CAA tends to narrow the lumen, because of thickening of the vessel wall, exacerbated in some cases by concentric separation of the amyloid-laden media and adventitia. Severe CAA may compromise the viability of affected blood vessels (Prior et al., 1996). Not surprisingly, therefore, CAA carries a risk of focal hemorrhage or infarction (Okazaki et al., 1979; Itoh et al., 1993; Cadavid et al., 2000). As would be expected from the distribution of the vascular amyloid, associated hemorrhages tend to be superficially situated within the brain parenchyma and to rupture into the subarachnoid space, or to occur primarily within the subarachnoid space (Okazaki et al., 1979; Yamada et al., 1993). CAA may also cause ischemic damage to the white matter, probably through a combination of luminal stenosis, thrombosis, loss of autoregulation, and vasospasm. APOE genotype is linked to several aspects of CAA pathology. In Alzheimer’s disease, the presence and severity of CAA are strongly associated with possession of APOE ε4 (Premkumar et al., 1996; Chalmers et al., 2003). In the absence of Alzheimer’s disease, this association is weak or absent (Love et al., 2003). In patients with CAA, possession

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of APOE ε2 is a risk factor for cerebral hemorrhage (Greenberg et al., 1998; Nicoll et al., 1997), probably because this allele is associated with the development of additional vasculopathic changes such as fibrinoid necrosis (Greenberg et al., 1998; McCarron et al., 1999). APOE ε4 has been reported to be associated with cerebral hemorrhage in patients with CAA in some populations (Greenberg et al., 1995) but not others (Itoh et al., 1996; Nicoll et al., 1997). However, interpretation of this latter association is complicated by the fact that possession of ε4 is also associated with increased mortality after cerebral hemorrhage (McCarron et al., 2003); series that are based largely on postmortem diagnosis of CAAassociated hemorrhage are therefore likely to be skewed toward the inclusion of ε4-positive cases. Figure 9 Darkly stained psammoma bodies in the choroid plexus

CHOROID PLEXUS Intracellular accumulations of amyloid fibrils are a constant finding in choroid plexus epithelium in the elderly (Eriksson and Westermark, 1986). They are usually abundant in Alzheimer’s disease (Miklossy et al., 1998; Wen et al., 1999). The fibrils form circular cytoplasmic inclusions (Figure 8) known as Biondi rings (Biondi, 1934; Eriksson and Westermark, 1990). Ependymal cells may also accumulate amyloid fibrils, but these take the form of slender wisps rather than rings. Ultrastructurally, Biondi rings consist of densely packed straight and paired helical filaments (Eriksson and Westermark, 1986; Miklossy et al., 1998; Wen et al., 1999). They are immunopositive for Aβ. Miklossy et al. (1998) found them also to react with antibodies to P component, ubiquitin, fibronectin and tau but not neurofilament proteins. With age, the choroid plexus tends to undergo multifocal mineralization, in the form of roughly spherical, concentrically laminated deposits known as psammoma bodies (Figure 9). These usually form in the fibrovascular cores of

the papillae. Kwak et al. (1988) found that the age-specific prevalence of choroid plexus mineralization in CT brain scans increased from 0 below 10 years, through 5.9% between 10 and 14 years, 17.4% between 15 and 19 years, 51.5% between 30 and 39 years, to 74.4% in patients over 80 years in age.

PINEAL During adolescence and early adulthood, the pineal may undergo cystic expansion. On review of MRI scans of 6023 subjects, Sawamura et al. (1995) found that pineal cysts were more common in women, in whom the prevalence was greatest (5.8%) between the ages of 21 and 30 years. The finding of cysts is less common in subsequent decades, reported figures for their overall prevalence ranging from 1.3% (Sawamura et al., 1995) to 2.4% (Golzarian et al., 1993). The cysts are usually incidental findings on radiological investigation or at autopsy. Rarely, they may compress the aqueduct and cause hydrocephalus, or produce Parinaud’s syndrome due to compression of the tectum of the midbrain (Fetell et al., 1991). Foci of mineralization (corresponding histologically to psammoma bodies) are radiologically detectable in a small percentage of children as early as the first 6 years of life (Winkler and Helmke, 1987). There is a steep rise in the incidence of pineal mineralization during the second decade of life after which the deposits may undergo remodeling (Schmid and Raykhtsaum, 1995), but there is no further significant change in their size or age-specific prevalence (Hasegawa et al., 1987; Galliani et al., 1989).

PITUITARY

Figure 8 Several birefringent Biondi rings (arrows) in the choroid plexus of an 84 year old

The effects of aging on hypothalamo-pituitary function are discussed in Chapter 119, The Pituitary Gland. A mild degree of fibrosis, due to interstitial deposition of collagen, is common in the anterior lobe of the pituitary in the elderly,


particularly in men (Sano et al., 1993). From early adulthood onwards, there is also a significant decline in the number and size of growth hormone-producing somatotroph cells in the lateral wings of the gland (Sun et al., 1984; Sano et al., 1993). Sano et al. (1993) did not find significant alterations in the relative numbers of other cell types in pituitaries of patients over 90 years of age. Zegarelli-Schmidt et al. (1985) observed thyrotroph hypertrophy and hyperplasia in some aged pituitaries but these changes bore no consistent relationship to the histological appearances of the thyroid gland in the same patients. Small intracellular and interstitial accumulations of endocrine-type amyloid may be found in the normal pituitary from the third decade onwards (Tashima et al., 1988). These become more numerous with increasing age and can be found in about two thirds of pituitaries in the elderly (Tashima et al., 1988; Bohl et al., 1991). Similar agerelated intracellular and interstitial accumulations of amyloid occur in other endocrine glands, including the adrenals and parathyroid glands (Bohl et al., 1991).

PERIPHERAL NERVE Jacobs and Love (1985) found little change in the total number of myelinated and unmyelinated nerve fibers in the sural nerve from childhood through middle age. Over the same period, there is, however, a gradual decline in the densities of myelinated and unmyelinated nerve fibers in the sural nerve (and other peripheral nerves that have been studied) as the amount of endoneurial collagen and the separation between adjacent nerve fibers increase (Ochoa and Mair, 1969a,b; Tohgi et al., 1977; Jacobs and Love, 1985). After 60 years, both the density and the absolute number of fibers tend to decrease, mild to moderate degeneration of myelinated and unmyelinated fibers becomes increasingly common and a small proportion of fibers shows changes of segmental demyelination and remyelination. The degeneration of myelinated fibers is accompanied by a variable amount of regenerative activity. These changes affect the relationship between the axon calibre and the myelin sheath thickness (g ratio), which is much more variable in old age than in younger age. Also affected is the normally linear relationship between internodal length and fiber diameter. The demyelination and remyelination causes marked variation in the internodal length along individual fibers, and the degeneration and regeneration produces relatively large fibers with long sequences of uniformly short internodes, 300–400 µm in length. Other findings in peripheral nerves of the elderly include a tendency to reduplication of endoneurial vascular basement membranes and some thickening of the basement membrane in the outer layers of the perineurial sheath (Jacobs and Love, 1985).

SYMPATHETIC GANGLIA Lipofuscin can be identified within sympathetic neurons as early as at 4 months of age (Koistinaho et al., 1986), and

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the amount increases steadily throughout life (Helen, 1983; Hervonen et al., 1986; Koistinaho et al., 1986). Hervonen and colleagues noted that the autofluorescent color of the lipofuscin under ultraviolet light changed from yellow to orange with increasing age, possibly due to the accumulation of neuromelanin in the noradrenergic neurons (Hervonen et al., 1986; Koistinaho et al., 1986). Another feature of aging in sympathetic ganglia is an increasing prominence of dystrophic preterminal axons (Schmidt et al., 1990; Schroer et al., 1992; Schmidt, 2002). These develop at an earlier age in patients with diabetes mellitus (Schroer et al., 1992). The swollen argyrophilic axons tend to cluster around scattered nerve cells, which may be indented by the swellings. They are more numerous in the celiac and other prevertebral ganglia than in paravertebral ganglia such as the stellate ganglion. Schmidt et al. (1990) found that the dystrophic axons could be labelled with antibodies to tyrosine hydroxylase and neuropeptide tyrosine (NPY), but not other neuropeptides (vasoactive intestinal peptide (VIP), substance P, gastrin-releasing peptide/bombesin or met-enkephalin). Other age-related changes that have been noted in the sympathetic ganglia include a reduction in the number of neurons innervated by enkephalin-immunoreactive nerve fibers (Jarvi et al., 1988) and, with the accumulation of lipofuscin, a decrease in the quantity of catecholamines in the neuronal perikarya (Hervonen et al., 1978).

KEY POINTS • Age is associated with progressive brain atrophy, much of which is due to loss of white matter. • The extent of neuronal loss varies in different parts of the brain and spinal cord. • Plaques, neurofibrillary tangles and Lewy bodies can occur in neurologically normal people but are much more numerous and extensive in Alzheimer’s disease and Lewy body diseases. • Other age-related changes include granulovacuolar degeneration and the formation of Hirano bodies in the hippocampus; dystrophy of axons in the posterior column and anterior horn of the spinal cord, in the substantia nigra and globus pallidus; accumulation of corpora amylacea; and development of cerebral amyloid angiopathy. • Amyloid fibrils in the choroid plexus and ependymal cells are a constant finding in the elderly.

KEY REFERENCES • Braak H & Braak E. Neuropathological stageing of Alzheimer related changes. Acta Neuropathologica 1991; 82:239 – 59. • Dickson DW, Crystal HA, Mattiace LA et al. Identification of normal and pathological aging in prospectively studied nondemented elderly humans. Neurobiology of Aging 1992; 13:179 – 89.

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• Love S, Siew LK, Dawbarn D et al. Premorbid effects of APOE on synaptic proteins in human temporal neocortex. Neurobiol Aging 2005, doi:10.1016/j.neurobiolaging.2005.04.008. • Neuropathology Group. Medical Research Council Cognitive Function and Ageing Study (MRC CFAS). Pathological correlates of late-onset dementia in a multicentre, community-based population in England and Wales. Lancet 2001; 357:169 – 75. • Terry RD, DeTeresa R & Hansen LA. Neocortical cell counts in normal human adult aging. Annals of Neurology 1987; 21:530 – 9.

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PART II

Human Aging: Social and Community Perspectives

9

The Demography of Aging Kenneth G. Manton Duke University, Durham, NC, USA

INTRODUCTION We examine several dimensions of past, current, and future demographic changes and the health dynamics of aging in the United States and other developed countries. Models of the demographic and health dynamics of elderly and oldest-old populations require updating as information about the characteristics of those populations accumulates from (a) demographic sources (e.g. population censuses and vital statistics), (b) specialized longitudinal surveys of elderly populations, (c) epidemiological and clinical studies of elderly subgroups, and (d) by integrating multiple data sources in comprehensive models of health, aging, and mortality (Manton et al., 1994b). This later approach will increase in importance with time as the linkage of biomolecular mechanisms with population dynamics becomes increasingly important in assessing the macro/population influences of accumulated knowledge from epidemiological, clinical, and basic science studies. This is neither meta-analysis (statistical study of multiple clinical data sets) nor bioinformatics (analyses of laboratory studies to find common patterns). It is a new scientific discipline born of the mathematical integration of medicine, mathematics, and biodemography. When populations are successfully modeled at micro (biomolecular), meso (organ systems and individuals), and macro (population) levels the models can be applied to economic and policy studies – in both government and commercial service (to optimize the effects of medicine and medical research on population health). To understand how these models will evolve we start with a discussion of the application of basic demographic techniques. Probably the most basic view of the demography of aging is that a trio of forces, each driven by multiple social and physiological processes, determines the current and future growth of the elderly and oldest-old populations in the United States and other developed countries. Two of these are the larger size of recent birth cohorts who will become the elderly in the near future, and decreases in mortality at earlier ages allowing larger proportions of birth cohorts to survive to

ages 65+. The third factor, discussed separately, is mortality declines at late ages, and their age variable relation to, and interaction with, changes in health and functioning. The first two forces are now well understood – though their magnitude is not appreciated. In the United States (as elsewhere), the oldest-old (85+) population in 2005 is composed of persons born in 1920 – or earlier. From the 1920 US birth cohort, 18.6% of males and 35.1% of females, or 796 100 persons, are expected to reach age 85. Since life expectancy (LE) at age 85 for this cohort is roughly 5.3 (males) to 6.6 (females) years, this implies a US population aged 85+ in 2005 of 4.9 million persons. The largest US baby boom cohort (1961) was 4.3 million persons. If 1920 male and female survival rates were applied to the 1961 birth cohort, then 1 154 550 persons would survive to 85 – or 45% more persons than from the smaller 1920 birth cohort. US survival improved from 1920 to 1960. Of persons born in 1960, 34.4% of males and 49.9% of females are expected to reach 85. Applying these proportions to the 1961 birth cohort implies 1 812 450 persons would reach 85 – an increase of 57.0% over the number surviving to 85 from the 1961 birth cohort than if 1920 mortality rates had not changed. Increased birth cohort size and reduced early mortality increases the number of persons passing 85 by 127.7%. If all cohorts were similar in size, these two forces would imply (assuming life expectancy at 85 increases to 7.5 years) 13.5 million persons aged 85+ – increases of 2.7 million persons due to larger cohort sizes and 5.9 million due to mortality declines. This increase would take 42+ years to realize, that is, the birth cohort of 1961 passes 85 in the year 2046. These simple calculations, using actuarial survival statistics and population counts, gives a sense of the relative contributions of birth cohort size and improved early mortality to increases in the size of future elderly populations. Uncertainty about exact changes in the size and composition of the elderly population is largely due to uncertainty about mortality declines at late ages. Some projections envision larger populations reaching ages 85+,


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for example, 40+ million persons might reach ages 85+ in 2050 if significant progress in improving known risk factors is assumed (Manton et al., 1994b). Thus, if US social, economic, and health conditions remain stable, the potential for large increases in the elderly and oldest-old population exists in the birth cohorts comprising the current US population and their early health and mortality experiences. Looking at the situation in reverse, the elderly and oldest-old populations currently being examined epidemiologically, clinically, and physiologically come from cohorts born long ago (e.g. in 1915, pre-WWI (World War I), and 1930, the beginning of the great depression), which were relatively small at birth, and which experienced what today would be extraordinary, and excessive, mortality risks and adverse early health experiences (e.g. exposures to many childhood diseases which are now prevented by vaccination, or for which there are effective medical treatments; for many European countries, there are also the effects of injuries suffered by combatant males in WWI and WWII). This brings us to the third force, that is, mortality experienced at late ages (e.g. ages 85, 95, and 100+) and antecedent health conditions. Late age mortality interacts with antecedent health and disability conditions (e.g. by mortality selection) which have dramatically changed across current elderly, and near elderly, cohorts. An understanding of the demography of aging requires appreciating the health dynamics, current and historical, characterizing cohorts forming the elderly population.

for males and females respectively, were already 5.0 years and 2.9 years above this “ultimate” limit to life expectancy. In Table 1, we present data (CIA, Central Intelligence Agency, Fact book http://www.cia.gov/cia/publications/ factbook/) on total, male, and female life expectancy in 2004. For the small country of Andorra, the total life expectancy of 83.5, and the female life expectancy of 86.7 years, causes one to think the ultimate limit to life expectancy of 85 years posited by Olshansky and Fries is too low. The female life expectancy of 84.5 years in Japan, and the total life expectancy of 81.0 years also suggests one be skeptical about “ultimate” life span limit estimates. Other authors suggested US stagnant male mortality conditions 1954–1968 reflected increased chronic disease risks due to the nature of industrial societies. Antonovsky discussed why risks might be elevated for cardiovascular diseases. Omran posited a model of the stages of the epidemiological transition of which the third, and end, stage characterized economically developed societies as having a high prevalence of chronic degenerative and manmade diseases with static life expectancy. Much of this pessimism was due, however, to congenital disorders, like Down’s syndrome, where life expectancy could increase past reproductive ages generating a “pandemic,” or cascade, of chronic degenerative disease. Many demographers generate model life tables to describe mortality and in estimating life expectancy “limits”. Bourgeois-Pichat projected a maximum life expectancy of 73.8 years for males, and 80.3 years for females, in 1978. A 1982 study of the Japanese economy used life expectancy limits of 79.8 years for males (not yet achieved) and 80.7 years for females. Japanese life expectancy at birth, among the world’s highest in 2004 (see Table 1), far exceeded limits assumed for females in 1982. In France, life expectancy in 2004 was 75.8 years for males and 83.3 years for females – exceeding Bourgeois-Pichat’s 1978 estimate of a female life expectancy limit by 3.0 years. Swedish data have been used to model late age mortality because of its high quality. Because vital statistic systems have now been computerized in many developed countries, for many years the Swedish data no longer have special status as the basis for “curve fitting” models to apply to other countries. Life expectancy limits estimated only from total and cause specific mortality trends were problematic (Manton et al., 1991). New models incorporating health data and biological mechanisms are necessary for forecasts (Manton, 2004a).

MODELS OF CHRONIC DISEASE AND MORTALITY TRENDS The idea that mortality, and other age-related health conditions, are mutable to late ages (i.e. age 85+) is relatively new (Lakatta, 1985). The idea that function can be regenerated, and the physiological clock run backwards, is even newer, although for open physical systems the possibility was identified by Prigogine and Stengers (1997). In the United States, mortality was thought to have reached irreducible levels by the late 1950s or early 1960s because male survival decreased in that period – though female survival continued to improve. Social Security actuaries assumed ultimate life expectancy limits would be reached in the United States in 2000 in Social Security Trust fund projections made in 1974. In 2001, the life expectancies of 74.6 and 80.0 years, Table 1 Life expectancy for selected industrialized countries (2004)

Country

Japan

Population (Millions) Life expectancy at birth (years) a

Total Male Female

Andorraa

Germany

France

Sweden

Canada

United States

127

0.1

82

60

9

33

81

83.5

78.5

79.4

80.3

80

77.4

77.7 84.5

80.6 86.6

75.6 81.7

75.8 83.3

78.1 82.8

76.6 83.5

74.6 80.4

Highest life expectancy in 2004 C.I.A. Fact book.

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THE DEMOGRAPHY OF AGING

Analyses of mortality to late ages suggest why human life expectancy limits are difficult to estimate. First, human life spans are long (e.g. it will take 120 to 130 years for a recent, large birth cohort to die out at current mortality levels in Japan, France, and other developed countries (Manton and Stallard, 1996)), making it difficult to get reliable data on the full mortality experience of a birth cohort (let alone for multiple birth cohorts). Second, human populations are free living and cannot be studied in experimentally controlled environments. Hence, the proportion of human life expectancy potential realized in any population is a smaller, and less certain, proportion of their biological potential than can be observed in animal models in experimental conditions (Carey et al., 1992). Third, for much of human history, fertility was a more dynamic factor controlling population growth, and shaping population structure, than mortality. Thus, after large increases in US life expectancy at birth from 1900 to 1950 (i.e. from 47.3 years in 1900 to 68.2 years in 1950, an increase of 20.9 years or 0.42 years of life per calendar year) the rate of increase in life expectancy at birth slowed (e.g. from 68.2 to 70.8 years for 1950 to 1970, or 0.13 years of age increase per calendar year). From 1970 to 2000, life expectancy increased from 70.8 to 77.0 (6.2 years), or 0.21 years per calendar year (a 50% acceleration over the 1950 to 1970 period), with recent increases accelerating owing to declines in cancer mortality. For certain periods, US male life expectancy declined. From 1954 to 1968, male mortality rates increased 0.2% per year; they declined 0.8% per year for females. From 1970 to 2001, life expectancy at age 65 for males and females combined increased (i.e. from 15.2 years in 1970 to 18.1 years in 2001, or 0.1 years of age per calendar year) and represented a larger proportion (45%) of the gain in life expectancy at birth (6.4 years) than before 1970. Gains were, in part, achieved by reducing mortality in “uncharted” territory, that is, ages 85+. The first welldocumented reports of centenarians occurred about 1800. The first reliably documented report of a survivor to 110 (a “super” centenarian) was in 1931. The first documented survivor to 120 (eventually dying at age 122 years) was recorded in 1995. It may be that a 130 year old is alive but not yet discovered. For the last 30 years, the centenarian population in the United States and several other developed countries (Manton and Stallard, 1996) has grown 7% per year. As higher proportions of larger, more recent birth cohorts survive to late ages, reductions in mortality at those ages will contribute proportionately more to life expectancy gains. In response, we redesigned the 1994, 1999, and now 2004 NLTCS (National Long Term Care Survey) to have over samples (540, 600, and ∼1600 cases respectively) at ages 95+ to have adequate precision to study both health care use and the biological processes determining health and mortality at advanced ages. What we observed about health changes in the 1982 to 1999 NLTCS was remarkable – and contrary to most models of human aging. In Figure 1(a) and (b), we show changes in (a) life expectancy and (b) active life expectancy (ALE) (i.e.

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period lived free of serious disabilities (Manton, 2004a)) in 1982 and 1999. The change in life expectancy was 4.5 years. The change in ALE was 3.8 years. Thus, most (84%) of the gain in life expectancy was in healthy years of life. In Figure 2, we look at the acceleration of the improvement of functioning from age 65 to 100. In Figure 2, we can examine rates of change in the difference between ALE and LE in 1982 and 1999. We see that differences between LE and ALE were similar in 1982 and 1999, never being much higher than 20% (left axis) – though 1999 differences shifted to the right about five years at age 85. Despite higher life expectancy at all ages 65+, the difference at age 85 is only slightly higher than (at age 80) in 1982. After age 85, the ratio of ALE and LE differences over age suggest a small difference, and stable rates of change from 1982 to 1999, up to age 105. This is why we can expect future declines in disability, and increases in ALE, that is, improvements are manifest to age 105. Further complicating efforts to predict life expectancy are gender and cause specific differences in mortality. From 1950 to 1970, male life expectancy at 65 increased 0.3 years (i.e. from 12.8 to 13.1 years) with life expectancy declining 1954 to 1968. Female life expectancy increases were 2.0 years from 1950 to 1970 (i.e. from 15.0 to 17.0). From 1970 to 2001, life expectancy at 65 for both US males (13.1) and females (17.0) increased 3.3 and 2.4 years – to 16.4 and 19.4, respectively. There were larger changes in cause specific mortality. US age-standardized heart disease mortality declined 57.8%, and stroke mortality 68.0%, from 1950 to 2001. Age-standardized cancer mortality increased 11.4% up to 1990. From 1990 to 2001, they declined over 9%. This decline was due to both social (smoking cessation) and treatment innovation – despite the criticism of the “war on cancer” (Bailar and Gornik, 1997). Weisenthal (2004) suggests application of “drug efficiency testing” at the individual level could improve the efficacy of chemotherapy by 20 to 1. An area recalcitrant to treatment until recently was neurodegenerative disorders, for example, Alzheimer’s disease. Recent analyses of the 1982 to 1999 NLTCS show large declines in severe cognitive impairment. In 1994 and 1999, severe cognitive impairment was found to map to four ICD9 (The Ninth Revision of the International Classification of Diseases) codes. Of these codes, those representing dementia due to circulatory disease (e.g. sequalae of stroke), or mixed processes, showed most of the declines, that is, Alzheimer’s disease alone was stable (Manton et al., 2004a; Manton and Gu, 2005a). Epidemiological studies showed supplemental vitamins C and E and aspirin reduced dementia by circa 90% (Zandi et al., 2004), ibuprofen by as much as 80% (in’t Veld et al., 2001), and statins by 73% (Wolozin et al., 2000), which is “proof of concept” that not just circulatory dementia could be reduced with existing medications but also, in the future, Alzheimer’s disease. This seems contradictory to many estimates of future Alzheimer’s disease risk (Manton, 2004a; GAO, 1998; Evans, 1990).

90

HUMAN AGING: SOCIAL AND COMMUNITY PERSPECTIVES 100 90 80 1999

70 Percent

60 50 40 1982

30 20 10 0 65

70

75

80

85

90

95

100

105

110

Age

(a) 100 90 80 1999

Percent

70 60 50 40

1982 30 20 10 0 65

70

75

80

85

(b)

90

95

100

105

110

Age

Figure 1 (a) 1982 and 1999 Life expectancy estimates; (b) 1982 and 1999 Active expectancy estimates

The nature of medical conditions evolved as more persons survived to late ages, for example, up to the 1940s and 1950s, much concern was directed to effects of rheumatic fever or syphilis on the heart, hypertension, and stroke (Kaplan and Keil, 1993). In the 1950s and 1960s, hypertensive heart disease declined while atherosclerotic heart disease increased. The mean age at which hip fractures occurred in Britain from 1944 to 1990 increased from 67 to 79 – a 12 year of age increase in 46 years. Concurrently, the nature of hip fractures shifted from intra- to extracapsular fractures. The nature of osteoporosis, the process underlying most US hip fractures, differs from ages 55 to 74, where it depends on postmenopausal change in estrogen levels, to ages 75+ where it is related to age-related defects in the vitamin D endocrine system. Clearly, more basic physiological processes were at work, and over a longer period of time, than anticipated by efforts to estimate life expectancy limits based on total and cause specific mortality trends, and by efforts to relate changes to significant, but recent, changes in “standard” chronic disease risk factors. One study suggested US stroke mortality started to decline by 1925 (Lanska and Mi, 1993). Fogel (1994)

showed US declines in chronic diseases may be even more long lived. He compared the prevalence of chronic diseases in Civil War veterans age 65 to 84 applying for pensions in 1910 (US birth cohorts of 1825 to 1844) with the prevalence of chronic diseases for WWII veterans over 65 assessed in the 1985–1988 National Health Interview Surveys (i.e. 1905 to 1924 cohorts). He found chronic disease prevalence at 65+ declined 6% per decade between 1910 and 1985–1988. The prevalence of heart diseases was 2.9 times higher in Civil War veterans aged 65+ in 1910 than in WWII veterans aged 65+ in 1985–1988. Declines in chronic diseases set the stage for subsequent declines in mortality up to several decades later. Fogel (1994) attributed changes in chronic morbidity to economic and productive factors affecting early nutrition which increased stature and body mass index (BMI) over time. Many changes between Civil War and WWII veterans predate documented US increases in cholesterol and fat consumption – estimated to have peaked in 1959. One possible explanation of the effects of nutrition on health was the impact of protein, micronutrient, and caloric deficiency on fetal development. This was attributed to effects of


91 1.6

25

Difference (%)

1.2 1.0

15

0.8 10

0.6 0.4

5 82

0.2

diff99/diff82

99

Ratio of differences (diff99/diff82)

1.4 20

0.0

0 65

70

75

80

85

90

95

100

105

Age Figure 2 Difference between LE and ALE

maternal nutritional deficiencies on the fetal development of organs such that a physiological priority was assumed to exist which dictated which organs received adequate nutrition under conditions of protein and caloric deprivation. If the central nervous system received the highest priority for nutrients, organs like the liver (affecting cholesterol metabolism and thrombolic factors) and pancreas (affecting glucose metabolism) might be susceptible to developmental restrictions that became manifest in chronic disease risks at later ages. There is evidence for this in studies relating the ratio of placental to birth weight, and of weight at one year of age to chronic disease at later ages. Barker and Martyn found higher weight at one year inversely related to ischemic heart disease, systolic blood pressure, and impaired glucose tolerance in adults, and possibly to fibrinogen levels in men aged 59 to 70. The relation of systolic blood pressure to placental weight for women and men age 46 to 56 was direct. Others suggest nutritional deficiencies affect persons most at ages where the most rapid physical growth occurs with the highest protein, caloric, and other nutrient needs. This is consistent with Fogel’s (1994) use of the Waaler curve to plot changes in BMI and chronic disease risks. It is also consistent with the results of Tango and Kurashina, who found Japanese male cohorts born 15 years before WWII (i.e. birth cohorts of the early SHOWA period 1925–1939; aged 5 to 20 during WWII when there were nutritional shortages in Japan) had elevated mortality from diabetes mellitus, ischemic heart disease, peptic ulcer, cirrhosis, and suicide. These cohort differences in male cause specific mortality are likely due to poor nutrition during early, critical stages of adolescent male growth spurts. Deficiencies involved gross energy (caloric), proteins, and micronutrients, for example, in periods of rapid skeletal growth, vitamin D serum levels are highest; and vitamin C (affecting collagen formation) and B (affecting methionine metabolism and growth hormone release) needs are elevated (McCully, 1983). One large-scale population experience that could be definitive in testing the Barker hypothesis is the Leningrad siege in WWII where there were roughly ∼250 000 survivors in 2004.

Two other models may help explain why chronic disease and mortality risks in specific birth cohorts may be related to nutritional and hygienic factors over long periods of time. One suggests that the effect of viral and bacterial infections on chronic disease has changed over time (as well as the natural history of the chronic diseases) due to changes in food processing and hygiene. Such arguments have been used to explain why some diseases have strong geographic patterns, for example, association of multiple sclerosis with temperate climates. For atherosclerosis, there is evidence to relate its initiation (i.e. injury to arterial endothelium starting inflammatory and wound building activity stimulated by dietary cofactors such as serum cholesterol and aggravating conditions such as hypertension) to viral and bacterial insults. This model derives support from evidence that atherosclerotic plaques have a monoclonal origin, suggesting a somatic mutation is involved in plaque initiation (Benditt and Benditt, 1973). Various infectious agents have been found in plaques; or in circulating immunological complexes in cases with circulatory disease versus controls. Among agents implicated are Chlamydia Pneumoniae, CMV (cytomegalovirus) (Mozar et al., 1990), and other herpes viruses. One mechanism that could be involved in infectious agent damage to arterial endothelium involves platelet derived growth factor (PDGF). PDGF may play a central role in atherogenesis because it is both a mitogen and chemoattractant. There is a striking homology (87%) between the amino acid sequence of PDGF and a protein from an oncogene (v-sis) in the simian sarcoma virus. This homology suggests PDGF is important in the proliferation of cells transformed by a virus. Cells transformed by retrovirus, DNA viruses, and cells with somatic mutations appear to secrete PDGF molecules. Cells virally transformed appear to express a previously repressed cellular gene (c-sis) for PDGF. An immunological factor identified as raising the risk of myocardial infarctions, especially for males, is null allele C4B*Q0. There is evidence to suggest immune mechanisms are involved in hypertension, with some data pointing to predisposing genes in the

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major histocompatability complex, either secondary to hypertension induced vascular damage (causing positive feedback in plaque growth) or as a primary abnormality. However involved, reductions in infectious disease exposures might reduce hypertension prevalence in recent cohorts. Data from Hiroshima suggest ionizing radiation is another exogenous stressor involved in hypertension and cardiovascular disease. In Hiroshima, there was acute γ radiation. In Chernobyl, the most damaging radiation is β (electrons) due to biological incorporation of 90 Sr in bone and 137 Cs in soft tissue. The radiation flux of these isotopes is relatively high though they have a long half-life, that is, about 30 years. With this type of radiation, there appears to be an acceleration of basic age processes (Manton et al., 2004a) consistent with the well-known free radical theory of aging. This syndrome involves cataracts, stroke, circulatory diseases, and neurodegeneration. Effects on neurodegeneration originally were not viewed as plausible because it was believed neurons seldom divided. There is now evidence neuronal regeneration occurs in several areas of the brain (e.g. in the hippocampus and the substanta nigra) for the brain is an area of high metabolic activity where baseline free radical production is high and where protein formation in synaptic gaps is sensitive to even very low doses of radiation (Manton et al., 2004a). The evidence suggests atherosclerotic circulatory diseases and their catastrophic manifestations are thrombotic, occlusive events leading to ischemia in critical organ systems, due to a multistage pathological process where initial damage to the arterial intima stimulates inflammatory and immunological responses, where LDL (low density lipoprotein) cholesterol becomes oxidized forming foam cells from monocytes/macrophages drawn to the site of the injury, which then are integrated in plaque. Involved in plaque elaboration are complex processes of autocrine and paracrine mechanisms of vascular response to injury (Dzau et al., 1993). Other stages of the process involve intracellular absorption of calcium leading to calcification of plaques and inflammatory responses leading to plaque rupture. Immunological responses to infectious agents directly stimulating plaque ruptures (and subsequent thrombotic events) are also suggested by the antiphospholipid syndrome. To explain how infectious disease involvement with atherosclerosis relates to long-term population health and mortality changes, Mozar et al. (1990) suggested changes in circulatory disease risk can be traced back at least to 1910, when 8% of US deaths were attributed to heart disease. This proportion rose to 30% by 1945, and to 54% by 1968. A similar trend occurred in the United Kingdom with diseases of the heart and blood vessels responsible for 11.4% of all deaths in 1910, rising to 36.3% in 1959. In the United States, the peak heart disease risk was reached in 1968. Mozar et al. (1990) suggest this was due to ingestion of atherogenic viruses during the prewar period (i.e. initial injuries led to processes with lengthy latency times; autopsy studies found fatty streaks and plaque development began at early ages, possibly as early as age 3 years in the aorta (Pathobiological Determinants of Atherosclerosis in Youth Research Group (PDAY), 1990), even in less developed countries where heart disease risks

do not increase late in life), which interacted with increased fat consumption and other risk factors (e.g. the methioninehomocysteine model of atherogenesis) up to 1970. The nutritional (hygienic) factor argued by Mozar et al. (1990) to be associated with declines in heart disease risk was commercial food processing – initiated before the turn of the century. The use of commercial food processing accelerated after WWII as economic conditions improved, large proportions of the US population moved from rural to urban areas, and efforts to control livestock infections such as vesicular xanthema (a viral disease of swine discovered in 1932) were started, for example, in California in 1945–1949. An outbreak of vesicular xanthema in 1952 mandated thermal preparation of food fed to swine. A hog cholera eradication program began in 1962. The Swine Health Protection Act passed in 1980. The risk of viruses and other infectious agents in chronic circulatory disease is not limited to injuries to the arterial endothelium but may involve stimulation of autoimmunological factors. A well studied infectious disease important in chronic disease risk that was a major concern in past years (i.e. rheumatic heart disease) are group A streptococci infections, especially of virulent strains, for example, M types 3 and 18 associated with rheumatic fever and M1 with toxic shock due to production of a pyrogenic exotoxin A. Certain strains (e.g. M1) disappeared in the United States 30 to 40 years ago. They recently reappeared in selected geographic areas in the United States, suggesting a cyclical decline and reemergence of virulent strains (Kaplan, 1993). This cyclical pattern can be related to the HLA (human leukocyte antigen) typing of individuals to see how autoimmunological responses relate to rheumatic heart disease. The disappearance of the most virulent strains about 1950 to 1960 is consistent with declines in cardiovascular mortality due to atherosclerosis beginning in 1968 – suggesting a role as a disease cofactor. Nutrition affects a host’s immunological competency. Poor nutrition, especially in childhood, might lead to less effective immunological responses to viral and bacterial challenges. The physiological response to the acute phase of infection requires energy. Poor nutrition can reduce efficacy of the host’s response to disease, allowing it to cause greater physiological damage requiring greater energy expenditures to fight the disease process and further reducing nutritional resources for normal development – setting the stage for future chronic disease. A third factor that could become important is ionizing radiation, not necessarily from atomic bombs or nuclear terrorism, but environmental contamination of water and food sources due to the leaking of radionucleides from storage sites (e.g. the Hanford plant) or as might occur during decommissioning of nuclear power plants. This is the type of damage that occurred in the former Soviet Union, for example, from the Mayak plutonium production facility in Chelyabinsk, Russia. As for cardiovascular disease, new genetic and molecular evaluation and assay techniques allow identification of viruses and other infectious agents causing several types of


cancer. Epstein-Barr virus is implicated in the etiology of human lymphoid and epithelial malignancies. H. pylori, a causative agent in peptic ulcers, is associated with gastric cancer, and possibly other malignancies (e.g. liver cancer). Both Rb and P53, growth regulating genes whose normal function is to arrest cell growth when mutations are detected, can be disturbed by viral infections allowing malignant growth. H. pylori is of interest in that its infection rate is related to water quality. Thus, long-term improvements in water quality may be responsible for US cohort specific declines in gastric cancer. Elevation of gastric cancer risks in the upper midwest of the United States may be due to the use of well water in rural areas (H. pylori grows well in still water in wells or cisterns). H. pylori remains highly prevalent in developing countries (e.g. West Africa) and has a high seroprevalence in elderly US cohorts. Thus, long-term trends in both circulatory and neoplastic disease and mortality appear to partly depend on viral and bacterial infections as initiating events or cofactors and may depend in the future on radioecological events. Reductions in standard chronic disease risk factors can only be documented, in the United States population, from the early 1960s (e.g. smoking declines, reduction of unhealthy fat consumption). Reductions in hypertension were first documented in the National Health and Nutrition Examination Surveys in 1960–1962. As genetic and molecular biological assays become more sensitive, we may find many other chronic diseases are dependent on a variety of infectious and other environmental agents. Changes in the human environment (e.g. improvement in water quality reducing H. pylori infection) or in food processing (e.g. elimination of viral infections in livestock, or thermal processing of food) may be partly responsible for large cohort related declines in circulatory diseases in the United States. Cancer risks are now decreasing in the United States. It has been proposed that common processes underlie both cancer and aging. Warner et al. (1995) related these processes to effects of caloric restriction (CR) on programmed cell death (PCD). They suggest CR upregulates expression of antioxidant genes and attenuates formation of reactive oxygen species – and possibly DNA and mitochondrial damage caused over age. The emphasis on effects of antioxidants on aging and cancer leads to a third model of changes in chronic disease risks and their contribution to late age health changes. Another hypothesis is that long-term changes in micronutrients alter chronic disease risk. Antioxidant vitamins A, C, and E seem to affect cardiovascular disease by lowering the potential for LDL cholesterol to become oxidized, consumed by macrophages, and trapped in atherosclerotic plaques as foam cells. Vitamin A and E are redifferentiating agents that repair some genetic damage and antioxidants preventing certain chemical reactions from causing somatic mutations or other cell damage. They may improve immunological responses at late ages (Beregi et al., 1991). Zandi et al. (2004) suggest that up to 93% of Alzheimer’s disease may be prevented by supplementation with vitamins C and E and low dose aspirin.

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Vitamin D, a vitamin/enzyme/hormone, has powerful effects on bone metabolism; especially in late onset (i.e. ages 75+) osteoporosis (type II) in females. This may interact with cardiovascular diseases by affecting cellular calcium metabolism, parathyroid hormone activity, and hypertension. It may interact with iron (Fe) and magnesium (Mg) metabolism (Moon et al., 1992) and is a powerful cellular differentiating agent. As such it (or, its antagonists) might prevent strontium 90 uptake in radioecological disasters as Chernobyl. Vitamin D supplementation in milk and other foodstuffs has been done for a long time in the United States and Canada. One strategy to examine its effects on chronic disease is to trace the epidemic of atherosclerosis and ischemic heart disease and the ratio of male to female deaths. In the United States, this ratio was near one until the mid1920s. Then the male predominance in ischemic heart disease increased steadily until 1968. Moon et al. (1992) pointed out that curative effects of cod liver oil on rickets were documented in 1917. In 1923, the United States imported 0.5 million gallons of fish liver oil, and in 1930, 2.8 million gallons. UV irradiated milk was introduced in the United States in 1924. Manufacture of vitamin D2 and D3 increased from 35 lbs in 1948 to 14 000 lbs in 1972. By 1970, vitamin D2 was added to many food products. There was a concurrent decline of Mg in the US diet. Mg mediates effects of vitamin D on cellular calcium absorption (Moon et al., 1992). Vitamin D hypervitaminatosis infers with Mg absorption. Oversupplementation of D aggravated Mg deficiencies in the United States diet. Mg deficiency may have additional effects on circulatory disease because it appears to stimulate renin release through the elevation of prostaglandins; and suppress aldosterone production by mobilizing intracellular calcium. In the late 1960s, the FDA began considering limiting vitamin D supplementation. Regulations restricting vitamin D supplementation were implemented in 1972 – coincident with the beginning of the decline in heart disease. The sex ratio of femoral neck fractures was used to trace origins of the US osteoporosis epidemic. This ratio suggests (based on Rochester, Minnesota, data) that osteoporosis began its upsurge in the late 1920s – about the same time ischemic heart disease began increasing. Vitamin D intake, its increase from 1920 to 1970 and its subsequent decrease, could explain the interaction of atherosclerosis and osteoporosis for females, and their joint trajectories. Vitamin D increases Fe absorption, which may lead to increased free radical generation and oxidation of LDL cholesterol. This might explain the rapid increase of atherogenesis in females postmenopausally, that is, Fe stores in females increase and, with excess vitamin D, increase calcification of atherosclerotic plaques. Another model for explaining long-term trends in circulatory diseases is the homocysteine theory (McCully, 1983). Ingestion of the sulfur based amino acid methionine (an essential amino acid for mammalian growth) produced, after demethylation, homocysteine. Elevated levels of homocysteine, due to genetic predisposition or dietary deficiency of vitamins B6 and B12 , had toxic effects on arterial

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endothelium. Lesions created by elevated homocysteine levels showed the characteristic fibrous nature of atherosclerotic plaques – but not with lipid deposition if cholesterol is not elevated. The theory suggests fibrous plaques are not produced unless vitamin B deficiency allows accumulation of homocysteine and a toxic metabolite, homocysteine thiolactone. The metabolism of homocysteine is affected by vitamin C. Though ascorbic acid is a potent reducing agent, after oxidative conversion to semidehydroascorbic acid, its physiological function is to oxidize the sulfur atom in homocysteine. Three stages for methionine utilization are (a) demethylation and dehydration of methionine to homocysteine thiolactone, (b) oxidation of homocysteine thiolactone to homocysteic acid by semidehydroascorbic acid, and (c) reaction of homocysteic acid with ATP (adenosine triphosphate) to form active coenzymes to synthesize sulfate esters of connective tissue proteoglycans. Methionine deficiency inhibits growth and wound healing – like scurvy. In scurvy, the lack of dehydroascorbic acid inhibits formation of sulfated proteoglycans. Increased conversion of methionine to homocysteine thiolactone increases production of sulfated proteoglycans matrix, deposited in atherosclerotic plaques, which accelerates growth and stature in homocystinuria. Age changes in homocysteine hepatic metabolism may explain why children in rapid growth phases are less susceptible to atherogenic effects of homocysteine. Stimulation of growth is due to homocysteic acid, which has a similar effect to somatomedin (the serum polypeptide mediating the effect of pituitary growth hormone on cartilage) on sulfate binding in cultured cartilage fragments – suggesting a relation of homocysteic acid, somatomedin, and the action of growth hormone. After normal growth ceases, and epiphyses ossify, growth stimulation affects cells of blood vessels (especially smooth muscle cells) rather than chondrocytes and osteocytes in growing bone. The homocysteine model also suggests a basis for the age dependence of osteoarthritic diseases and effects of growth hormone and somatomedin on the aging of connective tissue. Some evidence suggests the agent mediating the growth of smooth muscle cells is carried by platelets and released during platelet aggregation and adherence to injured intima. Calcification of fibrous connective tissue is stimulated as is the disruption of intermolecular cross-linking in newly synthesized collagen fibrils, which may be due to the reaction of homocysteine with allysine to form tetrahydrothiazine adducts. This may interfere with intermolecular cross-linking in collagen and elastin. The relation of this mechanism to increased heart disease in the twentieth century may be due to an increased dietary ratio of animal to plant protein (dietary intake of methionine is correlated with cholesterol intake). This may explain the relation of increased body size with atherosclerosis. Vitamin B6 levels decrease through life to the eighth decade because serum glutamine oxaloacetic transaminase activity decreases. When the elderly are treated with pyridoxine, transaminase levels return to levels of younger persons (McCully, 1983; von Eckardstein et al., 1994). Also, since pyridoxine is water soluble, as the lipid content of the diet increases, pyridoxine availability may decrease.

To explain US population trends in heart disease, quantities of synthetic pyridoxine hydrochloride were examined (McCully, 1983). US production increased from 1900 kg in 1944 to 30 000 kg in 1963. Imports increased from 9100 kg in 1963 to 17 700 kg in 1969, to 59 500 kg in 1972 (yielding a threshold consumption of 0.79 mg day−1 ) to 275 000 kg in 1978 (3.42 mg day−1 ). This increase is consistent with post-1968 declines in coronary heart disease. Since B6 supplementation will prevent arterial damage, but not reverse it, the decline in circulatory disease should increase as younger cohorts who had adequate supplementation reach older ages. Supplementation is also necessary because thermal food processing (which may have decreased viral exposures in animal protein) degrades natural pyridoxine. This is controllable by consuming adequate synthetic vitamin B6 and B12 (von Eckardstein et al., 1994). The problem increases with age due to altered vitamin intake, absorption, or metabolism. Dietary intake of at least two other trace minerals may affect long-term heart disease and stroke mortality trends by affecting blood pressure. One is reduced salt intake which lowers blood pressure and reduces abnormalities of calcium metabolism, incidence of renal stones and bone demineralization. Potassium, found in many fruits and vegetables, also decreases blood pressure. Increases in fruit consumption may be involved with early reductions in stroke. New explanations of these processes derive from better understanding of cellular bioenergetics – especially the function of the mitochondria. This suggests that, in addition to the CR model, they are the effects of thyroid hormone on mitochondrial function (Manton, 2004b). It is known thyroid hormone administration increases oxygen consumption by mitochondria (Venditti et al., 2003). The effect may be shortas well as long-term. Short-term influence (within minutes of the hormone treatment) results in enhanced expression of the mitochondrial genome. Thyroid hormone increases levels of mitochondrial transcription by elevating mRNA synthesis and improving their stability. Long-term influence (after 24 hours) involves the stimulation of mitochondriogenesis (Enriquez et al., 1999; Wrutniak-Cabello et al., 2001; Weitzel et al., 2003). This may explain why honey bees, where a nutritional intervention (royal jelly) containing a protein with partial structural similarity to human thyroid hormone, may stimulate production of cytochrome C in mitochondria with life span epigenetically increased 30-fold or more despite elevated metabolic rate (Manton et al., 2005). Intervention effects were shown in mice where mitochondrial functions of old mice was returned to that of young mice by administration of alpha lipoic acid (an antioxidant zwitterion) and L-acetylcarntine, an agent stimulating fatty acid metabolism (Hagen et al., 2002; Liu et al., 2002). Historically, deficiencies leading to explicit disease syndromes were prevalent until the role of specific vitamins and minerals in those diseases were identified and supplemental sources sought. At levels less deficient than those causing specific deficiency syndromes (e.g. scurvy, pellagra, osteomalacia, rickets), vitamin deficiencies may have contributed to long-term population changes in chronic disease risks.


To make the ebb and surge of specific chronic diseases over time consistent with the models described above, there had to be changes, not only in mortality at late ages, but also in the nature of age-related chronic disease processes over the past 150 years as nutrition (both macro and micronutrients), food hygiene (e.g. H. Pylori infections; toxins due to food spoilage), and viral and bacterial exposures changed. Changes may also affect the expression of genetic diseases by altering gene –environment interactions or by changing the inflammatory response of the host to stress, for example, altering serum levels of IL-6 (Cohen et al., 1997). The average health characteristics of the very elderly population may evolve in the future as different cohorts, with different early health experiences, enter this age group. As the profile of chronic diseases affecting elderly populations changes over their life span, one also is aware of long-term changes in age-related chronic disease – and in aging changes.

MORTALITY SELECTION AND TRAJECTORIES Hygiene and nutritional changes caused differences in chronic disease risks across birth cohorts. These, and other, factors (e.g. smoking) may have altered age trajectories of cohort mortality. Specifically, many demographic models use a Gompertz function to describe age increases in mortality. However, at late ages the trajectory of human mortality deviates from the Gompertz overpredicting increases in mortality (Manton and Stallard, 1996). One explanation of deviations from the Gompertz (beginning about age 85) is mortality selection. For example, the prevalence of the B gene of the fourth component of complement (C4B*Q0) is a risk factor, in men, for myocardial infarction. The prevalence of this gene dropped for males in the fifth and sixth decades of life due to adverse affects on longevity. Its prevalence declined at later ages in females. In Italian centenarians there was decreased thyroid autoantibodies compared to persons in their 80s (Marriotti et al., 1992). The prevalence of the ApoE-4 genotype in Finnish centenarians was lower than at earlier ages. In lung cancer, genetic susceptibility involves the cytochrome P450 enzyme system. The proportion of genetically related lung cancer cases declines sharply between ages 50 and 70. In Swedish twins (Marenberg et al., 1994), the relative risk of CHD (Congenial Heart Disease) mortality declined from 14 to 15 to 1 in midage to 1 to 1 above 85. Thus, many studies of genetically controlled diseases showed change in genotype prevalence due to mortality selection. In clinical examinations of long-lived groups, health at late ages (e.g. 80+) is often better than for persons, say, aged 70–79 (Campbell et al., 1993). Effects of mortality selection on the age trajectory of health parameters can be monitored in longitudinal studies where risk factors, or disabilities, are measured multiple times. In analyses of Framingham data (46 year follow-up), and of 18 years of follow-up in a nationally representative study of disabled elderly (1982 to 1999 NLTCS), the mortality

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selection of persons with adverse risk factor profiles, or poor functional status, was noted over age. At late ages (e.g. 95+) selection was so strong that prevalence of adverse risk factor profiles, or poor functioning, started to decrease because mortality rates for very elderly persons with impaired health were greater than the incidence of the adverse health state (Manton et al., 1994a). As a consequence of selection, whereas human mortality rates increase 8 to 10% per year in middle age, the rate of mortality increase at late ages is slower. In seven studies where mortality was observed to ages 100+, rates increased an average of 3.1% per year between 100 and 110 (Manton and Stallard, 1996). For US males, cohort mortality reached a high constant level at ages 100 to 110. US female cohort mortality increased 3.0% per year of age from 100 to 110. The average US cohort mortality rate at age 110 was 41%; the average for the seven studies was 45% (Manton and Stallard, 1996). The 1982 to 1999 NLTCS data show this plateau. We examined an alternate model where a plateau is due, not only to a genetically heterogeneous population, but also to a balance of degenerative and regenerative physiological processes (Manton et al., 2004b). This suggests engineering reliability models, such as the Weibull, are not sufficient in that they describe failure in a homogenous system – not a complex heterogeneous one. It is no longer sufficient to describe a plateau as a genetically determined trait but as a temporally (absolute clock-time – not simply age) changing equilibrium of decay and repair functions. In analyses of the actuarial experience of 11 large insurance companies, there was no credible evidence of human mortality rates exceeding 50% at any age. Recently the level of the plateau was fixed at 40%. Ungraduated insurance data suggest that, above 95, mortality reaches 25% for both genders and then fluctuates randomly. In animal models, similar phenomena were observed. Carey et al. (1992) found, in large experimental populations, mortality reached a high constant level after a large proportion (90%) of the population died. This is manifest in the United States by a decline in per capita, per annum Medicare expenditures at late ages, that is, expenditures were several fold higher at ages 65–70 than for centenarians. If human mortality rates increase very slowly at late ages, profound changes will be required in assessing elderly populations. One is that the number of extreme elderly persons will be larger than now anticipated. In developed countries with reliable data (Manton and Stallard, 1996), the centenarian population has grown 7% per year for 30 years. The number of US centenarians in 2000, 50 454, will increase to 150 000 by 2020 and to 313 000 by 2040 – without assuming large changes in life expectancy or dealing with the large post-WWII baby boom cohorts who become centenarians after 2047. In Social Security Trust fund projections, mortality rates are assumed to increase 5 to 6% per year of age above 100 – a rate of increase higher than in the data (Manton et al., 2004b). From 2035 to 2050, the US centenarian population is expected to grow to 0.6 million persons. The US population

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aged 95+ in 2050 would be 3.8 million persons. The 85+ population would be 18.9 million persons – or 4.8% of the US population. The 65+ population would be 20.4% of the total US population. These are “middle” range projections. Alternate series, assuming greater life expectancy increases, project 2.6 million centenarians in 2050 with 26.4 million persons 85+ and 93.1 million 65+; or 0.63, 6.4, and 22.7% of the total US population (i.e. based on life expectancy at birth in 2050 of 83.8 versus 91.1 years for males and females respectively; the intermediate assumption was 79.7 and 85.6 years for males and females respectively in 2050). Second, for individuals at late ages one will have to use different estimates of life expectancy than are available from actuarial estimates (Manton, 2004a). This could change calculations for assessing cost effectiveness of specific medical interventions at late ages. Third, the expectation about comorbid conditions, and the average health of individuals at specific ages, will have to be evaluated taking into account the birth cohorts from which the patient comes, and the likely prior health experiences of persons in that cohort who survive. It may be aging processes in such persons progress at slower rates than in the population.

FUTURE CHANGES IN THE DEMOGRAPHY AND HEALTH OF THE ELDERLY: POTENTIAL SOCIOMEDICAL RESPONSES With extreme elderly populations of the size discussed, the levels and mixes of services to be provided will have to be adjusted. Changes projected for the United States are not the most extreme. In Japan, using 2004 life expectancies at birth of 76.7 years for males and 84.5 years for females, the 65+ population will be more than 28% of the population in 2024. The implications of such changes are dramatic requiring coordinated changes in (a) societal views of aging, (b) monitoring health of persons at specific ages, (c) the organization of acute and LTC health services for elderly populations, and (d) how medical options are evaluated that are to be offered to persons at extreme ages. First, the popular perception of aging, and elderly persons, will change so sociomedical implications of age are less distinct, that is, individuals have to be assessed more on functional age, and less on chronological age, when considering the economic and social roles they play and how they should be medically treated. For this to have an effect, two other processes must operate. The first, consistent with evidence on the plasticity of aging parameters, is that physiological function is being preserved (and possibly promoted) to late ages. Fiatarone et al. (1994) showed resistance training and supplemental nutrition could improve muscle strength of elderly, frail individuals, for example, the average strength gain in the quadriceps of frail persons aged 86 to 96 was 174%. Kasch et al. showed declines in cardiovascular function for active persons were half the rate found in other studies. The image of “normal” aging

must also be changed in the mind of the elderly individual. By identifying elements of aging with treatable disease processes, senescence is transformed from a mysterious, global biological force into more manageable and specific disease mechanisms. With this image, individuals will be more likely to make lifestyle changes, and seek treatments, to modify health and function. The potential can be illustrated using the 1982, 1984, 1989, 1994, and 1999 NLTCS to estimate changes in chronic disability prevalence by age (Figure 3). In Figure 3 are estimates of changes in the US chronically disabled population representing (a) constant 1982 age and sex specific disability rates, and (b) extrapolating 1999 rates to 2004. The difference is a decline of 43% in the chronically disabled or institutionalized population by 2004 over what 1982 rates would have generated. At ages 65 to 74, the number of chronically disabled persons in 1999 is nearly constant despite a population increase of 30%. Growth of the disabled population is slowed at ages 75 to 84 and 85+. The difference in estimates is 2.6 million, that is, if rates had not changed from 1982 to 2004, there would be 9.9 million disabled persons in 2004 versus the 7.3 million using declines observed 1982 to 1999. Using the rate of decline in disability 1989 to 1999, the difference is 3.1 million (i.e. 9.9–6.8 million).

DISCUSSION The evidence suggests we can expect future elderly cohorts to live longer, and to have better health and functioning. This raises the question as to how health service systems will deal with this rapidly growing group and their changing health characteristics. What has happened in the United States is that health and LTC (long-term care) services have been redirected toward the community, and housing options have been defined to bridge the gap between traditional nursing homes and standard housing. This is reflected in changes in the US health care system. Medicare coverage is now often supplemented by private health insurance. Hospitalization rates and lengths of stay are down. What increased dramatically are Home Health Agency (HHA) and skilled nursing facility use, which, by 1995, constituted 8% of all Medicare expenditures – roughly $14 billion. Concurrently, growth of Medicaid reimbursed nursing home use declined. Most recently, we have found, despite arguments of some economists that more resources will be required to keep individuals healthy at late ages, per capita inflation adjusted Medicare expenditures declined for the nondisabled population and increased for the disabled populations. Efforts to prevent both morbidity and disability among the elderly should be extended. Medicare based demonstration programs show physical activity can be increased. Physical activity (actually the lack) is, itself, a primary risk factor for stroke – and possibly other chronic diseases.


97 9.9

10

9.2 A 8.3 7.5

8

B

7.1

7.0

7.0

7.3

C

6.8

6 6.4

4 1982 Total population age 65+ 26.9 million

1989 Total Population age 65+ 30.8 million

1994 Total population age 65+ 33.1 million

1999 Total population age 65 + 35.2 million

(Projected) 2004 total population age 65+ 36.4 million

Figure 3 Number of chronically disabled Americans aged 65 and over (in millions)

Better evaluations of the efficacy of treatments at late ages are needed. Hosking et al. showed surgical interventions in patients aged 90 to 103 had become less hazardous – intraoperative mortality dropped from 30 to 8% over 30 years. Ko et al. show the increasing efficacy of coronary interventions in elderly (80+) patients. Elayda et al. showed uncomplicated aortic valve operations were successfully performed in patients aged 80+. Long-term (five years) survival rates in persons with simple aortic valve replacement were better than the survival in SSA (Social Security Area) cohort life tables. As pacemakers increase in sophistication, their use in elderly patients improves outcomes. Dual chamber, demand driven pacemakers may be particularly useful for the elderly because of increased reliance with age on atrial function for cardiac output. There are interventions with low mortality that increase the function of elderly persons. Hip and knee replacements are in this category, as well as plastic lens implants for cataracts. Hence, the cost benefit ratios of medical procedures at late ages may be underestimated because the life expectancy of individuals at late ages, and the amount of functional capacity that can be regained, is underestimated (Manton and Gu, 2005b). A reason may be because trends in disability and mortality among populations with particular health characteristics may not be correctly represented in evaluations of patients for the medical and surgical procedures now available for elderly populations. Certain situations, such as long waiting periods for “elective procedures” in some European health care systems, may have more adverse effects at late ages than in younger populations and operate as a “self-fulfilling” prophecy about limitations to late age interventions. Such problems will emerge increasingly in the future as the number of very elderly persons increases

and prior health histories evolve. One factor to which recent changes in disability may be related is education. Education is projected by Preston to improve with the proportion of persons aged 85 to 89 with less than eight years of schooling declining from 60+% in 1980 to 10 to 20% by 2015. A number of health behaviors are associated with education; as well as the risk of dementia. The very elderly (95+) are a group for which we do not have extensive data from which to extrapolate effects of medical interventions. Studies focusing on the elderly, such as the isolated systolic hypertension intervention program, often find significant benefits in intervening in disease. Thus, evaluation of both future increases in health service needs for the elderly population, as well as evaluating potential gains for elderly individuals with specific health profiles, need to consider the implications of long-term demographic and health changes.

Acknowledgments Research reported in this paper was supported by the National Institute on Aging PO1 ROIAGO11519.

KEY POINTS • Vitality determines mortality and fertility. • Vitality links birth-death processes.

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• Vitality is driven by mitochondrial function under thyroid control. • Mitochondria are regulated by thyroid hormone. • Free radical chemistry is central to cellular bioenergetics.

KEY REFERENCES • Fogel RW. Economic growth, population theory, and physiology: the bearing of long-term processes on the making of economic policy. American Economic Review 1994; 84(3):369 – 95. • Kaplan GA & Keil JE. Socioeconomic factors and cardiovascular disease: a review of the literature. Circulation 1993; 88(4):1973 – 98. • Lakatta EG. Health, disease, and cardiovascular aging. America’s Aging: Health In An Older Society 1985, pp 73 – 104; National Academy Press, Washington. • McCully KS. Homocysteine theory of arteriosclerosis: development and current status. In AM Gotto Jr & R Paoletti (eds) Atherosclerosis Reviews 1983, vol 11, pp 157 – 246; Raven Press, New York. • Mozar HN, Bal DG & Farag SA. The Natural history of atherosclerosis: an ecologic perspective. Atherosclerosis 1990; 82:157 – 64.

REFERENCES Bailar J & Gornik H Cancer Undefeated. New England Journal of Medicine 1997; 336:1569 – 74. Benditt EP & Benditt JM. Evidence for monoclonal origin of human artherosclerotic plaques. Proceedings of the National Academy of Sciences 1973; 70:1753 – 6. Beregi E, Regius O & Rajczy K. Comparative study of the morphological changes in lymphocytes of elderly individuals and centenarians. Age Ageing 1991; 20:55 – 9. Campbell AJ, Busby WJ & Robertson C. Over 80 years and no evidence of coronary heart disease: characteristics of a survivor group. Journal of the American Geriatric Society 1993; 41:1333 – 8. Carey JR, Liedo P, Orozco D & Vaupel JW. Slowing of mortality rates at older ages in large medfly cohorts. Science 1992; 258:457 – 60. Cohen HJ, Pieper CF, Harris T et al. The association of plasma IL-6 levels with functional disability in community-dwelling elderly. Journals of Gerontology Series A, Biological Sciences and Medical Science 1997; 52:M201 – 8. Dzau VJ, Gibbons GH, Cooke JP & Omoigui N. Vascular biology and medicine in the 1990s: scope, concepts, potentials, and perspectives. Circulation 1993; 87(3):705 – 19. Enriquez JA, Fernandez-Silva P, Garrido-Perez N et al. Direct regulation of mitochondrial RNA synthesis by thyroid hormone. Molecular and Cellular Biology 1999; 19(1):657 – 70. Evans D. Estimated prevalence of Alzheimer’s disease in the United States. Milbank Quarterly 1990; 68:267 – 89. Fiatarone MA, O’Neill EF, Ryan ND et al. Exercise training and nutritional supplementation for physical frailty in very elderly people. New England Journal of Medicine 1994; 330(25):1769 – 75. Fogel RW. Economic growth, population theory, and physiology: the bearing of long-term processes on the making of economic policy. American Economic Review 1994; 84(3):369 – 95. Government Accounting Office Alzheimer’s Disease. Estimates of Prevalence in the United States, HEHS-98-16 1998; US Government Printing Office, Washington.

Hagen T, Liu J, Lykkesfeldt J et al. Feeding acetyl-L-carnitine and lipoic acid to old rats significantly improves metabolic function while decreasing oxidative stress. Proceedings of the National Academy of Science 2002; 99(4):1870 – 75. in’t Veld B, Ruitenberg A, Hofman A et al. Nonsteroidal Antiinflammatory drugs and the risk of Alzheimer’s disease. The New England Journal of Medicine 2001; 345(21):1515 – 21. Kaplan EL. Global assessment of rheumatic fever and rheumatic heart disease at the close of the century. Influences and dynamics of populations and pathogens: a failure to realize prevention? Circulation 1993; 88(4):1964 – 72. Kaplan GA & Keil JE. Socioeconomic factors and cardiovascular disease: a review of the literature. Circulation 1993; 88(4):1973 – 98. Lakatta EG. Health, disease, and cardiovascular aging. America’s Aging: Health In An Older Society 1985, pp 73 – 104; National Academy Press, Washington. Lanska DJ & Mi X. Decline in US stroke mortality in the era before antihypertensive therapy. Stroke 1993; 24(9):1382 – 8. Liu J, Head E, Gharib A et al. Memory loss in old rats is associated with brain mitochondrial decay and RNA/DNA oxidation: partial reversal by feeding acetyl-L-carnitine and/or R-a-lipoic acid. Proceedings of National Academy of Science 2002; 99(4):2356 – 61. Manton KG (2004a); Testimony, presented at the Joint Economic Committee of the U.S. Congress, Washington, 22nd July 2004. It can be viewed at this website (http://jec.senate.gov/− files/ Mantontestimony.pdf). Manton KG. Aging and longevity of human populations. In L Martini (ed) Encyclopedia of Endocrine Diseases 2004b, vol 1, pp 116 – 21; Elsevier, San Diego. Manton KG, Akushevich I & Kulminski A. Human mortality at extreme ages: new data and analysis. Demography 2004b (in review). Manton KG & Gu X. Change in physical and mental function: prospects. In HW Wahl, C Tesch-Romer & A Hoff (eds) New Dynamics in Old Age: Individual, Environmental, and Societal Perspectives, Society and Aging Series, J Hendricks (Series ed) 2005a; Baywood, Amityville. Manton KG & Gu X. Disability declines and trends in individual medicare expenditures. Ageing Horizons 2005b; 2:25 – 34. Manton KG & Stallard E. Longevity in the United States: age and sexspecific evidence on life span limits from mortality patterns: 1960 – 1990. Journal of Gerontology Series A – Biological Sciences and Medical Sciences 1996; 51(5):B362 – 75. Manton KG, Stallard E, Woodbury MA & Dowd JE. Time-varying covariates in models of human mortality and aging: multidimensional generalization of the Gompertz. Journal of Gerontology: Biological Sciences 1994a; 49:B169 – 90. Manton KG, Stallard E & Singer BH. Methods for projecting the future size and health status of the U.S. elderly population. In D Wise (ed) Studies of the Economics of Aging 1994b, pp 41 – 77; University of Chicago Press, Chicago. Manton KG, Stallard E & Tolley HD. Limits to human life expectancy: evidence, prospects, and implications. Population and Development Review 1991; 17(4):603 – 37. Manton KG, Volovyk S & Kulminski A. ROS effects on neurodegeneration in Alzheimer’s disease and related disorders: on environmental stresses of ionizing radiation. Current Alzheimer Research Lahiri DK (ed), 2004a; 1(4):277 – 93. Manton KG, Yashin A & Ukraintseva S. Conjectures about a new experimental model for population age changes in longevity, neurodegeneration and sensory loss: Apis Mellifera. Demographic Research 2005 (in review). Marenberg ME, Risch N, Berkman LF et al. Genetic susceptibility to death from coronary heart disease in a study of twins. New England Journal of Medicine 1994; 330(15):1041 – 6. Marriotti S, Sansoni P, Barbesino G et al. Thyroid and other organ-specific autoantibodies in healthy centenarians. Lancet 1992; 339:1506 – 8. McCully KS. Homocysteine theory of arteriosclerosis: development and current status. In AM Gotto Jr & R Paoletti (eds) Atherosclerosis Reviews 1983, vol 11, pp 157 – 246; Raven Press, New York. Moon J, Bandy B & Davison AJ. Hypothesis: etiology of atherosclerosis and osteoporosis: are imbalances in the calciferol endocrine system

THE DEMOGRAPHY OF AGING implicated. Journal of the American College of Nutrition 1992; 11(5):567 – 83. Mozar HN, Bal DG & Farag SA. The Natural history of atherosclerosis: an ecologic perspective. Atherosclerosis 1990; 82:157 – 64. Pathobiological Determinants of Atherosclerosis in Youth Research Group (PDAY). Relationship of atherosclerosis in young men to serum lipoprotein cholesterol concentrations and smoking. Journal of the American Medical Association 1990; 264:1018 – 24. Prigogine I & Stengers I. The End of Certainty, Time, Chaos and the New Laws of Nature 1997; The Free Press, New York. Venditti P, De Rosa R & Di Meo S. Effect of thyroid state on H2O2 production by rat liver mitochondria. Molecular and Cellular Endocrinology 2003; 205(1 – 2):185 – 92. von Eckardstein A, Malinow R, Upson B et al. Effects of age, lipoproteins, and hemostatic parameters on the role of homocyst(e)inemia as a cardiovascular risk factor in men. Arteriosclerosis, Thrombosis, and Vascular Biology 1994; 14(3):460 – 64.

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Warner HR, Fernandes G & Wang E. A unifying hypothesis to explain the retardation of aging and tumorigenesis by caloric restriction. Journal of Gerontology: Biological Sciences 1995; 50A:B107 – 9. Weisenthal L (2004); Cell culture drug resistance testing (CCDRT). In Chemosensitivity testing (http://virtualtrials.com/assay.cfm). Weitzel JM, Iwen KA & Seitz HJ. Regulation of mitochondrial biogenesis by thyroid hormone. Experimental Physiology 2003; 88(1):121 – 8. Wolozin B, Kellman W, Ruosseau P et al. Decreased prevalence of Alzheimer disease associated with 3-Hydroxy-3-methyglutaryl coenzyme a reductase inhibitors. Archives of Neurology 2000; 57:1439 – 43. Wrutniak-Cabello C, Casas F & Cabello G. Thyroid hormone action in mitochondria. Journal of Molecular Endocrinology 2001; 26: 67 – 77. Zandi P, Anthony J, Khachaturian A et al.Cache County Study Group. Reduced risk of Alzheimer disease in users of antioxidant vitamin supplements: the Cache County Study. Archives of Neurology, 2004; 61(1):82 – 8.

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Social and Community Aspects of Aging Rodney M. Coe, John E. Morley and Nina Tumosa Saint Louis University School of Medicine and Saint Louis Veterans’ Affairs Medical Center, St Louis, MO, USA

INTRODUCTION The interactions of social and community factors and aging are extraordinarily complex (Figure 1). It is important for the health-care professional to be aware of the impact of social and community factors on the health and well-being of the older person.

has resulted from improved sanitation, better nutrition, housing, and working conditions. More recently, vaccinations of children and older persons, treatment of infectious diseases, improved management of chronic conditions, enhanced neonatal survival and improved care for persons with disabilities have all further increased life span. The number of elderly people in a society depends primarily on the number of births 70+ years previously and the subsequent mortality of that cohort over those 70 years.

DEMOGRAPHY OF AGING Relative Aging The Graying of Nations The graying of nations (Butler, 1979) is a metaphor that has been used to describe the demographic changes that have taken place in all industrially developed countries during the past 100 years. It describes an increase both in the numbers of elderly people and in the proportion of the population that is elderly.

Absolute Aging In both developed and developing nations, there has been a rapid growth in the numbers of elderly people. This has led to a need to shift resources from young to old and to redesign communities to deal with the problems of disability and aging. The rate at which a nation has aged, its gross domestic product and the political will of the nation to recognize the geriatric imperative are all factors that decide the quality of life for older persons.

The Causes of Absolute Aging The increase in numbers of older people is primarily due to the increased expectation of life at younger ages that

The relationship of the number of older to the number of younger people in a society is of importance. Three factors determine the rate of relative aging: fertility rates, mortality rates, and, at a national level, patterns of migration. As a country develops economically, there is usually a decline in mortality, which increases the numbers of older people. However, it is not until fertility declines, usually about 20 years later, that the relative age of the population begins to increase. This has happened in all the developed countries, except those whose age structure has been significantly affected by immigration. Rising life expectancy and declining birth rate have noticeable effects on the age structure of a population. The old age dependency ratio, that is, the number of people aged over 65 per 100 persons of working age (15–64 years old), will increase by 2050 to over 2.5 times in the developed countries from just under 8.7 to over 22.6. In the developed countries, it will double to 4.4. The old age dependency ratio is most useful both for those primarily concerned with the management and planning of staff-intensive caring services and for economists and actuaries trying to forecast the financial consequences of pension policies (Figure 2). The demographic trend in many less-developed countries has a less dramatic effect on the economic systems than in many industrial countries, primarily due to the fact that lessdeveloped countries usually have no or only rudimentary


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HUMAN AGING: SOCIAL AND COMMUNITY PERSPECTIVES Income community supports Disasters

Environment Genome Phychosocial relationships

Disease

Disability

Depression anxiety

Death

Coping skills

Spirituality religion Figure 1 An illustration of the complex interrelationship between community/social aspects of aging, the genome and the progression of disease and disability toward death in the older person

pension systems. However, the societal implication of the demographic development in these countries remains precarious as a declining number of young people are available to take care of an increasing number of older people (UN website, 2004).

Retirement Migration

and to maintain friendship contacts. The second move is precipitated by moderate functional disabilities, complicated by widowhood, and is often toward the community in which an adult child resides. The third move is due primarily to severe disabilities, and is local and toward an institution such as a congregate living or custodial facility (see discussion on Housing Problems). In England, there has also been a southern migration, particularly to the southern coastal areas. Karn (1977) showed that people moved soon after retirement for a variety of reasons (Table 1). With the development of the European Union, many persons from the United Kingdom now migrate upon retirement to Southern Europe. The effect on aging of these diverse language, cultural, and health-care systems represents fascinating study for the future. Migration over the lifetime from a poor to a more advantaged community could improve the mortality of the migrants (Brimblecombe et al., 2000). While migration for functional elderly to better climates is on the whole positive, the development of disability often leads to frustration. With aging and the onset of cognitive and other problems, older persons often require Table 1 Main reasons for retirement move

Sample number Reasons for moving

The distribution of old people, and thus their proportion in the population, varies very much from one part of a country to another. Although the main reasons for this range are variations in mortality and fertility rates, the migration of retirees also affects distribution. In the United States, the general trend has been a migration from colder to milder climate, especially to Florida, South Carolina, Arizona, Nevada, and California. Longino (1990) described migration patterns of older people in terms of three moves. The first generally occurs at retirement, and involves moving for improved amenities (such as weather)

Better climate; cleaner air; sea air Health reasons Flat country To get away from town or live in a quiet place To live in a bungalow Having to leave a tied house The expense of living in the previous place To have a change To join friends or relations Other

Bexhill

Clacton

503

487

33 11 1 16

19 18 1 10

4 5 5 7 10 7

9 5 9 9 15 6

Reproduced from Karn V., Retiring to the Seaside, 1977, by permission of Taylor & Francis.

Elderly dependency ratio 50 Population aged 65 or over to the population aged 15−64

45 40

Total dependency ratio Least developed countries

Sum of the population aged 0−14 and that aged 65+ to the population aged 15−64

100 90

35 Other less 30 More developed developed countries countries 25

20 World

World

Other less developed countries

5

More developed countries

0 1950 1960 1970 1980 1990 2000 2010 2020 2030 2040 2050 Figure 2 Demographic dependency ratio (Source: UN (2004 Revision))

70 60

15 10

Least developed countries

80

50 40

1950 1960 1970 1980 1990 2000 2010 2020 2030 2040 2050

SOCIAL AND COMMUNITY ASPECTS OF AGING

an advocate to help them make health-care decisions and to deal with financial problems. The loss of the ability to drive safely dictates that choosing a place to migrate to, must take into account the availability of transportation and the juxtaposition of essential shopping and entertainment facilities. In the United States, a new profession of case manager has developed. Case managers are used extensively by concerned adult children to provide care for their older parents who live at a distance.

Effects of Immigration Two forms of immigration can affect the older person: (1) migration as an adult and (2) migration beyond pensionable age. Adult immigrants may have different rates of certain diseases in older age than the population they immigrated to, for example, immigrants from Yugoslavia and Hungary had a higher stroke incidence than Swedes living in Malmo, Sweden (Khan et al., 2004). Alternatively, immigration can lead to altered disease patterns. Japanese immigrants to Brazil have different cancer mortality rates than do Japanese in Japan (Iwasaki et al., 2004). Immigrants may or may not adapt to diet and health practices of their host country. For example, older Koreans in the United States often continue to utilize traditional Korean medicine (Hanbang) (Kim et al., 2002). Surprisingly, immigrants to the United States have a lower overall mortality than their American born counterparts (Singh and Siahpush, 2001). Quality of life may also change. Polish-American ethnic elderly had a significantly better subjective quality of life than Polish-immigrant elderly, who in turn had a better subjective quality of life than Poles in Poland (Berdes and Zych, 2000). Studies of Chinese immigrants to Canada and New Zealand have suggested a high rate of depression in older Chinese immigrants compared to the general population. Immigration has assorted effects on aging. These may either be beneficial or deleterious. Awareness of health attitudes and health problems specific to older immigrant populations are an essential part of the therapeutic armanterium of health-care professionals.

The Male-to-female Ratio The sex ratio of men to 100 women in the older age-groups is an aspect of population aging meriting special mention. The expectation of life at birth (Table 2) is about 5 years greater for females in most developed countries than it is for males. In Britain, the difference between the life expectancy at the age of 60 is about 3.5 years. In the United States, the sex ratio declines by 67% from ages 65–69 to 100+ (Figure 3). There are biological and social reasons for the differences in life expectancy and also for the fact that there are more older women than old men. Biologically, the high mortality of male fetuses and infants and the inhibitory effect of

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Table 2 Expectancy of life in males and females from birth

Country Australia Bangladesh Canada France Germany India Japan Netherlands Russia United Kingdom United States

Males

Females

77 61 76 75 75 63 78 76 62 76 76

83 61 83 83 81 64 84 82 73 81 80

From OECD Factbook: Economic, Environmental and Social Statistics (2005); http://fiordiliji.sourceoecd.org accessed 6/22/2005.

Age (years) 92

55–64

83

65–74

67

75–84

85 and over

46

Figure 3 Sex ratio of people 55 years and over by age: 2002 (Number of men per 100 women) (Source: US Bureau of the Census, Annual Demographic Supplement to the March 2002 Current Population Surveys)

estrogens on the development of atherosclerosis both play a part. However, social influences appear to be more important. In the early twentieth century, there were more men than women among the elderly of several developed countries, so the reversal of the sex ratio is a relatively recent phenomenon. The change would seem to have been due to the differing lifestyles of men and women. The prevalence of cigarette smoking, high alcohol consumption, and exposure to hazards of the workplace have penalized men in comparison to women. In some rapidly developing nations, such as India and Bangladesh, the ratio of older males to females is close to 1. A higher death rate of men than women during wars has also affected the ratio, while higher rates of mortality from homicide and road traffic accidents continue to have an effect during peacetime. This is particularly evident in modern Russia where there is an 11-year difference between males and females related to societal problems, following the fall of the Soviet Empire. Finally, decreased death rates during pregnancy and decreased number of pregnancies has dramatically decreased female mortality (Table 3). As the lifestyles of men and women become more alike, the gap will probably narrow; changes in female morbidity and mortality associated with increased consumption of

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HUMAN AGING: SOCIAL AND COMMUNITY PERSPECTIVES Table 3 Estimated average number of children to parents born in different years

Year of birth of parent 1871 1881 1891 1901 1911 1921

Average number of children

Average number of children surviving to age 45

4.8 4.1 3.3 2.6 2.2 2.0

2.7 2.5 2.2 2.0 1.7 1.6

Disease

Aging The social consequences of growing old

Source: Reprinted from Care of the Elderly: Meeting the Challenge of Dependency 4th edition, AN Exton-Smith, J Grimley Evans. Copyright 1977 with permission from Elsevier.

Disability

alcohol and cigarettes are trends already apparent in younger cohorts.

The Changing Family The structure of the modern family in the postindustrialization period has been influenced by increased age at marriage, increased divorce rate (50% in the United States), high geographic mobility, an increasing proportion of women in the labor force and fewer children. In the United States, these trends have been exacerbated in the “baby boomer” generation (those born between 1945 and 1965). These trends would seem to make it more difficult for people to look after their elderly relatives when they become dependent. In many cases, this has created the “Sandwich Generation”, where the middle-aged person needs to provide care for both dependent children and parents. Nevertheless, there is no evidence that the modern family in Britain or the United States cares less for its elders than did the family in the past. In fact, in the United States about 80% of older persons have living children, two-thirds of whom live within 30 minutes of the elderly parent. Furthermore, about 75% of those over 65 have some contact (personal or by telephone) each day. Support from adult children (transportation, financial and emotional) make it possible for 95% of people over 65 to live in the community and, of those, 54% live with spouse alone, 15% with other relatives, and 31% live alone (Administration on Aging, 2004). The vast majority (82%) live independently. Of those who need assistance for functional disabilities, 30% of the needs are met by family members, with the balance being met by a combination of family and formal community agency services. Only 4.5% of older persons in the United States live in nursing homes, belying myths that families do not provide at least as much support as they did in the past.

GROWING OLDER – THE SOCIAL PROCESS Although the distinction is arbitrary, it is useful to try to separate the effects of the physical processes affecting people as

Figure 4 Aging, disease, disability and the social consequences of growing old

they grow older from the effects of the social consequences of attaining an advanced chronological age. There are three of these physical processes – aging, disease, and disability – and these overlap with each other and with the social process which is often called growing old (Figure 4). In this chapter, we will consider the social problems that occur as a result of growing old.

A Life Course Perspective on Age It is useful to view older people as a product of life course events. These are depicted in Figure 5, in which life activities are arrayed against chronological age, representing what is culturally the “normal” course of events. Thus, infancy, childhood and adolescence occur in the first two decades of life and involve preparation for a job while living at home as a dependent. Adulthood and middle age bring with them increasing involvement in work, marriage and creating a family in an independent setting. Persons in old age, however, will have experienced departure of grown children, retirement, perhaps death of a spouse, family and friends and increasing dependency, especially from functional health limitations. From a social psychological perspective, the transition from youth to adulthood may be seen as increasing attachment to one’s social groups through meaningful and productive roles. Likewise, the transition from adulthood to old age may be seen as detachment from one’s social groups as these meaningful and productive roles are given up. This may help account for the reports that the very old are, or at least perceive themselves to be, isolated, a “burden to society” and to have feelings of unworthiness. In fact, clinical depression is a common problem for older people, which could be exacerbated by these perceptions.

SOCIAL AND COMMUNITY ASPECTS OF AGING 0

10

30

20

50

40

105

60

80

70

90

Chronological age (years) Childhood Infancy

Adolescence Young adulthood

Middle age

Later maturity

Old age

Life course

Job Occupational Preparation experimentation choice

Phasing out

Maximum involvement

Retirement can begin anywhere in here

Occupational cycle Occupational career

Retirement

Marriage usually occurs in here ‘‘At home’’ Family cycle

On your own

Parenthood

Dependent Economic cycle

Last child leaves

‘‘Empty Nest’’

Widowhood likely from here on

Independent Major purchases

Dependent Maintenance purchases

Figure 5 Relationships among age, life cycle, occupational cycle, and family cycle (These relationships fluctuate widely for specific individuals and for various social categories such as ethnic groups or social classes) (Reproduced from (Atchley RC, 1977). Copyright The Thomson Corporation)

Social Problems When people talk about the social problems of elderly people, they are usually referring to certain practical problems that occur more frequently among older people, principally poverty, housing problems, difficulties with transportation, and isolation. The reasons why older people suffer from certain types of social problems more frequently than younger people are listed in the following. Poverty

Many of the problems of older people are simply due to the inability to purchase needed services to maintain an acceptable quality of life. Immobility

The high prevalence of disabling disease combined with the difficulties older people have with public transport, compounded by poverty that restricts their use of cars and taxis, makes them less mobile than younger people. Immobility is the cause of many social problems.

Attitudes of Older People

Because of their upbringing, older people are, in general, less assertive than younger people. Because many were brought up in a culture in which the individual had fewer rights than he/she has today, many are less inclined to appeal against official decision, to seek the help of elected representatives, or to try to overcome bureaucratic inertia than younger people. In the United States, this is changing rapidly, with older persons becoming much more assertive. This began with the “gray panther” movement, and is expected to become even more prominent as the “baby boomers” generation reach old age.

POVERTY The word poverty is so commonly used that it may seem unnecessary to define, but the word has two aspects which need to be distinguished – poverty threshold and relative poverty – and this distinction is particularly important at a time when there are rapid fluctuations in prices and wages. Poverty threshold is defined by comparing a household’s income with the level of prices of the basic commodities

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necessary for life – the subsistence level, sometimes called the “poverty line” or “bread line”. Those whose incomes are below the minimum level necessary for subsistence are deemed to be living in poverty. The definition of relative poverty is made by comparing a household’s income with the average level of incomes in their society. Although individuals’ incomes may be sufficient to provide themselves and their dependents with the necessities of life, they may find their relative poverty upsetting because it symbolizes their low status. J. K. Galbraith, a famous American economist, has described the condition of relative poverty eloquently: “People are poverty stricken when their income, even if it is adequate for survival, falls markedly below that of the community. Then they cannot have what the larger community regards as the minimum necessary for decency and they cannot wholly escape, therefore, the judgment of the larger community that they are indecent. They are degraded, for in the literal sense they live outside the grades or categories which the community regards as acceptable”. In the United States, the median household income in persons over 65 years of age has increased from $16 882 to $23 152 (in 2002 dollars). Since the mid-1960s, poverty rates for persons 65 years and older have declined from nearly 30% to 10%. Older persons now have similar poverty rates to those seen in working persons. Over the same period, there has been an increase in poverty rates for those under 18 years of age (Figure 6). Between 1984 and 2001, the median net worth of households headed by a person age 65 years or more has increased by 82%. However, older white 35

30 65 years and over 25

Percent

Under 18 years 20

15

100 Income of household 65 (Income of household with head aged 50–59 expressed as 100%)

Age of household

36

31

26

50–59 60–64 65–69 70–74 Over 75

Figure 7 Income of household for various age-groups. From Age Concern (1977)

households have nearly 5 times the net worth of older black households. Social security provided 90% of income for one-third of Americans over 65 years of age. Other sources of income reported were assets (55%), private pensions (29%), government pensions (14%), and earnings (22%). What is hidden by a simple comparison of “pensioner households” with “young households” is that there is a very wide range of wealth within the group of pensioner households. In general, older people are poorer (Figure 7). The wide disparity is not due to a drop in income as people grow older, but to the fact that the proportion of people in each age-group who have an occupational pension decreases the older the age-group considered. This, in turn, is due to the fact that occupational pensions are a relatively recent innovation and it is therefore only younger retired people, those retiring more recently, who have qualified for them. The difference between the income of different age-groups of retired people is accentuated because men die younger than women, on average, so that the older groups consist of relatively more women, many of whom are eligible for neither national insurance nor occupational pensions and depend on a supplementary pension which is set at the lowest social security rate. Poverty is most common, therefore, among elderly women, particularly among those who never married.

10

HOUSING PROBLEMS

18–64 years 5

0

Environmental Problems 1966

1970

1975

1980 1985 Year

1990

1995

2002

Figure 6 Poverty rates by age: United States, 1966 – 2002. Note: Data shown are the percent of persons with family income below the poverty level. See Data Table for data points graphed and additional notes (Source: US Census Bureau, Current Population Survey)

For some older people, the cause of their housing problem is not their dwelling but its environment. Many of those who lived in the city centers when they were first married have seen the neighborhood change. Some feel that the area has “gone down”, that those who now live there do not have the same standards as they do, and that they are now aliens in a hostile environment in which they once felt at home.


The problems of elderly people in city centers and areas of urban deprivation are serious and difficult to remedy because often the best remedy is a move to another area in which the person may feel equally alien, although the majority of those who move do settle well and happily.

Structural Problems Often, it is the dwelling itself that is the principal cause of the older person’s concern. Common problems and their solutions can most easily be presented in a table (Table 4). The services listed here are not universally available, and even where such services exist, older people often have difficulty mobilizing them. Every health professional can help by being aware of the range of services available, suggesting ways in which the dwelling can be improved and helping the person to contact the appropriate services.

Difficulties Caused by Disability Sometimes the dwelling itself is suitable until the onset of disability, and the type of problem that most commonly causes a housing problem is the onset of a disabling disease that affects the older person’s ability to climb the stairs, either stairs inside the house leading to the bathroom and toilet or the stairs leading to an apartment. Sometimes the circulation space within the house is too small to allow easy movement from room to room for a person using a wheelchair or walking aid. The optimum solution to this type of difficulty is adaptation to the dwelling, and the domiciliary occupational therapist is the professional with the skill to do this. Solutions include the installation of ramps and indoor elevators. Adaptation of the kitchen and bathroom and addition of handrails can increase the safety of the house.

Table 4 Solutions to housing problems

Problem

Solution

Lack of toilet, bath, or hot water

The provision of grants and loans to help those who do not have the necessary capital Help from voluntary services with decorating and minor repairs Provisions of grants and loans for major repairs The provision of financial help with heating costs Adaptation of the dwelling, for example, ramps, rails, chair elevation Installation of more effective and efficient heating Improved insulation

Difficulties with decorating, minor repairs such as broken windows and major repairs such as rewiring The cost of rent and rates or property taxes Problems caused by disability

Difficulty with heating

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Making a Move The doctor’s opinion about housing decisions is often as highly respected as his or her opinion about health decisions, particularly on that most difficult decision – “should I move or stay put”? Obviously, each case is unique but it is possible to list guidelines for decision making. Tables 5 and 6 give good and bad reasons for moving. One of us (JEM) uses the analogy of bungee jumping. When living alone is no longer as safe as bungee jumping, then it is time to move to a protective environment. In general, every attempt should be made to solve the housing problem from which the old person feels he or she has to move away to remove the need for a move. That is not to say that there is never a need to move. Children often want their parents to move before it is necessary and older adults put off the move as long as possible. The development of “smart homes”, lifeline alarms, and so on, are further delaying the time to when a decision has to be made to move. The decision of whether an older adult should move into a relative’s home or to an institutional environment represents one of the hardest decisions associated with aging for both the older person and the caregiver. Sheltered or congregate housing in the United Kingdom and senior apartment buildings or assisted living facilities in the United States are the types of housing that most people think of when new housing for elderly people is mentioned, although many move to independent flats or bungalows. Congregate housing offers security and reassurance and a well-designed and heated environment to elderly people and thus meets the needs of many frail elderly people, particularly those who are: • nervous of living alone; • anxious that they are not able to call anyone if they should fall ill; • at risk of hypothermia or hyperthermia; Table 5 Bad reasons for moving

• Because of structural problems; the possibility of solving the structural problems should always be explored first • Because of financial problems; the provision of the full range of financial benefits may solve the problem • Because of disability; the advice of an occupational therapist should be sought • To move away from an area in which the old person feels “no one cares”; more people may be assisting than he or she is prepared to recognize

Table 6 Good reasons for leaving

• To move nearer a son, daughter, or relative who is willing and able to offer care • To move away from a dwelling that is impossible to repair, improve, or adapt • To move away from an environment that is causing severe depression or anxiety • To move to sheltered housing if living alone is no longer safe

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• isolated, although it should be said that some people feel just as isolated in sheltered housing as in an independent dwelling. Sheltered housing is not always suitable for the person who has antisocial tendencies or for the very confused person because the caregiver cannot cope with a large number of dependent people or with very dependent people. The fact that the caregiver lives on site has many benefits, but it also has its drawbacks because he or she may be called incessantly by a confused person. It may be that the provision of more staff, that is, the creation of “very sheltered housing”, will overcome some of the problems in sheltered housing, but it is always important to remember that the majority of disabled elderly people live and will continue to live in independent dwellings.

RETIREMENT The concept of retirement was developed by the German chancellor Otto von Bismarck in the nineteenth century. His generals had asked that at some time they might be allowed to stop leading troops into battle. Bismarck asked his actuaries to calculate the age at which a general was unlikely to still be alive. When they told him it was 65 years, he magnanimously told his generals that they would be allowed to retire at 65 years of age with a state pension. He then introduced a national pension scheme to undermine the growing power of the Socialist Democratic Party. Before World War II, retirement in Britain was a rarity with only the rich and those who were incapable of keeping a job retiring. In 1901, 60% of men over 65 years of age were in paid work. This number had declined to 48% in 1931 and to 13% by 1980. Following the passage of the Old Age Pensions Act of 1908, the first old age pensions were paid in England to just under half a million people (mainly women) in 1909. Following World War II, there was an increase in occupational pensions and deliberate attempts by employers and the government to force retirement. Technological developments were, in part, responsible for the erosions of the light work jobs often held by older persons. To some extent, the “Structured retirement” of the 1950s and 1960s was partly responsible for the marginalization of older people and their definition as a distinct, dependent social work. Toward the end of the twentieth century, retirement has become more acceptable, with many persons retiring in their early 50s. In the United States, retirement became a reality for most old persons with the introduction of Social Security. The concept of retirement to “the golf course” has become a glamorized component of American Life. While Social Security is the bedrock of American retirement, for many it is their pension from their employer and personal investment that has allowed earlier retirement. In the present, insecurity about the ability of the government to fund social security and the government health plans for the old (Medicare) and the

poor (Medicaid) is creating numerous, often scatterbrained, schemes on how to alter the retirement system. Some older Americans have, in retirement, been at the forefront of the modern globalization movement by retiring to Mexico or Costa Rico, where they can better leverage the buying power of the dollar.

THE ‘‘GOLDEN AGE’’ MYTH Not only are modern societies those in which work is seen to be important, they are also societies in which wealth is an important determinant of status. The low income of elderly people, therefore, not only symbolizes the low esteem in which they are held but also perpetuates it. There is a myth about old age in times past that states that there was at one time a “Golden Age” for elderly people, an age in which it was good to be old and in which elderly people were loved and respected. The myth has become elaborated with time and some people believe that the Golden Age was destroyed by the industrial revolution because the traditional skills of elderly men and women, which they passed on to the younger generations by the fireside and in the inglenook, were rendered redundant by the speed of change at that time (Fischer, 1977). Attractive though this myth is, there is no substance for it in fact. There never was a Golden Age for elderly people (Laslett, 1968). Rich and powerful elderly people were certainly able to hold onto their position of power and respect. Poor elderly people usually finished up in the workhouse, and it is important to remember that in many societies the proportion of elderly people living in this situation was higher in times past than it is today, and that the quality of care in modern institutions far surpasses that seen even a quarter of a century ago. If ever there was a “Golden Age” for older persons, it is today.

AGISM “Agism”, like “racism” and “sexism” is a prejudice. People who hold agist views believe that all people over the age of 65 are of declining intelligence, unable to change or learn, rigid, conservative, and dull. They assume that any physical or mental change is due to the aging process and is, therefore, untreatable. They also have a certain set of expectations about the way older people should behave, for example, that it is not normal for older people to drink to excess, show an interest in sex, or even to argue forcibly with people with whose views they disagree. Many people, both old and young, hold agist views and assume that all physical and mental changes are due to “old age”, that is, the aging process. It is only in the last few decades that health professionals have begun to appreciate the difference between the effects


of the aging process and the effects of disease; it is not surprising that many people assume that all the changes they see in old age are due to “old age”. It is extremely important to recognize that older persons, like young persons, show large variability in most characteristics. The two main effects of agist beliefs among older persons are: 1. Failure to seek help for treatable medical problems – “What else can you expect at my age”? 2. Failure to comply with medical advice – “It was kind of the doctor to give me tablets but there’s no point in taking them, it’s just old age that’s the problem”. Societal agist beliefs lead to undervaluing the contributions of older persons and providing inadequate societal resources for them. Political activism is needed to combat agism. Persons at all levels of the community and health professions often pay lip service to the aging demographic imperative, but fail to provide the financial benefits needed to overcome agist policies. Much of the media has recognized “agism” as politically incorrect and has tended to overcompensate by making older persons highly functional and cute. Some realistic movies about persons with Alzheimer’s disease have attempted to be more balanced.

THE EFFECT OF SOCIAL FACTORS ON THE AGING PROCESS George Valiant (2003) in his pioneering studies on aging in Harvard graduates and inner city persons living in Boston provided a framework for the effect of social relationships on aging successfully (Figure 8). He found that not smoking, exercise, not drinking alcohol to excess, obesity, and a stable marriage were the factors that predicted successful

109

aging. Modern studies support the concept that social connection and perceived social support have an effect on health but mainly in persons facing crises, stressors and/or adversity (Johnson and Krueger, 2005). When drosophila flies are placed in a stressful environment they have increased mortality (Parsons, 2002). In humans, social isolation or perceived lack of social support leads to more diseases and a higher mortality rate. Allostatic load is an index of wear and tear on the physiological systems of the body. Allostatic load has been shown in a longitudinal study to be related to heart disease, physical function, cognitive function, and death (Karlamangla et al., 2002). The degree of allostatic load could be significantly modulated in men with strong emotional supports. This was not true in women. Other studies have demonstrated the importance of perceived control and economic variables in modulating the health effects of the social environment. This has led to the development of the concept of socioeconomic resiliency. An example of these interrelationships was shown by Suda et al. (2001) when they found that having the person delivering meals-on-wheels sit with the older persons while they ate decreased both their nutritional risk and their dysphoria. Thus, the effect of social relationships on an older person developing and coping with disability depends not only on the strength of the relationship but also on the ability for the person to accept the relationship (e.g. are they depressed? Or did they have a lifelong inability to bond with others?) and their innate coping skills, as well as their economic status and the inherent severity of the disease process (Figure 9). Over half of men and women over 65 years of age do not engage in leisure-time physical activities (Figure 10). This is despite the fact that endurance and resistance exercise can modulate disease processes and slow down the development of frailty, disability, and death. Exercise enhances frontal lobe cognitive function and may slow down the development of cerebral atrophy. Thus, there is a need for increasing the awareness of the benefits of physical activity with aging. It is important that simple ways to improve physical fitness,

To age successfully Social relationships

Do not smoke

Get some exercise

Watch your weight

Strength of relationship (i.e. number of contacts/week)

Quality of relationship

Depression

Aging Disease potency Manage stress well

Do not abuse alcohol

Innate ability to bond

Disability Economic strength

Innate coping skills

Enjoy a stable marriage

Figure 8 Valiant, G – effect of social relationships on aging successfully

Figure 9 Factors modulating the ability of social relationships to modulate the aging process

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HUMAN AGING: SOCIAL AND COMMUNITY PERSPECTIVES 80 Men 60

Percent

65+ years 45−64 years 40 18−44 years 20

0

1998

2000

2002

80 Women

Percent

60

65+ years

Netherlands, while the lowest death rate was in Bentanzor, Spain, a city in which the percentage playing sports was only half of that in Culemborg, but alcohol intake was nearly double. Cross-sectional studies such as the SENECA represent an important tool to understand how social factors modulate disability and mortality. Another tool to examine the effects of social factors on aging is longitudinal studies in populations that are undergoing rapid change in their lifestyle. One such population is the Okinawans in Japan. This area, famous for its centenarians, has undergone rapid change from a caloric restricted, sweet potato-based diet to a rice and meat diet with greater calories and, at the same time, has decreased their energy expenditure. Early reports suggest that these lifestyle changes may be deleterious as males in Okinawa now have a life span that has sunk from 1st to 26th among the prefectures in Japan.

45−64 years 40

RELIGION AND SPIRITUALITY

18−44 years

20

0

1998

2000

2002

Figure 10 Adults not engaging in leisure-time physical activity by age and sex: United States, 1998 – 2002. Note: See Data Table for data points graphed, standard errors, and additional notes defining leisure-time physical activity (Source: Centers for Disease Control and Prevention, National Center for Health Statistics, National Health Interview Survey)

for example, climbing stairs rather than taking the elevator, can be as effective as organized activities. The importance of balance exercises, such as Tai Chi, to reduce falls needs also to be stressed.

LIFESTYLE, NUTRITION, AND HEALTHY AGING: LESSONS FROM THE SENECA STUDY The Survey in Europe on Nutrition and The Elderly: A Concerned Action (SENECA) examined lifestyle and nutrition in 19 towns throughout Europe, from Denmark to Portugal. All participants were born between 1913 and 1918. There was a large variation in lifestyle factors (de Groot et al., 2004). In Padua, Italy, 78% of older persons drink alcohol on most days compared to Culemborg in the Netherlands where less than 20% drank regularly. Smoking varied from 7% in Vila Franea de Xira in Portugal to 41% in Roskilde, Denmark. The percent of people who still played sports varied from 4% in Portugal to 32% in Yverdon, Switzerland. Physical activity and smoking habits both predicted death and dependency. However, the relationship varied greatly from town to town, with the highest mortality rate in males being in the

There is an emerging literature recognizing the role of religion and spirituality in the preservation of psychological and physical health of older persons. Thus, for example, Koenig et al. (1995) reported that in medical inpatients religiosity correlated with a lower likelihood of feeling downhearted and blue, boredom, loss of interest, restlessness, feeling hopeless or feeling as if other people were better off. Brown and Gary (1994) found that fewer depressive symptoms were associated with religious involvement in a group of urban African-American males. In Israel, religious orthodoxy was found to be protective against death from coronary heart disease, independent of lifestyle correlates (Goldbourt et al., 1993). Lack of comfort from religion and failure to participate in church events was associated with an increase in death following heart surgery (Oxman et al., 1995). In patients with lung cancer, prayer was, in part, responsible for psychological well-being (Meraviglia, 2004). Positive religious coping methods were found to be associated with health improvements. On the other hand, persons who were not at peace with religious issues, or saw God as punishing, had worse outcomes. Spirituality in Britain was shown to be a significant predictor of psychological well-being in frail older persons. Spirituality, but not religiosity, was associated with self-appraised good health (Daaleman et al., 2004). Spirituality is associated with a greater ability to deal with grief. In non-Judeo-Christian cultures, the role of spirituality is less clear; a study in Japan showed mixed effects; spirituality was positive in Thais (Pincharoen and Congdon, 2003; Kawa et al., 2003). Of interest, religious television or radio was associated with worse physical functioning and greater medical comorbidity (Koenig et al., 2004). Overall, the role of religion and spirituality can be summarized as predominantly improving psychological health with a lesser effect on physical health. There is a small literature suggesting that not all forms of religion are positive. The


most parsimonious model for describing the role of religion and spirituality on health is to assume that it increases coping skills and enhances access to support groups. Health-care professionals need to be aware of the religious and spiritual affiliations of their patients and, in appropriate cases, be prepared to incorporate them into a holistic model of health care. Prayer is a commonly used coping strategy for many older persons dealing with disability or life-threatening illnesses. Involvement of a person’s religious leader as part of the team approach to health care is important. In some countries, this may stretch to the need to involve the local shaman in the health-care team.

ANTIAGING MEDICINE Since the beginning of time, persons have sought the mythical fountain of youth (Fisher and Morley, 2002). This has led over the centuries to numerous unscrupulous people selling their version of “snake oil” to vulnerable older persons. Within recent times, pseudoscientific claims associated with the growth hormone and dehydroepiandrosterone as agents that will “reverse the aging process” regularly appear in newspapers, magazines, and books. Many of these claims are based on flawed studies originally published in mainstream medical journals. Others are based on hypotheses developed by scientists and published in mainstream literature and then translated as fact by the lay press. A recent example of this is the theories of Aubrey de Grey, which are futuristic and not yet ready for “prime time” (de Grey et al., 2002). In a 2003 book, Ronald Klatz and Robert Goldman claimed that “the future of antiaging medicine promises the elimination of the disability, deformity, pain, disease, suffering and sorrow of old age. In a few decades, the traditional enfeebled, ailing elderly person will be but a grotesque memory of a barbaric past”. Hyperbole such as this is reminiscent of the popular book, The Art of Living Long written by the Italian, Luigi Comaro, in 1550. The desire for longevity has led to eloquent claims by Linus Pauling that megavitamins will protect the cells from free radical damage. The concept that excess vitamins will rejuvenate remains alive today, despite studies suggesting that instead of prolonging life, they may shorten it. Within the next decade, we will be faced with the possibility that stem cells can reverse aging of muscle and cure Alzheimer’s disease. This research is accruing at increasing speed in Israel and South Korea, while under embargo in the United States. Such social factors will limit the rigor of scientific exploration into the role of stem cells and may eventually limit their use only to the very rich. From this brief recounting, it is clear that social factors have played, and will continue to play, a major role in the development of antiaging medicine. Further, its availability to the general public depends on the decision of regulatory agencies such as the Food and Drug Administration in the United States.

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THE ENVIRONMENT AND THE GENOME There is an increasing literature that the environment can modulate gene expression. Two examples of the environment interaction have been found with the APOE4 gene: (1) Head injury accelerates Alzheimer’s disease in persons who have the APOE4 allele (Mayeux et al., 1995); (2) APOE4 is a risk factor for ischemic heart disease predominantly in smokers (Humphries et al., 2001). The interaction of a major life event with a genetic predisposition increases the likelihood of major depression. Physical exercise produces different responses depending on the person’s angiotensin converting enzyme insertion deletion genotype. Similarly, the development of the fledgling science of pharmacogenomics has shown that the efficacy and side effects of drugs are associated with specific alleles. For example, persons with the apolipoprotein E allele have different responses to the antidepressant, paroxetine, dependent on the allele (Shanahan and Hofer, 2005). Side effects from paroxetine are related to the number of C alleles of HTR2α. These simple examples represent only the start of the exploration of gene/environment interactions. As shown by centenarians and other long-lived persons, it is both the genome and the environment that eventually determines the successful aging potential of a person. The new social science of aging in the twenty-first century will require the inclusion of the person’s genetic background to allow full interpretation of environmental effects.

ELDER ABUSE Approximately 5% of older persons suffer elder abuse. In most cases, this is not due to physical violence or theft (though these instances are unfortunately not rare), but are more often due to neglect. Thus, poor nutrition or worsening of pressure ulcers is commonly associated with poor care. Even health professionals have practiced elder abuse, ranging from the notorious English physician serial killer, Dr. Shipman, to the use of physical restraints. Overall, persons who abuse older persons are more likely to have been abused when they were young and to have a mental illness. The solutions to elder abuse are complex ranging from criminal prosecution and separation of the elder from the abuser to psychosocial therapies including such options as daycare, respite for the caregiver and increased home care.

THE INTERNET At present, older persons are much less likely to use the Internet than are middle-aged adults or children. However, this is changing rapidly. Many nursing homes offer Internet facilities for older persons to communicate with the children and grandchildren as well as to access the news. Older

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persons are also using the Internet to obtain health-care information. With the movement of the “baby boomers” in the United States into the young-old over the next decade, these uses are expected to increase exponentially. There will also be increased communication between physicians and their patients via the Internet. We can also expect to see an increase in telemedicine as a more technologically adept group of persons join the aging cohort.

CULTURAL COMPETENCY Shifts in populations have led to the requirement that health professionals acquire cultural competency and that social policy adapts to create more health professionals from ethnic minorities. A dramatic example of the effect of migration has been seen in the United Kingdom. In the 1950s, Bethnal Green was a predominantly white, workingclass neighborhood, whereas in the 1990s it had changed to Tower Hamlets, the home of large numbers of Bangladeshi immigrants. Woodford has transformed to the home for many affluent Asians and Wolverhampton now has a substantial population of persons of Caribbean origin. Changes such as these require training programs for health professionals in the beliefs of different cultures and how they impact the interactions between older persons and their health-care providers.

DISASTERS The events of 9/11 focused the attention of the world on the devastating effects of disasters. In all disasters, older persons are disproportionately affected. Studies in North Africa have shown that older persons are more likely to be left behind when genocide occurs and younger persons flee, creating separation between the generations. Older persons are also more likely to die during migrations from enemy troop areas and during periods of famine. In developed countries, heat waves are the most common disaster causing death. Over 400 older persons a year die from heat-associated death in the United States. Heat waves are often associated with power outages, which lead to air-conditioning being unavailable. This has been characterized as a “disaster within a disaster”. The appropriate measures for preventing heat-related deaths are outlined in Table 7. During disasters, such as hurricanes and earthquakes, onethird of older persons have a worsening of their medical conditions. The disruption of services following these disasters can lead to isolation of the older person, loss of home services and loss of access to prescription medicines. The appropriate contents of a disaster kit for older persons are listed in Table 8. Following disasters, there is an increase in myocardial infarctions. For example, the Hanshen-Awagi earthquake in Japan was associated with a threefold increase in myocardial infarctions.

Table 7 Preventing heat-related deaths

• When available, use home air-conditioning • If no home air-conditioning is available, try to go to an air-conditioned mall • Check frequently on persons at high risk • Wear lightweight, light-colored clothing • Reduce strenuous activities • Drink plenty of fluids • Avoid alcohol and caffeine • Take cool showers or baths frequently • Municipalities should develop a comprehensive heat emergency response plan including early warnings, appropriate health messages, and transportation to emergency shelters

Table 8 Items to be included in a senior disaster preparedness kit

Identification bracelet Extra pair of glasses/hearing aids List of medications List of diseases Set of emergency prescriptions 3 days to 1 week medication supply Flashlight Extra batteries Pet evacuation plan Family pictures Emergency numbers (including a contact for at least one family member who lives in another geographical area). A copy of FEMA’s “Are You Ready?” emergency preparedness handbook

Table 9 Symptoms of nerve agent

• • • • • • • • • • •

Excessive tearing and salivation Miosis Ptosis Nausea Vomiting Bronchospasm Bradycardia Muscle fasciculations Paralysis Restlessness Delirium

Deaths from fires are common in older persons. Persons living in mobile homes or old homes with faulty electrical work are at particular risk. Smoking and excessive alcohol use are human behaviors that are often associated with fires. Smoke detectors are a community action that can save lives. Terrorism affects many countries. While a bombing incident is easily recognized, there is a need for surveillance techniques to detect outbreaks of disease as was shown in the slow recognition of the salmonella outbreak by the terrorist cult in Oregon in 1980 and the anthrax outbreak in the United States in 2001. The anthrax outbreak demonstrated that older persons had a greater susceptibility to biological agents and a poorer outcome than young persons. Terrorist attacks may include (1) biological agents, for example, smallpox, ricen, anthrax, plague, salmonella, ebola; (2) chemical agents, for example, vesicants (blistering agents) such as lewisite or mustard gas or cholinesterase inhibitors from the G group (GB-Sann, GD-Soman) or the V-group (VX); (3) nuclear


weapons or attacks on nuclear power plants or nuclear waste transport systems. The symptoms produced by cholinesterase inhibitors are listed in Table 9. It is the responsibility of all to see that older persons are properly prepared for disasters, cared for during disasters, and returned to their homes after disasters.

KEY POINTS • Genome/environmental interactions play an important role in the development of disease and disability with aging. • Disasters have a disproportional effect on older persons. • Religion and spirituality have positive effects on aging.

KEY REFERENCES • Berdes C & Zych AA. Subjective quality of life of Polish, Polishimmigrant, and Polish-American elderly. International Journal of Aging & Human Development 2000; 50:385 – 595. • Brimblecombe N, Dorling D & Shaw M. Migration and geographical inequalities in health in Britain. Social Science & Medicine 2000; 50:861 – 78. • Iwasaki M, Mameri CP, Hamada GS & Tsugane S. Cancer mortality among Japanese immigrants and their descendants in the state of Sao Paulo, Brazil, 1999 – 2001. Japanese Journal of Clinical Oncology 2004; 34:673 – 80. • Kim M, Han HR, Kim KB & Duong DN. The use of traditional and Western medicine among Korean American elderly. Journal of Community Health 2002; 27:109 – 20. • Koenig HG, Cohen HJ, Blazer DG et al. Religious coping and cognitive symptoms of depression in elderly medical patients. Psychosomatics 1995; 36:369 – 75. • Meraviglia MG. The effects of spirituality on well-being of people with lung cancer. Oncology Nursing Forum 2004; 31:89 – 94. • Oxman TE, Freeman DH Jr & Manheimer ED. Lack of social participation or religious strength and comfort as risk factors for death after cardiac surgery in the elderly. Psychosomatic Medicine 1995; 57:5 – 15.

REFERENCES Administration on Aging. 2004, http://www.aoa.gov/prof/statistics/profile/ 2004/2004profile.doc. Age Concern. Profiles of the Elderly 1977, Vol 1; Age Concern, London. Atchley RC. The Social Forces in Later Life 1977; Wadsworth, Belmont. Berdes C & Zych AA. Subjective quality of life of Polish, Polish-immigrant, and Polish-American elderly. International Journal of Aging & Human Development 2000; 50:385 – 595. Brimblecombe N, Dorling D & Shaw M. Migration and geographical inequalities in health in Britain. Social Science & Medicine 2000; 50:861 – 78. Brown DR & Gary LE. Religious involvement and health status among African-American males. Journal of the National Medical Association 1994; 86:825 – 31.

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Butler RN. The Graying of Nations: Creative Responses 1979; Age Concern, London. Daaleman TP, Perera S & Studenski SA. Religion, spirituality, and health status in geriatric outpatients. Annals of Family Medicine 2004; 2:49 – 53. de Grey ADNJ, Baynes JW, Berd D et al. Is human ageing still mysterious enough to be left only to scientists? BioEssays 2002; 24:667 – 76. de Groot LCPMG, Verheijden MW, de Henauw S et al. Lifestyle, nutritional status, health, and mortality in elderly people across Europe: a review of the longitudinal results of the SENECA study. The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences 2004; 59A:1277 – 84. Exton-Smith AN & Grimley Evans J. Care of the Elderly: Meeting the Challenge of Dependency 1977; Academic Press, London. Fischer DH. Growing Old in America 1977; Oxford University Press, Oxford. Fisher A & Morley JE. Antiageing medicine: the good, the bad and the ugly. The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences 2002; 57A:M636 – 9. Goldbourt U, Yaari S & Medali JH. Factors predictive of longterm coronary heart disease mortality among 10,059 male Israeli civil servants and municipal employees. A 23-year mortality followup in the Israeli Ischemic Heart Disease Study. Cardiology 1993; 82:100 – 21. Humphries SE, Talmud PJ, Bolla M et al. Apolipoprotein E and coronary heart disease in middle-aged men who smoke: a prospective study. Lancet 2001; 358:115 – 9. Iwasaki M, Mameri CP, Hamada GS & Tsugane S. Cancer mortality among Japanese immigrants and their descendants in the state of Sao Paulo, Brazil, 1999 – 2001. Japanese Journal of Clinical Oncology 2004; 34:673 – 80. Johnson W & Krueger RF. Predictors of physical health: toward an integrated model of genetic and environmental antecedents. The Journals of Gerontology. Series B, Psychological Sciences and Social Sciences 2005; 60B(Spec Issue I):65 – 78. Karlamangla A, Singer B, McEwen B et al. Allostatic load as a predictor of functional decline. Journal of Clinical Epidemiology 2002; 55:699 – 710. Karn V. Retiring to the Seaside 1977; Routledge & Kegan Paul, London. Kawa M, Kayama M, Maeyama E et al. Distress of inpatients with terminal cancer in Japanese palliative care units: from the viewpoint of spirituality. Supportive Care in Cancer 2003; 11:481 – 90. Khan FA, Zia E, Janzon L & Engstrom G. Incidence of stroke and stroke subtypes in Malmo, Sweden, 1990 – 2000: marked differences between groups defined by birth country. Stroke 2004; 35:2054 – 8. Kim M, Han HR, Kim KB & Duong DN. The use of traditional and Western medicine among Korean American elderly. Journal of Community Health 2002; 27:109 – 20. Koenig HG, Cohen HJ, Blazer DG et al. Religious coping and cognitive symptoms of depression in elderly medical patients. Psychosomatics 1995; 36:369 – 75. Koenig HG, George LK & Titus P. Religion, spirituality, and health in medically ill hospitalized older patients. Journal of the American Geriatrics Society 2004; 52:554 – 62. Laslett P. The World We Have Lost 1968; Methuen, London. Longino CF. Geographical distribution and migration. In RH Binstock & LK George (eds) Handbook of Ageing and the Social Sciences 1990, 3rd edn; Academic Press, San Diego. Mayeux R, Ottman R, Maestre G et al. Synergistic effects of traumatic head injury and apolipoprotein-E4 in patients with Alzheimer’s disease. Neurology 1995; 45:555 – 7. Meraviglia MG. The effects of spirituality on well-being of people with lung cancer. Oncology Nursing Forum 2004; 31:89 – 94. OECD Factbook: Economic, Environmental and Social Statistics 2005, http://fiordiliji.sourceoecd.org accessed 6/22/2005. Oxman TE, Freeman DH Jr & Manheimer ED. Lack of social participation or religious strength and comfort as risk factors for death after cardiac surgery in the elderly. Psychosomatic Medicine 1995; 57:5 – 15. Parsons PA. Ageing: the fitness-stress continuum and genetic variability. Experimental Aging Research 2002; 28:347 – 59.

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Pincharoen S & Congdon JG. Spirituality and health in older Thai persons in the United States. Western Journal of Nursing Research 2003; 25:93 – 108. Shanahan MJ & Hofer SM. Social context in gene-environment interactions: retrospect and prospect. The Journals of Gerontology. Series B, Psychological Sciences and Social Sciences 2005; 60B(Spec Issue I):65 – 78. Singh GK & Siahpush M. All-cause and cause-specific mortality of immigrants and natives born in the United States. American Journal of Public Health 2001; 91:392 – 9. Suda Y, Marske CE, Flaherty JH et al. Examining the effect of intervention to nutritional problems of the elderly living in an inner city area. The Journal of Nutrition, Health & Aging 2001; 5:118 – 23. UN website, 2004, http://www.dbresearch.com/servlet/rewebz.reweb? rwkey=u896714.

Valiant GE. Ageing Well: Surprising Guideposts to a Happier Life from the Landmark Harvard Study of Adult Development 2003; Little, Brown & Company, New York.

FURTHER READING Comaro L. The Art of Living Long, 1550. Klatz R & Goldman R. The New Anti-Aging Revolution: Stopping the Clock for a Younger, Sexier, Happier You 2003, 3rd edn; Basic Health Publications, California.

11

Sexuality and Aging John E. Morley Saint Louis University School of Medicine and Saint Louis Veterans’ Affairs Medical Center, St Louis, MO, USA

INTRODUCTION Sexuality remains an important component of quality of life throughout the life span. The spectrum of sexuality and aging is outlined in Table 1. The full expression of sexuality is dependent on biological, psychological, and social factors. Testosterone is a driver of sexuality in both sexes, but its effect is modulated by psychological and social factors. The effects of aging on sexuality can create major anxiety, but with adequate education, sexuality can remain enjoyable throughout life. There is much misinformation about sexuality. While open discussion of sexuality has become much more common in the last 40 years, many older persons come from a generation where sexuality remains a taboo subject. This chapter will explore both the biology of sexuality and aging, as well as the emergence of the special needs of a substantial cohort of older gays and their unique needs. The role of disease in sexuality of older persons will be addressed. Finally, the problems faced by older persons who have had lifelong paraphilias will be considered.

SEXUALITY AND THE OLDER WOMAN The major sexual problems reported by older women include lack of orgasm, lack of sexual interest, a decline in lubrication, failure to find an appropriate partner, dyspareunia, problems with safe sex, sexual aversion, and extramarital affairs (Nusbaum et al., 2004). The number of older females who have intercourse decline from 30 to 78% at 60 to 70 years to 8–43% at 80 years. Most older persons who are still sexually active have intercourse on an average of once a week. Approximately 45% of older women masturbate. Of those still having intercourse, 73% enjoy intercourse and the rest tolerate it. Only 21% of women over the age of 75 years still have a partner. Most studies have shown that the majority of physicians do not include sexual concerns and questions as part of their general history taking. Figure 1 provides the spectrum of sexuality and the older female.

A number of diseases have a major impact on sexuality in women. The disease that most alters a woman’s selfimage is breast cancer. Up to 40% of women with breast cancer have a reduction in their sexual activity (Kaiser, 2003). The effect of breast cancer on sexuality is highly dependent on the relationship the woman has with her partner. Urinary incontinence can modify sexual interactions in up to a third of women. Severe incontinence may lead to the need for separate beds. Uterine prolapse is more likely than incontinence to alter sexual relationships. Urogenital atrophy, due to estrogen deficiency, leads to vaginal dryness, vaginal bleeding, urge incontinence, urinary frequency and dysuria, irritation and pruritus of the labia and mons, dyspareunia, and urinary tract infections. All of these changes can lead to sexual dysfunction. A number of lubricants are now available to allow women to overcome vaginal dryness. Estrogen creams, tablets, and rings may also be useful in the management of severe vaginal dryness. However, it must be remembered that vaginal estrogen is absorbed and may have all the effects of oral or parenteral estrogen. Menopause occurs in women with an average age of 52 years. Epidemiological studies have suggested that the older a woman is at menopause, the longer she will survive following menopause. Smoking is a major cause of an early menopause. The major symptom of menopause is hot flashes. These occur in 85% of women at the time of menopause. While in most women hot flashes last less than 5 years, a few women continue to have hot flashes into their 80s. Environmental factors such as spicy foods and hot weather, and psychological factors, for example, stress, can be precipitants of hot flashes. Menopause is not necessarily associated with a decline in libido. Some women find the cessation of menses liberating. Use of estrogen is declining following the results of the Women’s Health Initiative and the HERS study. These studies showed that both estrogen alone and estrogen plus progesterone were associated with an increase in myocardial


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infarction, stroke, pulmonary embolism, and breast cancer (Grady et al., 2002; Rossouw et al., 2002). This was balanced by a decrease in hip fracture and colon cancer. Unfortunately, estrogen also appears to accelerate the onset of cognitive impairment in older women (Espeland et al., 2004). Testosterone levels decline rapidly between the ages of 20 to 40 years in women (Morley and Perry, 2003). There is then a slight increase in testosterone levels in women between the ages of 60 to 80 years. Testosterone, tibilone (an estrogen-progestagen-testosterone), and dehydroepiandrosterone (DHEA) all improve libido in older women. Besides increasing libido, testosterone has also been reported to improve general well-being, decrease mastalgia, decrease headaches, and increase bone mineral density and muscle mass (Table 2). The testosterone products available for women are listed in Table 3.

Table 2 Testosterone and women

↑ Libido ↑ General well being ↓ Mastalgia ↓ Headaches ↑ Bone mineral density ↑ Muscle mass

Table 1 Sexuality and aging – the spectrum

Table 3 Testosterone products available for older women

• Biological • Hypgonadism • Erectile dysfunction • Disease • Psychological • Depression • Sexuality attitudes • Perception of sexual attractiveness • Social • Social interactions • Partner availability • Physical fitness • Community education • Awareness of sexuality

• Testosterone Compounded vaginal creams Gels Testosterone undecanoate Estratest (estrogen plus methyltestosterone) • Tibolone • (DHEA) DHEA, Dehydroepiandrosterone.

Female hypoactive sexual desire disorder is defined as persistently or recurrently deficient (or absent) sexual fantasies and desire for sexual activity. This must cause marked distress or interpersonal difficulty. The condition cannot be

Dyspareunia

Extramarital affairs Decreased libido Decreased orgasm

Safe sex

Menopause

Vaginal dryness

Lack of partners Sexual aversion

Psychosocial

Physical

Dysphoria Sexuality and the older female

Disease

Incontinence

Figure 1 Sexuality and the older female

Depression

Arthritis

Breast cancer

Dementia

SEXUALITY AND AGING Table 4 Management of sexual dysfunction in older women

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• • • •

Listen/ask Permission giving Provide information Specific suggestions • Vibrators • Paraclitoral stimulation • Lubricants • Sex therapy

better ascribed to another psychiatric condition, for example, depression, or to the effects of a substance, for example, medication or a general medical condition. The approach to the management of sexual dysfunction in older women is given in Table 4. It is important to recognize that for many older women intimacy and “cuddling” are more important than intercourse. The sensitive clinician needs to recognize the specific needs of the individual and then work with her to obtain her goals. Some women will choose to use complementary therapies such as black cohosh or dong quai soy. It is important to recognize that there is no long-term data on their efficacy or safety. At present, the use of estrogen in women over 60 years of age should be avoided whenever possible. There is a clear need for increased research on sexuality in older women.

ERECTILE DYSFUNCTION Erectile dysfunction is defined as the inability to attain or maintain a penile erection sufficient for sexual performance on at least two-thirds of occasions (Morales, 2003). Physiologically, older males have an increased time for development of erection and less full erections with a decreased pre-ejaculatory secretion. During orgasm, there is a decline in expulsive force and urethral contractions. Following ejaculation, there is a rapid tumescence with rapid testicular descent. The refractory period is markedly prolonged. A number of older males have an active sex life (Bortz et al., 1999). However, studies in Germany and South America have found that 53% of men 70 to 80 years have some degree of erectile dysfunction (Rosen et al., 2004). The Massachusetts Male Aging Study showed that at 40 years of age, severe erectile dysfunction was present in 5.1% and moderate erectile dysfunction in 17% (Derby et al., 2000). By the age of 70, 15% had severe dysfunction and 34% moderate dysfunction. In the Olmsted County Study, 30% of men over 70 years of age had no erections, and only 10% had intercourse more than once a week (Masumori et al., 1999). The major risk factors for developing erectile dysfunction are heart disease, diabetes mellitus, and hypertension. Erections occur when the smooth muscle of the corpora cavernosa relaxes, allowing pooling of blood. Figure 2 demonstrates the different neurotransmitters involved in producing penile erection. Approximately half the males with erectile dysfunction are found to have vascular disease as a cause. Other causes

Endothelin

Norepinephrine (a) Contraction

Corpora cavernosa

Relaxation GMP

PDE5 cGMP

Acetylcholine Nitric oxide

Vasoactive intestinal peptide

Nitric oxide synthase Testosterone

Figure 2 Neurotransmitters involved in producing a penile erection

include medications, psychogenic causes, neuropathy, diabetes mellitus, thyroid disease, and hyperprolactinemia. Thiazide diuretics is the number one medication-associated cause of erectile dysfunction worldwide. Tobacco use is associated with increased erectile function. In dogs, nicotine decreased cavernous nerve stimulation and increased erections. In humans, smoking two cigarettes decreases the quality of papaverine-induced erections. While low testosterone levels decrease the production of nitric oxide synthase, most studies have failed to show that hypogonadism is a major cause of erectile dysfunction (Slag et al., 1983). Nevertheless, persons with low testosterone have poor quality erections. Testosterone treatment improves the quality of erections produced by phosphodiesterase5 inhibitors. Table 5 lists the causes of erectile dysfunction and Table 6 lists the available management strategies for erectile dysfunction. Table 5 Causes of erectile dysfunction

Vascular

– Atherosclerosis – Vascular leak

Medications Neurological

– Peripheral neuropathy – Spinal cord disease – Temporal lobe epilepsy

Urologic Endocrine

– – – –

Diabetes mellitus Hypothyroidism Hyperthyroidism Hyperprolactinemia

Peyronies Disease Recreational Drugs

– Tobacco – Alcohol – Opiates

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Table 6 Treatment options for an older male with erectile dysfunction

1. Psychological 2. Drugs • Sildenafil/Vardenafil • Uprima (Apomorphine SR) • Phentolamine 3. Intracavernosal injections • Alprostadil • Papaverine • Phentolamine 4. Vacuum tumescence device 5. Penile prosthesis Table 7 Pharmacokinetics of the phosphodiesterase-5 inhibitors

T Cmax T 1/2

Sildenafil (hours)

Vardenafil (hours)

Tadalafil (hours)

1 4

1 4–6

2 17.5

Table 8 Side effects of phosphodiesterase-5 inhibitors

• • • • • • •

Headache Flushing Dyspepsia Rhinitis Visual disturbance Hypotension Death (avoid nitrates)

The most common treatment for erectile dysfunction is a phosphodiesterase-5 inhibitor. This works by blocking the breakdown of cyclic GMP that has been generated by nitric oxide. There are 3 phosphodiesterase inhibitors in general use viz sildenafil, vardenafil, and tadalafil. The pharmacokinetics of these drugs is given in Table 7. The major side effects of phosphodiesterase-5 inhibitors are headache, flushing, dyspepsia, rhinitis, visual disturbances, hypotension, and death (Table 8). Persons on nitrates and α-adrenergic blockers should avoid phosphodiesterase-5 inhibitors. With aging, all phosphodiesterase-5 inhibitors have increased plasma concentration or area under the curve. Vacuum tumescence devices are useful for older persons who wish to have intercourse rarely, for example, once a month. Intracavernosal injections with vasoactive agents can produce a response rate as high as 74% in older males. A number of complementary medicines claim to improve erections, such as canthandrin or ginsenorides. These do not work and can produce hematuria. Overall, modern medicine will allow the majority of older males to obtain an erection (Table 6). It is important to include the partner in decisions concerning which approach is best. It is important not to assume that an older male’s partner is his spouse.

ANDROPAUSE It is now recognized that testosterone levels decline at the rate of 1% per year (Matsumoto, 2002). This decline leads

to 3–5% of persons 40 to 50 years of age and 30 to 50% of persons over 70 years of age having biochemical hypogonadism. Other estimates suggest that 20% of persons 40 to 70 years of age are hypogonadal. When testosterone levels fall below the normal level for men 20 to 40 years of age and this is accompanied by symptoms, such as a decline in libido or fatigue, the person is recognized as having andropause or androgen deficiency in aging males (ADAM). Other terms that have been used historically, for example, climacteric or male menopause, are no longer considered acceptable. Two symptom-screening tests have been developed to screen for males with andropause. These are the aging male symptom (AMS) and the ADAM questionnaires (Morley et al., 2000) (Tables 9 and 10). Both have excellent ability to detect males with biochemical hypogonadism but also are answered positively by a large number of males who are not hypogonadal, for example, older persons with depression. The cause of the fall in testosterone with aging is multifactorial (Table 11). While levels of luteinizing hormone are slightly higher in hypogonadal older males, it is rarely out of the normal range. Thus, these males are considered to have secondary (hypothalamic-pituitary) hypogonadism. The major cause for this seems to be irregular (chaotic) secretion of gonadotrophin-releasing hormone from the hypothalamus. There is also an increase in negative feedback of testosterone at the pituitary level. A decline in testosterone response to human chorionic gonadotrophin is present in older men. There is a decrease in Leydig cell number. With aging, there is an increase in sex hormone binding globulin (SHBG). This leads to less testosterone being available to the tissues. Thus, the tissue available testosterone can either be measured directly using a free testosterone value by dialysis or a bioavailable testosterone (ammonium sulfate precipitation technique). Alternatively, tissue available testosterone can be calculated using an SHBG, total testosterone, and albumin by utilizing the program available at www.issam.ch. Most experts feel that some measure of tissue available testosterone is preferable to measuring a total Table 9 ADAM questionnaire

Yes

No

Yes Yes

No No

Yes Yes

No No

Yes Yes Yes

No No No

Yes

No

Yes

No

1. Do you have a decrease in libido (sex drive)? 2. Do you have a lack of energy? 3. Do you have a decrease in strength and/or endurance? 4. Have you lost height? 5. Have you noticed a decreased enjoyment of life? 6. Are you sad and/or grumpy? 7. Are your erections less strong? 8. Have you noticed a recent deterioration in your ability to play sports? 9. Are you falling asleep after dinner? 10. Has there been a recent deterioration in your work performance?

A positive answer represents yes to 1 or 7 or any 3 other questions. (Circle one)

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Table 10 AMS questionnaire Which of the following symptoms apply to you at this time? Please mark the appropriate box for each symptom. For symptoms that do not apply, please mark “none.”

Symptoms:

Mild

Moderate

Severe

Extremely Severe

Score =

1

2

3

4

5

1. Decline in your feeling of general well-being (general state of health, subjective feeling) 2. Joint pain and muscular ache (lower back pain, joint pain, pain in a limb, general backache) 3. Excessive sweating (unexpected/sudden episodes of sweating, hot flushes independent of strain) 4. Sleep problems (difficulty in falling asleep, difficulty in sleeping through, waking up early and feeling tired, poor sleep, sleeplessness). . . 5. Increased need for sleep, often feeling tired. . . 6. Irritability (feeling aggressive, easily upset about little things, moody). . . 7. Nervousness (inner tension, restlessness, feeling fidgety). . . 8. Anxiety (feeling panicky). . . 9. Physical exhaustion/lacking vitality (general decrease in performance, reduced activity, lacking interest in leisure activities, feeling of getting less done, of achieving less, of having to force oneself to undertake activities). . . 10. Decrease in muscular strength (feeling of weakness). . . 11. Depressive mood (feeling down, sad, on the verge of tears, lack of drive, mood swings, feeling nothing is of any use). . . 12. Feeling that you have passed your peak. . . 13. Feeling burnt out, having hit rock-bottom. . . 14. Decrease in beard growth. . . 15. Decrease in ability/frequency to perform sexually. . . 16. Decrease in the number of morning erections 17. Decrease in sexual desire/libido (lacking pleasure in sex, lacking desire for sexual intercourse). . . Have you got any other major symptoms? If Yes, please describe:

Yes

No

Table 11 Age-related changes in testosterone regulation

• • • • • •

None

Loss of circadian rhythm Asynchronous production of GnRH Increased inhibitory effect of T at pituitary Reduced GnRH release of LH Decreased T response to HCG Altered receptor and postreceptor effects

testosterone in making the diagnosis of andropause (Morley and Perry, 2003). It is essential to recognize that the response to testosterone depends on the ability of testosterone once it is in the cell to translocate to the nucleus and bind to the receptor, and the receptor responsiveness. The binding capacity of the receptor depends on the number of CAG repeats in the receptor. The lower the number of CAG repeats, the better the binding capacity of the receptor. The effect of aging on the intracellular trafficking of testosterone, the

ability of testosterone to bind to the receptor, and receptor responsiveness is just starting to be explored. The symptomatic concept of andropause has been recognized since the time of the Chinese Text of Internal Medicine. The major symptom of andropause is a decline in libido. A decline in libido may also be due to depression, illness, or death of a spouse. Testosterone replacement restores libido in 70–80% of persons. Testosterone is also essential for the production of nitric oxide synthase. Production of nitric oxide is essential for firmness of the erection. Thus, low testosterone levels can lead to soft erections or failure of phosphodiesterase-5 inhibitors to produce an erection. Low testosterone levels are associated with a low ejaculatory volume. The effects of testosterone in older males are listed in Table 12. Testosterone increases muscle mass and strength. Testosterone stimulates the stem cells to produce satellite cells (these are responsible for repair of skeletal muscle)

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HUMAN AGING: SOCIAL AND COMMUNITY PERSPECTIVES Table 12 Effects of testosterone in older males

• • • • • • • • • • • • •

Improved libido Improved erectile function Increased hematocrit Increased muscle mass Increased muscle strength Increased IGF-1 Decreased fat mass Decreased leptin Increased bone mineral density Decreased LDL and HDL cholesterol Increased brachial artery flow Decreased ST depression and angina Enhanced spatial cognition

Table 13 Testosterone therapies and the older male

• • • • • • •

Injections Patches Gel Oral Inhalation Pellets Buccal/sublingual

and also increase protein synthesis in skeletal muscle and inhibit the ubiquitin-proteasome system, which is responsible for muscle breakdown. Testosterone inhibits adipocyte precursor cells, resulting in a loss of fat mass. Testosterone may improve function, but at present, there is limited data in this regard. Testosterone increases bone mineral density in the lumbar spine and the hip. Testosterone improves visuospatial cognition. Testosterone increases the hematocrit. Testosterone may have beneficial effects on the cardiovascular system. Testosterone’s negative effects include gynecomastia, water retention, and possibly sleep apnea. The effects of testosterone on the prostate are uncertain. Testosterone cannot be given to persons with active prostate cancer. The history of testosterone replacement stretches from the end of the nineteenth century when Brown-Sequard injected himself with an animal extract of testosterone. During the early twentieth century “monkey gland,” goat testicle, and even human testicular transplants were done on the rich in an attempt to rejuvenate them. The available and experimental forms of modern testosterone replacement are listed in Table 13. At present, most men with andropause choose to use the testosterone gel forms of treatment. After the gel, the next most popular form of treatment is testosterone injections. Selective androgen receptor molecules (SARMs) have been developed to avoid the sexual stimulant properties of testosterone and enhance the anabolic features of testosterone replacement. These can be steroids, for example, nandrolone or oxandrolone, or a series of nonsteroid moleculares that can be ingested orally. Libido represents an important component of sexuality in older men. The treatment of depression, and where appropriate testosterone replacement, can markedly enhance libido in older men.

SEXUALITY AND DISEASE Disease can greatly alter the sexuality of an individual. Pain and disability can interfere with sexual intercourse. Fatigue reduces libido. Negative self-image is commonly associated with diseases. Depression, with or without other systemic diseases, can lead to a decline in libido or erectile function. Many systemic diseases reduce testosterone, leading to a decrease in libido (Morley and Tariq, 2003). Diabetes mellitus causes early onset of erectile dysfunction and a decreased libido. Males with diabetes mellitus have low testosterone. Women with diabetes mellitus have clitoral damage. Women with diabetes have a decline in libido and vaginal lubrication, but minimal change in the ability to attain orgasm. Amputations and dysphoria can further alter sexuality in persons with diabetes. Hip arthritis causes both stiffness and pain, which interfere with sexual intercourse. Judicious use of pain medication prior to intercourse, alterations in positions for intercourse, and positioning of pillows can all enhance the sexual experience for persons with arthritis. Persons with left cerebrovascular hemisphere strokes have a marked decrease in libido. Coital frequency is markedly decreased in two-thirds of persons following a stroke. Persons with a stroke can often have hemineglect and their partners need to be aware of this problem. Men and women with Parkinson’s disease have a high prevalence of sexual dysfunction. Very low testosterone levels have been reported in men with Parkinson’s disease. Death during sexual intercourse in persons with cardiovascular disease are extremely rare, with an estimated rate of 0.2 per 100 000 being reported in males (Jackson, 2000). Cardiovascular disease and hypertension are major risk factors for erectile dysfunction. Persons with two or three vessel disease have softer erections and more erectile dysfunctions than those with one vessel disease. In females, heart disease is associated with decreased libido, vaginal dryness, dyspareunia, orgasmic difficulty, and decreased genital sensation. Saint Louis University has developed a series of instructions for patients for resuming coitus following myocardial infarction (Table 14).

THE OLDER HOMOSEXUAL There are approximately 3 million older gays in the United States. It is estimated that approximately 4% of older women are lesbian and/or bisexual. Older gays tend to have a higher use of alcohol and tobacco. The Women’s Health Initiative found a slightly greater rate of obesity and dysphoria in older lesbians (Valanis et al., 2000). Breast cancer was more common in lesbians. Over 10% of AIDS cases occur in persons over the age of 65 years. Half of these cases are due to contaminated blood products. Condom use is extremely rare in gays over 50 years of age. HIV testing is rare in older gays.

SEXUALITY AND AGING Table 14 Instructions for patients and their spouses after myocardial infarction

• Sexual activity may be resumed as soon as you can bring your heart rate to 120 beats per minute without occasioning chest pain or shortness of breath, the equivalent of climbing two flights of stairs rapidly. • If chest pain develops during intercourse, take a nitroglycerine. If the pain does not subside within 15 minutes, consider that an emergency. • If chest pain regularly develops during sexual intercourse, take a nitroglycerine 10 minutes before attempting sex. • No sexual position is the best or is prohibited. Some patients may find one position preferable for their needs. • Altered desire after a heart attack is usually due to psychological factors, such as fear of another attack. Please discuss these problems with your physician. • Altered ability to obtain an erection after a heart attack may be due to medications or to vascular disease of the penis. These are both treatable. Please discuss this with your physician. • If the female has decreased vaginal lubrication or pain during intercourse, ask your physician to prescribe a lubricant or, in some cases, you may need estrogen replacement. • There is no time of day during which we know that sex is safer or more dangerous. Please be advised that sexual activity in a novel situation, for example, with a partner other than your spouse, appears to be associated with increased problems. • Discuss your sexual needs and concerns frankly with your spouse. • Any questions or concerns you have should be brought to the attention of your physician or nurse. It is best that both you and your spouse read these instructions. Feel free to have your spouse discuss his or her problems with the health professional team.

Homophobia leads to many older gays not identifying themselves to health-care providers. Many physicians assume that their older patients are heterosexual. Unmarried homosexual partners are often poor as they grow old as they are ineligible, in the United States, for social benefits such as Social Security. A major issue occurs when the partner becomes sick, as the homosexual partner often has no rights to make health-care decisions for their ill partner. It is important that older gays have a durable power of attorney for health, designating their partner as the decision maker.

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16 cases (Jenny et al., 1994). Pedophilia needs to be reported to the appropriate authorities.

SEXUALITY IN THE NURSING HOME Sexuality does not necessarily cease on entry into a nursing home. However, within the nursing home there are multiple barriers to sexuality (Hajjar and Kamel, 2004). These include lack of privacy, lack of a partner, staff and resident attitude, and knowledge concerning sexuality and family attitudes. Special ethical problems arise when two demented patients form a romantic liaison. Most ethicists feel that older persons should retain their right to continue appropriate sexual behavior in the nursing home. It has been suggested that older persons may wish to develop an advanced directive for sexual behavior. From the facility point of view, it is essential that staff are educated and taught to be accepting of sexual behavior. Residents of nursing homes are entitled to privacy and, where wanted, conjugal visits. Unfortunately, sexual abuse of residents, including rape, is also a problem in nursing homes. Maintenance of a healthy sexual environment in the nursing home is often extremely difficult. Society needs to come to terms with the sexual needs of older persons in nursing homes.

CONCLUSION Awareness of the sexual needs of older persons is an important quality-of-life issue. Health-care providers need to be open to discussing sexual needs of older persons and providing treatment where appropriate. Education of society and increased awareness of sexuality in elders is a key component of sexual health in the future.

KEY POINTS PARAPHILIAS Paraphilias are unusual sexual behaviors. The advent of the Internet has greatly increased awareness of persons indulging in these behaviors. The most common paraphilias are erotic talk on the telephone or the Internet. Substantial numbers of persons practice exhibitionism, voyeurism, sadomasochism, sexual bondage, anal eroticism, and fetishes. Many of these practices are still indulged in by older persons. Some become exaggerated as the older person develops dementia and loses the normal social sensibilities. The physician needs to be aware that many of these are variants of normal sexuality and be able to help the older person. Pedophilia is sexual abuse of a child by an adult. In one series of 261 cases, the child abuser was the grandfather in

• Sexuality remains important to quality of life throughout the life span. • There are biological, psychological, and social components of sexuality. • Depression is a major cause of disruption of sexual enjoyment. • Alternative sexual lifestyles are not unusual in older persons.

KEY REFERENCES • Kaiser FE. Women’s health issues. The Medical Clinics of North America 2003; 87:xi – xiii.

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• Matsumoto AM. Andropause: clinical implications of the decline in serum testosterone levels with aging in men. The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences 2002; 57A:M76 – 99. • Morales A. Erectile dysfunction: an overview. Clinics in Geriatric Medicine 2003; 19:529 – 38. • Morley JE & Perry HM III Andropause: an old concept in new clothing. Clinics in Geriatric Medicine 2003; 19:507 – 28.

REFERENCES Bortz WM II Wallace DH & Wiley D. Sexual function in 1,202 aging males: differentiating aspects. The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences 1999; 54A:M237 – 41. Derby CA, Araujo AB, Johannes CB et al. Measurement of erectile dysfunction in population-based studies: the use of a single question selfassessment in the Massachusetts male aging study. International Journal of Impotence Research 2000; 12:197 – 204. Espeland MA, Rapp SR, Shumaker SA et al. Conjugated equine estrogens and global cognitive function in postmenopausal women: women’s health initiative memory study. The Journal of the American Medical Association 2004; 291:2959 – 68. Grady D, Herrington D, Bittner V et al., HERS Research Group. Cardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/Progestin Replacement Study follow-up (HERS II). The Journal of the American Medical Association 2002; 288:49 – 57. Hajjar RR & Kamel HK. Sexuality in the nursing home, part I: attitudes and barriers to sexual expression. The Journal of the American Medical Directors Association 2004; 5(suppl 2):S42 – 7. Jackson G. Sexual intercourse and stable angina pectoris. The American Journal of Cardiology 2000; 86:35F – 7F. Jenny C, Roesler TA & Poyer KL. Are children at risk for sexual abuse by homosexuals? Pediatrics 1994; 94:41 – 4. Kaiser FE. Women’s health issues. The Medical Clinics of North America 2003; 87:xi – xiii. Masumori N, Tsukamoto T, Kumamoto Y et al. Decline of sexual function with age in Japanese men compared with American men – results of two community-based studies. Urology 1999; 54:335 – 44. Matsumoto AM. Andropause: clinical implications of the decline in serum testosterone levels with aging in men. The Journals of

Gerontology. Series A, Biological Sciences and Medical Sciences 2002; 57A:M76 – 99. Morales A. Erectile dysfunction: an overview. Clinics in Geriatric Medicine 2003; 19:529 – 38. Morley JE, Charlton E, Patrick P et al. Validation of a screening questionnaire for androgen deficiency in aging males. Metabolism: Clinical and Experimental 2000; 49:1239 – 42. Morley JE & Perry HM III Andropause: an old concept in new clothing. Clinics in Geriatric Medicine 2003; 19:507 – 28. Morley JE & Tariq SH. Sexuality and disease. Clinics in Geriatric Medicine 2003; 19:563 – 73. Nusbaum MR, Singh AR & Pyles AA. Sexual healthcare needs of women aged 65 and older. Journal of the American Geriatrics Society 2004; 52:117 – 22. Rosen RC, Fisher WA, Eardley I et al., Men’s Attitudes to Life Events and Sexuality (MALES) Study. The multinational Men’s Attitudes to Life Events and Sexuality (MALES) study: I. Prevalence of erectile dysfunction and related health concerns in the general population. Current Medical Research and Opinion 2004; 20:607 – 17. Rossouw JE, Anderson GL, Prentice RL et al., Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the women’s health initiative randomized controlled trial. The Journal of the American Medical Association 2002; 288:321 – 33. Slag, MF, Morley JE, Elson MK et al. Impotence in medical clinic outpatients. The Journal of the American Medical Association 1983; 249:1736 – 40. Valanis BG, Bowen DJ, Bassford T et al. Sexual orientation and health: comparisons in the women’s health initiative sample. Archives of Family Medicine 2000; 9:843 – 53.

FURTHER READING Schumaker SA, Legault C, Rapp SR et al., WHIMS Investigators. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the women’s health initiative memory study: a randomized controlled trial. The Journal of the American Medical Association 2003; 289:2651 – 62.

12

Physical Fitness and Exercise Maria A. Fiatarone Singh University of Sydney, New South Wales, Australia, Hebrew Rehabilitation Center for Aged, Roslindale, MA, USA, and Tufts University, Boston, MA, USA.

INTRODUCTION The interaction of physical activity, exercise, and physical fitness with health and aging is complex and multifaceted. Although many questions remain about mechanisms of effect and dose –response curves (Bouchard, 2001), a synthesis of the literature indicates many potentially positive effects of participation in physical activity on the aging process (Mazzeo et al., 1998. Most recent position stands and policy recommendations include physical activity prescriptions for health promotion and disease prevention (American College of Sports Medicine et al., 1998) as well as chronic disease treatment in older adults. However, there is still skepticism among some clinicians and investigators as to the actual potency of exercise for disease and/or disability prevention and treatment, particularly in already frail or near frail adults (Keysor and Jette, 2001). Exercise has not become fully integrated into usual geriatric medicine practice, and is still virtually absent from the core training of most geriatric medicine physicians and health-care professionals. Therefore, this chapter will attempt to provide a rationale for the use of exercise and physical activity for health promotion and disease prevention in older adults. Exercise will be discussed in terms of the specific modalities and doses that have been studied in randomized controlled trials for their role in the physiological changes of aging, disease prevention, and treatment of older persons with chronic disease and disability. Recommendations will be offered to address gaps in knowledge as well as clinical implementation needs in this field.

WHAT IS EXERCISE? Any discussion of these issues must begin with definitions of the terminology. Physical activity has been traditionally defined as any bodily movement produced by contraction

of skeletal muscle that significantly increases energy expenditure, although the intensity and duration can vary substantially. It should be noted that some forms of physical activity which may have particular relevance to an aging population (e.g. balance training) may not conform to this standard definition. This activity may be performed in leisure or occupational hours, and surveys for the older adult should capture both paid and unpaid (volunteer) work. Exercise is a subcategory of leisure time physical activity in which planned, structured, repetitive bodily movements are performed, with or without the explicit intent of improving one or more components of physical fitness. Recently, efforts have been focused on merging these formerly distinct entities in order to promote “lifestyle integration” of exercise as a means to enhance long-term adherence. For example, taking the stairs instead of the elevator, standing on one leg while doing the dishes, or slowly standing and sitting without use of the arms represent ways of incorporating aerobic, balance, and strengthening exercises, respectively, into everyday activities. Current investigations are exploring whether such prescriptive techniques are superior to standard approaches for the promotion of behavioral change in older adults. Physical fitness, by contrast, is defined as a set of attributes that contribute to the ability to perform physical work (e.g. cardiorespiratory endurance, muscle power, balance, flexibility, and body composition) or influence health status. “Metabolic fitness” has been advanced more recently as a term that encompasses a range of biologically important traits (increased insulin sensitivity, lipoprotein lipase activity, endothelial cell reactivity, heart rate variability, etc.) which may contribute to health status, but do not directly affect exercise capacity. Both genetic predisposition and lifestyle factors contribute to physical and metabolic fitness and the extent to which they are modifiable with exercise training. Dose –response relationships between changes in fitness and better health outcomes have been defined for some, but certainly not for all diseases and syndromes (Bouchard,


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2001). Some modalities or doses of exercise that are promoted for older adults (mild calisthenics, slow-paced walking) have little or no discernable effects on physical fitness, but may possibly yield benefits in some domains. This area of investigation is critical for defining threshold and optimal levels of activity that are necessary for health promotion and disease management. It should be recognized that what is suitable for prevention may be entirely inadequate for treatment, as is the case with pharmacological management of chronic diseases as well. For example, aspirin may reduce the risk of ischemic heart disease, but a host of potent agents may be required once coronary occlusive disease is present and symptomatic.

DOES EXERCISE INCREASE LIFE EXPECTANCY? The effects of exercise on total mortality are unlikely to ever be substantiated via randomized controlled clinical trials, given the impossibility of random assignment to various physical activity regimens over many decades. However, there is clear evidence of an inverse, linear dose –response relationship between the volume of physical activity reported in epidemiological studies (with sample sizes ranging from less than 500 to over 2.5 million individuals) and all-cause mortality rates. These relationships are demonstrable for both men and women, and for older as well as younger adults. Volumes of energy expenditure during exercise of at least 1000 kcal/week reduce mortality by about 30%, whereas reductions of 50% or more are seen with volumes closer to 2000 kcal/week, when more precise measures or estimates of physical activity participation incorporating fitness assessments are utilized instead of surveys. These changes in all-cause and cardiovascular mortality translate to an increase in life expectancy of approximately 2 years for those exercising at such volumes. Despite the consistency of the data from well-designed observational studies, many questions still remain regarding the minimum threshold for efficacy, the effect of exercise intensity, duration and frequency (apart from contributions to overall volume), the effect of nonaerobic modalities of exercise, and the mechanism of benefit. From a public health perspective, if small, effective doses of moderate-intensity activity are found to be as beneficial as longer bouts of vigorous activity, adoption of mortality-reducing physical activity recommendations by sedentary middle-aged and older adults may be more successful. Of particular relevance to the geriatric exercise prescription are studies which have demonstrated that a change from a sedentary to more active lifestyle in midlife or beyond is associated with a reduction in mortality. In the sections that follow, the focus is on changes in physical fitness and body composition, quality of life and disease burden, rather than on changes in longevity itself. It is in these domains that the centrality of physical activity patterns to optimal aging is perhaps most relevant to the concerns of the health-care professional and the older individual.

PRESERVING EXERCISE CAPACITY WITH AGE VIA AN ACTIVE LIFESTYLE There is a great similarity between the physiologic changes attributable to disuse and those which have been typically observed in aging populations, leading to the speculation that the way in which we age may be modulated with attention to activity levels (Bortz, 1989). The most important physiological changes associated with aging or disuse that impact upon exercise capacity are presented in Tables 1–4. In most physiologic systems, the normal aging processes do not result in significant impairment or dysfunction in the absence of pathology and under resting conditions. However, in response to a stress, or significant disuse, the age-related reduction in physiologic reserves (“homeostenosis”) may result in difficulty completing a task requiring near-maximal effort. Although changes in maximal work capacity (aerobic fitness, or maximal oxygen consumption) will be immediately noticeable and disastrous for an elite athlete, they may accrue insidiously in nonathletic populations because most sedentary individuals rarely call upon themselves to exert maximal effort in daily life. Women are particularly susceptible here, because their initial reserve of muscle mass is so much lower than that of men, due to gender differences in anabolic hormonal milieu as well as lifestyle/occupational factors. They will therefore cross this threshold where losses of Table 1 Changes in exercise capacity due to aging or disuse potentially modifiable by physical activity

Component of exercise capacity Maximal aerobic capacity Tissue elasticity Muscle strength, power, endurance, mass Oxidative and glycolytic enzyme capacity, mitochondrial volume density Gait speed, step length, cadence, gait stability

Effect of aging or disuse Decrease Decrease Decrease Decrease Decrease

Table 2 Changes in cardiorespiratory function due to aging or disuse potentially modifiable by physical activity

Cardiorespiratory function Heart rate and blood pressure response to submaximal exercise Maximal heart ratea Resting heart rate Maximal cardiac output, stroke volume Endothelial cell reactivity Heart rate variability Maximal skeletal muscle blood flow Capillary density Arterial distensibility Vascular insulin sensitivity Plasma volume, hematocrit Postural hypotension in response to stressors Total lung capacity, vital capacitya Maximal pulmonary flow ratesa a

Effect of aging or disuse Increase Decrease No change Decrease Decrease Decrease Decrease Decrease Decrease Decrease No change, decrease Increase Decrease Decrease

No evidence yet that exercise can prevent or reverse these changes of aging.

PHYSICAL FITNESS AND EXERCISE Table 3 Changes in metabolism and body composition due to aging or disuse potentially modifiable by physical activity

Metabolic/body composition change Resting metabolic rate Total energy expenditure Thermic effect of meals Total body water Total body potassium, nitrogen, calcium Protein synthesis rate, amino acid uptake into skeletal muscle, nitrogen retention, protein turnover Gastrointestinal transit time Appetite, energy intake Glycogen storage capacity, glycogen synthase, GLUT-4 transporter protein content, translocation to membrane Lipoprotein lipase activity Total cholesterol, LDL cholesterol HDL cholesterol Hormonal and sympathetic nervous system response to stress Growth hormone, IGF-1a Heat and cold tolerance, temperature regulatory ability

Effect of aging or disuse Decrease Decrease Decrease, no change Decrease Decrease Decrease

Increase Decrease, no change Decrease

Decrease Increase Decrease or no change Increase Decrease Decrease

LDL, low density lipoprotein; HDL, high density lipoprotein. a Most training studies show no change in growth hormone or circulating IGF-1 although tissue levels of IGF-1 may increase.

Table 4 Changes in central and peripheral nervous system due to aging or disuse potentially modifiable by physical activity

REM and slow wave sleep duration Cognitive processing speed, accuracy Attention span Memory Executive function Motor coordination, force control Neural reaction time, neural recruitment Autonomic nervous system function

Decrease Decrease or No change Decrease or No change No change, Decrease Decrease or No change Decrease Decrease Decrease

REM, rapid eye movement.

musculoskeletal capacity impact on functional status, at least 10 years before men do on average. (Guralnik et al., 1993). Another important consequence of age-related changes in physiologic capacity is the increased perception of effort associated with submaximal work (a lowering of the anaerobic threshold, or the approximate level at which significant dyspnea occurs). This changing physical capacity has the unfortunate negative side effect of increasing the tendency to avoid stressful activity. Such behavioral change compounds the sedentariness caused by changing job requirements or retirement, societal roles and expectations, and other psychosocial influences. Thus, a vicious cycle is set up: “usual” aging leading to decreasing exercise capacity, resulting in an elevated perception of effort, subsequently causing avoidance of activity, and finally feeding back to exacerbation of the age-related declines themselves secondary to the superimposition of disuse on biological aging. Many studies suggest that chronic adaptation to physical activity can markedly attenuate decrements in exercise capacity that would otherwise occur with aging (see

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Tables 1–4), with the notable exception of maximal heart rate (due to declining sensitivity to β-adrenergic stimulation in the aging heart (Scarpace et al., 1992)). Although peak exercise workload achievable is therefore always lower in aged individuals, the cardiovascular and musculoskeletal adaptations to chronic aerobic exercise enable the trained individual to sustain higher submaximal workloads with less of a cardiorespiratory response (heart rate, blood pressure, and dyspnea), as well as less overall and musculoskeletal fatigue. Musculoskeletal function (strength, power, muscle endurance) in aging is dictated largely by the size of the muscle mass which is contracting, and to a lesser extent by changes in surrounding connective tissue in the joint (cartilage, tendons, and ligaments) and neural recruitment, conduction velocities, glycolytic and oxidative enzyme capacities, and fatigue patterns. Sedentary individuals lose large amounts of muscle mass over the course of adult life (20–40%), and this process, termed sarcopenia, plays a major role in the similarly large losses in muscle strength observed in both cross-sectional and longitudinal studies (Asmussen and Heeboll-Nielsen, 1961; Hughes et al., 2002). However, unlike many other changes which impact on exercise capacity, muscle mass cannot usually be maintained into old age even with regular aerobic activities in either general populations or master athletes. Only overloading of muscle with weight-lifting exercise (resistance training) has been shown to largely avert losses of muscle mass (and also strength) in older individuals. For example, Klitgaard et al. (1990) found that elderly men who swam or ran had similar measures of muscle size, strength, and metabolism as their sedentary peers, whereas the muscle of older men who had been weight lifting for 12–17 years was almost indistinguishable, and even superior in some aspects, to healthy men 40–50 years younger than them. Clearly, habitual exercise has the potential to lessen the impact of biological aging on two of the major elements of exercise capacity: aerobic fitness and muscle strength. Similarly, there is evidence that balance training and flexibility training (American College of Sports Medicine et al., 1998) induce adaptations in associated declines in these areas.

OPTIMIZATION OF BODY COMPOSITION WITH AGING “Usual aging” is associated with significant losses of bone and muscle (lean mass), and increases in adipose tissue, along with central and visceral shifts in the regional distribution of adipose tissue stores. The extent to which these changes occur in an individual depends upon a combination of genetic, lifestyle, and disease related factors that are all interrelated. All of these body composition changes may negatively impact upon metabolic, cardiovascular, and musculoskeletal function (Hughes et al., 2001), even in the absence of overt disease, and therefore it is important to anticipate them and optimize lifestyle choices and other treatments

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which can counteract the negative effects of aging and/or disease on body composition. As detailed in the sections that follow and outlined in Table 5, one of the most potent pathways from physical activity to health status involves the modulation of these age-related shifts in body composition by habitual exercise patterns.

Role of Exercise and Physical Activity in Bone Health and Fracture Risk Age-related Changes in Bone

Bone mass begins to decrease well before the menopause in women (as early as the 20s in the femur of sedentary women), and accelerates in the perimenopausal years, with continued declines into late old age. Similar patterns are seen in men, without the acceleration related to loss of ovarian function seen in women. As with losses of muscle tissue (sarcopenia), many genetic, lifestyle, nutritional, and disease and medication-related factors enter into the prediction of bone density at a given age. Physical Activity and Bone Health

A wealth of animal and human data provide evidence for a relationship between physical activity and bone health at all ages. Mechanical loading of the skeleton generally leads to favorable site-specific changes in bone density, morphology, or strength, whereas unloading (in the form of bed rest, immobilization, casting, spinal cord injury, or space travel) produces rapid and sometimes dramatic resorption of bone, increased biochemical markers of bone turnover, changes

in morphology such as increased osteoclast surfaces, and increased susceptibility to fracture. Comparative studies of athletic and nonathletic populations usually demonstrate significantly higher bone density in the active cohorts, ranging from 5 to 30% higher, depending upon the type, intensity, and duration of exercise training undertaken, and the characteristics of the athletes studied. Exceptions occur with nonweight-bearing activities such as swimming, or amenorrheic or competitive distance runners, who appear similar to controls. Similarly, on a smaller scale, differences are often observed between habitually active and sedentary nonathletic individuals. Experimental evidence in animal models as well as some human data suggests that changes in bone strength not directly correlated with density may contribute to the overall benefits of mechanical loading for skeletal integrity and resistance to fracture (e.g. increased bone volume or altered trabecular morphology), so that evaluating bone density changes alone likely underestimates the skeletal effects of loading. Consistent with bone density findings noted above, hip fracture incidence has been observed to be as much as 30–50% lower in older adults with a history of higher levels of physical activity in daily life, compared to age-matched, less active individuals. For example, in the prospective epidemiology of osteoporosis study (EPIDOS) study of 6901 white women over the age of 75 followed for 3.6 years, investigators found that a low level of physical activity increased the risk for proximal humerus fracture by more than twofold. The relative risk of fracture in sedentary women (RR = 2.2) was greater than that attributable to low bone density (RR = 1.4), maternal history of hip fracture (RR = 1.8), or impaired balance (RR = 1.8). The interaction

Table 5 Exercise recommendations targeting optimal body composition for older adults

Exercise recommendations

Decreased adipose tissue mass and visceral deposition

Increased muscle mass and strength

Increased bone mass, density, and reduced fracture risk

Modality

Aerobic or resistance training

Resistance training

• Resistance training or aerobic traininga • High impact activities (jumping using weighted vest during exercise) if tolerated by joints • Balance training

Frequency

Aerobic: 3 – 7 days/week Resistance: 3 days/week

3 days/week

• Resistance or aerobic training: 3 days/week • Balance training: up to 7 days/week

Volume

Aerobic: 30 – 60 minutes/session Resistance: 2 – 3 sets of 8 – 10 repetitions of 6 – 8 muscle groups

2 – 3 sets of 8 – 10 repetitions of 6 – 8 muscle groups

• • • •

Intensity

Aerobic; 60 – 75% of maximal exercise capacity (VO2 max or maximal heart rate) or 13 – 14 on the Borg Scale of perceived exertion Resistance: 60 – 80% of maximal strength (one repetition maximum)

60 – 80% of maximal strength (one repetition maximum)

• 60 – 80% of maximal capacity (one repetition maximum) as load • 5 – 10% of body weight in vest during jumps; jumps or steps of progressive height • Practice most difficult balance posture not yet mastered

a b

30 – 60 minutes of aerobic training 2 – 3 sets of 8 – 10 repetitions of 6 – 8 muscle groups 50 jumps per session for high impactb 2 – 3 repetitions of 5 – 10 different static and dynamic balance postures

Aerobic exercise should be weight-bearing modalities of exercise with high ground-reaction forces (e.g. walking, jogging, running, stepping, rather than swimming or cycling). Thus far proven only in premenopausal women.

PHYSICAL FITNESS AND EXERCISE

of these risk factors is indicated by the fracture rate, which rose from about 5 per 1000 woman-years in individuals with either bone fragility or high fall risk to 12 per 1000 womanyears for women with both types of risk factors. Such data suggest the great potential utility of multifactorial prevention programs for osteoporotic fracture that can address both bone density and fall risk (sedentary behavior, sarcopenia, muscle weakness, poor balance, polypharmacy, etc.) simultaneously. Exercise Intervention Trials in Postmenopausal Women and Older Men

Metanalyses of the randomized controlled trials of exercise and bone density in postmenopausal women are outlined in Table 6. Significant changes in the femur, lumbar spine, and radius have been seen following aerobic training, resistance training, and combined programs of aerobic and resistive exercise. Unlike results obtained in younger women, isolated high impact training (jumping, skipping, heel drops) has not yet been found to be effective in studies of postmenopausal women. High dropout rates (30–50%) are problematic in these trials, raising the issue of generalizability and sustainability of the outcomes observed. This is particularly relevant to fracture prevention efficacy of exercise, as several studies have shown complete or partial reversal of gains in bone mineral density (BMD) after the cessation of training. For older men and women, a combination of decreased anabolic hormones (estrogen, testosterone, growth hormone), increased catabolic milieu (higher leptin and cortisol associated with visceral adipose tissue), the emergence of musculoskeletal and other diseases, retirement, and reduced recreational activities have a major negative impact on bone as well as muscle tissue. The majority of studies demonstrating the efficacy of aerobic or resistive exercise on bone density have been conducted in women between 50 and 70 years of age, and it is not yet known if efficacy would be similar in older women with multiple comorbidities, who have usually been excluded from such trials. Both types of exercise have approximately equivalent effects on bone health in postmenopausal women of about 1–1.5% per year between exercisers and nonexercisers in meta-analyses of well-designed trials (Kelley, 1998a,b; Wolff et al., 1999; Wallace and Cumming, 2000; Kelley et al., 2001). Optimal Exercise Modality and Intensity for Bone Health

The predominant exercise training factor that influences bony adaptation is the intensity and novelty of the load, rather than the number of repetitions, sets, or days per week, or even total duration of the program. This observation is also true for animal models of mechanical loading, in which bone is most sensitive to short periods of loading characterized by unusual strain distribution, high strain magnitudes, and rapid rate of loading. The relative efficacy of aerobic versus resistive exercise regimens for postmenopausal women may be perhaps best assessed via studies that have directly compared various

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intensities of these two exercise modalities in randomized subjects. Kohrt et al. (1997) found that both aerobic activities with high ground-reaction forces (walking, jogging, stair climbing) and exercises with high joint-reaction forces (weight lifting, rowing) significantly increased BMD of the whole body, lumbar spine, and Ward’s triangle, whereas only the ground-reaction group increased BMD at the femoral neck (Kohrt et al., 1997). The weight-lifting group preserved femoral neck BMD relative to controls, as has been seen in other resistance training studies (Kerr et al., 2001). However, lean mass and muscle strength increased only in the weight-lifting group, leaving overall benefits of these two types of exercise for ultimate fall and fracture prevention still unresolved. Kerr randomized 126 postmenopausal women to 2 years of high-intensity weight-lifting exercise, moderate-intensity aerobic training (circuit training and stationary cycling), or sedentary control condition. Total hip and intertrochanteric BMD was improved only by strength training, and was significantly different from aerobic training or control groups (+3.2% at 2 years). As most comparative studies other than Kohrt’s (Kohrt et al., 1997) and Kerr’s (Kerr et al., 2001) have not sought to optimize both modalities, it is still not possible to definitively choose one best modality for all bone sites. In general, the older the individual, the more favorable the resistance training appears, due to its broader benefits on muscle, bone, balance, and fall risk, relative to aerobic training. If aerobic training is chosen, however, activities that are weight bearing and higher impact have a greater efficacy than nonweight-bearing or low-impact aerobic activities. It is important to consider not only the optimal modality of exercise, but also the relative intensity, as the skeletal adaptation is critically linked to the intensity of the loading (whether due to increased amount of weight lifted during resistance training, or higher ground-reaction forces during aerobic/jumping activities). Interesting results have been reported recently by Cussler et al. (2003), in a randomized trial of 140 postmenopausal women participating in a multimodal exercise program (high-intensity resistance training, and a weight-bearing circuit of moderate-impact activities including walking/jogging, skipping, hopping, stair climbing/stepping with weighted vests). Bone density improvements at the femoral trochanter were significantly and linearly related to total weight lifted during the 12 months, as well as total weight lifted in leg press, squats, and military press exercises, but not to volume or quality of the nonresistance training components of the program. High-intensity resistance training is also more beneficial than low-intensity training for muscle strength gains and muscle hypertrophy, as well as associated gait disorders, functional impairments, and disability, making it ideal as a multiple risk factor intervention strategy for injurious falls in osteopenic women. Exercise in the Treatment of Osteoporotic Fracture

In older men and women who have already sustained an osteoporotic fracture, exercise is still extremely important to assist in recovery of function as well as prevent recurrent

Healthy women >50 years of age without osteoporosis

Postmenopausal women



Pre and postmenopausal women

Pre- and postmenopausal women

Pre- and Postmenopausal women

Berard et al. (1997)

Kelley (1998a)

Kelley (1998a)

Kelley (1998b)

Wolff et al. (1999)

Wallace and Cumming (2000)

Kelley et al. (2001)

Prospective controlled trials

Randomized controlled trials

Prospective controlled intervention trials

Prospective controlled intervention trials Prospective controlled intervention trials Randomized controlled trials

Prospective controlled intervention trials

Studies included

29 studies 1966 – 1998, 1123 women

32 studies, 1966 – 1998

10 trials 1975 – 1994; 330 subjects 6 studies, 1978 – 1995 11 studies 1975 – 1995; 719 subjects 25 studies, 1966 – 1996

18 trials 1966 – 1996

Total number of trials, subjects

Resistance training

Impact (aerobic or heel drops) and strength training

Aerobic, high impact, or strength training at least 16 weeks duration

Aerobic or strength training

Aerobic exercise

Walking, running, physical conditioning, aerobics Aerobic activity

Type of exercise

Hip 5 pounds/year perform MNAa ∗ ∗ ∗∗ Do each visit Do each visit

∗ ∗ ∗∗

Do each visit

Do each visit

Discuss periodically with caregiver

∗ ∗ ∗∗

Do each visit

Do each visit

Do each visit

Do each visit

Do yearly Consider yearly Consider yearly Do yearly Do yearly

Do yearly Consider yearly Consider yearly Do yearly Do yearly

Do each visit Consider yearly Consider yearly Do yearly Consider yearly

Do each visit ∗ ∗ ∗∗ ∗ ∗ ∗∗ Do yearly ∗ ∗ ∗∗

Do initially; do if symptomatic Do initially; do if symptomatic Do initially; do if symptomatic Do yearly and as needed Do yearly Do once; consider repeat every 6 years for patients with chronic diseases Do primary series if not vaccinated before and booster every 10 years Do yearly Do every 1 – 2 years up to 80 years

Do initially; do if symptomatic Do initially; do if symptomatic Do initially; do if symptomatic Do yearly and as needed

Do initially Do initially; do if symptomatic Do initially; do if symptomatic Do yearly and as needed

Consider if symptomatic Do initially; do if symptomatic Do if symptomatic

Do yearly Do once

Do yearly Do once

Do primary series if not vaccinated before

Do primary series if not vaccinated before

∗ ∗ ∗∗

Do yearly Consider every 1 – 2 years up to age 75 ∗ ∗ ∗∗

Do yearly Consider every 1 – 2 years up to age 70 ∗ ∗ ∗∗

∗ ∗ ∗∗ ∗ ∗ ∗∗

Consider yearly ∗ ∗ ∗∗

Consider yearly ∗ ∗ ∗∗

∗ ∗ ∗∗ ∗ ∗ ∗∗

Discuss pros and cons with patient Do at least once

Discuss pros and cons with caregiver Do at least once

∗ ∗ ∗∗

Consider 1 – 3 pap smears if patient has never had pap smears Do yearly Consider every 5 years Discuss pros and cons with patient Do at least once; Consider every 2 years

∗ ∗ ∗∗ Do each visit Do each visit

Do yearly and as needed Do yearly Consider vaccination once

∗ ∗ ∗∗

∗ ∗ ∗∗

(continued overleaf )

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MEDICINE IN OLD AGE

Table 1 (continued)

Recommendations: Highest   Lowest

Do Discuss Consider ∗ ∗ ∗∗

Robust elderly Life expectancy >5 years and functionally independent

Frail Life expectancy 5 years and functionally independent

(see text for further explanation) Cholesterol screening

TSHa Fasting blood glucose

Sleep apnea

Consider screening for patients 65 – 75 years if have additional risk factors (e.g. smoking, diabetes, hypertension) Do every 2 years Do, if symptomatic or every 3 years if have risk factors Do yearly

Consider screening for patients 65 – 75 years if have additional risk factors (e.g. smoking, diabetes, hypertension)

∗ ∗ ∗∗

∗ ∗ ∗∗

Do every 2 years Do, if symptomatic or every 3 years if have risk factors Do yearly

Do every 3 years Do, if symptomatic or every 3 years if have risk factors ∗ ∗ ∗∗

Consider Consider if symptomatic ∗ ∗ ∗∗

a

MNA, Mini Nutritional Assessment; OTC, Over the Counter; ADLs, Activities of Daily Living; IADLs, Instrumental Activities of Daily Living; ADAM, Androgen Deficiency in Adult Males; PSA, Prostate-specific Antigen; TSH, Thyroid-stimulating Hormone.

consensus. All areas of the Glidepath underwent a Delphi process (Flaherty et al., 2002).

OFFICE VISITS Although there is no direct evidence available on how often Robust elderly versus Frail or Moderately Demented elderly need office visits, because other screening procedures need to be done, the minimum frequency should be once a year. “Do as needed” is recommended for elderly at the End of Life because of potential limitations or inability on the part of the patient to get to the office. As will be discussed below, yearly British Health Checks are one model that has been recommended for community-dwelling elderly.

BLOOD PRESSURE (BP) INCLUDING ORTHOSTATIC MEASUREMENTS Doing BP measurements in all age-groups is recommended at each visit. While this pertains to screening for hypertension in all four categories, it also pertains to hypotension (and associated symptoms) in the Frail, Moderately Demented, and End of Life categories. Recommendations for hypertension screening are based on organizational guidelines. Although most organizations agree on the importance of screening for hypertension, they do not agree on how often. For example, the American College of Physicians (ACP) recommends BP screening in all adults with office visits at least every 1–2 years (Littenberg et al., 1990). The United States Preventive Services Task Force (USPSTF) recommends periodic BP screening, and reports that the current expert opinion is that adults who are believed to be normotensive should have

BP measurement at least once every 2 years if their last BP reading was below 140/85 mmHG; and screening should be annual if the last diastolic BP was 85–89 mmHg (United States Preventive Services Task Force, 1996). Screening for orthostatic hypotension (OH) is based on evidence that OH is prevalent among older patients (13–30%) and that there is an association between OH and adverse outcomes (Hale and Chambliss, 1999; Luukinen et al., 1999; Davis et al., 1987). Although no studies have been done to show improved outcomes if this screening is done, the cost and risk of the intervention is low enough that postural BP measurements are recommended.

WEIGHT Weight loss in older patients has significant adverse effects on mortality, morbidity, and other unfavorable outcomes (e.g. loss of muscle mass; decreased muscle strength; altered immune function; decreased wound healing) (Morley, 1996). The data on the benefit and outcome of nutrition management is somewhat controversial, but mostly positive. Oral nutritional supplement was shown to improve weight in nursing home elderly, supplementation was shown to improve weight and reduce falls in frail elderly living in the community, and dietary supplementation led to moderate weight gain and improvements in general well-being in homebound elderly (Johnson et al., 1993; Gray-Donald et al., 1995, 1994). However, another study of frail elderly showed that nutrient-dense foods and exercise were not able to improve appetite or sensory perception, and no functional change was found by nutritional supplementation (De Jong et al., 2000). Since screening for weight loss is very low in cost and risk and the benefits of interventions are mostly positive, it should be done for patients in all categories except End of

PREVENTIVE GERIATRICS

Life. In addition to weighing the patient, the Mini Nutritional Assessment (MNA) is a validated nutritional screening tool that can identify patients who are malnourished or at risk for malnutrition (Garry and Vellas, 1999) (Rubenstein, 1998).

HEIGHT Since measuring height is a low-cost screening intervention, and as bone loss occurs height may decrease, it may be an effective and economical method to identify early osteoporosis of the spine for the Robust and Frail elderly. However, there is no clear evidence to determine what amount of loss is significant (Ismail et al., 1999); (Hunt, 1996); (Ettinger et al., 1994).

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Physicians should ask patients about smoking and should clearly and directly advise all smokers to quit. Patients who want to quit should be assisted with self-help materials, choosing a quit date, and a possible referral to community programs (Rimer et al., 1994). In order to screen for alcohol problems, either the CAGE questionnaire or the Michigan Alcohol Screening Test can be used (Ewing, 1984; Pokorny et al., 1972). The CAGE questionnaire for alcoholism screening asks the following questions: (1) Do you feel you ought to Cut down on drinking? (2) Are you Annoyed by people criticizing your drinking? (3) Do you feel Guilty about drinking? (4) Do you have a drink first thing in the morning (Eye-opener)? Areas of education for injury prevention include the use of seat belts, alcohol-related risks in relation to driving, environmental hazards in the home which may aid the prevention of falls and the dangers of firearms (United States Preventive Services Task Force, 1996).

PAIN Pain should now be considered the fifth vital sign and should be checked at every visit for patients in all categories (Anonymous, 1999c). Use of Likert scales (e.g. 1–10) or pictorial scale (e.g. facial expressions) can be useful to quantify pain. Even patients with dementia can be evaluated for pain (Won et al., 1999; Anonymous, 1998b).

MEDICATION REVIEW INCLUDING OTCs AND HERBAL MEDICINES The risk of adverse drug events, poor compliance, drug–drug interactions, and even the risk of hospitalization are most associated with number of drugs, while underlying comorbidities and to some extent age contribute to this risk (Hanlon et al., 1997; Nolan and O’Malley, 1998; Col et al., 1990; Flaherty et al., 2000). Thus, medication review including OTCs and herbal medicines should be done for patients in all four categories at every visit.

LIFESTYLE EDUCATION Recommendations about areas of lifestyle education in general apply mainly to the Robust and Frail elderly, with a lower level of recommendation for the Moderately Demented elderly. Activity level should be queried about because a low level of activity is a significant predictor of mortality among older adults (Fraser and Shavlik, 1997). Walking can be recommended to most older persons; sustained walking for 30 minutes a day can result in health improvement. Even small increases in exercise can be beneficial in inactive older persons, including wheelchair and institutionalized elderly. Exercises can include endurance (walking, climbing stairs), strength, balance, flexibility, and posture (Green and Crouse, 1995; Ettinger et al., 1997).

MAINTAIN AWARENESS OF ELDER ABUSE Physicians and other health-care professionals should maintain awareness at all times for patients in all categories. This is based on the fact that elder abuse and neglect is prevalent, may often be missed, and may be “asymptomatic”. The term “awareness” is used because no particular standardized evaluation tool for elder abuse has been shown to be better than others (Lachs and Pillemer, 1995; Joshi and Flaherty, 2005).

ASSESS ADLs AND IADLs Prevention of functional decline is one of the hallmarks of geriatric care. Loss of function among older persons is associated with long-term care placement, morbidity, and mortality (Corti et al., 1994). Thus, although there is no direct evidence on how often to screen older patients in each of the four categories for functional change, given the importance of this health parameter, it is recommended for patients in all categories at the intervals as noted in the table. Two commonly used measurements of function are activities of daily living (ADLs) (bathing, dressing, toileting, transferring, continence, feeding) and instrumental activities of daily living (IADLs) (telephone, shopping, food preparation, housekeeping, transportation in the community, taking medications, handling finances) (Katz et al., 1963; Lawton and Brody, 1969).

VISUAL ACUITY AND AUDITORY TESTING Although both visual acuity and auditory testing are an accepted part of the CGA, the level of recommendation for testing these areas is “consider” for patients in all categories There is evidence that decreased vision is associated with

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negative outcomes. However, according to one systematic review of randomized controlled trials, the inclusion of a visual screening component in the assessment resulted in only a small reduction (11%) in the number of older people with improved self-reported visual problems (Smeeth and Iliffe, 1998). Likewise, although there is evidence that decreased hearing is common and associated with negative outcomes, there is a lack of evidence-based medicine that screening will improve outcomes (Murlow and Lichtenstein, 1991).

ASK ABOUT URINARY INCONTINENCE The level of recommendation is the highest for all categories because urinary incontinence is common among women and may occur in men, is easy to screen for (usually one to two questions), and multiple effective treatments are available (Nasr and Ouslander, 1998; Schmidbauer et al., 2001; Miller et al., 1995).

MALES: SCREEN FOR ERECTILE DYSFUNCTION AND HYPOGONADISM It is recommended that this be done for males in Robust and Frail categories, but should only be considered in males with Moderate Dementia. Erectile dysfunction is common and multiple treatments are available (Montague et al., 1996). Male hypogonadism is also common and is associated with muscle weakness and osteoporosis (Morley and Perry, 2000). The ADAM (Androgen Deficiency in Aging Males) screen for hypogonadism has high sensitivity and adequate specificity (Morley et al., 2000; see Chapter 121, Ovarian and Testicular Function).

COGNITIVE SCREENING Screening for cognitive impairment is part of a CGA and should be done at initial visits for patients in all categories, except for those at End of Life, where it should be considered. The Mini-mental State examination is a commonly used screening tool (Folstein et al., 1975), but may have limited utility if the cut-off score is set too high (White et al., 2002). For elderly with high education levels, the Saint Louis University Mental Status (SLUMS) examination (see chapter on dementia for details) may be used. The term “symptomatic” refers to any complaint given by the patient or caregiver, or any problem observed/illicited by the clinician.

DEPRESSION SCREENING Depression screening should be done at initial visits for patients in all categories. There is evidence that detection

of depression is higher for older patients compared to younger patients when screening data were made available and effective treatments are available. (German et al., 1987). Screening for depression is part of a CGA. There is no strong evidence for one particular screening instrument for depression (Mulrow et al., 1995; Lyness et al., 1997). The Geriatric Depression Scale (GDS) may be one of the easiest to administer (Yesavage et al., 1982–1983). However, the GDS does not maintain its validity for patients with dementia and the Cornell scale (a 19-item clinicianadministered instrument) is recommended (Burke et al., 1989; Alexopoulos et al., 1988). Symptomatic refers to any complaint given by the patient or caregiver or any problem observed/elicited by the clinician.

SCREENING FOR GAIT AND BALANCE The evidence to screen for gait and balance problems at initial visits in all categories except at End of Life is based on the fact that falls are associated with decreased function, increased nursing home admission, and increased morbidity and mortality in populations similar to patients in these categories (Robbins et al., 1989). One of the best “screeners” for gait and balance problems is to ask patients if they have fallen (Tinetti et al., 1986). The “Get Up and Go Test” may quantify functional mobility as well as testing balance, and may also be useful in following clinical change over time (Mathias et al., 1986; Podsiadlo and Richardson, 1991).

ADVANCED DIRECTIVES Although the evidence is not strong that advance directives make a difference in outcomes (e.g. one study showed that systematic implementation of a program to increase use of advance directives reduced health-care services utilization without affecting satisfaction or mortality) (Molloy et al., 2000), there are ways to increase discussions and completions of advanced directives (Dexter et al., 1998; Rubin et al., 1994). Advanced directives are especially important for patients in the Frail, Moderately Demented, and End of Life categories.

INFLUENZA VACCINE This should be done yearly for patients in all categories. More than 90% of the deaths attributed to pneumonia and influenza during epidemics occurred among persons aged 65 and older. Influenza vaccination in the elderly has been shown to reduce hospitalization rates, to be cost-effective, and to reduce influenza-associated mortality (Fedson et al., 1993; Foster et al., 1992; Barker and Mullooly, 1980). In the nursing home, while vaccination is only 40% effective in preventing clinical illness, it is more effective in preventing


pneumonia, hospitalization, and death. Vaccinating more than 80% of nursing home residents has been shown to prevent influenza outbreaks (Saah et al., 1986; Gross et al., 1988).

PNEUMOCOCCAL VACCINE The recommendations about pneumococcal vaccine are based on some evidence and on the probable life expectancy in various categories. Although pneumococcal vaccination increases antibody levels in older adults to a lesser degree than younger adults, and levels decrease more rapidly in the elderly, vaccination has been shown to be effective in reducing the incidence of pneumococcal bactremia in older, high-risk patients who have good antibody response to the vaccine. Most organizations recommend that one dose of the 23-valent pneumococcal vaccine be given for all adults over age 65. Older patients who received the earlier 14-valent vaccine should be revaccinated with the 23-valent vaccine if they fall into any of those two groups. If patients have had the 23-valent vaccination before age 65, the recommendations for revaccination are controversial (United States Preventive Services Task Force, 1996; American College of Physicians, 1994). The ACP reports that there is currently insufficient data on repeated revaccination every 6 years in healthy elderly, and most other organizations do not provide specific recommendations for revaccination. However, since older patients with chronic diseases may occasionally be “Robust” for other reasons, clinicians should “consider repeating” every 6 years (American College of Physicians, 1994).

TETANUS Recommendations regarding adult tetanus/diphtheria vaccination do not vary for older persons from recommendations for younger adults. Over half of the cases of tetanus occur in persons 60 years or older. All adults should complete a primary series of tetanus/diphtheria toxoid (Td). If an individual had an incomplete series or an uncertain history, it is recommended that the entire primary series be given. Primary series for adults consists of 0.5 cc of Td intramuscularly as the initial dose and at 2 and 6 months later. Booster doses need to be given every 10 years (United States Preventive Services Task Force, 1996; American College of Physicians, 1994).

BREAST CANCER SCREENING There is no evidence for or against clinician’s recommending self-examination, or the clinician doing the clinical breast exam. Given the low cost and low risk (but not zero risk, e.g. a patient with dementia who may misperceive the exam), this should be done on a yearly basis for patients in all categories except for those in the End of Life category.

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Levels of recommendation differ for the different categories. This is because of lack of agreement among organizations regarding screening with mammography. For example, the ACP recommends screening up to age 75 (Eddy, 1989). The American Geriatric Society (AGS) recommends that physicians strongly consider recommending annual or at least biennial mammography until age 75 and biennially or at least every 3 years thereafter with no upper age limit for women with an estimated life expectancy of 4 or more years (American Geriatrics Society Clinical Practice Committee, 2000). The USPSTF recommends screening up to age 69, every 1–2 years, mammography alone, or combination of mammography and clinical breast exam. The USPSTF also notes that evidence is lacking to recommend for or against screening women 70 years or older, but doing this for high-risk patients may be made on other grounds (United States Preventive Services Task Force, 1996).

CERVICAL CANCER SCREENING The low levels of recommendation for Robust (consider) and “Don’t Do” for the other categories are based on lack of evidence and organizational recommendations. The ACP and the USPSTF recommend no further Papanicolaou smears for women over age 65 who have had previous regular screening with consistently normal results (United States Preventive Services Task Force, 1996; Eddy, 1990). The AGS position statement says that regular Pap smear screening at 1- to 3-year intervals until at least the age of 70 seems reasonable. Beyond age 70, there is little evidence for or against screening women who have been regularly screened in previous years. An older woman of any age who has never had a Pap smear may be screened with at least two negative Pap smears 1 year apart (American Geriatrics Society, 2001).

COLON CANCER SCREENING Since the clinician’s choice of screening procedure for colon cancer depends on extrinsic factors (e.g. transportation, availability of a gastroenterologist, patient willingness to do one procedure over the other), clinicians can choose to follow recommendations for either fecal occult blood test or colonoscopy. Recommendations for either of these procedures are the lowest level for patients in most categories because they are based on organizational guidelines. Both the ACP and the USPSTF recommend annual fecal occult blood testing or periodic flexible sigmoidoscopy, or both. The ACP recommends sigmoidoscopy, colonoscopy, or air-contrast barium enema every 10 years from the ages of 50 to 70 years (Annals of Internal Medicine, 1997). The USPSTF recommends sigmoidoscopy, but does not recommend an interval for screening. There is also no upper age limit (United States Preventive Services Task Force, 1996). The American Cancer Society recommends

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either one of the following: total colon examination (aircontrast barium enema or colonoscopy) every 10 years or fecal occult blood tests annually and flexible sigmoidoscopy every 5 years. There is no upper age limit (Anonymous, 1999a; Anonymous, 1999b).

PROSTATE CANCER SCREENING The level of recommendation for prostate cancer screening is to “Discuss the pros and cons” for patients in the Robust, Frail, and Moderately Demented categories, and “Don’t Do” for End of Life. The evidence for screening is not strong enough to recommend this routinely (Ilic et al., 2004). Furthermore, there is no agreement among organizations about this issue. For example, neither the ACP nor the USPSTF recommend prostate-specific antigen (PSA) as a screening test for prostate CA (United States Preventive Services Task Force, 1996). However, many urologic organizations tend to recommend it. Digital rectal examination (DRE) has not been demonstrated to be an effective screening test for prostate cancer. The American Cancer Society believes that health-care providers should offer patients the PSA blood test and the DRE yearly for patients over age 50, if they have at least a 10-year life expectancy (Smith et al., 2000; Eyre, 1997). There is insufficient evidence regarding the use of transrectal ultrasonography to consider this a screening tool.

OSTEOPOROSIS The recommendations to do screening at least once for patients in all categories except End of Life is based on studies that show inadequate rates of diagnosing and treatment. However, there is lack of evidence to show that mass screening of all elderly women and men will be cost-effective or improve outcomes related to osteoporosis (Kanis, 1994). Bone densitometry studies are accurate screening tools to diagnose early osteoporosis before bone loss exceeds 3%. The dual-energy X-ray (DEXA) absorptiometry and the single-energy X-ray (SXA) absorptiometry provide safe, lowlevel radiation. These tools are approximately 94% accurate in diagnosing bone deterioration. Both the DEXA and SXA scans are painless and noninvasive procedures that predict patients who are at high risk for developing bone fractures (Yeap et al., 1998; Kanis and Gluer, 2000).

population is lacking. Some organizational recommendations exist. For example, the USPSTF recommends screening healthy men and women up to age 65, and reports that there is insufficient evidence to recommend for or against routine screening for asymptomatic persons over age 65. The USPSTF also reports that clinicians should consider screening for persons aged 65 to 75 who have additional risk factors (US Preventive Services Task Force, 2001). The ACP recommends screening up to age 65, reports that there is insufficient evidence for or against screening for persons aged 65–75, and advises against screening after age 75 (Annals of Internal Medicine, 1996; Garber et al., 1996). The most appropriate interval for screening is not known.

THYROID-STIMULATING HORMONE (TSH) Screening all older adults is not currently recommended by the USPSTF, on the basis of lack of data, but notes that screening may be made on other grounds (United States Preventive Services Task Force, 1996). The ACP recommends thyroid function testing in persons aged 50 or over with symptoms suggestive of thyroid disease. The ACP also notes that screening can detect symptomatic but unsuspected thyroid dysfunction (Helfand and Redfern, 1998; Anonymous, 1998a). The yield is highest for women older than 50 years of age. In this group, 1 in 71 women screened could benefit from relief of symptoms. However, evidence of the efficacy of treatment for subclinical thyroid dysfunction is inconclusive. The American Thyroid Association recommends routine screening every 5 years after age 35, but notes that more frequent screening may be appropriate in individuals at higher risk of developing thyroid dysfunction (Ladenson et al., 2000). Many geriatricians advocate screening high-risk population such as nursing home population, frail elderly, and patients with dementia (Mokshagundam and Barzel, 1993). The sensitive TSH assay is probably the screening test of choice.

FASTING BLOOD GLUCOSE This recommendation is based on organizational recommendations only. Although the USPSTF recommends against routine screening in asymptomatic individuals, it notes that clinicians may decide to screen selected persons at high risk of diabetes on other grounds (United States Preventive Services Task Force, 1996). The American Diabetes Association has recommended fasting plasma glucose measurement every 3 years in adults with one or more of a long list of risk factors (http://www.diabetes.org/for-healthprofessionals-and-scientists/cpr.jsp, 2005).

CHOLESTEROL SCREENING The reason for a low-level recommendation (i.e. consider) and a targeted approach (only for Robust and Frail with additional risk factors) is because the data for primary prevention in this area for many segments of the elderly

SLEEP APNEA Because of the low cost of screening (in the form of asking about symptoms of sleep apnea during the routine history and


physical or to use a screening questionnaire tool such as the Epworth Sleepiness Scale) (Johns, 1991) and the potential to miss this diagnosis among older patients, it is recommended for robust and frail elderly (Baumel et al., 1997). However, there is no evidence to date that screening for sleep apnea is cost effective or will change outcomes related to this problem.

BRITISH HEALTH CHECKS The British Health Check model has its origins in the many studies over the past 50 years that have consistently identified high levels of unreported and unrecognized physical, mental, social, and environmental problems among older people living in the community (Williamson et al., 1964; Williams and Wallace, 1993). Thus, repeated annual assessments will detect on average about two new medical problems and one psychosocial problem per person per year (Stuck et al., 2004). The findings have led to numerous randomized controlled trials of general practice-based case finding and intervention, with an emphasis on identifying people with functional loss and dependency, rather than detection of disease. Most of these trials have reported some positive results, for example, with benefits in reduced mortality, fewer nursing home admissions, fewer and briefer hospitalizations, improved functional health status and quality of life outcomes. However, the results have not all been consistent and recent systematic reviews have come to contradictory conclusions (van Haastregt et al., 2000; Elkan et al., 2001; Stuck et al., 2002b). The most effective programs seem to involve an enthusiastic professional (general practitioner or nurse), repeated comprehensive assessment, with the same person responsible for identification of problems and arranging intervention and long-term follow-up. In 1990, the new contract for general practitioners working in the UK National Health Service established an annual health check to be offered to all patients aged 75 years and over (Freer, 1990). Furthermore, this specified the broad areas that were to be addressed: – A home visit, at least annually, to see the home environment and to find out whether carers and relatives are available; – social assessment (lifestyle, relationships); – mobility assessment (walking, sitting, use of aids); – mental assessment; – assessment of the senses (hearing and vision); – assessment of continence; – general functional assessment; – review of medication. Unfortunately, the policy did not give guidance on appropriate methods or levels of assessment and it was implemented haphazardly, though nearly half the patients who were screened had problems for which some action was taken (Brown et al., 1997).

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Table 2 The single assessment process: standardized domains of need (NSF)

User’s perspective • Problems and issues in the user’s own words • User’s expectations and motivation Clinical background • History of medical problems • History of falls • Medication use Disease prevention • History of blood pressure monitoring • Nutrition • Vaccination history • Drinking and smoking history • Exercise pattern • History of cervical and breast screening Personal care and physical well-being • Personal hygiene, including washing, bathing, toileting, and grooming • Dressing • Pain • Oral health • Foot care • Tissue viability • Mobility • Continence • Sleeping patterns Senses • Sight • Hearing • Communication Mental health • Cognition including dementia • Mental health including depression Relationships • Social contacts, relationships, and involvement • Caring arrangements Safety • Abuse or neglect • Other aspects of personal safety • Public safety Immediate environment and resources • Care of the home • Accommodation • Finances • Access to local facilities and services

Those general practitioners who were enthusiastic about the potential benefits of the over-75s checks provided comprehensive screening to all of their patients by invitation, often establishing special clinics and appointing specialist health visitors to help with detailed assessment and followup at home. Most general practitioners, however, delegated responsibility to practice nurses. Many adopted a 2-stage targeted approach, using a brief initial screening schedule administered to all the population, to identify the minority thought to justify more detailed assessment. The first stage often used a postal questionnaire, sometimes accompanying a birthday card, while other schemes used volunteers to collect information, or integrated the process into routine care. The latter approach was based on the fact that over 90% of over 75-year olds have contact with their general

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practitioner during the year and the nonattenders are generally fit and well (Ebrahim et al., 1984). At worst, this opportunistic method means that only 10% require to be specially contacted. A recent trial involving over 40 000 general practice patients compared the universal versus the targeted approach and subsequent management by a hospital-based geriatric team versus the general practitioner and showed few important differences after 3 years of follow-up (Fletcher et al., 2004). However, the study once again confirmed the high frequency of unreported need amongst the elderly study participants. The latest General Medical Services General Practice Contract does not include over 75 checks, but the National Service Framework (NSF) for Older People (Department of Health, 2001) envisages that the new Single Assessment Process will incorporate case finding. This aims to provide a more standardized assessment across health- and socialcare services so that older people’s needs are “assessed in the round” at first contact, using the two-stage targeted approach to explore a wide range of specified domains of need (Table 2). The NSF also aims to ensure that older people have fair access to programs of disease prevention and health promotion, including cancer screening, BP management, smoking cessation, influenza immunization, advice about lifestyle including nutrition and physical activity, and falls prevention. While the targeting of the older over-75s population will maximize the yield of significant problems, some of these people will be identified too late for effective intervention. Certainly, benefit in terms of reduced mortality associated with preventive home visits in clinical trials appears to be restricted to the younger old. Health risk appraisal combined with reinforcement of recommendations has been suggested to be best suited to those aged 60–75 years, using a selfadministered questionnaire to identify potentially modifiable risk factors for functional status decline (Stuck et al., 2002a).

status based on life expectancy and functional status: Robust, Frail, Moderately Demented and End of Life. The Glidepath also allows for decisions to be made on a “graded” rather than an “all or nothing” basis by using four levels of recommendations: Do, Discuss, Consider, Don’t Do. • The second model discusses the background of the British Health Checks, which is community based, and focuses on comprehensive geriatric assessment for all people over 75 years of age. • Although the original British Health Checks have historically been effective in identifying unreported and unrecognized physical, mental, social, and environmental problems among older people living in the community, the latest General Medical Services General Practice Contract does not include over 75 checks. The new Single Assessment Process under the National Service Framework for Older People (Department of Health, 2001) aims to provide a more standardized assessment across health and social-care services and access to programmes of disease prevention and health promotion.

KEY REFERENCES • Brown K, Boot D, Groom L & Williams E. Problems found in the over75s by the annual health check. British Journal of General Practice 1997; 47:31 – 5. • Flaherty JH, Morley JE, Murphy DJ & Wasserman MR. The development of outpatient clinical glidepaths. Journal of the American Geriatrics Society 2002; 50(11):1886 – 901. • Freer CB. Screening the elderly. British Medical Journal 1990; 300:1447 – 8. • Gillick M. Choosing Medical Care in Old Age: What Kind, How Much, When to Stop 1994, 1st edn; Harvard University Press, Cambridge. • Stuck AE, Beck JC & Egger M. Preventing disability in elderly people. Lancet 2004; 364:1641 – 2.

KEY POINTS • This chapter presents two models of preventive geriatrics that deal with the challenge of heterogeneity seen among older persons, the dichotomy between the treatment of populations and the wishes of the individual, and the unclear areas or “gray zones” of preventive geriatrics? • The first model is called the Health Maintenance Clinical Glidepath which is primarily for officebased practices, and addresses screening for geriatricspecific areas (e.g. cognition, gait and balance, etc.) as well as screening for common medical illnesses and diseases (e.g. certain cancers, heart disease, etc.). • Instead of using strict chronological age to tell clinicians when to do certain preventive measures, the Clinical Glidepath helps guide clinicians in their decision making by utilizing four categories of health

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Johnson LE, Dooley PA & Gleick JB. Oral nutritional supplement use in elderly nursing home. Journal of American Geriatrics Society 1993; 41(9):947 – 52. Johns MW. A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep 1991; 14(6):540 – 55. Joshi S & Flaherty JH. Elder abuse and neglect in long term care. Clinics in Geriatric Medicine 2005; 21:333 – 54. Kanis JA, WHO Study Group. Assessment of fracture risk and its application to screening for postmenopausal osteoporosis: synopsis of a WHO report. Osteoporosis International 1994; 4(6):368 – 81. Kanis JA & Gluer CC, Committee of Scientific Advisors, International Osteoporosis Foundation. An update on the diagnosis and assessment of osteoporosis with densitometry. Osteoporosis International 2000; 11(3):192 – 202. Katz S, Ford AB, Moskowitz RW et al. Studies of illness in the aged. The index of ADL: A standardized measure of biological and psychosocial function. Journal of the American Medical Association 1963; 185:914 – 9. Kerridge I, Lowe M & Henry D. Ethics and evidence based medicine. British Medical Journal 1998; 316(7138):1151 – 3. Lachs MS & Pillemer K. Abuse and neglect of elderly persons. New England Journal of Medicine 1995; 332(7):437 – 43. Ladenson PW, Singer PA, Ain KB et al. American Thyroid Association guidelines for detection of thyroid dysfunction. Archives of Internal Medicine 2000; 160:1573 – 5. Lawton MP & Brody EM. Assessment of older people: self-maintaining and instrumental activities of daily living. Gerontologist 1969; 9:179 – 86. Liberman UA, Weiss SR, Broll J et al., The Alendronate Phase III Osteoporosis Treatment Study Group. Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. New England Journal of Medicine 1995; 333(22):1437 – 43. Littenberg B, Garber AM & Sox HC Jr. Screening for hypertension. Annals of Internal Medicine 1990; 112(3):192 – 202, (www.acponline.org/scipolicy). Luukinen H, Koski K, Laippala P & Kivela SL. Prognosis of diastolic and systolic orthostatic hypotension in older persons. Archives of Internal Medicine 1999; 159(3):273 – 80. Lyness JM, Noel TK, Cox C et al. Screening for depression in elderly primary care patients. A comparison of the CES-D and the GDS. Archives of Internal Medicine 1997; 157:449 – 54. Mathias S, Nayak US & Isaacs B. Balance in elderly patients: the “getup and go” test. Archives of Physical Medicine and Rehabilitation 1986; 67(6):387 – 9. Miller DK, Brunworth D, Brunworth DS et al. Efficiency of geriatric case findings in a private practitioners office. Journal of American Geriatrics Society 1995; 43:533 – 7. Molloy DW, Guyatt GH, Russo R et al. Systematic implementation of an advance directive program in nursing homes: a randomized controlled trial. Journal of the American Medical Association 2000; 283(11):1437 – 44. Mokshagundam S & Barzel US. Thyroid disease in the elderly. Journal of American Geriatrics Society 1993; 41(12):1361 – 9. Montague DK, Barada JH, Belker AM et al., The American Urological Association. Clinical guidelines panel on erectile dysfunction: summary report on the treatment of organic erectile dysfunction. Journal of Urology 1996; 156(6):2007 – 11. Morley JE. Anorexia in older persons. Drugs and Aging 1996; 8(2):134 – 55. Morley JE, Charlton E, Patrick P et al. Validation of a screening questionnaire for androgen deficiency in aging males. Metabolism: Clinical and Experimental 2000; 49(9):1239 – 42. Morley JE & Perry HM III. Androgen deficiency in aging men: role of testosterone replacement therapy. The Journal of Laboratory and Clinical Medicine 2000; 135(5):370 – 8. Murlow CD & Lichtenstein MJ. Screening of hearing impairment in the elderly. Rational and strategy. Journal of General Internal Medicine 1991; 6:249 – 58. Mulrow C, Williams JW Jr, Gerety MB et al. Case-finding instruments for depression in primary care settings. Annals of Internal Medicine 1995; 122:913 – 21. Murphy D. Honest Medicine: Shattering the Myths of Aging and Healthcare 1995, 1st edn; Atlantic Press, New York.

Nasr SZ & Ouslander JG. Urinary incontinence in the elderly. Causes and treatment options. Drugs and Aging 1998; 12(5):349 – 60. Nolan L & O’Malley K. Prescribing for the elderly: part 1. Sensitivity of the elderly to adverse drug reactions. Journal of American Geriatrics Society 1998; 36:142 – 9. Pitt B, Zannad F, Remme WJ et al., Randomized Aldactone Evaluation Study Investigators. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. New England Journal of Medicine 1999; 341(10):709 – 17. Podsiadlo D & Richardson S. The timed “Up & Go”: a test of basic functional mobility for frail elderly persons. Journal of American Geriatrics Society 1991; 39(2):142 – 8. Pokorny AD, Miller BA & Kaplan HB. The brief MAST: a shortened version of the Michigan Alcoholism Screening Test. American Journal of Psychiatry 1972; 129(3):342 – 5, (http://www.americancancersociety. org.). Rimer BK, Orleans CT, Fleisher L et al. Does tailoring matter? The impact of a tailored guide on ratings and short-term smoking-related outcomes for older smokers. Health Education Research 1994; 9(1):69 – 84. Robbins AS, Rubenstein LZ, Josephson KR et al. Predictors of falls among elderly people. Results of two population-based studies. Archives of Internal Medicine 1989; 149:1628 – 33. Rubenstein LZ. Development of a short version of the Mini Nutritional Assessment. In B Vellas, PJ Garry & Y Guigoz (eds) Mini Nutritional Assessment (MNA): Research and Practice in Elderly. Nestlé Clinical and Performance Nutrition Workshop Series 1998, Vol 1, pp 101 – 11; Lippincott-Raven, Philadelphia. Rubin SM, Strull WM, Fialkow MF et al. Increasing the completion of the durable power of attorney for health care. A randomized, controlled trial. Journal of the American Medical Association 1994; 271(3):209 – 12. Saah AJ, Neufeld R, Rodstein M et al. Influenza vaccine and pneumonia mortality in a nursing home population. Archives of Internal Medicine 1986; 146:2353 – 7. Schmidbauer J, Temml C, Schatzl G et al. Risk factors for urinary incontinence in both sexes. Analysis of a health screening project. European Urology 2001; 39(5):565 – 70. Smeeth L & Iliffe S. Effectiveness of screening older people for impaired vision in community setting: systematic review of evidence from randomized controlled trials. British Medical Journal 1998; 316(7132):660 – 3. Smith RA, Mettlin CJ, Davis KJ & Eyre H. American cancer society guidelines for the early detection of cancer. Cancer 2000; 50(1):34 – 49. Stuck AE, Beck JC & Egger M. Preventing disability in elderly people. Lancet 2004; 364:1641 – 2. Stuck AE, Elkuch P, Dapp U et al., Pro-age pilot study group. Feasibility and yield of a self-administered questionnaire for health risk appraisal in older people in three European countries. Age and Aging 2002a; 31:463 – 7. Stuck AE, Egger M, Hammer A et al. Home visits to prevent nursing home admission and functional decline in elderly people: systematic review and meta-regression analysis. Journal of the American Medical Association 2002b; 287:1022 – 8. Tinetti ME, Williams TF & Mayewski R. Fall risk index for elderly patients based on number of chronic disabilities. American Journal of Medicine 1986; 80:429 – 34. United States Preventive Services Task Force. Guide to Clinical Preventive Services 1996, 2nd edn; Williams and Wilkins, Baltimore, (http://ahrq.gov/clinic/uspstfix.htm). U.S. Preventive Services Task Force. Screening for lipid disorders: recommendations and rationale. American Journal of Preventive Medicine 2001; 20(3S):73 – 6, (http://ahrq.gov/clinic/uspstfix.htm) or (http://www.elsevier.com/locate/ajpmonline). van Haastregt JCM, Diederiks JPM, van Rossum E et al. Effects of preventive home visits to elderly people living in the community: a systematic review. British Medical Journal 2000; 320:754 – 8. Walter LC, Brand RJ, Counsell SR et al. Development and validation of a prognostic index for 1-year mortality in older adults after hospitalization. Journal of the American Medical Association 2001; 285(23):2987 – 94. White N, Scott A, Woods RT et al. The limited utility of the Mini-Mental State examination in screening people over the age of 75 years for

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FURTHER READING Brown K & Groom L. General practice health checks of elderly people: a county-wide survey. Health Trends 1995; 27(3):89 – 91. Department of Health and the Welsh Office. General Practice in the National Health Service: A New Contract 1989; HMSO, London. Guigoz Y, Vellas BJ & Garry PJ. Assessing the nutritional status of the elderly: the Mini-Nutritional Assessment as part of the geriatric evaluation. Nutrition Reviews 1996; 54:S59 – 65, (http://www.mnaelderly.com). McEwan RT & Forster DP. A review of the costs and effectiveness of assessing the elderly in general practice. Family Practice 1993; 10(1):55 – 62. McGarry J & Arthur AN. Can over-75 health checks identify unmet need? Nursing Standard 1999; 13(33):37 – 9. Wilkieson CA, Campbell AM, McWhirter MF et al. Standardization of health assessments for patients aged 75 years and over: 3 years’ experience in the forth valley health board area. British Journal of General Practice 1996; 46(406):307 – 8.

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Polypharmacy, is this Another Disease? Oscar A. Cepeda and John E. Morley Saint Louis University School of Medicine and Saint Louis Veterans’ Affairs Medical Center, St Louis, MO, USA

INTRODUCTION

PHARMACOKINETICS

Geriatric patients are frequently prescribed multiple drugs in complex dosage schedules. In some instances, this is justified because of the presence of multiple chronic medical conditions, the proven efficacy of an increasing number of drugs for these conditions, and practice guidelines that recommend their use. In many instances, however, complex drug regimens are unnecessary; they are costly and predispose to noncompliance and adverse drug reactions. Many older patients are prescribed multiple medications, take overthe-counter drugs, and are then prescribed additional drugs to treat the side effects of medications they are already taking. Although persons aged 65 and older comprise only about 12% of the US population, they consume one-third of all prescribed drugs and more than a half of over-the-counter medicines. Overall, more than 80% of all communitydwelling elders use prescription drugs, with the average older person using between 3 and 8 drugs (Morley, 2003). The devastating consequences of medical errors have been clearly detailed in the book To Err is Human by the Institute of Medicine. Medical errors are not uncommon, leading to a number of deaths ranging between 44 000 to 98 000 at a cost to the United States of $17–29 billion a year. A Harvard study done in 51 New York hospitals involving 30 000 patients reported that 3.7% had a treatment adverse event and there was a doubling in the number of undesirable treatment effects in persons over 65 years of age. Most errors are preventable; errors of omission are as important as errors of commission (Morley, 2003). In addition to concerns about the risks of excessive and inappropriate drug prescribing, there are also concerns about the consequences of underprescribing potentially beneficial drugs. With the increasing numbers of patients surviving to older ages and comprising such a large proportion of drug use, a clear understanding of the risks, benefits, and consequences of drug therapy in older patients is needed.

Pharmacokinetics (the study of the action of a drug in the body over time) changes with age. The physiologic changes that accompany aging alter the pharmacologic processes of absorption, distribution, metabolism, and elimination. The effects of these age-related changes are variable and difficult to predict. Some of these physiologic changes are related solely to aging, whereas others are most likely caused by the combined effect of age, disease, and the environment. Even though increasing age is often accompanied by reductions in the physiologic reserve of many organ systems, independent of the effects of disease, these changes are not uniform; substantial variability exists from individual to individual, which makes some older patients more vulnerable than others (Schmucker, 1985). Of the four traditional components of pharmacokinetics – absorption, distribution, metabolism, and excretion – only the last three are meaningfully affected by age. In the absence of malabsorptive syndromes, traditional oral formulation of drugs are absorbed as well in old age as in youth, indeed the well-reported changes in gastric motility and blood flow to the gut with aging do not appear to alter the efficiency with which medications move (mainly by passive diffusion) from the gastrointestinal tract into the systemic circulation. More important changes occur from the concurrent administration of several medications at the same time. However, some drugs commonly used for older persons require food for optimum absorption, for example, megestrol acetate which is used to stimulate appetite and weight gain has minimal absorption without food (Table 1). Unlike absorption, drug distribution is affected by age in clinically meaningful ways. Serum albumin, the major drug binding protein, declines in sick patients due to cytokine excess. Even in healthy patients where there is a small decline, this can substantially increase the amount of free drugs available for action. This effect is of particular relevance for highly protein-bound drugs, especially when they are used simultaneously and compete for


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Table 1 Relevant changes in aging and pharmacology

Pharmacological parameter

Table 2 Volume of distribution for commonly used medications

Age-related changes

Clinical effect

Decreased volume

Increased volume

Tissue sensitivity

Alterations in: Receptor number and affinity Nuclear responses Second messenger function

Patients are more sensitive or less sensitive to a given medication

Absorption

Decrease in: Splachnic blood flow Absorptive surface GI motility Increased gastric Ph

Minimal changes associated with aging

Ethanol Gentamicin Digoxin Cimetidine Phenytoin Quinine Theophyline Meperidine

Diazepam Oxazepam Prazocin Acetaminophen Salicylates Tolbutamide Chlordiazepoxide Thiopental

Decrease in: Total body water Serum albumin Lean body mass Increased fat

Higher concentration of drugs Longer elimination half-life of lipid soluble drugs

Metabolism

Decreased liver blood flow and enzyme activity

Decreased biotransformation and first-pass metabolism

Excretion

Decreased renal perfusion, glomerular filtration rate and tubular secretion

Decreased renal elimination of drugs

Distribution

Note: If the volume of distribution is higher, drug levels are higher.

GI, gastrointestinal.

protein-binding sites (Schmucker, 1985). In long-term-care residents, diphenylhydantoin toxicity with low serum levels can occur because the decrease in albumin. Thus, measuring a free dilantin level can be essential in these situations. The relative increase in body fat and decrease in lean body mass alters drug distribution, such that fat-soluble drugs distribute more widely and water-soluble drugs less widely; this fact can potentially lead the health-care professional to the wrong decision due to misinterpretation of serum drug levels. Many assays measure the total amount of drug that is present in serum, both protein-bound and unbound (free). The unbound concentration is more clinically relevant than the total concentration because only unbound drug is pharmacologically active (Grandison and Boudinot, 2000). For a patient with hypoalbuminemia or another deficiency in binding protein, any given serum drug level reflects a greater concentration of unbound drug than the same level would signify in a patient with normal protein-binding capacity. A hypoalbuminemic patient with a normal total serum drug concentration may actually have an unbound drug concentration that is unacceptably high. By contrast, the same patient with a slightly lower than normal total serum concentration may have an unbound drug concentration that is in reasonable range (Grandison and Boudinot, 2000; Table 2). In evaluating serum drug levels in the older patient, it is also important to recall that the therapeutic range routinely reported on such assays may not be an accurate guide to either efficacy or toxicity in the geriatric patient. Such ranges have typically been defined in nonelderly subjects and cannot take into account pharmacodynamic differences or idiosyncratic aspects of specific agents (Beyth and Shorr, 2002).

The other important aspect is the drug distribution, which varies importantly with age; volume distribution is a virtual space in a given patient which a particular drug occupies. Age-related changes in body composition can prominently affect pharmacology by altering the volume of distribution (Vd); the elimination half-life of a drug varies with the ratio Vd:drug clearance. Thus, even if the same rate of clearance of a drug is unchanged with age, changes in Vd can affect a drug’s half-life and duration of action. Because the total body water and lean body mass decline with increasing age, drugs that distribute in this compartments, such as antibiotics, digoxin, lithium, and alcohol, may have a lower Vd and can, therefore, achieve higher concentrations from given amounts of drugs. On the other hand, drugs that distribute in body fat, such as many of the psychotropic agents, have a large Vd in the geriatric patients. The larger Vd will thus cause a prolongation of the halflife unless the clearance increases proportionately, which is unlikely to happen with age (Beyth and Shorr, 2002). As a good example of the necessary precautions that needs to be implemented in elderly patients, warfarin is an excellent candidate because it has been used more often in older persons. Warfarin inhibits the 4 vitamin K –dependent coagulant proteins, factors II, VII, IX, X, and it is highly protein-bound (97–99%) which could be a problem in malnourished patients, metabolized in the liver and with a half-life of 42 hours, its onset of action is approximately 36–72 hours, with a peak effect within 5–7 days. Warfarin has been proven to be effective in prophylactic or therapeutic anticoagulation, but the risk of major bleeding with increasing levels of (prothrombin time/International Normalized Ratio) PT/INR is a major concern; they are increased by the presence of comorbid conditions such as heart failure, liver or kidney failure, or cancer. Warfarin dose should be highly individualized and may have to be adjusted several times, based on laboratory test results depending on the target INR for the patient’s condition; strict adherence to the prescribed dosage schedule is necessary and patients should be informed not to take or discontinue any other medications, except on the advice of a physician or pharmacist. In elderly patients, initial doses of warfarin typically are lower, and INR monitoring should be performed more frequently, and because warfarin possesses numerous drug interactions, some of which increase the effects of warfarin

POLYPHARMACY, IS THIS ANOTHER DISEASE?

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Table 3 Metabolism of some drugs by the hepatic cytochrome P450 system is altered by aging

Cytochrome P450 CYP1A2

CYP2C9

CYP2C19

CYP2D6

CYP3A4

Substrates

Olanzapine Theophyline

Phenytoin Warfarin

Diazepam Omeprazole Phenytoin

Codeine Desipramine Haloperidol Metoprolol Paroxetine Risperidone

Alprazolam Nifedipine Terfenadine Triazolam Verapamil

Inducers

Omeprazole Smoking

Rifampin

Inhibitors

Cimetidine Ciprofloxacin

Amiodarone Fluconazole

and others that decrease its effects, caution must be observed when any drug, herbal, nutritional supplement or dietary changes are made to existing regimen of a patient receiving warfarin.

METABOLISM AND DRUG CLEARANCE The liver represents the major site of metabolism for many medications. Hepatic transformations of drugs are categorized into phase I (preparative) and phase II (synthetic) reactions. Phase I reactions include oxidations (hydroxylation, N-dealkylation, and sulfoxidation), reduction and hydrolyses. Phase II reactions involve conjugation of the drug molecule to glucoronides, sulfates, or acetates. There is evidence of decline in phase I reactions with increasing age, and that the decline is more prominent in men than in women. In contrast, the second phase of drug metabolism appears to be less affected by age. There is also evidence that the ability of environmental factors (most importantly smoking) to induce drug-metabolizing enzymes declines with age (Routledge and O’Mahony, 2003). Significant age-related declines in liver size and in liver blood flow have been described; in terms of absolute hepatic blood flow, reductions of 25 to 47% reported in persons between the ages of 25 and 90. This decrease is clinically important because hepatic metabolism is the rate-limiting step that determines the clearance of most metabolized drugs. This effect is especially relevant for drugs that undergo rapid hepatic metabolism (e.g. propranolol). Also, drugs that undergo extensive first-pass metabolism are likely to reach higher blood levels if hepatic blood flow is decreased. The cytochrome P450 (CYP) system located in the smooth endoplasmic reticulum of hepatocytes, is the main catalyzer of phase I reactions. Many isoforms of CYP exist; the most important being CYP 3A4, approximately 60% of CYP enzymes are found in the liver and the remainder are found in the intestine, kidney, and brain. Many commonly prescribed medications serve as substrates for these enzyme systems. Phase I metabolism often undergoes a substantial decrease in activity in elderly patients as a result of illness or drug interactions; drugs that are metabolized through

Phenytoin St. John’s Wort Erythromycin

phase I enzymatic activity will have prolonged half-lives, but there is no easy way to predict the effects of changes in phase I metabolism in an individual patient or to adjust maintenance doses of drugs that undergo this form of metabolism (Routledge and O’Mahony, 2003; Table 3). In contrast, phase II hepatic metabolism involves the conjugation of drugs or their metabolites to organic substrates. The elimination of drugs that undergo phase II metabolism by conjugation is generally less altered with age. Thus, drugs that require only phase II metabolism for excretion do not have a prolonged half-life in older people (Beyth and Shorr, 2002).

ELIMINATION AND RENAL EXCRETION Unlike those of metabolism, the effects of aging on renal functions are somewhat more predictable. The tendency for renal function to decline with increasing age can affect the pharmacokinetics of several drugs (and their active metabolites) that are eliminated predominantly by the kidney. Clearance of drugs from the body occurs more slowly, their half-lives are prolonged, and there is a tendency to accumulate to higher drug concentrations in the steady state (Table 4). Although blood urea nitrogen (BUN) and serum levels may be useful (albeit crude) markers of renal function, it must be remembered that each is susceptible in its own way to perturbations that can occur with aging but have nothing to Table 4 Medications with decreased renal excretion

Triamterene Sotalol Procainamide Ranitidine Pancuronium Phenobarbital Penicillin Lithium Kanamycin Hydrchlorothiazide

Atenolol Amantadine Ampicillin Cimetidine Cephradine Ceftriaxone Digoxin Furosemide Doxycicline Gentamicin

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do with renal function itself. For example, the BUN reflects the concentration of urea in the blood. However, the origin of much of this urea is ingested protein, so that a malnourished older patient may not consume enough nitrogen to produce an appropriate rise in BUN, even in the face of renal impairment. Similarly, creatinine is produced by muscle, and if a patient has a markedly diminished muscle mass, whether because of chronic illness or any other cause, he or she may not produce enough creatinine to reflect a change in the ability of the kidney to excrete this substance. This, overreliance on normal appearing BUN and creatinine in older patients can severely underestimate the degree of renal impairment. Further decrement in renal function is common in the elderly because they frequently have chronic illnesses that affect the kidney such hypertension, diabetes mellitus, and atherosclerosis. Early cross-sectional studies of renal function in aging suggested that there is a linear decrease in renal function between young adulthood and old age, amounting on average to a reduction in glomerular filtration rate by nearly a third. The average clearance declines by 50% from age 25 to 85, despite the serum concentration that in healthy adults remains unchanged. Because the serum levels tend to overestimate the actual clearance in older persons, the commonly cited formula devised by Cockcroft and Gault may be used to estimate clearance in older adults (Muhlberg and Platt, 1999). However, it should be recognized that this equation represents a poor approximation of renal function in the old-old. CrCl =

(140-age) × weight (kg) 70 × serum Cr

(for women, multiply ×0.85) Altered renal clearance leads to two clinically relevant consequences: (1) the half-lives of renally excreted drugs are prolonged and (2) the serum levels are increased. For drugs with large therapeutic indexes (e.g. penicillin), this is of little clinical importance; however, for drugs with narrower therapeutic index (e.g. digoxin, cimetidine, aminoglycosides), side effects may occur in older patients if a dose reduction is not made. Thus, digoxin is the drug that most often causes side effects in the elderly, especially when doses exceed 0.125 mg day−1 . To further define dose requirements, therapeutic drug monitoring is useful for doses of drugs with a low therapeutic index (Muhlberg and Platt, 1999). A common goal of pharmacotherapy in older persons is to achieve and maintain a therapeutic steady-state serum concentration. The steady-state drug concentration is proportional to the medication dosing rate and is inversely proportional to drug clearance. This equality has a number of important ramifications for the prescriber. Although drug clearance is a biologically determined characteristic of each patient over which the prescriber has no control, dose and dosing interval are variables that can be modified. To prevent the excessive accumulation of a drug when its clearance is reduced, one can reduce the dose, increase the interval between doses or both, depending on the situation.

PHARMACODYNAMICS A proportion of the drug or its active metabolite will eventually reach its site of action. Age-related changes at this point, that is, responsiveness to given drug concentrations (without regard to pharmacokinetic changes) are termed pharmacodynamic changes. Pharmacodynamics has been less extensively studied in older patients than pharmacokinetics. Generalizability is not straightforward; the effect of age on drug sensitivity or the binding of drug to receptor sites varies with the drug studied and the response measured. These differences in sensitivity occur in the absence of marked reductions in the metabolism of the drug and its related compounds (Beyth and Shorr, 2002). Older persons are often said to be more sensitive to the effects of drugs. For some drugs, this appears to be true; however, sensitivity to drug effects may decrease rather than increase with age. For example, older persons may be more sensitive to the sedative effects of given blood levels of benzodiazepines but less sensitive to the effect of drugs mediated by β-adrenergic receptors; thus, the sensitivity to drug effects may either increase or decrease with increasing age. Other possible explanations offered for these differences are alterations in second messenger function and cellular and nuclear responses. In general, and because the response of older patients to any given medication is variable, medications should be used with caution to achieve the goal of minimizing risks. This problem could be minimized by knowing the pharmacology of the drugs prescribed, limiting the number of medications used, determining the dosage and preparation on the basis of the characteristics of each individual patient, with downward adjustment for known hepatic or renal illness, and by surveying for side effects (Table 5).

PHARMACOGENETICS This novel area of research and development in the medical sciences has been defined as the identification of differences in drug effects that have a genetic basis, but also development of simple methods by which susceptible individuals can be recognized before the drug is administered. Table 5 Examples of adverse drug reactions

Type of drug

Common adverse reaction

Aminoglycosides Anticholinergics Narcotics Diuretics

Renal failure, hearing loss Dry mouth, delirium, constipation Constipation, sedation Dehydration, hyponatremia, hypokalemia, Incontinence Excessive sedation, delirium, increased risk for falls Diarrhea, urinary retention Delirium, sedation, extrapyramidal movements

Sedative-hypnotics Antiarrhytmics Antipsychotics


It has been said that the major concern of pharmacogenetics is related to using information about how the effect of variations in the genetic makeup could affect the clinical efficacy of drugs, the required dose of drugs, the choice of the correct agent and the risk for side effects to drugs (David, 2004). The fundamental theory of pharmacogenetics states that genotype effects expression of genes resulting in a phenotype, and the expression of genes is modified by agents in the environment as well. Conversely, the expression of the gene may influence the efficacy of a drug by effecting its metabolism, availability at its site of action, and by how the drug binds to its target receptors and achieves a desired pharmacologic action. The rapid growth of pharmacogenetics has been helpful in terms of rapid identification and gene sequencing for drug targets, including receptors, transport proteins, ion channels, and enzymes that metabolize drugs (David, 2004). Current available data on pharmacogenetic research has shown that it will be useful in the near future since the therapeutic-pharmacological approach in many chronic diseases is promising. For example, in chronic conditions or environmental exposures like nicotine addiction, the response of smokers to drugs for smoking cessation differ according to variations in genes encoding several receptors and enzymes. Genetic variation that affects the function and availability of proteins (dopaminergic DRD2-C32806T receptors, and the enzymes dopamine β-hydroxylase DBHG1368A) could increase the efficacy of drugs for smoking cessation (David, 2004). In the specific case of Alzheimer’s disease, several mutations and polymorphisms, including apolipoprotein E4, have been associated with increased risk for Alzheimer’s disease. Furthermore, clinical trials demonstrate that carriers of the APOE E3 allele respond better to cholinesterase inhibitors than those who lack the allele. There is also evidence that treatment response to noncholinergic drugs is affected by the APOE gene and that response to cholinesterase inhibitors is influenced by interactions with other genes involved in drug metabolism. Another example of how pharmacogenetics is helpful is in the treatment of hyperlipidemia, where genetic variations at the APOE locus has been associated with fasting and postprandial plasma lipoprotein concentrations and with cardiovascular disease. The APOE E2 polymorphism is associated with an increased lipid-lowering response to statin therapy, whereas E4 polymorphism is associated with a decreased response to therapy. However, testing for this genetic variation is not yet part of routine clinical care. In the near future, pharmacogenetics will give the chance to provide to our patients information about their probability of responding to treatment with a particular medication, given their genotype. Although the discipline is beginning to come of age, only some of pharmacogenetic applications are available currently in clinical settings, whereas many promise to enter the realm of clinical practice in the next few decades (David, 2004).

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PRESCRIBING FOR GERIATRIC PATIENTS The Beers Criteria, a Useful Consensus for Inappropriate Medication Use in the Elderly The purpose of this initiative was to revise and update criteria for potentially inappropriate medication use in adults aged 65 and older in the United States. The reviewed criteria covered two types of statements: (1) medications that should be avoided in persons older than 65 years and (2) medications that should NOT be used in persons known to have specific medical conditions (Fick and Cooper, 2003). The Beers criteria identifies 48 individual medications or classes of medications to avoid in older adults and their potential concerns and 20 diseases and conditions and medications to be avoided in older adults with these conditions. Adverse drug events have been linked to preventable problems in the elderly patients, such as depression, constipation, falls, immobility, confusion, and hip fractures. The 1997 study on adverse drug reactions found that 35% of ambulatory older adults experienced an adverse drug event and 29% required health-care services; some nursing facility residents have one of these events over a 4-year period. In summary, these criteria have been extensively used for evaluating and intervening in medication use in older adults over the past decade. However, owing to the continuous arrival of new medications in the market, increased knowledge about older drugs and side effects from the new ones needs to be updated periodically in order to keep physicians updated on how to avoid undesirable medication side effects in the elderly population (Table 6; Fick and Cooper, 2003).

Clinical Strategies The quality of life for the older patient can be greatly enhanced with the intelligent use of medications and keeping certain key points in mind. A major problem when facing elderly populations is the fact of prescribing multiple and occasionally unnecessary medications with increased risk of significant drug interactions; establishing a diagnosis is critical to avoid treating a symptom with hit or miss drugs versus treating a specific condition. Discussions about geriatric pharmacology are frequently centered around age-related changes in drug pharmacokinetics and pharmacodynamics; nonetheless, nonpharmacological factors can play an even greater role in the safety and effectiveness of drug therapy in the geriatric population. Frequently, neither the patients nor the health-care provider have a clear picture of the total drug regimen. New patients undergoing initial geriatric assessment should be asked to empty their medicine cabinets and to bring all bottles to their first appointment. When asking the patient about their medication, it is important to be specific about prescription medications, over-the-counter products, as needed medications, vitamins, minerals herbal products and home remedies (Cassel and Leipzig, 2003).

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Table 6 Inappropriate medication use in older adults: considering conditions and diagnoses

Disease

Drug

Comment

Heart failure

Disopyramide and high sodium content drugs (alginate, bicarbonate, phosphate) Phenylpropanolamine hydrochloride (removed on 2001), pseudoefedrine, diet pills, and amphetamines NSAIDS and aspirin >325 mg per day

Negative inotropic effect. Potential to promote fluid retention and exacerbation of heart failure May produce elevation of blood pressure secondary to sympathomimetic activity May exacerbate existing ulcers or produce new ones. (cox-2 excluded) May lower seizure thresholds May prolong clotting time and elevate INR values or inhibit platelet aggregation resulting in increased potential for bleeding May decrease urinary flow, leading to urinary retention May produce polyuria and worsening of incontinence

Hypertension Gastric or duodenal ulcers Seizures or epilepsy Blood clotting disorders, or on anticoagulant therapy

Clozapine, chlorpromazine, thioridazine Aspirin, NSAIDS, dipiridamol, ticlopidine, clopidogrel

Bladder outflow obstruction

Anticholinergics and antihistamines, GI antispasmodics, muscle relaxants, anticholinergics, antidepressants α-blockers, anticholinergics, tricyclic antidepressants, and long acting benzodiazepines Tricyclic antidepressants

Stress incontinence Arrhythmias Insomnia Parkinson disease Cognitive impairment Depression Anorexia and malnutrition Syncope/falls SIADH/hyponatremia Obesity COPD Chronic constipation

Decongestants, theophylline, methylphenidate, and amphetamines Metoclopramide, conventional antipsychotics Barbiturates, anticholinergics, antispasmodic, muscle relaxants Long-term benzodiazepine use, sympatholitic agents (methyldopa, reserpine) CNS stimulants, fluoxetine, methylphenidate Short to intermediate acting benzodiazepines, tricyclic antidepressants Fluoxetine, citalopram, fluvoxamine, paroxetine, sertraline Olanzapine Long acting benzodiazepines, propranolol Tricyclic antidepressants, anticholinergics, calcium channel blockers

Proarrhythmic effect and ability to produce QT interval syndrome Concern to CNS stimulant effects Concern about anticholinergic/dopaminergic effect Concern due to CNS altering-effects May exacerbate depression Concern due to appetite suppressing effects May induce ataxia, impaired psychomotor activity May May May May

cause SIADH stimulate appetite induce respiratory depression exacerbate constipation

Source: From Archives of Internal Medicine 163(22); Dec 2003, pg 2716 – 24. NSAIDS, nonsteroidal anti-inflammatory drugs; CNS, central nervous system; SIADH, syndrome of inappropriate ADH secretion; COPD, chronic obstructive pulmonary disease.

Compliance Compliance is a major problem in all persons, and particularly so in many older persons. Cognitive impairment, depression, decreased hearing, and poor vision can all lead to failure to take a drug or for the drug to be taken inappropriately. Instructions on how to take drugs need to be written in large letters with legible handwriting. The healthcare professional needs to check that the patient understands the instructions. Pill boxes need to be set up for older persons having problems remembering to take their medicines. When choosing the dose of a medication for an older patient, always remember to start slow, go slow, and do not stop too soon. Initially, doses should be modified on the basis of pharmacokinetic predictions, but actual pharmacodynamic responses to the medication should be used to adjust the dose. If the pharmacokinetic information is not available, doses can be initiated at one half the usual dose of adult dose; this can be achieved by splitting tablets or by extending the dosing interval. Minimizing the number of doses per day is easier for the patient and can improve compliance. The use of sustained release dosage forms or taking advantage of prolonged elimination half-lives in older persons can decrease the number of doses per day (Table 7). Cost is key factor in compliance. Drug costs need to be noted at the time of prescribing. Patients need to be asked if they can afford the drug. It is useful to remember

Table 7 General recommendations for geriatric prescribing

[Table not available in this electronic edition.]

that cheap drugs (e.g. thiazides, β-blockers and reserpine) often perform approximately as well as more expensive drugs. Most pharmaceutical companies have programs to help persons obtain drugs they cannot afford. There is an increasing recognition that failure to appropriately treat an older person may be as bad as over treating. For example, failure to use β-blockers following myocardial infarction would be a clear error of omission. Most older persons in nursing homes have osteopenia or


osteoporosis, yet they do not receive calcium with vitamin D, and neither biphosphonates. Many older persons have anemia and chronic renal failure; despite evidence that treatment with erythropoietin or darbopoeitin α improves outcomes including quality of life, they are rarely prescribed. But, the other side of the coin is overtreatment of conditions, for example, there is no evidence for treating blood pressure below 160/90 mmHg in older persons and even less for primary prevention of heart disease by lowering cholesterol in octogenarians (Morley, 2003). There are many factors that contribute to the underuse of beneficial therapies in the geriatric patient population. Physicians may fail to prescribe potentially beneficial medications to elderly patients owing to the scarcity of data on which to base pharmacotherapeutic decisions or for fear of causing adverse drug events in patients who are already using multiple medications. While some may consider this practice to represent therapeutic nihilism, others may consider this to be prudent prescribing. A fair and balanced assessment of the issue of undertreatment of elderly patients must give consideration to three important areas: (1) the lack of highquality evidence derived from clinical studies with relevance to treating the older patient with multiple chronic medical conditions; (2) the need for systems of care that improve drug safety and enhance adherence in elderly persons on complex medication regimens; and (3) the persistence of financial barriers to access to medications (Morley, 2003; Cassel and Leipzig, 2003). The Division of Geriatrics at Saint Louis University has developed many different resources to teach physicians and patients as well in the field of geriatric medicine. The developing of mnemonics, that is the mnemonic developed toward avoiding polypharmacy, has been very successful. GUIDELINES FOR PROPER MEDICATION PRESCRIBING AND MEDICATION REDUCTION Alternatives Vague history or symptoms OTC (over-the-counter) medications have side effects too Interactions (drug–drug, drug–disease) Duration Therapeutic vs Preventive Once a day versus twice or four times a day Other doctors Money Adverse effects of other drugs Need Yes/No (Is the person actually taking the medication?) The use of large numbers of medications will always be a key factor of the medical–scientific care of the growing older population around the world. However, there is always a gray area where there is concern about avoiding the excessive use of drugs and providing access to therapeutic guidelines that might have beneficial effects on morbidity and mortality,

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function and quality of life. The health system should address this issue focusing on including more elderly people in clinical trials, especially patients with multiple comorbidities. The implementation of efforts toward the development of interdisciplinary teams to care for elderly patients and the use of information technology to improve medication adherence and safety should be encouraged.

KEY POINTS • Older persons take more medications than their younger counterparts. • The older body does not accommodate drugs in the same manner as the younger body does. • There is no such thing as an absolutely safe drug. • Elderly patients are more likely to experience undesirable side effects from drugs than are younger persons. • Always “start slow, and go up slow”.

KEY REFERENCES • Fick D & Cooper J. Updating Beers criteria for potentially inappropriate medication use id older adults: results of a US consensus panel of experts. Archives of Internal Medicine 2003; 163:2716 – 24. • Routledge PA & O’Mahony MS. Adverse drug reactions in elderly patients. British Journal of Clinical Pharmacology 2003; 57:121 – 6. • Schmucker DL. Aging and drug disposition: update. Pharmacology Review 1985; 37:133 – 48.

REFERENCES Beyth R & Shorr R. Principles of drug therapy in older patients: rational drug prescribing. Clinics in Geriatric Medicine 2002; 18:557 – 92. Cassel C & Leipzig R. Geriatric Medicine: An Evidence Based Approach 2003, 4th edn; Springer-Verlag. David S. Pharmacogenetics. Primary Care Clinics 2004; 31:543 – 59. Fick D & Cooper J. Updating Beers criteria for potentially inappropriate medication use id older adults: results of a US consensus panel of experts. Archives of Internal Medicine 2003; 163:2716 – 24. Grandison MK & Boudinot FD. Age-related changes in protein binding of drugs: implications for therapy. Clinical Pharmacokinetics 2000; 38:271 – 90. Morley JE. Conundrums of polypharmacy. Aging Successfully 2003; 12(2):1 – 19. Muhlberg W & Platt D. Age-dependent changes of the kidneys: pharmacological implications. Journal of Gerontology 1999; 45:243 – 53. Routledge PA & O’Mahony MS. Adverse drug reactions in elderly patients. British Journal of Clinical Pharmacology 2003; 57:121 – 6. Schmucker DL. Aging and drug disposition: update. Pharmacology Review 1985; 37:133 – 48.

FURTHER READING Kane R, Abrass I & Ouslander J. Essentials of Clinical Geriatrics 2004, 5th edn; McGraw-Hill. Percy L & Fang M. Geropharmacology for the rheumatologist. Rheumatic Disease Clinics of North America 2000; 26:433 – 51.

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The Problem-Orientated Approach to Geriatric Medicine Cameron G. Swift King’s College London, London, UK

INTRODUCTION The transitional decades leading into the twenty-first century have seen a period of major organizational change in healthcare systems, with a major focus on economic concerns. The health-care needs of aging populations have been economically, if not scientifically, prominent within this process. The compulsion to justify patterns of clinical practice with hard evidence has grown, while this in turn has led to the more widespread development and application of sets of clinical management guidelines and the need for more consistent documentation in clinical practice. To some extent, the professions concerned with the care of older people have welcomed the impetus to record and quantify their activity in this way, thus to achieve greater consistency, to promote greater recognition of the skilled processes involved (and of the corresponding standards), and to make the case for more appropriate resource provision in the field for services, training, and research. On the other hand, much organizational change (including the growth of documentation) has to some extent generated bureaucracy and impaired flexibility of interaction among the professions and agencies involved. The need, therefore, not only to sustain the best qualities of clinical practice enshrined within geriatric medicine but also to grasp the opportunities presented by a changing organizational climate to categorize and promote those standards is clear. There has, as a result, been some progress in the development of methodologies to measure activity, but with a distinct slant toward what is required either for cost prediction or cost containment, for the management of defined diagnostic categories, or for modeling the activity of single professions. Examples have included the system concepts of diagnosis-related groups (Goldfarb et al., 1983; Wood and Estes, 1990; Price, 1994), managed care (Wan, 1989;

Curtiss 1989) and critical care pathways (Falconer et al., 1993; Bowen and Yaste, 1994; Tallis and Balla, 1995; Anders et al., 1997) – most commonly for application to defined disorders or clinical situations. There is still a need for better methods of scrutinizing the quality and effectiveness of overall service provision for older people –the largest and most rapidly expanding segment of population healthcare need. Categorization is not, however, synonymous with the achievement of standards, although it is a useful instrument in the right hands for service delivery, training, and research. This chapter, therefore, discusses some key principles of problem-orientated decision making in the care of older people (which have not themselves fundamentally altered over this period) rather than pursuing a primary emphasis on measurement methodology, although some measurement tools will be referred to. This somewhat didactic emphasis reflects not only a concern to focus on consensus standards but also the relative paucity of focused evaluative work in this area specific to the health needs of older people. There is a pressing need for comparative trials of delivery models using such standards as end-points, not least because every available indicator suggests that the costeffectiveness of health services for older people is directly proportional to the expertize and quality of specialist practice achieved.

RATIONALE: PROBLEM ORIENTATION – WHY AND WHAT? The concept of problem orientation as a practical approach to clinical decision making was elaborated by Lawrence Weed in his system of problem-orientated medical records (POMR) (Weed, 1969). Targeted particularly at clinicians, it was in some respects a precursor of the current fashion


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for “protocols”. The motivating principle was a recognition that the traditional “ideal medical model” (syndrome → pathological basis → etiology → treatment → resolution) is in the real world a gross oversimplification of the decisionmaking process, based as it is on a single train of thought arising from a single encounter with the patient. In real life clinical practice, the clinician is often faced with several related and/or unrelated problems simultaneously, while the patient is faced with several encounters over a period of time with several clinicians (across a range of professions) before some or all of these problems are properly resolved. There is, therefore, a need for accurate and cohesive documentation. This is to provide a reliable and consistent framework of information on which to base decisions and also to achieve a measure of continuity across periods of time, as well as among different clinicians and departments. The key components of the original Weed system are:

of chronically infirm elderly people, and, as a result, that of angry and frustrated clinical colleagues hampered (as they saw it) in practising “proper” medicine in hospitals and in teaching it to their junior staff and medical students. Thus, the issue was perceived as one of accommodation, not at all as one of diagnosis and intervention. What in fact took place was a shift in focus and orientation, recognizing the agenda in terms of the health-care problems of older people themselves, an emphasis that the clinicians of the day had omitted to address. Skill in diagnosis was combined with systematic identification of the functional and social consequences of ill health and a plan of management agreed in conjunction with an organized team of allied professionals. The success of this changed emphasis is now legendary (Brocklehurst, 1992) and has been replicated and refined many times over, particularly when brought into the arena of early acute intervention.

1. an accurate list of presenting problems; 2. a “defined database” (full coverage of agreed categories, e.g. in case history taking or examination); 3. statements of plans of investigation and/or management related to each presenting problem; 4. progress notes comprising a systematic assessment of progress and a statement of further plans in relation to each problem (McIntyre, 1979).

2. The complex nature of health-care needs in late life • Exacerbation, relapse, recovery: The proportion of medical conditions alleviated rather than eradicated increases with advancing age. Successive clinical encounters thus tend to become the rule. • Cumulative pathology: Case record folders, best measured in kilograms rather than pages, commonly testify to the numerous departments previously involved in the care of a majority of older patients. • Masked and/or late presentation of disorders. • Multidimensional impact: The management of pathology alone is insufficient to achieve a satisfactory outcome in most circumstances. Hence, the scope of the “database” has to encompass the problem of functional autonomy and social relationships arising not only from disease, but from aging itself. • Multiagency/multiprofessional involvement: Access to reliable information is required by all. • Orchestration/coordination of multiple assessments and therapeutic objectives. Problem orientation is thus, to some extent, built into the heart of geriatric medicine. Weed (1969) emphasized the importance of dividing problems into medical and social. For the geriatrician, the overriding objectives of autonomy and self-determination for older people add an additional dimension, that of “function”. The definition of a problem thus includes any observation or finding that poses a threat to the health or autonomy of an older individual. The approach does not, of course, supplant the search for unitary diagnosis. It does, however, recognize parallel priorities that may sometimes take precedence.

Historically, the fully developed system of POMR did not find its way into the routine practice of most clinicians, nor into all teaching programs. Opponents claimed that the database was too diffuse, that the “catalog” of problems inhibited diagnostic reasoning, or that the day-to-day implementation of POMR was too unwieldy and heavily structured to be routinely workable (Feinstein, 1973). The advocates maintained that comprehensive patient care, interdisciplinary professional working, and clinical audit were fundamentally advanced by POMR (McIntyre, 1979). It is certainly the case that the system properly implemented is more than a style of medical record keeping and is, in fact, a structured approach to clinical decision making, based on a standardized system of documentation. Information technology advances present enhanced opportunities for using such methods more effectively, both in clinical practice and medical education (Weed, 1996). The concept of problem orientation still strikes a chord, therefore, with experienced geriatricians, many of whom consider it to be a cornerstone of effective modern clinical practice in the field. The main reasons for this are: 1. The historical failure of the “Ideal Medical Model” to meet the needs of older people The key to resolving any problem lies in its correct initial identification. The agenda presented to the earliest geriatricians was characterized as a process problem affecting the health-care system, namely overcrowding in poor law institutions, “blockage” of beds in “acute” hospitals, and waiting lists and delays affecting dependent elderly people in the community. The “geriatric problem” was seen as that of health-care providers facing a seemingly inexorable tide

APPLICATION: PROBLEM IDENTIFICATION AND MEASUREMENT Assessment as Problem Orientation The approach to comprehensive patient care adopted within geriatric medicine is commonly given the label “assessment.”

THE PROBLEM-ORIENTATED APPROACH TO GERIATRIC MEDICINE

(The particular area of functional assessment is elaborated in greater detail in Chapter 131, Multidimensional Geriatric Assessment; Chapter 132, Function Assessment Scales). Assessment is in essence the preparation of a problem list in the following categories: 1. 2. 3. 4.

Problems Problems Problems Problems

of of of of

medical, surgical, and psychiatric diagnosis. autonomous function or competence. relationships. living conditions and environment.

Successful assessment should be factual, prompt, efficient, and dynamic (i.e. subject to regular review as a health problem pursues its clinical course, or as new information becomes available). Its components should take place simultaneously, and from the moment of presentation. Assessment as an afterthought to acute medicine is far too late. In the context of emergency hospital admission, the process may well be initiated by ambulance personnel. Preparation of the “database” will incorporate a thorough scrutiny of previous case records and a highly systematic review of a patient’s functional and social background. The latter may entail the acquisition of information from many sources, more closely resembling a piece of journalistic research than a consultation. Weed (1969) advocated the inclusion of a “personal patient profile” in the database. This is desirable in all branches of medicine, but is mandatory in geriatric medicine. The whole process is likely to take considerable professional time and effort; thus, any sense of day-to-day inertia in a unit caring for older people indicates that the work is not being covered. All clinical professionals, especially physicians, need to adopt this comprehensive, multidimensional approach in a systematic way. In order to achieve this, it is highly probable that an acceptable structured form of documentation will be required.

Problem Identification and the Multidisciplinary Team The composition of a more or less typical multidisciplinary team is indicated in Figure 1. This core team composition has so far stood the test of time as reflecting the blend of competence required to provide information, expertize, and advice in the four problem domains itemized earlier. It is sufficiently small to achieve consensus and make efficient decisions, but depends on ad hoc contributions from many other professionals, including dietitians, clinical pharmacists, home-help organizers, prosthetists, transport and portering staff, housing and environmental officers, residential home and sheltered housing supervisors, as well as from various informal supporters and voluntary organizations. Within the team, each professional retains his or her traditional competence, but there is sometimes modification of that function, and invariably heightened awareness of the competence of others arising from cross-fertilization and the team context. The multidisciplinary team is the mandatory core unit central to both problem identification and to decision making and to

Patient

225

++

Clinical psychology

Relatives and carers

Social work staff

Nurses and health visitors Administration

Therapists Medical staff

Voluntary and statutory workers Figure 1 The multidisciplinary network

efficient therapeutic management. (The respective roles of some of its constituent members are considered briefly in the following).

Objectives and Pitfalls Problem identification with no prospect of constructive intervention is an academic and largely pointless exercise. Conversely, efficient “management by objective” distinguishes a problem from a mere observation by the existence of at least some possibility of resolution. Successful problem orientation recognizes and avoids the following well recognized pitfalls, which are more or less common themes across the professions: Diagnostic overindulgence: Consultant physicians rely heavily on their junior staff to sharpen both their knowledge base and their diagnostic acumen: they have, however, a timehonored duty to protect patients (particularly older ones) from the overzealous pursuit of diagnosis with no prospect of therapeutic benefit. Similarly, for therapists, preoccupation with the use of a “perfect” functional assessment tool to quantify an impairment, the clinical or potential therapeutic relevance of which is dubious, should be avoided. Therapeutic overindulgence: This is the targeting of some isolated “ideal” therapeutic objective for an individual at the expense of the broad aim of that individual’s overall recovery of autonomy. Examples might include total abolition of extrasystoles on a 24-hour ECG, or the relentless pursuit of impeccable gait symmetry before hospital discharge after stroke. Collective introspection: There is considerable scope in an interdisciplinary context for lengthy in-depth case analyses of individual patients, consisting of a sequential series of explanations from every conceivable discipline as to why

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no help can be offered with the particular problem. “Case conferences” in this mold have more to do with professional self-interest than patient well-being and should not be held. Bureaucracy and delay: The notion that ill older people are less “acute” and that waiting lists for services are “acceptable” has compromised the effectiveness of clinical and social services for decades. A night sitter in 3 months’ time is of no use to a caring spouse facing a crisis of sleep deprivation. A waiting list of 8 weeks for the installation of stair rails may do untold damage to the resettlement program of a stroke sufferer. Thus, the 2001 England National Service Framework for Older People correctly set standards for prompt and integrated community equipment supply (Department of Health, 2001a). Successful problemorientated assessment promotes anticipation, planning, interaction, and flexibility of response among professionals and agencies. Timing may be critical, both to the individual and to the service, and its mastery is a hallmark of effectiveness in the care of older people. A central agenda item for multidisciplinary teams is therefore the agreement of a finite and preferably rapid timetable for the individual care plan. Inappropriate expectations: Consumer choice in medical care is a topical political issue. It is also a proper objective for physicians, but there is a compelling obligation to identify the choices correctly. A clinician may, for example, have a hard battle to persuade an older person or her relatives that recovery of autonomous function and a return to community living are among the options! Conversely, it may be necessary to dispel unrealistic expectations of miracle recovery, wonder drugs, or costly biotechnology. The clinician’s advisory role may be the less popular one of offering limited (but important) improvement through persistence with clear, if modest, objectives. A frequent further element is an appropriate culture of risk taking, without which no rehabilitative program can proceed.

CONTENT: PROBLEM CATEGORIES The modifying effect of age on the presentation of many specific disorders is covered elsewhere in this volume. In addition, the medical, functional, and social aspects of the health of older people are in a continuous state of dynamic balance and interaction. A problem in any one category seldom exists in isolation without impact on one or both of the other two. Presentation may be functional when the root cause is medical; for example, reduced mobility or falls may result from infection or adverse drug reactions. Conversely, stasis leg ulceration or venous thromboembolism may be caused by impaired function (loss of mobility). Poor housing may be responsible for osteomalacia or hypothermia, while problems of continence or pressure sores may be the culmination of intolerable stress on a caring relative. Exclusion of any one dimension of concern from the assessment is therefore to invite failure.

Medical Problems Geriatric medicine is rightly concerned with a whole range of clinical situations, including acute life-threatening illness, acute exacerbations of chronic disease, subacute, or chronic health problems, disabling disorders of high prevalence among older people, the assessment and management of special clinical problems (e.g. the “geriatric giants” of cognitive impairment, immobility, and incontinence) and the preventative medicine of old age. Both the importance and the difficulty of careful and accurate diagnosis are well recognized. Principles of diagnosis: The opposing extremes of academic interest and diagnostic apathy, therapeutic overoptimism and therapeutic nihilism, are unacceptable pitfalls in clinical practice from which older people have suffered extensively. Thorough investigation may be justified on the grounds of (1) therapeutic potential, (2) practical management, and (3) (under certain circumstances) prognosis. In considering any investigation, particularly if at all invasive, the question “how will the results influence management”? is always legitimate, but interpreting the answer for an older patient increasingly requires careful review of recent advances and should invariably be a flexible and sensitive exercise. Therapeutic potential: It is now clear for many interventions, both medical and surgical, that conservatism based on chronological age alone has no foundation in scientific evidence. Large-scale clinical trials have shown for a whole range that results and cost-effectiveness are at least as satisfactory in older as in younger patients. Examples include: • effective control of hypertension (SHEP Cooperative Research Group, 1991; Amery et al., 1986; Lever and Brennan, 1993; Dahlof et al., 1993; Julius et al., 2004), • antithrombotic agents in atrial fibrillation (Ezekowitz et al., 1993; Stroke Prevention in Atrial Fibrillation Study, 1991; Connolly et al., 1991), • thrombolytic agents and aspirin in myocardial infarction (Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico, 1990; ISIS-2 (Second International Study of Infarct Survival) Collaborative Group, 1988; ISIS-3 (Third International Study of Infarct Survival) Collaborative Group, 1992; The GUSTO Angiographic Investigators, 1993), • angiotensin converting enzyme inhibitors and angiotensin2 antagonists in left ventricular dysfunction and after myocardial infarction (ISIS-4 (Fourth International Study of Infarct Survival) Collaborative Group, 1995; Granger et al., 2003; Pfeffer et al., 2003), • lipid lowering agents in cardiovascular risk (Shepherd et al., 2002), • bone antiresorptive agents and calcium and Vitamin D in fracture prevention (Chapuy et al., 1994; Larson et al., 2004). Persuading surgical colleagues of therapeutic potential from surgery in older people is now far less often a problem


than formerly, as a result of advances in anesthetic and surgical techniques and of rapidly expanding experience of surgery in the age-group. An excellent example is carotid endarterectomy after stroke (Alamowitch et al., 2001; Aune et al., 2003). Logistics: In view of the above, there can be no justification for the organization of services in such a way as to exclude older people from sophisticated diagnostic and treatment facilities, or to undertake their care in less technically well supported environments (Working Party of the Royal College of Physicians, 1994). Equally, the role in interdisciplinary practice of physicians trained in the care of older people is clear. The difficulties of prompt diagnosis are well recognized. Symptomatology is notoriously unreliable. The “presenting complaint” frequently bears no relation to the real problem. Occult disease and presentation as stereotypes of aging pose a constant challenge. Physical signs may be modified, unreliable, or absent. As suggested earlier, any unexplained change in function in an older person should prompt the search for a medical diagnosis. The place of structured models of clinical decision making in medicine is yet to be established and would require specific evaluation for older patients. The relative merits of different processes of diagnostic logic have been considered (McCartney, 1987). Problem orientation has been criticized as having some affinity with the “blunderbuss” approach (uncritical listing of clinical observations and ordering of every conceivable test). This criticism arises mainly from a perception of the database as a cataloguing process to prevent missing any abnormalities. This is unfair to the original concept. It also assumes that the database is totally prescribed rather than flexibly determined for different categories of patient. There is no evidence that problem orientation has a negative effect on diagnosis in the elderly. Other approaches (e.g. the hypothetico-deductive model, algorithmic diagnosis, and league-table diagnosis or its mathematical equivalent, Bayesian probability analysis) (McCartney, 1987) are all potentially compatible with a problem-orientated approach. The traditional systematic enquiry taught to medical students may be a sterile exercise in real life diagnosis (Hoffbrand, 1989), especially with older patients, for whom its verbal content requires considerable adaptation. Conversely, with the comparative rarity of single problems, the clinician will probably always need to explore a fairly large problem space both in history taking and physical examination to be sure of picking up the important points (Harrington, 1989). Common omissions from the medical assessment include failure to elicit abnormalities of mental status and their timescale, impairment of the special senses, scrutiny of drug therapy, dietary intake and alcohol consumption, examination of the locomotor system (especially the hip joints) and gait, problems of continence and their timescale, and detailed examination of the feet and hands. Important components of functional and social status (see following text) are also commonly overlooked.

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Practical approaches to the application of these principles within geriatric medicine are discussed in other chapters in this text and elsewhere. The justification for a structured medical record as an absolute minimum seems incontestable.

Functional Problems A detailed interest in levels and components of function is a strong distinguishing feature of modern geriatric medicine. It is unusual for health problems to have no short- or longerterm impact on an older person’s range of activity. Measurement tools for the assessment of function are discussed in Chapter 132, Function Assessment Scales and the more difficult issues of their relative merits will not be considered here. There are considerable differences of opinion as to how broad functional status should be measured and documented and how change should be quantified. Largely because of this difficulty, the tendency both in service delivery and in health services research has been to opt for an increasingly widely accepted core set of “lowest common denominator” scales for the measurement of change, such as the Barthel Index, the Instrumental Activities of Daily Living scale or (in psychiatry) the Clifton Assessment Procedure for the Elderly (Pattie and Gilleard, 1975). Such tools are clearly not intended for more specialized measurement of impairments, or very specific disabilities, for which they lack sensitivity. Instead, they cover a key range of abilities, including, for example, the special senses and continence and/or their consequences for an individual’s range of activities. In principle, there are analogies in this field with the medical model; overemphasis on “diagnostic” categorization should not stand in the way of pragmatic problem-orientated assessment, but those measures that are required should be applied alongside it. The technical skills within the multidisciplinary team for specialized functional assessments reside predominantly with physiotherapists, occupational therapists, speech and language therapists, and clinical psychologists, but other team members, including medical and nursing staff, require a level of competence in the assessment and recognition of functional problems, for which the capacity to use a minimum set of more globally applicable instruments is necessary. An example of a shorthand form of operational documentation for multidisciplinary decision making is shown in Figure 2, the essence of which is its problem-orientated emphasis. The domains covered are in common with a most general functional assessment scales, but each category of function is graded on a five point scale, the components of which attempt to quantify problems in terms of requirement for assistance or supervision from a third party, that is, “to what extent is the dysfunction an active problem requiring outside intervention?” Thus, if an individual is able independently to travel from point A to point B using a wheelchair, then “ambulatory function” is classed as unimpaired. Similarly, if he or she has an indwelling catheter, which is independently managed without difficulty and with

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Week:

1 2 3 4 5 6 7 8 9 10

Week:

1 Transfer Independent Supervision 1 support 2 support Lift

7 Verbal communication 1 2 3 4 5

No disability Slight Moderate Severe Nil

2 Ambulation Independent Supervision 1 assist 2 assist Nil


1 2 3 4 5

disability

1 2 3 4 5

10 Urinary continence No disability Occasional Regular/nightly Frequent/daily Total/intractable

1 2 3 4 5

problem

1 2 3 4 5

problem

1 2 3 4 5

11 Bowel continence No disability Occasional Regular Frequent/daily Total/intractable

1 2 3 4 5

12 Dwelling

6 Domestic activity Self-sufficient Occasional Frequent/daily support Day and night Continuous dependency


1 2 3 4 5

5 Personal care Self-sufficient Occasional Frequent/daily support Day and night Continuous dependency

disability

1 2 3 4 5

9 Visual function

4 Psycho-social function Self-sufficient Occasional Frequent/daily support Day and night Continuous dependency

disability

1 2 3 4 5

8 Auditory function

3 Cognitive function Unimpaired Occasional Frequent/daily support Day and night Continuous dependency

1 2 3 4 5 6 7 8 9 10

1 2 3 4 5

Satisfactory Minor adjustments Short-term modifications Major/structural work Relocation

1 2 3 4 5

Figure 2 A shorthand operational chart for interdisciplinary decision making

no problems of bypassing or spillage, then urinary continence is classed as unimpaired. Where the criterion of extrinsic assistance is less clear-cut (e.g. in the case of auditory dysfunction), but the category of function is considered to be of major importance, then it is also included. The display and content are designed to be visual and operational rather than quantitative and specific, allowing any member of the team a rapid impression of a patient’s functional status, as well as an indication of change over time. Similar pragmatic and operational approaches to multidimensional assessment, decision making and documentation have been elaborated elsewhere, for example, in the context of community care (Donald, 1997) and rehabilitation (Turner-Stokes and Nyein, 1999; Nyein and TurnerStokes, 1999). As with medical diagnosis and treatment, functional assessment and the resulting rehabilitative strategies should be clearly linked to finite and time-limited objectives.

Relationship Problems Although in this context the skills of social workers and clinical psychologists are vital, the cumulative information to be obtained from all professionals who interact with patients and/or their relatives is indispensable. It is salutary to observe how often the “social prognosis” is good. This reflects the phenomenal contribution to patient care (including “continuing care”) made by the army of spouses, relatives, friends, neighbors, and other informal carers who provide governments with major annual savings. Contrary to popular perception, most families in the majority of countries in both the developed and the developing world still consider it the norm to be involved in the care of their older people and as a result, constitute the best possible target for the investment of money, manpower, and time by governments. The health-care services should be their enablers.


Presenting problems in these categories can often be traced to changed circumstances or failure of adequate provision. For older people on their own, the difficulties are often those of isolation or bereavement. Where others are involved, the problems include loss or withdrawal of support, carer stress, rejection (root causes of which may be simple, e.g. remediable disability, incontinence or sleep disturbance, or more complex, such as a long-standing failure of marital relationship) or relocation. Health-related events in older people commonly precipitate an acute imbalance in a fragile structure of family and social relationships. Failure to recognize and address these problems successfully contributes substantially to poor clinical and functional outcome and to health-care costs.

Environmental and Housing Problems Poor quality: Responding successfully to problems of environment and housing remains a major difficulty in the health care of older people. Some of the more common problems are itemized in an earlier chapter. Housing design for late life has been inadequately addressed in the past and is still at a comparatively rudimentary stage (Frain and Carr, 1996). In addition, the capacity to carry out significant adaptations to existing homes is typically fraught with delay, lack of financial commitment, and bureaucracy. Although, in the United Kingdom, older people are more likely than their younger counterparts to occupy housing that lacks basic amenities, is unfit, old, and in poor repair (Department of the Environment, 1988) (especially private sector housing), adaptations can make a profound difference to the prospects for even the very disabled to remain in their own homes or return there after illness (Statham et al., 1988). Unfortunately, the scale and nature of an individual’s need for reorganization or adaptation of their home often cannot be determined until some time after the acute phase of illness, when a “plateau” of functional recovery has been reached. Assessment: A common and important practice for older people undergoing hospital treatment is the home assessment visit prior to discharge. The work of the occupational therapist is paramount in this, both in assessing the individual’s performance and advising on what changes, if any, are required. Not infrequently, the needs for rearrangement are minor inexpensive additions, such as grab rails or stair rails, but where there are problems of access, structural alterations may be necessary. Relocation: Relocation to another area takes place among very elderly people more often than is commonly realized (Graham and Livesley, 1986). This may or may not be for good reasons (such as proximity to family, particularly where the latter have moved out of inner-city areas to the suburbs). Relocation at any time of life is known to be a stressful event and brings its own range of problems, such as loss of previous social contacts and difficulty in establishing new circles. The same may well be true of

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rehousing within the district or relocation into an institutional setting, although there is evidence that relocation between institutional settings well managed need not be deleterious (Harwood and Ebrahim, 1992). Individual choice: Some older people are extremely reluctant to consider moving to new housing, even though the “ancestral” home may be falling around their ears. They may also be reluctant to consider structural alteration or even minor adaptations. The writer recalls an octogenarian double amputee, staked out in an ancient caravan heated by a paraffin stove in the middle of a farmer’s field in the South West of England; he developed substantial cortical blindness as the result of occipital lobe infarctions. In spite of everyone’s best efforts, he could not be persuaded to relocate and accepted the installation of a new electric mains cable and a safer form of heating, only with the greatest reluctance. In functional terms, however, his abilities within the caravan, the layout of which he knew well, proved to be superior to those within the hospital department, and the decision to support him in his endeavors was subsequently shown to be the correct one. The patient’s wishes and preferences are commonly pivotal in housing and environmental matters and should be respected. Having identified the problems, a general rule of thumb is to err on the side of supporting an individual in his or her wish to take certain risks, provided everything possible has been done to minimize their scale. The option of institutional care may appear at first sight highly preferable when environmental problems are identified, and there is commonly a range of pressures to pursue a “custodial” course under the pretext of greater safety. If other options are open, however, even to those with severe disability, there is a responsibility to identify these and to ensure that the choice which an individual makes is fully informed (Wanklyn, 1996). Too often, older people feel under constraint to “go into a home” because they have no apparent choice. The decision may subsequently be regretted for many years – life with no problems may not be life at all! The institutional environment: Although there are improvements, institutional design has far to go before optimal standards are universally available. Many old converted premises are totally unsuitable for disabled people and carry their own hazards. There is a very high incidence of falls among elderly people living in institutional settings (Askham et al., 1990) and it is simplistic to equate the institutional environment with “safety”. Thankfully, very large numbers settle comfortably and happily into residential and nursing homes, but such a radical decision for an older person should never be made without careful consideration of the alternatives in the framework of a comprehensive problem-orientated assessment. Housing and environmental problems should be addressed in detail and resolved wherever possible, rather than compounded by ill-founded decisions in the direction of institutional care. Social and environmental issues often require skilled counseling of older individuals, their relatives, and their supporters. This, like all other aspects of successful care,

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should be an informed and coordinated team effort. All professionals involved in the medical care of older people should acquire counseling skills. It is well known that many complaints addressed to hospital administrators and managers can be traced back to inept communication.

IMPLEMENTATION: PROBLEM MANAGEMENT – ORGANIZATIONAL IMPLICATIONS Information and Communication Records: A central function of POMR is to make available to the clinician the necessary information for decision making more or less at a glance. Such information will be factual, reliable, and relevant, and presented in a format that can be quickly digested. Because of the complexities of a program of investigation and treatment for an older person with multiple problems, this facility is indispensable to the practice of geriatric medicine. The records departments of many large district general and teaching hospitals have so far been unsuccessful or incompletely successful in achieving this objective. A major problem has been to achieve a synthesized account of functional assessments. The generation of a centralized, multidisciplinary problem-orientated patient record in a variety of formats is a practice that is becoming more widespread. The ideal objective is to have information sited with the individual and available for scrutiny by all professionals, whether in an inpatient setting (i.e. at the end of the bed) or in the community (i.e. with the individual in his or her home). This is one of the aims of the “Single Assessment Process” recommended in the England National Service Framework for Older People. (Department of Health, 2001b) The capacity to make such information available in electronic format (e.g. as “smart cards”) presents significant opportunities for improved continuity of care of older people and warrants further evaluation in a service context. Communications base: It is a common practice of many departments of geriatric medicine to run their own liaison offices. These serve as a central communication point for all enquiries and decisions requiring access to recent patient information. They commonly contain hard copy of recent discharge summaries and outpatient letters, together with other information such as day hospital discharge information or domiciliary assessment correspondence. Contact between professionals (such as a general practitioner-tohospital telephoned referral) can thus be supported by instant access to a large body of recent summarized patient data on diagnosis, treatment and progress, medication, support services, social and environmental data – in fact, the components of a good problem-orientated record. This arrangement permits rapid decisions on assessment and practical management (including decisions on hospital admission) to be fully informed, thus, reducing the scale

of misplacement, duplication of investigations, and delay in diagnosis. Liaison office staff (normally trained administrative and clerical officers) progressively acquires the skills of handling enquiries and of interprofessional contact, and find a combination of such activity with record keeping both challenging and rewarding. Computerization of patient records has brought further advances allowing access (including out-of-hours access) for designated staff from remote terminals on wards and elsewhere. This contrasts sharply with the situation in some emergency departments and receiving wards, where older people, whose complex background is unknown and who are too ill or incapacitated to provide the necessary information themselves, undergo numerous (often duplicated) investigations and sometimes inappropriate treatment strategies, before the true nature of their underlying problems comes to light some days later. Whatever organizational structure is adopted, the advantages of a coordinated single entry point to geriatric services are clear, particularly where such services are diverse. Written interagency exchange: Such access to information is a cardinal requirement of problem-orientated clinical practice. Equally important is the quality and content of information exchanged between different treatment settings. An adequate medical discharge summary, for example, should incorporate a clear problem list, a short narrative section on presentation, progress, and management, a list of ongoing drug therapy with dosages, a clear statement of functional ability, relationships, environmental setting and any aids, adaptations or appliances, a list of domiciliary support services, and a clear statement of the future program of monitoring and follow-up. It should be brief, readable, and accurate.

Multidisciplinary Work Patterns The multidisciplinary team is the nucleus not only of problem identification but also of management and implementation. Precise work patterns vary between departments, but every mainstream setting for the medical care of older people (e.g. the acute general hospital ward or day hospital) requires the support of a multidisciplinary team to be successful. It is common practice for the team to convene in association with every ward round or day hospital review. The meeting should be no more than a focus for ongoing and continual communication between team members. A program of mobilization for a patient will, for example, go badly wrong if nursing staff and physiotherapists fail to maintain an effective dialogue and to agree identical approaches around the clock. If medical and social work staff are at cross-purposes in discussing options with patients and their relatives, then irreparable damage may be done to any strategies for return to the community. In the best departments, strong team identity develops with the recognition of mutual interdependence, flexibility over “demarcation” between disciplines, clear lines of accountability and not


uncommonly a little healthy interprofessional rivalry. Direct dialogue is one of the major strengths, for which written referrals or communications are no substitute. Medicine: The physician within the team, who will require both training, experience, and specific skills in interdisciplinary practice, exercises the traditional functions of diagnostician, therapeutician, and prognostician, but recognizes that none of these can be satisfactorily achieved without substantial input from team colleagues. Their trained observations are crucial in diagnosis. The physician’s knowledge and experience of the natural history of disease processes in late life are essential, particularly in assessing prognosis. In most settings, the physician carries the ultimate clinical and medicolegal responsibility for the admission and discharge of patients and has therefore a critical role in holding an overview, in realistic goal setting, and in timing the various stages of assessment and management. Nursing: The nurse is in the best possible position to acquire a comprehensive day-to-day understanding of the problems confronting individual patients, because of the continuity of contact entailed (McGovern, 2002). He or she is best able to make the close and detailed observations on which correct diagnosis may depend and to obtain an understanding of psychological and emotional problems. The nurse will acquire first-hand awareness of a patient’s personal care capacity and motivation and will have an enabling role in communication with the individual, with visitors and with all other professional staff involved. The “key worker” concept is often most readily applicable to the nurse and underlies modern approaches to primary nursing (McGovern, 2002). The therapies: The expertize of therapists is paramount in defining and assessing problems of functional disability. They have the skills, necessary equipment, and measurement techniques to quantify the challenges involved in regaining autonomy, to present an accurate picture of performance capacity and to determine the strategies, facilitated relearning programs and therapeutic procedures required. Social work: The role of the social worker in defining the contribution of problems of relationships (or lack of relationships), economic, and environmental problems, is critical. The wealth, variety, and fascination of casework in the field of geriatric medicine make it one of the social work’s most exciting challenges. Recent organizational changes leading to a preoccupation with the division of costs between health and social services have in some cases placed this key interdisciplinary function in jeopardy to the extent that social work staff have become caught up in a costdriven bidding process for “packages of care” and perceive themselves to have little or no time for “family work”. Any suggestion that social work for older people requires fewer professional skills or presents fewer intellectual and clinical challenges than other areas of practice, but rather entails the dispensing of aids and support services is supremely outdated and uninformed. A skilled operator in the field regularly

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transforms the perception of a patient by the multidisciplinary team and radically alters its decisions. Liaison: Specialist liaison health visitors or nurses have historically played a valuable part in bridging the hospitalcommunity interface. Feedback from follow-up visits of older people resettled in their homes after illness is invaluable self-audit for the hospital-based team. It maintains an indispensable community perspective and frequently enables early troubleshooting where errors or omissions may have occurred, or where aspects of the assessment may have been miscalculated. This function has latterly been undertaken by a variety of personnel, including case managers or discharge coordinators, but the basic concept is the same – a coordinating role among other professionals and agencies, based in the community rather than the hospital. Many holders of the newer posts have a professional background in nursing. In summary, effective teamwork is fundamental to problem-orientated practice in the medicine of old age. Even the most successful teams get it wrong some of the time, but in clinical settings where team work is underdeveloped or present only in token form the error rate is substantially greater.

Clinical Care Settings In the United Kingdom the most efficient structural unit containing all the necessary facilities for investigation, treatment, access to other specialties, exchange of information and the presence of on-site multidisciplinary staff is the general hospital. There is ample evidence that the effectiveness of district geriatric medical services depends on the degree of access to acute general hospitals available to competent clinicians in the field (Evans, 1983). Many new technologies, for example, in noninvasive organ imaging and surgery, have particular applicability and effectiveness in the management of older people. Access to these techniques (always assuming careful stewardship) and to other specialties such as vascular surgery, is accepted as necessary and appropriate for the practice of geriatric medicine (Evans, 1983). This degree of “centralization” is an economic necessity, since many of the facilities cannot be cost-effectively dispersed across the community. Provided the service is clearly targeted at the local population, the advantages generally outweigh the disadvantages (e.g. those of transport). Ready access for older people to technically sophisticated and comprehensive medical care is a strong imperative, for which quality “care in the community” should never be perceived as a substitute (as distinct from a parallel partnership). The need to generate cohesive specialist teams immediately available to ill older people constitutes a strong argument for the positioning of acute assessment units within the acute hospital. Where the acute medical care of older people is wholly integrated (i.e. older patients receiving care in a common pool of general acute beds alongside their younger counterparts) then specific arrangements are necessary to

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ensure their prompt access to a fully accountable multidisciplinary process (for example, a team attached to a medical “firm” and incorporating that firm’s physician with specialist responsibility for the medicine of old age) (Evans, 1983). The need to position specialized acute assessment and/or rehabilitation facilities in acute hospitals lies in the development of a “tailored” inpatient environment for older people and the maintenance of a clear focus for standards, for training, and for the dissemination of clinical and interdisciplinary skills. The potential for these disciplines to extend into an increasingly wider range of settings is now being evaluated, with a strong impetus from the desire to reduce costly hospital bed-days. In addition to established practice within geriatric medical rehabilitation units and dayhospitals, the application of different models of the team (problem-orientated) approach, for example, to early or supported hospital discharge and “hospital-at-home” schemes (Hyde et al., 2000) continuing care in the community and strategies for stroke rehabilitation (Kalra et al., 2000) have been investigated. Such applications have potential in so far as they build on established standards and expertize, can be shown to make a measurable, equivalent contribution to the total service (or core need), do nothing to delay or prevent ready access to mainstream medical care and are not primarily “cheaper,” unsustainable, short-term alternatives. In terms of cost-benefit and cost-effectiveness, such questions are so far unresolved.

Risk Taking As already implied, the restoration of autonomy to an older person invariably implies the taking of at least some risk. The concept of restrictive custodialism has now thankfully become unacceptable in most developed and developing societies, but in the past has been the cause of much fear and apprehension among older people. Specific initiatives have been undertaken to minimize or abolish the use of the various forms of restraint, both physical and pharmacological (Dunbar et al., 1996; Brooks, 1993). There is in any case ample evidence that such practices are not only ineffective, but generate their own risks (Frank et al., 1996). Positive approaches to rehabilitation have instead come of age. Within these, the aim of the problem-orientated approach is to identify and quantify the risks correctly, to take all reasonable treatment and preventative measures to minimize them, and to set a high premium on an individual’s successful return to autonomy – in her or his own home wherever possible. Where some risk is entailed, an individual’s choice should weigh substantially against the anxieties of others and (perhaps even on occasions the attentions of the legal profession). The success rate of this approach is high. Modern departments of the medicine of old age have become increasingly interventionist, with a substantial relative decline in their custodial role. Those aspects of the organization of facilities and of clinical practice discussed earlier are a direct consequence of this orientation.

EVALUATION: PROBLEM RESOLUTION – SUCCESS OR FAILURE? The capacity for activities associated with health care to become self-perpetuating means that this interventional approach, like any other, should have its effectiveness tested. Given that the problem-orientated approach finds its expression predominantly in interdisciplinary practice, the following questions are pertinent: 1. What are the short-, medium-, and long-term benefits for patients? 2. What is the wider impact on older populations at an epidemiological level? 3. How can the standard of practice be assessed? 4. What are the effects on the service in terms of efficiency and cost? These areas of enquiry broadly reflect the Donabedian categorization of audit criteria – structure, process, and outcome (Donabedian, 1980). Although “health care –technology assessment” is an expanding discipline, the earlier questions remain to be comprehensively answered with respect to Geriatric Medicine. “Outcome measures”, in particular, are the subject of much ongoing debate and the health economic aspects are extremely complex. Such answers as exist so far have emerged sporadically in the context of service development rather than as a result of any clear research strategy. A number of UK departments of Geriatric Medicine providing comprehensive services (and adopting problemorientated interdisciplinary service patterns) published reports (mainly in the 70s and 80s) showing substantial changes in hospital-based activity consequent on their development (Hodkinson and Jeffreys, 1972; Bagnall et al., 1977; Rai et al., 1985; Mitchell et al., 1987). The changes included substantial increases in patient throughput per year, with concurrent reductions in total bed numbers, duration of patient stay and hospital bed occupancy. It was also possible to demonstrate a facilitating effect of this pattern of service on other areas of clinical activity, most notably acute general medicine, in which the numbers of patients treated also grew as a result of the resolution of “bed blockage”. The descriptive content of these models included elements of structure (notably provision of inpatient and day patient places, of places in homes in the community and also the levels and skill-mix of available multidisciplinary staff) and process (notably clear definition of operational policy, patterns of interdisciplinary practice, community and socialservices links and specific geriatric service components, e.g. respite care, dementia caseload). Their reports demonstrated the capacity to translate the principles of problem-orientated practice and interdisciplinary activity into viable services, with a measurable positive impact on adjacent clinical services (Swift and Severs, 1997). Detailed conclusions concerning clinical outcome, with the exception of mortality statistics, were by inference, although it is unlikely that service viability would have been sustainable had the clinical


this general approach to the care of all patients with complex need. A further example is the application of interdisciplinary assessment strategies in the prevention of falls among older people. In a controlled study, consecutive older people presenting to a London accident and emergency department were randomized to existing discharge and communication procedures or to a subsequent single bi-disciplinary, problemorientated risk identification and referral protocol comprising a full medical examination and an occupational therapy assessment at home (Close et al., 1999). In only 16% of the assessments was no further action considered necessary. Analysis showed that the odds of a fall in the 12 month follow-up period were reduced in the intervention group by a factor of 2.5 (95% CI; 1.5–4.3) relative to the control group after adjusting for differences in Barthel and AMT scores at baseline and number of falls in the 12 months prior to the index fall (Figure 4). The odds of recurrent falling (3 or more falls) were reduced in the intervention group by a factor of 3.0 (95% CI; 1.5–6.1). There is now a substantial literature indicating the capacity for falls prevention at population level using multidimensional, multidisciplinary approaches (Chang et al., 2004). There is much discussion about measuring the broader epidemiological impact of the problem-orientated approach. One of the difficulties is getting consensus on the most appropriate measure of achieved autonomy or health over a given time span. One proposal is to develop the concept of measuring Healthy Active Life Expectancy (HALE) within served populations (Evans, 1993). The proliferation of guidelines may prove to be of limited or little value in the scrutiny of services if no account is taken of the degree of expertize and competence applied. The mere presence of an operating theater, a team of individuals, and a textbook of operative surgery gives no guarantee of the outcome of a series of surgical procedures. The same principal holds in the health care of older people for the existence of a defined service structure, organized “teams” and agreed guidelines. Effectiveness requires the work to be underpinned by good training, professional commitment, research and development, and well-developed career structures. There have been a number of instances where schemes put in place

150 SRU

123.2

GMW

104.6

100 48.7

50

52.3

13.2 14.6 0 5

Figure 3 A randomized prospective study showing the effect of stroke-unit based interdisciplinary practice (SRU) compared with care on dispersed general wards (GMW) on duration of hospital stay after stroke (From data of Kalra et al., 1993)

Falls

Mean length of stay (days)

consequences been broadly unacceptable to patients and to the local communities concerned. Such process data are a fundamental component of evaluation, even though the need for more information on clinical outcome is accepted. The published models have to some extent set standards for resource use efficiency and bear careful scrutiny with respect to this. The delivery of a service will invariably require some balancing of benchmark criteria of practice with the availability of finite resources. There is little point in setting up the “perfect” model if it can only be available to a small proportion of those who need it. The concept of a service entails its ready accessibility to the total population served in relation to need. More recent health care –technology research has allowed prospective experimental evaluation of the problem-orientated/interdisciplinary approach in randomized controlled clinical studies. A good example is a study of the efficacy of stroke units (as a model of focused interdisciplinary practice) (Figure 3) (Kalra et al., 1993). This work, using a stratified design based on a validated prognostic scale of severity, showed that assessment and rehabilitation in stroke units versus dispersed wards resulted in more rapid discharge from hospital to community, a reduced requirement for long-term institutional care and an improved and more rapid functional outcome (for those with intermediate stroke severity) as well as a reduction in late mortality (for those with more severe stroke). These operational and clinical outcomes were achieved without the requirement for increased therapy staff or total therapy time. It is important to stress that the findings were set in the context of a comprehensive district geriatric service with corresponding specialist leadership. They do not constitute a carte blanche for the universal deployment of stroke units, but rather provide evidence of the effectiveness of focused problem-orientation and interdisciplinary practice. This leaves the way open for a range of alternative strategies based on these principles, ranging from well-run generic geriatric medical units to peripatetic teams bridging the hospital–community interface (Kalra et al., 2000) and strengthens the case for investment in

233

400 350 300 250 200 150 100 50 0

354

Control Intervention 203 151 50

0− 4 months

123 73

4 − 8 months Follow-up period

Total

Figure 4 Reduction in the incidence of falls in older people in a randomized prospective study of an interdisciplinary assessment protocol (Reproduced from Close et al., 1999). Copyright Elseveir

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(e.g. for community care) have achieved short-term results, but have proved unsustainable in the medium term because of difficulties of professional recruitment and gradual deskilling. In this context it is gratifying that Geriatric Medicine (where well developed) is no longer a shortage specialty. It is probably correct that success or failure of continued professional recruitment is an invaluable, if indirect, service audit criterion. In conclusion, the skilled application of a system of problem orientation substantially defines decision-making expertize in the practice of Geriatric Medicine, perhaps more than in any other speciality. The evidence underpinning its effectiveness continues to grow, but on the whole too slowly in relation to the explosion of population need. There is still insufficient consensus among geriatricians on the best measures of effectiveness, minimum datasets and comparative standards of service performance to enable the necessary comparison of “like with like”. This remains an urgent and major challenge for clinical age research. In the meantime, it is incumbent on clinicians concerned with the care of older people to ensure that they have well defined and well-used systems in place to optimize and monitor their own practice.

KEY POINTS • The accurate identification and documentation of “problems” and the resulting application to multidisciplinary decision making constitutes the core method of clinical practice in geriatric medicine. It may be well or badly implemented and the potential pitfalls should be recognized and avoided. • The four interdependent problem domains fundamental to effective practice are those of diagnosis and treatment, functional autonomy, human relationships, and living environment. The level of skilled practice and experience within each domain and the capacity of multidisciplinary teams to collaborate successfully are the principal determinants of outcome for patients. • Pragmatic problem-orientated decision support tools (as distinct from solely measurement and assessment instruments) may enable best practice. • The success, efficiency, and cost-effectiveness of health-care systems for older people are directly proportional to the extent to which they are organized to promote, support, and facilitate such activity rather than constrain and inhibit it. A major presence in the acute general hospital and dedicated communication/liaison systems have both been found to be pivotal. • The effectiveness for patients and for health systems of implementing the approach within organized service models is now well proven both by audit of routine data and in randomized controlled prospective studies.

KEY REFERENCES • Chang JT, Morton SC, Rubenstein LZ et al. Interventions for the prevention of falls in older adults: systematic review and meta-analysis of randomised clinical trials. British Medical Journal 2004; 328:680 – 6. • Department of Health. Integrated community equipment services. National Service Framework for Older People 2001a, pp 36 – 7; DOH, London. http://www.doh.gov.uk/nsf/olderpeople.htm. • Kalra L, Evans A, Perez I et al. Alternative strategies for stroke care: a prospective randomized controlled trial. Lancet 2000; 356:894 – 9. • McIntyre N. The principles of the problem-orientated medical record. In JC Petrie & N McIntyre (eds) The Problem-Orientated Medical Record 1979; Churchill-Livingstone, Edinburgh. • Swift CG & Severs MP. The challenges of service provision. Age Ageing, 1997; 26(Suppl 4):30 – 42. • Turner-Stokes L & Nyein K. The Northwick Park Care Needs Assessment (NPCNA): a directly costable outcome measure in rehabilitation. Clinical Rehabilitation 1999; 13:253 – 67.

REFERENCES Alamowitch S, Eliasziw M, Algra A et al., 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 – 60. Amery A, Birkenhager W, Brixko P et al. Influence of antihypertensive drug treatment on morbidity and mortality in patients over the age of 60 years. European Working Party on high blood pressure in the Elderly (EWPHE) results: sub-group analysis on entry stratification. Journal of Hypertension Supplement 1986; 4(6):S642 – 7. Anders RL, Tomai JS, Clute RM & Olson T. Development of a scientifically valid coordinated care path. The Journal of Nursing Administration 1997; 27(5):45 – 52. Askham J, Glucksman E, Owens P et al. A Review of Research on Falls Among Elderly People 1990; Department of Trade and Industry, London. Aune S, Laxdal E, Pedersen G & Dregelid E. Patient characteristics, operative complications and long term survival of patients aged 75 or over subjected to carotid endarterectomy. International Angiology 2003; 22:421 – 5. Bagnall WE, Datta SR, Knox J & Horrocks P. Geriatric medicine in hull: a comprehensive service. British Medical Journal 1977; ii:102 – 4. Bowen J & Yaste C. Effect of a stroke protocol on hospital costs of stroke patients. Neurology 1994; 44(10):1961 – 4. Brocklehurst JC. The geriatric service and the day hospital? In JC Brocklehurst, RC Tallis & HM Fillit (eds) Textbook of Geriatric Medicine and Gerontology 1992, 4th edn, pp 1005 – 101; Churchill-Livingstone, Edinburgh. Brooks TR. Drug prescribing for the elderly outpatient and for those confined to convalescent hospitals. How the new OBRA laws will change some established habits. Journal of the National Medical Association 1993; 85(12):921 – 7. Chang JT, Morton SC, Rubenstein LZ et al. Interventions for the prevention of falls in older adults: systematic review and meta-analysis of randomised clinical trials. British Medical Journal 2004; 328:680 – 6. Chapuy MC, Arlot ME, Delmans PD et al. Effects of calcium and cholecalciferol treatment for three years on hip fractures in elderly women. British Medical Journal 1994; 308:1081 – 2. Close J, Ellis M, Hooper R et al. Prevention of falls in the elderly trial (PROFET): a randomised controlled trial. Lancet 1999; 353:93 – 7. Connolly SJ, Laupacis A, Gent M et al. Canadian Atrial Fibrillation Anticoagulation (CAFA) study. Journal of the American College of Cardiology 1991; 18(2):349 – 55. Curtiss FR. Managed health care. American Journal of Hospital Pharmacy 1989; 46(4):742 – 63. Dahlof B, Hansson L, Lindholm LH et al. Swedish Trial in Old Patients with Hypertension (STOP-Hypertension) analyses performed up to 1992. Clinical and Experimental Hypertension 1993; 15(6):925 – 39.

THE PROBLEM-ORIENTATED APPROACH TO GERIATRIC MEDICINE Department of Health. Integrated community equipment services. National Service Framework for Older People 2001a, pp 36 – 7; DOH, London. http://www.doh.gov.uk/nsf/olderpeople.htm. Department of Health. The single assessment process. National Service Framework for Older People 2001b, pp 30 – 5; DOH, London, http://www.doh.gov.uk/nsf/olderpeople.htm. Department of the Environment. English House Conditions Survey: 1986 1988; HMSO, London; Tinker AM. Housing for frail elderly people. Public Health 1992; 106(4):301 – 5. Donabedian A. Exploration in Quality Assessment and Monitoring. The Definition of Quality and Approaches to its Assessment 1980, vol 1; Health Administration Press, Ann Arbor. Donald IP. Development of a modified Winchester disability scale – the elderly at risk rating scale. Journal of Epidemiology and Community Health 1997; 51(5):558 – 63. Dunbar JM, Neufeld RR, White HC & Libow LS. Retrain, don’t restrain: the educational intervention of the National Nursing Home Restraint Removal Project. The Gerontologist 1996; 36(4):539 – 42. Working Party of the Royal College of Physicians. Ensuring equity and quality of care for elderly people. The interface between geriatric medicine and general (internal) medicine. Journal of the Royal College of Physicians of London 1994; 28(3):194 – 6. Evans JG. Integration of geriatric with general medical services in Newcastle. Lancet 1983; i:1430 – 3. Evans JG. Hypothesis: Healthy Active Life Expectancy (HALE) as an index of effectiveness of health and social services for elderly people. Age and Ageing 1993; 22:297 – 301. Ezekowitz MD, Bridgers SL, James KE et al., Veterans Affairs Stroke Prevention in Nonrheumatic Atrial Fibrillation Investigators. Warfarin in the prevention of stroke associated with nonrheumatic atrial fibrillation. The New England Journal of Medicine 1993; 327(20):1406 – 12. Falconer JA, Roth EJ, Sutin JA et al. The critical path method in stroke rehabilitation: lessons from an experiment in cost containment and outcome improvement. Quality Review Bulletin 1993; 19(1):8 – 16. Feinstein AR. The problems of the “Problem-Orientated Medical Record”. Annals of Internal Medicine 1973; 78:751 – 62. Frain JP & Carr PH. Is the typical modern house designed for future adaptation for disabled older people? Age and Ageing 1996; 25(5):398 – 401. Frank C, Hodgetts G & Puxty J. Safety and efficacy of physical restraints for the elderly. Review of the evidence. Canadian Family Physician 1996; 42:2402 – 9. Goldfarb MG, Hornbrok MC & Higgins CS. Determinants of hospital use: a cross-diagnostic analysis. Medical Care 1983; 21(1):48 – 66. Graham H & Livesley B. Changes in the population aged over 75 of an urban general practice. British Medical Journal 1986; 292:453. Granger CB, McMurray JJV, Yusuf S et al., The CHARM Investigators and Committees. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensinconverting-enzyme inhibitors: the CHARM-Alternative trial. Lancet 2003; 362:772 – 6. Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico. GISSI-2: a factorial randomised trial of alteplase versus streptokinase and heparin versus no heparin among 12,490 patients with acute myocardial infarction. Lancet 1990; 336(8707):65 – 71. Harrington M. System review (letter). British Medical Journal 1989; 298:1180 – 1. Harwood RH & Ebrahim S. Is relocation harmful to institutionalized elderly people? Age and Ageing 1992; 21(1):61 – 6. Hodkinson HM & Jeffreys PM. Making hospital geriatrics work. British Medical Journal 1972; 4:536 – 9. Hoffbrand BI. Away with the system review: a plea for parsimony. British Medical Journal 1989; 298:817 – 9. Hyde CJ, Robert IE & Sinclair AJ. The effects of supporting discharge from hospital to home in older people. Age and Ageing 2000; 29:271 – 9. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. Lancet 1988; 2(8607):349 – 60.

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ISIS-3 (Third International Study of Infarct Survival) Collaborative Group. ISIS-3: a randomised comparison of streptokinase vs tissue plasminogen activator vs anistreplase and of aspirin plus heparin vs aspirin alone among 41,299 cases of suspected acute myocardial infarction. Lancet 1992; 339(8796):753 – 70. ISIS-4 (Fourth International Study of Infarct Survival) Collaborative Group. ISIS-4: a randomised factorial trial assessing early oral captopril, oral mononitrate, and intravenous magnesium sulphate in 58,050 patients with suspected acute myocardial infarction. Lancet 1995; 345(8951):669 – 85. Julius S, Kjeldsen SE, Weber M et al., The VALUE Trial Group. Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial. Lancet 2004; 363:2022 – 31. Kalra L, Dale P & Crome P. Improving stroke rehabilitation: a controlled study. Stroke 1993; 24:1462. Kalra L, Evans A, Perez I et al. Alternative strategies for stroke care: a prospective randomized controlled trial. Lancet 2000; 356:894 – 9. Larson ER, Mosekilde L & Foldspang A. Vitamin D and calcium supplementation prevents osteoporotic fractures in elderly community dwelling residents: a pragmatic population-based three year intervention study. Journal of Bone and Mineral Research 2004; 19(3):370 – 8. Lever AF & Brennan PJ. MRC trial of treatment in elderly hypertensives. Clinical and Experimental Hypertension 1993; 15(6):941 – 52. McCartney FJ. Diagnostic logic. British Medical Journal 1987; 295:1325 – 31. McGovern R. The role of the nurse. In AJ Squires (ed) Rehabilitation of the Older Person: A Handbook for the Multidisciplinary Team, 3rd edn 2002, pp 216 – 31; Nelson Thornes, Cheltenham, UK. McIntyre N. The principles of the problem-orientated medical record. In JC Petrie & N McIntyre (eds) The Problem-Orientated Medical Record 1979; Churchill-Livingstone, Edinburgh. Mitchell J, Katetz K & Rossiter B. Benefits of effective hospital services for elderly people. British Medical Journal 1987; 295:980 – 3. Nyein K & Turner-Stokes L. The Northwick Park Care Needs Assessment (NPCNA): a measure of community care needs: sensitivity to change during rehabilitation. Clinical Rehabilitation 1999; 13:482 – 91. Pattie AH & Gilleard CJ. A brief psychogeriatric assessment schedule. Validation against psychiatric diagnosis and discharge from hospital. The British Journal of Psychiatry 1975; 127:489 – 93. Pfeffer MA, McMurray JJV, Velazquez EJ et al., The Valsartan in Acute Myocardial Infarction Trial Investigators. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. The New England Journal of Medicine 2003; 349:1893 – 906. Price MA. Casemix classification and health care of the elderly. The Medical Journal of Australia 1994; 161:S23 – 6. Rai GS, Murphy P & Pluck RA. Who should provide hospital care of elderly people? Lancet 1985; i:683 – 5. 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 (SHEP). Journal of the American Medical Association 1991; 265(24):3255 – 64. Shepherd J, Blauw GJ, Murphy MB et al., PROSPER Study Group. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet 2002; 360:1623 – 30. Statham R, Korczek J & Moynihan P. House Adaptations for People with Physical Disabilities 1988; HMSO. Stroke Prevention in Atrial Fibrillation Study. Final results. Circulation 1991; 84(2):527 – 39. Swift CG & Severs MP. The challenges of service provision. Age Ageing, 1997; 26(Suppl 4):30 – 42. Tallis G & Balla JI. Critical path analysis for the management of fractured neck of femur. Australian Journal of Public Health 1995; 19(2):155 – 9. The GUSTO Angiographic Investigators. The effects of tissue plasminogen activator, streptokinase, or both on coronary-artery patency, ventricular function, and survival after acute myocardial infarction. The New England Journal of Medicine 1993; 329(22):1615 – 22.

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Turner-Stokes L & Nyein K. The Northwick Park Care Needs Assessment (NPCNA): a directly costable outcome measure in rehabilitation. Clinical Rehabilitation 1999; 13:253 – 67. Wan TT. The effect of managed care on health services use by dually eligible elders. Medical Care 1989; 27(11):983 – 1001. Wanklyn P. Homes and housing for elderly people. British Medical Journal 1996; 313(7051):218 – 21.

Weed LL. Medical records. Medical Education and Patient Care Year Book 1969; Medical Publishers, Chicago. Weed LL. New premises and new tools for medical care and education. Journal of Dental Education 1996; 60(1):64 – 7. Wood JB & Estes CL. The impact of DRGs on community-based service providers: implications for the elderly. American Journal of Public Health 1990; 80(7):840 – 3.

PART III

Medicine in Old Age Section 1

Eating Disorders and Nutritional Health

22

Oral Health Janet E. Griffiths University Dental Hospital, Cardiff, UK

INTRODUCTION Healthy teeth and oral tissues and the need for oral health care are as important for older people as any other section of society. Tooth loss can have a profound impact on quality of life (Davis et al., 2000), whereas good oral health has real health gains in that it can improve self-image and social interaction, and contribute to general health and quality of life (Fiske et al., 2000). Older people perceive oral health as being important to quality of life in a variety of ways (McGrath and Bedi, 2002). However, priority must be given to the elimination of disease, and abnormality; comfort, mastication, and aesthetics are paramount in helping the individual to maintain an overall perception of self-esteem and dignity, and generate confidence in making regular use of the services that are available.

DEMOGRAPHIC POPULATION CHANGES AND ORAL HEALTH CARE Improvements in life expectancy in developed countries have led to an increase in an aging population (see also Chapter 9, The Demography of Aging). In the 2001 United Kingdom (UK) census, over 12 million people were aged 60 and over, approximately 20.8% of the population (ONS, 2002). The proportion of people aged 65 and above in 2001 is predicted to rise from 16.9% to 19.3% in 2020 (GAD, 2002). Population projections based on declining fertility may need to be revised in the light of migration, and medical advances in the treatment of conditions such as dementia may reduce the burden of care (Tinker, 2003). Nevertheless, there will be an overall increase in the numbers and percentages of older people, of very old people, and of older people from black and ethnic minority groups, and a continued preponderance of older women. Similar increases are noted in other industrialized societies. This will have an impact on most forms of health care provision and will

place increasing demands to develop systems that cater for all aspects of health care, including dental services. Future development of oral health care services will need to consider the diversity of demand and need within this aging population (BDA, 2003).

IMPAIRMENT AND DISABILITY In discussing the oral health needs of older people and their use of services, the self-evident increase in impairment and disability with age must be considered. The 2001 UK census estimates that almost 9.5 million people in England and Wales have some form of disability (ONS, 2002), significantly higher than previous estimates. Of these, 18.2% reported a long-term illness, a health problem or disability that limits their daily activities. Over a third of respondents aged 65 to 74 and approximately a half aged over 75 reported long-term illness that limited their lifestyle (ONS, 1999). Physical and mental health influence access to services, including oral health care. Loss of mobility increases with age, with the greatest decline in people aged 75 and above (ONS, 1999). Immobility is a frequent pathway by which many diseases lead to further disability (Walsh et al., 1999) (see also Chapter 112, Gait, Balance, and Falls). Sensory impairments are more common with advancing years (see also Chapter 101, The Older Patient with Down’s Syndrome; Chapter 104, The Epidemiology of Hearing in Aging Population; Chapter 105, Auditory System; Chapter 106, Disorders of the Vestibular System). Approximately 80% of the population over 60 have some form of visual impairment, 75% have a hearing impairment, and 27% experience both visual and hearing impairment (Living in Britain, 1994). Cognitive impairment increases sharply with age affecting 1 person in 20 over the age of 65 and 1 in 5 over the age of 80, and this is predicted to increase Alzheimer’s Disease Association (ADS, 2004) (see also Chapter 94, Mild Cognitive Impairment;


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Chapter 95, Vascular Dementia; Chapter 96, Other Dementias). Older people are distinguished by functionality in the National Service Framework (NSF) for Older People, which refers to the functionally independent and the frail or functionally dependent regardless of age (DoH, 2001a). This classification is used by the British Dental Association (BDA) in addressing the diverse oral health needs and demands of older people for the next two decades (BDA, 2003). This chapter primarily addresses the needs of the frail and functionally dependent older population.

ORAL AND DENTAL STATUS Tooth loss is irreversible although stem cell research still in its infancy offers future potential for implantation of the patient’s own cells to grow and replace missing teeth. Prevalence of edentulousness (total tooth loss) in the general population over time and dental status, together with patterns of dental attendance, can be used to predict dental service needs. Comparison of the UK national surveys confirm a steady decline in tooth loss in adults (Table 1). In 1988, the dental status of older people in the United Kingdom was primarily one of edentulousness. However, the number of older people who are edentulous is declining. In 1968, 79% aged 65 to 74 were edentulous as compared to 36% in 1998, and in people aged over 75, edentulousness fell from 88% to 58% over the same period (Todd and Lader, 1991; Kelly et al., 2000). Retention of some natural teeth is sufficiently common amongst the “younger –old” population; nearly two-thirds (64%) in the 65 to 74 age group and almost half of all the people of “pensionable” age in the United Kingdom (54%) have some natural teeth (Steele et al., 2000). Age is highly correlated with dental status. Other factors include sex, social class, region of residency, ethnicity, and dental attendance. Social class differences in total tooth loss were much greater among men than women, and particularly noticeable amongst older men compared with older women; it is suggested that differences arise from social values attributed to appearance (Steele et al., 2000). Women from unskilled working backgrounds were most likely to have the lowest proportion of natural teeth. Regional differences in Table 1 People aged 45 and over with no natural teeth (1968 – 1998)

Age group Year 45 – 54 55 – 64 65 – 74

England & Wales 1968

England & Wales 1978

United Kingdom 1978

United Kingdom 1988

United Kingdom 1998

41% 64% 79%

29% 48% 74%

32% 56%

17% 37% 57%

6% 20% 36%

80%

58%

a

79% 75+

88%

87%

a

(Based on data from Todd and Lader, 1991; Kelly et al., 2000) a No separate data for age groups in 1978. In 1978, 79% over the age of 65 had no natural teeth.

social class structure may account for regional differences in total tooth loss but the highest proportion of retained natural teeth is still in the South of England. Despite a trend toward retaining some natural teeth into later life, a small but varied group of people will continue to become edentulous and these are more likely to be in the older age groups. Similar trends of tooth retention are recorded in other developed societies. Variability is strongly influenced by place of residence, geographic region, and cultural factors; however, edentulousness is more frequently associated with lower socioeconomic status. Not only has the number of dentate adults in older age groups increased, the number of undiseased and filled teeth have increased (Nunn et al., 2000). It is suggested that increased experience of dental treatment among older people is largely reflected by a lower experience of dental extractions. In older people, a significant proportion of the caries burden falls on exposed root surfaces although there is also an increase in coronal caries often recurring around existing fillings. Prevalence of toothwear increases with age, affecting 89% of the dentate population aged over 65. In 1998, older people had more restored teeth, often large and complex restorations requiring time and advanced professional skill to maintain them. Fifty percent of the teeth of dentate adults aged 45 years and over are filled and crowned, and many will retain their teeth for life (Pine et al., 2001). It appears that regular dental attenders benefit in real terms over a lifetime in terms of tooth retention (Kelly et al., 2000). Periodontal disease is a major concern in the older dentate population. Seventy-eight percent of dentate adults over 65 had visible plaque and 83% had visible calculus, which can only be removed by professional dental treatment (Morris et al., 2001). Depth of pocketing around teeth is also an indicator of periodontal disease but gingival recession is likely to be a common feature in older age groups, reflecting a lifetime’s disease history. The high prevalence of periodontal disease needs to be viewed in the context of larger numbers of dentate older people who are now potentially at risk. Control of periodontal diseases, whether mild or moderate, will be a central issue if large numbers of teeth are to be retained into old age. It seems that older people are now more concerned with preserving their natural dentition (Kelly et al., 2000). In 1998, dentate adults over 55 were the most likely to say that they attend regular checkups; the proportion reporting this has more than doubled over the last 20 years (Bradnock et al., 2001). A greater proportion aged over 55 have expectations of retaining some or all of their natural teeth for life, and older age groups would consider having more extensive restorative treatment such as crowns and bridges in order to achieve this expectation. Dental attendance does appear to be of substantial benefit in retaining teeth (Steele et al., 2000). Greater awareness of oral and dental health measures together with a greater desire to remain dentate will create an increasing demand for dental services. In the older UK population, three broad cohorts in relation to oral health are described:

ORAL HEALTH

• People who are old and very old, of whom a large proportion are edentulous, • Those now entering old age, who have retained much or most of their natural dentition, but in a condition that requires a lot of maintenance, • Those in middle age and younger, who are retaining a sound dentition, and assuming the status quo, are unlikely to need complex oral health care, but who may opt for cosmetic dentistry (BDA, 2003). Whereas the “new older” health consumer will be more informed and more demanding, for a significant proportion of older people, the maintenance of an aging dentition will pose significant challenges to the dental profession. It is the frail and functionally dependent that have a significant normative treatment need and that pose even greater challenges to their identification and service delivery. It is generally agreed that poor standards of oral hygiene and lack of access to professional dental care contribute to poor oral health amongst the frail and functionally dependent population (Fiske et al., 2000). Surveys within nursing and hospital care report high levels of oral disease, heavy deposits of plaque and debris, oral mucosal pathology related to inadequate denture hygiene and inadequate support to maintain oral health or access services (Frenkel et al., 2000; McNally et al., 1999; Simons et al., 1999). Poor oral health is also identified in the frail and housebound living in the community (Chalmers et al., 2002). The dental profession is concerned about the oral health of this client group, and in particular, those who rely on professionals for personal care and activities of daily living (BDA, 2003; Frenkel et al., 2001; Fiske et al., 2000; Simons et al., 1999). Oral health does not have a high profile in the context of personal care. Lack of training for health professionals in oral health care is reported (Longhurst, 1998; Travers et al., 1997). Gaps between theory and practice are noted in pre and postregistration nursing practice and education (White, 2000; Frenkel, 1999; Longhurst, 1998). This has led to a range of initiatives to address the issues and raise standards of oral health care for this client group (BDA, 2003; WAG, 2003; DoH, 2001b; Fiske et al., 2000).

BARRIERS TO ORAL HEALTH CARE Many older citizens face barriers to oral health care. These include attitudes developed in early life that place oral health as a low priority in the context of other factors such as past dental experiences, dental attendance patterns, lack of information, in addition to practical and financial barriers. Lack of perceived need is an important barrier. Social problems that influence perceived need are related to age, socioeconomic factors, and residence. The presence of natural teeth, residential status, and age were statistically significant independent variables for the time since the previous reported dental visit (Lester et al., 1998). There is a trend toward decreased perceived need in older populations;

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this was found to be a barrier to care for 86% of frail and dependent older adults (Lester et al., 1998) although the new elderly have significantly more favorable attitudes to dental care. Uptake of dental care is greater among patients of higher socioeconomic status. Cost, lack of perceived need, and transport were the most frequently quoted barriers by housebound subjects although the true implications of cost were poorly appreciated (Lester et al., 1998). Removal of the examination charge as a financial barrier to screening and, if possible, care is recommended (Walls and Steele, 2001; BDA, 2003). Legislation in Wales has removed the fee for a dental examination for the population aged 60 and over; it remains to be seen whether this alone will increase the uptake of care. Lack of perceived need and inability to express need are identified within residential care facilities and housebound persons in the community (Lester et al., 1998; Fiske et al., 2000). Fewer dental attendances in this population are in part attributed to the inadequacy of carers’ perception of their clients’ oral health needs and lack of knowledge of the benefits of oral health and access to dental services. The prevailing management culture that gives oral health a low priority reported in residential care may be a contributory factor. A dental emergency rather than a routine dental check was the usual reason for requesting a dentist’s services for a resident (Frenkel et al., 2000). Fear and anxiety are commonly cited as reasons for irregular dental attendance. Over 12% of older people in the United Kingdom express dental anxiety associated with their use of services and self-reported oral health status (Bedi and McGrath, 2000). This must be viewed in the context of past dental experiences prior to the foundation of the National Health Service (NHS) when the practice of extracting teeth and replacement with dentures was considered to be the most effective form of treatment as opposed to the current philosophy of maintaining and restoring the dentition. Impaired mobility, access to transport, and ability to reach services have implications for access to dental care for housebound and disabled persons. Inequalities in the distribution of general dental services pose problems for availability of care. This is particularly true of rural areas where transport difficulties and costs create disincentives. Difficulties registering for NHS dental treatment are being widely encountered by the general population. Older people with mobility problems may experience even greater difficulty in accessing NHS care owing to poor physical access to premises that do not comply with the requirements of the Disability Discrimination Act (1995) (Griffiths, 2002). Domiciliary dental care services are not widely known about and yet frail and functionally dependent older adults expressed a preference for treatment in their own home (Lester et al., 1998). Illness and impairment only become disabling if dental services fail to take them into consideration. The provision of adequate domiciliary dental services will be essential to provide professional advice and treatment to residents in care facilities and increasing numbers of frail people living at home or in sheltered accommodation (BDA, 2003).

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Figure 1 Loss of vertical dimensions in a 68-year-old female who had been edentulous for more than 20 years

Figure 2 Loss of vertical dimensions in a 68-year-old female who had been edentulous for more than 20 years

Beliefs about lifespan and expectations of dentures may contribute to reasons for low levels of dental attendance among the edentulous. Inadequate advice following the provision of dentures may contribute to this. Misconceptions exist about the management and lifespan of dentures, even though denture-induced stomatitis and mucosal lesions are known to be associated with old, worn, and ill-fitting dentures. Lifespan of dentures is variable and depends upon individual changes in hard and soft tissues. Resorption of alveolar bone and occlusal wear can occur gradually with resultant reduction in vertical dimensions which may be associated with unsatisfactory aesthetics, an overclosed facial appearance, problems with mastication, cheek-biting and possibly tempero-mandibular joint dysfunction (Figures 1 and 2). Gradual adaptation and muscular control allow many people to compensate for loss of dentition. With gradual oral changes and habituation to changing oral status, it comes as no surprise that worn and ill-fitting dentures are perceived as functional and cosmetically acceptable. This, combined with an exaggerated expectation of the lifespan, may contribute to a fall in dental attendance with advancing age, particularly among the edentulous.

Carer-related barriers include deficiencies in knowledge of basic oral hygiene among health care professionals and carers, chronic inadequate oral hygiene practices, and limitations of workloads on long-term care staff (Fiske et al., 2000; Frenkel et al., 2000; Longhurst, 1998). Lack of information on how to access dental services and difficulties in arranging dental care are reported (Lester et al., 1998). Professional barriers are also identified (BDA, 2003; Fiske et al., 2000). Older patients are less likely to receive restorative treatment than younger patients. Lower socioeconomic groups are less likely to receive advanced dental care, and previous dental attendance patterns influence treatment patterns. Negative stereotypes of older people and lack of confidence in treating older patients with more complex medical histories may contribute to limitations in treatment planning and reluctance to provide dental care. Reasons given for not providing dental services for people with impairments are that it is too time consuming in relation to remuneration, and lack of experience and training (Oliver and Nunn, 1995). The level of dental remuneration for NHS dental care is increasingly being regarded as financially

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nonviable and many dentists are opting out of providing NHS coverage (Walls and Steele, 2001). Therefore, vulnerable groups who are frail and functionally dependent are likely to be the most disadvantaged by reduced access to NHS dental care. Barriers to oral health and dental behavior are complex. The mechanisms by which these barriers may be lowered should be investigated in order to address the unmet oral health care needs and demands of older people (Lester et al., 1998). Good oral health and access to dental care should be available to all older people on the basis of clinical need regardless of age, geography or home circumstances (BDA, 2003).

CLINICAL ORAL HEALTH CARE The principle underlying oral health care for older people is to provide a service and standard of care that is qualitatively and quantitatively equal to that available to the population at large. This is acknowledged by the BDA in its policy document for the next two decades (BDA, 2003). Provision of oral health care requires a sound knowledge of clinical and preventive dentistry in the adult. Understanding of the aging processes associated with normality and disease, cognitive and attitudinal changes that may accompany aging, and socioeconomic influences in later life are fundamental in providing appropriate care. Knowledge of the effects of organic disease, treatments, and tissue changes on physical and mental well-being is essential. Functional changes that accompany the aging process and an increasing tendency toward organic disease are well documented (Walsh et al., 1999). Deteriorating oral health should not be accepted as an inevitable consequence of aging, and the benefits of good oral health as a contribution to holistic health are recognized. Oral changes that occur with age are frequently the consequences of earlier disease, wear, and habits. Muscle activity may decline and is hastened by early tooth loss. Speech may be affected by tooth loss and taste perception may be reduced. Xerostomia and a subjective feeling of dry mouth are receiving increasing attention. Age and medication are significant risk factors for xerostomia but medication is a better predictor of risk than age (Field et al., 2001). Xerostomia is more prevalent among institutionalized populations and those on multiple prescribed medications (Locker, 2003). Onset of xerostomia is usually associated with other oral symptoms, problems with eating, communication, and social interaction. Saliva has an important role in preserving oral health. Its functions include • lubrication of soft tissues in speech and mastication; • mechanical flushing of food and debris; • neutralization of acids created by breakdown of sugars by bacterial plaque; • remineralization of enamel surface; • bacteriostatic and bactericidal effect; • denture adhesion and retention.

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A reduction in salivary secretion therefore increases the potential for dental caries, periodontal disease, oral infections, and problems with the retention and comfort of dentures. Composition of saliva with age appears to have fewer protective properties and combined with xerostomic sideeffects of medication can have a significant negative impact on oral health status and quality of life (Locker et al., 2002a; Locker, 2003). Masticatory ability may be reduced by opposing tooth loss, lack of posterior teeth, poor or ill-fitting dentures, or even the absence of dentures (Figures 1 and 2) (see also Chapter 24, Epidemiology of Nutrition and Aging). While the loss of teeth does not conclusively lead to malnutrition, lack of masticatory efficiency does lead people to modify or adapt their diet to avoid material which is tough and fibrous. Poor diet and impaired food choice is associated with declining number of teeth and increasing age (Daly et al., 2003). Edentulous subjects and those with poor oral health are more likely to report limitations in chewing ability (Locker et al., 2002b). Surveys of frail and functionally dependent older people report high levels of oral pathology, high levels of plaque, and moderately severe gingivitis in dentate subjects unable to perform their own oral hygiene (Frenkel et al., 2000; Simons et al., 1999; McNally et al., 1999). Much oral pathology in edentulous subjects is associated with inadequate denture hygiene (Figure 3), denture misuse, and loose or ill-fitting dentures and is significantly related to clinically diagnosed denture stomatitis (Simons et al., 1999) (see also Chapter 23, Oral Disease). The incidence of oral cancer is increasing in Europe and throughout the developed world. It is primarily a disease of older age groups with a mean age of diagnosis of approximately 60 years (see also Chapter 23, Oral Disease; Chapter 128, Cancer and Aging). Incidence in males is around twice that in females although rates in women are rising. Smoking is a major risk factor (see also Chapter 14, Smoking in the Elderly). Pipe smoking has been linked to lip cancer, and chewing tobacco to intra-oral cancers. Alcohol also features as a risk factor and acts synergistically with tobacco (see also Chapter 15, Alcohol Use and Abuse). Chewing betel nut products and quat, practices that occur in certain ethnic minority groups, are implicated in oral malignancy. Long exposure to sunlight is also linked with lip cancer. Cancerous and precancerous oral lesions are frequently painless until the more advanced stages of disease. Signs and symptoms include persistent oral ulceration, warty lumps and nodules, and red, white, speckled or pigmented lesions (see also Chapter 23, Oral Disease). Onset of symptoms may be associated with difficulty with speech or swallow and enlarged cervical lymph nodes. Early diagnosis and treatment improve prognosis and therefore regular oral examination is recommended as a screening strategy, which should target people who are not in regular contact with dental services. The dental team is in a unique position to screen for oral cancer and premalignant conditions. However, other health professionals should be trained to distinguish between

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inconvenience at initial assessment, and reduce the stress to patient or carer associated with dental care. It may be difficult to assess the benefits of treatment to improved quality of life; however, relief of pain and discomfort is a priority and treatment plans may be modified as a result of physical and mental illness, and pharmacology. The individual’s ability to maintain oral hygiene and cooperate in the provision of clinical dental care are factors that influence treatment planning. Lengthy clinical techniques may be contraindicated and the retention of decayed teeth advised. Dentists unfamiliar with the socio-medical factors associated with aging may find difficulty in adjusting their normative assessment to the needs and abilities of the individual. However, the overall physical and psychological well-being of the patient must be a constant consideration.

Restorative Care

Figure 3 Fresh and old food deposits and bacterial plaque present on the fit surface of dentures being worn by a frail and dependent older patient in continuing hospital care

healthy and diseased tissue and screen for abnormalities as part of routine oral assessment, with a care pathway for referral when abnormalities are noted.

CLINICAL DENTAL CARE Older people are not a homogenous group and treatment planning must take account of subjective need and demand and the individual’s mental and physical health in order to achieve a successful outcome that is acceptable to the patient. A detailed medical and social history is essential, and when appropriate, information on care and support services is desirable. Advice and support from family, carers, and the multidisciplinary team should be sought for patients with cognitive impairment in order to clarify the individual’s capacity for informed consent to the proposed treatment plan. It is the clinician’s responsibility to assess the patient’s capacity for informed consent, to consult widely, and to act in the best interests of the patient (BSDH, 2004). Detailed referrals help reduce unnecessary ambiguity or

The principal features associated with the aging dentition are attrition, erosion, and abrasion. Increased length of clinical crowns as a consequence of long-standing periodontal disease and gingival recession, over-eruption of unopposed teeth, tooth mobility, and exposed root surfaces make oral hygiene measures more complicated and increase susceptibility to caries and periodontal disease. Restoration of the dentition can pose problems due to structural changes in dentine, which becomes harder and more brittle with age. Sclerosis may cause narrowing of the root canals with consequences for the success of endodontic treatment. Provided that roots and periodontal tissues are relatively sound, preservation of the dentition is recommended. Partial dentures should be designed before restoring teeth so that features for retention can be incorporated into tooth restoration. Complex partial dentures are generally contraindicated for patients with impaired comprehension or manual disability. The decision to render someone edentulous is not taken lightly. Older people exhibit a reduced learning ability, which influences adaptation to dentures. If complete dentures are proposed, gradual transition via partial dentures assists the process of adaptation and learning. The advantages of tooth and root retention lie in preserving the periodontal membrane, which provides proprioceptive feedback in chewing and helps to maintain alveolar support for dentures or over-dentures. Age-related oral changes require extra clinical care in extracting teeth. Soft tissues are more fragile and exhibit slower healing. Teeth are more brittle and more prone to fracture if heavily restored. Extraction of maxillary roots close to the maxillary antrum may lead to the development of an oro-antral fistula. Chronic periodontal disease leads to hypercementosis, which increases risk of fracture during extraction, and osteoporosis poses risks of pathological fracture. Surgical extraction may therefore be necessary except when teeth are mobile through periodontal disease. The extraction of asymptomatic retained roots may be contraindicated in the presence of other risk factors; however, pain relief remains a priority.

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Extractions must be considered in the light of medical complications and pharmacology, and are best carried out under local anesthesia with a sympathetic and reassuring approach. Mild sedation may be necessary to relieve anxiety and increase cooperation. If multiple surgical extractions are indicated in anxious or uncooperative patients, treatment should be provided under sedation or general anesthesia, with due assessment of the medical history and associated risks. Generally, simple rather than complex restorations are more successful; the final assessment must be based on the individual’s choice, their ability to receive treatment, and standard of oral hygiene. New materials and atraumatic restorative techniques (ART) require minimal tooth preparation. More complex restorative techniques need to be considered in relation to the number of visits, the duration of clinical time, and the potential for deterioration in self-care with impairment or disability. If minimal intervention and clinical time is indicated, partial dentures may be the choice to restore occlusion. They should be designed for ease of insertion and removal, and incorporate design features for cleanliness and plaque reduction. Keeping gingival margins free from food residues reduces the risk of plaque accumulation (Figure 4). Clasps should be designed or modified to ensure atraumatic insertion and removal. Reduced dexterity or manual disability may require further design modifications so that the denture can be inserted and removed by wearer or carer. Recurrent coronal caries and carious activity at the margins of existing restorations are prominent features in the neglected dentition. Large intracoronal restorations are avoided due to brittleness of dentine. Rather than replacing and extending existing restorations, it is better to add to them, repairing marginal deficiencies as necessary. For more advanced restorative treatment, the patient must be capable of maintaining good oral hygiene. Cervical and root caries are significant problems in the presence of gingival recession and poor oral hygiene. Restoration may be complicated by erosion or toothbrush

Figure 4 Gingival hyperplasia associated with nifedipine therapy, and complicated by a poorly designed denture with the clasp lying too close to the gingival margin and encouraging plaque accumulation

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abrasion (Figure 5). Amalgam is not the material of choice for aesthetic restoration of anterior teeth. Restorative techniques for cervical caries have improved with new materials that bond directly to enamel and dentine, and require less invasive tooth preparation. However, they do have limitations in their bonding capacity. Attrition due to excessive wear may be the result of earlier tooth loss placing abnormal loads upon the remaining teeth (Figure 5). Sensitivity may develop as a result of loss of occlusal or incisal enamel surfaces. Reduction in vertical facial dimensions gives an overclosed appearance. Preventing further tooth wear is a priority, although the level of attrition must be considered in relation to the person’s age and ability to accept treatment (Figures 5 and 6). Slight wear does not necessarily merit treatment; moderate wear is usually treated conservatively. In extreme cases, attrition is repaired by crowning or with adhesive filling materials. If bruxism is a

Figure 5 Self-caring 85-year-old male with attrition and abrasion. Attrition (wear of the incisal and occlusal surfaces) caused by loss of posterior teeth. Abrasion at the cervical margins caused by horizontal toothbrushing

Figure 6 The same 85-year-old male with no denture experience, successfully wearing a partial upper cobalt chrome denture to restore the loss of posterior teeth. Denture design keeps gingival margins as free as possible

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feature, a soft vinyl occlusal guard worn at night may prevent further wear and interrupt the habit. With excessive loss of vertical dimension, it is advisable to acclimatize the patient gradually to the increased vertical height by providing a removable bite-raising appliance to cover occlusal surfaces. An over-denture retained on existing teeth or a cast cobalt chrome splint covering occlusal surfaces may be an alternative to multiple crowns (Figure 7). Major restorative measures are contraindicated if the patient cannot accommodate to increased vertical dimensions. Erosion caused by excessive intake of acidic food, recurrent vomiting or reflux may cause sensitivity. Medical history and dietary analysis should establish the cause, although it may more rarely be related to previous occupational exposure to acid aerosols. Topical fluoride preparations to remineralize enamel surfaces and relieve sensitivity, and dietary advice, and protective splints may be required.

Figure 9 After treatment: upper anterior teeth restored with porcelain veneers and a partial acrylic denture (By courtesy of A. Ali)

Figure 7 A cobalt chrome bite-raising appliance which fits over the lower teeth to prevent further occlusal attrition

Figure 10 Male aged 68 with fractures and worn maxillary incisors (By courtesy of A. Gilmour)

Figure 8 Before treatment: a neglected mouth with gross gingival recession, toothbrush abrasion in the lower arch, and erosion and tooth loss in the upper arch (By courtesy of A. Ali)

Abrasion caused by vigorous or incorrect toothbrushing action creates distinctive cavities in the cervical area (Figure 5). Abrasion superimposed on cervical caries may

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complicate restoration, and tooth-brushing techniques need to be modified to prevent further damage. Porcelain veneers are effective in cosmetically restoring labial enamel surfaces (Figures 8 and 9). The technique is less destructive of coronal tissue than conventional crowning and the veneer is bonded or cemented to the labial surface. The technique does not produce very aesthetic results with excessive gingival recession. Teeth and roots may be restored or crowned and retained beneath an over-denture (Figures 10 to 15; the figures provide a case study to illustrate an over-denture in a 68-yearold male). Endodontic treatment may not be necessary and unsuccessful if root canals are sclerosed. Modification of coronal tissue to support a partial denture or the construction of crowns to receive precision attachments retaining a partial denture are accepted and useful methods of improving denture stability and distributing occlusal forces (Figure 16). Complex bridge work is more rarely indicated. Tooth preparation involves lengthy clinical procedures and

Figure 11 Porcelain crowns in the lower jaw and loss of posterior teeth have contributed to the excessive wear of the upper anterior teeth (By courtesy of A. Gilmour)

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Figure 13 Complete upper over-denture retained by clips. The extra retention permits a palatal free design (palatal view) (By courtesy of A. Gilmour)

Figure 14 Close-up of over-denture in situ (By courtesy of A. Gilmour)

supporting teeth will need to withstand the extra occlusal load. Oral hygiene requirements are more stringent and may be difficult for the individual with limited dexterity or diminished self-care. Adhesive bridges require minimal tooth preparation and less destruction of abutment teeth; they provide an acceptable method of replacing one or two missing teeth (Figures 17 and 18) although problems of adhesion to enamel occur in older agegroups. Bonding the crown of an extracted tooth to adjacent teeth acts as a temporary solution (Figure 19); however, the bond must be secure to reduce the risk of displacement and accidental inhalation.

Periodontal Treatment

Figure 12 Rotherman eccentric clips on gold posts in situ (palatal view) (By courtesy of A. Gilmour)

Periodontal health is maintained by effective tooth brushing to control bacterial plaque. With diminished ability for selfcare, oral hygiene tends to deteriorate, and coupled with a

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periodontal disease or gross sepsis may result (see also Chapter 23, Oral Disease). The prevalence and severity of periodontal disease increases with age; however, there are problems of differentiating between the aging process and the effects of disease. Since periodontal health can be maintained by good plaque control, it is a matter of concern that older people who are dependent for personal care do not receive appropriate assistance with oral hygiene (Frenkel et al., 2000). Resorption and gingival recession lead to an increase in the interdental space and a tendency to greater plaque accumulation, pocketing, and ultimately tooth mobility unless plaque is controlled effectively. Ill-fitting or poorly designed partial dentures increase the tendency for plaque accumulation (Figure 4). These areas are more difficult to clean by conventional brushing methods. Individual oral hygiene advice and instruction is essential.

Figure 15 Completed treatment with upper over-denture and lower partial denture to replace missing posterior teeth (By courtesy of A. Gilmour) Figure 17 Before: malocclusion and tooth loss causing problems for construction of an aesthetic partial denture

Figure 16 Partial upper cobalt chrome denture retained by precision attachments to canine and premolar crowns (By courtesy of A. Ali)

lack of dental health education and a belief in the inevitability of tooth loss, can lead to a significant deterioration in periodontal health. Pain or sensitivity due to recession,

Figure 18 After: Maryland adhesive bridges which are bonded to the palatal surfaces of maxillary incisors and canines, and to the labial surfaces of mandibular incisors. The patient’s high lip line concealed the visible metal attachments of the bridge in the lower jaw and produced an acceptable aesthetic result

ORAL HEALTH

Figure 19 The crown of an extracted tooth used as a temporary bridge, cemented to adjacent crowns with composite resin (By courtesy of A. Ali)

Thorough and regular prophylaxis may be preferable to extensive periodontal surgery. Professional removal of plaque and calculus, and oral hygiene instruction is best delivered by a dental hygienist with good communication skills, and carried out under the written prescription of a dentist. It is essential that hygienists receive appropriate training to provide care for older people. Toothbrush modification may be necessary for people with impaired dexterity; simple adaptations and commercial aids are described (Griffiths and Boyle, 2005a). Interdental brushes may be more effective for cleaning isolated areas. Electric toothbrushes with a wide grip may be more acceptable. Flossing is a technique requiring manual dexterity, and gauze or tape may be easier to handle and more effective for cleaning around isolated teeth. Chlorhexidine gluconate has a specific effect in inhibiting the formation of dental plaque and is an effective adjunct to plaque control, particularly if oral hygiene deteriorates and mechanical cleansing is inadequate. Commercial brands are available as mouthwash (0.2%), mint flavored mouthwash (0.12% and 0.2%), gel (1%), and spray (0.2%); spray delivery is useful when access is limited, and gel for dysphagic patients. Long-term use of Chlorhexidine stains teeth and in rare cases produces idiosyncratic mucosal irritation but the benefits in reducing plaque far outweigh the sideeffects. Effective mechanical plaque control and dietary control of sugar intake are the most effective methods for prevention of periodontal disease and dental caries. COMA (1992) recommends that “elderly people should restrict the amount and frequency of consumption of non-milk extrinsic sugars because their teeth are more likely to decay due to exposure of tooth roots and reduced salivary flow ”. It is important that dietary advice for oral health does not jeopardize the health and well being of the individual. A significant energy intake is derived from sucrose and fats, foods with little or no nutrient density. Guidelines for putting oral health into the context of healthy eating for older people can be

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adapted for particular client groups and care settings (Fiske and Lewis, 1995). Prescription of sugar-based medicines for dentate persons is also a matter of concern, and of even greater concern if taken with xerostomic medication (Field et al., 2001). Sugarfree alternatives should be considered. Food supplements taken orally to ensure adequate nutritional intake are a risk factor for dental caries in dentate persons of all ages as many of the these products contain cariogenic sugars and carbohydrates. In order to encourage intake, cartons may be sipped at frequent intervals throughout the day, thus increasing the tooth–food contact time. Aggressive preventive measures are therefore essential for dentate persons on xerostomic medication, long-term sugar-based medication or cariogenic food supplements. Toothpaste containing fluoride or monofluorophosphate is advocated routinely to remineralize and strengthen surface enamel, increasing its resistance to decay. Sensitivity due to recession can be relieved by toothpastes containing strontium chloride hexahydrate or formalin. However, oral hygiene products may appear expensive and have a low priority for people managing on reduced domestic budgets. Topical fluorides confer significant resistance to decay and reduce dentine sensitivity but should not be prescribed without prior reference to the fluoride content of the local water supply; fluoridation is currently confined to approximately 10% of water supplies in the United Kingdom (West Cumbria, West Midlands, and the North East). Fluoride varnish is applied professionally. Fluoride mouthwashes (sodium fluoride 0.05% daily and 0.2% weekly) are available as pharmacy medicines. Concentrated fluoride mouthwash (sodium fluoride 2%) is not recommended for people who have difficulty preparing the correct dilution. Brush on fluoride gel (0.4% stannous fluoride) may be more suitable for self-administered prevention. The older dentate person who is medically compromised or at risk of caries or periodontal disease due to diminished self-care or reduction in salivary flow, will benefit from preventive measures which include topical fluorides, chemical plaque control and saliva substitutes. Oral care procedures and a guide to assessment for the dependent patient are summarized (Tables 2 and 3) (Griffiths and Boyle, 2005b; Griffiths and Lewis, 2002). It is important to ensure that toothpaste residue is removed after brushing because of the drying effect.

Prosthetic Treatment Normative prosthetic need is high; however, demand is considerably lower. Denture replacement will be concentrated more and more in the elderly population, and adults needing a full clearance will be increasingly elderly. Treatment should aim to eliminate pathology and provide comfort, improve aesthetics and masticatory ability, but with due consideration of the individual’s needs, previous denture experience and ability for self-care.

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Table 2 Summary of oral care for the dependent patient (Griffiths and Boyle, 2005b)

NB: Gloves should be worn for all oral hygiene procedures Prepare appropriate oral hygiene materials Place the patient in a sitting or semi-fowler’s position to protect the airway Protect the patient’s clothing Remove dentures or other removable appliances • Dentate patient If necessary insert a mouth prop to gain access Floss interproximal surfaces of teeth, taking care not to traumatize gingivae Brush all surfaces using Fluoride toothpaste or Chlorhexidine gel. (Remember that traditional foaming agents in toothpaste inactivate chlorhexidine so use one or other or alternate their use, at different times of the day). Rinse or aspirate to remove saliva and toothpaste • Dentate and edentulous patients Gently retract cheeks and brush inside surfaces with soft, gentle strokes Using gauze to hold the tongue, gently pull the tongue forward and brush surface gently from rear to front Gently brush palate Towel or swab mouth if toothbrushing is not possible Aspirate throughout procedures if airway is at risk

Figure 20 Dolder bar anchoring the crowns of mandibular canines (By courtesy of A. Ali)

• Dentures and removable appliances Brush vigorously with unperfumed household soap Pay particular attention to clasps Rinse well in cold water Saliva substitute may be required before replacing denture in the mouth • Intubated patients Reposition tube frequently to prevent lip soreness Ensure tube is secure before proceeding with oral care Proceed with oral care as appropriate Source: Reproduced shancocksltd.com.

by permission of Stephen

Hancocks Limited www.

Successful restoration of occlusion with partial or complete dentures will depend upon patient motivation and the ability to learn the skills necessary to control and use them. Aesthetics may be of more importance to some patients than function. Improved aesthetics and masticatory ability should be stressed and may be effective in improving motivation. Previous successful denture experience is a useful indicator of likely success with new dentures; the main difficulty is in making an accurate assessment of the patient’s motivation and adaptability. It may be necessary to approach this through the multidisciplinary team and enlist the advice and support of relatives and carers, particularly if the patient is confused or cognitively impaired. Learning to wear dentures is more difficult for the older person as muscular patterns are established and learning ability is decreased. Gradual rather than sudden changes in the dentition make adaptation easier. Failure of partial dentures is frequently due to overloading abutment teeth and plaque accumulation leading to periodontal disease, but patient motivation and regular recall are as important as design in determining success rates. With poor motivation, extraction and the provision of dentures may be contraindicated.

Figure 21 The fit surface of the lower denture which is anchored by the Dolder bar and helps to maintain denture stability (By courtesy of A. Ali)

Over-dentures that cover retained roots and suitably adapted crowns are beneficial in retaining proprioceptive feedback and tactile sensation. Modifications or attachments to the existing teeth help locate the denture and improve stability with obvious consequences for patient satisfaction (Figures 20 and 21). Good oral hygiene must be maintained particularly at the fit surface of the over-denture. If extraction and progression to full dentures is proposed, it should, if possible, be carried incrementally by first providing a training appliance to allow gradual acclimatization before progressing to the edentulous state and complete dentures (Figure 22). Immediate addition of teeth to the training appliance when natural teeth are extracted can provide uninterrupted function and gentle adaptation. If a more rapid transition is required, extractions followed by insertion of immediate complete dentures may be indicated. Pre-extraction models permit a more accurate copy of the previous dentition both in terms of anatomical position of teeth and appearance.

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251

Table 3 Oral Assessment Guide (Griffiths and Lewis, 2002)

IS THE PATIENT CAPABLE OF PERFORMING OWN MOUTH CARE?

YES Will patient initiate mouth care?

YES

NO

NO Encourage/assist with mouth care twice daily

Using the assessment tool below, establish level of care required

Ensure patient has toothbrush, toothpaste, towel, water, plastic cup, receiver, mouthwash (if required), denture pot etc as necessary

COMPLETE ORAL HEALTH ASSESSMENT

Are there any oral abnormalities eg. colour and appearance of oral tissues, texture, any lesions, bleeding, amount and consistency of saliva, appearance of teeth and dentures

YES. Refer for further examination

NO. Move on to next stage

IS THE PATIENT INTUBATED?

YES. Reposition tube frequently and ensure secure before proceeding with oral care

NO. Move on to next stage

DOES THE PATIENT HAVE THIER OWN NATURAL TEETH?

YES. Place patient in appropriate position. Prepare materials. Protect clothing. Lubricate lips.

NO. Soft tissues still require oral care. Place patient in appropriate position. Protect clothing. Lubricate lips.

Retract lips/tongue with gauze. Brush all surfaces of teeth with Fluoride toothpaste/Chlorhexidine gel. NB. Do not use toothpaste and Chlorhexidine gel together. Gently brush palate and soft tissues.

Retract lips/tongue with gauze. Gently brush palate and soft tissues. If not possible, use gauzed finger soaked in Chlorhexidine gel or mouthwash

Rinse with water (10 ml syringe). Aspriate using Yankauer. On completion, clean patient's face. Lubricate lips.

DOES THE PATIENT HAVE DENTURES?

YES. Clean over a basin of cold water to prevent breakage. Brush with unperfumed household soap. Rinse well before replacing. Clean after every meal. NB. Overuse of dentures cleaners will blench/discolour dentures. Dentures should be labelled with the patient's name. Store denture overnight in cold water in a labelled pot.

Continue with oral care as specified above every ......... hours. Frequency to be based on individual assessment. Source: Reproduced by permission of British Society for Disability and Oral Health.

NO

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Figure 22 Clear acrylic partial training appliance constructed for a 58-year-old male with cerebral palsy and intellectual impairment

Figure 23 Old worn acrylic resin dentures showing gross occlusal wear and abrasion (above) and new dentures (below)

For the edentulous patient, complete dentures can restore function and aesthetics. Patients frequently do not complain about ill-fitting dentures because of gradual adaptation to

progressive oral changes; therefore, it may be difficult for the older denture wearer to adapt to new dentures (Figure 23). In the absence of major defects, ill-fitting dentures can be relined. Temporary linings allow a more even distribution of occlusal forces and allow damaged soft tissue to recover before permanent reline or replacement. Permanent soft linings of silicone or plasticized acrylic resin may improve comfort if the mandible is atrophic. However, these materials lose their plasticity and should be replaced at regular intervals. Contrary to popular belief, denture construction requires considerable skill and a significant level of cooperation. Impression taking can be distressing and requires compliance to obtain an accurate functional record. The copy technique provides a less invasive method of replacing dentures, while maintaining the contours to which the patient has become habituated but eliminating unsatisfactory features such as wear, poor occlusion or loss of fit due to alveolar resorption. It involves taking an impression of an existing denture. Therefore, a previous set of dentures, however old or unsatisfactory, is essential. Denture retention relies upon the size and shape of alveolar ridges. Gross alveolar resorption reduces retention and stability. Anatomical features that interfere with retention can be eliminated with preprosthetic sulco-plasty or surgical removal of the mylohyoid ridges and benefit healthy patients who can tolerate the procedure. Assessment of the patient’s motivation to wear dentures is essential before considering surgery. Reduced salivation impairs retention and causes discomfort; saliva substitutes provide symptom relief and may improve retention. Pilocarpine is effective in stimulating salivary flow post irradiation and may provide relief for druginduced xerostomia. However, some patients fail to adapt to new dentures in spite of good anatomical features for success. An upper “social” denture may satisfy the needs of patient or family in restoring appearance and speech. Older people who lose teeth in later life and have difficulty retaining and controlling dentures may benefit from implant-supported dentures provided that wound healing is not compromised by other medical problems. Denture hygiene is a significant problem. Many denture wearers do not clean their dentures effectively. Nurses lack information on effective methods for denture hygiene (Barber et al., 2002). Denture-related stomatitis may resolve with good denture hygiene, removal at night, and by ensuring adequate oral lubrication. Candidal infection is the most common pathogen in denture stomatitis (see also Chapter 23, Oral Disease); antifungal therapy may be necessary in conjunction with the above measures. When immediate or new dentures are fitted, patients are advised to wear them continuously for a limited period but with regular removal to allow scrupulous cleaning. After a period of acclimatization, patients should be advised to routinely remove dentures at night. Denture cleaning procedures should be simple, consistent, and carried out after meals and at night. Cleaning over a sink of cold water reduces the risk of accidental fracture. Recommendations are summarized in Table 4; with the exception

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253

Table 4 Care of dentures (Gloves should be worn when handling a patient’s dentures)

Denture hygiene techniques √

Metal and acrylic resin √

Temporary soft linings Permanent soft linings √ √

Remove debris by brushing with soft brush using

Unperfumed household soap and water


Do not brush. Rinse well in cold water


Soak in alkaline hypochlorite solution (Milton or Dentural) OR Soak in alkaline peroxide solution (Steradent) using hand hot warm water

20 min

10 min

20 min

20 min

15 min √

15 min. Do not use acid cleaners √

Do not use alkaline peroxide cleaners √

√

√

√

√

√

Rinse after every meal with cold water

Rinse well with cold water before insertion Store in cold water over night

Acrylic resin (plastic)

of temporary soft linings which are easily damaged, brushing is the most effective method of cleaning dentures. Effervescent cleaning tablets can be confused with sweets and were implicated in the accidental death of an elderly inpatient (Mackenzie, 1982). Hard calculus deposits cannot be removed by brushing and require professional attention. Immersion in an ultrasonic cleaning bath is effective but care must be taken to ensure dentures are labeled to avoid possible confusion (Figure 24). Clear advice about denture management and hygiene, both verbal and written, should be provided to patient and/or carer. Advice should cover expectations, limitations and lifespan, pain management, problems with speech and salivation, denture hygiene, and labeling. Soft tissues need oral care in the dentate and edentulous (Tables 2 and 3). Gentle brushing with a soft toothbrush will remove plaque and food debris which tend to accumulate mainly in the buccal sulci. A sweeping action with a gauze-covered finger using chlorhexidine gluconate gel or mouthwash may be substituted if brushing cannot be tolerated. There is little scientific value in the use of foam mouth sticks except for uncooperative and terminally ill patients (Bowsher et al., 1999). Recommendations are made for routinely naming dentures particularly on admission to residential or continuing care

(Barber et al., 2002; Fiske et al., 2000). Few dentures are marked in construction despite long-standing recommendations; when asked, patients are generally in favor of having them named. There are additional benefits in identification at postmortem or of unconscious or amnesic persons. In the author’s experience of working in acute and continuing care hospital services most referrals for replacement of lost dentures are from acute wards. The emotional distress of being without dentures for several weeks while new dentures are being made cannot be quantified. Denture construction is both labor intensive and costly; it involves a minimum of five visits and presupposes the patient’s mental and physical ability to cooperate with treatment. In a number of cases, this is a contraindication to treatment. Naming dentures is a cheap and simple procedure using a proprietary marking kit. Results are not as durable as laboratory methods and renaming should be carried out at regular intervals. If carried out on admission, it can reasonably be assumed that the dentures are the patient’s property. It would help reduce the problem of confused patients wearing the wrong denture or when dentures have been erroneously collected “en masse”’ for cleaning. The British Society for Disability and Oral Health (BSDH) recommends a policy for denture care that includes labeling and responsibility for the cost of replacement dentures (Fiske et al., 2000). Naming dentures does not prevent loss, but if found, they can be returned to the owner (Table 5).

PEOPLE REQUIRING SPECIAL CARE Functionally independent healthy adults make up the majority of the older population; they will have increasing expectations about maintaining good oral health and appearance, and many will have the resources to take advantage of advances in cosmetic dentistry (BDA, 2003). However, frail and functionally dependent older people will largely fall within the remit of special care dentistry, which is evolving as a speciality concerned with the oral health needs of specific groups. Special care is defined as Figure 24 Labeled denture

“those who by virtue of illness, disease and/or its treatment, disability, lifestyle or cultural practices, who are at greater risk of poor

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Table 5 Recommendations to develop local standards for oral health in residential and continuing care

1. Liaison between health, social, and voluntary agencies to identify residential and continuing care establishments without a dental service or with inadequate access to dental services. 2. Screening programs to identify baseline data for dental service planning and oral health promotion strategies appropriate to residents’ needs. 3. Oral assessment criteria on admission to identify (a) risk factors for oral health; (b) individual oral care needs and develop an oral care plan; (c) appropriate oral hygiene equipment; (d) preventive and palliative measures; (e) need for and access to dental services. 4. A policy on the care and safe-keeping of a resident’s dentures to include (a) denture labeling on admission with the resident’s consent; (b) responsibility for the cost of replacement dentures if lost or mislaid. 5. Dental input to multi/inter-disciplinary assessment where appropriate including (a) procedures for access to pain relief, appropriate general and specialist dental services, oral hygiene advice, and support; (b) support for health professionals and carers in oral care; (c) procedures for ensuring continuity of dental care on discharge. 6. Training for health care professionals in (a) the scientific basis of oral health and disease; (b) oral assessment criteria and tools for oral assessment; (c) identification of risk factors and stressors for oral health; (d) current oral care practices appropriate to individual needs; (e) practical oral care to motivate, encourage, support, and assist residents to carry out oral, dental, and denture hygiene; (f) eligibility for free or partial exemption for the cost of NHS dental care; (g) accessing local dental services. 7. Oral health advice and support for residents, family, and carers, appropriate to their needs. 8. Oral health education and promotion for residents, carers, and health professionals which address (a) the oral health needs of residents; (b) dietary issues in the context of healthy eating for oral and general health. 9. Facilities for privacy, dignity, and comfort for personal oral hygiene and on-site dental screening, assessment, and treatment. 10. Negotiated standards and procedures for oral health which promote structure and process for putting theory into practice and which can be monitored/audited (Fiske et al., 2000) Source: Reproduced from Gerodontology by permission of Blackwell Publishing and the editor.

oral health, for whom the management of dental care poses other health risks or who experience barriers to the access and receipt of dental care” (Griffiths, 2000).

Gerodontology is a well-established specialty developed in response to the oral health needs and provision of care for older people with chronic debilitating physical or mental illness, pharmacology, and psychosocial problems. Both specialities are raising awareness of the oral health needs of frail and functionally dependent older people in residential care and in the community. Identification of those in the community presents the greatest challenge and it is therefore essential that the dental profession works closely with statutory and voluntary agencies to ensure people are aware of oral health care services available to them, and address the training needs of personal and professional carers. A comprehensive assessment is essential at the start of any health intervention. Oral assessment is necessary at the first episode of care to identify existing oral health needs, risk factors, and appropriate preventive measures. During an acute phase of illness, the need for oral care requires monitoring and later during the phases of recovery and rehabilitation. There is no single assessment tool that weighs the different factors, quantifies risk status and subsequently translates

into the degree and type of intervention required. Assessment tools which alert health professionals to problems can be adapted to different client groups and assist in the development of an oral care plan (Table 6) (Griffiths, 2002). More complex assessments require training to recognize the signs and symptoms of oral pathology. Furthermore, assessment facilitates the identification of individuals who might benefit from services. Key areas that give an indication of oral health status and point toward objectives for care include • presence of existing symptoms and signs of oro-dental disease including early changes to dental and soft tissues; • current mouth care practices and preventive behaviour, including dental service attendance patterns; • presence of risk factors including systemic disease, medication, impairment, and disability; • presence of key stressors for oral health (Griffiths and Boyle, 2005c). Oral assessment with consideration of the likely prognostic course of the disease at an early stage will help alleviate later problems and permit gradual adjustment to changes in dental status. Oral health assessment should be incorporated into routine assessment. It need not be confined to

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255

Table 6 Oral health assessment by health professionals provides a mechanism for opportunistic identification of clients who have oral and/or dental problems, are not receiving regular dental care and/or are at risk of poor oral health. Subjective indicators include the ability to speak, smile or eat without pain or discomfort. This example of an Oral Health Assessment may be adapted to suit any client group or adapted for self-assessment. It is recommended that risk assessments are used in collaboration with local dental services in order to facilitate access to an appropriate dental service. The Community Dental Service is best placed to fulfill the role of facilitator. A response in a highlighted area signifies a need for further investigation or action (Griffiths and Lewis, 2002)

1. Does the client have natural teeth?

NO

YES

Don’t Know

2. Does the client wear dentures?

NO

YES

Don’t Know

Specify

Upper

Lower

(a) YES, are dentures labelled?

YES

NO

Don’t Know

(b) If YES, how old are dentures?

>5 yrs

1 yr

1,650)

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75 70 65 60 55 50 45 Old aids, old service

Digital aids new service

Figure 6 Average benefit of modern digital hearing aids

were using their aids for more time, finding them more helpful, and more satisfied with the result.

THE NEW SERVICE As a result of the MHAS program, patients are fitted to nationally agreed protocols that ensure that the technology is used to specifically tailor the hearing aid to each individual’s hearing loss. The audiologist spends longer with each patient, and there are now standardized national systems to monitor patient outcomes. In addition to the equipment and hearing aids, NHS services were given additional funding to recruit extra staff to fit the new hearing aids; furthermore, in order to be able to fit the new hearing aids to their patients, a comprehensive national training package was delivered, including hands-on training within the individual hearing aid department. This has effectively meant that every audiologist in England has been fully trained to fit digital hearing aids to NHS patients.

EVIDENCE-BASED CHANGE Modern digital hearing aids provide users with an “intelligent” amplifier, the performance of which is programed and fine-tuned by an audiological professional to meet their individual needs. The hearing aid will constantly adapt to changes in the sounds it picks up. In addition, it offers the user a means of choosing the most helpful settings for each listening environment that they encounter in daily life. The differential benefit to patients was measured using a standardized questionnaire (The Glasgow Hearing Aid Benefit Profile). This questionnaire captures how much of the time each person uses their hearing aid, how much it helps in different everyday situations and how satisfied they are with the result. The composite score is shown in Figure 6. An independent evaluation of the MHAS program by the MRC found that people fitted with high-quality digital hearing aids in the modernized service reported 41% greater overall benefit compared to those with analog aids. They

DISCUSSION The public health priority of hearing impairments and tinnitus in adults should be substantially higher than it presently appears, because hearing disorders comprise the most prevalent chronic impairment in the population, with over 8 million people in the United Kingdom (i.e. about 20%) having an impairment. The major factor associated with this high prevalence is age, with noise being the major preventable factor, especially in young people. Because age is the major factor, prevalence of hearing impairments in the whole population will increase over the next 20 years by up to 20% because of the change in demographics (Doyle and Gough, 1991). The data show that the need is great at most levels of severity of hearing impairment and particularly for the over-60s. Demand and supply seem to be increasing, which will be driven by the changing demographics of the aging population over the next 20 years. The implications for hearing-aid and rehabilitation budgets are quite substantial even if the same annual incidence of referral for a hearing aid is maintained and not increased using screening, education, or awareness programs so that some of the unmet need can be fulfilled. There seems to be no reason why elderly people cannot cope with rehabilitation for their hearing disorders, both hearing and tinnitus, unless other factors affecting morbidity interfere. The elderly benefit as much from hearing aids as those who are younger and have about the same usage rates, unless there are other problems that interfere with maintenance of their hearing aids. There is no evidence that central dysfunction handicaps the elderly who are not hospitalized. However, the usage rates are disappointingly low in this group. The implications for service provision are, perhaps, that the hearing aid service for the elderly should be situated increasingly in the community and thought should be given as to how individual care plans can be enacted, which take a client-oriented approach to individual facets of the

THE EPIDEMIOLOGY OF HEARING IN AGING POPULATION

disability that are presented by clients. There is little evidence on the effectiveness of different styles of rehabilitation on their costs and benefits. The comments received from the 318 individuals who had a hearing aid in the 1990’s study suggest that more thought should be given to meeting specific needs (including detailed training in tactics and handling skills) and less emphasis be placed on technology as the primary means to these ends. In terms of research requirements, there is an urgent need to build up a better evidence base in order to suggest guidelines for better and more acceptable rehabilitation services for the elderly who have a hearing problem. There are very few studies of whole population samples or randomized control trials on which to base good practice. Such trials should be given an urgent priority to consider why take-up and access are so poor and also to determine what factors can increase systematic use of hearing aids for example, early detection and intervention.

KEY POINTS • Prevalence of hearing impairment is expected to increase by up to 25% by 2020. • The major factor associated with its high prevalence is age. • A study of the prevalence is most important for service provision. • The quality of digital hearing aids in the modernized service in the United Kingdom reported 41% greater overall benefit compared to analog aids. • The elderly benefit as much from hearing aids as those who are younger and have same usage, unless there are other problems that interfere with maintenance of their hearing aids.

KEY REFERENCES • Davis AC. The prevalence of hearing impairment and reported hearing disability among adults in Great Britain. International Journal of Epidemiology 1989; 18:911 – 7. • Davis AC. Epidemiology. In SDG Stephens (ed) Scott-Brown’s Otolaryngology 1997, vol 2, chapter 3, Adult Audiology, 6th edn; Butterworth-Heineman, Oxford. • Sorri M, Jounio-Ervasti K, Uimonen S & Huttunen K. Will hearing health care be affordable in the next millennium? Scandinavian Audiology 2001; 30:203 – 4. • Taylor R & Paisley S. The Clinical and Cost Effectiveness of Advances in Hearing Aid Technology. 2000; Report to the national Institute for Clinical Excellence United Kingdom. (www.nice.org.uk).

REFERENCES Alpiner JG. Audiological problems of the aged. Geriatrics 1963; 18:19 – 27. Audit Commission. Fully Equipped: the provision of equipment to older or disabled people by the NHS and Social Services in England and

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Wales 2000, http://www.audit-commission.gov.uk/reports/NATIONALREPORT.asp. Barton GR, Davis AC, Mair IWS & Pa M. Provision of hearing aid services: a comparison between the Nordic countries and the United Kingdom. Scandinavian Audiology. Supplementum 2001; 30:16 – 20. Brooks D. Adult Auditory Rehabilitation 1989; Chapman and Hall, London. Coles RRA, Smith P & Davis AC. The relationship between noise induced hearing loss and tinnitus and its management. In B Berglund & T Lundvall (eds) Noise as a Public Health Problem 1990, pp 87 – 112; Swedish Council for Building Research, Stockholm. Davis AC. The prevalence of hearing impairment and reported hearing disability among adults in Great Britain. International Journal of Epidemiology 1989; 18:911 – 7. Davis AC. Epidemiological profile of hearing impairments: the scale and nature of the problem with special reference to the elderly. Acta Otolaryngologica (Stockholm) 1991; (suppl 476):103 – 9. Davis AC. Hearing Impairment in Adults 1995; Whurr, London. Davis AC. The aetiology of tinnitus: risk factors for tinnitus in the UK population – a possible role for conductive pathologies? In GE Reich & JA Vernon (eds) Proceedings of the Fifth International Tinnitus Seminar 1996; American Tinnitus Association, Portland. Davis AC. Epidemiology. In SDG Stephens (ed) Scott-Brown’s Otolaryngology 1997, vol 2, chapter 3, Adult Audiology, 6th edn; Butterworth-Heineman, Oxford. Davis AC, Ostri B & Parving A. Longitudinal study of hearing. Acta Otolaryngologica 1991; (suppl 482):103 – 9. Davis AC & Roberts H. Tinnitus and health status: SF-36 profile and accident prevalance. In GE Reich & JA Vernon (eds) Proceedings of the Fifth International Tinnitus Seminar 1996; American Tinnitus Association, Portland. Davis A, Stephens D, Rayment A & Thomas K. Hearing impairments in middle age: the acceptability, benefit and cost detection (ABCD). British Journal of Audiology 1992; 26:1 – 14. Dillon H, James A & Ginis J. Client orientated scale of improvement (COSIE) and its relation to several other methods of hearing aid benefit and satisfaction. Journal of the American Academy of Audiology 1997; 8:27 – 43. Doyle L & Gough I. A Theory of Human Need 1991; Macmillan Education, Basingstoke. Gatehouse SG. Application of quality standards to hearing aid services. Outcome measures should be based on listeners’ needs. British Medical Journal 1994; 308:1454. Gatehouse SG & Davis AC. Clinical pure-tone vs three-inferred forced choice thresholds: effects of hearing level and age. Audiology 1992; 31:30 – 44. Gates GA, Cooper JC, Kannel WB & Miller NJ. Hearing in the elderly: the Framingham cohort, 1983 – 1985. Ear and Hearing 1990; 11:247 – 56. Gray R. Surveys of Hearing: Technical Report 1995, Published by: NatCen, p 1401 http://www.natcen.ac.uk. Haggard MP. Research in the Development of Effective Services for Hearing-Impaired People 1993; Nuffield Provincial Hospitals Trust, London. Hart FS. The Hearing of Residents in Homes for the Elderly – South Glamorgan (Report) 1980; University of Wales. Martin D & Peckford B. Hearing impairment in homes for the elderly. Social Work Service 1978; 17:52 – 62. Quaranta A, Asennato G & Sallustio V. Epidemiology of hearing problems among adults in Italy. Scandinavian Audiology 1996; 25(suppl 42):7 – 11. Reich GE & Vernon JA. In GE Reich & JA Vernon (eds) Proceedings of the Fifth International Tinnitus Seminar, Portland, Oregon 1995; American Tinnitus Association, Portland. Rosenhall U, Jönsson R & Söderlind O. Self-assessed hearing problems in Sweden: a demographic study. Audiology 1999; 38:328 – 34. Salomon G. Hearing problems and the elderly. Danish Medical Bulletin 1986; 33(suppl 3):1 – 22.

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Schow RL & Norbonne MA. Introduction to Aural Rehabilitation 1989; 2nd edn; Pro-Ed, Texas. Sorri M, Jounio-Ervasti K, Uimonen S & Huttunen K. Will hearing health care be affordable in the next millennium? Scandinavian Audiology 2001; 30:203 – 4. Soucek S & Michaels L. Hearing Loss in the Elderly 1987; Springer-Verlag, London. Stephens SDG, Callaghan DE, Hogan S et al. Hearing disability in people 50 – 65: effectiveness and acceptability of early rehabilitation intervention. British Medical Journal 1990; 300:508 – 11. Taylor R & Paisley S. The Clinical and Cost Effectiveness of Advances in Hearing Aid Technology. 2000; Report to the national Institute for Clinical Excellence United Kingdom. (www.nice.org.uk). Tolson D, McIntosh J & Swan IRC. Hearing impairment in elderly hospital residents. British Journal of Nursing 1992; 1(14):705 – 10. Uimonen S, Huttunen K, Jounio-Ervasti K & Sorri M. Do we know the real need for hearing rehabilitation at the population level? Hearing impairments in the 5- to 75- year-old cross-sectional Finnish population. British Journal of Audiology 1999; 33:53 – 9.

FURTHER READING Davis AC, Spencer H & Paulson J. Cost implications in setting a target for hearing aid provision in England and Wales. Poster presented at The Scientific Basis of Health Services, International Conference, London, 2 – 4th October 1995. Davis AC & Thornton ARD. The impact of age on hearing impairment: some epidemiological evidence. In JH Jenson (ed) Proceedings of 14th Danavox Symposium. Presbyacusis and Other Age-Related Aspects 1990, pp 69 – 89; Danavox Jubilee Foundation, Copenhagen. Gatehouse S. Rehabilitation: identification of needs, priorities and expectations, and the evaluation of benefit. International Journal of Audiology 2003; 42:2S77 – 2S83. Haggard MP & Gatehouse SG. Candidature for hearing aids: justification for the concept and a two-part audiometric criterion. British Journal of Audiology 1993; 27:303 – 18. Reeves D, Mason L, Prosser H & Kiernan C. Direct Referral Systems for Hearing Aid Provision 1994; HMSO, London.

105

Auditory System R. Gareth Williams University Hospital of Wales, Cardiff, UK

INTRODUCTION The auditory system is one of the special senses, which, together with the visual system, is largely responsible for the way in which we perceive our environment. In addition to audition, the system encompasses the vestibular apparatus with special senses for the detection of gravity and movement (see also Chapter 106, Disorders of the Vestibular System). The auditory system is responsible for the detection of sound energy, its effective transfer from the surrounding air to the inner ear fluid and the subsequent conversion of this physical stimulus to a psychoacoustic sensation, which we perceive as sound. Abnormalities of the auditory system can result in a variety of symptoms, the most frequent of which are hearing impairment and tinnitus. Assessment of the auditory system is directed toward 1. the identification of the pathological processes and their anatomical location; 2. quantifying the impairment and disability; 3. reducing the handicap by the most appropriate means.

ACOUSTICS AND HEARING The transmission of sound through air involves the oscillation of air molecules, producing regions of alternating pressure changes traveling away from the sound source. If these sound waves reach a normal functioning ear, a noise is heard. The human ear is capable of detecting sound wave oscillations of varying frequency and amplitude. Variations in frequency of vibrations are perceived as variations in pitch of sound; similarly, variations in amplitude of vibrations are perceived as a variation in loudness.

Pitch The frequency of sound wave vibration is measured in Hertz (Hz or cycles per second). Some human ears are able to

detect a sound frequency as low as 20 Hz, but hearing is not normally tested for sounds below about 100 Hz. Similarly, sound is not easily detected at frequencies above 10 000 Hz although some individuals can hear up to 20 000 Hz. Puretone audiometry (PTA) assesses the ability to hear tones presented to each ear individually and is normally done using between 7 and 11 pure tones in the range between 125 and 8000 Hz.

Loudness Sound pressure is a physical measure that relates to the perception of loudness. The sound pressure level at which the human ear is able to detect sound is approximately 10 million times smaller than the loudest level that can be tolerated. As a result, it is not practical to refer to actual sound pressure levels when measuring the variations in the threshold and tolerance of sound amongst the human population. The alternative and more practical method is the decibel (dB) scale. The basis of this scale is the comparison of a sound pressure to a reference sound pressure level, usually that at the threshold of normal human hearing (2 × 10−4 dynes cm−2 ), and converting the ratio into a logarithmic scale (the Bel), then dividing by 10 (the decibel). Using this scale, a sound pressure at the threshold of normal hearing is represented by a decibel score of 0 dB. If the sound pressure being tested is less than the reference level, such that the test to reference ratio is less than 1, the resulting decibel score will be negative. A 10-fold increase in sound pressure level equates to an increase of 20 dB. Sound frequencies in the midrange of normal human hearing are heard better than those at the extreme ends of the range. In order to simplify the graphical representation of normal hearing levels, a decibel scale is used that uses different reference sound pressure levels for each frequency tested, thus providing a means of representing normal hearing as a horizontal line on an audiogram chart. The decibel scale


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used is known as the Hearing Level scale (dB HL) and was initially achieved by testing otologically normal, young adults.

sound transmitted across the skull. This can be mistaken for a conductive loss and is known as a false Rinne negative result. Weber Test

MEASUREMENT OF HEARING LOSS Clinical assessment of hearing usually begins with free-field voice tests and tuning fork tests. The approximate loudness of the whispered voice is 15 dB at 2 ft and 35 dB at 6 in. Similarly, a conversational voice is approximately 50 dB at 2 ft and 60 dB at 6 in. A loud voice is about 75 dB at 2 ft. Using these figures as a guide, it is possible to estimate the hearing loss by simple voice tests, presenting simple words or numbers to one ear at a time and occluding the opposite ear and rubbing the tragus to help mask the nontest ear.

Tuning Fork Tests Common tuning fork test that can be helpful in differentiating conductive from sensorineural deafness are the Rinne and Weber tests. Rinne Test

This test compares the effective transmission of sound through the normal route of the outer and middle ear (air conduction) against the transmission through bone. A tuning fork placed onto the mastoid bone transmits sound to the cochlea through the skull. In the presence of a functioning cochlea, a sound will be heard until the loudness of the tone reduces to the individual’s hearing threshold. If the tuning fork is then placed next to the ear canal and heard, it indicates that the normal conductive mechanism is intact. Alternatively, the perceived loudness of sound is compared by alternating the position of the tuning fork between the mastoid and ear canal. In the presence of a conductive deafness, the sound may appear louder by bone conduction than by air conduction. The magnitude of conductive deafness at which the perceived loudness shifts from air to bone conduction is about 20 dB HL (Browning and Swan, 1988). By convention, the “normal” result (air conduction perceived as louder than bone conduction) is a Rinne positive result. If bone conduction sounds louder than air conduction, the result is Rinne negative. Sound transmission through bone means that sound presented anywhere on the skull will travel to both ears. If a sound source is placed on the right mastoid bone, sound will be transmitted to the right and left cochlea. Therefore, even if the right cochlea is not functioning, the sound will be heard – by the left ear. When the sound is presented to the right ear by air conduction, no sound will be heard because the left ear will not detect the sound. In this situation, the sound will appear louder by bone conduction than air conduction, by virtue of the fact that the opposite ear has detected

When a tuning fork is placed centrally on the skull, sound is transmitted to both ears equally. Whether the sound is perceived equally depends on the sensitivity of hearing in both ears. The transmission of sound to the cochlea by bone conduction is not only directly through the skull vault to the cochlea, but also via the skull to the middle ear and then through the ossicular chain to the cochlea. As a result, the transmission of sound by bone conduction is affected by abnormalities of the middle ear. When sound reaches the middle ear through the skull, it will travel through the ossicular chain in both directions, resulting in some loss of sound outwards through the ear canal. Any process that affects the transmission of sound through the middle ear (i.e. a conductive deafness) will reduce the loss of sound from the middle and outer ear. This is one explanation for the phenomenon of increased loudness in the ear with a conductive deafness when the sound of a tuning fork is presented to the vertex of the skull. The magnitude of conductive deafness at which the perceived loudness shifts from midline to the affected ear is about 12 dB(HL) (Stankiewicz and Mowry, 1979). In the absence of a conductive deafness, the loudness of the tone will be determined by the relative sensitivities of both cochlea. Therefore, the lateralization of the Weber test may be because of a conductive loss in the affected ear or a sensorineural loss in the opposite ear.

Pure-tone Audiometry Hearing thresholds can be assessed using audiometry. The commonest method used is pure-tone audiometry (PTA), which measures the subjective threshold of hearing of various pure-tone frequencies. The results are usually presented graphically and normally include both air conduction and bone conduction. Air conduction refers to the detection of sound as presented through the normal anatomical pathway, via the outer ear. The sound may be presented either through standard earphones, or alternatively through insert earphones or using free-field sound from speakers. Bone conduction measures the threshold of sound applied directly to the skull. The pure-tone audiogram graphically represents the magnitude of hearing loss at different frequencies. It is convenient to summarize the average hearing loss as a single figure, and by convention, the thresholds over the midrange of 0.5, 1, 2, and 4 kHz are used. On this basis, hearing impairment can be described according to the severity of the average loss (see Table 1; Browning, 1998). In healthy state, the air conduction is similar to bone conduction. In broad terms, hearing loss may be due to abnormalities of the sound conduction mechanisms affecting the outer or middle ear, resulting in a conductive deafness, or

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Table 1 Classification of deafness based on pure-tone average hearing thresholds at 0.5, 1, 2, and 4 kHz)

Description

0 – 24 25 – 50 51 – 70 71 – 90 91 – 110 >110

Normal Mild Moderate Severe Profound Total

Type C Admittance

Pure-tone average (dB)

Type A

Type B

alternatively, may be due to abnormalities of the cochlea or neural pathways resulting in a sensorineural deafness. Differentiation between conductive and sensorineural deafness identifies the anatomical part of the auditory pathway at fault and in turn allows a suitable management plan to be made. Most conductive losses are associated with identifiable changes affecting the outer and middle ear, including the tympanic membrane.

Acoustic Admittance and Tympanometry The ability to measure the ease with which sound energy travels through the middle ear has been developed into a clinical application that is easily used to assess so-called acoustic admittance of the ear. Acoustic tympanometers are used to measure admittance, a parameter that is influenced by changes in the stiffness, mass, and resistance of the tympanic membrane and middle ear. The test is performed automatically using a sealed probe inserted into the ear canal, which measures the changes in intensity to an 85 dB SPL (sound pressure level) tone at 226 Hz as the pressure in the ear canal between probe tip and drum are adjusted from −400 daPa to +200 daPa, relative to atmospheric pressure. Acoustic admittance will vary as the pressure changes, because of the splinting effect of the increase or decrease in pressure on the eardrum. When the pressure in the outer ear is similar to the middle ear pressure, the acoustic admittance will be highest. A graphical representation of this series of measurements is the tympanogram, and is clinically useful because it provides information about middle ear pathologies and can identify normal and abnormal contraction of middle ear muscles. Examples of different tympanograms are shown in Figure 1. The normal pattern, known as a type A curve, has a distinctive peak in the vicinity of atmospheric pressure. The height of the peak represents the acoustic admittance of the middle ear and is affected by changes in stiffness and mass. A low peak is seen in conditions that fix the ossicles such as otosclerosis. A flat curve is known as a type B tympanogram, and is seen in the presence of middle ear fluid, but can also occur if there is a perforated drum or impacted wax. If the peak of the tympanogram is shifted to the left, it indicates that acoustic admittance is best when the pressure in the outer ear canal has been reduced below atmospheric, and, by inference, corresponds to the middle ear pressure. A peak below −100 daPa is a type C tympanogram and may occur in the presence of Eustachian tube obstruction associated with

− 200

0 Pressure (daPa)

+200

Figure 1 Classification of tympanogram shapes. (a) Normal tympanogram with peak centred at atmospheric pressure. (b) Flat curve due to middle ear fluid. (c) Negative peak due to eustachian tube dysfunction associated with a negative middle ear pressure

a negative middle ear pressure due to a failure to replace middle ear air lost by absorption through the middle ear mucosa. Tympanometry can be used to assess the integrity of the stapedius muscle contraction by virtue of the fact that this muscle can be made to contract in response to a loud sound; contraction alters the middle ear mechanics, resulting in reduced acoustic admittance. The introduction of a loud sound and measurement of acoustic admittance constitutes an acoustic reflex test, the afferent arm of which is the stimulation of the acoustic nerve and the efferent arm is triggered by a bilateral brain stem (superior olivary complex) reflex to the facial nerve, which supplies the stapedius muscle. The test will assess the integrity of both the 7th and 8th cranial nerves and can be performed ipsilaterally (stimulus and tympanometry in same ear) or contralaterally (stimulus and tympanometry probe in opposite ears).

Speech Audiometry The assessment of speech perception is perhaps a more appropriate test of hearing than PTA when assessing impairment. A speech audiometer can assess the ability to perceive and understand the complex and rapidly changing spectrum of sound that constitute speech. The test is usually performed using headphones and asking the patient to repeat words presented at varying loudness levels. Words may be presented as single words from standard word lists (e.g. Boothroyd word lists) or as sentences. When using sentences, key words in the sentence are used for scoring. The ability to understand words presented within the context of a meaningful sentence is easier than words presented in isolation. Speech audiometry can also be assessed using visual presentation as well, combining the speech signal with a recorded image of the speaker in a standard audiovisual test. Because of the varied ways in which speech tests are performed and reported, the results must be interpreted within

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the context of the test material and with the PTA results. The results of speech audiometry tests are reported as either the highest score that can be achieved by the individual no matter how high the volume, or as a decibel level indicating the loudness level at which the individual correctly hears half the test words. The highest score that can be achieved is known as the optimal discrimination score (ODS ) and in normal individuals, it is achieved using a loudness level about 30 dB above the pure-tone threshold. Results of speech audiometry can also be presented graphically as a performance-intensity function graph, as shown in Figure 2. Such a graph will indicate whether the individual achieves 100% speech recognition score and the loudness level at which the maximum score is achieved. The normal shape to the speech audiogram performance-intensity graph is a rapid increase in speech recognition over a 20–30 dB increase in loudness, to the maximum speech recognition level of 100%. Two common abnormalities are seen using this type of graph, a shift to the right in the presence of a conductive loss or a reduced speech recognition score seen in sensorineural deafness. Speech audiometry is particularly useful when assessing hearing disability and the value of interventions such as hearing aids or surgery. Because speech recognition is a phenomenon largely regulated by neural processing beyond the cochlea, abnormalities affecting the cochlear nerve or central auditory pathways will have a greater affect on speech recognition than on the detection of pure tones, which is a much more basic audiological function. Therefore, hearing loss caused by a retrocochlear pathology will result in a greater-than-expected loss of speech discrimination, than that predicted by the pure-tone audiogram. With retrocochlear pathology, the discrimination of speech may in fact deteriorate with increasing loudness, resulting in another type of speech audiogram curve where the speech recognition score decreases after reaching its peak, so-called rollover 100

B

A

Score (%)

C

D

50

(Figure 2). Speech audiometry is therefore useful in that it reflects the site of the disorder as well as degree of disability.

THE SYMPTOMS OF EAR DISEASE Hearing Loss One of the commonest symptoms of ear disease is hearing loss. The broad classification of hearing loss is conveniently categorized according to the anatomical site within the auditory pathway affected. Deafness caused by any abnormality affecting the transmission of sound to the cochlear is a conductive deafness, whereas abnormalities of the cochlea or subsequent neural pathways result in sensorineural deafness. The distinction is useful as it conveniently allows the clinician to focus on the different potential pathological processes and management approaches that are required for the two types of deafness.

Conductive Hearing Loss Most causes of conductive deafness can be identified on otoscopy. Common causes are listed in Table 2. Wax (Cerumen)

Wax is an uncommon cause of deafness because it either has to completely occlude the ear canal or impinge against the eardrum. Wax is produced by the ceruminous glands, found in the outer third of the ear canal. Wax will become impacted if attempts are made to clean ears using blunt objects such as cotton tipped probes or tissues. Wax can become impacted by hearing aid molds if there is excessive wax production. Wax should be removed either by syringing or manual removal using suitable wax hooks, ear forceps, or microsuction. Hard occlusive wax is best softened first, using oil or sodium bicarbonate. Syringing should not be performed in the presence of a known perforation or if the ear is effectively the only hearing ear, in which case, patients are best referred to an otologist for careful manual removal (Aung and Mulley, 2002). Table 2 Causes of conductive deafness according to site

0 20

40

60

80

Loudness (dB HL) Figure 2 Speech audiometry, examples of various performance-intensity curves. (a) normal hearing individual reaching maximum score of 100%. (b) conductive deafness causing displacement of curve to the right by 25 dB. (c) sensory deafness in a patient whose score reaches 80% at 50 dB. (d) neural deafness in a patient with rollover, representing deterioration in discrimination with increasing loudness

Site Pinna Ear canal Tympanic membrane Middle ear

Description Atresia, perichondritis Wax occlusion, otitis externa, osteoma, foreign body, tumor (“ceruminoma”) Myringitis, perforation, calcification (tympanosclerosis) Otitis media, ossicular fixation (otosclerosis or ankylosis), ossicular disruption, tumor (e.g. glomus)

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Otitis Externa

Acute Infective Otitis Media

The accumulation of infected debris and soft tissue occlusion of the ear canal in otitis externa may result in conductive deafness. Infection may be bacterial, viral, or fungal. Acute bacterial otitis externa is a very painful condition. Discomfort and irritation of the ear canal precedes the most severe period of pain, and discharge often precedes the onset of deafness. The mainstay of treatment is removal of debris and wax, usually by gently syringing or microsuction, and instillation of topical antibiotic and steroid drops. Ear swabs for bacteriology should be taken beforehand so that recalcitrant infection can be treated appropriately. The commonest bacterial pathogens are Staphylococcal and Pseudomonas (Roland and Stroman, 2002), over 90% of which remain sensitive to aminoglycosides and quinolones. Therefore, topical gentamicin or ciprofloxacin (0.3% solution) is often effective. Topical treatments are only effective after the removal of infected debris and discharge. Fungal otitis externa is most often seen following prolonged antibiotic treatment. Careful cleaning and removal of fungal hyphae and spores will maximize the chances of resolution. Topical antifungal treatments using clotrimazole or clioquinol are important adjuncts. Systemic treatment is only needed in invasive infection in immunocompromised patients.

Acute infection of the middle ear cleft is usually viral. This may take the form of infection of the middle ear cleft itself or nasopharyngeal infection affecting Eustachian tube function. Secondary bacterial infection can occur, resulting in a prolonged episode requiring systemic antibiotics. Viral to bacterial conversion in acute otitis media occurs in about 10–20% of cases. In the majority of cases, therefore, all that is required is analgesia until the acute viral episode resolves after 2–3 days. Bacterial otitis media is characterized by increasing pain and toxicity, often culminating in tympanic membrane perforation and mucopurulent discharge from the ear. Common bacterial pathogens are Streptococcus pneumoniae, Hemophilus influenzae, and Moraxella catarrhalis. First-line treatment should be with amoxicillin or erythromycin for 5 days (O’Neill, 1999).

Myringitis

Inflammation or infection of the tympanic membrane is not uncommon, and tends to be mistaken for otitis media by virtue of the fact that the appearances can be similar. Acute myringitis is usually viral in origin and may be accompanied by bullae on the outer surface of the drum. A common form of myringitis is characterized by hemorrhagic bullae associated with severe, sudden onset otalgia and conductive hearing loss, so-called myringitis haemmorhagica bullosa. It may be associated with sensorineural deafness in up to 40% cases. Granular myringitis has the typical appearance of vascular granulations on the outer surface of a de-epithelialized drum. This may respond to the application of topical steroid, repeated cauterization using silver nitrate carefully applied using an otological microscope or it may require surgical skin grafting (Blevins and Karmody, 2001). Otitis Media

Infection or inflammation of the middle ear cleft is a common cause of conductive deafness. The distinction between inflammatory and infective otitis media is useful in that treatment options and symptoms differ between the two pathologies, although both coexist much of the time. Infective otitis media is usually followed by an inflammatory process before full resolution, characterized by a middle ear effusion that may take a few weeks to fully resolve. Conversely, inflammatory otitis media is characterized by the production of a sterile middle ear effusion, which may become secondarily infected.

Chronic Otitis Media

Chronic middle ear infections are conveniently divided into those associated with cholesteatoma and those associated with middle ear mucosal disease and tympanic membrane perforations, the latter type is referred to as tubotympanic otitis media. The distinction between these types of chronic infection is not absolute and both may coexist. Historically, a distinction was made because cholesteatoma was thought to have a greater likelihood of leading to intracranial infection, but this is not the case. The serious complications of facial nerve palsy and meningitis are just as common with mucosal disease (Sing and Maharaja, 1993). The actual risk of developing intracranial infection from active chronic otitis media is between 0.5 and 1% over a 60-year period (Nunez and Browning, 1989). Conductive deafness in chronic otitis media has a number of potential mechanisms. A number of causes may coexist, requiring a combined medical and surgical approach (see Table 3). Management of Chronic Otitis Media

Examination of the ear should begin by carefully looking for a postaural scar. Acute mastoid infections were much more common years ago, and many elderly patients will have undergone mastoid surgery as children. Many of these will have been cortical mastoidectomies, whereby infection in the Table 3 Pathological causes of conductive deafness in chronic otitis media and the otological procedures for their correction

Pathology

Treatment

Perforated drum Disrupted ossicular chain Mucosal edema Active infection

Myringoplasty Ossiculoplasty Topical steroid Antibiotics Mastoid surgery with Tympanoplasty Ossiculoplasty

Tympanosclerosis and fixed ossicular chain

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mastoid was drained through a postaural incision removing bone from the outer table of the mastoid, but not opening the cavity into the ear canal. Surgery to deal with cholesteatoma usually leaves an open cavity communicating with the ear canal, allowing inspection and cleaning of the cavity. Findings on otoscopy direct the investigations and management principles. It is usually possible on inspection to determine if there is active infection or not. With inactive chronic otitis media, the commonest findings are: dry perforations of the tympanic membrane, patchy calcification of the drum (tympanosclerosis), retraction of the tympanic membrane. Retraction of the pars tensa may occur in the central portion of the drum or near the margin, most often the posterior margin. Deep retractions can mimic perforations, the distinction being that retractions are lined with a thin layer of dry squamous epithelium, whereas moist middle ear mucosa can be seen through perforations. Retraction of the pars flaccida in the upper part of the drum (the attic) is more often associated with accumulation of squamous epithelium and recurrent infection and may be the precursor of cholesteatoma or the only external feature of an extensive mastoid cholesteatoma. It is advisable to inspect the ear with an otological microscope where there is a marginal or attic retraction. Purulent discharge should be cultured and treated using systemic antibiotics such as amoxicillin initially. Persistent infection usually signifies loculations of infected debris, inappropriate antibiotic, or poor penetrance into the middle ear cleft. Careful cleaning and removal of debris from the ear is essential in these cases. The outer ear canal can be dry mopped using cotton wool wrapped/mounted on a probe such as a Jobson Horne probe. It is much more difficult to clean debris lying against the drum or in the middle ear cleft, and this usually requires microsuction using the otoscopic microscope. Topical antibiotics can then be administered. Many of these contain potentially ototoxic antibiotics and are not recommended by manufacturers or the Committee on Safety of Medicines (CSM) in the presence of a perforation. Nevertheless, specialists have used topical aminoglycosides for many years to good effect and consider the presence of pus and active infection in the middle ear to be a greater risk to the hearing than the short-term use of these drops (Lundy and Graham, 1993). A nonototoxic alternative is ciprofloxacin 0.3% or ofloxacin 0.3% (both available as ophthalmic solutions but unlicensed for otitis media), especially as Pseudomonas is a common pathogen in chronic otitis media (Ghosh et al., 2000). Referral to a specialist is recommended in the presence of persistent granulations on the tympanic membrane or middle ear mucosa, or if there is continued drainage despite topical antibiotics.

Extracranial Complications Acute Mastoiditis. Because the mastoid air cells are confluent with the middle ear space, infection within the mastoid is almost inevitable following otitis media. Improvements in imaging over the last few years have highlighted the frequency of mastoiditis and serve as a reminder that most cases of mastoiditis go undiagnosed and are successfully treated along with the otitis media. Treatment should be modified if there is involvement of the periosteum of the postauricular area with associated erythema and protrusion of the pinna. These features indicate spreading infection and demand a change in antibiotic therapy as well as consideration of intravenous administration. If the tympanic membrane is intact, a myringotomy with drainage of middle ear pus will aid resolution and provide material for microbiology. Progress beyond this stage with osteitis results in increasing fever, postauricular swelling, and downward protrusion of the pinna and requires surgical drainage (mastoidectomy). Chronic Mastoiditis. Chronicity following simple acute otitis media is uncommon. A more common scenario is an acute infection on a background of chronic disease. Bacterial infection in chronic mastoiditis is more often mixed, anaerobic bacteria can be isolated in the majority of cases, and Pseudomonas is quite prevalent. Acute Labyrinthitis. The pathological progress of inner ear infection allows a distinction to be made between so-called serous labyrinthitis and suppurative labyrinthitis. Serous labyrinthitis results from bacterial toxins and other chemical changes disrupting the normal chemical equilibrium within the perilymph of the inner ear. It is potentially reversible and therefore results in temporary vertigo and a fluctuating sensorineural hearing loss. Conversely, suppurative labyrinthitis refers to bacterial invasion and manifests itself with severe vertigo and profound hearing loss. Meningitis may develop if infection spreads along perilymph channels to the internal auditory canal or through the cochlear aqueduct to reach the CSF. Labyrinthitis secondary to otitis media is today a very rare occurrence, in contrast to a reported 4% incidence at the turn of the last century (Whitehead, 1904). Facial Palsy in Otitis Media. Only about 5% of all facial palsies are caused by otitis media (Table 4 – causes of facial palsy). Facial weakness rarely occurs in acute otitis media, Table 4 Causes and incidence of acute facial palsy, excluding true idiopathic (“Bell’s palsy”), which still accounts for about 20% of facial palsies (Reproduced from Peitersen E, Bell’s palsy, Acta Otolaryngol Suppl . (2002) 549, 4 – 30, by permission of Taylor & Francis)

Causes

Complications of Otitis Media Complications of otitis media are uncommon but can be serious. They fall into two broad groups – extracranial and intracranial.

Herpes simplex virus type 1 Herpes zoster virus Trauma Otitis media or cholesteatoma Rare and unusual conditions

Incidence (%) 75 15 4 5 1

AUDITORY SYSTEM

but it may occur when the facial nerve canal is dehiscent in the middle ear. In chronic otitis media, the thin bone overlying the facial nerve may be eroded by osteoclastic activity resulting in neuropraxia. The overall incidence of facial nerve palsy increases with age, from approximately 1 per 10 000 at the age of 20 to about 6 per 10 000 at age 60. Facial nerve weakness resulting from middle ear infection will sometimes respond to the treatment targeted toward the middle ear infection. One of the most important prognostic predictors is the degree of paralysis. Over 90% of partial palsies make a full recovery, whereas the likelihood of recovery reduces to about 60% if the palsy is complete. The rate of recovery of complete facial palsy secondary to middle ear infection improves with surgical intervention. In acute otitis media, a myringotomy should be performed to aspirate middle ear mucopus, sending pus for microbiology. In chronic otitis media, surgery should be performed after radiological investigations, with CT being the most appropriate as it demonstrates bone erosion and cholesteatoma; surgery can then be targeted appropriately. Petrositis. Extension of infection into the petrous part of the temporal bone may be a cause of persistent otorrhea associated with deep otalgia. Irritation of the trigeminal nerve as it crosses the apex of the petrous temporal bone results in orbital pain and more extensive involvement of the ophthalmic division of the trigeminal nerve. The abducent nerve may also be involved, resulting in a lateral rectus palsy. The combination of trigeminal pain, 6th nerve palsy and deep otalgia constitutes Gradenigo’s Syndrome. Diagnosis is confirmed by radiology and requires immediate antibiotic therapy, although the duration of medical treatment before considering surgery is controversial. Access to the petrous apex is difficult and therefore surgery should only be considered if there is a deterioration clinically and radiologically, despite appropriate medical treatment. Intracranial Complications

Intracranial complications are rare in otitis media, occurring in about 0.3% of all cases (Kangsanarak et al., 1995). When intracranial complications do occur, they are often multiple. Meningitis (see Chapter 148, Infections of the Central Nervous System). This is the commonest intracranial complication of otitis media, accounting for about a half of all intracranial complications. Treatment must be directed primarily toward the meningitis (Heyderman et al., 2003), using intravenous cefotaxime or cefriaxone. A CT scan will determine whether there are associated complications and whether surgery to drain the ear or mastoid is necessary. Intracranial Abscess (see Chapter 148, Infections of the Central Nervous System). Subdural, extradural, and parenchymal brain abscesses are less common than meningitis and require the input of neurosurgeons. The mortality

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of patients with intracranial abscess formation following chronic otitis media is close to 10%. Lateral Sinus Thrombosis. Thrombosis of the lateral (sigmoid) sinus is diagnosed by MRI or CT scan. Thrombosis may extend into the internal jugular vein and very rarely results in septic emboli. It requires aggressive antibiotic treatment and may require surgery to deal with the mastoid infection and infected clot if symptoms persist. Altered venous drainage may result in raised intracranial pressure and so-called “otitic hydrocephalus”, with papilloedema, vomiting, headache, and 6th nerve palsy. It is a misnomer as the ventricles are reduced in volume because of the generalized raised intracranial pressure. It occurs more often in younger patients and is treated by CSF drainage and anticoagulation.

Sensorineural Deafness Hearing loss in the elderly is predominantly a form of degenerative deafness to which the term “presbycusis” applies. The potential causes of sensorineural deafness increase with increasing age by virtue of the fact that many of the causes are more likely to have occurred in the older population. With increasing age, people are more likely to have been exposed to noise, ototoxic drugs, ear infections, vascular disorders, neural disorders, and trauma. The term presbycusis is reserved for those cases of hearing loss for which there is no identifiable cause and in whom the cause is thought to be related to a degenerative change associated with aging. What is ‘‘Normal’’ in the Aging Population?

Various epidemiological studies have examined the pattern of hearing loss in the aging population (see Chapter 104, The Epidemiology of Hearing in Aging Population). Agerelated hearing loss (ARHL) affects virtually all people to a varying degree. Studies have shown that the loss with age is greater in men than in women and greater in manual workers even after allowing for noise exposure (Davis, 1989). Figure 3 illustrates the mean hearing thresholds in the typical UK adult male and female population based on the MRC National Study of Hearing (Davies, 1995). The greatest change in hearing with age disproportionately affects the higher frequency hearing thresholds. The audiograms in Figure 4 illustrate the expected range of hearing in the cohort of men aged 40–49 years compared to the 70–79 year age-group. The shaded areas represent the range of hearing in the 25–75th percentile of these population cohorts (data from MRC National Study of Hearing (NSH) database). These audiograms demonstrate how the individuals with the least amount of ARHL in the 70–79 year age-group have similar hearing to those individuals with the worst ARHL in the 40–49 year age-group. The pathological processes responsible for ARHL have been divided into four main groups – sensory, neural, strial, and cochlear conductive (Schuknecht, 1993).

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MEDICINE IN OLD AGE Mean hearing thresholds with age 40

Mean hearing threshold (Av 0.5,1.2.4 kHz) dB HL

35 30 25 20 15 10 5 0 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54 56 58 60 62 64 66 68 70 72 74 76 Age (years)

0

0

10

10

20

20 Hearing level (dB)

Hearing level (dB)

Figure 3 Graph showing mean hearing thresholds against age for men (solid line) and women (dashed line); data from UK MRC National Study of Hearing

30 40 50 60

30 40 50 60

70

70

80

80

90

90 250 Hz 500 Hz 1 kHz 2 kHz 4 kHz 8 kHz Average hearing thresholds in 40 – 49 year males

250 Hz 500 Hz 1 kHz 2 kHz 4 kHz 8 kHz Average hearing thresholds in 70 –79 year males

Figure 4 Audiograms illustrating the range of hearing (25th – 75th centiles) in two 10-year cohorts of men, aged 40 – 49 years and 70 – 79 years (based on MRC National Study of Hearing)

The different types are based on patterns of histological change associated with characteristic patterns of hearing loss. This is a useful classification in that it helps with the understanding of pathophysiology and may be useful in explaining why similar magnitudes of hearing loss can result in markedly different degrees of discriminatory loss.

loss tends to occur near the basal end of the cochlea, accounting for high-frequency loss. There is relative sparing of the neuronal and supportive elements within the cochlear, which accounts for the reason why many of these types of hearing loss may have quite good speech discrimination. Neural Presbycusis

Sensory Presbycusis

Sensory presbycusis is predominantly caused by loss of sensory epithelium within the organ of Corti. Most of the

Neural presbycusis, on the other hand, is associated with a loss of speech discrimination, which is more marked for a given loss in pure-tone threshold compared to sensory

AUDITORY SYSTEM

presbycusis. Loss of cochlear neurones is almost inevitable with increasing age, although pure-tone threshold appears not to be affected until about 90% have disappeared. The commonest pattern of pure-tone loss is similar to that seen in sensory presbycusis, a high-frequency loss. Strial Presbycusis

Degeneration and atrophy of the stria vascularis is believed to affect the homeostatic control of inner ear endolymph and glucose metabolism and has been described as a pathological feature in some forms of familial hearing loss. The pattern of hearing loss affects all frequencies equally, producing a so-called flat loss on PTA. Preservation of the neuronal population results in good speech discrimination relative to the pure-tone hearing loss. Cochlear Conductive Presbycusis

A fourth pathological variety of presbycusis is proposed on the basis that some individuals with a significant hearing loss have no obvious histopathological changes other than changes to the cochlear likely to result in changes to its mechanical properties, such as fat deposition and calcification in the basilar membrane. Altered electromechanical properties affecting the outer hair cells, which are responsible for the cochlear amplification process, may contribute to this type of hearing loss. These changes are proposed as an explanation for some cases of high-frequency loss without significant loss of sensory epithelium or neuronal population.

Patterns in Hearing Loss Progressive Bilateral Loss

Overall, it is estimated that about half of all patients with progressive bilateral sensorineural deafness have a genetic cause, and of these, the majority are nonsyndromic (70 vs 30% syndromic), and the majority of these are autosomal recessive (75 vs 25% autosomal dominant). In the remaining patients, environmental factors and certain diseases may be implicated, for instance, noise-induced deafness, ototoxic drug exposure (e.g. aminoglycosides) and viral or bacterial infections. Progressive bilateral deafness is the commonest pattern of hearing loss seen in the adult population. In the majority of cases, the etiology is unknown, but because the prevalence of this type of impairment increases with age, the cause is often thought to be an age-related degeneration (“presbycusis”). Age-related deafness tends to affect the higher frequencies first, the commonest pattern of hearing loss on a pure-tone audiogram being a sloping line downward to the right, which, if severe, is sometimes referred to as a ski-slope loss. The loss of predominantly low frequency hearing is unusual, although it is associated with Meniere’s syndrome. The term Meniere’s syndrome refers to the triad of sensorineural hearing loss, tinnitus, and episodic vertigo, and has

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been associated with the pathological changes of endolymphatic hydrops in which the endolymph compartments within the inner ear are expanded relative to the perilymph compartments. Although Meniere’s syndrome often affects both ears, it does so in a varied way such that some patients will have an asymmetric loss (see the following text). Very few general diseases have a proven association with bilateral sensorineural deafness, but they include diabetes (Tay et al., 1995), Paget’s disease, and neurosyphilis. Asymmetrical Hearing Loss

In most individuals with a hearing impairment, there is no noticeable difference between the two ears. An average difference of about 15 dB between ears will be detectable by most people, and the majority of cases of asymmetric hearing loss in the population are due to a conductive deafness. The incidence in the UK population of asymmetric sensorineural deafness is about 3% (MRC NSH data). In the majority of cases, the cause of the hearing loss cannot be identified even after extensive investigations. In about 5% of cases, the deafness can be attributed either to a congenital cause, head injury, previous labyrinthitis, or noise exposure, or to ototoxic drugs. Rather surprisingly, ototoxicity from aminoglycoside drugs predominantly affects one ear in 60% of cases (Lerner et al., 1983). A small number of patients with asymmetrical sensorineural deafness will have an acoustic neuroma. This benign tumor arising from shwann cells of the vestibular nerve is more correctly termed vestibular schwannoma and accounts for 6% of all intracranial tumors. The peak incidence is in the 7th decade, with a slightly higher incidence in females compared to males in the 8th decade. The commonest presenting symptom is an asymmetric hearing loss (90%), or unilateral tinnitus (70%). As the tumor enlarges, it may compress the facial nerve or affect the trigeminal nerve resulting in some facial weakness or paresthesia. Some tumors will enlarge, so as to become life threatening, and, therefore, this is a condition that needs to be identified and treated if necessary. Age alone should not dictate whether or not a patient with appropriate symptoms is investigated. Knowledge of the diagnosis, even if no treatment is offered, may help in patient management. Once established, the most appropriate investigation of a patient with asymmetrical hearing loss is an MRI scan. Specialized audiometric investigations such as auditory brainstem responses (ABR) have a high sensitivity and specificity (over 90%) in the diagnosis of acoustic neuromas; however, the false negative rate of ABR, especially for small neuromas, is unacceptably high and approaches 17% (Wilson et al., 1997). Nevertheless, it may be useful in patients who cannot undergo MRI. CT may not detect small tumors (70 years) with type 2 diabetes are lacking. The majority of the studies conducted in older populations have involved patients of Caucasian ancestry affected by type 2 diabetes. The applicability of these results to the elderly type 1 diabetic patient or to the non-Caucasian type 2 diabetic patient remains to be assessed. However, no randomized controlled trials assessing the impact of achieving optimal glucose control on primary prevention of cardiovascular outcomes are available in the elderly diabetic patient.

Table 8 Care plan for initial management of diabetes in an elderly person

1. Establish realistic glycemic and blood pressure targets 2. Ensure consensus with patient, spouse or family, general practitioner, informal carer, community nurse, or hospital specialist 3. Define the frequency and nature of diabetes follow-up 4. Organize glycemic monitoring by patient or carer 5. Refer to social or community services as necessary 6. Provide advice on stopping smoking, increasing exercise, and decreasing alcohol intake

up to a maximum age of 74 years only. In a large proportion of older people with type 2 diabetes, excess cardiovascular risk is evident and active intervention should be considered. A summary of the therapeutic areas for intervention and the relevant evidence base is provided in Table 9, and a table indicating the main types of insulin regimes employed is given in Table 10. The treatment algorithm that should be used as a framework for glucose regulation in older people with type 2 diabetes is shown in Appendix 1. In the United Kingdom, the license for thiazolinediones (TZD) (pioglitazone and rosiglitazones) has recently been modified to allow “triple” therapy (a TZD and both a sulphonylurea and metformin to be coprescribed). Appendix 1: Algorithm for Glucose regulation based on reference – European Diabetes Working Party for Older People, 2001–2004 On the basis of these studies and interpretation of the likelihood that older people with type 2 diabetes may benefit (derived from the European Diabetes Working Party for Older People, 2001–2004), a number of major recommendations on therapy can be made.

Glucose Regulation The management of blood glucose must form part of a multifaceted approach to dealing with the metabolic disorder of type 2 diabetes in older people since most patients have evidence of other cardiovascular-risk factors and at least half are likely to satisfy the criteria for the

Recommendations The following represent some of the more important recommendations on glucose regulation taken from the European Guidelines (European Diabetes Working Party for Older People, 2001–2004): 1. At initial assessment and annually thereafter, older patients with type 2 diabetes should have a cardiovascularrisk assessment and evaluation of both microvascular and macrovascular complications. Evidence level 2++; Grade of recommendation C. Evidence in subjects older than 75 years is lacking and a lower Grade of recommendation (D) may be applicable. 2. For older patients with type 2 diabetes, with single system involvement (free of other major comorbidities), a target HbA1c (DCCT aligned) range of 6.5–7.5% and a fasting glucose range of 5–7.0 mmol l−1 should be aimed for. The precise target agreed will depend on existing cardiovascular risk, presence of microvascular complications, and ability of individual to selfmanage. 3. For frail (dependent; multisystem disease; care home residency including those with dementia) patients where the hypoglycemia risk is high and symptom control and avoidance of metabolic decompensation is paramount, the target HbA1c range should be >7.5 to ≤8.5%, and the fasting glucose range >7 to ≤9.0. 4. Glibenclamide should not be prescribed for newly diagnosed cases of type 2 diabetes in older adults (>70 years) because of the marked risk of hypoglycemia. 5. In older adults with diabetes, the use of premixed insulin and prefilled insulin pens may lead to a reduction in dosage errors and an improvement in glycemic control. 6. Where the risk of hypoglycemia is considered moderate (renal impairment, recent hospital admission) to high (previous history, frail patient with multiple comorbidities, resident of a care home) and a sulphonylurea is considered, use an agent with a lower hypoglycemic

TYPE 2 DIABETES MELLITUS IN SENIOR CITIZENS

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Table 9 Treatment targets and intervention studies for elderly diabetic patients

Blood glucose levels No specific studies in older people with diabetes

UKPDS: HbA1c 85) patients because of the presence of multiple comorbidities, high dependency levels, care home residency and/or end-stage dementia (“frailty model”) (Sinclair, 2000). In these situations, limited life expectancy or competing noncardiovascular causes for mortality (for example, cancer or infections), may mask or remove any benefit from lipid lowering and increase the likelihood of adverse drug reactions. Lipid regulation on an individual basis is required.

Initial Assessment of the Older Patient Initial assessment should include enquiry about alcohol consumption, presence or not of renal, thyroid, or liver

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disease. An estimate of the level of physical activity is important, and overweight (and obese) subjects should be encouraged to lose weight and given exercise advice relative to their capability and overall functional status. Dietary modification may be of benefit as part of a revised lifestyle plan. Assessments of total cholesterol, HDL-C, LDL-C, and triglycerides are usually required as part of the annual review process (Grade of recommendation C) and should preferably be fasting samples at the start of treatment for those with abnormal profiles. For these Guidelines, an abnormal lipid profile in older subjects can be regarded as a total cholesterol of 5.0 mmol l−1 or higher, a LDL cholesterol of 3.0 mmol l−1 or higher, or triglycerides of 2.3 mmol l−1 or higher. In general, pharmacological therapy of abnormal lipid levels should not be delayed or ignored because of the age of the individual and should be regarded as part of the routine interventions in managing older people with diabetes. In patients prescribed a statin, the clinician must always be alert to the potential side effects of treatment including reversible myositis and myopathy.

RECOMMENDATIONS Some of the principal recommendations related to the use of statins and fibrates in older people with diabetes can be summarized as follows: 1. Statin therapy is well tolerated and can be safely used in older subjects with diabetes. 2. Primary Prevention: in subjects with no history of cardiovascular disease, a statin should be offered to patients with an abnormal lipid profile if their 10-year cardiovascular risk is >15%. There is little evidence at the present time for primary preventative strategies for subjects aged greater than 80 years. 3. Secondary Prevention: a statin should be offered to patients with an abnormal lipid profile who have proven cardiovascular disease. 4. A fibrate should be considered in patients with an abnormal lipid profile who have been treated with a statin for at least 6 months but in whom the triglyceride level remains elevated (≥2.3 mmol l−1 ). 5. A fibrate should be considered in patients with proven cardiovascular disease who have isolated high triglyceride levels (≥2.3 mmol l−1 ). 6. For patients with cardiovascular disease who have persistent raised fasting triglycerides above 10 mmol l−1 , referral to a specialist lipid or diabetes clinic is recommended.

Table 12 Concerns and deficiencies in diabetes care – institutional facilities

• • • • • •

Increasing number of institutionalized diabetic elderly Lack of specialist medical follow-up Inadequate dietary care and lack of structured health professional input Lack of individualized diabetes care plans Lack of educational and training programs for care home staff No major intervention studies assessing the benefits of metabolic control and/or educational strategies • Few national standards of diabetes care

the majority of care homes with many underlying reasons accounting for this rather dismal situation. These include organizational difficulties within the institutions, lack of clarity relating to medical and nursing roles and responsibilities, funding issues, and a lack of a coherent professional framework for delivering diabetes care. Several deficiencies of diabetes care within institutional settings have been identified (see Table 12). They represent a series of concerns that highlight the need for standards of diabetes care to be established. A recent UK study highlighted problems in diabetes care delivery (Sinclair et al., 1997). This study involved a medical examination of and semistructured interview with residents with diabetes of long-term care facilities in South Wales, which revealed a prevalence of known diabetes of 7.2%. A third of residents with diabetes tested had a HbA1c >11.0%, 40% of those on oral hypoglycemic agents were taking the long-acting sulphonylureas, chlorpropamide or glibenclamide, and none of the homes had a policy in place for recording hypoglycemic events. Only 8 out of 109 diabetic residents had a specialist follow-up arranged. Other health professional input was minimal. More recently, a retrospective, cross-sectional study using the SAGE (Systematic Assessment of Geriatric Drug Use via Epidemiology) database reported that 47% of residents with diabetes were receiving no antidiabetic medication and that the presence of advanced age, being black, having a low ADL score, cognitive impairment, and a low body mass index (BMI) (7 to ≤ 9.0 mmoI/L

Target HbA1c >7.5 to ≤ 9.0%

Frail

Fasting glucose 5.0 – 7.0 mmoI−1L

Target HbA1c 6.5 – 7.5%

Single system involvement

Risk of hypoglycaemia: glibenclamide > glimepiride > gliclazide

Depending on symptom control, continue to measure HbA1c at Six monthly intervals

YES

Add in TZD or metformin (avoid metformin in patients BMI 25) for a TZD, be alert to a further deterioration in glycaemic control

NO

Measure HbA1c every 6 months

Start insulin: maintain either metformin or insulin secretagogue if transferring from combination of OADs. NB. TZDs are contraindicated with insulin

NO

Glycaemic targets achieved?

YES NO

YES

Add insulin secretagogue (usually a sulphonylurea)

NO



YES

YES



YES



Pathway B Metformin should be considered as first line monotherapy, except when renal impairment (serum creatinine > 130 µmol/I) or other contra indications are present, then choose pathway A

Choose either pathway A or B depending on clinician's choice and patient characteristics

Pathway A Consider insulin secretagogue, e.g. a sulphonylurea Metformin should be particularly avoided in patients with even mild renal impairment, dehydration, infection and heart failure.

BMI >25 ( over weight)

BMI 22 – 25 ( normal weight)

BMI 30 IU/l is generally considered to be the postmenopausal range.

THE MENOPAUSE AND THE HRT (HORMONE REPLACEMENT THERAPY) Menopause is defined as the permanent cessation of menstruation. The word menopause is derived from the greek words menos (the month) and pausos (ending). It is a retrospective diagnosis since a woman is menopausal only after 12 months of amenorrhea. The average age of menopause is 51 years and the female life expectancy is now over 80 years. Postmenopausal women spend more than 30 years in a profound estrogen-deficient state. The early symptoms of menopause are vasomotor symptoms, mainly hot flushes, night sweats, insomnia, and so on. The long-term consequences are osteoporosis, urogenital atrophy, and connective tissue atrophy.

Vasomotor symptoms There is good evidence from randomized placebo-controlled studies that estrogen is effective in treating hot flushes and

improvement is noted within four weeks (MacLennan et al., 2001). Relief of vasomotor symptoms is the commonest indication for HRT and is used for less than 5 years. It must be remembered that as old age approaches, the symptoms of the menopause appear to resolve spontaneously, though of course, the risk of osteoporosis increases.

Osteoporosis Osteoporosis has been defined by WHO as a “disease characterized by low bone mass and micro-architectural deterioration of bone tissues, leading to enhanced bone fragility and a consequent increase in fracture risk”. In postmenopausal women, there is an accelerated bone loss, so that by the age of 70 years, 50% of bone mass is lost. The risk factors for osteoporosis are family history, low body mass index (BMI), cigarette smoking, alcohol abuse, early menopause, sedentary lifestyle, corticosteroids, and so on. Fractures are the clinical consequences of osteoporosis. The most common sites of osteoporotic fractures are the distal forearm (wrist or Colles fracture), proximal femur and vertebrae. Vertebral fractures lead to loss of height and curvature of the spine with typical dorsal kyphosis (“Dowager’s hump”). This can affect their quality of life and ultimately impair the respiratory function. There is evidence from randomized controlled trials that HRT reduces the risk of osteoporotic fractures (Cauley et al., 2003; The Women’s Health Initiative Steering Committee, 2004). But recent advice from regulatory authorities has been that HRT should not be used for osteoporosis prevention as the risks of such treatment outweigh the benefits (Managing the Menopause – British Menopause Society Council, 2004). After the publication of the Million Women study in 2003, the Committee on Safety of medicines (CSM) pronounced that HRT was no longer to be considered as first line therapy for the prevention of osteoporosis. Bisphosphonates are probably the best choice for the over 60s, though there is actually less data on long-term safety.

Urogenital symptoms Symptoms such as vaginal dryness, soreness, superficial dyspareunia and urinary frequency and urgency respond well to local estrogen, in the form of pessaries, gel, and so on.

Risks of HRT Breast Cancer

HRT appears to confer a similar degree of risk as that associated with late natural menopause. In absolute terms, the excess risk in the Womens Health Initiative (WHI) study with continuous combined HRT at 50–59 years was 5; 60–69 years, 8; and 70–79 years, 13 cases of breast cancer

GYNECOLOGY AND THE OLDER PATIENT

per 10 000 women per year (Chlebowski et al., 2003). The unopposed estrogen only arm of this study did not show any evidence of an excess increase in breast cancer risk. The Million Women study found an increased risk with all HRT regimens, the greatest degree of risk was with combined HRT (Million Women Study Collaborators, 2003). So the addition of progestogen increases breast cancer risk compared with estrogen alone but this has to be balanced against the reduction in risk of endometrial cancer provided by combined therapy (Chlebowski et al., 2003; Li et al., 2003). Irrespective of the type of HRT prescribed, breast cancer risk falls after cessation of use, risk being no greater than that in women who have never been exposed to HRT by 5 years.

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Table 1 Common symptoms in the elderly

Postmenopausal bleeding Discharge per vagina Pelvic mass Prolapse Urinary incontinence Vulval soreness or itching Vulval pain

COMMON SYMPTOMS IN THE ELDERLY Older women are usually reluctant to approach their practitioners due to embarassment when they suffer from the symptoms as in Table 1.

Endometrial Cancer

Unopposed estrogen replacement therapy increases endometrial cancer risk. Most studies have shown that this excess risk is not completely eliminated with monthly sequential progestogen addition especially when continued for more than 5 years. No increase has been found with continuous combined regimens (Anderson et al., 2003). Venous Thromboembolism

HRT increases risk of venous thromboembolism (VTE) twofold with the highest risk occurring in the first year of use. Advancing age and obesity significantly increase this risk. The absolute rate increase is 1.5 VTE events per 10 000 women in 1 year. Cardiovascular Disease (Coronary Heart Disease and Stroke)

The role of HRT either in primary or secondary prevention remains uncertain and currently should not be used primarily for this indication. WHI study showed an early transient increase in coronary events. The excess absolute risk at 50–59 years was 4; 60–69 years, 9; and 70–79 years, 13 cases of stroke per 10 000 women per year. However, the timing, dose, and possibly, type of HRT may be crucial in determining cardiovascular effects. Therefore, HRT should currently not be prescribed solely for possible prevention of cardiovascular disease. The merits of long-term use of HRT need to be assessed for each woman at regular intervals. It should be targeted to the individual woman’s needs. Alzheimer’s Disease

While estrogen may delay or reduce the risk of Alzheimer’s disease, it does not seem to improve established disease. WHI study found a twofold increased risk of dementia in women receiving the particular combined estrogen and progestogen regimen. However, this risk was only significant in the group of women over the age of 75. More evidence is required before definitive advice can be given in relation to Alzheimer’s disease.

POSTMENOPAUSAL BLEEDING (PMB) Postmenopausal bleeding is defined as bleeding from the genital tract after 1 year of amenorrhea. A woman not taking hormone replacement therapy who bleeds after the menopause has a 10% risk of having a genital cancer’ (Gredmark et al., 1995). In the vast majority of cases, the cause is benign, mainly atrophic vaginitis. The causes are as in Table 2.

Diagnosis History should include the symptoms, drug history, and smear history. Examination may be difficult in an elderly patient and is further complicated by dementia, immobility, obesity, and arthritis. General examination including BMI, abdominal examination for masses, pelvic examination, both speculum and bimanual examination should be carried out.

Investigation The principal aim of investigation is to exclude the possibility of cancer. Transvaginal ultrasound measurement Table 2 Causes of postmenopausal bleeding

Atrophic

– Senile vaginitis Decubitus ulcer from a prolapse

Neoplasia – Endometrial cancer Cervical cancer, vaginal cancer Vulval cancer, estrogen-secreting tumors, ovarian tumors Fallopian tube cancer, secondary deposits Endometrial polyps Iatrogenic – Bleeding on HRT Bleeding on tamoxifen Ring, shelf pessary Infection – Vaginal, endometrial Others – Hematuria, rectal bleeding, trauma, foreign body

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of endometrial thickness will help in directing the need for an endometrial biopsy. An endometrial thickness of less than 5 mm is reassuring that the cavity is empty. The myometrium and ovaries can also be visualized for evidence of tumors. Investigation should also include a smear. Hysteroscopy is now the “gold standard” investigation for postmenopausal bleeding. The procedure can be carried out under general anesthetic or as an outpatient, although cervical stenosis associated with atrophic change may cause failures. It is mandatory for recurrent bleeding, and cystoscopy and sigmoidoscopy may be necessary if there is any doubt about the source of the bleeding.

Classification Anterior vaginal wall prolapse Urethrocele – Urethral descent Cystocele – Bladder descent Cystourethrocele – Descent of bladder and urethra Posterior vaginal wall prolapse Rectocele – Rectal descent Enterocele – Small bowel Apical vaginal prolapse Uterovaginal – Uterine descent with inversion of vaginal apex Vault – Posthysterectomy inversion of vaginal apex

Treatment Treatment depends on the cause. If atrophic vaginitis, treatment is by local estrogen therapy. If any carcinoma, management is usually centralized in cancer units staffed by experienced gynecological oncologists.

DISCHARGE PER VAGINA Vaginal discharge is a common gynecological complaint seen in the elderly. The causes are as in Table 3. Owing to the loss of vaginal tissue elasticity and shrinkage of the vagina, atrophic vaginitis is very common. Infective vaginitis is also common due to colonization by pathogenic bacteria when the vaginal pH shifts from acid to alkali.

UTEROVAGINAL PROLAPSE Uterovaginal prolapse is a herniation of the female genital tract. It is extremely common with an estimated 11% of women undergoing at least one operation for this condition. The factors responsible for the development of prolapse are weakening of fascia and muscle support following the menopause and damage occurring during childbirth. Raised intra-abdominal pressure from an abdominal mass or cough is a contributory factor in some women as is congenital or postoperative weakness. Uterovaginal prolapse is commonly associated with urinary incontinence. Table 3 Causes of discharge per vagina

Atrophic

– Postmenopausal vaginitis

Infective

– Bacterial vaginosis, candida, trichomoniasis.

Tumors

– Cervical polyp, intrauterine polyp Cervical cancer, endometrial cancer, Fallopian tube cancer – rare

Fistulae

– Vesicovaginal fistula, rectovaginal fistula

Pyometra

– associated with carcinoma of the endometrium

Others

– Foreign body, pessary

Diagnosis Most commonly, the presenting symptom is a feeling of a lump coming down the vagina. They also present with a dragging or bearing down sensation of gradual onset which is worse with activity and settles with rest. A minor prolapse may become symptomatic in the presence of marked atrophic vaginitis. Trophic ulceration may occur with discharge and bleeding. Urinary symptoms such as frequency, urgency, incontinence, incomplete, or slow emptying result from distortion of the prolapsed bladder and urethra. Digital replacement of the anterior or posterior vaginal wall is sometimes necessary before micturition or defecation respectively. A detailed obstetric history and sexual history to ascertain whether they are sexually active is important to decide the treatment. Also, a medical history like constipation, cough, and any major medical illness should be ruled out. A detailed social history is also important. General examination: To assess if surgery is safe, to check BMI, and cardiorespiratory system examination. Abdominal examination: Looking for pelvic masses. Pelvic examination: Prolapse may be obvious when examining the patient in the dorsal position if it protrudes beyond the introitus, ulceration, and/or atrophy may be apparent. The anterior and posterior vaginal walls and cervical descent should be assessed with the patient in the left lateral position, using a firm Sims speculum. Combined rectal and vaginal digital examination can be an aid to differentiate rectocele from enterocele. Vaginal examination should be performed and pelvic mass excluded. Urine culture and sensitivity, cystometry, and cystoscopy to be considered when symptoms include both stress and urge incontinence and especially prior to consideration of surgery.

Management The management of prolapse depends on the severity of symptoms, the degree of incapacity and the patient’s


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operative fitness. Operative treatment by repair of prolapse with or without vaginal hysterectomy is most effective. Obesity, heavy smoking, and constipation require improvement before surgery. Most patients tolerate surgery very well because of improved anesthetics and minimal postoperative morbidity. When such surgery is undertaken in an older woman, it is important to ascertain the level of sexual activity as this will influence the degree of narrowing achieved by surgery. Age per se is not a contraindication to surgery. Medical disorders develop with advanced age and these dictate any reasons for avoiding anesthesia. When surgery is contraindicated or declined, conservative methods may be used. A polyvinyl ring pessary will be successful, providing there is adequate perineum to retain the pessary. Some patients, particularly those with large prolapses and very little perineum, may do better with a shelf pessary. Either type needs changing at 4–6 months interval and the vagina should be inspected to ensure no ulceration has occurred. If ulceration occurs, the pessary should be removed for a few weeks and local estrogen used daily to allow epithelial healing.

and this is common in the early postmenopausal years. In many women, the two conditions exist together.

Physiotherapy: Pelvic floor exercises are useful for the prevention and improvement of incontinence. But they require good patient motivation. Physiotherapy may improve symptoms from a small prolapse but it is unlikely to help with more degree of herniation.

Genuine Stress Incontinence (GSI)

URINARY INCONTINENCE Urinary Incontinence is defined as the involuntary loss of urine that is objectively demonstrable and is a social or hygiene problem. The causes are as in Table 4. The prevalence increases with age, with approximately 10% of those aged between 45 and 64 years of age being affected, rising to 20% of those greater than 65 years. It is even higher in women who are institutionalized and may affect up to 40% of those in residential nursing homes. This places huge financial demands on health resources, with 2% of the total budget being spent on incontinence services alone. Many women will not seek advice because of embarrassment. Uninhibited detrusor muscle contractions are usually the cause in geriatric patients owing to age-related changes in the central nervous system. Genuine stress incontinence (GSI) occurs when the bladder pressure exceeds the maximum urethral pressure in the absence of any detrusor contraction Table 4 Causes of urinary incontinence

1. Genuine/urodynamic stress incontinence – Bladder neck hypermobility, urethral sphincter weakness 2. Detrusor instability – Idiopathic, secondary to neurological disease – hyperreflexia 3. Retention with overflow – motor neurone lesions, drugs, pelvic mass, severe prolapse 4. Fistulae – Ureteric, vesical, urethral 5. Miscellaneous – Urinary infection

Assessment A good history will help to differentiate GSI from detrusor instability to some extent. Examination to rule out any associated prolapse or pelvic mass should be carried out in these patients. Urodynamic studies are necessary to confirm the diagnosis, especially prior to any surgical treatment.

Management Simple measures like exclusion of urinary tract infection, restriction of fluid intake, modifying medication like diuretics when possible play an important role in the management of urinary incontinence.

Conservative management : The treatment of GSI should be nonoperative initially, and the best results for mild/ moderate leakage are with pelvic floor exercises. The rationale behind pelvic floor education is the reinforcement of cortical awareness of the levator ani muscle group, hypertrophy of existing fibers and a general increase in muscle tone and strength. Motivation and good compliance are the key factors associated with success. Local estrogen therapy may have a small effect by improving the urethral mucosa in women with estrogen deficiency. Surgical Management – the Aims of Surgery: • Restoration of the proximal urethra and bladder neck to the zone of intra-abdominal pressure transmission • To increase urethral resistance. The procedures are Burch’s colposuspension, transvaginal tape (TVT), periurethral bulking using collagen, macroplastique.

Detrusor Instability (DI) DI can be treated by bladder retraining and biofeedback, all of which tend to increase the interval between voids and inhibit the symptoms of urgency. Drug treatment is mainly by Anticholinergics like Oxybutynin, Tolteridine, Regurin combined with local estrogen.

SEXUALITY AND OLD AGE In the past, it was mistakenly assumed that a woman well past the menopause will not be sexually active. In

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1953, Kinsey et al. described reduced sexual activity in elderly women. In this group of women, orgasm was more likely to be achieved by masturbation than by coitus (Kinsey et al., 1953). In fact, sexual drive is not exhausted with aging, and as life expectancy increases, it is necessary to recognize that continued sexual activity is an important requirement to promote satisfactory relationships, personal well-being and quality of life (Brown and Cooper, 2003). Many older people were grown up in sexually restricted times so that ignorance is widespread. The organization of institutions for elderly people does not recognize their sexuality, so their needs are ignored (White, 1982). It has been proved that sexual activity remains relatively constant within a stable relationship and declines only following death or illness of the partner (George and Weiler, 1981).

sexual desire. Disfiguring and mutilating operations, especially of the breasts, genitals and reproductive organs, often have a deleterious effect on a woman’s self image and sexuality. Dyspareunia can be a major problem, not only because of lack of arousal or secondary vaginismus after surgery but also because of the amount of scar tissue within the pelvis. Women who have a stoma-like colostomy or ileostomy also experience psychological problems. Patients’ greatest fears are loss of control, bad odor, noise, leaking bags, and their partner’s feelings toward them. Healthy adaptation to a stoma depends on preoperative and postoperative counseling and understanding by stoma nurses.

Management

In the elderly, the changes of vasocongestion, pudendal swelling, and vaginal lubrication are reduced and delayed, and resolution occurs more rapidly. Also, vaginal lubrication diminishes and there is less vaginal elasticity leading to shrinkage of the vagina. Coital trauma to the vagina and urethra causes dyspareunia, dysuria, and postmenopausal bleeding. Lesions of the vulva like lichen sclerosus (LS) and surgical scarring may make intercourse impossible for some older women.

A detailed sexual history including the problem, the duration, the couple’s past life together and emotional relationship should be taken. Early experiences, difficulties with previous partner and any episode of sexual assault is also important. Examination should aim to look for a physical cause of the sexual problem. Behavioral techniques play an important part in the management of sexual dysfunction. Ignorance about sexuality is common. Changing negative attitudes resulting from past experiences, parental or religious influences will help. Talking to each other about sexual anxieties or needs, and discussion with a therapist increases their mutual understanding and ability to communicate.

Health Factors that Inhibit Sexual Activity in Elderly People

Psychological Therapy

Sexual Response and Aging

Physical factors • • • • • • •

Stress incontinence Diminishing mobility Decreasing muscle tone Uterine prolapse Skin tone and sensitivity Diseases like diabetes and cardiovascular problems Chronic conditions like arthritis.

Psychological factors • Sense of unattractiveness • Facing mortality; depression, bereavement, and grief reactions • Loss of partner or friends • Lack of contact with others and loneliness.

Effect of Chronic Illness and Surgery on Sexuality Chronic urological and gynecological conditions causing pain on intercourse, chronic anxiety and stress, neurological disorders, depression and fatigue can result in loss of

The psychological approaches include giving accurate information, general counseling, psychosexual therapy, behavioral therapy, sexual and relationship therapy. Before any operation, it is essential to discuss with the woman, preferably with her partner, the full implications of the operation on their sexual life. This helps to minimize sexual dysfunction after the operation.

Pharmacological Therapy There is now evidence from randomized controlled studies that testosterone therapy improves sexual satisfaction and mood in surgically menopausal women treated with concurrent estrogen (Burger et al., 1987; Davis et al., 2003). However, long-term safety data for combined estrogentestosterone therapy are lacking, and the effects of testosterone-only therapy on such factors as plasma lipids in postmenopausal women are unknown. The use of appropriate creams to help with vaginal soreness – such as estrogen cream, KY Jelly, or aromatic oils may enable a woman and her partner to enjoy sexual activity much more fully.


VULVAL DISORDERS As the lower genital tract undergoes atrophic changes, the labia majora lose their fat and elastic tissue content and become smaller. The vulval epithelium becomes thin, leading to vulval irritation. Other symptoms are itching and soreness. The conditions affecting the vulva can be a part of a more widespread problem, such as psoriasis or conditions specific to the vulva. Vulval disorders are important because of the chronicity and severity of symptoms and the association with carcinoma. The common vulval disorders are as follows: 1. 2. 3. 4.

Lichen sclerosus Squamous cell hyperplasia Other dematoses Vulvodynia or chronic vulval pain.

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is common in elderly women. The etiology is uncertain but psychological and physical factors play a role. Depression is also a compounding factor. Treatment initially is empirical using topical steroids, anesthetic and estrogen cream. The use of antidepressants should be considered. A multidisciplinary approach involving specialists in dermatology, pain relief, psychiatry, and gynecology is essential for intractable cases.

GYNECOLOGICAL CANCER The most common types of gynecological malignancies are cervical cancer, ovarian cancer, endometrial cancer, and vulval cancer. Occasionally, skin cancers or sarcomas can also be found in the female genitalia.

Lichen Sclerosus (LS)

Cervical Cancer

LS is a chronic skin condition characterized by the thinning of the epithelium with loss of keratin which frequently extends around the anus. The etiology is uncertain, but there is an association with genetic and hormonal factors and autoimmune disease (Meyrick et al., 1988). The clinical signs include pale ivory white plaques often with a crinkly atrophic surface, purpura, and scarring with gradual destruction of the normal vulval architecture. Complications include narrowing of the introitus and rarely squamous cell carcinoma. Punch biopsies should be taken of any suspicious areas. Squamous cell carcinoma is more likely when there is ulceration, raised lesions or lymph node involvement. The most effective treatment is to use topical steroid ointment clobetasol propionate 0.05% plus a soap substitute.

Worldwide, cervical cancer is the most common gynecological malignancy. The etiological factors include multiple sexual partners, early age of coitus, human papilloma virus (HPV) 16 and 18 infection. In developed countries, there is an overall decline in incidence and mortality from cervical cancer as a result of the cervical screening program. There is a defined premalignant stage, namely, cervical intraepithelial neoplasia – CIN1, CIN2 and CIN3. Screening for cervical cancer is by cervical smear. Liquid-based cytology and HPV testing are new developments taking place in this field. Abnormal cytological findings are an indication for further investigation by colposcopy and if necessary, directed biopsies or excision biopsy. Approximately 500 000 new cases of cervical cancer are diagnosed each year in the world with 80% of these occurring in the less developed world (Cancer Statistics, 2003). More than 80% of cervical cancers are squamous cell carcinomas. The presenting symptoms are postcoital bleeding, vaginal discharge, or postmenopausal bleeding. Pain is experienced late and is due to pelvic infiltration or bony metastases. The first sign of this cancer may be obstructive renal failure from hydronephrosis due to advanced disease. On inspection, cancer of the cervix presents as an ulcer, growth, or a friable warty looking mass which bleeds on touch. As the carcinoma progresses, the mobility of the cervix is affected and the cervix eventually becomes fixed. Diagnosis is by biopsy of suspicious areas, preferably under general anesthesia so that clinical staging can be done. Treatment for clinical invasive carcinoma of the cervix is by surgery, chemoradiotherapy or a combination of all three. The management of gynecological cancer patients is now mostly centralized in units staffed by gynecological oncologists, so that all the treatment modalities can be offered to patients. If the disease is in an early stage confined to the cervix, then either surgery or radiotherapy may be offered since the prognosis is equally good for both. Surgery is by radical hysterectomy and pelvic node dissection, that is, Wertheim’s hysterectomy. In the elderly, radiotherapy is usually offered because of the fear of

Squamous Cell Hyperplasia The skin is usually reddened with exaggerated folds. In certain areas, after rubbing, lichenification can be seen. The term squamous cell hyperplasia is applied for those women who have histological evidence for the cause.

Other Dermatoses The most common general diseases causing vulval itching or discomfort are diabetes, uraemia, and liver failure. Other causes are allergic dermatitis caused by irritants like perfumed soap, washing powder, and so on. General skin diseases like psoriasis, lichen planus, and scabies may also affect the vulva.

Vulvodynia (Vulval Pain) Vulvodynia is defined as chronic pain, discomfort or burning in the absence of a relevant skin condition. This condition

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surgical complications. However, a fit patient will tolerate the procedure well and age by itself should be no bar to surgery. If the disease is in a late stage, then chemo-radiotherapy is the treatment of choice. In an unfit patient with advanced disease, palliative care may be the only option.

CT scan. Solid areas within an ovarian cyst and ascites are strongly suggestive of malignancy. The final diagnosis is by laparotomy.

Management Endometrial Cancer Carcinoma of the endometrium is considered as the gynecological cancer with a relatively favorable prognosis because of its early presentation with postmenopausal bleeding. The median age of patients with endometrial cancer is 61 years, with 80% of women being postmenopausal. The risk factors are obesity, diabetes mellitus, hypertension, nulliparity, late menopause, unopposed estrogen therapy and prior history of polycystic ovary syndrome. The presenting symptom in the elderly is almost always postmenopausal bleeding. Late diagnosis include pain and discharge from a pyometra. The diagnosis is by transvaginal ultrasound determination of endometrial thickness and outpatient endometrial biopsy. Outpatient hysteroscopy also may be undertaken, but if there is cervical stenosis, then hysteroscopy should be done under general anesthesia. Early disease is treated by total abdominal hysterectomy and bilateral salpingo-oophorectomy. In a poorly differentiated tumor or if the myometrium is involved beyond the inner third, postoperative radiotherapy is given. Advanced cancers are treated with radiotherapy. Progestational agents are used for recurrent disease to control vaginal bleeding and to reduce the pain from bony metastases.

The mainstay of treatment is by debulking of the tumor with bilateral salpingo-oophorectomy, total hysterectomy, and omentectomy. Postoperative chemotherapy is used in all but early stages and indeed many patients will have residual disease after surgery. Taxol and Carboplatin are the chemotherapeutic agents of choice. Radiotherapy is limited to patients with symptomatic recurrence and is used only for palliation.

Vulval Cancer Vulval cancer is a less common cancer and is most frequently seen in the 60–70 year age-group. The presenting symptoms are soreness, pruritus, irritation, ulceration, lump, or bleeding. Many women present very late because of embarrassment. Ninety-five percent of vulval carcinomas are squamous cell carcinomas, but basal cell carcinoma, malignant melanoma and adenocarcinoma of the Bartholin’s gland may occur rarely. Diagnosis can be confirmed only by vulval biopsy.

Management Ovarian Cancer Carcinoma of the ovary is common in developed countries. The peak incidence is in the 50–70 year age-group. Ovarian cancer remains the most lethal gynecological malignancy despite trials of many different treatment regimens to try to improve the poor prognosis. Most women present with advanced disease. There is no satisfactory screening method for ovarian neoplasia, but women with a family history of breast or ovarian cancer should be offered regular ultrasonic assessment and measurement of the tumor marker, Ca 125. This test is not sensitive or specific enough to be applied to the general population. 90% of ovarian carcinomas in older women are epithelial adenocarcinomas, but sex cord and germ cell tumors may also be seen in this age-group. Also, metastases may be seen from elsewhere, particularly colon and breast. Granulosa cell tumor is the most common sex cord tumor. This produces estrogen which can cause postmenopausal bleeding due to the resulting endometrial hyperplasia. The presenting symptoms are often vague including abdominal discomfort, swelling, malaise, and weight loss. Later symptoms include abdominal pain and distension, ascites, and pleural effusion. Investigations include hematological, biochemical, imaging techniques like ultrasound and

Radical vulvectomy with bilateral groin node dissection is the treatment of choice. The common complications are wound breakdown and infection. The primary tumor is resected and separate groin node dissections are performed to improve wound healing and reduce infection. The other complications are deep vein thrombosis, osteitis pubis, secondary hemorrhage, and so on. For patients unfit for surgery, wide excision of the lesion may be used as palliation. Pelvic irradiation is available for extensive nodal involvement.

HIV AND OLD AGE The majority of those infected and affected by HIV are younger adults. The ability of highly active antiretroviral therapies (HAART) to extend survival means that those infected when younger may reach older age and so an increase in numbers of older individuals living with HIV is expected. There is evidence that older individuals engage in risky sexual behaviors and are drug users, suggesting potential for HIV transmission (Dougan et al., 2004). For older women after menopause, condom use becomes unimportant, and normal aging changes such as a decrease in vaginal lubrication and thinning vaginal walls


can put them at higher risk during unprotected sexual intercourse. Doctors may not discuss with their older patients about HIV/AIDS because they do not think they are at risk or they presume symptoms to be age related. As a result, many older people are diagnosed at a later stage in their infection, and many have an AIDS diagnosis the first time they become aware of their HIV infection. Older people are more likely to be diagnosed with HIV at a generally higher viral load and lower CD4+ cell count, making them more susceptible to opportunistic infections. More aggressive therapy may be required to successfully suppress the virus. Data from the Center for Disease Control (CDC) HIV/ AIDS surveillance report showed that 11% of all AIDS cases reported in 1999 were among people aged 50 and above (Centre for Disease Control, 1998). This percentage has remained stable since 1991. However, the CDC notes an alarming trend in that older AIDS patients had a greater increase in opportunistic infections than did younger AIDS patients. The report also says a higher proportion of people aged 50 and above died within 1 month of AIDS diagnosis. These deaths can be attributed to original misdiagnosis and immune systems that naturally weaken with age. These statistics seem to confirm the idea that older adults are naive about their risk of contracting HIV and their providers aren’t discussing that risk with them. A 1997 study of Texas doctors found that most physicians rarely or never discussed HIV and risk factors with their older patients (Skiest and Keiser, 1997). Compounding the problem, AIDS symptoms often are more difficult to diagnose in older people because they mimic some common diseases associated with old age. Because of the stigma, it can be difficult for women to disclose their HIV status to family, friends, and their community. For these reasons, physicians should keep HIV in mind as a possibility, even with their older patients. HIV experts recommend that physicians routinely ask all patients about their sexual behaviors during the annual physical or gynecological examination. Providers should educate the population over 50 years about possible exposures to HIV and safer sex practices.

CONCLUSION Gynecology for the elderly patient includes the whole spectrum of gynecological disorders of which cancer, prolapse, urinary incontinence, and the problems of late menopause are the most important ones. The advice given for such women changes with each decade. Of particular note is our increasing reluctance to give long-term HRT and our increasing likelihood of undertaking surgery in women who are healthy despite their age. Many women, through fear and embarrassment avoid telling their problems to general practitioners, geriatricians, or gynecologists and so present with long standing disease.

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KEY POINTS • The female aging process is unique in that it represents a combination of the aging processes and hormone deficiency. • Managing the menopause should be targeted to individual women’s needs. Hormone replacement still offers the potential for benefit to outweigh the harm, provided the appropriate regimen has been instigated in terms of dose, route, and combination. • Age per se should not be a contraindication to surgical management for any gynecological problem. • There is no age limit for the expression of sexuality. The management of sexual problems should be guided by the same principles irrespective of age and condition of the patient. • Older women, out of fear and embarrassment neglect early symptoms of gynecological diseases, some of which are potentially lethal.

KEY REFERENCES • Brown ADG & Cooper TK. Gynaecological Disorders. Geriatric Medicine: Women’s health Section 2, chapter 90, 2003, pp 1135 – 44, Churchill Livingstone. • Dening T & Barapatre C. Mental health and the ageing population. The Journal of the British Menopause Society 2004; 10:49 – 53. • Managing the Menopause – British Menopause Society Council. Consensus Statement on Hormone Replacement Therapy, June 2004. • Million Women Study Collaborators. Breast cancer and hormone replacement therapy in the Million Women Study. Lancet 2003; 362:419 – 27. • Stanton SL. Gynaecology in the elderly. Gynaecology 1997, 2nd edn, pp 915 – 9; Churchill Livingstone.

REFERENCES Anderson GL, Judd HL, Kaunitz AM et al., Women’s Health Initiative Investigators. Effects of estrogen plus progestin on gynaecologic cancer and associated diagnostic procedures: the Women’s Health Initiative randomised trial. The Journal of the American Medical Association 2003; 290:1739 – 48. Brown ADG & Cooper TK. Gynaecological Disorders. Geriatric Medicine: Women’s health Section 2, Chapter 90, 2003, pp 1135 – 44, Churchill Livingstone. Burger HG, Hailes J, Nelson J & Menelaus M. Effect of combined implants of oestradiol and testosterone on libido in postmenopausal women. British Medical Journal 1987; 294:936 – 7. Cancer Statistics. Cervical Cancer-UK January 2003; Cancer Research UK, London. Cauley JA, Robbins J, Chen Z et al., Women’s Health Initiative Investigators. Effects of estrogen plus progestin on risk of fracture and bone mineral density: the Women’s Health Initiative randomised trial. The Journal of the American Medical Association 2003; 290:1729 – 38. Centre for Disease Control. AIDS among persons aged greater than or equal to 50 years- United States, 1991 – 1996. Morbidity and Mortality Weekly Report 1998; 47:21 – 7.

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Chlebowski RT, Hendrix SL, Langer RD et al. Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women. The Women’s Health Initiative randomised trial. The Journal of the American Medical Association 2003; 289:3243 – 53. Dantas A, Kasviki-Charvati P, Papanawiotou P & Marketos S. Bacteriuria and survival in old age. The New England Journal of Medicine 1981; 304:939 – 43. Davis S, Rees M, Ribot J & Moufarege A. Efficacy and safety of testosterone patches for the treatment of low sexual desire in surgically menopausal women. 59th Annual Meeting of the American Society for Reproductive Medicine, San Antonio, 11 – 15th October 2003. Dening T & Barapatre C. Mental health and the ageing population. The Journal of the British Menopause Society 2004; 10:49 – 53. Dougan S, Payne LJ, Brown AE et al. Past it? HIV and older people in England, Wales and Northern Ireland. Epidemiology and Infection 2004; 132(6):1151 – 60. George L & Weiler SJ. Sexuality in middle and late life. Archives of General Psychiatry 1981; 38:919 – 23. Gredmark T, Kvint S, Havel G & Mattsson L-A. Histopathological findings in women with postmenopausal bleeding. British Journal of Obstetrics & Gynaecology 1995; 102:133 – 6. Kinsey AC, Pomeroy WB, Martin CE & Gebhard PH. Sexual Behaviour in the Human Female 1953, WB Saunders, Philadelphia. Li CI, Malone KE, Porter PL et al. Relationship between long durations and different regimens of hormone replacement therapy and risk of

breast cancer. The Journal of the American Medical Association 2003; 289:3254 – 63. MacLennan A, Lester S & Moore V. Oral oestrogen replacement therapy versus placebo for hot flushes. Cochrane Database of Systematic Reviews 2001; 1:CD002978. Managing the Menopause – British Menopause Society Council. Consensus Statement on Hormone Replacement Therapy, June 2004. Meyrick TRH, Ridley CM, McGibbon DH et al. Lichen sclerosis et atrophicus and autoimmunity; a study of 350 women. The British Journal of Dermatology 1988; 118:41 – 6. Million Women Study Collaborators. Breast cancer and hormone replacement therapy in the Million Women Study. Lancet 2003; 362:419 – 27. Skiest DJ & Keiser P. Human immunodeficiency virus infection in patients older than 50 years. A survey of primary care physicians’ beliefs, practices, and knowledge. Archives of Family Medicine 1997; 6:289 – 94. Stanton SL. Gynaecology in the elderly. Gynaecology 1997, 2nd edn, pp 915 – 9; Churchill Livingstone. The Women’s Health Initiative Steering Committee. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomised controlled trial. The Journal of the American Medical Association 2004; 291:1701 – 12. White CB. Sexual interest, attitudes, knowledge and sexual history in relation to sexual behaviour in the institutionalised aged. Archives of Sexual Behavior 1982; 11:11 – 22.

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The Aging Bladder James M. Cummings and Kimberly C. Berni Saint Louis University, St Louis, MO, USA

INTRODUCTION The increase in human life expectancy unmasked a variety of genitourinary complaints. Most physicians are familiar with lower urinary tract symptoms (LUTS) suffered by the aging male related to prostatic enlargement. Equally debilitating though are bladder symptoms found in both sexes totally unrelated to obstruction of any kind. Symptoms of frequency, urgency and urge incontinence, commonly lumped together under the term “overactive bladder” are very prevalent in the aging patient and confront the physicians who care for them on a daily basis. A multitude of other influences on the bladder also exist that affect its performance over a lifetime. Certainly, injury from infection or surgery can affect vesical function over both long and short-term horizons. Changes in the bladder outlet via prostatic obstruction in males or overzealous surgery in women can have effects ranging from mild to devastating, on detrusor function. Alterations in the neurological milieu of the lower urinary tract can profoundly alter bladder function. These variations, when severe enough, can not only create difficult symptomatology for the patient but can also occasionally be detrimental to renal function. In this chapter, we hope to examine the aging bladder from a number of angles. The alterations in vesical anatomy, both gross and microscopic, are important in dysfunctional voiding and incontinence associated with aging. Neuronal and hormonal changes influence the aging bladder. Pharmaceutical agents are under intense scrutiny as to their effect in the urinary tract as well as their side effects in the elderly patient. Finally, special disease states found mostly in the older population have specific effects on the urinary tract that must be considered in the overall therapy for those diseases.

ANATOMY OF THE AGING BLADDER The normal bladder is characterized grossly by its pelvic position in the adult. In the older male, the macroscopic

anatomy of the bladder is most commonly affected by the growth of the prostate gland. Although most commonly, benign prostate growth occurs in the transition zone surrounding the urethra, occasionally this growth becomes unrestrained in a cephalad manner and pushes the trigone superiorly to give the bladder an elevated appearance radiographically. Gross inspection of the bladder interior often demonstrates a trabeculated appearance (Cockett et al., 1992). Trabeculations are often thought to be a sign of chronic obstruction in males, but have been observed in the female bladder as well (Groutz et al., 2001). In women, the anatomical position of the bladder is most often altered by defects in the pelvic floor musculature. This leads to the presentation of cystoceles, effectively a herniation of the bladder through the anterior vaginal muscle layers. This defect, as well as rectoceles and enteroceles are commonly noted in parous individuals, although the impact of aging, obesity, and possibly, neurological dysfunction can be substantial (Pinho et al., 1990; Constantinou et al., 2002; Cummings and Rodning, 2000; Bakas et al., 2001). Perucchini has demonstrated localized striated urethral muscle loss with aging at the bladder neck and dorsal wall of the urethra (Perucchini et al., 2002). Others have shown an increase in paraurethral connective tissue in elderly females with a reduction of blood vessels (Verelst et al., 2002). Falconer has demonstrated altered collagen production in women with stress incontinence with poor quality collagen seen in postmenopausal women possibly contributing to disorders related to prolapse in the elderly (Falconer et al., 1994, 1996). The histologic appearance of the aging bladder can give clues about its ultimate ability to function as a storage facility for urine. Ultrastructural changes in the aging bladder include collagen deposition, muscle degeneration, and axonal degeneration (Elbadawi et al., 1993). The degree of these changes may correlate with specific abnormalities in voiding and incontinence such as detrusor overactivity and impaired contractility (Elbadawi, 1995). Chronic ischemia of the bladder may play a large causative role in these changes (Azadzoi et al., 1999a,b).


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MEDICINE IN OLD AGE Table 1 Anatomical changes of the aging bladder

Gross anatomical changes Trabeculations Cystocele (females) Muscle loss at bladder neck (females) Histologic changes Collagen deposition Muscle degeneration Axonal degeneration

Surgical procedures in both sexes can alter vesical anatomy. In females with pelvic prolapse and/or stress incontinence, certainly operations can successfully reposition the bladder and other pelvic organs toward normalcy. They also can cause difficulties if, for example, bladder neck prolapse is overcorrected and obstruction occurs. Certain women will suffer urgency and frequency symptoms even if no obstruction is present (Dunn et al., 2004). In males, relief of obstruction at the level of the prostate may improve symptoms but changes in bladder configuration may not occur at the same rapid rate seen in symptom reduction. Furthermore, radical prostatectomy in the man with prostate cancer may alter bladder dynamics as well as cause sphincteric incontinence (Sebesta et al., 2002). The anatomical changes of the aging bladder are summarized in Table 1.

BLADDER PHYSIOLOGY AND CORRELATION TO ANATOMY OF THE AGING BLADDER Bladder function involves both the storage of urine and the expulsion of urine at a socially appropriate time. To maintain continence, the storage of urine must occur under low pressures and the bladder must empty adequately. Unfortunately, aging results in changes that occur intrinsically and extrinsically to the bladder that affect continence and emptying. Pathologic changes are seen in the bladder because of aging. In addition, nerve transmission can be altered because of age, disease states, surgical procedures, or drugs. Anatomic obstruction or lack of adequate support of the bladder neck also changes the ability of the bladder to empty and store urine. The bladder consists of two parts: the body and the base or bladder neck. The smooth muscle fibers of the body are arranged randomly and those of the bladder neck are arranged in an inner longitudinal and outer circular layer. In the male urethra, the sphincter consists of both smooth muscles and striated muscles. The external sphincter consists of the periurethral striated muscle and the intramural striated muscle or rhabdosphincter. In the female, these muscles are attenuated. DeLancey proposes that female continence is created by a combination of muscular coaptation and passive compression of the urethra by the pubourethral hammock (DeLancey, 1989). During urine storage, low level afferent bladder stimulation signals sympathetic contraction of the bladder neck and

relaxation of the detrusor muscle or body of the bladder. This results in storage of urine under low pressure. The voiding reflex is initiated when afferent activity becomes intense. The pontine micturition center stimulates the parasympathetic pathway and inhibits the sympathetic pathway resulting in relaxation of the bladder outlet and contraction of the detrusor muscle and thus bladder emptying. The striated external sphincter, which has separate innervation from the bladder neck, is also influenced by the pontine micturition and storage centers. The voiding reflex results in inhibition of the external sphincter and the storage reflex results in activation of the pudendal nerve. The bladder must be able to distend and contract adequately, for proper functioning. Structural changes in the tissues and abnormalities in bladder shape can alter urine storage and emptying. Bladder compliance is a measurable value defined as the change in volume divided by the change in intravesical pressure. A normally functioning bladder fills under a low pressure; therefore the bladder is compliant. Compliance is greatly affected by tissue composition, innervation, and vascular supply. Histologic studies have shown that as collagen levels increase, compliance is lost (Macarak and Howard, 1999). Landau demonstrated that in bladders with poor compliance, the ratio of Type III to Type I collagen was significantly higher than that of normal bladders (Landau et al., 1994). The aged bladder has a higher deposition of collagen; in addition, innervation of the detrusor smooth muscle changes with age. Neurochemical studies of human detrusor strips have shown an increase in purinergic neurotransmission and a decrease in cholinergic neurotransmission with age. It is felt that the shift in neurochemical transmission may change the resting tone of the bladder and contribute to the overactive bladder symptoms in aged bladders (Yoshida et al., 2004). Bladder wall blood flow is affected by intramural tension. A bladder with poor compliance has increased intravesical pressure and intramural tension, and therefore, a greater decrease in bladder blood flow (Ohnishi et al., 1994). Ischemia can result in diminished contractility and patchy denervation (Van Arsdalen et al., 1983). The end result is a bladder that empties inadequately and may have detrusor instability (Brading, 1997). Injured areas of the bladder can become weak and form diverticulum, resulting in ineffective bladder emptying. The complexity of voiding dysfunction in the aged bladder makes it difficult to distinguish between the changes in the bladder that are secondary to the normal aging process and changes as a result of bladder outlet obstruction, or changes caused by diseases affecting the nervous system and/or vascular supply. Certainly, the LUTS of obstruction, instability, and impaired detrusor function often overlap. The changes seen in bladder function with aging must certainly overlap as well. A study by Homma found the symptoms of urgency, frequency, and nocturia increased with age in both men and women. The cystometric capacity declined with age in both sexes (Homma et al., 1994). Histologic changes in the aged bladder have been documented, including increased collagen deposition, widened

THE AGING BLADDER

spaces between muscle fibers, and ultrastructural changes of the smooth muscle cell membrane (Levy and Wight, 1990; Elbadawi et al., 1993). Elbadawi et al. showed that aged bladders without urodynamic evidence of obstruction had muscle cell membranes with dominant dense bands and depleted caveolae (Elbadawi et al., 1993). These findings were reproducible and different from the ultrastructural changes seen with obstructed, overactive or hypocontractile bladders (Hailemariam et al., 1997). These findings are thought to represent dedifferentiation of the smooth muscle fibers. Changes in bladder compliance, nerve transmission, and vascularity, occur as the bladder ages. Certainly, multiple disease processes may worsen these changes. With advanced age, the expected bladder symptoms might include increasing frequency and urgency with a decreased bladder capacity.

SPECIAL DISEASE STATES Several disease states especially affect the bladder in the geriatric population. Irrespective of whether it is caused by neurological disease, endocrine problems, iatrogenic intervention, or the aging process itself, these problems exact a particular morbidity on the lower genitourinary tract. The following conditions are particularly important.

Parkinson’s Disease Parkinson’s disease affects 1% of all patients over the age of 60 and is rarely seen in those under 40. In addition to the characteristic tremors and motion deficits, the loss of dopaminergic neurons in the substantia nigra of the basal ganglia affects voiding by reducing the inhibitory effect of the basal ganglia on the micturition reflex as demonstrated in several animal studies (Albanese et al., 1988; Yoshimura et al., 1992). The voiding symptoms of Parkinson’s disease are frequency, urgency, and urge incontinence. These irritative symptoms are present in well over half of all patients with the disorder (Pavlakis et al., 1983). A significant problem from a diagnostic viewpoint is the presence of these symptoms in elderly males. These irritative voiding symptoms mimic the LUTS associated with bladder outlet obstruction related to Benign Prostatic Hyperplasia (BPH). Without urodynamic evaluation, the neurogenic component to the symptoms may be overlooked, or not quantified well, and inappropriate therapy instituted. Furthermore, men with multiple systems atrophy rather than true Parkinson’s disease may actually have mild detrusor-sphincter dyssynergia, which again could mimic the obstructive symptoms of BPH (Stocchi et al., 1997). The typical urodynamic findings of Parkinson’s are detrusor hyperreflexia on filling cystometry. As much as 79% of bladder dysfunction in these patients can be related to hyperreflexia (Araki et al., 2000). Other findings are not uncommon though. Hyporeflexia is present in 16% of patients in

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Araki’s study (Araki et al., 2000). Obstruction can also be present particularly in the male with prostatic enlargement or stricture disease from previous interventions. Multichannel urodynamics is essential to the evaluation of voiding dysfunction in patients with Parkinson’s Disease.

Cerebrovascular Accident (CVA) Stroke can be considered a major health problem among elderly patients. Roughly three-fourths of the 400 000 stroke patients per year in the United States are over the age of 65. The impact of this disorder on voiding and continence can range from mild to profound. When occurring in the aged patient, its effects can magnify preexisting bladder conditions and cause great confusion as to what the proper therapy should be. Depending on the location of the ischemic event, the bladder may range from hyperreflexic to areflexic. One can therefore present with an entire range of symptoms anywhere from nocturia and urgency/urge incontinence to voiding difficulties and urinary retention (Sakakibara et al., 1996). The presence of urinary incontinence in the acute phase of a Cerebrovascular Accident (CVA) is a powerful predictor of a negative outcome (Wade and Hewer, 1985). The patient presenting with LUTS following a CVA can be a diagnostic dilemma. In one study, detrusor hyperreflexia was seen in 68% of patients, detrusor-sphincter dyssynergia in 14%, and uninhibited sphincter relaxation in 36% (Sakakibara et al., 1996). In that same study, there were patients with retention who were noted to have detrusor areflexia with an unrelaxing sphincter. No correlation was seen between site of lesion and urodynamic findings. In the elderly postCVA male, neurogenic bladder problems may coexist with obstruction from the prostate gland. Nitti found in a group of men with a mean age of 70 with voiding complaints following a stroke that detrusor hyperreflexia was present in 82% of the group, but pressure-flow characteristics of definite obstruction were present in 63% (Nitti et al., 1996). Multichannel urodynamics can be an important adjunct in the urologic management of these patients.

Nocturia Nocturia is commonly listed as a symptom by the older patients. In males, it is often perceived as related to prostate enlargement. But this symptom is also commonly noted among aging women (Lose et al., 2001). Menopausal status may contribute to the presence of nocturia (Chen et al., 2003). In all likelihood, nocturia is a manifestation of normal aging. Other factors impacting the presence of nocturia in the aging individual include sleep difficulties and nocturnal polyuria. Sleep disturbances are common in the elderly population and nocturia may be more related to those problems, rather than to a urinary tract dysfunction. Furthermore, the patient with nocturia, whatever be its cause, will have poorer sleep (Middelkoop et al., 1996). The problem of nocturnal

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polyuria in many of the elderly, which is reported as nocturia, can be difficult to manage. With lower renal concentrating ability, poorer conservation of sodium, loss of the circadian rhythm of antidiuretic hormone secretion, decreased production of renin-angiotensin-aldosterone, and increased release of atrial natriuretic hormone, there is an age-related alteration in the circadian rhythm of water excretion, leading to increased nighttime urine production in the older population. Exacerbated by age-related diminution in functional bladder volume and detrusor instability, nocturnal polyuria often leads to a dramatic version of nocturia (Miller, 2000).

is rising almost exponentially. The number of prescriptions for one particular overactive bladder drug alone surpasses 50 000 per month, many presumably to older sufferers of the condition (Alza, 1999). Clearly, an understanding of how the common drugs for these urinary conditions work is essential for proper prescription and monitoring. Proper use of pharmaceuticals for urinary conditions can give maximum benefit to the patient’s symptoms and pathology without engendering any undue risk in the aging population.

Dementias

The pharmacology of the bladder is primarily related to either the bladder itself or to the nervous innervation of the organ. At the level of the bladder itself, a number of receptor sites exist to varying degrees. These receptors govern to a great degree the function of the lower urinary tract and become more prominent in the elderly patient as various bladder conditions become more prevalent. Among the adrenergic receptors, α- and β-receptors are found in the bladder although it has been thought that β-receptors predominate in the bladder body and α-receptors in the bladder base and bladder neck region. Urine storage is facilitated by relaxation caused by β-stimulation and tonic contraction in the area enriched by α-receptors (Khanna et al., 1981). More recent work has elucidated (at least in the rabbit) that the division by receptors into bladder base and body may be overly simplistic and that further regionalization of the bladder based on differing mixes of α- and β-receptors might be more appropriate (Chou et al., 2003). α-receptors are also well characterized in the prostatic urethra and stroma. Stimulation of these receptors causes contraction and thus possibly obstruction of the bladder neck (Caine, 1988). Muscarinic receptors are the other major group of receptors influencing bladder behavior. These receptors, particularly the M2 and M3 subtypes are responsible for bladder contraction (Ehlert, 2003). The pharmacology of these receptors is influenced by their ubiquity. They are also found in gastrointestinal, airway, and salivary gland smooth muscle. Table 2 gives a summary of receptors located within the bladder and the effects of aging on these receptors.

The elderly patient with dementia faces the dual difficulties of having to face the consequences of an aging bladder and in addition, the difficulties caused by an altered perception of his or her internal and external environments. This can lead to urinary incontinence or retention depending on what is influencing it, bladder factors or a central neurologic inability to properly perceive the urinary activity. The difficulties in the management of these patients’ other significant conditions often pushes concerns about incontinence aside, but the fact remains that incontinence issues are the primary reason for institutionalization of the elderly patient. Evidence of combined cerebral and urinary tract dysfunction comes from perfusion studies in elderly patients. From positron emission tomography (PET) scan studies, it has been demonstrated that the pontine micturition center in the dorsomedial pontine tegmentum, the periaqueductal gray matter and the pre-optic area of the hypothalamus are all active during various phases of micturition (Blok and Holstege, 1998). Furthermore, urge incontinence has been associated with underperfusion of the frontal areas of the brain (Griffiths, 1998). Clearly, cerebral atrophy, irrespective of the cause, can lead to disinhibition of the bladder and resulting incontinence. Treatment routines combining anticholinergic medications with prompted or timed voiding have been utilized to circumvent the loss of cerebral control over the micturition process in elderly patients afflicted with bladder dysfunction (Burgio et al., 1998; Schnelle and Leung, 2004).

PHARMACOLOGY AS IT RELATES TO THE AGING BLADDER With so many elderly at risk for bladder dysfunction, the use of medications among the elderly for urinary tract problems

Receptors

Adrenergic Stimulation/blockade

α-stimulation in the elderly patient is most often a deleterious side effect from a pharmaceutical designed for action elsewhere. With the rich supply of α-receptors in the prostate, stimulation can cause contraction, and thus obstruction and

Table 2 Bladder receptors and aging

Receptor

Location

Action

Effect of aging

α-adrenergic

Prostate

Contraction smooth muscle

α-adrenergic β-adrenergic Muscarinic

Bladder base Bladder body Detrusor muscle (primarily M3)

Contraction smooth muscle Relaxation smooth muscle Relaxation smooth muscle

Stimulation-causes urinary retention Blockade-improves urine flow Shift in subtype may ameliorate bladder symptoms Unknown at present Urinary retention Worsening of side effects at other locations

THE AGING BLADDER

urinary retention (Beck et al., 1992). α-blockade, although originally designed with hypertension in mind, has become a mainstay in the therapy of LUTS related to prostatic enlargement (Dunn et al., 2002). One effect of aging is the possible change in the type, sensitivity, and number of these receptors. With increasing age, α-adrenoceptor responsiveness either decreases or remains unchanged (Docherty and O’Malley, 1985). Furthermore, α-receptors in the aging bladder itself show a shift from the α-1a subtype to an α-1d predominance (Hampel et al., 2004). If α-blockers have an effect in the bladder that aids in relief of LUTS as well as its effect on obstruction itself, then this change with aging could have implications for both short-term as well as long-term use in elderly men with prostate disease. Antimuscarinics

Antimuscarinics are drugs that are utilized primarily in the therapy of symptoms of overactive bladder. Although the M2 subtype is the predominant population, it appears that the smaller population M3 subtype is the functionally important group (Fetscher et al., 2002). Although several antimuscarinic agents exist in oral, intravesical, and transdermal forms, the lack of bladder M3 selectivity remains a problem. In the elderly, antimuscarinic can be very effective for symptoms of frequency, urgency, and urge incontinence (Wein, 2003). Changes in the aging patient may, however, alter the pharmacology of these drugs in an adverse manner. Side effects such as dry mouth and constipation may be of more concern and less well tolerated in the elderly individual. Decreases in force of detrusor contraction in the aging male with an enlarged obstructing prostate gland may well push the patient into urinary retention. At least one of these agents crosses the blood-brain barrier and thus, particularly in the aging patient, could effect a higher incidence of confusion as a side effect (Todorova et al., 2001). These effects could play a role in limiting the usefulness of the antimuscarinics in treating bladder dysfunction. 5-α Reductase Inhibitors

This group of drugs, although having therapeutic activity in the prostate gland, is known for their beneficial effect on bladder complaints caused by obstruction from the prostate gland. These agents inhibit the conversion of testosterone to dihydrotestosterone in the prostate gland and thus cause reduction in the size of the periurethral prostatic tissue (Tempany et al., 1993). This leads to improvement in urinary flow and BPH related symptomatology. In the proscar longterm efficacy and safety study (PLESS), the main side effects in all age-groups are sexual side effects, particularly ejaculatory disturbances (Wessells et al., 2003). This may be more profound in the elderly male with borderline sexual dysfunction although this was not borne out in the PLESS study.

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SURGICAL DISEASE OF THE AGING BLADDER Lower urinary tract surgery in the aged patient is common for two conditions having a large impact on the bladder – stress urinary incontinence in women and bladder outlet obstruction from prostatic enlargement in men. The elderly suffer disproportionately from these disorders but have benefited from advances in therapy for these conditions. With proper selection of treatment, this group of patients can enjoy great improvement in their quality of life related to their lower urinary tract.

Female Stress Urinary Incontinence Stress incontinence occurs when abdominal pressure generated by such actions as coughing, sneezing, or other Valsalva maneuvers causes bladder pressure to exceed urethral pressure without a detrusor contraction and urine is expelled. Stress incontinence is associated with parturition, previous pelvic surgery and aging. Previously, major abdominal surgery was the only method considered for treatment and older age could be considered a relative contraindication. But with newer therapies, elderly women can be considered excellent candidates for realizing improvement in their condition. Pelvic Floor Conditioning

Pelvic floor exercises have become a mainstay of conservative therapy for stress incontinence. They are absolutely safe and can be performed either alone or with biofeedback. Effectiveness as measured both subjectively by patient report as well as objectively with pad weights has been demonstrated in several studies (Bo et al., 1999; Aksac et al., 2003). Some concern over the effectiveness in the elderly of pelvic floor rehabilitation can be raised. The reduction in estrogen effect on the vaginal tissues may reduce the benefit of these exercises in the elderly woman. Furthermore, the overall reduction of muscle tone with aging may also make these exercises less efficacious (Dimpfl et al., 1998; Aukee et al., 2003). Patients with significant intrinsic sphincter deficiency may not respond as well to pelvic floor conditioning. These exercises, however, are essentially risk-free, which makes them especially appealing as a first line effort for the elderly woman. Pharmacologic Management

Stress urinary incontinence has been remarkably resistant to drug therapy in the past. Pharmacologic agents with α-adrenergic properties such as pseudoephedrine were occasionally utilized with moderate success in women with mild incontinence (Cummings, 1996). These medications were effective due to the presence of α-receptors in the bladder neck. These agents though, have recently been pulled

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out of use owing to adverse events and so are not readily available. Estrogen therapy may also play a role in the medical management of stress incontinence in the older, postmenopausal woman (Ishiko et al., 2001) but its true benefit has been disputed in some studies (Jackson et al., 1999). Anticholinergic agents, although truly indicated for urgency and urge incontinence, are often prescribed for stress incontinence. These drugs may be helpful in women with mixed incontinence (urge and stress incontinence) by reduction of the urge component and thus improving overall continence. Patients with pure stress incontinence may perceive a worsening of the problem in that the bladder capacity will increase, and they will leak larger volumes of urine with stress maneuvers (Chutka and Takahashi, 1998). Although it is appealing to consider these pharmaceuticals as first line therapy for stress incontinence in the aging woman, one must consider certain factors. α-adrenergic agents have been associated with CVAs and increases in blood pressure (Cantu et al., 2003; Beck et al., 1992). Certain anticholinergic medications cross the blood-brain barrier and can cause confusion and drowsiness in the older patient (Yarker et al., 1995). These adverse effects may outweigh the usually small benefits these drugs provide for stress incontinence. The serotonin-norepinephrine reuptake inhibitors (SNRI) are being shown to have a therapeutic effect in female stress incontinence. These drugs have been shown to facilitate urine storage and facilitate rhabdosphincter activity. Thus, a positive effect on stress incontinence could be expected and trials are under way to study this possibility (Thor and Donatucci, 2004). Safety in the geriatric population would also need evaluation. Injection Therapy

The concept of injecting substances at the bladder neck to aid in coaptation and thus improve continence dates back to the use of sodium morrhuate by Murless in the 1930s (Murless, 1938). This led later to the use of Teflon popularized by Politano with good results (Lopez et al., 1993). Concerns over the safety of Teflon injection led to the use of glutaraldehyde cross-linked bovine collagen and later development of other injectables such as carbon beads. Injection treatments have been shown to have an improvement rate of about 40% (Groutz et al., 2000) with best results occurring in women without low leak point pressures or maximum urethral closure pressures (Gorton et al., 1999). This therapy may be a good alternative for the older female. It is minimally invasive with a low rate of complications. The anesthetic requirements are not significant, with some reporting use of local anesthetic only. The major downside, especially for the geriatric patient is the frequent need for multiple injections to achieve success. Still, this is an excellent option for the older woman desiring aggressive treatment, but reluctant to undergo major surgical procedures (Khullar et al., 1997).

Operative Therapy

With multiple procedures described for female stress urinary incontinence, it is difficult to discern what the role of surgery might be for the aging female. Several factors are clear though. Older women are, as a rule, healthier now and thus better able to tolerate surgery. Surgery offers the best chance for successful resolution of stress incontinence. Finally, modifications of many procedures have allowed good results with less morbidity than was seen with earlier operations. Sling procedures have evolved from being a procedure designed only for those with severe incontinence to a rational alternative for all women desiring operative therapy (Morgan et al., 2000). The procedure is commonly done today with alternative materials for the sling such as cadaveric fascia or dermis as opposed to the classic descriptions of harvesting the patient’s own fascia. Bone anchors are now commonly available for fixation of the sling, allowing for a lower degree of invasiveness via an exclusively transvaginal approach. The taping procedures for stress incontinence have also shown good results with minimal morbidity and may be ideal alternatives for the elderly female. The tension-free vaginal tape procedure as popularized by Ulmsten (Ulmsten et al., 1998) and its modifications (suprapubic tapes and transobturator tapes) place a sling-like material at the midurethra and are often done under local anesthetic with light sedation only (Tash and Staskin, 2003). These procedures have been shown to be safe enough and have quite good results to be a reasonable alternative for the more active older female who requires aggressive treatment, but desires minimal morbidity (Walsh et al., 2004).

Benign Prostatic Hyperplasia (BPH) in the Older Male Benign enlargement of the prostate gland in the human male is a condition inexorably linked with aging. When the vesicourethral junction becomes obstructed by the growing tissue, symptoms such as slowing of the urinary stream, hesitancy, straining to void and a sensation of incomplete emptying result. Furthermore, irritative symptoms such as urinary frequency, urgency, and nocturia may also become common. It is estimated that the prevalence of symptoms related to BPH may be as high as 50% in a multinational survey (Rosen et al., 2003). Medical Therapy

Two broad classes of drugs are utilized for therapy for BPH, α-receptor blockers and 5-α reductase inhibitors. The bladder neck region in males is rich in α-receptors and blockade of these causes relaxation of the smooth muscle in the prostatic urethra. This results in a decrease in the tonic luminal pressure in the prostatic fossa and allows for more efficient urine outflow from the bladder (Debruyne, 2000). Early α-antagonists were designed primarily for use as antihypertensives and thus a major side effect when used

THE AGING BLADDER

for relief of voiding dysfunction from BPH was orthostasis. Normotensive men complained also of asthenia and fatigue (Lepor et al., 2000). In older men with hypertension, attempted medical management of BPH along with hypertension became complex. Over the last several years, the introduction of α-adrenergic antagonists selective to the prostatic α-receptors has broadened the population that can be managed with these agents and includes many elderly men, ensuring also safe usage. (Dunn et al., 2002). The 5-α reductase inhibitors block the conversion of testosterone to dihydrotestosterone in the prostate gland, which is the active form stimulating prostate growth. With blockade, the prostate gland involutes and a reduction in prostate volume of up to 30% may be seen. This can result in an improvement in urinary flow and a decrease in symptomatology. The safety profile of these drugs is very good, making them a good choice in the older male, particularly those with very large prostate glands (Roehrborn et al., 2004). Combination therapy may also be of benefit in the elderly male. The recently completed Medical Therapy of Prostate Symptoms (MTOPS) study demonstrated a 66% decrease in acute urinary retention compared to placebo. α-blockade alone and 5-α reductase therapy alone showed 39% and 34% reductions respectively (McConnell et al., 2003). Acute urinary retention in the elderly is a morbid event with an impact on quality of life similar to that of myocardial infarction; so prevention by means of a combined therapy may be worthwhile for the older population with LUTS related to BPH. Minimally Invasive Therapy

A plethora of minimally invasive treatments for BPH now exist. Many are safe enough to be office-based and thus particularly applicable to the older male population. These therapies involve the delivery of energy to the prostate gland in order to heat the tissues to greater than 60 ◦ C, which leads to protein denaturation and ultimately destruction of prostatic tissue and relief of obstruction. The differences in the methods lie in the type of heat delivery system; whether by externally generated microwaves (Osman et al., 2003) or internally placed systems generating radiofrequency energy (Hill et al., 2004) or laser energy (Costello et al., 1999). Safety makes these procedures particularly appealing for the older male (Berger et al., 2003). Most of the complications center around irritative voiding symptoms. Bleeding essentially does not occur but postprocedure retention can be a problem. Furthermore, it takes several weeks before improvement in symptoms and flow occurs. Transurethral Resection of the Prostate Gland (TURP)

The TURP procedure is still considered the “gold standard” of treatment for bladder outlet obstruction from BPH (Minardi et al., 2004). It works quickly, since the obstructing tissue is removed immediately at the time of surgery.

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Symptom scores drop rapidly and flow rates are instantly improved. Although not without morbidity, improvements in instrumentation and optics have made this procedure much safer for the elderly patient, and in those with severe symptoms or retention, it is still the best choice for therapy, no matter what the age of the patient is, if he can reasonably tolerate anesthesia.

CONCLUSION The effects of aging on lower urinary tract function can be profound. Anatomic variations, both at the macroscopic and ultrastructural levels occur frequently and induce functional changes. Disease states commonly seen in the older patient have significant impact on the bladder, which should be recognized as a major portion of the syndromes. Bladder changes from aging significantly impact on pharmaceutical effectiveness and alter the ability to manage many conditions. A multimodal approach including surgery to treat common geriatric disorders of the lower urinary tract can be both safe and very effective.

KEY POINTS • Bladder anatomy changes with aging both macroscopically because of prostate enlargement in men and pelvic prolapse in women, as well as microscopically because of collagen deposition. • Changes in anatomy lead to physiologic changes such as loss of compliance and variation in response to neurotransmitters and pharmaceuticals. • Certain extravesical disease processes common in the older patient have a profound effect on the bladder. • The common lower urinary tract symptom complexities of stress incontinence in women and obstructive voiding in women can be safely treated by a variety of means including surgery.

KEY REFERENCES • Burgio KL, Locher JL, Goode PS et al. Behavioral vs drug treatment for urge urinary incontinence in older women: a randomized controlled trial. The Journal of the American Medical Association 1998; 280:1995 – 2000. • Elbadawi A, Yalla SV & Resnick NM. Structural basis of geriatric voiding dysfunction. II. Aging detrusor: normal versus impaired contractility. The Journal of Urology 1993; 150:1657 – 67. • Thor KB & Donatucci C. Central nervous system control of the lower urinary tract: new pharmacological approaches to stress urinary incontinence in women. The Journal of Urology 2004; 172:27 – 33. • Yoshida M, Miuamee K, Iwashita H et al. Management of detrusor dysfunction in the elderly: changes in acetylcholine and adenosine triphosphate release during aging. Urology 2004; 63(3 suppl 1):117 – 23.

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THE AGING BLADDER The Journal of Pharmacology and Experimental Therapeutics 1981; 216:95 – 100. Khullar V, Cardozo LD, Abbott D & Anders K. GAX collagen in the treatment of urinary incontinence in elderly women: a two year follow up. British Journal of Obstetrics and Gynaecology 1997; 104:96 – 9. Landau EH, Jayanthi VR, Churchill BM et al. Loss of elasticity in dysfunctional bladders: Urodynamic and histochemical correlation. The Journal of Urology 1994; 152:702 – 5. Lepor H, Jones K & Williford W. The mechanism of adverse events associated with terazosin: an analysis of the Veterans Affairs cooperative study. The Journal of Urology 2000; 163:1134 – 7. Levy BJ & Wight TN. Structural changes in the aging submucosa: new morphologic criteria for the evaluation of the unstable human bladder. The Journal of Urology 1990; 144:1044 – 55. Lopez AE, Padron OF, Patsias G & Politano VA. Transurethral polytetrafluoroethylene injection in female patients with urinary continence. The Journal of Urology 1993; 150:856 – 8. Lose G, Alling-Moller L & Jennum P. Nocturia in women. American Journal of Obstetrics and Gynecology 2001; 185:514 – 21. Macarak EJ & Howard PS. The role of collagen in bladder filling. Advances in Experimental Medicine and Biology 1999; 462:215 – 23. McConnell JD, Roehrborn CG, Bautista OM et al. Medical Therapy of Prostatic Symptoms (MTOPS) Research Group. The long-term effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia. The New England Journal of Medicine 2003; 349:2387 – 98. Middelkoop HA, Smilde-van den Doel DA, Neven AK et al. Subjective sleep characteristics of 1,485 males and females aged 50 – 93: effects of sex and age, and factors related to self-evaluated quality of sleep. The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences 1996; 51:M108 – 15. Miller M. Nocturnal polyuria in older people: pathophysiology and clinical implications. Journal of the American Geriatrics Society 2000; 48:1321 – 9. Minardi D, Galosi AB, Yehia M et al. Transurethral resection versus minimally invasive treatments of benign prostatic hyperplasia: results of treatments. Our experience. Archivio Italiano Di Urologia, Andrologia 2004; 76:11 – 8. Morgan TO Jr, Westney OL & McGuire EJ. Pubovaginal sling: 4-year outcome analysis and quality of life assessment. The Journal of Urology 2000; 163:1845 – 8. Murless BC. The injection treatment of stress incontinence. The Journal of Obstetrics and Gynaecology of the British Empire 1938; 45:67 – 73. Nitti VW, Adler H & Combs AJ. The role of urodynamics in the evaluation of voiding dysfunction in men after cerebrovascular accident. The Journal of Urology 1996; 155:263 – 6. Ohnishi N, Kishima Y, Hashimoto K et al. A new method of measurement of the urinary bladder blood flow in patients with low compliant bladder. Hinyokika Kiyo. Acta Urologica Japonica 1994; 40:663 – 7. Osman Y, Wadie B, El-Diasty T & Larson T. High-energy transurethral microwave thermotherapy: symptomatic vs urodynamic success. BJU International 2003; 91:365 – 70. Pavlakis AJ, Siroky MB, Goldstein I & Krane RJ. Neurourologic findings in Parkinson’s disease. The Journal of Urology 1983; 129:80 – 3. Perucchini D, DeLancey JO, Ashton-Miller JA et al. Age effects on urethral striated muscle. II. Anatomic location of muscle loss. American Journal of Obstetrics and Gynecology 2002; 186:356 – 60. Pinho M, Yoshioka K, Ortiz J et al. The effect of age on pelvic floor dynamics. International Journal of Colorectal Disease 1990; 5:207 – 8.

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Rosen R, Altwein J, Boyle P et al. Lower urinary tract symptoms and male sexual dysfunction: the multinational survey of the aging male (MSAM-7). European Urology 2003; 44:637 – 49. Roehrborn CG, Bruskewitz R, Nickel JC et al. Proscar Long-Term Efficacy and Safety Study Group. Sustained decrease in incidence of acute urinary retention and surgery with finasteride for 6 years in men with benign prostatic hyperplasia. The Journal of Urology 2004; 171:1194 – 8. Sakakibara R, Hattori T, Yasuda K & Yamanishi T. Micturitional disturbance after acute hemispheric stroke: analysis of the lesion site by CT and MRI. Journal of the Neurological Sciences 1996; 137:47 – 56. Schnelle JF & Leung FW. Urinary and fecal incontinence in nursing homes. Gastroenterology 2004; 126(1 suppl 1):S41 – 7. Sebesta M, Cespedes RD, Luhman E et al. Questionnaire-based outcomes of urinary incontinence and satisfaction rates after radical prostatectomy in a national study population. Urology 2002; 60:1055 – 8. Stocchi F, Carbone A, Inghilleri M et al. Urodynamic and neurophysiological evaluation in Parkinson’s disease and multiple system atrophy. Journal of Neurology, Neurosurgery, and Psychiatry 1997; 62:507 – 11. Tash J & Staskin DR. Artificial graft slings at the midurethra: physiology of continence. Current Urology Reports 2003; 4:367 – 70. Tempany CM, Partin AW, Zerhouni EA et al. The influence of finasteride on the volume of the peripheral and periurethral zones of the prostate in men with benign prostatic hyperplasia. The Prostate 1993; 22:39 – 42. Thor KB & Donatucci C. Central nervous system control of the lower urinary tract: new pharmacological approaches to stress urinary incontinence in women. The Journal of Urology 2004; 172:27 – 33. Todorova A, Vonderheid-Guth B & Dimpfel W. Effects of tolterodine, trospium chloride, and oxybutynin on the central nervous system. Journal of Clinical Pharmacology 2001; 41:636 – 44. Ulmsten U, Falconer C, Johnson P et al. A multicenter study of tension-free vaginal tape (TVT) for surgical treatment of stress urinary incontinence. International Urogynecology Journal and Pelvic Floor Dysfunction 1998; 9:210 – 3. Van Arsdalen KN, Wein AJ & Levin RM. The contractile and metabolic effects of acute ischemia on the rabbit urinary bladder. The Journal of Urology 1983; 130:180 – 2. Verelst M, Maltau JM & Orbo A. Computerised morphometric study of the paraurethral tissue in young and elderly women. Neurourology and Urodynamics 2002; 21:529 – 33. Wade DT & Hewer RL. Outlook after an acute stroke: urinary incontinence and loss of consciousness compared in 532 patients. The Quarterly Journal of Medicine 1985; 56:601 – 8. Walsh K, Generao SE, White MJ et al. The influence of age on quality of life outcome in women following a tension-free vaginal tape procedure. The Journal of Urology 2004; 171:1185 – 8. Wein AJ. Diagnosis and treatment of the overactive bladder. Urology 2003; 62(5 suppl 2):20 – 7. Wessells H, Roy J, Bannow J et al. PLESS Study Group. Incidence and severity of sexual adverse experiences in finasteride and placebo-treated men with benign prostatic hyperplasia. Urology 2003; 61:579 – 84. Yarker YE, Goa KL & Fitton A. Oxybutynin. A review of its pharmacodynamic and pharmacokinetic properties, and its therapeutic use in detrusor instability. Drugs & Aging 1995; 6:243 – 62. Yoshida M, Miuamee K, Iwashita H et al. Management of detrusor dysfunction in the elderly: changes in acetylcholine and adenosine triphosphate release during aging. Urology 2004; 63(3 suppl 1):117 – 23. Yoshimura N, Sasa M, Yoshida O & Takaori S. Dopamine D-1 receptormediated inhibition of the micturition reflex by central dopamine from the substantia nigra. Neurourology and Urodynamics 1992; 11:535 – 45.

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Prostate Diseases Timothy D. Moon and Jennifer L. Maskel University of Wisconsin and Veterans’ Affairs Medical Center, Madison, WI, USA

INTRODUCTION The prostate is perhaps the most diseased organ in the male body. The lifetime risk of being diagnosed with prostate cancer is approximately 16% while a 65-year-old male has about a 40% likelihood of having a focus of prostate cancer. Benign prostatic hyperplasia as an histological entity will affect almost all men if they live long enough and 25% will receive treatment during their lifetime. Prostatitis has a clinical prevalence of 16% in men over 65 while its histological prevalence is close to 100%. The above perhaps underscores the importance of prostatic pathology upon the well being of older men. This chapter will review these basic diagnostic entities and the approach to treatment of the aging male.

BENIGN PROSTATIC HYPERPLASIA Benign prostatic hyperplasia (BPH) has generally been used as a synonym for lower urinary tract symptoms (LUTS) (Abrams, 1994). While BPH is one cause of LUTS, agerelated detrusor dysfunction, neurogenic disease, and diabetes are other major causes (Kelly and Zimmern, 2003). This chapter will address LUTS rather than BPH per se.

Anatomy The prostate is a golf ball–sized organ, which lies between the bladder and the pelvic floor anterior to the rectum (Figure 1). The transition zone is situated around the urethra and is responsible for hyperplastic growth (benign prostatic hyperplasia). This may take the form of lateral lobes encroaching on the urethral lumen, or less frequently, a middle lobe of prostate, which may enlarge and develop like a tongue within the bladder (Figure 2). This may then act like a ball valve during urination.

The two major requirements for prostatic growth are androgens and aging. For a more detailed review of the molecular biology of prostatic growth this is reviewed in detail elsewhere (Roehrborn and McConnell, 2002). Histologically prostatic growth is both epithelial and stromal (Roehrborn and McConnell, 2002). Most patients have varying degrees of stromal and glandular hyperplasia but with both elements usually being present.

Prevalence BPH usually starts during the early 40s and increases thereafter. Several autopsy studies have been published demonstrating almost no existence before age 40, 50% prevalence by age 60, and with a peak of 90% by age 90 (Berry et al., 1984). Clinically, the Baltimore longitudinal study of aging demonstrated a prevalence of 30% by the fifth decade, 50% in the sixth, and reaching 80% in the eighth decade of life (Arrighi et al., 1991). The prevalence of moderate to severe symptoms for patients in various studies performed globally is enormous ranging from 10 to 60% for men in their sixth decade (Roehrborn and McConnell, 2002). A US study from Olmstead County demonstrated moderate to severe BPH symptoms in 31% of men in their sixth decade rising to 44% in their eighth decade (Chute et al., 1993). Overall, from the patient perspective, the main criterion for initiating treatment is “bother”; how much do these symptoms intrude upon the patient’s lifestyle? As patients react differently to the same set of symptoms, how the symptoms affect the patient is more important than an absolute count of the symptoms.

Natural History The question, which most patients and physicians pose, is what will happen to my symptoms with time? Will I go into acute retention? One study evaluated LUTS in


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risk (McConnell et al., 2003). Patients with a PSA less than 1.4 mg ml−1 had a very low risk of acute urinary retention.

Patient Evaluation

Seminal vesicles Bladder Rectum Prostate

Pelvic floor muscles

Figure 1 Sagitaal section of male pelvis

Bladder Ureteral orifices

Middle lobe Prostate (a)

The key elements to patient evaluation are shown in Table 1. Urinary symptomatology may be evaluated using the international prostate symptoms score (Table 2). For an assessment of symptoms along with an impact score the BPH impact score can be used (Table 3) as an assessment of bother. For most patients, treatment is based upon the negative quality of life impact that they have (bother) rather than any absolute symptomatic criteria. Additionally, it is important to evaluate the rest of the patient’s medical history to determine if other medical conditions may lead to bladder dysfunction, polyuria, and so on (Table 4). A symptom score of 0–7 is considered mild while 8–19 is considered moderate, and 20–35, severe. The impact (Table 3) score should be used in conjunction with the International Prostate Symptom Score. For example, a patient with moderate symptoms but without any bother probably does not warrant treatment, while a patient who is bothered by his symptoms should at least have a discussion of treatment options along with their attendant risks and side effects. Physical examination should include a rectal examination as well as a focused neurologic examination and evaluation of the patient’s mental status. Clearly, dementia amongst many neurologic conditions will affect urinary symptomatology. Many demented patients are referred for incontinence while their bladder function is essentially normal for their age. Treatment of these patients will often be behavioral such as timed voiding (initiated by the caregiver), rather than interventional.

(b)

Figure 2 Coronal section of prostate and bladder (a) normal (b) with prostatic and middle lobe enlargement

community-dwelling men over age 60 years (Lee et al., 1996). Of interest, 23% of men with severe symptoms at baseline were asymptomatic 1 year later. Most natural history data, however, comes from the placebo arms of randomized controlled trials for the treatment of LUTS (Flanigan et al., 1998; McConnell et al., 1998; McConnell et al., 2003). The most significant of these is the recently published medical therapy of prostate symptoms (MTOPS) trial (McConnell et al., 2003). Of the 737 men involved in the placebo arm only 18 men went into acute urinary retention during this study (5 years). This rate was 0.6 per hundred person years. The comparison rate in the best treatment arm (finasteride plus doxazosin) was 0.1 per hundred person years. These data demonstrate not only the natural history but also that while medical treatment decreased the acute urinary retention rate by a significant percentage (80%), the absolute risk is relatively small to begin with. Additionally, prostate size as measured by PSA, also correlates with acute urinary retention

Laboratory Evaluation Urinalysis is a specifically recommended test to rule out a urinary tract infection or bladder cancer (presence of hematuria). Additionally, the presence of glycosuria in diabetic patients may identify problems for management, not only of diabetes but secondarily, with associated lower urinary tract symptomatology. Patients with primarily irritative urinary symptoms (frequency, urgency, nocturia) should be considered for urinary cytology as well as all men with hematuria. Microscopic hematuria alone should lead to a formal urologic Table 1 Patient evaluation (AUA Practice Guidelines Committee, 2003)

• Medical history of voiding dysfunction Identify other etiologies and comorbidities for voiding dysfunction Obtain international prostate symptom score • Physical Examination Include DRE, focused neurologic examination • Urinalysis • PSA for select patients Life expectancy greater than 10 years or those for whom PSA measurement would change treatment options

PROSTATE DISEASES

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Table 2 AUA BPH symptom score (AUA Practice Guidelines Committee, 2003)

1. Over the past month, how often have you had a sensation of not emptying your bladder completely after you finished urinating? 2. Over the past month, how often have you had to urinate again less than two hours after you finished urinating? 3. Over the past month, how often have you found you stopped and started again several times when you urinated? 4. Over the past month, how often have you found it difficult to postpone urination? 5. Over the past month, how often have you had a weak urinary stream? 6. Over the past month, how often have you had to push or strain to begin urination? 7. Over the past month, how many times did you most typically get up to urinate from the time you went to bed at night until the time you got up in the morning?

Not at all

Less than 1 time in 5

Less than half the time

About half the time

More than half the time

Almost always

0

1

2

3

4

5

0

1

2

3

4

5

0

1

2

3

4

5

0

1

2

3

4

5

0

1

2

3

4

5

0

1

2

3

4

5

None

1 time

2 times

3 times

4 times

5 or more times

Total Symptom Score

Table 3 BPH impact index (AUA Practice Guidelines Committee, 2003)

1. Over the past month how much physical discomfort did any urinary problems cause you? 2. Over the past month, how much did you worry about your health because of any urinary problems? 3. Overall, how bothersome has any trouble with urination been during the past month? 4. Over the past month, how much of the time has any urinary problem kept you from doing the kind of things you would usually do?

None

Only a little

Some

A lot

None

Only a little

Some

A lot

Not at all bothersome Bothers me a little None of the time A little of the time Some of the time

Bothers me some Bothers me a lot Most of the time All of the time

Table 4 Medical diseases affecting urinary symptoms

Cardiac Disease Diabetes Neurologic disease Mental disease Other urologic conditions

Especially CHF. Peripheral edema will revascularize at night adding to nocturia Poorly controlled diabetes will act as osmotic diuretic MS, SCI, PID with nerve compression Dementia, Alzheimer’s OAB, bladder cancer

CHF, Congestive Heart Failure; MS, Multiple Sclerosis; SCI, Cord Injury; PID, prolapsed intervertebral disc; OAB, overactive bladder.

workup generally consisting of a CT urogram, cystoscopy, and urinary cytology. These studies will evaluate the kidneys, ureters, bladder, and complete lower urinary tract for pathology. Previously a serum creatinine was recommended, but studies have shown that in the absence of other medical issues this is not a helpful test (AUA Practice Guidelines Committee, 2003). European urologists (European Association of Urology, 2004), however, continue to recommend its collection as did the 4th International Consultation of Benign Prostatic Hyperplasia in 1997 (Koyanogi et al., 1998). The measurement of PSA remains controversial. In the BPH guidelines (AUA Practice Guidelines Committee, 2003), the general recommendations is for patients with a life

expectancy of greater than 10 years or where measurement would make a difference to treatment. For example, in octogenarians, the diagnosis of prostate cancer is not usually a basis for treatment. However, if the patient had severe urinary tract symptomatology then it may be that treatment of the prostate cancer would be appropriate treatment for the LUTS. Patients whose symptoms are complex or who fail medical therapy may require further urodynamic evaluation. Either way this would require referral to an urologist. Measurement of urinary flow rates, post void residuals, ultrasounds, and other urodynamic studies are not generally considered routine.

Treatment The treatment for LUTS may be separated into four groups: watchful waiting, medical therapy, minimally invasive treatment, and invasive surgical therapy (Table 5).

Watchful Waiting For patients with mild symptoms and no complications (e.g. renal insufficiency, urinary tract infection) and who are not

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Table 5 Treatment options for BPH

Watchful waiting

Medical therapy α blockers 5α reductase inhibitors Phytotherapy Minimally invasive surgery Microwave Radiofrequency

Invasive surgery TUIP TURP Open prostatectomy

Symptoms minimal (IPSS < 8) and there is little bother. These are not mandatory indications for treatment Symptoms and/or bother are moderate but the patients wants treatment

Moderate to severe symptoms/bother Comorbid indications for surgery: Bleeding Renal failure Recurrent UTI Urinary retention Moderate to severe symptoms Indications for surgery Failure of other therapies

IPSS, International prostate symptom score; UTI, Urinary Tract infection; TURP, Transurethral Resection of Prostate; TUIP, transurethral incision of prostate.

bothered by their symptoms, monitoring of the symptoms without active intervention is appropriate. Generally, this would include all patients with symptom scores less than 8 and many with symptom scores between 8 and 19.

Medical Therapy (Lepor and Lowe, 2002) Medical therapy consists of α-blockers, 5-α-reductase inhibitors, and phytotherapy.

α-blockers The basis for this treatment utilizes the fact that the prostate and bladder neck are richly innervated by α1a receptors. The bladder body is primarily innervated with α1d receptors while α1b receptors are present on blood vessels throughout. By blocking the α1a and α1d receptors, the prostate and detrusor smooth muscle will relax, allowing for a better flow and reduced irritative urinary symptomatology. The effect on α1b receptors tends to cause vascular relaxation and potentially hypotension. Indeed, the earliest drugs (terazosin and doxazosin) were first approved by the FDA as hypotensive agents. Most of the α-blockers are non-subtype selective (alfuzosin, doxazosin, terazosin). Because of their effect upon blood vessels, the dose needs to be increased over several weeks. Even so, many patients, especially the elderly, may have problems with dizziness and postural hypotension. Alfuzosin (long acting) and tamsulosin, because of less effect upon blood pressure, do not require dose titration. Tamsulosin is a different class of drug and is primarily α-1a/d specific. As such, it has less potential interaction with hypotensive agents than the other drugs. Overall, the efficacy of the drugs are similar, although the side effect profiles differ somewhat with perhaps tamsulosin having the best side effect profile. Of special note is the interaction between α-blockers and the phospho-diesterase-5 inhibitors (Sildenofil, Tadalafil, and

Vardenofil). Sildenofil (Viagara), tadalafil (cialis) and vardenafil (levitra) are contraindicated within 6 hours of taking α-blockers. Levitra is contraindicated with all α-blockers though work is underway to try and remove this FDA proscription. Tamsulosin is the only α-blocker approved by the FDA for use in combination with Cialis.

5-α-reductase Inhibitors These drugs block the conversion of testosterone to dihydrotestosterone (the active metabolite). Two enzymes exist: type I in the skin and liver and type II in the reproductive organs. Dutasteride blocks both enzymes, while Finasteride blocks only the type II enzyme. Despite this difference, the overall suppression of testosterone is similar. Because of the mechanism of action, it takes 3–6 months for full clinical effect. Further, these drugs are most efficacious on large prostates (>50 g).

Combination Therapy The recent MTOPS trial demonstrated maximal effect in reducing prostate size and improving symptoms by combining both an α-blocker (doxazosin) with a 5-α-reductase inhibitor (finasteride) (McConnell et al., 2003). While the differences in risk for symptom progression and urinary retention were large (approximately 25% greater than single treatment alone (McConnell et al., 2003)) the absolute reductions were relatively small: nine episodes to five episodes per 100 patient years for urinary retention and 25 per 100 patient years for symptom progression (>4 points on the symptom score). Two features of practical utility did stand out. Patients with small prostates had little risk of going into retention irrespective of treatment option. PSA has also been demonstrated to be a surrogate for prostate size. Patients with low PSA’s (less than 1.4 ng ml−1 ) also have small prostates and minimal risk of retention. Conversely, patients with large prostates had a much greater risk of retention and therefore are likely to benefit more from this aspect of 5-α-reductase therapy.

Phytotherapy A variety of plant extracts have been utilized for the treatment of LUTS. Unfortunately, because they are designated as food additives and not regulated by the Food and Drug Administration no good randomized prospective clinical trials have been performed. Despite this, several compounds do appear to have real activity. These are currently being studied in the Complimentary and Alternative Medicine (CAMUS) trial funded by the National Institutes of Health (NIH). This study will randomize patients to placebo, Saw Palmetto, Africanum Pygeum, or an α-blocker/5-α-reductase inhibitor combination. The results of this study will unfortunately not be available for several years.

PROSTATE DISEASES

Perhaps the most widely used plant is Seranoa Repens (Saw Palmetto). The extracts of this plant contain a mixture of fatty acids, sterols, flavenoids, and other compounds (Lowe and Fogelman, 2004). Its mechanism of action suggests 5-α-reductase inhibition, anti-inflammatory action and effects upon apoptosis. One of the largest problems with these unregulated drugs is batch-to-batch variation and also manufacturer-tomanufacturer variation. Studies have been performed analyzing the active ingredients from multiple manufacturers demonstrating that the content varies between excess of that stated on the package to none at all.

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reported study of microwave thermotherapy demonstrated that over a 5-year period, 29% underwent additional treatment while only 59 of 150 patients remained in the study (Miller et al., 2003). While these dropout rates are similar to dropout rates for medical (drug) therapy the economic impact is greater. If drug therapy is stopped the cost (of the drug) also stops. Once a relatively expensive treatment is performed the total cost has already been incurred. Despite all the cautionary notes mentioned earlier, Medicare has approved both TUNA and microwave thermotherapy for reimbursement. Because they are generally performed in the office/surgicenter setting, utilization has increased dramatically over the last few years.

Minimally Invasive Therapy Surgical therapies are generally out with the scope of practice for gerontologists. For that reason, the following discussion will center on information, which will help the physician guide, the patient toward the best therapy for them. More detailed reviews of the subject have been published (Fitzpatrick and Mebust, 2002). The most commonly utilized methods for minimally invasive treatment are transurethral needle ablation (TUNA) and microwave thermotherapy. Both act by heating the prostatic tissue. The TUNA device is a rigid cystoscope like instrument passed transurethrally under vision. Two needles (which look a bit like snake fangs) can be extended from the instrument into the prostatic tissue. Utilizing a radiofrequency signal the tissue is heated between 46 and 100 ◦ C. The microwave devices look like a urinary catheter with a normal balloon area (to seat it at the bladder neck) but with the microwave area distal to that. Using microwave energy the prostatic tissue is heated to 69 ◦ C. Overall, tissue heated to greater than 45 ◦ C will lead to hemorrhagic necrosis. These procedures are generally performed in the office or a surgicenter under local anesthetic or conscious sedation. Overall, most studies show a marked reduction in Symptom Score (50% or more) and with improvement in peak flow from 30 to 100%. Comparative studies have not yet been performed, however, the NIH is sponsoring the trial of minimally invasive surgical therapy (MIST), which will compare TUNA with microwave thermotherapy with combined medical therapy (α-blocker plus 5-α-reductase inhibitor). The results of this trial however will again not be available for several years. Given that most patients are treated for “bother” rather than absolute need the complication rates are extremely important. The complications of TUNA include postoperative urinary retention with rates of 13– 42%. Forty percent will have retention for the first 24 hours. Likewise, 40% of patients will have irritative urinary symptoms early on after treatment. Up to 14% of patients will undergo another form of therapy within 2 years. To the extent that some patients without benefit will not undergo additional therapies this perhaps underscores the lack of efficacy rate. The complications of microwave thermotherapy include 36% catheterization rate for 1 week postoperatively. Satisfaction rates have dropped off to 34% at 2 years. One recently

Invasive Surgical Therapy In today’s society most patients with lower urinary tract symptomatology will first be tried on medical therapy. Depending upon the experience of the urologist, equipment availability, or the patient circumstances some patients may next be treated with minimally invasive therapy. If that fails or is not appropriate patients may proceed to invasive therapy namely transurethral incision of the prostate or transurethral resection of the prostate (TURP). Both of these procedures are performed in the hospital operating room under spinal or general anesthesia. The patients are generally admitted for at least one night postoperatively. If the prostate is small and especially if there is a high bladder neck (between the prostate prostatic urethra and bladder) then a transurethral incision of the prostate may be preferable. Not only is this a single cut from the bladder trigone to the verumontanum of the prostate simple, but there is much less blood loss than with a TURP. Additionally, because the whole bladder neck has not been resected the risk for bladder neck scarring and stricture formation is much less. In general, bladder neck contractures are seen more frequently after resections of small prostates rather than with large prostates. Additionally, men will usually have antegrade ejaculation afterwards, which is a major issue for many men of all ages (including octogenarians). A transurethral resection of prostate entails resecting the tissue from the bladder neck to the prostatic apex. The “surgical capsule” represents the boundary between the transition and peripheral zones of the prostate. Most men have a catheter in for 1–2 days and take about 6 weeks to fully recover. Significant postoperative bleeding occurs in about 10% and may occur 10–14 days postoperatively. Because the lower urinary tract symptomatology is often associated with prostatic problems and bladder neck dysfunction the symptomatic improvement may not be as marked as urologists would like to think. Indeed, for the occasional patients with primarily irritative symptoms these may even become worse postoperatively. In general, however, the dysuria, frequency, and urgency routinely experienced postoperatively will resolve within 2 months. More recently lasers have been used to resect the prostate. The technique entails resecting “the benign adenoma” and

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delivering it into the bladder where it is then morcellated and extracted. Overall, the surgical process is slower than traditional electrocautery but there is much less bleeding. For a detailed review of technical issues associated with these invasive surgical procedures this may be found elsewhere (Lepor and Lowe, 2002).

Open Prostatectomy For patients with very large glands (>100 g), it is difficult to treat the adenoma within a reasonable time frame. For these patients an open suprapubic approach is best. A lower midline incision is made. Next a midline incision is made in the bladder, which may be extended into the prostatic capsule. The benign adenoma is then shelled out using finger disection. Major bleeders are oversewn and the bladder neck often reconstructed as part of oversewing of the bleeding vessels. A three-way irrigating catheter is inserted. There is often significant bleeding at the time of enucleation (≤500 ml). Otherwise the risks/complications are broadly the same as for a TURP.

PROSTATE CANCER Prostate cancer is the most common cause of malignancy in men in the United States (Jenal et al., 2003). The incidence of prostate cancer increases with age making this a pertinent topic in the geriatric population. Advances in diagnosis and treatment allow for earlier detection and improved treatment of the disease. The unique challenge in the geriatric population is patient selection for continued screening and choice of treatment modalities.

Epidemiology Prostate cancer incidence in the United States has risen dramatically in the past three decades. The incidence of prostate cancer increased 2.7% annually from 1973 to 1988 (Jenal et al., 2003). From 1988 to 1992 it increased 16.2% annually and then fell to 11.7% from 1992 to 1995. Since then data suggests that incidence rates may have leveled off and perhaps are following the curve established before the spike in 1992, which was almost certainly driven by the introduction of widespread use of PSA. African-American males have the highest rate of prostate cancer incidence in the United States (Jenal et al., 2003). Prostate cancer incidence is also age dependent. In men under 65 years the annual incidence is 58.8 cases per 100 000 men. In men over age 65, the incidence increases to 982.2 cases per 100 000 males per year (Jenal et al., 2003). While screening and treatment advances have recently focused on the younger male, prostate cancer remains predominately a disease of the older male.

Screening and Detection Early prostate cancer rarely causes symptoms as cancers generally arise in the peripheral portion of the gland. Symptoms from prostate cancer tend to arise with advanced or metatstatic disease. Often these take the form of urinary symptoms. Symptoms may include obstructive urinary symptoms, irritative urinary symptoms, hematuria, hematospermia, bone pain, weight loss, spinal cord compression, and fecal or urinary incontinence. Thus, screening for prostate cancer has become widespread and widely accepted. However, the method of screening and the population to be screened remain controversial. The challenge for the geriatric population is to define the population who will benefit from screening. Prior to the widespread use of prostate-specific antigen (PSA) only individuals with palpable nodules, or symptoms resulting from prostate cancer underwent transrectal ultrasound guided biopsy (TRUS). Today, screening measurement of PSA often prompts the performance of prostate biopsies. PSA, although widely utilized as a screening tool, is still controversial. The American Urological Association (AUA), American Cancer Society, and American College of Physicians all support the use of PSA as a screening modality as long as the patient has been given counseling regarding the use of PSA for early detection and treatment (Thompson et al., 2000; Smith et al., 2000; Coley et al., 1997). The AUA recommends screening only for men with a 10-year life expectancy. Using life assurance tables this approximates to age 74 years. The reason for 10 years is based upon the fact that for periods of less than 10 years it is difficult to show outcome differences for treated versus untreated patients. Thus, for the young geriatric population (65–75 years) recommendations are similar to those for younger men. For the true elderly (>75 years), the approach to screening needs to be individualized. Certainly, as population longevity increases it may be appropriate to screen, diagnose, and treat much older patients.

Prostate-specific Antigen Prostate-specific-antigen (PSA) is a serine protease produced by both normal and malignant prostate cells. It functions in the liquefaction of the seminal coagulum (Han et al., 2004). Approximately 90% of PSA exists bound to α-1-antichymotrypsin and α-2-macroglobulin. The remainder exists in the unbound or “free” form. Routine PSA assays detect all forms of PSA (Han et al., 2004). The normal range for PSA has generally been considered 0–4 ng ml−1 ; however, age-specific cutoffs have been proposed (only for men 2 but ≤5 cm) or multiople nodes with none 5 cm in dimension Distant metatstatic spread Distant metastases cannot be assessed No evidence of distant metastases Distant metastases Involvement of nonregional lymph nodes Involvement of bones Involvement of other distant sites

T1B T1C T2 T2A T2B T3 T3A T3B T3C T4 T4A T4B N (+) NX N0 N1 N2 N3 M (+) MX M0 M1 M1A M1B M1C

Staging of Prostate Cancer Stage is determined using the TNM staging system. This is shown in Table 7. Once biopsy confirms prostate cancer, the clinician’s goal is to accurately assign a clinical stage, which will predict prognosis and aid in selection of appropriate therapy. The clinical stage is based on the digital rectal exam (DRE), PSA, and pathologic information as well as imaging modalities if indicated. For patients with a Gleason score of 7 or greater, we will obtain a bone scan. For PSA’s in excess of 20–25 ng ml−1 a CT scan may help identify pathologic lymph nodes. The PSA, Gleason grade, and TNM stage can be utilized to predict final pathologic stage. There are complex nomograms to help predict the probability of organ confinement, seminal vesical invasion, lymph node involvement (Partin et al., 1997), and extracapsular spread (Partin et al., 1997).

Natural History In general, prostate cancer is considered to be a slow growing tumor. Indeed, the cliché that most people die with prostate cancer rather than from it holds true. The need for treatment

is very much predicated upon life expectancy with 10 years being the threshold defining need for treatment. Two papers have been published demonstrating the relatively benign course with no treatment (Johansson et al., 1997; Albertsen et al., 1998). Patients with Gleason 6 cancers have a 95%) with prostatitis do not have an infection. • Prostatitis is probably a catchbag for multiple pathologic entities.

KEY REFERENCES • Albertsen PC, Hanley JA, Gleason DF & Barry MJ. Competing risk analysis of men aged 55 to 74 years at diagnosis managed conservatively for clinically localized prostate cancer. The Journal of the American Medical Association 1998; 280(11):975 – 80. • AUA Practice Guidelines Committee. AUA Guideline on management of benign prostatic hyperplasia. Chapter 1: diagnosis and treatment recommendations. The Journal of Urology 2003; 170:530 – 47.

Abrams P. In support of pressure flow studies for evaluating men with lower urinary tract symptoms. Urology 1994; 44:153 – 5. Albertsen PC, Hanley JA, Gleason DF & Barry MJ. Competing risk analysis of men aged 55 to 74 years at diagnosis managed conservatively for clinically localized prostate cancer. The Journal of the American Medical Association 1998; 280(11):975 – 80. Alexander RB, Propert KJ, Schaeffer AJ et al. A randomized trial of Ciprofloxacin and tamsulosin in men with chronic prostatitis/chronic pelvic pain syndrome. The Journal of Urology 2004; 171(4):232. Anderson RU. Treatment of prostatodynia (pelvic floor myalgia or chronic non-inflammatory pelvic pain syndrome). In JC Nickel (ed) Textbook of Prostatitis 1999, pp 357 – 64; Isis Medical Media Limited, Oxford. Arrighi HM, Metter EJ, Guess HA & Fozzard JL. Natural history of benign prostatic hyperplasia and risk of prostatectomy. The Baltimore longitudinal study of aging. Urology 1991; 38(suppl 1):4 – 8. AUA Practice Guidelines Committee. AUA Guideline on management of benign prostatic hyperplasia. Chapter 1: diagnosis and treatment recommendations. The Journal of Urology 2003; 170:530 – 47. Barbalias GA, Nikiforidis G & Liatsikos EN. α-Blockers for the treatment of chronic prostatitis in combination with antibiotics. The Journal of Urology 1998; 159:883 – 7. Berry SJ, Coffey DS, Walsh PC & Ewing LL. The development of human benign prostatic hyperplasia with age. The Journal of Urology 1984; 132:474 – 9. Blasko J, Grimm P & Ragde H. Brachytherapy and organ preservation in the management of carcinoma of the prostate. Seminars in Radiation Oncology 1993; 3:240 – 9. Blasko JC, Radge H & Grimm PD. Transperineal ultrasound-guided implantation of the prostate: morbidity and complications. Scandinavian Journal of Urology and Nephrology. Supplementum 1997; 137:113 – 8. Bundrick W, Heron SP, Ray P et al. Levofloxacin versus Ciprofloxacin in the treatment of chronic bacterial prostatitis: a randomized double-blind multicenter study. Urology 2003; 62(3):537 – 41. Carter HB & Partin AW. Diagnosis and staging of prostate cancer. In PC Walsh (ed) Campbell’s Urology 2002, 8th edn, vol. 4, pp 3055 – 73; W.B. Saunders, Philadelphia. Carter HB, Pearson JD, Metter JE et al. Longitudinal evaluation of prostate specific antigen levels in men with and without prostate disease. The Journal of the American Medical Association 1992; 267:2215. Catalona WJ, Carvalhal GF, Mager DE & Smith DS. Potency, continence, and complication rates in 1,870 consecutive radical retropubic prostatectomies. The Journal of Urology 1999; 162(2):433 – 8. Catalona WJ, Partin AW, Slawin KM et al. Use of the percentage free prostate-specific antigen to enhance differentiation of prostate cancer from benign prostatic disease: a prospective multicenter clinical trial. The Journal of the American Medical Association 1998; 279:279 – 1542. Catalona WJ, Partin AW, Slawin KM et al. Percentage of free PSA in black versus white men for detection and staging of prostate cancer: a prospective multicenter clinical trial. Urology 2000; 55:372. Chute CG, Panswer LA, Girman CJ et al. The prevalence of prostatism: a population-based survey of urinary symptoms. The Journal of Urology 1993; 150:85 – 9. Coley C, Barry MJ & Mulley AG. Clinical Guidelines: Part III: Screening for prostate cancer. Annals of Internal Medicine 1997; 126:480.

PROSTATE DISEASES Diamond TH, Bucci J, Kersley JH et al. Osteoporosis and spinal fractures in men with prostate cancer: risk factory and effects of androgen deprivation therapy. The Journal of Urology 2004; 172(2):529 – 32. European Association of Urology. 2004, Www.uroweb.org. Fitzpatrick JM & Mebust WK. Minimally invasive and endoscopic management of benign prostatic hyperplasia. In PC Walsh (ed) Campbell’s Urology 2002, 8th edn, Vol 2, chapter 40, pp 1379 – 422; W.B. Saunders, Philadelphia. Flanigan RC, Reda DJ, Wasson JH et al. 5-year outcome of surgical resection and watchful waiting for men with moderately symptomatic benign prostatic hyperplasia: a department of veteran’s affairs cooperative study. The Journal of Urology 1998; 160:12 – 7. Gleason DF, & Mellinger GT, Veterans Administration Cooperative Urological Research Group. Prediction of prognosis for prostatic adenocarcinoma by combined histologic grading and clinical staging. The Journal of Urology 1974; 111:58 – 64. Han M, Gann PH & Catalona WJ. Prostate-specific antigen and screening for prostate cancer. The Medical Clinics of North America 2004; 88(2):245 – 65. Jani AB & Hellman S. Early prostate cancer: clinical decision making. The Lanet (London) 2003; 361(9362):1045. Jenal A, Murray T, Samuels A, Cancer Statistics 2003. CA: A Cancer Journal for Clinicians 2003; 53:5 – 26. Johansson JE, Holmberg L, Johansson S et al. Fifteen-year survival in prostate cancer: a prospective, population-based study in Sweden. The Journal of the American Medical Association 1997; 277(6):467 – 71. Kelly CE, Zimmern PE. Clinical evaluation of lower urinary tract symptoms due to benign prostatic hyperplasia. Atlas of the Prostate 2003, 2nd edn, chapter 2, pp 11 – 23: Current Medicine Philadelphia PA, USA. Koyanogi T, Artiboni W, Correa R et al. In L Denis, K Griffith, S Khoury et al. (eds) Proceedings of the Fourth International Consultation of BPH, Paris, July 1997 1998, pp 179 – 265; Health Publications, Plymouth. Krieger JN, Nyberg L Jr & Nickel JC. NIH consensus definition and classification of prostatitis. The Journal of the American Medical Association 1999; 2841(3):236 – 7. Krupski TL, Smith MR, Lee WC et al. Natural history of bone complications in men with prostate carcinoma initiating androgen deprivation therapy. Cancer 2004; 101(3):541 – 9. Lee AJ, Russell EB, Garraway WM & Prescott RJ. Three-year follow-up of a community-based cohort of men with untreated benign prostatic hyperplasia. European Urology 1996; 30:11 – 7. Lepor H & Lowe FC. Evaluation and non-surgical management of benign prostatic hyperplasia. In PC Walsh (ed) Campbell’s Urology 2002, 8th edn, vol 2, chapter 39, pp 1337 – 78; W.B. Saunders, Philadelphia. Litwin MS, McNaughton Collins M, Fowler FJ Jr et al. The national institutes of health chronic prostatitis symptom index: development and validation of a new outcome measure. The Journal of Urology 1999; 162:369 – 75. Lowe FC & Fogelman F. Permixon: a review. Current Prostate Reports 2004; 2:132 – 6. McConnell JD, Bruskewitz RC, Walsh P et al. The effect of Finasteride on the risk of acute urinary retention and the need for surgical treatment among men with benign prostatic hyperplasia. The New England Journal of Medicine 1998; 338:557 – 63. McConnell JD, Roehrborn CG, Bautista OM et al. The long-term effect of Doxazosin, Finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia. The New England Journal of Medicine 2003; 349:2387 – 98. McNaughton Collins M, Meigs JB, Barry MJ et al. Prevalence and correlates of prostatitis in the health professionals follow-up study cohort. The Journal of Urology 2002; 167:1363 – 6. Miller PD, Kastner C, Ramsey EW & Parsons K. Cooled thermotherapy for the treatment of benign prostatic hyperplasia: durability of results obtained with the targis system. Urology 2003; 61(6):1160 – 5. Moon TD. Alpha-blockers in prostatitis. Current Prostate Reports 2004; 2:143 – 7. Moon TD, Hagen L & Heisey DM. Urinary symptomatology in younger men. Urology 1997; 50(5):700 – 3.

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Morgan TO, Jacobsen SJ, McCarthy WF et al. Age-specific reference ranges for prostate-specific antigen in black men. The New England Journal of Medicine 1996; 335:304. Neal DE Jr & Moon TD. Use of terazosin in prostatodynia and validation of a symptom score questionnaire. Urology 1994; 43(4):460 – 5. Nickel JC. Prostatitis and related conditions. Campbell’s Urology 2002, pp 603 – 30; W.B. Saunders. Nickel JC, Alexander R, Anderson R et al. Prostatitis unplugged? Prostate massage revisited. Techniques in Urology 1999; 5(1):1 – 7. Nickel JC, Alexander RB, Schaeffer AJ et al. Leukocytes and bacteria in men with chronic prostatitis/chronic pelvic pain syndrome compared to asymptomatic controls. The Journal of Urology 2003; 170:818 – 22. Nickel JC, Downey J, Hunter D & Clark J. Prevalence of prostatitis-like symptoms in a population-based study using the national institutes of health chronic prostatitis symptom index. The Journal of Urology 2001; 165:842 – 5. Oesterling JE, Jacobsen SJ, Chute CG et al. Serum prostate-specific antigen in a community-based population of healthy men: Establishment of age-specific reference ranges. The Journal of the American Medical Association 1993; 270:860. Partin AW, Kattan MW, Subong EN et al. Combination of prostate-specific antigen, clinical stage, and Gleason score to predict pathological stage of localized prostate cancer. A multi-institutional update. The Journal of the American Medical Association 1997; 277:1445 – 51. Pilepich MV, Krall J, George FW et al. Treatment-related morbidity in phase III RTOG studies of extended-field irradiation for carcinoma of the prostate [Clinical Trial Journal Article]. International Journal of Radiation Oncology, Biology, Physics 1984; 10(10):1861 – 7. Riehmann M, Rhodes PR, Cook TD, Analysis of variation in prostatespecific antigen values. Urology 1993; 42(4):390 – 7. Roach M, Chinn DM, Holland J et al. A pilot survey of sexual function and quality of life following 3D conformational radiotherapy for clinically localized prostate cancer. International Journal of Radiation Oncology, Biology, Physics 1996; 35:869 – 74. Roberts RO, Lieber MM, Rhodes T et al. Prevalence of a physicianassigned diagnosis of prostatis: the olmstead county study of urinary symptoms and health status among men. Urology 1998; 51(4):578 – 84. Roehrborn CG & McConnell JD. Etiology, pathopysiology, epidemiology, and natural history of benign prostatic hyperplasia. In PC Walsh (ed) Campbell’s Urology 2002, 8th edn, vol 2, Chapter 38, pp 1297 – 336; W.B. Saunders, Philadelphia. Scherr D, Bosworth J, Steckel J. Complications of brachytherapy in the treatment of localized prostate cancer. Complications in Urologic Surgery: Prevention and Management 2001, 3rd edn, pp 419 – 26; W.B. Saunders, Philadelphia. Selch MT. Complications of radiation therapy for urologic cancer. Complications of Urologic Surgery: Prevention and Management 2001, 3rd edn, pp 133 – 41; W.B. Saunders, Philadelphia. Smith RA, Mettlin CJ, Davis KJ et al. American Cancer Society guidelines for the early detection of cancer. CA: A Cancer Journal for Clinicians 2000; 50:34. Taneja SS, deKernion JB. Complications of radical retropubic prostatectomy. Complications of Urologic Surgery: Prevention and Management 2001, 3rd edn, pp 408 – 18; W.B. Saunders, Philadelphia. Thompson I, Carroll P, Coley C et al. Prostate-specific antigen (PSA) best practice policy. American Urological Association. Oncology 2000; 14:267. Thompson IM, Pauler DK, Goodman PJ et al. The New England Journal of Medicine 2004; 350:2239 – 46. Prevalence of prostate cancer among men with a prostate-specific antigen level ≤4.0 ng per milliliter. Walsh PC. Anatomic radical retropubic prostatectomy. In PC Walsh (ed) Campbell’s Urology 2002, 8th edn, vol 3, pp 3107 – 28; W.B. Saunders, Philadelphia. Walsh PC, Partin AW & Epstein JI. Cancer control and quality of life following anatomical radical retropubic prostatectomy: results at 10 years. The Journal of Urology 1994; 152:1831 – 6.

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Urinary Incontinence Margaret-Mary G. Wilson Saint Louis University Health Sciences Center and Veterans’ Affairs Medical Center, St Louis, MO, USA

Some men there are love not a gaping pig, Some that are mad if they behold a cat, And others when the bagpipe sings i’th’ nose Cannot contain their urine. William Shakespeare (1564 – 1616), Shylock, in The Merchant of Venice, act 4, sc. 1.

INTRODUCTION Unlike other parameters of geriatric health, such as cognition, balance, and mood, continence is an attribute that is rarely appreciated until there is almost complete failure of the underlying physiological regulatory mechanisms. Additionally, despite the great strides that have been made in dissociating social stigma from a variety of diseases, including sexually transmitted diseases and acquired immune deficiency syndrome, urinary incontinence (UI) continues to suffer from the reluctance of both patient and provider to address the problem. Embarrassment, lack of awareness of the associated serious comorbidity and mortality, as well as ignorance regarding the availability and efficacy of several therapeutic options have been implicated as factors that deter due attention to this deadly disease (Dugan et al., 2001; Horrocks et al., 2004; Kinchen et al., 2003; Shaw et al., 2001). With the advent of the “baby boomers” and the projected increase in the proportion of older adults, UI and the attendant consequences will loom large on the horizon of geriatric disease. Thus, in this climate, health-care providers who fail to identify and adequately treat older adults with UI are delivering substandard care. UI in older adults is a potentially devastating disease. Affected adults may exhibit significant functional decline and frailty, resulting in increased risk of institutionalization and death. Abundant data confirms the negative effect of UI on the quality of life of affected elders (Bradway, 2003; Johnson et al., 2000).

Reported prevalence for UI varies from 15% among relatively healthy community-dwelling older adults to 65% among the frail elderly (Brandeis et al., 1997; Holroyd-Leduc et al., 2004; Landi et al., 2003; Sgadari et al., 1997). In the United States, more than 17 million adults suffer from UI (Hu et al., 2004). However, available figures most likely underestimate the true prevalence of this syndrome for a variety of reasons. Major reasons identified for inaccurate reporting of the true prevalence of UI include failure to perceive the significance and ominous implications of UI by affected elders, and also the misconception that UI is an expected consequence of aging. Patient embarrassment, discomfort, and lack of awareness of effective treatment options are other barriers to self-reporting (Dugan et al., 2001). Annually, the direct cost of UI exceeds US $20 billion, with approximately 74% of this amount being spent on incontinence care in women. Two-thirds of the direct cost for UI care in women is spent on community-dwelling women (Hu et al., 2004; Wilson et al., 2001). Overall, the incremental lifetime medical cost of treating an older adult with UI approaches US $60 000 (Birnbaum et al., 2003). Indirect costs arising from factors such as reduced work productivity of the patient or the caregiver elevate the economic burden of UI even further. Of paramount importance in estimating the societal cost of UI is the recognition of associated intangible costs reflected in compromised quality of life, decreased feeling of well-being, psychological instability, and loss of self-esteem (Hu et al., 2004).

RISK FACTORS UI is less frequent in men. Zunzunegui Pastor et al. reported a prevalence of UI of 14% in older community-dwelling men compared to a prevalence of 30% among their female counterparts. Nevertheless, advancing age is associated with a higher frequency of UI in men, but not in women.


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Additional associated factors include coexisting morbidity, cognitive dysfunction, functional impairment, gait abnormality, diuretic therapy, and obesity (Zunzunegui Pastor et al., 2003). Notably, most independent risk factors for UI are potentially reversible (Landi et al., 2003). The onus lies with providers to identify and treat such risk factors in all patients being evaluated for UI.

Predisposing factors • Gender • Anatomic • Cultural • Environmental

Promoting factors

PATHOPHYSIOLOGY OF URINARY INCONTINENCE IN THE ELDERLY

• Constipation • Occupation • Obesity • Surgery • Disease • Drugs

Inciting factors • Neurological disease • Tissue disruption • Radical surgery

Age related factors • Dementia • Debility • Disease • Environment • Medications

Several age-related changes threaten lower urinary tract function in the elderly. These include an increase in the frequency of uninhibited detrusor contractions, impaired bladder contractility, abnormal detrusor relaxation patterns, and reduced bladder capacity. An increase in nocturnal urine production also occurs. Anatomically, prostatic size increases in men, while urethral shortening and urethral sphincter weakening occurs in women. In addition to these physiological and anatomical age-related changes, the increased frequency of lower urinary tract disease in older patients further increases the risk of UI (Enriquez, 2004; Kevorkian, 2004; Klauser et al., 2004; Lluel et al., 2003; Patel et al., 2002; Tan, 2003; Whishaw, 1998; Yoshida et al., 2004). Although providers tend to defer screening for UI until later in life, the framework for UI is often laid much earlier in life. Predisposing factors for UI should be sought in all patients regardless of age. Female gender is an irreversible predisposing factor and mandates routine enquiry for UI in all women regardless of age. The presence of structural congenital abnormalities such as hypospadias, epispadias, and ambiguous genitalia may also compromise bladder continence. With aging and the increased likelihood of disease, inciting factors such as cerebrovascular disease, radical pelvic surgery and autonomic degeneration further increase the risk of UI (Allen et al., 2004; Ayed et al., 1995; McLoughlin & Chew, 2000; Mouriquand et al., 2003). Available data indicates that the occurrence of cerebrovascular disease doubles the risk of UI in older females. Obesity, frailty, and diabetes are other strong predictors of the occurrence of UI (Enriquez, 2004; Klausner and Vapnek, 2003; Landi et al., 2003; Namikawa, 1999; Ouslander, 2000). Additionally, older adults are more likely to become incontinent following the onset of UI-promoting factors such as constipation, obesity, and polyuria from uncontrolled hyperglycemia, hypercalcemia, or diuretic therapy. Traditional geriatric pathophysiological factors such as impaired cognitive function, functional impairment, and frailty may also precipitate incontinence as a manifestation of global decompensation.

loss. Several mnemonics have been developed for the causes of transient or reversible incontinence (Figure 1; Table 1). Previously, continent patients who experience incontinence in the acute-care setting are likely to have underlying reversible causes of incontinence. Acute-care protocols that incorporate screening and detection of such risk factors are critical to reducing the incidence of incontinence in acutely hospitalized elders. Classification of UI in this manner also facilitates efficient and cost-effective intervention, as recognition and correction of causes of transient incontinence prevents unnecessary and expensive investigations and invasive studies. Mechanistic classification of UI results in five major categories: UI associated with overactive bladder (OAB), stress incontinence, overflow incontinence, and functional incontinence. Combinations of these categories constitute the fifth category that is referred to as mixed incontinence. Bladder overactivity and impaired contractility frequently occur in conjunction in patients with diabetes mellitus. Similarly, benign prostatic enlargement often presents with symptoms of bladder overactivity as well as urinary retention (Johnson and Ouslander, 1999; Nasr and Ouslander, 1998; Ouslander, 2000; Ouslander and Schnelle, 1995).

CLASSIFICATION

Urinary Incontinence Associated with Overactive Bladder

Accurate classification of UI should include reference to both the temporal course and the mechanistics of involuntary urine

Overactive bladder occurs in 1 of 4 adults over the age of 65, and is the most common cause of UI in the elderly,

Figure 1 Risk factors for urinary incontinence Table 1 Causes of reversible urinary incontinence

D Delirium I Infection A Atrophic vaginitis P Pharmaceuticals P Psychological disorders E Endocrine disorders R Restricted mobility S Stool impaction

D Delirium R Restricted mobility, retention I Infection, inflammation, impaction P Polyuria, pharmaceuticals

Reproduced by permission of American College of Physicians.

URINARY INCONTINENCE

accounting for 40–70% of all cases. Characteristically, overactive bladder results from involuntary contractions of the detrusor muscle, resulting in a strong urge to pass urine in unusually low volumes. Clinically, OAB manifests with urgency, frequency, and nocturia with or without urge incontinence (Newman, 2004; Teleman et al., 2004; Tubaro, 2004; Yoshida et al., 2004). Persons with urge incontinence present with involuntary urine loss preceded by a sudden, urgent, and strong desire to void. Electrical field stimulation studies have identified at least three different mechanisms of detrusor muscle contraction. The major mechanism is cholinergic, and is mediated through the effect of acetylcholine (Ach) on muscarinic bladder receptors. A second mechanism (purinergic) involves adenosine triphosphate (ATP)-mediated bladder contraction. A third and poorly defined mechanism is thought to be nonneuronal and attributed to local urothelial Ach production and a paracrine effect on local muscarinic receptors located in the bladder. Age-related reduction in cholinergic and purinergic bladder transmission has been identified. However, purinergic transmission appears to play a greater role in bladder contraction in older adults, indicating disproportionate agerelated compromise in cholinergic function. Available data also indicates an age-related compromise of nonneuronal uroepithelial Ach production (Wuest et al., 2005; Yoshida et al., 2004).

Stress Incontinence Stress incontinence is the underlying cause in 25% of women with UI, and results from anatomical or pathological disruption of the angle between the bladder neck and the urethra, thereby disrupting continence. Causes of stress incontinence include vaginal childbirth, and pelvic surgery such as hysterectomy or prostate surgery (Jackson et al., 2004; Molander et al., 2002; Van der Varrt et al., 2002). Characteristically, stress incontinence presents with involuntary urine loss resulting from increases in intra-abdominal pressure in the presence of a relatively incompetent urethral sphincter mechanism. Thus, involuntary urine loss may occur when the patient laughs, coughs, or sneezes. In severe cases, UI may occur with a change in posture from supine or sitting to standing.

Overflow Incontinence Overflow incontinence results from bladder outlet obstruction, resulting in massive bladder distension. Consequently, involuntary urine loss results from a buildup of intravesical pressure until the mechanical outlet obstruction is overcome by sheer pressure. Persons with overflow incontinence complain of persistent trickling of urine in the presence of suprapubic distension. In men, prostatic enlargement is the most common cause of overflow incontinence. Pelvic masses, such as uterine fibroids, or cystoceles may cause

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similar obstructive symptoms in women (Borrie et al., 2001; Chapple, 2001; Grosshans et al., 1993).

Functional Incontinence Functional incontinence refers to involuntary urine loss resulting from inability to gain access to toileting facilities for a variety reasons including limited mobility, impaired cognition, lack of motivation, environmental barriers, or restricted access. This is a common cause of incontinence in frail elders with dementia, cerebrovascular disease, Parkinson’s disease, or delirium. Altered mental status from narcotics, sedatives, or narcoleptic agents are also frequently implicated (Chadwick, 2005; Vickerman, 2002). Inappropriate use of physical or chemical restraints, poor vision, depression, reduced exercise tolerance, gait abnormality, or fear of falling are other miscellaneous causes of functional incontinence.

COMPLICATIONS AND CONSEQUENCES OF URINARY INCONTINENCE Deleterious effects of UI are far reaching and multidimensional. Various aspects of quality of life are affected. Older adults with UI frequently suffer from embarrassment and loss of self-confidence and self-esteem. Sixty percent of older adults with UI develop depressive symptoms. Unpredictable involuntary urine loss frequently results in the affected elders becoming increasingly isolated as a result of voluntary restriction of social interaction and travel. Limitation of physical activity in affected elders may compromise functional status and hasten progression to frailty. Intimate relationships may also be adversely affected by the onset of incontinence, as affected persons avoid sexual activity with partners for fear of involuntary urine loss during intercourse. Indeed, available data highlights an independent association between sexual dysfunction and UI in older men (Bradway, 2003; Hogan, 1997; Johansson et al., 1996; Miner, 2004; Saltvedt et al., 2002). Financially, the economic costs of UI may be extremely burdensome. Protective garments and beddings are relatively expensive, and are often not covered by insurance plans. The productivity of older adults in the workforce may be negatively affected by the threat of frequent and unpredictable episodes of incontinence. Likewise, the productivity of caregivers of patients with UI may be compromised by their inability to cope with the demands of a relative with UI. Indeed, available data highlights UI as the most common cause of institutionalization of elders. Likewise, in long-term care facilities, the resident with UI imposes an additional annual financial burden of approximately $5000 to total health-care costs (Bradway, 2003; Hogan, 1997; Johansson et al., 1996; Miner, 2004; Saltvedt et al., 2002).

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MEDICINE IN OLD AGE Table 2 Complications of urinary incontinence

• • • • • • • • • • • • • •

Recurrent urinary tract infections Skin infections Balanitis Pressure ulcers Falls Fractures Depression Decreased libido and sexual dysfunction Acute hospitalization Social isolation Caregiver stress Reduced feeling of well-being Institutionalization Increased health-care costs

Medical complications further compromise health-care related quality of life. In women with incontinence aged over 65, the incidence of falls and fractures increases significantly. Approximately, 20–40% of women with UI will fall within 12 months and of these about 10% will result in fractures, usually of the hip. Available data also indicates a strong association between UI, acute hospitalization, and institutionalization (Gray, 2003; Wilson, 2003, 2004). Thirty percent of women with UI over the age of 65 are likely to be hospitalized within 12 months. Older men are twice as likely to be hospitalized over a 12-month period (Saltvedt et al., 2002). Of the myriad complications associated with UI, the most alarming is the independent association between UI and increased mortality (Table 2).

CLINICAL DETECTION OF UI Older adults with UI rarely volunteer this information as a presenting complaint. The onus is therefore on the providers to screen for UI in all older adults. Several older patients labor under the misconception that UI is part of the normal aging process. Other patients may be embarrassed by the nature of the complaint, especially when interacting with a health-care provider of the opposite gender. Decreased awareness of available therapeutic options may also discourage the patient from complaining. As a result of these factors, delayed presentation is typical, with most patients with severe continence, manifesting with loss of large volumes of urine, present themselves after 2 years or more after the onset of symptoms (Miller et al., 1999; Resnick et al., 1994; Rodriguez et al., 2003).

In most cases, a detailed history will enable accurate classification of UI (Table 3). Specific inquiry should be made regarding volume of urine lost, strength of urinary stream, position in which urine loss is most likely to occur, number of pads used, and associated fecal incontinence. Quality of life and caregiver burden should also be assessed. Additional information should be sought regarding risk factors, and predisposing factors (Figure 1). Enquiry should also be made as to a coexisting history of diabetes mellitus, hypercalcemia, impaired cognition, functional disability, or impaired sensory perception. Medication history is critical (Table 4). Diuretics and hyperosmolar agents such as mannitol may contribute to polyuria. Anticholinergic agents may cause obstruction and consequent overflow incontinence. Narcotics, sedative, and hypnotics may impair cognition or cloud consciousness. An accurate voiding diary is an important tool that facilitates the quantification of severity and classification of UI. Serial diaries also facilitate assessment of response to intervention. Although 7-day diaries are still done, available evidence indicates that shorter voiding diaries (48 or 72 hours) are comparable in reliability and validity to the 7-day diaries and are perceived as less burdensome by patients (Ku et al., 2004; Nygaard & Holcomb, 2000; Singh et al., 2004). Physical examination of the patient with UI must include a complete neurological, abdominal, urogenital, pelvic, and rectal examination. The integrity of relevant superficial spinal reflexes, the anal and bulbocavernosus reflexes, should be assessed. Response to the cough reflex can easily be evaluated during pelvic examination, facilitating exclusion of stress incontinence. Persons with stress incontinence may actually be observed to lose urine during coughing. Patients with intact perineal sensation and reflexes will exhibit reflex tightening of the anal sphincter during coughing. Bedside measurement of postvoid residual (PVR) volumes is helpful in the diagnosis or exclusion of overflow Table 4 Some common medications that may cause incontinence

• • • • • • • • • • •

Diuretics Anticholinergics Antihistamines Antipsychotics Antidepressants Sedatives/hypnotics Alcohol Narcotics α-adrenergic agonists/antagonists Calcium channel blockers Hyperosmolar intravenous infusions

Table 3 Clinical differentiation of urinary incontinence

Symptoms

OAB/urge

Stress

Overflow

Functional

Urgency Leakage during activity or cough Volume leaked Ability to reach toilet in time Nocturia

Yes No Large Reduced Yes

No Yes Small Normal No

No Variable Small/dribble Normal Variable

Variable No Large Reduced Yes


incontinence due to bladder outlet obstruction. Postresidual volumes greater than 150 cc in older adults suggest inadequate bladder emptying. PVR volumes greater than 200 cc are highly indicative of urinary retention. Where available, ultrasound measurements of PVR volumes are preferred over direct measurement using a urethral catheter due to the less invasive nature of bladder scans and the consequent lower risk of urinary tract infection (Lehman and Owen, 2001; Sullivan and Yalla, 1996).

PRACTICAL APPROACH TO THE INVESTIGATION AND MANAGEMENT OF UI Diagnostic Evaluation Comprehensive physical examination should yield preliminary information relating to PVR volumes and urethral sphincter competence. The primary care provider should also remain alert to other specific indications for specialist urological evaluation and ensure prompt referral. Thus, urinary retention due to obstructive uropathy, hematuria, prostate disease, recent pelvic surgery, recurrent urinary tract infections, and stress incontinence should prompt early referral for urological examination. However, the majority of older patients with functional UI or urge incontinence associated with overactive bladder can be effectively managed by geriatric or primary care providers. Although urodynamic studies in the assessment of patients with UI are routinely conducted by urologists, available data indicates that results of this test are unlikely to alter management in a significant proportion of older adults. In older adults with UI, urodynamic studies are likely to be most helpful in patients being considered for surgical intervention or in patients in whom the diagnosis remains unclear after a thorough history and physical examination (Lovatsis et al., 2002; Thompson et al., 2000). Guidelines issued by the Agency for Healthcare Policy and Research recommend limitation of initial diagnostic work-up to urinalysis and measurement of PVR volumes. The American Medical Director Association’s guidelines (AMDA) for the management of UI are even more conservative in recommending urinalysis only in patients with suspected urinary tract infection and new or worsening UI. AMDA guidelines recommend PVR measurements only in men and female patients at risk of retention due to coexistent neurologic disorders or diabetes mellitus (AMDA, 2000; Resnick et al., 2004). Bedside cystometric studies have fallen out of favor mainly due to poor diagnostic accuracy, as evidenced by lack of correlation with results of urodynamic studies and failure of cystometry results to alter management initiatives based exclusively on clinical criteria (Byun et al., 2003; Resnick et al., 1996). The associated increased risk of urinary tract infection associated with urethral catheterization is an additional disadvantage of bedside cystometry (Hung et al., 2005; Ouslander et al., 1987).

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Management Effective management incorporates both nonpharmacological and pharmacological strategies. Although, traditionally, pharmacological therapy was withheld until nonpharmacological strategies proved effective, there is emerging controversial evidence that suggests that the parallel institution of both strategies may yield better results (Goode, 2004; Ouslander et al., 2001). Nevertheless, the increased risk of adverse drug effects and interactions in older adults justifies caution with this approach. Thus, an initial trial of nonpharmacological therapy alone remains the conventional approach to treatment. However, inadequate response to nonpharmacological management should prompt consideration of drug therapy. Invasive procedures or definitive surgical intervention are occasionally warranted in older adults who can tolerate such procedures.

Nonpharmacological Intervention The nature of nonpharmacological intervention varies with the type of incontinence. In patients diagnosed with overactive bladder, the mainstay of nonpharmacological management is behavior modification, tailored to suit the individual patient. Mentally competent, functional and highly motivated persons are good candidates for patient-dependent intervention such as biofeedback therapy. In dependent or cognitively impaired patients, caregiver-dependent toileting protocols are more appropriate and likely to be more effective. Prompted voiding is a caregiver-dependent strategy that offers the patient a regular opportunity to use the toilet. The designated caregiver offers toileting assistance at scheduled intervals, usually starting with a short period of about 2 hours. Prompted voiding has the added advantage of providing the patient an opportunity for social interaction and positive reinforcement. Habit training is a more complex variant of this method, where persons with UI are encouraged to link voiding to specific activities, such as meals, drinks, or just before outings. Eventually, regular toileting becomes a “habit”, and involuntary urine loss is preempted. Older adults who are more severely cognitively impaired may be unable to respond appropriately to communication, and thus a simple timed toileting schedule may be more appropriate. In such cases, the caregiver toilets the patient consistently at predetermined intervals. Prompted voiding and habit training are also helpful in the management of older adults with functional incontinence. Environmental assessment, and modification if indicated, is a pivotal component of the management of functional incompetence. Adaptive equipment and assistive appliances may help facilitate efficient toileting and reduce incontinent episodes. Rehabilitative exercises focusing on pelvic muscles and biofeedback therapy may be helpful in patients with stress incontinence or mixed incontinence. In patients with mixed incontinence, a combination of pelvic floor exercises and bladder sphincter biofeedback therapy has been shown

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to result in a reduction in episodes of involuntary loss (Teunissen et al., 2004).

Pharmacological Therapy Detrusor muscle contraction is dependent on the action of Ach on bladder muscarinic receptors. Thus, antimuscarinic drug treatment is appropriate for urge incontinence due to bladder overactivity being poorly responsive to nonpharmacological intervention. Traditionally, antimuscarinic drugs have formed the mainstay of management for this variant of UI. However, until recently, serious and prohibitive side effects such as delirium, cognitive impairment, orthostatic hypotension, falls, and cardiac arrhythmias have rendered this group of agents an unsafe choice to use in older adults. The emergence of selective antimuscarinic agents provides a safer alternative, although in older patients the occurrence of delirium, dry mouth, urinary retention, constipation, and blurring of vision are still troubling concerns. Five different muscarinic receptor subtypes have been cloned (Table 5). M1, M4, and M5 receptor subtypes are found primarily, although not exclusively, in the nervous system. M2 and M3 receptors predominate in smooth muscle, although they are also present relatively small numbers in the brain and salivary glands. M2 and M3 receptors are also the major cholinergic receptors in the bladder. M3 receptors mediate direct detrusor muscle contraction, while M2 receptors appear to play a role in the inhibition of bladder relaxation and modulation of bladder contraction in pathological conditions, such as denervation injury or spinal cord disease. Differences in receptor subtype distribution are particularly important when considering adverse events associated with antimuscarinic agents in older adults. Overall, oxybutynin and tolterodine are the two most commonly used antimuscarinic agents in the treatment of urge incontinence. Oxybutynin is a relatively nonselective antimuscarinic agent and acts primarily on M1, M2, and M3 receptor subtypes. Although oxybutynin has been shown to reduce episodes of UI by almost 50% in 60–80% of patients, there is a relatively high incidence of side effects, with approximately 75% of patients reporting discomfort arising from dry mouth. Tolerability is low, as evidenced by the high discontinuation rate (25%) due to peripheral anticholinergic side effects such as dry mouth, constipation, and blurred vision. Notably, central nervous system (CNS) side effects such as dizziness, cognitive dysfunction, delirium, and psychotic reactions have been reported in several studies, rendering oxybutynin a poor choice for the geriatric patient. Table 5 Distribution of muscarinic receptors

• • • • •

M1: M2: M3: M4: M5:

Cortex, hippocampus, salivary glands Hindbrain, heart, smooth muscle Brain, salivary glands, heart, smooth muscle Basal forebrain, striatum Substantia nigra

Tolterodine is a more selective antimuscarinic agent that affects predominantly M2 and M3 receptor subtypes. Efficacy of tolterodine is comparable to oxybutynin. However, the incidence of peripheral anticholinergic side effects, such as dry mouth, is much lower. Additionally, only three case reports of cognitive dysfunction related to tolterodine use exist in the literature. Available data favor the use of the extended release formulations of tolterodine over the immediate release due to greater efficacy, higher tolerability, and higher adherence rates (Hartnett & Saver, 2001; Rovner and Wein, 2002). More recently, two M3 selective inhibitors, darifenacin and solifenacin have emerged as viable pharmacological therapeutic options for overactive bladder. Available data suggests comparable efficacy with the older agents. However, adverse effects such as constipation and blurred vision, in conjunction with the notable paucity of safety and tolerability data in older adults preclude objective comment regarding prescription of these agents in geriatric practice (Jimenez Cidre, 2004; Robinson & Cardozo, 2004). Trospium has recently been approved by the Federal Drug Administration in the United States for the treatment of overactive bladder in the elderly. However, this drug has been in use in Europe over the past three decades, and available literature indicates a relatively clean safety profile. Unlike the M2/M3 selective agents that are lipophilic, tertiary amines, trospium is a hydrophilic, quaternary amine. These unique biochemical properties render the blood-brain barrier relatively impermeable to trospium, thereby reducing the risk of unwanted CNS side effects. Additionally, available evidence indicates that trospium may exert a significant local effect on nonneuronal cholinergic receptors located in the detrusor muscle. Trospium is not metabolized by the cytochrome p450 system and, therefore, is less prone to drug interactions. Although available global data suggests that trospium is an effective agent and may be well suited for the treatment of urge incontinence in the elderly, further studies specifically relating to safety and tolerability in the frail elder are needed (Gaines, 2005; Rovner, 2004; Scheife and Takeda, 2005).

INVASIVE PROCEDURES AND SURGICAL MANAGEMENT Periurethral sphincter collagen injections and vaginal pessaries are viable and reasonably effective options for older adults unable to tolerate surgery. Sacral neuromodulation involves surgical implantation of a “bladder pacemaker” in the patient’s hip attached to a lead wire that is threaded to a site within the sacral canal at the base of the spine. External programming results in the delivery of a painless electrical stimulus to the sacral nerves, which regulate bladder function. This allows patients to control urine storage and expulsion. For some patients with stress or overflow incontinence, surgery may be the only effective treatment. Older men with


overflow incontinence due to obstructive uropathy arising from prostatic enlargement may experience considerable relief following prostatectomy. Although several techniques have been described to treat stress incontinence, none of them is entirely satisfactory. The best long-term success rate has been documented following bladder neck slings. Prolene suburethral sling insertion is a new promising technique, with a documented cure rate of more than 80%. However, published follow-up does not exceed 3 years. Surgical complications of this procedure include retropubic hematoma, urinary tract infections and fibrosis, pubic osteomyelitis, urinary fistula, and transient postoperative urinary retention. Late complications include dysuria, urinary retention and detrusor instability, genital prolapse, sexual disorders, chronic pain, chronic urinary tract infections, and complications related to the use of biomaterials, including screws, synthetic tape, and artificial urinary sphincter. Nevertheless, quality of life studies after surgery for stress incontinence in younger patients shows consistent improvement. Data in older adults is lacking. Tension-free vaginal tape (TVT) surgery, is a highly effective and minimally invasive alternative for treating patients with stress UI. Surgical complications include bladder perforation, urinary retention, pelvic hematoma suprapubic wound infection, persistent suprapubic discomfort, and intravaginal tape erosion (Abouassaly et al., 2004; Ayoub et al., 2004; Krissi et al., 2004; Ouslander et al., 1987).

KEY POINTS • Urinary incontinence is a highly prevalent syndrome in older adults. Age-related physiological changes in bladder regulation and lower urinary tract dysfunction in the presence of coexisting morbidity increase the likelihood of urinary incontinence with aging. • Urinary incontinence is classified into five major types: urge, stress, functional, overflow, and mixed incontinence. The most common type of incontinence in older adults is urge incontinence resulting from bladder overactivity. • Routine screening for urinary incontinence is a critical component of routine geriatric evaluation. A comprehensive history and physical examination usually enables accurate diagnosis and classification. Initial diagnostic work-up should include urinalysis and postvoid residual measurements. Urodynamic studies are not indicated routinely and should be reserved for selected cases only. • Treatment modalities comprise nonpharmacological, pharmacological, and surgical modalities. Selective antimuscarinic agents are the preferred pharmacological therapeutic option. Invasive modalities include periurethral collagen injections, vaginal pessary insertion, and sling procedures for stress incontinence.

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KEY REFERENCES • Klausner AP & Vapnek JM. Urinary incontinence in the geriatric population. The Mount Sinai Journal of Medicine 2003; 70(1):54 – 61. • Scheife R & Takeda M. Central nervous system safety of anticholinergic drugs for the treatment of overactive bladder in the elderly. Clinical Therapeutics 2005; 27(2):144 – 53. • Teunissen TA, de JA, van WC & Lagro-Janssen AL. Treating urinary incontinence in the elderly – conservative therapies that work: a systematic review. The Journal of Family Practice 2004; 53(1):25 – 30, 32. • Tubaro A. Defining overactive bladder: epidemiology and burden of disease. Urology 2004; 64(6 suppl 1):2 – 6. • Wilson MM. Urinary incontinence: bridging the gender gap. The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences 2003; 58(8):752 – 5.

REFERENCES Abouassaly R, Steinberg JR, Lemieux M et al. Complications of tensionfree vaginal tape surgery: a multi-institutional review. BJU International 2004; 94(1):110 – 3. Allen L, Rodjani A, Kelly J et al. Female epispadias: are we missing the diagnosis? BJU International 2004; 94(4):613 – 5. AMDA. American Medical Directors Association issues how-to guide for protocols on long-term care resident assessment. LTC Regulatory Risk & Liability Advisor 2000; 8(25):7 – 8. Ayed M, Ben AF, Loussaief H et al. Female hypospadias. Apropos of 3 cases. Journal d’urologie 1995; 101(5 – 6):244 – 7. Ayoub N, Chartier-Kastler E, Robain G et al. Functional consequences and complications of surgery for female stress urinary incontinence. Progres en Urologie 2004; 14(3):360 – 73. Birnbaum H, Leong S & Kabra A. Lifetime medical costs for women: cardiovascular disease, diabetes, and stress urinary incontinence. Women’s Health Issues 2003; 13(6):204 – 13. Borrie MJ, Campbell K, Arcese ZA et al. Urinary retention in patients in a geriatric rehabilitation unit: prevalence, risk factors, and validity of bladder scan evaluation. Rehabilitation Nursing 2001; 26(5):187 – 91. Bradway C. Urinary incontinence among older women. Measurement of the effect on health-related quality of life. Journal of Gerontological Nursing 2003; 29(7):13 – 9. Brandeis GH, Baumann MM, Hossain M et al. The prevalence of potentially remediable urinary incontinence in frail older people: a study using the minimum data set. Journal of the American Geriatrics Society 1997; 45(2):179 – 84. Byun SS, Kim HH, Lee E et al. Accuracy of bladder volume determinations by ultrasonography: are they accurate over entire bladder volume range? Urology 2003; 62(4):656 – 60. Chadwick V. Assessment of functional incontinence in disabled living centres. Nursing Times 2005; 101(2):65, 67. Chapple CR. Lower urinary tract symptoms suggestive of benign prostatic obstruction – triumph: design and implementation. European Urology 2001; 39(suppl 3):31 – 6. Dugan E, Roberts CP, Cohen SJ et al. Why older communitydwelling adults do not discuss urinary incontinence with their primary care physicians. Journal of the American Geriatrics Society 2001; 49(4):462 – 5. Enriquez EL. A nursing analysis of the causes of and approaches for urinary incontinence among elderly women in nursing homes. Ostomy/Wound Management 2004; 50(6):24 – 43. Gaines KK. Trospium chloride (Sanctura) – new to the U.S. for overactive bladder. Urologic Nursing 2005; 25(1):64 – 5, 52. Goode PS. Behavioral and drug therapy for urinary incontinence. Urology 2004; 63(3 suppl 1):58 – 64. Gray ML. Gender, race, and culture in research on UI: sensitivity and screening are integral to adequate patient care. The American Journal of Nursing 2003; 103(suppl):20 – 5.

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Grosshans C, Passadori Y & Peter B. Urinary retention in the elderly: a study of 100 hospitalized patients. Journal of the American Geriatrics Society 1993; 41(6):633 – 8. Hartnett NM & Saver BG. Is extended-release oxybutynin (Ditropan XL) or tolterodine (Detrol) more effective in the treatment of an overactive bladder? The Journal of Family Practice 2001; 50(7):571. Hogan DB. Revisiting the O complex: urinary incontinence, delirium and polypharmacy in elderly patients. Canadian Medical Association Journal 1997; 157(8):1071 – 7. Holroyd-Leduc JM, Mehta KM & Covinsky KE. Urinary incontinence and its association with death, nursing home admission, and functional decline. Journal of the American Geriatrics Society 2004; 52(5):712 – 8. Horrocks S, Somerset M, Stoddart H & Peters TJ. What prevents older people from seeking treatment for urinary incontinence? A qualitative exploration of barriers to the use of community continence services. Family Practice 2004; 21(6):689 – 96. Hu TW, Wagner TH, Bentkover JD et al. Costs of urinary incontinence and overactive bladder in the United States: a comparative study. Urology 2004; 63(3):461 – 5. Hung JW, Tsay TH, Chang HW et al. Incidence and risk factors of medical complications during inpatient stroke rehabilitation. Chang Gung Medical Journal 2005; 28(1):31 – 8. Jackson RA, Vittinghoff E, Kanaya AM et al. Urinary incontinence in elderly women: findings from the Health, Aging, and Body Composition Study. Obstetrics and Gynecology 2004; 104(2):301 – 7. Jimenez Cidre MA. Urinary incontinence: anticholinergic treatment. Revista de Medicina de la Universidad de Navarra 2004; 48(4):37 – 42. Johansson C, Hellstrom L, Ekelund P & Milsom I. Urinary incontinence: a minor risk factor for hip fractures in elderly women. Maturitas 1996; 25(1):21 – 8. Johnson TM, Bernard SL, Kincade JE & Defriese GH. Urinary incontinence and risk of death among community-living elderly people: results from the National Survey on Self-Care and Aging. Journal of Aging and Health 2000; 12(1):25 – 46. Johnson TM & Ouslander JG. Urinary incontinence in the older man. Medicine Clinics of North America 1999; 83(5):1247 – 66. Kevorkian R. Physiology of incontinence. Clinics in Geriatric Medicine 2004; 20(3):409 – 25. Kinchen KS, Burgio K, Diokno AC et al. Factors associated with women’s decisions to seek treatment for urinary incontinence. Journal of Women’s Health (Larchmt.) 2003; 12(7):687 – 98. Klauser A, Frauscher F, Strasser H et al. Age-related rhabdosphincter function in female urinary stress incontinence: assessment of intraurethral sonography. Journal of Ultrasound in Medicine 2004; 23(5):631 – 7. Klausner AP & Vapnek JM. Urinary incontinence in the geriatric population. The Mount Sinai Journal of Medicine 2003; 70(1):54 – 61. Krissi H, Borkovski T, Feldberg D & Nitke S. Complications of surgery for stress incontinence in women. Harefuah 2004; 143(7):516 – 9 548. Ku JH, Jeong IG, Lim DJ et al. Voiding diary for the evaluation of urinary incontinence and lower urinary tract symptoms: prospective assessment of patient compliance and burden. Neurourology and Urodynamics 2004; 23(4):331 – 5. Landi F, Cesari M, Russo A et al. Potentially reversible risk factors and urinary incontinence in frail older people living in community. Age and Ageing 2003; 32(2):194 – 9. Lehman CA & Owen SV. Bladder scanner accuracy during everyday use on an acute rehabilitation unit. SCI Nursing 2001; 18(2):87 – 92. Lluel P, Deplanne V, Heudes D et al. Age-related changes in urethrovesical coordination in male rats: relationship with bladder instability? American Journal of Physiology Regulatory, Integrative and Comparative Physiology 2003; 284(5):R1287 – 95. Lovatsis D, Drutz HP, Wilson D & Duggan P. Utilization of preoperative urodynamic studies by Canadian gynaecologists. Journal of Obstetrics and Gynaecology Canada 2002; 24(4):315 – 9. McLoughlin MA & Chew DJ. Diagnosis and surgical management of ectopic ureters. Clinical Techniques in Small Animal Practice 2000; 15(1):17 – 24. Miller JM, Ashton-Miller JA, Carchidi LT & DeLancey JO. On the lack of correlation between self-report and urine loss measured with standing

provocation test in older stress-incontinent women. Journal of Women’s Health 1999; 8(2):157 – 62. Miner PB Jr. Economic and personal impact of fecal and urinary incontinence, Gastroenterology 2004; 126(1 suppl 1):S8 – 13. Molander U, Sundh V & Steen B. Urinary incontinence and related symptoms in older men and women studied longitudinally between 70 and 97 years of age. A population study. Archives of Gerontology and Geriatrics 2002; 35(3):237 – 44. Mouriquand PD, Bubanj T, Feyaerts A et al. Long-term results of bladder neck reconstruction for incontinence in children with classical bladder exstrophy or incontinent epispadias. BJU International 2003; 92(9):997 – 1001. Namikawa M. Pathophysiology of established urinary incontinence (UI) in the elderly and an ameliorative method for disuse syndrome including UI seen in the bed-ridden elderly – using prone position and its variations. Nippon Ronen Igakkai Zasshi 1999; 36(6):381 – 8. Nasr SZ & Ouslander JG. Urinary incontinence in the elderly. Causes and treatment options. Drugs & Aging 1998; 12(5):349 – 60. Newman DK. Report of a mail survey of women with bladder control disorders. Urologic Nursing 2004; 24(6):499 – 507. Nygaard I & Holcomb R. Reproducibility of the seven-day voiding diary in women with stress urinary incontinence. International Urogynecology Journal and Pelvic Floor Dysfunction 2000; 11(1):15 – 7. Ouslander JG. Intractable incontinence in the elderly. BJU International 2000; 85(suppl 3):72 – 8. Ouslander JG, Greengold B & Chen S. Complications of chronic indwelling urinary catheters among male nursing home patients: a prospective study. The Journal of Urology 1987; 138(5):1191 – 5. Ouslander JG, Maloney C, Grasela TH et al. Implementation of a nursing home urinary incontinence management program with and without tolterodine. Journal of the American Medical Directors Association 2001; 2(5):207 – 14. Ouslander JG & Schnelle JF. Incontinence ins the nursing home. Annals of Internal Medicine 1995; 122(6):438 – 49. Patel MD, Coshall C, Rudd AG & Wolfe CD. Cognitive impairment after stroke: clinical determinants and its associations with long-term stroke outcomes. Journal of the American Geriatrics Society 2002; 50(4):700 – 6. Resnick NM, Beckett LA, Branch LG et al. Short-term variability of self report of incontinence in older persons. Journal of the American Geriatrics Society 1994; 42(2):202 – 7. Resnick NM, Brandeis GH, Baumann MM et al. Misdiagnosis of urinary incontinence in nursing home women: prevalence and a proposed solution. Neurourology and Urodynamics 1996; 15(6):599 – 613. Resnick B, Quinn C & Baxter S. Testing the feasibility of implementation of clinical practice guidelines in long-term care facilities. Journal of the American Medical Directors Association 2004; 5(1):1 – 8. Robinson D & Cardozo L. The emerging role of solifenacin in the treatment of overactive bladder. Expert Opinion on Investigational Drugs 2004; 13(10):1339 – 48. Rodriguez LV, Blander DS, Dorey F et al. Discrepancy in patient and physician perception of patient’s quality of life related to urinary symptoms. Urology 2003; 62(1):49 – 53. Rovner ES. Trospium chloride in the management of overactive bladder. Drugs 2004; 64(21):2433 – 46. Rovner ES & Wein AJ. Once-daily, extended-release formulations of antimuscarinic agents in the treatment of overactive bladder: a review. European Urology 2002; 41(1):6 – 14. Saltvedt I, Mo ES, Fayers P et al. Reduced mortality in treating acutely sick, frail older patients in a geriatric evaluation and management unit. A prospective randomized trial. Journal of the American Geriatrics Society 2002; 50(5):792 – 8. Scheife R & Takeda M. Central nervous system safety of anticholinergic drugs for the treatment of overactive bladder in the elderly. Clinical Therapeutics 2005; 27(2):144 – 53. Sgadari A, Topinkova E, Bjornson J & Bernabei R. Urinary incontinence in nursing home residents: a cross-national comparison. Age and Ageing 1997; 26(suppl 2):49 – 54. Shaw C, Tansey R, Jackson C et al. Barriers to help seeking in people with urinary symptoms. Family Practice 2001; 18(1):48 – 52.

URINARY INCONTINENCE Singh M, Bushman W & Clemens JQ. Do pad tests and voiding diaries affect patient willingness to participate in studies of incontinence treatment outcomes? The Journal of Urology 2004; 171(1):316 – 8. Sullivan MP & Yalla SV. Detrusor contractility and compliance characteristics in adult male patients with obstructive and nonobstructive voiding dysfunction. The Journal of Urology 1996; 155(6):1995 – 2000. Tan TL. Urinary incontinence in older persons: a simple approach to a complex problem. Annals of the Academy of Medicine, Singapore 2003; 32(6):731 – 9. Teleman PM, Lidfeldt J, Nerbrand C et al. Overactive bladder: prevalence, risk factors and relation to stress incontinence in middle-aged women. British Journal of Obstetrics and Gynaecology 2004; 111(6):600 – 4. Teunissen TA, de JA, van WC & Lagro-Janssen AL. Treating urinary incontinence in the elderly – conservative therapies that work: a systematic review. The Journal of Family Practice 2004; 53(1):25 – 30, 32. Thompson PK, Duff DS & Thayer PS. Stress incontinence in women under 50: does urodynamics improve surgical outcome? International Urogynecology Journal and Pelvic Floor Dysfunction 2000; 11(5):285 – 9. Tubaro A. Defining overactive bladder: epidemiology and burden of disease. Urology 2004; 64(6 suppl 1):2 – 6. Van der Varrt C, Van der Bom JG, de L Jr, et al. The contribution of hysterectomy to the occurrence of urge and stress urinary incontinence

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symptoms. British Journal of Obstetrics and Gynaecology 2002; 109(2):149 – 54. Vickerman J. Thorough assessment of functional incontinence. Nursing Times 2002; 98(28):58 – 9. Whishaw M. Urinary incontinence in the elderly. Establishing a cause may allow a cure. Australian Family Physician 1998; 27(12):1087 – 90. Wilson MM. Urinary incontinence: bridging the gender gap. The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences 2003; 58(8):752 – 5. Wilson MM. Urinary incontinence: a treatise on gender, sexuality, and culture. Clinics in Geriatric Medicine 2004; 20(3):565 – 70. Wilson L, Brown JS, Shin GP et al. Annual direct cost of urinary incontinence. Obstetrics and Gynecology 2001; 98(3):398 – 406. Wuest M, Morgenstern K, Graf EM et al. Cholinergic and purinergic responses in isolated human detrusor in relation to age. The Journal of Urology 2005; 173(6):2182 – 9. Yoshida M, Miyamae K, Iwashita H et al. Management of detrusor dysfunction in the elderly: changes in acetylcholine and adenosine triphosphate release during aging. Urology 2004; 63(3 suppl 1):17 – 23. Zunzunegui Pastor MV, Rodriguez-Laso A, Garcia de Yebenes MJ et al. Prevalence of urinary incontinence and linked factors in men and women over 65. Atencion Primaria 2003; 32(6):337 – 42.

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Renal Diseases 2 Carlos G. Musso1 and Juan F. Mac´ıas-Nunez ´ 1

Hospital Italiano de Buenos Aires, Buenos Aires, Argentina, and 2 University Hospital of Salamanca, Salamanca, Spain

INTRODUCTION As the term ‘Giants’ in Geriatric Medicine has been coined to define the most frequent clinical conditions, there is also a group of renal conditions that we believe deserve the term “Nephrogeriatric Giants”. For instance, although more than 50% of aged kidneys are normal in appearance, not all of them are actually normal because approximately 14% display cortical scars scattered across their surface (Griffiths et al., 1976). Usually, if these scars are detected in a young person, they suggest pathology such as pyelonephritis, but in the aged kidney, in the absence of other abnormalities, these scars are a consequence of the normal aging process. Another aspect of the renal aging process is the change in kidney weight and size. The weight of the kidney slowly decreases to less than 300 g in the ninth decade of life. Renal length diminishes by 2 cm between the age of 50 and 80 years. The cortex is more affected than the medulla. In the latter, an increase is seen in the interstitial tissue; this is accompanied by fibrosis and increased fat content at the level of the renal sinus (McLachlan, 1987). A constant finding is the presence of cysts along the distal nephron (Baert and Steg, 1977). After the age of 30, there is a gradual reduction in renal functional capacity. By the age of 60, these functions decrease to half the value they were at the age of 30 (Musso et al., 2001). The deterioration of renal function with age can be explained in terms of either the progressive loss of functioning nephrons alone, or a decrease in the number of energy-producing mitochondria, lower concentration of adenosine triphosphatase activity and other enzyme levels, or decreased tubular cell transport capacity as observed in kidneys of old animals (Beauchene et al., 1965). It is important to understand that these changes are not representative of any pathology, but only the normal aging process leading to a reduction in kidney function. As has been previously stated, all the structural and functional changes of the aged kidney may be summarized

under the heading of “Nephrogeriatric Giants”; six conditions that are so called because they are conditions in which there are profound modifications of renal physiology which occur in the majority of the elderly population (Musso, 2002): 1. 2. 3. 4. 5. 6.

Senile hypofiltration Renal vascular alterations Tubular dysfunction Tubular frailty Medullary hypotonicity Obstructive uropathy.

NEPHROGERIATRIC GIANTS Senile Hypofiltration Glomerular sclerosis begins at approximately 30 years of age. The percentage of obsolete glomeruli varies between 1 and 30% in persons aged 50 years or more (McLachlan et al., 1977). The glomerular tuft appears partially or totally hyalinized, and this is the basis of glomerulosclerosis which accompanies aging (Rosen, 1976). With age, there is a reduction in the length and surface of the glomerulus, which affects the effective filtration surface (Goyal, 1982). On microangiographic examination, there is obliteration, particularly of juxtamedullary nephrons, but not of those sited more peripherally, with the formation of a direct channel between afferent and efferent arterioles in this area of the kidney (Takazakura et al., 1972). This presumably contributes to the maintenance of medullary blood flow. The mesangium, which accounts for 8% of glomerular volume at 45 years, increases to nearly 12% at the age of 70 (McLachlan, 1987). Owing to the aforementioned changes, aging is accompanied by a decrease of glomerular filtration rate (GFR), renal plasma flow (RPF) and renal blood flow (RBF) (Cohen


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and Ku, 1983). The GFR evaluation with 51 Cr EDTA confirms that the elderly have lower GFRs than the young. At the third decade of life, GFR reaches approximately 140 ml/minute/1.73 m2 , and from then on, GFR progressively declines at a rate of 8 ml/minute/1.73 m2 per decade (Rowe et al., 1976a). The fall in creatinine clearance (Ccr) is followed by a decrease in creatinine production, and the relationship between blood and urine creatinine levels changes with age (Swedko et al., 2003). This may be the reason serum creatinine concentration of 1 mg dl−1 reflects a GFR of 120 ml/minute in a person 20 years old and 60 ml/minute at the age of 80. If an elderly person has a normal adult creatinine level, it should be remembered that the GFR is diminished and hence the dose of drugs metabolized/eliminated through the kidney should be corrected to the true GFR (Musso and Enz, 1996). To calculate the Ccr in the elderly, the nomogram of Cockcroft and Gault is quite useful in daily clinical practice (Cockcroft and Gault, 1976): Ccr =

(140 − age) × (body weight) 72 × serum creatinine

patient at increased risk for the development of glomerulosclerosis through promotion of vascular or mesangial hypertrophic changes or increased intraglomerular pressure, despite an associated reduction in systemic blood pressure (Weir, 1992). Sometimes, renal function deteriorates suddenly and unexpectedly in hypertensive patients. This condition is commonly due to destruction of main renal arteries by atheroma, a cause of so-called renovascular renal failure. In hypertensive patients, poorly controlled blood pressure on several medications or rapid acceleration of hypertension can suggest renovascular disease. The classic association is a reversible renal failure after use of angiotensin-converting enzyme (ACE) inhibitors and unequal sized kidneys on echography. The importance of making the diagnosis is that it is often possible to regain some renal function, even in end-stage renal disease (ESRD), by intervention on the renal artery (Meyrier, 1996).

Tubular Dysfunction

In women, it is 15% lower. It is of paramount importance to know that although creatinine clearance diminishes with age, the value of plasma creatinine remains stable and comparable to young adults, ranging from 0.9 to 1.3 mg dl−1 . Therefore, if we only take into account plasma creatinine levels without calculating creatinine clearance, we may falsely interpret the GFR as normal, thereby failing to recognize reduced renal function. For patients with a normal plasma creatinine level, one simple way to calculate GFR is 130 – age in years, but for patients with plasma creatinine >1.5 mg dl−1 , it is mandatory to calculate GFR according to the nomograms or 24-hour urine collection.

Renal tubules undergo fatty degeneration with age, showing an irregular thickening of their basal membrane (McLachlan, 1987). By microdissection, the existence of diverticulae arising from the distal and convoluted tubules has been demonstrated, and this becomes more frequent with age. It has been suggested that these may serve as reservoirs for recurrent urinary tract infections in the elderly (Darmady et al., 1973). There are also increasing zones of tubular atrophy and fibrosis, which may relate to the defects in concentration and dilution observed as part of the normal renal aging process (McLachlan, 1987).

Renal Vascular Alteration

Sodium (see Chapter 117, Water and Electrolyte Balance in Health and Disease)

In apparently normal elderly individuals, prearterioles, from which afferent arterioles arise, show subendothelial deposition of hyaline and collagen fibers resulting in an intimal thickening (McLachlan et al., 1977). Small arteries exhibit a thickening of the intima due to proliferation of the elastic tissue. This is associated with atrophy of the media, which virtually disappears when intimal thickening is prominent. Afferent arterioles show reduplication of elastic tissue, with thickening of the intima preceding the subendothelial deposition of hyaline material. Another characteristic of the aging kidney is the formation of anastomoses among afferent and efferent arterioles of the capillary tuft (Darmady et al., 1973). Ischemic nephropathy from nonmalignant nephrosclerosis has emerged as an important cause of terminal renal failure in the elderly patient with essential hypertension (Ritz and Fliser, 1992). Antihypertensive agents may impair renal blood flow (through plasma volume contraction) and further aggravate the age-related decline in renal perfusion. A worsening of renal perfusion may activate counterregulatory neurohormonal mechanisms, such as the reninangiotensin-aldosterone system, which in turn may place the

Hypernatremia and hyponatremia are probably the commonest and most well known disturbances of the internal milieu in the elderly. In spite of the lower sodium tubular load, 24-hour urinary sodium output and fractional excretion of sodium are significantly greater in old and very old people (Macias et al., 1987; Musso et al., 2000). This suggests that the renal tubule of the elderly is unable to retain sodium adequately, either in absolute terms or when corrected to glomerular filtration. The mean half-time for a reduction of sodium excretion is 17.7 hours in persons under 30 years, reaching 30.9 hours in persons over 60, apparently mediated by the concomitant reduction in GFR (Meyer, 1989). As GFR declines with age and the amount of filtered sodium is lower than in young subjects; a salt load given to an elderly person takes longer to eliminate (Fish et al., 1994). However, when sodium is restricted to 50 mmol/day, the period required to achieve equilibrium is 5 days in the young and 9 days in the elderly. As a result of these slow adaptations, both hypernatremia and hyponatremia are frequent findings in patients in geriatric wards (Solomon and Lye, 1990; Roberts and

RENAL DISEASES

Robinson, 1993). Under normal conditions, the elderly are not salt depleted because of replacement of renal sodium losses by salt contained in the diet. Problems may arise when patients are salt restricted for therapeutic reasons or when they become ill and lose their appetite. Both situations may easily lead to salt and volume depletion and even to acute renal failure (ARF). The incompetence of the aging kidney to conserve sodium may explain the facility with which the aged develop volume depletion (Macias et al., 1980). The capacity of the aging kidney to adapt to a low salt intake (50 mmol/24 hour) is clearly blunted (Macias et al., 1978). The proximal nephron behaves similarly in the young, old, and very old, whereas in the “distal nephron” (thick ascending limb of Henle’s loop), a clear-cut difference in the handling of sodium in the elderly is evident, present in 85% of a study population of healthy elderly people (De Santo et al., 1991; Musso et al., 2004). The diminished capacity to reabsorb sodium by the ascending limb of Henle’s loop in healthy elderly people has two direct important consequences. First, the amount of sodium arriving at more distal segments of the nephron (distal convoluted and collecting tubules) increases; and second, the capacity to concentrate in the medullary interstitium is also diminished, causing elderly subjects to exhibit both increased sodium excretion and an inability to maximally concentrate urine. Despite the elderly being more prone to an exaggerated natriuresis, total body sodium is not significantly decreased with age (Fulop et al., 1985). Kirkland et al. (1983) found greater urinary elimination of water and electrolytes during the night in the elderly, which can, at least in part, explain the nocturia observed in 70% of elderly persons. Basal plasma concentrations of renin and aldosterone and the response to stimuli such as walking and salt restriction are also diminished in old age (Macias et al., 1987). Thus, a dual effect of low aldosterone secretion and a relative insensitivity of the distal nephron to the hormone could account for diminished sodium reabsorption at this site. Atriopeptin in the elderly elicits a greater increase in natriuresis, calciuresis, diuresis, urinary, and plasma cyclic Guanydine monophosphate (cGMP) concentrations than in the young (Heim et al., 1989). Potassium (see Chapter 117, Water and Electrolyte Balance in Health and Disease)

Potassium content of the body is lower in the old than in the young and the correlation with age is linear (Cox and Shalaby, 1981). As 85% of potassium is deposited in muscle, and muscular mass diminishes with age, this may largely account for the fall in total body potassium, with other factors such as poor intake also playing some role (Lye, 1981). Under normal conditions, plasma potassium is normal in the elderly, but when diuretics are taken, they develop hypokalemia more rapidly than do the young (Kirkland et al., 1983). The possible explanation for the tendency to develop potassium deficiency is an inability of the kidney to conserve potassium. On the other hand, it has been observed that the total renal excretion of potassium is significantly lower in the aged population than in the

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young. The clinical consequence of the tendency to excrete less potassium by the aging kidney, when total potassium urinary output is considered, is the vulnerability of elderly people to develop hyperkalemia (Lowental, 1994). This electrolyte disturbance is particularly frequent when elderly individuals are treated (either alone or in combination) with the following drugs: nonsteroidal antiinflammatory drugs (NSAIDs), ACE inhibitors, nonselective β-blockers (particularly during exercise) or potassium-sparing diuretics (especially in diabetics) (Andreucci et al., 1996). Recently, a hyperfunction of the H+-K+ ATPase of the intercalar cells in the collecting tubules was described in old rats, generating a greater excretion of H+, and a greater reabsorption of potassium. This mechanism may also explain the trend in old people to develop hyperkalemia (Eiam-Ong and Sabatini, 2002). Urinary Acidification

Macias et al. did not find differences in titratable acid, ammonia, or net acid excretion in response to an acute acid overload in old people, with respect to young controls. The maximal values of ammonia and titratable acid excretion, however, were reached four hours following the acid load in the young, and between six and eight hours in the old. The elderly subjects took longer to reach peak excretion, and experienced a greater fall in blood bicarbonate following the same dose of ammonium chloride (Macias et al., 1983). Lindeman (1990) suggests that renal ammonium ion secretion in response to acid load is not different in healthy elderly subjects. Calcium, Phosphate, and Magnesium

In general, it is a usual clinical finding to observe relatively low blood calcium and high phosphate levels in old age. In the urine, hyperphosphaturia is often found. Regarding calcium urinary output, some authors refer to the same range as for the young population, others have observed a tendency for it to be higher and other groups have found hypocalciuria (Galinsky et al., 1987). These discrepancies may be explained by different calcium intake (dairy products) with or without the addition of vitamin D in these products. These changes in the metabolism of calcium and phosphate may be related to low levels of 1,25-dihydroxy-vitamin D found in the elderly, probably as a result of a deficit of renal 1-α-hydroxylase as an expression of the normal aging process. Serum levels of 24,25-dihydroxy-vitamin D are also low in the elderly. In addition, low plasma phosphate may lead to mild hyperparathyroidism, with further loss of bone mass (Perez del Molino and Alvarez, 2002; De Toro Casado and Mac´ıas Nún˜ ez, 1995). It is known that in old age, magnesium supplements are often required, probably because of a combination of diminished spontaneous intake of magnesium, poor intestinal absorption and increased urinary output. Approximately 80% of magnesium is filtered, 25% reabsorbed by proximal tubuli, and 65% by the thick

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ascending limb of Henle’s loop, which is functionally altered in the elderly. Consequently, a diminution of the reabsorptive capacity of the ascending limb may account for the negative balance of magnesium if oral intake is lower than optimal (Seeling and Preuss, 1994). Erythropoietin Hormone

Erythropoietin hormone is mainly produced by the peritubular interstitial cells near the proximal convoluted tubules. There is no difference in plasma erythropoietin levels among healthy young, old, and very old people (Musso et al., 2004). Urea

In healthy old and very old people, fractional excretion of urea (FEU) is increased in comparison to the younger population: 65 and 50% respectively. This phenomenon could be secondary to a senile alteration in the UT1 (urea channels) that perhaps produces an increase in urea permeability at the collecting tubules (Musso et al., 2004).

Medullary Hypotonicity Aging reduces the capacity of the kidney to concentrate the urine (Rowe et al., 1976b). The maximum urinary concentration remains constant until about the third decade and then falls by about 30 mosmol/kg for each subsequent decade. The diminution of the concentrating ability has been related to the decrease in GFR that occurs with age. The relative increase in medullary blood flow could contribute to the impairment of renal concentration capacity. The defect in sodium chloride reabsorption in the ascending limb of Henle’s loop, which is the basic mechanism for the adequate function of the countercurrent concentration mechanism, may be an important factor for the decrease in the capacity to concentrate urine, as seen in the aged. Moreover, the increased FEU in this group of people could contribute to their medullary hypotonicity, since normally urea accounts for 50% of the interstitial tonicity (Musso et al., 2004). The decrease in responsiveness of collecting duct tubular epithelium to circulatory antidiuretic hormone (ADH), is another explanation for impairment of urine concentrating ability, and it may also explain why plasma vasopressin levels are higher in the elderly compared to the younger population (Bengele et al., 1981; Andreucci et al., 1996). When healthy active elderly volunteers are water restricted for 24 hours, the threshold for thirst is found to be increased and water intake reduced in comparison with a control group of younger subjects (Phillips et al., 1984). Dryness of the mouth, a decrease of taste, alteration in mental capacity or cortical cerebral dysfunction, and a reduction in the sensitivity of both osmoreceptors and baroreceptors may all contribute to the increased threshold for thirst. Finally, angiotensin concentration, a powerful generator of thirst, is lower in the elderly (Andreucci et al., 1996). Total body

water is slightly diminished with age, so that it comprises only 54% of total body weight, probably because old people have a greater proportion of body fat than the young. The diminution seems to be predominantly intracellular. Males have a higher volume than females, regardless of age (Macias et al., 1987; Andreucci et al., 1996; Shannon et al., 1984). Thus, a low plasma volume in an elderly subject is almost always the result of disease (Macias et al., 1987). Urinary dilution has not been extensively investigated in the old, but it has been found to be decreased. There is a minimum urine concentration of only 92 mosmol kg−1 in the elderly compared with 52 mosmol kg−1 in the young (Dontas et al., 1972). Maximum free water clearance was also reduced in the elderly from 16.2 ml/minute to 5.9 ml/minute. Again, the functional impairment of the diluting segment of the thick ascending limb described above seems to account for the remainder of the diminution in the capacity to dilute urine as observed in the aged (Macias et al., 1978).

Tubular Frailty Tubular cells are frail in the elderly, and because of that they progress easily to acute tubular necrosis (ATN), and they also recover slowly from this histological alteration. Owing to these reasons, ARF is a frequent disturbance in the elderly (Musso, 2002; Mac´ıas Nún˜ ez et al., 1996). The commonest causes of ARF in the old population are (Mac´ıas Nún˜ ez et al., 1996; Musso and Mac´ıas Nún˜ ez, 2002): 1. Prerenal causes: loss of fluids (vomiting and diarrhea, diuretics); inadequate fluid intake; loss of plasma (burns); loss of blood (hemorrhage); shock (cardiogenic and septicemic). 2. Renal causes: ATN due to the persistence of the state of prerenal uremia and/or to nephrotoxins; rapidly progressive damage due to collagen disorders, Goodpasture’s syndrome, Henoch-Schonlein purpura; arterial or venous thrombosis; acute interstitial nephritis (toxicity with drugs). 3. Postrenal (obstructive) causes: stones, clot, tumor, stricture, prostatic hypertrophy. Prerenal and postrenal causes of ARF are of particular importance since their early identification and treatment may prevent the development of established ATN (Musso and Mac´ıas Nún˜ ez, 2002). The incidence of ARF in the elderly is higher than in the young, because of the frequency of systemic illnesses, poly pharmacy, and because of the renal aging process itself (Kafetz, 1983). There is also the intriguing role played by accumulation of superoxide radicals with aging. Some illnesses may predispose the aged kidney to develop ARF: cardiac insufficiency, diabetes mellitus, myeloma, prostatic enlargement, vasculitis, rapidly progressive idiopathic glomerulonephritis (GN), mesangiocapillary GN, and the proliferative variety of systemic lupus erythematosus (Frocht and Fillit, 1984). Other etiological agents are septic shock, postsurgical ARF and cardiogenic

RENAL DISEASES

shock. Poly pharmacy includes the use of diuretics, laxatives, analgesics, NSAIDs, and ACE inhibitors, which are all frequently taken by the elderly. The cause of ARF in a particular individual is often multifactorial, that is, inadequate fluid replacement before surgery, followed by dehydration, hypotension, infection, or inappropriate antibiotics (particularly aminoglycosides). In the old, the renal indices for diagnosing ARF may be slightly different from those accepted for younger populations. For instance, in the elderly, a urinary sodium output lower than 70 mmol l−1 in a patient with clinical and biochemical findings of ARF suggest a prerenal cause or acute reversible renal hypoperfusion. When urinary sodium output is higher than 70 mmol l−1 one should think in terms of ATN (Mac´ıas Nún˜ ez et al., 1996; Musso and Mac´ıas Nún˜ ez, 2002; Musso et al., 1996). Initial treatment involves rapid correction of fluid and electrolyte balance. If diuresis is not restored with volume expansion, frusemide can be administered. Other measures, such as administration of low dose dopamine infusion (2–7 µg/kg/minute), may be employed to increase renal tubular flow and promote glomerular vasodilation (Musso and Mac´ıas Nún˜ ez, 2002). Sometimes renal replacement therapy is needed. A greater than 40% survival was achieved in critically ill elderly patients with severe ARF by the use of continuous hemodiafiltration (Bellomo et al., 1994). These findings support an aggressive renal replacement approach in such patients and suggest that continuous hemodiafiltration may be ideally suited to their management. Age per se is not an important determinant of survival in patients with ARF (Druml et al., 1994). Prophylaxis is of paramount importance: maintenance of an adequate extracellular volume and drug dosage regimen tailored to the patient’s GFR are essential (Mac´ıas Nún˜ ez et al., 1996; Musso and Mac´ıas Nún˜ ez, 2002).

Obstructive Uropathy (see Chapter 125, Prostate Diseases) Prostatic hypertrophy occurs to some extent in almost all aging males, but in a proportion it provides a slow obstruction to urinary outflow, with entry into uremia. It is often not recognized until it is too late, largely because the patient becomes polyuric rather than oliguric (Sacks et al., 1989). By the time it is diagnosed, irreversible damage may have taken place, so that even with the relief of obstruction, renal function recovers only partially. The use of α-blockers may help to relieve bladder outlet obstruction and reduce the need for catheterization. Other causes of urinary tract obstruction include uterine prolapse, stones, strictures, and neurogenic bladder due to diabetes mellitus and posterior column dysfunction (Klahr, 1987). Urinary Tract Infection in the Elderly

Urinary tract infection is the most common infectious disease of the elderly and is especially prevalent in debilitated, institutionalized old individuals. The pathogenesis

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is strongly related to obstructive uropathy or its treatment: abnormal bladder function, bladder outlet obstruction, urolithiasis, tumors, use of long-term indwelling catheters. Moreover, the incidence of bacteriuria increases with advancing age since there are nonobstructive mechanisms that predispose aged people to urinary infection such as: vaginal and urethral atrophy and puddling related to bed rest. Infection is usually asymptomatic, and there is currently no indication for the treatment of usually asymptomatic bacteriuria except before invasive genitourinary procedures. Catheter-acquired bacteriuria should probably be treated following catheter removal. These individuals are always bacteriuric, usually with a complex polymicrobial flora. For symptomatic infection, the goal of treatment is relief of symptoms and not sterilization of the urine. Treatment has not been shown to prevent subsequent symptomatic episodes, is associated with antimicrobial adverse effects, and promotes the emergence of resistant organisms. Overuse of antimicrobials should be avoided (Rodr´ıguez Pascual and Olcoz Chiva, 2002; Nicolle, 1994).

CHRONIC RENAL FAILURE (CRF) Introduction CRF is a syndrome characterized by progressive and generally irreversible deterioration of renal competence due to destruction of nephronal mass. CRF is predominantly a disease of the elderly, because the population incidence of CRF rises steadily with age, being at least 10 times more common at the age of 75 than at 15–45 years (Feest et al., 1990). The causes of ESRD in the elderly differ substantially from those in younger populations (Verbeelen et al., 1993). The most common disorders that lead to renal failure in old age are hypertension, diabetes mellitus, nephrosclerosis, and obstructive uropathy although in as many as one-third of cases it proves impossible to identify any specific cause. Two common causes of ESRD in the elderly are vascular disease of the main renal arteries and prostatic. A further problem worth noting is that of amyloidosis (Labeeuw et al., 1996). Pathogenic mechanisms by which the failing kidney may produce specific clinical features are as follows: (1) As the sclerosis of the glomeruli advances, glomerular hyperfiltration appears in the remaining nephrons. In this manner, it is possible to eliminate more intoxicating products per functioning nephron. This mechanism appears beneficial in the first instance, but the price paid for hyperfiltrating is an acceleration of glomerular sclerosis (Anderson and Brenner, 1987). (2) Retention of uremic toxins (polyamines, guanidines, middle molecules, and hormonal peptides). (3) High levels of parathormone (PTH) is currently accepted as the major uremic toxin-Erythropoietin and 1,25dihydroxycholecalciferol deficiencies result in anemia and low calcium, respectively.

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(4) Phosphate retention leads to secondary hyperparathyroidism and renal osteodystrophy. Clinically, it is convenient to divide CRF into three phases. In the early phase, until GFR reaches 50 ml/minute, there are no clear clinical symptoms. The reduction of creatinine clearance is a laboratory finding. As CRF progresses and creatinine clearance falls to about 25 ml/minute, the clinical picture of CRF appears. During this period, polyuria with clear urines and nocturia are present in nearly all patients. With GFR lower than 15 ml/minute, the full clinical picture becomes evident. The skin acquires a characteristic yellow –brown pallor and pruritus is frequent. Soft-tissue calcifications due to high calcium phosphate production are very common. In the eyes, conjunctival and corneal calcifications occur when the calcium phosphate product is raised, producing the “red eye of renal failure”. Patients complain of asthenia, anorexia, and vomiting. In the cardiorespiratory system, pulmonary edema, hypertension, heart failure, coronary disease, and arrhythmia may be seen. The nervous system shows polyneuropathy, clonus, and even uremic coma in the most advanced period of the disease. Secondary hyperparathyroidism, carbohydrate intolerance, hypothyroidism, hyperprolactinemia, and hypogonadism are frequent endocrinological disturbances. A deficit of cellular immunity, polynuclear dysfunction, and clotting alterations are also present. In the late phase, all the above problems increase and when creatinine clearance is lower than 10 ml/minute, it is necessary to start replacement therapy (Musso and Mac´ıas Nún˜ ez, 2002; Glickman et al., 1987). Management

A low protein diet, proposed to relieve uremic symptoms, has shown little effect, and protein restriction in the elderly is associated with a high risk of malnutrition; as a result, we should provide a diet with a protein content between 0.6–1 g kg−1 body weight. Concerning secondary hyperparathyroidism, it remains necessary to suppress PTH secretion with calcitriol, a lowphosphate diet, and phosphate binders. Calcium acetate is preferable as a phosphate binder, because calcium carbonate needs hydrochloric acid to get converted into active calcium chloride, so there is a risk that this drug will remain ineffective in the elderly, who are frequently affected by low gastric acid secretion. The new calci-mimetic drugs should also be of value, although at the moment there is no clinical experience in aged patients. When urinary output falls below 2 l/day, sodium and potassium intake must be restricted, adding loop diuretics. Calcium blockers and ACE inhibitors are recommended to lower high blood pressure and to slow down the progression of renal disease (Vendemia and D’Amico, 1995). Dialysis

During the 1970s, older patients with ESRD were almost never considered as candidates for renal replacement therapy

(RRT), due to limited resources, whereas during the last decade, patients aged 75 and over with ESRD have been accepted routinely on to dialysis programs. Up to one-third of new patients entering dialysis throughout the world are now older than 65 years (D’Amico, 1995). Today, almost all clinicians believe that the majority of elderly uremics can be rehabilitated satisfactorily, and that age by itself does not constitute a major impediment to dialysis and/or transplantation (Piccoli et al., 1993). Elderly patients on dialysis are prone to develop more serious forms of bone disease than the young, because of osteopenia, unbalanced diet, reduced physical activity and lack of exposure to sunlight. Malnutrition is frequently present and cachexia may contribute to death. Of routine laboratory tests, a low serum albumin is the most powerful independent risk factor for mortality. To prevent this, it is advisable to provide more than 1 g kg−1 body weight of proteins for patients on hemodialysis (HD), and more than 1.2 g for those on chronic ambulatory peritoneal dialysis (CAPD), with a diet containing more than 6.3 g/day of essential amino acids(Musso and Mac´ıas Nún˜ ez, 2002). The most common practical problems during treatment by HD of people aged 65 or more are (Ismail et al., 1993; Lerma et al., 1995; Vandelli et al., 1996): 1. Difficulty in surgical fashioning of the arteriovenous fistula due to concomitant arteriosclerosis or insufficient venous dilatation. As a general rule, it is wise to plan surgery for fistula early, when the creatinine clearance is around 20–15 ml/minute. If all local access fails, transposition of a saphenous vein graft to the radial or cubital artery in a loop may allow hemodialysis, and seems to give better results than other artificial grafts. 2. Some 50–60% of elderly patients complain of weakness, hypotension, headaches and vomiting, cramps, and cardiovascular instability in the first two hours of HD. Such episodes can be alleviated by maintenance of a hemoglobin level over 10 g dl−1 and an albumin level about 4 g dl−1 , careful titration of “dry weight”, gentle and slow ultrafiltration, avoidance of vasodilator drugs in the predialysis period, and of course, the use of bicarbonate instead of acetate will also help. 3. Angina is frequent in older patients with coronary artery disease, and this may be facilitated by anemia, left ventricular hypertrophy and perhaps the higher free radical production exhibited by the elderly treated by hemodialysis. To prevent these episodes, it may be useful to maintain a high hematocrit above 30% by transfusion, intravenous iron, androgens, and/or administration of erythropoietin hormone. 4. Arrhythmias are very frequent in the elderly during dialysis because metastatic calcification, amyloid infiltration, cardiac hypertrophy and hypertension are more frequent than in younger patients. Hypokalemia and acidosis are contributory factors to the development of supraventricular and ventricular rhythm disturbances.

RENAL DISEASES

5. The commonest causes of gastrointestinal bleeding in elderly patients are angiodysplasia and gastritis provoked by uremia and worsened by intake of NSAID. 6. Impaired cellular immunity may lead to a higher incidence of viral infections and malignant tumors. CAPD is also not without complications in the aged (Ismail et al., 1993; Grapsa et al., 2000): 1. dialysate leakage and formation of hernias; 2. peritonitis is the most common complication, but its incidence is not significantly different in elderly and young patients. The use of a Y-connector reduces the risk of infection, even in handicapped elderly patients; 3. exit site and tunnel infections requiring antibiotic treatment occur with the same frequency in young and in elderly patients, and catheter survival is also similar in both groups; 4. diverticulitis due to the frequency of intestinal diverticulosis in the elderly. Constipation is common, and is almost invariable in the elderly on dialysis; 5. backache, probably related to increased lordosis, secondary to carrying 2 l of dialysate fluid in the peritoneal cavity; 6. hypotension and worsening of peripheral vascular disease, particularly in those with preexisting ischemia of the lower limbs; 7. peritoneal dialysis imposes a nutritional stress in that from 8 to 15 g of first-class protein, mainly albumin, are lost each day in dialysate, and this amount increases during and following episodes of peritonitis. CAPD is better for patients with residual diuresis, severe hypotension, complicated and/or short-lived vascular access, intradialytic arrhythmias, angina, or cardiovascular instability. CAPD is a satisfactory alternative treatment for elderly ESRD patients. Most studies confirm that survival of elderly patients on CAPD and HD is similar. Other forms of peritoneal dialysis include chronic cycling peritoneal dialysis (CCPD) and nightly automated peritoneal dialysis (APD); the latter can be an alternative treatment for more vulnerable elderly patients (Grapsa and Oreopoulos, 2000; Carrasco et al., 1999). Transplantation

Renal transplantation in the elderly remains controversial, despite being recognized as the most successful and cheapest treatment for patients with ESRD. Until the beginning of the 1980s, patients as young as 45 years were considered to be a “high-risk” group: allograft survival in this agegroup was only 20% at 1 year, due to a high incidence of infections and cardiovascular complications (Simmonds et al., 1971). These ideas are no longer present due to improved care of transplant recipients and the introduction of cyclosporin. However, the reality is that only 4% of patients aged 65–74 under treatment for ESRD receive a renal transplant. The USRDS report for 1991 notes that the

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actual 10-year survival for transplant recipients aged 55–59 was only 22%, only 10.5% for those aged 60–64, and 8% for those aged 65–69 years (Cameron et al., 1994; USRDS, 1991). Triple therapy regimen (prednisolone, azathioprine, and cyclosporin A, all in relatively low doses) used in most European transplant units can be used in the elderly almost without modification. It is prudent to lower the dose of both cyclosporin, to avoid toxicity, and prednisolone, to avoid the many side effects of these drugs, especially on skin and bone. Elderly patients have decreased hepatic enzyme activity, especially the P450 system, and therefore require a lower cyclosporin dose. Because of that, other new drugs such as mycofenolate or rapamycine may be of help although clinical trials of the effect of these drugs in renal transplant in persons aged over 65 are lacking. It is unclear whether antilymphocyte globulin or monoclonal antibodies such as OKT3 should be used in the elderly. The success of transplantation in geriatric ESRD patients over the last decade is due to improved patient selection as well as the use of cyclosporin A and lower doses of corticosteroids, with achievement of 1-year patient and graft survival rates of 85 and 75%, respectively. For patients older than 60 or 65 years, the 5-year “functional” graft survival is 55–60%. Although overall results are excellent, the management of transplantation in the elderly requires an understanding of pharmacology, immunology and physiology peculiar to this age-group. Although elderly patients experience fewer rejection episodes than younger patients, graft loss in the elderly transplant recipient is due mainly to patient death. Most common causes of death in the elderly transplant recipient are cardiovascular disease and infection related to peaks of immunosuppression (Morris et al., 1991; Ismail et al., 1994).

AGED KIDNEY ALTERATIONS Secondary to Systemic Diseases Many features of common renal syndromes are different in elderly subjects. In a comparison of the elderly with patients of younger age-groups, it appeared that amyloidosis, MN, vasculitis, hypertension, and diabetes mellitus had a significantly higher incidence in the elderly. However, apart from greater critical water and electrolyte balance and tendency to develop cardiac failure, the causes, symptomatology, and investigations are largely the same as in the young. Hypertension (see Chapter 48, Hypertension)

Renal diseases, including acute and chronic failure, may cause hypertension but on the other hand, hypertension itself can result in renal damage (Parfrey et al., 1981). It accounts for 33% of ESRD in the elderly (Labeeuw et al., 1996). A pathological rise in arterial pressure with age in Western society may result from an increase in dietary sodium or

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decreased dietary potassium, or both. A renal lesion develops later, possibly as a consequence of this primary increase in blood pressure. This is associated with resetting of pressure natriuresis, so that higher blood pressure is needed to maintain a given sodium excretion. It seems that renal hemodynamics in essential hypertension are adjusted mainly to ensure a consistent GFR. Albuminuria and renal dysfunction have recently been recognized as important complications in the patient with essential hypertension. Albuminuria is associated with more severe hypertension, with evidence of more advanced target organ damage (e.g. left ventricular hypertrophy), and is more prevalent in high-risk groups (e.g. older people). Ischemic nephropathy from nonmalignant nephrosclerosis has emerged as an important cause of terminal renal failure in the elderly patient with essential hypertension (Ritz and Fliser, 1992). Antihypertensive agents may impair renal blood flow (through plasma volume contraction or reduction) and further aggravate the age-related decline in renal perfusion. An understanding of the antihypertensive actions in an elderly patient may have a significant influence on renal function. A worsening of renal perfusion may activate counterregulatory neurohormonal mechanisms, such as the renin-angiotensin-aldosterone system, which in turn may place the patient at increased risk for the development of glomerulosclerosis through promotion of vascular or mesangial hypertrophic changes or increased intraglomerular pressure, despite an associated reduction in systemic blood pressure (Weir, 1992). Atheroembolic Disease of the Elderly

Atheroembolism of the kidney occurs when plaque material breaks free from the diseased vessel and enters the distal microcirculation. Cholesterol crystals are the most easily recognizable of the embolic material, and usually vessels of about 80 mm diameter are affected. Diagnosis is made in a vasculopathic patient aged over 60 years, who has undergone an angiographic procedure or vascular surgery, and fever, muscle pain, weight loss, leucocytosis with eosinophilia, consumption of platelets, hypocomplementemia, and appearance of autoantibodies. Livedo reticularis and digital infarcts occurred in more than 30% of patients. Skin, muscle, and kidney biopsies remain the main tools for diagnosis. Confusion with vasculitis is not rare. Recovery of renal function rarely occurs and the mortality is very high (Cameron, 1995). Diabetic Nephropathy (see Chapter 122, Type 2 Diabetes Mellitus in Senior Citizens)

Renal disease is now one of the commonest fatal complications of diabetes, especially in the elderly, where it causes about 22% of the ESRD cases (Labeeuw et al., 1996). The condition of intercapillary glomerulosclerosis was first described by Kimmelstein and Wilson. Clinically, longstanding proteinuria with gradual decline in renal function leads to development of nephrotic syndrome, hypertension, and heart failure (Airoldi and Campanini, 1993). Results of

treatment of ESRD in patients with non-insulin-dependent diabetes mellitus (type 2) showed a survival rate of 58% at 1 year and 14% at 5 years, independent of treatment modality. Patients who received a renal allograft had a higher survival rate as compared with patients on HD treatment (5-year survival, 59 vs 2%, P < 0.005). Renal transplantation improved survival of elderly diabetic patients without vascular complications and should be the treatment of choice in this specific group of patients (Hirschl et al., 1992). Collagen Disorders

These are chronic multisystem inflammatory diseases that commonly involve the kidney. The lesion is always some form of vasculitis. In systemic lupus erythematosus, necrosis and thrombosis of small vessels lead to ischemic changes. In progressive systemic sclerosis, there is obliterative thickening of the interior of small arteries and thickening of basement membrane due to fibroblastic proliferation and deposition of collagen. Rheumatoid arthritis commonly affects the kidney with proteinuria and renal impairment. In systemic vasculitis in elderly patients, it is not uncommon that kidney involvement, glomerulitis or necrotizing vasculitis, and circulating antineutrophil cytoplasm activity (ANCA), is what leads to diagnosis of the disease. Hematuria is almost a constant in vasculitis nephropathy. ANCA-related renal disease can be treated successfully with cyclophosphamide and steroids, and elderly patients should not be excluded from treatment, including dialysis if necessary (Musso and Mac´ıas Nún˜ ez, 2002; Garrett et al., 1992). Primary Glomerulopathies and Nephrotic Syndrome

During the past decade, controversy has raged about the necessity of renal biopsy for the management of the idiopathic nephrotic syndrome. The debate has centered on whether a precise diagnosis is imperative for steroid treatment or whether such therapy can be given blindly. There is a positive approach to the performance of a renal biopsy in the management of the nephrotic syndrome in the elderly (Moran et al., 1993). Firstly, because at present it is known that the indications for renal biopsy, and the incidence of biopsy complications are the same for elderly and young adults. Secondly, because steroid therapy is not free of complications in the old population, it is therefore better to use this medication with histological support. Consequently, renal biopsy and histological observations are useful aids in estimating the prognosis and therapy selection for renal disorders even in elderly patients (Labeeuw et al., 1996; Moulin et al., 1991). When the number of glomerulopathy cases are properly related to the size of the general population of corresponding age-group, primary GN in the elderly was found to be the most diffuse biopsy-proven renal disease, even more frequent than primary GN in the adult (Vendemia et al., 2001). Incidence of immunoglobulin A (IgA) nephropathy is three- to fourfold higher in patients aged 20–60 years than in the elderly. In contrast,

RENAL DISEASES

membranous nephropathy (MN) is 3 times more frequent in the elderly than in young people (Simon et al., 1995). Nephrotic syndrome accounts for 50% of renal biopsy indications in elderly patients, with its most frequent causes being: MN, minimal change disease and amyloidosis (Labeeuw et al., 1996). MN in some patients is related to drugs or an underlying malignancy (20%). Usually the tumor, most commonly adenocarcinoma of the lung or colon, is obvious at the time of presentation (Labeeuw et al., 1996; Vendemia et al., 2001). Regarding minimal changes disease, it has some particular characteristics when it appears in the elderly: senile structural renal changes make its histological diagnosis difficult; its clinical presentation is usually “atypical”, that means in the context of hypertension, microhematuria and/or renal failure; it may be associated with drugs (NSAID) or malignancies (lymphoma) (Labeeuw et al., 1996). Crescentic GN reaches its greatest incidence in older people aged 60–79 years, and its typical clinical presentation is an ARF of rapid evolution. Steroids and other immunosuppressive drugs (cyclophosphamide, etc.) can be used in the old as in the young, though paying special attention to its side effects (Labeeuw et al., 1996; Vendemia et al., 2001). Plasma Cell Dyscrasias and Primary Amyloidosis

Myeloma has been recognized for many years as a cause of renal disease in the elderly, usually ARF or CRF accompanied by proteinuria. Recovery from ARF is common in myeloma, perhaps because dehydration and desalination plays a role, itself the result of mobilization hypercalcemia. However, once ESRD has been reached, return of renal function is rare. Other types associated with abnormal plasma cell products are light chain nephropathy and fibrillary or immunotactoid nephropathy. In both conditions, the marrow is usually of normal to ordinary cytology, but there are often paraprotein spikes in serum or light chains in the urine. Finally, in primary amyloidosis patients are nephrotic and often develop renal failure (Musso and Mac´ıas Nún˜ ez, 2002; Kafetz, 1983; Frocht and Fillit, 1984; Musso et al., 1996; Bellomo et al., 1994; Druml et al., 1994; Sacks et al., 1989; Klahr, 1987; Rodr´ıguez Pascual and Olcoz Chiva, 2002; Nicolle, 1994; Feest et al., 1990; Verbeelen et al., 1993; Labeeuw et al., 1996; Anderson and Brenner, 1987; Glickman et al., 1987; Vendemia and D’Amico, 1995; D’Amico, 1995; Piccoli et al., 1993; Ismail et al., 1993; Lerma et al., 1995; Vandelli et al., 1996; Grapsa and Oreopoulos 2000; Carrasco et al., 1999; Simmonds et al., 1971; Cameron et al., 1994; USRDS, 1991; Morris et al., 1991; Ismail et al., 1994; Parfrey et al., 1981; Cameron, 1995).

DRUGS AND THE KIDNEY The kidneys in elderly subjects are particularly susceptible to the toxic effect of drugs and other chemical agent for the following reasons: (1) there is a rich blood

1503

supply; (2) drugs are concentrated in the hypertonic medulla; (3) drug accumulation is associated with impaired renal function; (4) hypersensitivity reaction with vasculitis is common in the kidney; (5) concomitant inhibition of hepatic enzymes increases drug toxicity. There is evidence that metabolic activation of some drugs within the kidney is responsible for nephrotoxicity while other drug reactions seem to be immunologically mediated (Evans, 1980). The high rates of drug-induced ARF, worsening chronic renal dysfunction and systemic toxicity of renal excreted drugs can be minimized by carefully assessing renal function, avoiding potentially nephrotoxic drugs as much as possible and closely monitoring drug concentrations and renal function when drugs must be used (Thomson, 1995). NSAIDs may induce a variety of acute and chronic renal lesions. Acute interstitial nephritis can follow the use of nearly all NSAIDs, but the number of reported cases is low. Most of these patients are elderly and develop a nephrotic syndrome with ARF while taking NSAIDs for months. Renal biopsy shows acute tubulo-interstitial lesions with minimal changes in the glomeruli. The renal signs usually improve after discontinuing the drug, with or without steroid therapy, but chronic renal insufficiency or even ESRD are possible hazards. Interstitial nephritis results mainly from a delayed hypersensitivity response to NSAID, and nephrotic syndrome results from changes in glomerular permeability mediated by prostaglandins and other hormones. Patients taking NSAIDs for months or years may develop papillary necrosis, chronic interstitial nephritis, or even ESRD (Kleinknecht, 1995). The use of ACE inhibitors has increased greatly during recent years, and they are used in the treatment of elderly patients who often have generalized atherosclerosis. During treatment with ACE inhibitors, kidney function must be controlled before and following 1 to 2 weeks of treatment, since treatment with ACE inhibitors can cause pronounced changes in renal hemodynamics and kidney function (Rasmussen et al., 1995). ACE inhibitors reduce angiotensin II production, with a decrease in total renal vascular resistance. The mechanism of ARF involves two major factors: sodium depletion and reduction in renal perfusion pressure. ARF is usually asymptomatic, nonoliguric, associated with hyperkalemia, and in nearly every case, completely reversible after discontinuation of the ACE inhibitors. The use of ACE inhibitors in the elderly should be practised with caution (Toto, 1994).

Toxicity of Drugs Administered to Patients with Renal Impairment This depends on multiple factors, particularly the proportion of the drug normally excreted by the kidneys and the likely toxic effect of drugs. Thus the elderly are more susceptible to ototoxicity and nephrotoxicity with aminoglycosides, neuropathy with nitrofurantoin, and hypoglycemia with chlorpropamide (Castleden, 1978). Digoxin is mainly excreted by the kidney and, consequently, the same dose of

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MEDICINE IN OLD AGE

digoxin produces higher blood levels and a longer blood halflife in old subjects than in the young. Its cardiac toxicity is enhanced by hypokalemia, a very common association due to the concomitant use of diuretics and the known tendency of the elderly to take a diet deficient in potassium. Dose adjustment may be achieved by reducing the amount given at the same intervals or by giving the same dose at longer intervals (Musso and Enz, 1996).

CONCLUSIONS The aging kidney becomes less efficient in coping with stressful situations such as overload or deprivation. If attention is not paid to this decrease in functional capacity, it is possible to predispose elderly patients to situations such as ARF or congestive cardiac failure. In elderly patients, drug abuse is frequent, dehydration is very common, and renal artery stenosis and urinary outflow obstruction are important but often symptomless. With clinical experience, it is possible to overcome these difficulties and prevent renal failure. Kidney transplantation in elderly patients shows that longterm survival is at least as good, quality of life is improved and treatment is cheaper than HD or CAPD.

Acknowledgment The authors are very grateful for the assistance of Sarah Dunt, Anna-Louise Nichols, and Tom Wingfield in the preparation of this chapter, enabled by the successful Erasmus-Socrates Exchange Program between The University of Salamanca, Spain, and The University of Liverpool, UK.

KEY POINTS • The “Nephrogeriatric Giants” are six conditions that represent profound structural and physiological renal modifications which occur in the majority of the elderly population. These conditions are senile hypofiltration, renal vascular alteration, medullary hypotonicity, obstructive uropathy, tubular dysfunction, and frailty. • Indications for renal biopsy, and the incidence of biopsy complications are the same for elderly and young adults. • Main causes of renal failure in the old population are hypertension, atheroembolic disease, diabetes mellitus, vasculitis, plasma cell dyscrasias, and nephrotoxic drugs. • CRF is predominantly a disease of the elderly and age by itself does not constitute a major impediment to dialysis and/or transplantation.

KEY REFERENCES • Macias JF, Garcia-Iglesias C, Bondia A et al. Renal handling of sodium in old people: a functional study. Age and Ageing 1978; 7:178 – 81. • Mac´ıas Nún˜ ez JF, López Novoa JM & Mart´ınez Maldonado M. Acute renal failure in the aged. Seminars in Nephrology 1996; 16:330 – 8. • Musso CG. Geriatric nephrology and the “nephrogeriatric giants”. International Urology and Nephrology 2002; 34:255 – 6. • Musso CG, Fainstein I, Kaplan R & Mac´ıas Nún˜ ez JF. Tubular renal function in the oldest old. Revista Espanola de Geriatria y Gerontologia 2004; 39(5):314 – 9. • Vendemia F, Gesualdo L, Schena FP & D’amico G. Epidemiology of primary glomerulonephritis in the elderly. Report from the Italian registry of renal biopsy. Journal of Nephrology 2001; 14:340 – 52.

REFERENCES Airoldi G & Campanini M. Microalbuminuria: theoretical bases and new applications. Recenti Progressi in Medicina 1993; 84:210 – 24. Anderson S & Brenner BM. The aging kidney: structure, function, mechanisms, and therapeutic implication. Journal of the American Geriatrics Society 1987; 35:590 – 3. Andreucci V, Russo D, Cianciaruso B & Andreucci M. Some sodium, potassium and water changes in the elderly and their treatment. Nephrology, Dialysis, Transplantation 1996; 11(suppl 9):9 – 17. Baert L & Steg A. Is the diverticulum of the distal and collecting tubules a preliminary stage of the simple cyst in the adult? The Journal of Urology 1977; 118:707 – 10. Beauchene RE, Fanestil DD & Barrows CH. The effect of age on active transport and sodium-potassium-activated ATPase activity in renal tissue of rats. Journal of Gerontology 1965; 20:306 – 10. Bellomo R, Farmer M & Boyce N. The outcome of critically ill elderly patients with severe acute renal failure treated by continuous hemodiafiltration. The International Journal of Artificial Organs 1994; 17:466 – 72. Bengele HH, Mathias RS, Perkins JH & Alexander EA. Urinary concentrating defect in the aged rat. The American Journal of Physiology 1981; 240:147 – 50. Cameron JS. Renal disease in the elderly: particular problems. In G D’Amico & G Colasanti (eds) Issues in Nephrosciences 1995, pp 111 – 7; Wichting, Milano. Cameron JS, Compton F, Koffman G & Bewick M. Transplantation in elderly recipients. Geriatric Nephrology and Urology 1994; 4:93 – 9. Carrasco M, Garc´ıa Ramón R & Gonzalez Rico M. Diálisis peritoneal en el anciano. In J Montenegro & J Olivares (eds) La Diálisis Peritoneal 1999, pp 479 – 90; Dibe, Spain. Castleden CM. Prescribing for the elderly. Prescribers’ Journal 1978; 18:90. Cockcroft DW & Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976; 16:31 – 41. Cohen MP & Ku L. Age-related changes in sulfation of basement membrane glycosaminoglycans. Experimental Gerontology 1983; 18:447 – 50. Cox JR & Shalaby WA. Potassium change with age. Gerontologie 1981; 27:340 – 4. D’Amico G. Comparability of the different registries on renal replacement therapy. American Journal of Kidney Diseases 1995; 25:113 – 8. Darmady EM, Offer J & Woodhouse MA. The parameters of the ageing kidney. The Journal of Pathology 1973; 109:195 – 207. De Santo N, Anastasio P, Coppola S et al. Age-related changes in renal reserve and renal tubular function in healthy humans. Child Nephrology and Urology 1991; 11:33 – 40. De Toro Casado R & Mac´ıas Nún˜ ez JF. Physiologic characteristics of the renal ageing: clinical consequences. Anales de Medicina Interna 1995; 12:157 – 9. Dontas AS, Marketos S & Papanayioutou P. Mechanisms of renal tubular defects in old age. Postgraduate Medical Journal 1972; 48:295 – 303.

RENAL DISEASES Druml W, Lax F, Grim G et al. Acute renal failure in the elderly 1975-1990. Clinical Nephrology 1994; 41:342 – 9. Eiam-Ong S & Sabatini S. Effect of ageing and potassium depletion on renal collecting tubule k-controlling ATPases. Nephrologie 2002; 7:87 – 91. Evans DB. Drugs and the kidney. British Journal of Hospital Medicine 1980; 24:244 – 51. Feest TG, Mistry CD, Grimes DS & Mallick NP. Incidence of advanced chronic renal failure and the need for end-stage renal replacement treatment. British Medical Journal 1990; 301:897 – 903. Fish LC, Murphy DJ, Elahi D & Minaker KL. Renal sodium excretion in normal aging: decreased excretion rates lead to delayed sodium excretion in normal aging. Journal of Geriatric Nephrology and Urology 1994; 4:145 – 51. Frocht A & Fillit H. Renal disease in the geriatric patient. Journal of the American Geriatrics Society 1984; 32:28 – 43. Fulop T, Worum I, Csongor J et al. Body composition in elderly people. Gerontology 1985; 31:6 – 14. Galinsky D, Meller Y & Shany S. The aging kidney and calcium regulating hormones: vitamin D metabolites, parathyroid hormone and calcitonin. In JF Macias & JS Cameron (eds) Renal Function and Disease in the Elderly 1987, p 121; Butterworths, London. Garrett PJ, Dewhurst AG, Morgan LS et al. Renal disease associated with circulating antineutrophil cytoplasm activity. The Quarterly Journal of Medicine 1992; 85:731 – 49. Glickman JL, Kaiser D & Bolton K. Aetiology and diagnosis of chronic renal insufficiency in the aged: the role of the renal biopsy. In JF Macias & JS Cameron (eds) Renal Function and Disease in the Elderly 1987, pp 485 – 508; Butterworths, London. Goyal VK. Changes with age in the human kidney. Experimental Gerontology 1982; 17:321 – 31. Grapsa E & Oreopoulos DG. Continuous ambulatory peritoneal dialysis in the elderly. In R Gokal & K Nolph (eds) The Textbook of Peritoneal Dialysis 2000, pp 419 – 33; Kluwer Academic Publishers, Dordrecht. Griffiths GJ, Robinson KB, Cartwright GO & McLachlan MSF. Loss of renal tissue in the elderly. The British Journal of Radiology 1976; 49:111 – 7. Heim JM, Gottmann K, Weil J et al. Effects of a bolus of atrial natriuretic factor in young and elderly volunteers. European Journal of Clinical Investigation 1989; 19:265 – 71. Hirschl MM, Heinz G, Sunder-Plassmann G & Derfle K. Renal replacement therapy in type 2 diabetic patients: 10 years. American Journal of Kidney Diseases 1992; 20:564 – 8. Ismail N, Hakim RM & Helderman JH. Renal replacement therapies in the elderly: Part II. Renal transplantation. American Journal of Kidney Diseases 1994; 23:1 – 15. Ismail N, Hakim RM, Oreopoulos DG & Patrikaerea A. Renal replacement therapies on the elderly: Part I. Hemodialysis and chronic peritoneal dialysis. American Journal of Kidney Diseases 1993; 22:759 – 82. Kafetz K. Renal impairment in the elderly: a review. Journal of the Royal Society of Medicine 1983; 76:398 – 401. Kirkland JL, Lye M, Levy DW & Banerjee AK. Patterns of urine flow and electrolyte secretion in healthy elderly people. British Medical Journal 1983; 285:1665 – 7. Klahr S. Obstructive uropathy in the elderly. In JF Macias & JS Cameron (eds) Renal Function and Disease in the Elderly 1987, pp 432 – 55; Butterworths, London. Kleinknecht D. Interstitial nephritis, the nephrotic syndrome, and chronic renal failure secondary to nonsteroidal anti-inflammatory drugs. Seminars in Nephrology 1995; 15:228 – 35. Labeeuw W, Caillette A & Dijoud F. La biopsie rénal chez le sujet aˆ gé. La Presse Médicale 1996; 25:611 – 4. Lerma JL, Tabernero JM, Gascon A et al. Influence of age and hemodialysis on the production of free radicals. Geriatric Nephrology and Urology 1995; 5:93 – 6. Lindeman RD. Overview: renal physiology and pathophysiology of ageing. American Journal of Kidney Diseases 1990; 16:275 – 82. Lowental DT. Vulnerability to hyperkalemia. Journal of Geriatric Nephrology and Urology 1994; 4:121 – 5. Lye M. Distribution of body potassium in healthy elderly subjects. Gerontologie 1981; 27:286 – 92.

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Macias JF, Bondia A & Rodriguez Commes JL. Physiology and disorders of water balance and electrolytes in the elderly. In JF Macias & JS Cameron (eds) Renal Function and Disease in the Elderly 1987, pp 67 – 93; Butterworths, London. Macias JF, Garcia-Iglesias C, Bondia A et al. Renal handling of sodium in old people: a functional study. Age and Ageing 1978; 7:178 – 81. Macias JF, Garcia-Iglesias C, Tabernero JM et al. Renal management of sodium under indomethacin and aldosterone in the elderly. Age and Ageing 1980; 9:165 – 72. Macias JF, Garcia-Iglesias C, Tabernero JM et al. Behaviour of the ageing kidney under acute acid overload. Nefrologia 1983; 3:11 – 6. Mac´ıas Nún˜ ez JF, López Novoa JM & Mart´ınez Maldonado M. Acute renal failure in the aged. Seminars in Nephrology 1996; 16:330 – 8. McLachlan MSF. Anatomic structural and vascular changes in the ageing kidney. In JF Macias & JS Cameron (eds) Renal Function and Disease in the Elderly 1987, pp 3 – 26; Butterworths, London. McLachlan MSF, Guthrie JC, Anderson CK & Fulker MJ. Vascular and glomerular changes in the ageing kidney. The Journal of Pathology 1977; 121:65 – 77. Meyer BR. Renal function in ageing. Journal of the American Geriatrics Society 1989; 37:791 – 800. Meyrier A. Renal vascular lesions in the elderly: nephrosclerosis or atheromatous renal disease? Nephrology, Dialysis, Transplantation 1996; 11(suppl 9):45 – 52. Moran D, Korzets Z, Bernheim J et al. Is renal biopsy justified for the diagnosis and management of the nephrotic syndrome in the elderly? Gerontology 1993; 39:49 – 54. Morris GE, Jamieson NV, Small J et al. Cadaveric renal transplantation in elderly recipients: is it worthwhile? Nephrology, Dialysis, Transplantation 1991; 6:887 – 92. Moulin B, Dhib M, Sommervogel C et al. Intérêt de la biopsie rénal chez le vieillard. La Presse Médicale 1991; 20:1881 – 5. Musso C & Enz P. Pharmacokinetics in the elderly. Revista Argentina de Farmacolog´ıa Cl´ınica 1996; 3:101 – 5. Musso C, Fainstein I & Kaplan R. The patient with acid-base and electrolytes disorders. In JF Macias, F Guillén Llera & JM Rivera Casado (eds) Geriatrics Since the Beginning 2001, pp 245 – 52; Glosa, Barcelone. Musso CG, Fainstein I, Kaplan R & Mac´ıas Nún˜ ez JF. Tubular renal function in the oldest old. Revista Espanola de Geriatria y Gerontologia 2004; 39(5):314 – 9. Musso CG. Geriatric nephrology and the “nephrogeriatric giants”. International Urology and Nephrology 2002; 34:255 – 6. Musso CG & Mac´ıas Nún˜ ez JF. The aged kidney: morphology and function. Main nephropathies. In A Salgado, F Guillén & I Ruipérez (eds) Geriatrics Handbook 2002, pp 399 – 412; Masson, Barcelone. Musso CG, Mac´ıas Nún˜ ez JF & Mayorga M. Worth of the urinary sodium in the differential diagnosis between renal and pre-renal acute renal failure in the elderly. Revista Argentinade Geriatr´ıa y Gerontolog´ıa 1996; 16:129 – 36. Musso CG, Mac´ıas Nún˜ ez JF, Musso CAF et al. Fractional Excretion of sodium in old old people on a low sodium diet. Federation of American Societies for Experimental Biology 2000; 14:A659. Nicolle LE. Urinary tract infection in the elderly. The Journal of Antimicrobial Chemotherapy 1994; 33:99 – 109. Parfrey PS, Markandu ND, Roulston JE et al. Relation between arterial blood pressure, dietary sodium intake and renin system in essential hypertension. British Medical Journal 1981; 283:94. Perez del Molino P & Alvarez L. Metabolic bonne diseases in the elderly. In A Salgado, F Guillén & I Ruipérez (eds) Geriatrics Handbook 2002, pp 447 – 58; Masson, Barcelone. Phillips PA, Rolls BJ, Ledingham DM et al. Reduced thirst after water deprivation in healthy elderly men. The New England Journal of Medicine 1984; 311:753 – 9. Piccoli G, Bonello F, Massara C et al. Death in conditions of cachexia: the price for the dialysis treatment of the elderly? Kidney International 1993; 43:282 – 6. Rasmussen K, Heitmann M, Nielsen JI & Mogelvang JC. Renal function during treatment with angiotensin converting enzyme inhibitors. Ugeskrift for Laeger 1995; 157:5377 – 81.

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Ritz E & Fliser D. Clinical relevance of albuminuria in hypertensive patients. Clinical and Investigative 1992; 70:s114 – 9. Roberts MM & Robinson AG. Hyponatremia in the elderly: diagnosis and management. Geriatric Nephrology and Urology 1993; 3:43 – 50. Rodr´ıguez Pascual C & Olcoz Chiva M. Infectious diseases in geriatric patients. In A Salgado, F Guillén & I Ruipérez (eds) Geriatrics Handbook 2002, pp 542 – 8; Masson, Barcelone. Rosen H. Renal disease of the elderly. The Medical Clinics of North America 1976; 60:1105. Rowe JW, Andres R, Tobin JD et al. The effect of age on creatinine clearance in man: a cross-sectional and longitudinal study. Journal of Gerontology 1976a; 31:155 – 63. Rowe JW, Shock NW & De Fronzo RA. The influence of age on the renal response to water deprivation in man. Nephron 1976b; 17:270 – 8. Sacks SH, Aparicio SAJR, Bevan A et al. Late renal failure due to prostatic out flow obstruction: a preventable disease. British Medical Journal 1989; 298:180 – 9. Seeling MS & Preuss HG. Magnesium metabolism and perturbation in the elderly. Geriatric Nephrology and Urology 1994; 4:101 – 11. Shannon RP, Minaker KL & Rowe JW. Aging and water balance in humans. Seminars in Nephrology 1984; 4:346 – 53. Simmonds RL, Kjellstrand CM, Buselmeier TS et al. Renal transplantation in high risk patients. Archives of Surgery 1971; 103:290 – 8. Simon P, Ramee MP, Autuly V et al. Epidemiology of primary glomerulopathies in a French region. Variations as a function of age in patients. Nephrologie 1995; 16:191 – 201.

Solomon LR & Lye M. Hypernatremia in the elderly patient. Gerontology 1990; 36:171 – 9. Swedko P, Clark H, Paramsothy K & Akbari A. Serum creatinine is an inadequate screening test for renal failure in the elderly patients. Archives of Internal Medicine 2003; 163:356 – 60. Takazakura E, Sawabu N, Handa A et al. Intrarenal vascular changes with age and disease. Kidney International 1972; 2:224 – 30. Thomson NM. Drugs and the kidney in the elderly. The Medical Journal of Australia 1995; 162:543 – 7. Toto RD. Renal insufficiency due to angiotensin-converting enzyme inhibitors. Mineral and Electrolyte Metabolism 1994; 20:193 – 200. USRDS (United States Renal Data System). Annual data report. American Journal of Kidney Diseases 1991; 18(suppl 2):38 – 48. Vandelli L, Medici G, Perrone S & Lusvarghi E. Haemodialysis in the elderly. Nephrology, Dialysis, Transplantation 1996; 11(suppl 9):89 – 94. Vendemia F & D’Amico G. Management of chronic renal failure in the elderly. In G D’Amico & G Colasanti (eds) Issues in Nephrosciences 1995, pp 119 – 26; Wichting, Milano. Vendemia F, Gesualdo L, Schena FP & D’amico G. Epidemiology of primary glomerulonephritis in the elderly. Report from the Italian registry of renal biopsy. Journal of Nephrology 2001; 14:340 – 52. Verbeelen D, de Neve W, van der Niepen P & Sennessael J. Dialysis in patients over 65 years of age. Kidney International 1993; 43:s27 – 30. Weir MR. Hypertensive nephropathy: is a more physiologic approach to blood pressure control an important concern for the preservation of renal function? The American Journal of Medicine 1992; 93:s27 – 37.

PART III


Cancer

128

Cancer and Aging Claudia Beghe1,2 and Lodovico Balducci1,3 1

University of South Florida College of Medicine, Tampa, FL, USA, 2 James A. Haley Veterans’ Hospital, Tampa, FL, USA, and 3 H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA

Cancer is the second most common cause of death and a major cause of disability for individuals aged 65 and older (Yancik and Ries, 2004). Cancer control is a key to a more prolonged and more active survival. After reviewing the epidemiology of cancer in the elderly and the biologic interactions of cancer and age, we will examine effectiveness and safety of cancer prevention and treatment in the older aged person.

EPIDEMIOLOGY The incidence of most common cancers increases with age (Figure 1) up to age 80–85 and plateaus thereafter (Yancik and Ries, 2004). Autopsy studies suggest that after age 95 cancer ceases to be a major cause of morbidity and mortality, and even the incidence of occult malignancies may decrease (Stanta et al., 1997). Seemingly, the prevalence of common cancers increases also with age, as early diagnosis and new forms of treatment have transformed many neoplasms into chronic diseases that may influence the function and the quality of life of older individuals. This area deserves more investigation (Caranasos, 1997). Four epidemiological facts may have clinical implications. First, while cancer incidence has increased both among people younger than 65 and those 65 and older since 1950, cancer-related mortality has decreased for the young but increased for the old ones (Wingo et al., 2003). This may be due in part to remediable causes, including the fact that older individuals are less likely to undergo cancer screening and to receive aggressive antineoplastic treatment. For example, breast cancer is diagnosed at a more advanced stage in women over 70 despite the fact that this neoplasm becomes more indolent with age (Randolph et al., 2002). Second, the incidence of some neoplasms, including nonHodgkin’s lymphomas and malignant brain tumors, has increased since 1970 mainly in older individuals (Yancik and Ries, 2004; Wingo et al., 2003). This phenomenon, that

so far is unexplained, should alert the practitioner that with the aging of the population certain diseases may become more common and that age may be associated with increased susceptibility to certain neoplasias. Third, an age-related shift in incidence and mortality has been seen for some cancers. For example, lung cancer –related mortality has declined by more than 10% in individuals 50 and younger, but has increased around 20% for those 70 and older (Wingo et al., 2003). Nowadays, lung cancer in elderly ex-smokers is becoming progressively more common. Smoking cessation has likely resulted in reduced death rate from cardiovascular and chronic obstructive lung diseases, and in reduced growth rate of occult cancer. In support of this hypothesis, lung cancer may be more indolent in older individuals. The emergence of more indolent lung cancer with a prolonged preclinical phase justifies new studies of early detection of lung cancer in ex-smokers. Fourth, cancer may affect preferentially older individuals in good general condition. In Italy, Ferrucci et al., (2003) and Repetto et al., (1998) demonstrated that cancer patients aged 70 and older were less likely to present functional dependence or comorbidity than age-matched individuals without cancer. The Surveillance, Epidemiology and End Result study (SEER) showed that women aged 80 and older with breast cancer had a more prolonged survival than women of the same age without breast cancer (Diab et al., 2000). These findings support cancer prevention and treatment in older individuals as they indicate that cancer is indeed a cause of death and morbidity for the elderly.

BIOLOGICAL INTERACTIONS OF CANCER AND AGING These interactions may occur in two areas: carcinogenesis, and tumor biology.


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MEDICINE IN OLD AGE Prostate

1200

500

Colon Lung/ Bronchus Urinary/ Bladder

500 400 300 200

Rectum Stomach Pancreas

100 0 (a)

per 100,000

per 100,000

600

400

Breast Colon

300

Lung/ Bronchus

100 0

35 40 45 50 55 60 65 70 75 80 85+ Age

Rectum Pancreas Urinary/ Bladder Stomach Ovary

200

(b)

35 40 45 50 55 60 65 70 75 80 85+ Age

Figure 1 (a) Cancer incidence rates in men. (b) Cancer incidence rates in women

Aging and Carcinogenesis Carcinogenesis is a stepwise process that involves a number of serial genomic changes, including activation of cellular oncogenes and inhibition of antiproliferative genes (antioncogenes) (Anisimov, 2005). These changes are effected by substances called carcinogens that in experimental models have been distinguished into early- and late-stage carcinogens. The action of the latter is reversible and is the focus of a modern strategy of cancer control, chemoprevention. The association of aging and cancer may be explained by three, nonmutually exclusive mechanisms. First, as carcinogenesis is time consuming, cancer is more likely to become manifest late in life. Second, aging is associated with molecular changes similar to those of carcinogenesis, including formation of DNA adducts and DNA hypermethylation. Older individuals harbor a larger concentration of cells primed to the action of late-phase environmental carcinogens. Both experimental and clinical data support this hypothesis (Anisimov, 2005). A possible explanation for the increased incidence of lymphoma and malignant brain tumors recently observed in older individuals is that these individuals are a natural monitoring system for new environmental carcinogens, that is, in the presence of new carcinogens older individuals develop cancer at an earlier time. Third, paradoxically, proliferative senescence, that is the loss of self-replicative ability of the aging cells, may predispose to cancer, as senescent cells may become immortalized (Hornsby, 2004). The pathogenesis of slowly growing neoplasms, such as follicular lymphoma, may be traced to the loss of programmed cell death (apoptosis) by the aging lymphocytes (Balducci and Aapro, 2004).

Age and Tumor Biology The clinical behavior of some neoplasms may change with the age of the patient (Table 1) (Balducci and Aapro, 2004). At least two mechanisms may explain these changes. If one thinks of a tumor as a plant, the growth of the plant may be determined by the nature of the seed (the tumor cell), and of the soil (the tumor host). In the case of acute

Table 1 Example of neoplasms whose biology may change with aging

Cancer

Change in prognosis

Mechanism

Acute myelogenous leukemia

Worse, increased resistance to chemotherapy

Seed: 1. Increased prevalence of MDR1 2. Increased prevalence of stem-cell leukemia

Non-Hodgkin’s lymphoma

Worse, decreased response rate to chemotherapy, decreased disease-free survival

Soil: Increased circulating concentration of IL-6

Breast

Better: More indolent disease

Seed: 1. Higher prevalence of hormone-responsive tumors 2. Lower proliferation rate 3. Higher prevalence of well-differentiated tumors Soil: 1. Endocrine senescence 2. Immune senescence

Ovary

Worse: reduced response to chemotherapy and disease-free survival

Unknown

Lung, nonsmall cell

Better, presentation at earlier stages, more indolent disease

Seed: More differentiated, slowly growing tumor

Note: MDR, multi drug resistance.

myelogenous leukemia (AML), the prevalence of resistance to cytotoxic chemotherapy increases after age 60, which may explain the poor outcome of AML in the elderly (Lancet et al., 2000). The prognosis of NHL (Non Hodgkin’s Lymphoma) may worsen through a “soil” mechanism: age is associated with increased circulating concentrations of interleukin-6 (IL-6), an independent poor prognostic factor (The International Non-Hodgkin’s Lymphoma Prognostic Factors Project 1993; Preti et al., 1997), as IL-6 stimulates lymphoid proliferation. In the case of breast cancer, both a “seed” and a “soil” mechanism may conspire to

CANCER AND AGING

generate a more indolent tumor (Balducci et al., 2004): the prevalence of well-differentiated-hormone-receptor-rich tumors increases with age, and at the same time endocrine senescence may disfavor the growth of hormone-responsive neoplasms. As already mentioned, lung cancer is more likely to affect elderly ex-smokers, whose tumor has undergone a lower number of mutations and is less aggressive. A major breakthrough in tumor biology has been the development of microarray techniques, able to reveal the full genetic profile of a tumor. The overexpression of certain genes has been associated with different biologic behaviors, including growth rate and susceptibility to cytotoxic chemotherapy (Sikic, 1999). Microarrays may allow identification of biologic differences between the tumor cells of younger and older patients. Little is known about the host-related changes that may influence tumor growth. In addition to endocrine senescence, immune senescence and proliferative senescence of the stromal cells may play a role. Immune senescence may favor the growth of highly immunogenic tumors, while proliferative senescence of fibroblasts is associated with increased production of tumor growth factors (Hornsby, 2004). It is also worthwhile remembering that frailty is associated with increased concentration of catabolic cytokines in the circulation (Cohen et al., 2003) and with sarcopenia (Stanta et al., 1997) that may inhibit tumor growth. The mechanisms by which age may influence tumor aggressiveness represent a widely open research area. Two considerations are clinically pertinent: (i) Aging may be associated with more indolent as well as more aggressive tumors. (ii) Age itself is a poor predictor of tumor behavior and each cancer should be managed according to the individual characteristics of the tumor and of the patient. If it is true that 67% of AML in individuals aged 60 and older present MDR (Multi Drug resistance), it is also true that 33% of these patients have a neoplasm sensitive to chemotherapy. If 80% of breast cancer patients aged 65 and older have a hormone-receptor-rich tumor for which cytotoxic chemotherapy produces limited benefits, 20% of these women have aggressive hormone-receptor-poor tumors that may need front-line cytotoxic chemotherapy.

CANCER PREVENTION Cancer prevention represents the most obvious way to reduce the impact of cancer on mortality, disability, and quality of life. Primary prevention involves elimination of environmental carcinogens or block and reversal of carcinogenesis with chemoprevention. Secondary prevention involves early detection of cancer at a curable stage by screening asymptomatic individuals at risk.

Chemoprevention of Cancer Chemoprevention appears the most practical form of primary cancer prevention (Beghe’ and Balducci, 2004). Potential

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Procarcinogen

Carcinogen DNA repair DNA damage Cell death Inactive metabolites

Cancer Inhibits Facilitates

Figure 2 Mechanism of action of chemoprevention

drawbacks include cost and toxicity of treatment. Figure 2 illustrates the possible mechanisms of action of chemopreventative agents. Chemoprevention may inhibit the reactions that activate procarciongens into carcinogens and facilitate those that catabolize carcinogens. The crossroad of chemical, radiation, and light-induced carcinogenesis, electrophylic DNA adducts, may be reversed by DNA repairing enzymes, whose activity is enhanced by selenium, calorie restriction, and epigallocatechin galate (Hursting et al., 1999). Endogenous substances that influence carcinogenesis, such as reactive oxygen species, hormones, growth factors, and eicosenoids, represent another target of chemoprevention. Three groups of agents were proven to prevent cancer in humans: hormonal agents, retinoids, and NSAIDs. In randomized controlled studies, the SERM tamoxifen (Lippman and Brown, 1999) has prevented breast cancer, and the reductase inhibitor finasteride prostate cancer (Thompson et al., 2003). Other hormonal agents of interest for the prevention of breast cancer include the SERM raloxifen that unlike tamoxifen does not cause endometrial cancer, and the aromatase inhibitors. In randomized controlled studies, retinoic acid has reversed preneoplastic lesions and delayed the occurrence of secondary cancers in the upper airways (Oridate et al., 1986). In a prospective study, the COX-2 inhibitor rofecoxib has caused regression of preneoplastic polyps (Steinbach et al., 2000); two large retrospective studies suggest that aspirin may prevent death from cancer of the large bowel (Thun et al., 1991; Chemoprevention Working Group, 1999) and another retrospective study that it may reduce the risk of breast cancer (Terry et al., 2004). Furthermore, NSAIDs and aromatase inhibitors appear synergistic in vitro. These encouraging results cannot be translated as yet into clinical indications. Tamoxifen prevents only indolent well-differentiated hormone-responsive tumors and has not reduced breast cancer-related mortality. Though rare, the complications of tamoxifen have been potentially serious, including endometrial cancer, deep vein thrombosis, and

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cerebrovascular accidents (Lippman and Brown, 1999). Finsteride has reduced the incidence of, but not the mortality from, prostate cancer, may have enhanced the risk of poorly differentiated aggressive neoplasms, and causes hot flushes and loss of libido (Thompson et al., 2003). Retinoic acid has caused severe cutaneous and hepatic toxicity, and has delayed rather than prevented cancer of the upper airways (Oridate et al., 1986). For what concerns the NSAIDs, there is no information related to the dose, the treatment duration, and the potential complications.

Secondary Cancer Prevention Secondary prevention of cancer is based on a threefold assumption (Beghe’ and Balducci, 2004): • Clinical manifestations of cancer are preceded by a prolonged preclinical phase, including invasive cancer and premalignant lesions. • Screening tests may diagnose cancer in the preclinical and even the premalignant phase. • Early diagnosis of cancer is associated with improved chances of surgical curability. A reduction in cancer-related deaths in randomized clinical trials is considered the definitive proof that secondary prevention is effective. This end point has been criticized for two reasons. First, it may take several years and result in unnecessary loss of lives and the conclusions of the trial may be obsolete, because by the time of completion new and more sensitive screening techniques might have been developed. Second, one may wonder how meaningful a reduction of cancer-related mortality is in elderly individuals when overall mortality is unaffected. This issue is exemplified by a randomized study of radical prostatectomy versus observation in men up to age 75 in Sweden that demonstrated radical prostatectomy is associated with a reduction in cancer-related but not overall mortality (Holmberg et al., 2002). For a number of older men with prostate cancer, maybe the majority, prostatectomy is costly, dangerous, and without appreciable benefit. At the same time, however, screening may improve patient quality of life even when it does not seem to affect mortality. It is possible that early detection of some cancers, such as breast cancer, might reduce the risk of cancer-related complications. Age itself has diverging effects on the outcome of screening (Beghe’ and Balducci, 2004). On one hand, the positive predictive value of screening tests may increase with age, owing to increased prevalence of common cancers. On the other hand, reduced life expectancy and development of more indolent tumors may lessen the benefits of screening. Also, the yield of screening tests decreases with the number of times they have been performed, as the initial tests have eliminated most prevalence cases. Two combined approaches may help identify asymptomatic older individuals for whom cancer screening is indicated. The first involves an estimate of the effects of

screening on quality of life. Chen et al. have identified a profile of older patients for whom the benefits of screening may overwhelm the risk of complications (Chen et al., 2003). These are the so-called risk takers, who are willing to undergo dangerous forms of cancer treatment even when the benefits are minimal. The second approach identifies patients at higher risk of development of a certain type of cancer. In a decision analysis, Kerlikowske et al. demonstrated that mammography is most beneficial for women in the upper quintile of bone density, who are those at higher breast cancer risk (Kerlikowske et al., 1999). Randomized and controlled clinical trials have demonstrated that screening mammography reduces the mortality of breast cancer in women aged 50–70 (Kerlikowske et al., 1995) and screening for colorectal cancer with fecal occult blood reduces the mortality for individuals aged 50–80 (Frazier et al., 2000). Presumably, serial endoscopies may be at least as effective as examination of stools for occult blood, and are the preferred form of screening in many centers (Frazier et al., 2000). In the absence of data, it appears prudent to screen persons with a life expectancy of five years or longer for breast and colorectal cancer, as the earliest benefits of screening have been observed five years after the institution of the screening program (Walter et al., 2004). Controversy lingers on the benefits of screening asymptomatic men for prostate cancer: in any case it is unlikely that this intervention may reduce cancer-related mortality in men over 70. Screening for cervical cancer after age 60 is another area of controversy. It is recommended in women at risk, because they are sexually active, especially if they have multiple partners, and for those who have never been screened before age 60. No proof exists of the value of screening for lung, ovarian, or endometrial cancer. In these cases, screening is justified only in the context of clinical trials.

CANCER TREATMENT Local treatment of cancer involves surgery and radiation therapy; systemic treatment involves cytotoxic chemotherapy, and hormonal, biological, and targeted therapy. Cancer therapy may have different goals including curative, adjuvant, and palliative. Adjuvant treatment is administered to prevent recurrence of cancer in patients at high risk of recurrence after definitive therapy: Palliative treatment is aimed at relieving symptoms and prolonging the survival of patients with incurable cancer. Two new treatment approaches deserve mention: neoadjuvant and combined modality treatment. Neoadjuvant treatment mainly involves chemo and hormonal therapy and is administered prior to definitive therapy, with the goal of making this more effective and less radical. Neoadjuvant chemotherapy of breast cancer has allowed breast preservation in the majority of patients. Combined modality treatment that generally involves a combination of cytotoxic chemotherapy and radiation therapy has been used to allow organ preservation and to obtain better outcome than with

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either individual forms of treatment. Combined modality treatment has allowed organ preservation in patients with resectable cancer of the head and neck area, of the esophagus, and of the anus, and has prolonged the survival of patients with locally advanced cancer of the lung and of the head and neck.

Surgery The incidence of surgical complications, including mortality, increases after age 70, according to Medicare data (Berger and Roslyn, 1997). The majority of these complications should be ascribed to emergency surgery, however, mainly related to large bowel obstruction and resulting Gram-negative sepsis (Berger and Roslyn, 1997). With the exception of pneumonectomy, most elective surgical procedures appear well tolerated by older individuals (Berger and Roslyn, 1997; Kemeny et al., 2000). Unfortunately, the risk of emergency abdominal surgery increases with age, which underlines the importance of regular screening for colorectal cancer, as early detection would minimize the risk of colonic obstruction. Recent advances in anesthesia and in surgical techniques have reduced the risk of postoperative complications in the elderly. The addition of amnesic drugs to the anesthetic cocktail has allowed reducing the dose of traditional anesthetics and opioids, and has minimized the risk of respiratory and cardiovascular complications of anesthesia even in centenarians (Miguel and Vila, 2004). Furthermore, a number of procedures, including mastectomy, may be performed under local anesthesia and are accessible also to patients with severe respiratory diseases. The advent of sentinel lymphnode mapping to recognize patients at risk for lymph-node metastases has allowed the foregoing of full lymph-node dissection in patients with cancer of the breast and melanoma (Singletary et al., 2004). The value of this approach is being explored also in cancer of the head and neck areas and in gynecological cancer. The extent of surgery has become more limited for several cancers, including rectal cancer that seldom requires nowadays an abdominal-perineal resection. Laser endoscopic surgery may be curative in early stages of esophageal and bronchial cancer and may maintain the patency of these organs through the latest stages of the disease. Radiosurgery (γ knife) proved as effective as standard surgery for small brain tumors and is investigated in other malignancies (Hevezi, 2003). Radio-frequency ablation (RFA) that may be performed in many patients without general anesthesia and under CT guidance was proven effective in the management of primary and secondary liver tumors, and may be utilized also for small kidney cancers (Tranberg, 2004).

Radiation Therapy A number of retrospective studies in Europe and in the United States have shown that external beam irradiation is

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well tolerated even in individuals over 80, more than threequarters of whom are able to receive full doses of radiation (Zachariah and Balducci, 2000). The risk of mucositis may increase with age during radiation of the chest, involving the esophagus, and of the pelvis. In these cases it is extremely important to assure hydration and nutrition. Prophylactic peg tubes are recommended in patients undergoing treatment of the upper digestive tract and of the esophagus. The advent of conformational radiation therapy has minimized toxicity of normal tissues and maximized therapeutic efficacy. Brachytherapy, that is delivering of radiation by implant of radioactive material, is another safe and effective form of treatment. Of special interest for older men is brachytherapy of prostate cancer (Zachariah and Balducci, 2000). New forms of radiation therapy include hyper fractionated radiation therapy that may improve therapeutic efficacy by reducing the time intervals between treatments, and also lead to reduced treatment duration. The safety of this form of treatment in elderly patients is being explored. Together with radiation therapy one should mention radioisotopes that have gained new momentum in the last few years. Radioactive strontium and sumerium relieve pain from multiple bone metastases and are generally well tolerated, though they may cause myelosuppression and limit the use of cytotoxic chemotherapy (Roque et al., 2003). In addition, monoclonal antibodies targeted to the CD20 antigens, in combination with radioactive yttrium (Zevelin) or Iodine (Bexaar), induce remission in 40% of patients with low-grade lymphomas resistant to cytotoxic chemotherapy (Harris, 2004). The use of these agents as front-line treatment is being explored. These compounds may cause prolonged and substantial myelodepression.

Hormonal Therapy Breast, prostate, and endometrial cancer may respond to hormonal therapy. Estrogen deprivation is the mainstay breast cancer treatment. For almost 30 years this has been achieved with SERM, tamoxifen, and toremifene. These compounds have reduced the recurrence rate of breast cancer after surgery and the development of contralateral breast cancer by almost 50%, and have relieved the symptoms and prolonged the survival of 50–60% of patients with metastatic breast cancer (Buluwela et al., 2004). SERMs still represent the preferred form of hormonal treatment of breast cancer in men. Tamoxifen and toremifene prevent bone loss, but cause hot flushes and vaginal discharge in the majority of patients. In addition, they increase the risk of endometrial cancer, deep vein thrombosis and ischemic strokes, especially in presence of obesity, but these complications are rare. In postmenopausal women, the aromatase inhibitors that prevent the transformation of androgen into estrogen were proven superior to tamoxifen both in the adjuvant and the metastatic setting (Arora and Potter, 2004). These compounds appear better tolerated than the SERMs in terms of vasomotor and genitourinary

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complications, and have not been associated with endometrial cancer, thrombosis, or stroke. The nonsteroidal aromatase inhibitors anastrozole and letrozol increase the rate of bone loss and bone fracture, while examestane, which has a steroidal configuration, may delay bone loss. A new SERM, faslodex, is also available. Unlike tamoxifen and toremifene, faslodex is a complete estrogen antagonist and does not cause endometrial cancer or hypercoagulability, and is effective in about a fourth of the patients whose disease has progressed while taking tamoxifen (Buluwela et al., 2004). Though the role of this compound vis-a-vis the aromatase inhibitors is not clear, parenteral (intramuscular) administration every 4 weeks makes faslodex particularly suitable for older women with poor compliance for oral medications. Progestins are still used as third line treatment of metastatic breast cancer, while the role of estrogen at high doses and androgen has become extremely limited. The mainstay treatment of prostate cancer is androgen deprivation that may be effected by orchiectomy, oral estrogen, LH-RH (luteinizing hormone-releasing hormone) analogs, LH-RH antagonists (abarelix), and ketoconazol in high doses (Hellerstedt and Pienta, 2003). Currently, the LH-RH analogs are almost universally used as front-line treatment of metastatic prostate cancer, whereas ketoconazol is indicated for patients whose disease has progressed with LH-RH analogs. The only current indication for the use of abarelix is metastasis causing impending urinary obstruction or epidural compression. In these cases, the LH-RH analogs, which cause initially a spate in testosterone concentration, may stimulate tumor growth and precipitate a life-threatening complication. Long-term complications of androgen deprivation including osteoporosis, fatigue, and hot flushes (Holzbeierlein et al., 2003) are seen with increased frequency as androgen deprivation is initiated in patients experiencing a PSA recurrence of prostate cancer whose life expectancy is in excess of 10 years (Han et al., 2001).

Cytotoxic Chemotherapy Cytotoxic chemotherapy destroys preferentially tissues with high concentration of proliferating cells (Cova and Balducci, 2004). While preferentially harmful to neoplastic tissues, chemotherapy may also affect a number of normal tissues. Age is associated with a number of pharmacologic changes affecting effectiveness and toxicity of chemotherapy. These include pharmacokinetics, pharmacodynamics, and susceptibility of normal tissues to antineoplastic drugs (Table 2). Biological availability of oral drugs does not appear to change at least up to age 80 (Carreca and Balducci, 2002). Oral formulation of antineoplastic agents is becoming increasingly common, and appears particularly suitable for older individuals, thanks to home administration and more flexible dose titration. As the GFR declines almost universally with age, it is recommended to adjust the doses of medication to renal function, with the provision to increase the dose in subsequent treatment cycles in absence of toxicity, to avoid the risk of undertreatment (Balducci, in press). The volume of

Table 2 Pharmacologic changes of age

Pharmacokinetics

1. Reduced intestinal absorption 2. Reduced renal excretion 3. Reduced volume of distribution of hydrosoluble drugs 4. Reduced hepatic uptake and reduced activity of cytochrome p450 reactions

Pharmacodynamics

1. Reduced rate of DNA repair 2. Reduced intracellular catabolism of drugs

Susceptibility of normal tissues

1. Increased duration and severity of myelotoxicity 2. Increased risk of cardiomyopathy from anthracyclines 3. Increased risk of peripheral (platinol, alkaloids, taxanes, epipodophyllotoxins), and central nervous toxicity (cytarabine in high doses) 4. Increased risk of mucositis (fluorouracil, fluorouridine, anthracyclines)

distribution of hydrosoluble agents declines owing to reduced water content; consequently, the shape of the AUC (Area Under Curve) is changed with higher peak concentrations of free drug. Anemia may exacerbate this problem, as many agents are bound to red blood cells. For this reason, it is recommended that the hemoglobin of older patients receiving chemotherapy be maintained at 12 gm dl−1 or higher (Balducci, in press). Myelosuppression, mucositis, peripheral neuropathy, and cardiomyopathy are the complications of chemotherapy that become more common with age. The risk of neutropenic infections as well as the duration and complications of hospitalization from neutropenic infections increase after age 65. Fortunately, hemopoietic growth factors and, in particular, flilgrastim are effective also in older individuals. A pegylated form of filgrastim, peg-filgrastim, is particularly suitable for older individuals, as it requires a single administration per cycle of chemotherapy (Balducci, in press). Anemia is also a common manifestation of myelosuppression that is associated with fatigue and functional dependence (Balducci, 2003; Knight et al., 2004), and may enhance the risk of chemotherapy related toxicity. Epoietin or darbepoietin ameliorate anemia in 60–70% of the patient. Mucositis may lead to dehydration from lack of fluid intake and diarrhea, with serious and even lethal consequences (Stein et al., 1995). Prevention of mucositis may involve the use of oral capecitabine in lieu of intravenous fluorouracil and management with an oral solution of lysine. A keratynocute growth factor is undergoing clinical trials with promising results. In any case, an older person presenting with dehydration should be immediately admitted to the hospital for aggressive fluid resuscitation. No antidotes to neurotoxicity are available. Precautions include avoidance of combination of neurotoxic drugs (e.g. cisplatin and paclitaxel), and timely discontinuance of a neurotoxic drug in the presence of weakness. Age is a risk factor for anthracycline induced cardiomyopathy (Hequet et al., 2004). Though this

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complication is rare for total doses of doxorubicin lower than 300 mg m−2 , it increases steeply with higher doses. Furthermore, a recent study in patients with lymphoma revealed that asymptomatic myocardial dysfunction may affect up to one-fourth of patients treated with doxorubicin. Cardiomyopathy may be prevented by infusional doxorubicin (which is cumbersome), by concomitant administration of the antidote desrazoxane, which may increase the risk of myelodepression and mucositis, and by substitution of doxorubicin by pegylated liposomal doxorubicin (doxil) with a much more favorable toxicity profile (Theodoulou and Hudis, 2004). Finally, it should be underlined that a number of new cytotoxic agents are particularly suitable for older individuals, even for frail individuals. These include capecitabine, vinorelbine, gemcitabine, weekly taxanes, and pegylated liposomal doxorubicin (doxil). Most of these medications do not cause alopecia or severe nausea and vomiting or myelotoxicity.

Targeted Therapy These agents target specific components or processes of the neoplastic cells, leading to their destruction or to inhibition of their proliferation. As the targets are specific to or overexpressed in neoplastic cells, these compounds promise to spare normal tissues. For practical purposes, we may distinguish monoclonal antibodies and small molecules antagonizing specific processes (Table 3). Monoclonal antibodies may be naked or tagged (Harris, 2004). Naked antibodies may cause immune destruction of the cells or antagonize growth factor receptors. Tagged Table 3 Targeted therapies

Group of compounds

Target

Indication(s)

Monoclonal antibodies a. Naked Rituximab Trastuzumab (Herceptin) Alemtuzumab (CamPath)

CD20 HER-2 neu CD52

Cetuximab Bevacizumab

EGFR VEGF

B-cell lymphoma Breast cancer CLL; low-grade lymphoma Colorectal cancer Colorectal cancer

b. Tagged Gemtuzumab ozogamicin (Mylotarg) I-131 tositumomab (Bexaar) Ibitumomab tiuxetan (Zevalin) Small molecules Imanitib mesylate (Gleevec) Gefitinib (Iressa) Bortezomib (Velcade) Thalidomide (Talidomid)

CD33 CD20

Acute myelogenous leukemia Low-grade lymphoma

CD20

Low-grade lymphoma

Tyrosine kinase

CML, Gastric stromal cell tumors Lung cancer Multiple myeloma Multiple myeloma, myelodysplasia, malignant gliomas

EGFR-TK 26-S proteasome Angiogenesis

Note: EGFR-TL, epithelial growth factor receptor – associated tyrosine kinase.

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antibodies are used as carriers of toxins, cytotoxic agents, and radioisotopes. Rituximab targets the CD20 antigen, mainly expressed on B-lymphocytes. As single agent, rituximab induces a response rate of approximately 40% in low-grade lymphoma; in combination with chemotherapy, it improves the response rate in virtually all forms of B-cell lymphomas Alemtuzumab is directed against the CD52 antigen, overexpressed on B-lymphocytes, but also in normal hemopoietic precursors. This drug has an approximately 30% response rate in patients with CLL (Chronic Lymphocytic Leukemia) refractory to chemotherapy, but is associated with significant myelotoxicity. Tositumomab (Bexaar) and Ibitumomab tiuxetan (Zevalin) are also monoclonal antibodies targeting CD20 and they are bound respectively to radioactive iodine and Yttrium. They have produced prolonged remissions in patients with low-grade lymphomas, refractory to other forms of treatment, including rituximab, but their use has been complicated by substantial myelotoxicity. Mylotarg targets the CD33 antigen of myelopoietic cells and is active in patients with AML refractory to chemotherapy, but induces substantial myelosuppression Cell proliferation may be inhibited by targeting the growth factor receptors (Trastuzumab, Herceptin), the activation of these receptors (cetuximab, erbitux), the intracellular signal transduction (gefitinib, Iressa, farnesyl transferase inhibitors), and the surface tyrosine phosphokinase (Imanitib) (Herbst, 2004; Ravandi et al., 2004). Imanitib, an inhibitor of the tyrosine phosphokinase encoded by the hybrid Bcr/abl oncogene, has resulted in higher rate of hematological remission and improved survival in patients with chronic myelogenous leukemia (CML) (Sledge, 2004). Trastuzumab has shown significant activity in those 30% of women with breast cancer that overexpress the growth factor receptor, genfitinib is indicated in a small group of patients with adenocarcinoma of the lung (Murray et al., 2004), and cetuximab is indicated in carcinoma of colon and rectum (Folprecht and Kohne, 2004). Proteosome inhibition may also lead through cell destruction through apoptosis (Adams, 2004) or programmed cell death. Bortezomib (velcade) produces a response in approximately 40% of multiple myeloma patients refractory to other forms of treatment. Another important target of antineoplastic therapy is angiogenesis, as tumor cells cannot survive without the production of new vessels (Drevs et al., 2002). Thalidomide, an inhibitor of angiogenesis, proved effective in patients with multiple myeloma and those with myelodysplasia, whereas bevacizumab (Avastin), a monoclonal antibody directed against the vascular endothelial growth factor (VEGF), in combination with chemotherapy, has prolonged the survival of patients with colorectal cancer (Hurwitz et al., 2004).

CONCLUSIONS Cancer in the older person is an increasingly common problem, to the point that it has been proposed to consider cancer

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a geriatric syndrome. Preventative and treatment strategies should be tailored to the situation of each patient, based on life expectancy and treatment tolerance. Chemoprevention is a promising cancer prevention strategy that may benefit older individuals, but its clinical use at present is limited. Screening for breast and colorectal cancer appear beneficial for people with a life expectancy of 5 years and longer; screening for other common cancers (prostate, lung, cervix, ovary) is the object of ongoing studies. Elective surgery, with the possible exception of pneumonectomy, and radiotherapy appear well tolerated by persons of any age, while the risks of emergency surgery increase with age. Early detection of colorectal cancer may minimize the need of emergency surgery. A number of advances have improved the tolerance of cytotoxic chemotherapy by older individuals: these include myelopoietic growth factors, that minimize neutroopenia and neutropenic infections, recombinant epoietin and darbepoietin for the treatment of anemia and the prevention of functional dependence, and the development of newer and safer drugs. In particular, capecitabine should be used in lieu of fluorouracil in older individuals and pegylated liposomal doxorubicin “in lieu” of other anthracyclines, when indicated. Targeted therapy represents a very promising and novel approach to the treatment of cancer that may be particularly beneficial to older individuals. With proper patient selection and adequate support, antineoplastic treatment may be as effective in older patients as it is in younger patients and age should not be considered a contraindication.

KEY POINTS • The biologic interactions of cancer and age include carcinogenesis and tumor biology. Older individuals may be more susceptible to environmental carcinogens as they harbor a higher concentration of cells in advanced carcinogenetic stages than younger individuals. Breast and lung cancer are more indolent; AML, B-cell lymphoma and ovarian cancer are less responsive to treatment. • Chemoprevention is promising, but clinical indications are wanted. Screening for breast and colorectal cancer is indicated for persons with a life expectancy of 5 and more years. • New surgical techniques (radiosurgery, RFA) and radiation therapy techniques (brachytherapy) are minimally invasive and may prove particularly beneficial for older patients. • Patients aged 65 and older receiving moderately cytotoxic chemotherapy should receive support with hemopoietic growth factors (filgrastim, pegfilgrastim, epoietin α, darbepoietin).

• New chemotherapy drugs, including capecitabine, pegylated liposomal doxorubicin, weekly taxanes, vinorelbine, and gemcitabine, may be safely used even in frail individuals.

KEY REFERENCES • Anisimov VV. Biologic interactions of aging and cancer. In L Balducci & M Extermann (eds) Biological Basis of Geriatric Oncology 2005, pp 17 – 50 Springer New york. • Balducci L. Guidelines for the management of the older cancer patient. Journal of the National Comprehensive Cancer Network (in press). • Beghe’ C & Balducci L. Biological basis of cancer prevention in the older adult. In L Balducci & M Extermann (eds) Biological Basis of Geriatric Oncology 2004; Kluwer.

REFERENCES Adams J. The proteasome: a suitable antineoplastic target. Nature Reviews Cancer 2004; 4:349 – 60. Anisimov VV. Biologic interactions of aging and cancer. In L Balducci & M Extermann (eds) Biological Basis of Geriatric Oncology 2005, pp 17 – 50 Springer New york. Arora A & Potter JF. Aromatase inhibitors: current indications and future prospects for treatment of post-menopausal breast cancer. Journal of the American Geriatrics Society 2004; 52:611 – 16. Balducci L. Anemia, cancer and aging. Cancer Control: Journal of the Moffitt Cancer Center 2003; 10:478 – 86. Balducci L. Guidelines for the management of the older cancer patient. Journal of the National Comprehensive Cancer Network (in press). Balducci L & Aapro M Epidemiology of cancer and aging. In L Balducci & M Extermann (eds) Biological Basis of Geriatric Oncology 2004; Kluwer. Balducci L, Silliman RA & Diaz N. Breast cancer in the older woman: the oncologist viewpoint. In L Balducci, GH Lyman, WB Ershler & M Extermann (eds) Comprehensive Geriatric Oncology 2004, 2nd edn; Harwood Academic Publishers, Amsterdam. Beghe’ C & Balducci L. Biological basis of cancer prevention in the older adult. In L Balducci & M Extermann (eds) Biological Basis of Geriatric Oncology 2004; Kluwer. Berger DH & Roslyn JJ. Cancer surgery in the elderly. Clinics in Geriatric Medicine 1997; 13:119 – 42. Buluwela L, Constantinidou D, Pike J et al. Estrogen receptors and antiestrogen therapy. Cancer Treatment Research 2004; 119:271 – 92. Caranasos GJ. Prevalence of cancer in older persons living at home and in institutions. Clinics in Geriatric Medicine 1997; 13:15 – 32. Carreca I & Balducci L. Oral chemotherapy for the older patient with cancer. American Journal of Cancer 2002; 1:101 – 8. Chemoprevention Working Group. Prevention in the next millenium: report of the Chemoprevention Working Group to the American Association for Cancer Research. Cancer Research 1999; 59:4743 – 58. Chen H, Cantor A, Meyer J et al. Can older cancer patients tolerate chemotherapy? Cancer 2003; 97:1107 – 1114. Cohen HJ, Harris F & Pieper CF. Coagulation and activation of inflammatory pathways in the development of functional decline and mortality in the elderly. American Journal of Medicine 2003; 114:180 – 87. Cova D & Balducci L. Cytotoxic chemotherapy in the older patient. In L Balducci, GH Lyman, WB. Ershler & M Extermann (eds)

CANCER AND AGING Comprehensive Geriatric Oncology, 2004, pp 463 – 488 2nd edn; Taylor & Francis. Diab SG, Elledge R & Clark GM. Tumor characteristics and clinical outcome of elderly women with breast cancer. Journal of the National Cancer Institute 2000; 92:550 – 6. Drevs J, Laus C, Mendinger M et al. Antiangiogenesis: current clinical data and future perspectives. Onkologie 2002; 25:520 – 27. Ferrucci L, Guralnik GM, Cavazzini C et al. The frailty syndrome: a critical issue in geriatric oncology. Critical Reviews in Oncology Hematology 2003; 46:127 – 137. Folprecht G & Kohne CH. The role of new agents in the treatment of colorectal cancer. Oncology 2004; 66:1 – 7. Frazier AL, Colditz GA & Fuchs CS. Cost-effectiveness of screening for colorectal cancer in the general population. Journal of the American Medical Association 2000; 284:1954 – 59. Han M, Partin AW, Pound CR et al. Long term biochemical diseasefree and cancer-specific survival following anatomic radical retropubic prostatectomy. The 15-year Johns Hopkins experience. Urology Clinics of North America 2001; 28:555 – 65. Harris M. Monoclonal antibodies as therapeutic agents for cancer. Lancet Oncology 2004; 5:292 – 302. Hellerstedt BA & Pienta KJ. The truth is out there: an overall perspective on androgen deprivation. Urology Oncology 2003; 21:272 – 81. Hequet O, Le QH, Moullet I et al. Subclinical late cardiomyopathy after doxorubicin therapy for lymphoma in adults. Journal of Clinical Oncology 2004; 22:1864 – 71. Herbst RS Review of epidermal growth factor receptor biology. International Journal of Radiation Oncology Biology Physics 2004; 59(2 suppl):21 – 6. Holmberg L, Bill-Axelson A, Hegelsen F et al. A randomized trial comparing radical prostatectomy with watchful waiting in early prostate cancer. New England Journal of Medicine 2002; 347:781 – 9. Holzbeierlein JM, Castle EP & Thrasher JB. Complications of androgen deprivation therapy for prostate cancer. Clinics in Prostate Cancer 2003; 2:147 – 52. Hornsby PJ. Replicative senescence and cancer. In L Balducci & M Extermann (eds) Biological Basis of Geriatric Oncology 2004; Kluwer. Hevezi JM. Emerging technology in cancer treatment: radiotherapy modalities. Oncology (Huntington) 2003; 17:1445 – 56. Hursting SD, Slaga TJ, Fisher SM et al. Mechanism-based cancer prevention approaches: targets, examples, and the use of transgenic mice. Journal of the National Cancer Institute 1999; 91:215 – 25. Hurwitz H, Fehrenbacher L, Novotny W et al. Bevacizumab plus irinotecan, fluorouracil and leucovorin for metastatic colorectal cancer. New England Journal of Medicine 2004; 350:2335 – 42. Kemeny MM, Busch-Devereaux E, Merriam LT et al. Cancer surgery in the elderly. Hematology Oncology Clinics of North America 2000; 14:193 – 212. Kerlikowske K, Grady D, Rubin SM et al. Efficacy of screening mammography. A meta-analysis. Journal of the American Medical Association 1995; 273:149 – 54. Kerlikowske K, Salzman P, Phillips KA et al. Continuing screening mammography in women aged 70 to 79 years. Journal of the American Medical Association 1999; 282:2156 – 63. Knight K, Wade S & Balducci L. Prevalence and outcomes of anemia in cancer: a systematic review of the literature. American Journal of Medicine 2004; 116(suppl 7A):11s. Lancet JE, Willman CL & Bennett JM. Acute myelogenous leukemia and aging. Hematology Oncology Clinics of North America 2000; 14:251 – 67. Lippman SM & Brown PH. Tamoxifen prevention of breast cancer: an instance of the fingerpost. Journal of the National Cancer Institute 1999; 91:1809 – 19. Miguel R & Vila H. Anesthesia in older cancer patients. In L Balducci, GH Lyman, WB Ershler & M Extermann (eds) Comprehensive Geriatric Oncology 2004, 2nd edn; Harwood Academic Publishers.

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Murray N, Salgia R & Fossella FV. Targeted molecules in small cell lung cancer. Seminars in Oncology 2004; 33(Suppl 1):106 – 11. Oridate N, Lotan D, Xu XC et al. Differential induction of apoptosis by all-trans-retinoic acid and N-(4-Hydroxiphenyl)retinamide in human head and neck squamous cell carcinoma cell lines. Clinical Cancer Research 1986; 2:855 – 63. Preti HA, Cabanillas F, Talpaz M et al. Prognostic value of serum interleukin 6 in diffuse large-cell lymphoma. Annals of Internal Medicine 1997; 1127:186 – 94. Randolph WM, Mahnken JD, Goodwin JS et al. Using Medicare data to estimate the prevalence of breast cancer screening in older women: comparison of different methods to identify screening mammograms. Health Services Research 2002; 37:1643 – 57. Ravandi F, Kantarjian H, Giles F et al. New agents in acute myeloid leukemia and other myeloid disorders. Cancer 2004; 100:441 – 54. Repetto L, Granetto C, Venturino A et al. Prognostic evaluation of the older cancer patient. In L Balducci, GH Lyman & WB Ershler (eds) Comprehensive Geriatric Oncology 1998, pp 281 – 6; Harwood Academic Publishers, Amsterdam. Roque M, Martinez MJ, Alonso P et al. Radioisotopes for metastatic bone pain. Cochrane Database System Review 2003; 4CDOO3347. Sikic BI. New approaches in cancer treatment. Annals of Oncology 1999; 10(suppl 6):149 – 53. Singletary SE, Dowlatshahi K, Dooley W et al. Minimally invasive operation for breast cancer. Current Problems in Surgery 2004; 41:394 – 447. Sledge JW. HERe-2 stay: the continuing importance of translational research in breast cancer. Journal of the National Cancer Institute 2004; 19(96):725 – 7. Stanta G, Campagner L, Cavallieri F et al. Cancer of the oldest old: what we have learned from autopsy studies. Clinics in Geriatric Medicine 1997; 13:55 – 68. Stein BN, Petrelli NJ, Douglass HO et al. Age and sex are independent predictors of 5-fluorouracil toxicity. Cancer 1995; 75:11 – 17. Steinbach G, Phillips R.KS & Lynch PM. The effect of Celecoxib, a cyclooxygenase 2 inhibitor in familial adenomatous polyposis. New England Journal of Medicine 2000; 342:1996 – 52. Terry MB, Gammon MD, Zhang FF et al. Association of frequency and duration of aspirin use and hormone receptor status with breast cancer risk. Journal of the American Medical Association 2004; 291:2433 – 40. The International Non-Hodgkin’s Lymphoma Prognostic Factors Project. A predictive model for aggressive non-Hodgkin’s lymphoma. New England Journal of Medicine 1993; 329:987 – 94. Theodoulou M & Hudis C. Cardiac profiles of liposomal anthracyclines: greater cardiac safety versus conventional doxorubicin? Cancer 2004; 100:2052 – 63. Thompson IM, Goodman DJ, Tanger CM et al. The influence of finasteride on the development of prostate cancer. New England Journal of Medicine 2003; 349:215 – 24. Thun MJ, Namboodiri MM, Heath CW Jr et al. Aspirin use and reduced risk of fatal colon cancer. New England Journal of Medicine 1991; 325:1593 – 96. Tranberg KG. Percutaneous ablation of liver tumours. Best Practices Research Clin Gastroenterol 2004; 18:125 – 45. Walter LC, Linquist K, Covinsky KE et al. Relationship between health status and use of screening mammography and papanicolau smears among women older than 70 years of age. Annals of Internal Medicine 2004; 140:681 – 8. Wingo PA, Cardinez CJ, Landis SH et al. Long term trends in cancer mortality in the United States, 1930 – 1998. Cancer 2003; 97(S21):3133 – 3275. Yancik R & Ries L. Cancer in the older person: an international issue in an aging world. Seminars in Oncology 2004; 31:128 – 136. Zachariah B & Balducci L. Radiation therapy of the older patient. Hematology Oncology Clinics of North America 2000; 14:131 – 67.

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Oncological Emergencies and Urgencies Samuel Spence McCachren Thompson Cancer Survival Center, Knoxville, TN, USA

INTRODUCTION Studies of cancer in the “very old” (older than 80 years) have been hampered by several factors including inaccuracies in death certificates, failure to diagnose malignancy in the setting of multiple illnesses, and a reduction in frequency of seeking medical attention in this age-group. It is known that nearly half of all cancers and almost two-thirds of all cancer deaths in the United States occur in people more than 65 years old (Yancik, 1983). Moreover, the incidence appears to be increasing with age. During the past three decades there has been a noteworthy increase in our desire as well as the technology to treat some cancers (Bailar and Smith, 1986). Extrapolating from therapeutic progress in the 1980s and 1990s, we should anticipate further enhancement in our capacity to treat an even larger number of individuals with malignant disease, especially those with somewhat more resistant solid tumors, which are most common at older ages. These facts, coupled with steady growth in the size of the elderly population, indicate a need to prepare for more oncological crises. Moreover, a predominance of certain neoplasms, particularly solid tumors of breast, lung, colon, and prostate, with their particular attendant acute complications, could swell the number of emergencies even further. Simultaneously, physicians have witnessed a remarkable gain in the ability to deal with and effectively manage the intensive care needs of patients with any disease. Early on, as intensive care units (ICU) attempted to cope with unmanageable numbers of referrals, there developed an unwritten and sometimes unspoken attitude about rationing beds, a policy which not infrequently precluded individuals with incurable forms of malignancy, especially if the patient was “old”. With enlightenment and an increase in the numbers of ICU beds, this obstacle to heroic clinical management in the setting of cancer has begun to disappear (Pontoppidin et al., 1976), especially for young patients who have leukemia or lymphoma.

Neoplastic diseases can bring about both acute and chronic complications either by their natural progression or by our treatment of them. They have the capacity to invade contiguous structures, such as blood vessels or viscus organs; cause a host of mechanical events by obstruction or compression; secrete a variety of ectopic hormones, some resulting in severe metabolic effects; and proliferate so extensively that vital organs are literally replaced. In addition, we have a therapeutic armamentarium that can irreversibly damage any of the vital organs or severely compromise the host’s defenses. These statements prevail no matter what age-group one is discussing. There appears to be nothing particularly different in this regard about elderly patients. Although older patients may have more obvious cerebral dysfunction in the setting of fever, sepsis, hypotension, or hypercalcemia, and their marrow reserve may be less robust, there is no valid evidence that age alone is a criterion for withholding intensive life support or for that matter withholding treatment of the basic disease process (Cohen et al., 1983; Peterson, 1982; Kennedy, 1985). A growing volume of literature (Vaeth and Meyer, 1985) discusses cancer and its management in the elderly. There is also literature now written specifically about the concept of malignant disease in the emergency department (Brown et al., 1983) but few publications specifically address the management of medical or surgical emergencies that occur in people over 65 as a consequence of a malignancy. From experience in our own emergency departments, it is possible to list in order of decreasing frequency the more common reasons for attendance by adult patients with a known neoplasm. There is first fever and a close second is fever with granulocytopenia already defined by their referring physician; inability to eat or drink; pain; dyspnea from advancing cancer in the lung, nausea and/or vomiting following recent chemotherapy; general decline in performance status due to several factors (“failure to thrive”); weakness associated with severe anemia in need of blood transfusion; demonstrated thrombocytopenia in need of platelet transfusion; hypercalcemia; intestinal dysfunction


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(including gastric outlet obstruction and partial or complete obstruction of small more often than large bowel); request by the family that the patient be allowed to die in the hospital; gastrointestinal bleeding from various sites and for several different reasons; altered mental status; spinal cord compression; and hemoptysis. Some, of course, come for a second opinion about their diagnosis of cancer and are already under therapy by a physician at another university or community hospital. In this chapter, we discuss the life-threatening complications associated with cancer in the elderly and how to manage such events. Both the reader and the author must be mindful of those potentially fatal intercurrent problems that are independent of neoplasia and that occur more frequently in the old than in the young. Urosepsis with shock, myocardial infarction, pulmonary embolism, rupture of an abdominal or thoracic aortic aneurysm, upper gastrointestinal hemorrhage, perforation of large bowel, cardiac arrhythmias, and massive stroke with aspiration are specific examples. They require consideration in differential diagnosis far more often than in the young. From a review of several major treatises on the subject of oncological emergencies (Yarboro and Bornstein, 1981; Yarboro et al., 1978), it is clear that urgencies, true emergencies, and various serious problems are usually extensively intermixed. Although there is room for debate about the definition of the term medical emergency, most can agree about what items should be included in that category. For example, ventricular fibrillation, respiratory arrest, status epilepticus, intracranial (transtentorial) herniation, tension pneumothorax, septic shock, hemorrhagic shock, advanced pulmonary edema, pericardial tamponade, and massive hemoptysis all demand therapeutic action within seconds to minutes. We think about malignant tumors being capable of occasionally producing many of these events, but certain ones in particular are more commonly associated. Cancers erode into a carotid artery with exsanguination or into a pulmonary artery with death by asphyxiation. Intracranial metastases have been relatively silent until their size produces intractable seizures or uncal herniation. Pericardial involvement can cause a gradual filling of the pericardial space by fluid with modest symptoms until a critical volume rapidly results in total compromise of cardiac dynamics. And severe granulocytopenia, especially during cytotoxic chemotherapy, may lead to sepsis with profound hypotension. Only a few entities in emergency medicine are unique to malignancy: cerebral and pulmonary leukostasis (McKee and Collins, 1974), tumor lysis syndrome (Kalemkerian et al., 1997; Zusman et al., 1973) and, usually, superior vena cava (SVC) syndrome (Bell et al., 1986). The situations selected for inclusion are not unique to the older population, although some are more commonly seen in the later years of life. Disseminated intravascular coagulation (DIC) is frequently associated with advanced carcinoma of the prostate, clearly an older man’s affliction. Hyperviscosity syndrome, with its attendant cerebral and cardiac consequences, generally is less well tolerated in the elderly patient.

It should be pointed out that there are two distinct settings in which one of these acute changes in clinical course might occur. The ideal would be for the patient to appear first in his/her personal physician’s office. That doctor, thoroughly familiar with the clinical course to date, is quite prepared to decide about the appropriate intensity of investigation and support for the patient, and dispatches the patient to the hospital, calling ahead with orders and a plan of action. The second common scenario takes place in an emergency department and is more difficult for the patient and the physician, who has neither knowledge about this person’s course to date nor about the many other factors that might bear on a decision to intervene in heroic ways. Because the latter setting is a more typical arena for the suddenness that characterizes emergencies and because of the extra challenge created by seeing a new physician, we have elected to discuss recognition and management of many oncological emergencies as though the reader is a physician in an emergency room (ER) seeing each patient for the first time.

FIRST TIME PRESENTATION BECAUSE OF ACUTE SYMPTOMS Even though it is much less common that patients present with an urgent manifestation of a heretofore undiagnosed neoplasm, it certainly can and still does happen. In that situation it is always best to treat aggressively since critical questions about the quality of life or the reversibility of the acute process usually cannot be answered quickly in the emergency setting (Kalia and Tintinalli, 1984). Such is clearly the case for acute cecal dilatation as occurs in patients with a competent ileocecal valve and distal colonic occlusion by an adenocarcinoma. This is not an insignificant matter when one considers that the incidence of colorectal cancer is highest in the elderly; that the disease can be relatively “silent”, especially if one ignores constipation; and that localized “potentially curable disease” is found in nearly two-thirds of patients presenting as emergencies although the perioperative mortality is twice as high as in those who undergo elective operation (Waldron et al., 1986). There are other instances wherein a combination of denial and minimal morbidity during early stages of a primary malignancy has resulted in presentation of an acute manifestation due to advanced disease before patient or clinician is aware of the diagnosis. This certainly happens with breast cancer, which, for example, can metastasize to pericardium causing tamponade. Another example of an unusual first time presentation of acute symptoms has been reported for previously undetected laryngeal carcinoma that declared itself by impending obstruction of the airway that was successfully managed by an “emergency” laryngectomy (Griebie and Adams, 1987). Fortunately, physicians who work principally or only in large and busy accident rooms have a practiced, sensible approach to these types of unusual presentations, that is, rapid formulation of a differential

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diagnosis while quickly mobilizing urgent procedures and consultations.

SPINAL CORD COMPRESSION A diagnosis of this catastrophe is an easy matter by the time paraplegia and loss of sphincter control have occurred, but an optimal outcome requires much earlier recognition. In the face of vague or isolated symptoms, one must have much more clinical acumen in order to prevent one of the worst disasters that can befall a patient with cancer, namely, loss of locomotion and continence. Such deficits could be even more devastating for the widow or widower who had until that moment been able to manage an independent existence despite having a malignant disease. Presenting symptoms of metastatic cord compression are generally shared by all primary tumors (Mullins et al., 1971; Torma, 1957). A prodromal phase, present in almost every case, is characterized by pain somewhere along the spinal axis, with or without an accompanying radicular pattern. More importantly, many patients have a sense of dysfunction in their lower extremities even when there are no definite neurological findings. This subtle awareness by the patient may not be volunteered, or worse, if reported may be discounted as an acceleration in a natural process of aging because of the general systemic effects by a tumor with attendant weight loss and decrease in activity. Pain can antedate rapid deterioration of spinal cord function by days, weeks, and even months while other symptoms typically occur days to weeks before the critical sign that brings the patient to an ER. If these early subtle warnings were recognized it could turn emergency medicine into elective medicine. Once clinical suspicions are aroused, one must follow through the appropriate diagnostic pathway. Although at least two-thirds of plain radiographs of the spine will show bony abnormalities, such as erosion of pedicles, partial to complete vertebral collapse, or a paraspinous soft-tissue abnormality, they do not establish the exact boundaries of cord compression. For appropriate neurosurgery or irradiation treatment, the exact boundaries of the compression must be known. This is easily determined by magnetic resonance imaging (MRI) when it is available. If MRI is unavailable, then myelography (either routine or with computed tomography) is needed. Selection of the appropriate treatment depends upon the rapidity of onset, the severity as well as the duration of neurological deficit, the level of block, and the primary tumor. A first step in therapy of every case is relief of probable edema with corticosteroids. Dexamethasone, 100 mg intravenously as an initial “bolus” is probably excessive and unproved in any scientific study but has become accepted as standard in many places. That large dose is followed by 20 mg every six hours (by mouth or intravenously). A radioresponsive tumor detected early on predicts for excellent outcome using radiation therapy plus corticosteroids (Gilbert et al., 1978; Ushio et al., 1977).

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More importantly, that approach avoids surgery with risk of mortality ranging between 6 and 13% and the prolonged debility or lengthy incapacitation that often characterizes the postoperative course of elderly individuals who undergo laminectomy. Chemotherapy is often useful in cases due to lymphomas or other chemotherapy responsive malignancies. Obviously, laminectomy should be performed in four situations: malignancy is suspected but the tumor type is unknown (needle biopsy may suffice for diagnosis); prior high dose radiation at that level of the cord; individuals with rapidly progressing or acute as well as severe neurological deficits found to have a complete block at myelography; and patients who fail to show a rapid response to radiation. Because laminectomy rarely results in complete removal of tumor, postoperative irradiation should be considered in all cases (Wild and Porter, 1963; Wright, 1963).

MASSIVE HEMOPTYSIS Infectious disorders have dominated any listing by etiology for causes of massive hemoptysis, but the oncological category is becoming more important along with pulmonary tuberculosis, bronchiectasis, and chronic necrotizing pneumonia (Conlan et al., 1983). Emergency physicians readily consider tuberculosis when confronted with hemoptysis, particularly in older patients and especially in residents of or refugees from underdeveloped countries. However, the elderly represent that fraction of the world’s population which is enlarging the fastest; and they are the most likely to get cancer. At the current time, they may (hopefully they do) represent the last male generation of heavy smokers but it is recognized that a history of smoking combined with advanced age increases the incidence of lung cancer. It is noteworthy that the definition used to quantify serious hemoptysis by such terms as significant or massive varies from 2 dl (Yoh et al., 1967) to more than 3 dl or up to 5–6 dl (Crocco et al., 1968). Clearly some patients can survive quite striking episodes of expectoration of blood, up to 600 ml in 12 hours, while others have instantaneous death with sudden first hemoptysis even when the cause is not neoplastic (Bobrowitz et al., 1983). Regardless of the definition used for massive, the danger is asphyxiation due to obstruction of the tracheobronchial tree rather than exsanguination, although that too can occur. Finally, any amount of hemoptysis can be excessive to the patient with underlying lung disease who has also sustained loss of parenchyma by tumor, surgery, and/or irradiation. In that setting, even as little as 150 ml can lead to a clot capable of occluding a mainstem bronchus with resultant lethal pulmonary insufficiency. In rare cases, a patient may present with life-threatening bronchial hemorrhage that is due to previously undiagnosed pulmonary neoplasms. However, the probable etiologic diagnosis should be obvious in almost all patients with profuse hemoptysis due to lung cancer because bleeding directly from bronchogenic carcinoma early on is rarely brisk and tumor erosion into a major blood vessel is usually a late sign. In

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any event, except in the unusual situation where a patient has a living will or durable power of attorney and can express or has previously expressed wishes that no further intervention take place, emergency management should proceed as for any critical patient: the ABCs (airway, breathing, circulation) must be secured. Whereas in an elective surgical situation an experienced anesthetist may selectively intubate each lung with a double lumen Carlen’s or Robertshaw tube, in the most urgent setting with severe respiratory distress, intubation of the mainstem bronchus of the nonbleeding lung must be achieved as rapidly as possible. The patient is then positioned with the “suspected” side dependent. That, combined with suctioning, affords the only opportunity to prevent further drowning of the normal lung. Next, large bore intravenous catheters are inserted for resuscitation by crystalloid followed by blood products. Then and only then can one be more deliberate about further studies. There are differences of opinion in the literature about surgical versus medical approaches to treatment even when the etiology of pulmonary hemorrhage is infectious (Bobrowitz et al., 1983). However, even for the most aggressive thoracic surgeon there are some contraindications to resection including inadequate pulmonary reserves and very late stage disease, while cancer itself poses special problems, especially if it was deemed irresectable at the time of initial diagnosis and there has been subsequent radiation. All of these compromising descriptors are frequently the rule for lung cancer patients over age 70. So, after resuscitation with both the patient and the situation under control, there may be time for more definitive study of the site that is hemorrhaging and time to consider a nonsurgical therapeutic intervention such as bronchial artery embolization or laser bronchoscopy if the endobronchial growth itself is bleeding. The expectoration of huge quantities of blood is usually much more frightening than hematemesis or copious hematochezia for both the patient and family, but also for the physician. There is nothing more distressing or taxing than trying to have a meaningful dialogue in an ER about a patient’s wishes when that person is repeatedly coughing up large amounts of blood. Yet, our staff has had to do just that on several occasions in order to help the individual and/or family sort out whether they wanted heroic measures including intubation or merely sedation because it was clear that the malignancy was very advanced and no longer amenable to standard modalities of therapy. In general, both geriatricians and oncologists should be urging upon almost all patients the concept and the execution of two legal instruments, a living will and a durable power of attorney. Hopefully, one or both would be in place when and if this cataclysmic event of massive hemoptysis occurs in any patient with advanced lung cancer.

HYPERCALCEMIA (see Chapter 108, Age-related Changes in Calcium Homeostasis and Bone Loss) Hypercalcemia is a common complication of a number of neoplasms, whether associated with skeletal metastases,

ectopic parathyroid hormone (PTH), PTH-like substances, interleukin-1 (as in adult T-cell leukemia/lymphoma), other humoral factors, or coincidental hyperparathyroidism. Although hypercalcemia occurring during the course of malignancy is usually attributable to the neoplasm, one must not forget to consider benign causes such as primary hyperparathyroidism, vitamin D intoxication and sarcoidosis. In any case, treatment in an emergency is similar, with definitive management requiring a later diagnosis. Once a clinician considers hypercalcemia in the differential diagnosis of apathy, depression, malaise, somnolence, confusion, personality change, new polyuria –polydipsia, or rapidly evolving anorexia with nausea plus constipation, it is easy to establish the presence of a significant elevation in serum calcium. Changes in mental faculties and strength are more easily recognized in younger individuals, whereas in the elderly such events can be too easily blamed on many things including their poor tolerance of analgesics, anxiolytics, hypnotics, and antiemetics. This is especially true when symptoms occur very gradually. On rare occasion, elevations in serum calcium can appear with such rapidity that the event can be fatal within a few days (Cornbleet et al., 1977). Because normal serum calcium is maintained with 95% confidence limits of 2.24 to 2.58 mmol l−1 (9.0–10.5 mg dl−1 ) for men and 2.22 to 2.57 (8.9–10.4 mg dl−1 ) for women, it is important to consider a level of 2.64 mmol l−1 (10.6 mg dl−1 ) as a signal of abnormal calcium homeostasis. Values above 2.74 mmol l (11.0 mg dl−1 ) should be considered an indication to initiate treatment. (Each local laboratory confirms its own range of normal values, so that the above should be taken only as a guideline.) Although the hypercalcemic crisis is still reversible, it is easier to treat earlier before renal effects, with azotemia, or cardiovascular effects, with Mobitz II and other arrhythmias, have developed. It should be remembered that both the inotropic and toxic effects of digitalis preparations are potentiated by calcium and that digitalis preparations are commonly prescribed for elderly patients. Essentially all patients will have become dehydrated and benefit from intravenous saline to restore vascular volume, with a consequent improvement in calcium excretion. Unless clearly contraindicated, this approach should be initiated immediately. Since large volumes of saline may be required and are usually administered rapidly, there is a need for careful monitoring of cardiac status. Potassium balance must be observed carefully. Once adequate hydration is assured, frusemide (furosemide) augments the calciuresis by decreasing renal tubular resorption of sodium and calcium. Thiazides should not be used since they inhibit calciuresis. Before the availability of potent antiresorptive agents it was common to suggest a fluid intake and output of 4–6 l daily. We now aim to maintain normovolemia and a more modest fluid flux. This minimizes the risk of volume overload in the debilitated patient and edema in the hypoalbuminemic patient. Glucocorticoids can be helpful in the management of hypercalcemia caused by lymphoma, myeloma, and sometimes breast cancer. It is usual to prescribe prednisone in a


dose of 60 mg daily, but the response is slower than with saline and diuretics, occurring over several days, so that this agent should be started promptly along with rehydration. We are less dependent on glucocorticoids since the advent of potent antiresorptive agents. Salmon calcitonin in a dose of 8 IU kg−1 body weight, by intramuscular injection every six hours for several days, has been useful in controlling hypercalcemia in some patients. Intramuscular administration gives more reliable absorption than the subcutaneous route. Tachyphylaxis may occur, limiting the effectiveness of this treatment. However, the efficacy of calcitonin in managing hypercalcemia due to epidermoid carcinoma has been questioned (Warrell et al., 1988). The use of bisphosphonates such as pamidronate and zolendronate has been a major advance in management of hypercalcemia of malignancy (Harvey, 1995). These agents very effectively reduce bone resorption. Increases in serum phosphate may occur during treatment, a potentially useful side effect in those patients with hypophosphatemia. Pamidronate 60–90 mg is administered intravenously over 2–4 hours, after rehydration. Zolendronate 4 mg iv may be administered over 15 minutes. Adequate saline should be used to ensure continued calciuresis. The dose can be repeated if required. Bisphosphonates are now our first line of therapy after rehydration. The most recent addition to our armamentarium is gallium nitrate, administered at a dose of 200 mg m−2 day−1 over 24 hours for five consecutive days. Its use is contraindicated in patients with significant renal insufficiency. Although some combination of the measures discussed will generally control the excessive serum calcium, occasionally for prolonged periods of time, ultimately the underlying disease must be managed. One must consider early administration of specific treatment for the malignant tumor. Following the early clinical recognition of its ability to lower serum calcium in most patients with hypercalcemia caused by malignancy, plicamycin (mithramycin) became a standard therapy. The availability of bisphosphonates has greatly reduced its use. Whereas most texts recommend a dose of 25 µg kg−1 body weight by intravenous “push” every 24 hours for two to three doses, often we find a lower dose of 15 µg kg−1 body weight will suffice. It can be useful in older patients in whom fluid balance is precarious. Plicamycin may be difficult to obtain, and is myelosuppressive. It is no longer a part of our armamentarium. For patients in the truly terminal stage of a tumor refractory to standard therapy, especially if complicated by skeletal pain, hypercalcemia may contribute to analgesia and on occasion may allow a more comfortable, dignified demise. Knowledge of a patient’s wishes and clinical course to date therefore assumes critical importance.

HYPONATREMIA (see Chapter 117, Water and Electrolyte Balance in Health and Disease) At serum sodium levels below 115 mmol l−1 (115 mEq l−1 ), especially when the fall is rapid, brain edema can occur.

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Hyponatremia of this severity leads to alteration in mental status with lethargy and, in severe cases, coma, seizures, and death. The elderly are more susceptible to the effects of hyponatremia, and may manifest mental status impairment at higher levels of serum sodium. Other physical findings are generally unhelpful in the diagnosis, and routine evaluation of serum electrolytes is mandatory in patients with otherwise unexplained alterations of mental status. Hyponatremia may be seen in several situations: water redistribution associated with mannitol infusions; pseudohyponatremia due to hyperparaproteinemia or hyperlipidemia; and acute water intoxication. More common causes are renal sodium loss due to diuretic therapy, extrarenal sodium loss during vomiting/diarrhea, and sudden withdrawal of glucocorticoid therapy. The hyponatremia in these situations is usually not life threatening. The syndrome of inappropriate antidiuretic hormone (SIADH) secretion can cause a severe decrease in sodium that may be life threatening. Diagnostic features include (i) hypo-osmolality of serum; (ii) inappropriately high osmolality of urine for the concomitant plasma hypo-osmolality; (iii) normal renal function; (iv) continued renal excretion of sodium; (v) clinical normovolemia; and (vi) normal adrenal function. SIADH is most frequently seen with small cell undifferentiated carcinoma of the lung, but abnormalities in water homeostasis have been reported with many neoplasms, and especially in association with pulmonary or central nervous system metastases. Optimal therapy is to correct the underlying disease by chemotherapy and/or radiotherapy while restricting “free water” intake to 500–1000 ml day−1 . Correction by this method may take 7 to 10 days. More serious hyponatremia can be reversed in an average of three to four days with the addition of demeclocycline, an antidiuretic hormone (ADH) antagonist (Trump, 1981). For potentially fatal hyponatremia, such as in patients with seizures, coma, or other neurological abnormalities, more rapid correction is required. We utilize infusions of 3% saline combined with frusemide 0.5–1.0 mg kg−1 intravenously, with careful attention to intravascular volume, until the serum sodium is above a critical level (Hantman et al., 1973).

SUPERIOR VENA CAVA (SVC) SYNDROME Although SVC obstruction was seen with benign disease (such as tuberculosis and aneurysms) in the past, most cases in the developed world are now due to malignancy. Most neoplastic SVC obstruction is due to bronchogenic carcinoma, but Hodgkin’s disease, non-Hodgkin’s lymphoma, and other malignancies may be associated. Benign causes include thrombosis complicating central venous catheters (becoming more common as permanently implanted catheter use is increasing), and mediastinal fibrosis (primary, or secondary to radiation or surgery). The SVC and tributaries are easily compressed by expanding

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masses, causing impaired venous return and eventually tracheal, facial, and arm edema. Cerebral edema may occur in severe cases. With gradual obstruction a rich collateral circulation develops, and signs and symptoms may be subtle. With more rapid obstruction, the patient may present as a true emergency. Signs and their frequency of appearance at presentation include: thoracic vein distention (67%), neck vein distention (59%), facial edema (56%), tachypnea (40%), facial plethora (19%), cyanosis (15%), upper extremity edema (10%), vocal cord paralysis (4%), and Horner’s syndrome (2%). Vocal cord paralysis and Horner’s syndrome usually imply involvement of adjacent structures. The syndrome is rarely so severe that immediate definitive treatment is necessary. For patients who initially present with SVC obstruction, there is usually time to search for a diagnosis. Sputum cytology and bronchoscopy usually provide a diagnosis. Often easily biopsied masses are found elsewhere in the body. In patients without tracheal edema, mediastinoscopy or even thoracotomy may be performed safely, notwithstanding older literature which suggests that an unacceptable risk of bleeding accompanies these procedures. “Blind” supraclavicular node biopsies may afford a diagnosis in up to 60% of cases. Emergency treatment, without awaiting a diagnosis, is indicated when there is cerebral dysfunction, symptomatic impairment of cardiac output or upper airway edema. Adequate oxygenation and circulation should be obtained. If intubation of the edematous trachea is required, it should be performed by an experienced anesthetist under controlled conditions to avoid trauma. For patients known to have small cell carcinoma of the lung or lymphoma, chemotherapy is the treatment of choice (unless the tumor is known to be resistant). When the history is unknown, radiation therapy is promptly administered. We proceed with diagnostic maneuvers during the initial stages of radiation. Responses are usually seen within seven days, and are obtained in 70% of patients with bronchogenic carcinoma and 95% of patients with lymphoma. Lack of improvement in spite of tumor regression on radiographic studies suggests that thrombosis of the SVC may have developed. The usefulness of prophylactic anticoagulation in preventing SVC thrombosis must be weighed against the risk of hemorrhage in a venous system under increased pressure. We do not routinely anticoagulate patients with SVC obstruction. Corticosteroids have been recommended to reduce accompanying inflammation and edema, but there are no controlled trials to support their use. A recent advance has been the development of intravascular SVC stents to relieve obstruction (Stock et al., 1995). Relief is typically rapid. We have found this approach useful in patients who have previously received mediastinal radiation, and who lack other life-threatening comorbid conditions. Catheter-associated SVC thrombosis is best treated by immediate thrombolytic therapy, administered when possible directly to the thrombus to minimize systemic fibrinolysis. An alternative is anticoagulation and catheter removal.

MALIGNANT PERICARDIAL EFFUSIONS AND CARDIAC TAMPONADE Although many patients with metastatic cancer are found to have cardiac or pericardial metastases at autopsy, only about 30% of these patients had symptoms attributable to this involvement, and in less than 10% was the diagnosis of malignant pericardial effusion made before death. The most common tumors associated with tamponade are bronchogenic carcinoma, breast cancer, lymphoma, leukemia, melanoma, gastrointestinal malignancy, and sarcomas. Occasionally tamponade may be due to cardiac encasement by tumor or to postirradiation pericarditis. Eventually there is interference with diastolic filling and the stroke volume decreases, with subsequent fall in blood pressure and compensatory tachycardia. As ventricular pressure rises, the mean pressures rise and eventually equalize in the left atrium, the pulmonary circulation, and the vena cava. The major complaint of patients is typically dyspnea, often with cough, or retrosternal chest pain. Hiccups, hoarseness, nausea, vomiting, and epigastric pain are occasional complaints. Eventually there is a decrease in cerebral blood flow which may result in seizures or altered mental status. There is often peripheral cyanosis, engorged neck veins, pulsus paradoxus, facial plethora, low systemic and pulse pressures, and distant heart sounds. With persistent increases in venous pressure, edema, ascites, and hepatosplenomegaly may occur. A chest radiograph is abnormal in most patients, showing either an enlarged cardiac shadow, mediastinal widening, or hilar adenopathy. The electrocardiogram may be normal or show sinus tachycardia, low QRS voltage, ST segment elevation, T wave changes, or electrical alternans. If any suspicion of tamponade arises, an echocardiogram is the test of choice. With optimal techniques of echocardiography, right heart catheterization is rarely necessary to differentiate tamponade or constriction from cardiomyopathy. Immediate removal of pericardial fluid should be performed as an emergency if there is cyanosis, shock, dyspnea, a pulse pressure less than 20 mm Hg, a paradox greater than 50% of pulse pressure, or peripheral venous pressure greater than 13 mm Hg (Spodick, 1967). Typically, this has been performed by pericardiocentesis using a subxiphoid approach and insertion of a Silastic catheter over a guide wire (Davis et al., 1984). This is a temporary measure, but may allow stabilization of a patient, as well as a diagnosis by pericardial fluid cytology. Pericardiectomy with creation of a pericardial window, generally utilizing a subxiphoid approach, provides long-term control of the tamponade, and provides diagnostic material in cases in which tumor cells are not shed into the pericardial fluid (Osuch et al., 1985). In our center, this is also the preferred method for emergency management of tamponade, since an experienced surgical team is immediately available. Pericardiocentesis remains a viable temporary measure for situations in which access to pericardiectomy is not immediately available.


HYPERVISCOSITY SYNDROME Emergency department visits because of altered mental status, visual disturbance, ischemic neurological symptoms, purpura, ecchymoses, epistaxis, or gastrointestinal bleeding are common for older patients. One cause to be considered, especially in elderly patients, is hyperviscosity syndrome due to high serum levels of an abnormal monoclonal immunoglobulin (McGrath and Penny, 1976). Plasma cell neoplasms, multiple myeloma, and Waldenström’s macroglobulinemia occur predominantly in the elderly. In these patients, there is frequently expansion of plasma volume, which can create an appearance of congestive heart failure. There is also renal dysfunction in many individuals. Usually plasma viscosity must be increased to four times normal before disturbances in hemostasis or circulation becomes evident (Crawford et al., 1985). Ancillary laboratory abnormalities often include varying degrees of cytopenia with the expanded plasma volume contributing to the reduction in packed red cell volume. Examination of a blood film always demonstrates rouleaux formation; and the sedimentation rate is elevated. Diagnosis is completed by examination of the bone marrow aspirate and by serum protein electrophoresis and immunofixation electrophoresis. One should not delay treatment while waiting for results of laboratory studies. Physical examination is usually unhelpful in diagnosis, since the classic “boxcar” pattern of circulation in the retinal vessels is seen only in the most severe forms of hyperviscosity syndrome. Plasma viscosity may be rapidly and acutely reduced by plasmapheresis. Despite anemia, patients with hyperviscosity syndrome must undergo plasmapheresis before transfusion since red cell infusions will increase viscosity and may aggravate disturbances in perfusion.

PATHOLOGICAL FRACTURES Fractures of weight-bearing bones are common in the elderly due to osteopenia. This tendency is enhanced in patients with cancer due to local metastatic disease or to tumor enhanced osteopenia. In pathological fractures of the axial skeleton, there is danger of neurological damage due to bony instability, and patients should be immobilized until surgical consultation is obtained. Pain control with rapidly acting narcotic analgesics is usually required. In these situations, particularly with vertebral pedicle involvement, surgical stabilization may be required (Drew and Dickson, 1980). Long bone lesions often cause pain with weight bearing on use of that extremity and there is always a risk of pathological fracture. In the lower extremity, we consider prophylactic internal fixation and/or radiation therapy for areas of destruction more than 3 cm in length or when involvement exceeds 30% of the thickness of the cortex. (For the upper extremity, the corresponding dimensions are 5 cm and 50%.) Once a pathological fracture occurs, internal fixation is usually necessary for adequate healing and pain

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relief. In patients who present with pathological fractures, one immobilizes the affected extremity, provides adequate analgesia, establishes an intravenous line to ensure adequate hydration, estimates blood loss around the fracture site, and prepares for internal fixation as soon as practical if the patient’s general condition is stable. Rapid fixation permits rapid mobilization. Radiation therapy to the involved site is begun as soon as feasible.

HEMATOLOGICAL EMERGENCIES Leukostasis This is an uncommon problem in a general medical setting, essentially occurs primarily in the situation of previously undiagnosed acute leukemia, and must be recognized rapidly for appropriate therapy. Patients present with varying degrees of mental confusion, and are sometimes even comatose; they may have respiratory insufficiency and often demonstrate evidence of inadequate peripheral perfusion. White blood cell counts are greater than 100 × 109 /l and composed predominantly of blasts indicative of acute leukemia. This syndrome is rarely if ever a problem in chronic leukemia with similar leukocyte counts, since cells are smaller and possibly have greater deformability. Therapy is directed toward reduction of circulating blasts and maintenance of perfusion. Patients should not be transfused initially, even if profound anemia is present. It is better to wait until leukocyte counts are falling and the clinical condition is improving, since early red cell transfusions can increase blood viscosity at presentation and even be fatal. While maintaining careful fluid balance, arrangements should be made for urgent therapeutic leukopheresis under the care of an oncologist or hematologist. Chemotherapy should be instituted promptly after diagnosis, to help prevent the progression of leukostasis after leukopheresis. In the case of acute promyelocytic leukemia, chemotherapy may induce a coagulopathy, and the combination of leukopheresis and retinoid therapy may be appropriate as well.

Thrombocytopenia (see Chapter 38, Disorders of Hemostasis) There is no consensus regarding precise platelet counts below which transfusion of platelets is mandatory. Thrombocytopenia predisposes to bleeding at platelet counts less than 50 × 109 /l but especially below 20 × 109 /l if the level has fallen rapidly. If platelet function is abnormal, bleeding is frequently seen in this range, and is an indication for platelet transfusion. If platelet function is normal, then lower counts may be tolerated. Thrombocytopenia may occur because of marrow suppression by drugs, other marrow dysfunction or peripheral platelet destruction. When uncertain, a bone marrow aspirate is required for evaluation. Acutely, one transfuses platelets immediately for any bleeding or significant headache (which may be due to an early intracranial

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hemorrhage) and avoids salicylates or nonsteroidal antiinflammatory agents that interfere with platelet function. Six pooled platelet concentrates or a single donor platelet aphereis collection will usually raise the platelet count some 40–60 × 109 /l in an average sized adult (Kruskall et al., 1988). Definitive therapy then is directed toward the cause of the thrombocytopenia.

Neutropenia This is relatively uncommon except in acute leukemia or a setting of cytotoxic drug therapy, although extensive marrow involvement with tumor may also be a cause. Bone marrow failure in the elderly may also present in this manner. Definitive diagnosis and treatment of the underlying cause may require specialty consultation. Once the granulocyte count falls below 1 × 109 /l, risk of infection increases dramatically. Therefore, any fever should prompt immediate examination; culture of blood, urine, and sputum; a chest radiograph; and prompt empiric broad-spectrum antibiotic therapy. Evaluation of the cerebrospinal fluid may be advisable in selected cases.

DISSEMINATED INTRAVASCULAR COAGULATION (DIC) DIC crosses several clinical boundaries including infection, obstetrical catastrophes, neoplasia, shock, acidosis, and even heat stroke. DIC is certainly a well-recognized complication of malignant neoplasm. Cancer of the lung, pancreas, breast, prostate, stomach, and colon are particularly likely to precipitate a disturbance of coagulation by release of thromboplastic material from tumor tissue (Levi, 2004). The one hematological malignancy most likely to trigger DIC is acute promyelocytic leukemia and of all the neoplastic processes, it should be the most easily recognized. Between 13 and 25% of patients with chronic DIC have underlying prostate carcinoma (Sack et al., 1977). Moreover, prostate cancer is the second most common form of malignancy in American males over the age of 50 years and the incidence increases each decade thereafter. Therefore, since prostate cancer increases with age, and because DIC is a frequent complication of that malignancy, physicians in ERs should expect occasionally to see an elderly man with a life-threatening bleeding disorder or thrombotic disorder that is clearly related to cancer only. Inclusion of this topic in a chapter devoted to oncological emergencies is appropriate but much more difficult to discuss than other problems because its clinical presentation can be variable and quite enigmatic; well-defined criteria for the diagnosis of acute and chronic DIC do not exist; coagulation tests are not infrequently deranged in random studies of patients with a broad spectrum of cancers (Peck and Reizuam, 1973); and treatment of this intricate coagulopathy remains controversial. Either thrombotic or fibrinolytic

events may predominate in a patient with DIC, resulting in a picture of either thrombosis or of bleeding. The balance may shift from time to time, and, not infrequently, sites of thrombosis and of bleeding exist simultaneously. Clinically significant expressions of the syndrome are usually manifest by bleeding, often from a combination of sites. Systemic signs of consumption coagulopathy can be quite inconstant since they reflect both the cause of the disordered clotting scheme and the organ dysfunctions that are secondary to defibrination as well as thrombosis. In a patient with cancer, one should evaluate primary roles for sepsis, shock, hemorrhage, venous thrombosis, embolism, thromboembolism, or the tumor itself, not to mention potential intra-abdominal disasters such as a perforated viscus of more rarely acute pancreatitis. This disorder is an extremely complex disarray of the hemostatic mechanisms, in which there can be evidence of accelerated coagulation without overt bleeding such that the formation of microthrombi overshadows activation of fibrinolysis. Although criteria for diagnosis vary, basic tests for DIC center around three areas: assays for clotting factors, studies of cellular elements, and determination of fibrinolysis. We initially evaluate the prothrombin time, activated partial thromboplastin time, thrombin clot time, and serum fibrinogen level. These may be abnormal in DIC and the degree of abnormality is a clue to the severity of the condition. Fibrin D-dimer measurement detects the lysis of cross-linked fibrin, and if elevated confirms the presence of a fibrinolytic component in the clinical situation. Inspection of the blood film is mandatory to evaluate the presence of schistocytes, which connote microvascular thrombosis with intravascular red cell fragmentation. The platelet count is also often depressed due to consumption in the coagulation process. These studies do not usually define the exact pathophysiologic processes underway in the patient, but provide a “snapshot” of the situation at a single moment. Observation of changes in these tests over several hours or days is necessary to appropriately treat the hemostatic abnormalities. Aggressive effort to trace and treat the underlying precipitating disorder is the best method to initiate therapy. Septicemia and shock may be difficult to treat but disseminated cancer is even less easily ablated. We strive to maintain reasonably normal levels of clotting factors, by transfusions if necessary, but also by anticoagulation if it appears that factors are being consumed due to extensive intravascular thrombosis. For situations in which excessive fibrinolysis plays a role, antifibrinolytic agents might be appropriate. The target is a moving one, and expert hematological consultation and access to a capable coagulation laboratory greatly facilitate managing patients with clinically significant DIC.

CENTRAL NERVOUS SYSTEM EVENTS Mass lesions of the brain in patients with cancer may be due to a primary brain tumor, metastatic disease, postirradiation


brain necrosis, hemorrhage, or abscess. Lung and breast primaries account for most metastases and symptoms are related to location of masses and the rate of increase in intracranial pressure. Headache is often throbbing and present on awakening, clearing in hours but recurring periodically during the day. It is exacerbated by cough, Valsalva, or sudden movements. Headaches of a fleeting or stabbing nature, or those that increase in severity throughout the day, are unusual for tumor. Any new onset of seizures (usually focal) without obvious cause in a patient over 30 years of age suggests tumor, especially in an individual known to have malignant disease. Other more classical findings in brain metastasis are focal neurological deficits or papilledema. Computed tomography (CT) of the brain is generally the initial test. MRI scans are less readily available, and more expensive, although more sensitive. MRI scans may be most helpful in determining the exact number of lesions in patients being considered for excision of brain metastases or for stereotactic radiation. Once a mass lesion is identified, its origin must still be determined. At 6–12 months posttherapy, postirradiation brain necrosis can mimic a return of the original tumor but papilledema is not present. A biopsy may be required to distinguish between them. Positron-emission tomography is helpful in this situation but its availability is limited. In the setting of long-term steroid therapy or recurrent neutropenia, an abscess may present merely as a mass lesion without fever. A variety of disorders can mimic potential brain metastasis upon presentation, including: other kinds of headaches; ethanol withdrawal seizures; cerebrovascular accidents; pseudotumor cerebri; subdural hematomia; encephalitis and arachnoiditis. All should be evaluated appropriately. If a mass lesion felt to be a tumor is demonstrated, initial therapy with dexamethasone is begun as for spinal cord compression. If herniation is imminent, then mannitol 12.5–25 g is given intravenously along with dexamethasone and neurosurgery and radiation oncology are consulted immediately. Cerebrovascular complications in patients with cancer originate from several different causes, have been well described, and will be overlooked if not considered in the appropriate setting (Graus et al., 1985). Nonbacterial thrombotic endocarditis and attendant cerebral infarction should not have any age dependence but atherosclerosis is the most frequent cause of cerebral infarction found at autopsy and certainly is more age related. Usual risk factors for cerebrovascular disease are often overshadowed in a patient with malignancy because frequently there are several other things going on. There are perhaps two clues in the approach to the diagnosis of cerebrovascular disease in patients with cancer: first, the clinical presentation is often a diffuse encephalopathy rather than an acute focal deficit and secondly, the type of event is related sometimes to the primary tumor, but also to the extent of cancer, evidence of central nervous system infiltration, or the presence of superimposed complications such as immunosuppression,

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infection, coagulopathy, and any recent invasive procedures (Graus et al., 1985).

GASTROINTESTINAL EMERGENCIES Major gastrointestinal calamities in the setting of cancer are related to obstruction, perforation, hemorrhage, and inflammation. These may be due to effects of tumor or therapy. Obstruction of the bowel may result from primary tumor, recurrent or metastatic tumor, adhesions, or scarring from radiation. Patients present with combinations of pain, nausea, vomiting, constipation, and distention. The greatest threat is in those individuals with a competent ileocecal valve and a distal obstruction wherein cecal perforation may occur. Immediate surgical decompression is indicated should cecal dilatation to 12–14 cm be seen on a plain film of the abdomen. When the ileocecal valve is not competent, large bowel obstruction as well as small bowel dilatation respond well to suction, along with fluid and electrolyte replacement, such that surgery can be delayed or sometimes avoided. In patients presenting to an ER with abdominal pain, 2% were discovered to have cancer (usually of the colon) and there was rarely obstruction or perforation (DeDombal et al., 1980). Of patients older than 50 years presenting with abdominal pain, 7% developed cancer. Data from a cooperative study in Scotland, England, and Denmark suggest that 10% of all patients with gastrointestinal malignancies present to an ER and 3% do so with an intra-abdominal catastrophe. The remainder present as acute “unexplained” abdominal pain. Characteristics more common in those found to have cancer were pain lasting longer than 48 hours, intermittent pain, worsening pain, constipation, abdominal distention, and an abdominal mass (DeDombal et al., 1980). Surgery, when performed as an emergency in the elderly, especially for gastrointestinal malignancies, was believed to carry a higher risk. However, recent studies have shown no change in morbidity or mortality by decade if patients of similar nutritional status without coexisting organ system disease are compared (Boyd et al., 1980). Complications are less related to age than to preoperative nutritional status and preoperative impairment of other organ systems. However, emergent surgery overall does have a higher risk than for similar procedures performed electively. The lesson here is that with proper attention, the elderly can undergo appropriate procedures with similar morbidity and mortality as patients who are younger but with similar coexisting conditions. Conditions that adversely affect risk include pulmonary insufficiency, cardiac dysfunction, hypertension, renal insufficiency, hepatic disease, diabetes, or previous major surgery (Boyd et al., 1980).

VENOUS THROMBOSIS AND EMBOLISM (see Chapter 55, Venous Thromboembolism) Thromboembolic events are common in patients with malignancies and can be attributed to a lack of activity and to a

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hypercoagulable state which characterizes some neoplasms (Di Nisio et al., 2004). It is important to realize that a predisposition to thrombosis may be present and that the presentation may be gradual. For instance, multiple small pulmonary emboli may be responsible for worsening pulmonary insufficiency. Yet in patients with malignancies one sometimes avoids thrombolytic therapy since many patients have had surgery, have structural lesions, or have coexisting cytopenias, and often life expectancy as well as mobility are greatly limited such that prevention of a postphlebitic syndrome is of less concern than in other patients. Age alone is not a contraindication to appropriate thrombolytic therapy or anticoagulation, although it may complicate management. The elderly patient is more likely to fall, complicating anticoagulation. The appetite and diet may be variable, complicating control of oral anticoagulation. There may also be an increased risk of gastrointestinal bleeding in these patients. If anticoagulation is contraindicated or unsuccessful, then insertion of a caval filter may at least prevent subsequent pulmonary embolism.

EMERGENCIES DUE TO NEOPLASMS OF THE HEAD AND NECK Squamous cell carcinomas of the floor of the mouth, the tongue, the tonsils, and the larynx essentially occur during middle and older life. Therefore, two disasters, upper airway obstruction and external massive hemorrhage from the carotid system, are not unusual in the elderly. However, the usually slow growth of epidermoid carcinoma in the head and neck region provides ample warning of such complications, and more than enough time to decide how or whether to treat it. Unfortunately, a specific plan for such an exigency is uncommon or rarely transcribed. Tracheostomy is indicated in every patient in whom there is or it is expected that there will be airway compromise. By following this principle, it should be possible to perform tracheostomy under controlled circumstances in the operating room, thereby avoiding having to do it under emergency and uncontrolled circumstances. There are rare exceptions, such as patients with bilateral thyroid cancer and primary or metastatic pulmonary neoplasms that might be seen with airway obstruction at the glottic level due to bilateral vocal cord paralysis in the adducted position. In that setting, it is possible to have more subtle signs and the etiology of the recurrent laryngeal nerve dysfunction might not be immediately apparent. For the patient with a tracheostomy tube already in place, there are still two more threats. Rarely a life is lost because of the inability to reinsert tubes during the changing of them before the tract is well defined or when there is high-grade airway obstruction. Finally, dislodgement of a tube can be catastrophic and has characteristic signs including recurrent airway obstruction, despite an earlier tracheostomy; absence of airflow via the tube during attempts at deep respiration; inability to suction pulmonary secretions from it; and a

normal voice. A proper instruction sheet warns of these signs and advises the patient and/or family to alert their physician promptly or to call for help through a number for emergency medical services. Hemorrhage may ensue from extensive cancers that erode major vessels or because of necrosis of vessel walls subsequent to injury by some combination of exposure, radiation, surgery, cytotoxic chemotherapy, and oral cutaneous fistula formation. Attempts at local control or grafting of the vessel are of no avail. Carotid artery hemorrhage by tumor erosion is the most life-threatening emergency seen in oncological disorders. However, it rarely occurs de novo, being heralded by a small transient bleed prior to the final disruption. Certainly there is more than enough time for the physician of a patient with head and neck cancer to decide whether hemorrhage from the carotid system is going to be accepted as the terminal event should it occur. Unfortunately, decisions like that are both painful and distasteful, resulting in heroic attempts by emergency teams in the absence of such decision making and in the absence of written orders. A deeply invasive tumor at the base of the tongue, with erosion of branches of the external carotid system, is one of the most common causes of major arterial hemorrhage from the mouth. This type of hemorrhage may require ligation of both external carotid arteries in order to stop the bleeding, since there is such extensive cross circulation.

UTILIZATION OF INTENSIVE CARE UNITS (ICUs) Early in the course of neoplastic disease, when expectations of a successful outcome are real, there is almost never any reason to withhold supportive measures, including an ICU, in order to overcome an early complication of the disease per se or its treatment. On the other hand, it is legitimate to ask what to do about that patient with advanced cancer who is in the third trimester of the illness and whose intercurrent problems suddenly escalate. There appears to be no simple stopping point in the progression of attempts at diagnostic or therapeutic intervention. Often there is a clinical temptation to believe that just a bit more intervention, such as endotracheal intubation, open lung biopsy and aggressive support on an ICU, will surmount the complication. This is a scene played out frequently, leading to marginally useful results and extraordinarily high costs. Of the many controversies that attend this highly charged decision about admitting cancer patients to intensive care wards is one still incompletely resolved even by the courts: which patient has the right to refuse life-saving extraordinary therapy (Emanuel, 1988). Another challenge faced by critical care specialists who often control access to these units is the matter of unattainable certainty in formulating prognosis upon which life-and-death decisions should be based (Reuben et al., 1988). It is impossible to give specific advice in this area of the practice of medicine since physicians are waiting for a societal commitment to the solution of certain problems (Bayer et al., 1983). Nevertheless, physicians should not practice emergency medicine in


the field of oncology without first carefully reflecting about the issues involved in the use of ICUs, and without examining/understanding the policies for control of the ICUs at their own hospital.

EMERGENCY MEDICAL SERVICES AND CANCER The interface between emergency medical services and the dying patient is both complex and difficult. It ranges from the extreme, where an ambulance delivers paramedical staff to the bedside of a patient experiencing dyspnea, coma, or shock, to the appearance of a patient in an ER with varied or several complaints (usually reported by a relative or caregiver rather than the individual who has the malignancy). In the first scenario, the paramedical staff may be told about a living will, but the existence of such cannot be immediately documented. Sometimes a family member might just report that this individual patient would not want to be resuscitated. At such times, there is not comfortable agreement about what to do and in many states living wills were designed for use in hospital rather than as instruments to instruct medical technicians after a request for emergency care has already been initiated. Today general legal and ethical standards offer these paramedical personnel no truly safe alternative than to initiate life-saving techniques upon encountering an unresponsive patient or one in severe physiological distress. In the second setting, a visit to an ER, the reason for attendance may turn out to be plural, something we call a multifactorial presentation. Everything seems to be going a little bit wrong and actually it is a matter of family or caregivers wearing out or refusing to cope any longer. The problem then becomes one of dealing with a chronic disease in an inappropriate setting, by a busy physician who has limited knowledge about the patient’s previous course. Our capabilities for intervening are great and increase steadily with each decade. One challenge is to intervene appropriately and not let a potentially reversible crisis progress to irreversibility. We also must be wise enough not to make a bad situation worse. All of this requires an intense effort toward preventing individual pieces of the medical care system from becoming disconnected. Physicians can do that by remaining aware of their responsibilities especially in the area of communication. Certainly patients having an acute event during a chronic illness should rarely turn up in an ER unannounced. Finally, in the realm of therapy, we should all do well to remember the words of Max Born (Born, 1968): “intellect distinguishes between the possible and the impossible; reason distinguishes between the sensible and the senseless; even the possible can be senseless”. There should be no real doubt about some of the sensible goals of treatment in patients with cancer whether they are in the first or the tenth decade of life. They are: activate every important modality of treatment in an attempt at cure; preserve locomotion and continence; protect the ability to think; relieve pain or suffering; and support dignity (Silberman, 1986).

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KEY POINTS • The presentation of cancer in the elderly may be as a urgent problem with either an anatomic or metabolic cause. • Hypercalcemia may have subtle symptoms in the elderly, and requires a high index of suspicion. • Weakness may be a result of spinal cord compression, central nervous system metastases, metabolic derangements due to cancer, or be unrelated to a patient’s malignancy. • Cancer is associated with a pronounced tendency towards thrombosis. • Encourage patients and families to formally make known their wishes regarding end of life care, before an urgent situation arises.

KEY REFERENCES • Di Nisio M, Squizzato A, Klerk CPW et al. Antithrombotic therapy and cancer. Current Opinion in Hematology 2004; 11:187 – 91. • Graus F, Rogers LR & Posner JB. Cerebrovascular complications in patients with cancer. Medicine 1985; 64:16 – 35. • Harvey HA. The management of hypercalcemia of malignancy. Support Care Cancer 1995; 3:123 – 9. • Stock KW, Jacob AL, Proske M et al. Treatment of malignant obstruction of the superior vena cava with the self-expanding Wallstent. Thorax 1995; 50:1151 – 6. • Yarboro JW & Bornstein RS. Oncologic Emergencies 1981; Grune and Stratton, New York.

REFERENCES Bailar JC & Smith EM. Progress against cancer? The New England Journal of Medicine 1986; 314:1226 – 32. Bayer R, Callahan D, Fletcher J et al. The care of the terminally ill: morality and economics. The New England Journal of Medicine 1983; 309:1490 – 94. Bell DR, Woods RL & Levi JA. Superior vena caval obstruction: a 10-year experience. The Medical Journal of Australia 1986; 145:566 – 568. Bobrowitz ID, Ramakrishna S & Shim Y-S. Comparison of medical v surgical treatment of major hemoptysis. Archives of Internal Medicine 1983; 143:1343 – 6. Born M. My Life and My Views 1968; Charles Scribner and Son, New York. Boyd JB, Bradford B & Watne AL. Operative risk factors of colon resection in the elderly. Annals of Surgery 1980; 192:743 – 46. Brown MW, Bradley JA & Calman KC. Malignant disease in the accident and emergency department. The British Journal of Clinical Practice 1983; 37:205 – 8. Cohen HJ, Silberman HR, Forman W et al. Effect of age on response to treatment and survival in multiple myeloma. Journal of the American Geriatrics Society 1983; 31:272 – 7. Conlan AA, Hurwitz SS, Krige L et al. Massive hemoptysis. The Journal of Thoracic and Cardiovascular Surgery 1983; 85:120 – 4. Cornbleet M, Bondy PK & Powels TJ. Fatal irreversible hypercalcemia in breast cancer. British Medical Journal 1977; i:145 – 9.

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Crawford J, Cox EB & Cohen HJ. Evaluation of hyperviscosity in monoclonal gammopathies. The American Journal of Medicine 1985; 79:13 – 22. Crocco JA, Rooney JJ, Fankushen DS et al. Massive hemoptysis. Archives of Internal Medicine 1968; 121:495 – 8. Davis S, Rambotti P & Grignani F. Intrapericardial tetracycline sclerosis in the treatment of malignant pericardial effusion. An analysis of 35 cases. Journal of Clinical Oncology 1984; 2:631 – 6. DeDombal FT, Matharu SS, Stuniland JR et al. Presentation of cancer to hospital as ‘acute abdominal pain’. The British Journal of Surgery 1980; 69:413 – 16. Di Nisio M, Squizzato A, Klerk CPW et al. Antithrombotic therapy and cancer. Current Opinion in Hematology 2004; 11:187 – 91. Drew M & Dickson RB. Osseous complications of malignancy. In J Lohick (ed) Clinical Cancer Management 1980, p 18; GR Hall, Boston. Emanuel EJ. A review of the ethical and legal aspects of terminating medical care. The American Journal of Medicine 1988; 84:291 – 301. Gilbert RW, Kim JH & Posner JB. Epidural spinal cord compression from metastatic tumour: diagnosis and treatment. Annals of Neurology 1978; 3:40 – 51. Graus F, Rogers LR & Posner JB. Cerebrovascular complications in patients with cancer. Medicine 1985; 64:16 – 35. Griebie MS & Adams BL. ‘Emergency’ laryngectomy and stomal recurrence. The Laryngoscope 1987; 97:1020 – 4. Hantman D, Rossier B, Zohlman R et al. Rapid correction of hyponatremia in the syndrome of inappropriate secretion of antidiuretic hormone – an alternative treatment to hypertonic saline. Annals of Internal Medicine 1973; 78:870 – 5. Harvey HA. The management of hypercalcemia of malignancy. Support Care Cancer 1995; 3:123 – 9. Kalemkerian GP, Darwish B & Varterasian ML. Tumor lysis syndrome in small cell carcinoma and other solid tumors. American Journal of Medicine 1997; 103:363 – 8. Kalia S & Tintinalli J. Emergency evaluation of the cancer patient. Annals of Emergency Medicine 1984; 13:723 – 30. Kennedy BJ. Specific considerations for the geriatric patient with cancer. In P Calabresi, P Schein & S Rosenberg (eds) Medical Oncology 1985, pp 1433 – 45; Macmillan, New York. Kruskall MS, Mintz PD, Bergin JJ et al. Transfusion therapy in emergency medicine. Annals of Emergency Medicine 1988; 17:327 – 35. Levi M. Current understanding of disseminated intravascular coagulation. British Journal of Haematology 2004; 124:567 – 76. McGrath MA & Penny R. Paraproteinemia: blood hyperviscosity and clinical manifestations. The Journal of Clinical Investigation 1976; 58:1155 – 9. McKee LC & Collins RD. Intravascular leukocyte thrombi and aggregates as a cause of morbidity and mortality in leukemia. Medicine 1974; 53:463 – 78. Mullins GM, Glynn MB, El-Mahdi AM et al. Malignant lymphoma of the spinal epidural space. Annals of Internal Medicine 1971; 74:416 – 23. Osuch JR, Khandehar JN & Fry WA. Emergency subxyphoid pericardial decompression for malignant pericardial effusion. The American Surgeon 1985; 51:298 – 303. Peck SD & Reizuam CW. Disseminated intravascular coagulation in cancer patients: supportive evidence. Cancer 1973; 31:1114 – 19.

Peterson BA. Acute non-lymphocytic leukemia in the elderly. In CD Bloomfield (ed) Biology and Treatment in Adult Leukemias 1982, pp 199 – 235; Martinus Nijhoff, The Hague. Pontoppidin H, Abbott W, Brewster D et al. Optimum care for hopelessly ill patients. In Report of the Clinical Care Committee of the Massachusetts General Hospital. The New England Journal of Medicine 1976; 295:362. Reuben DB, Mor V & Hiris J. Clinical symptoms and length of survival in patients with terminal cancer. Archives of Internal Medicine 1988; 148:1586 – 91. Sack GH, Levin J & Bell WR. Trousseau’s syndrome and other manifestations of chronic disseminated coagulopathy in patients with neoplasms: clinical pathologic and therapeutic features. Medicine 1977; 56:1 – 37. Silberman HR. Minimizing the economic hardships of diagnosis and treatment. In J Laszlo (ed) Physician’s Guide to Cancer Care Complications 1986; Marcel Dekker, New York. Spodick DH. Acute cardiac tamponade pathologic physiology diagnosis and management. Progress in Cardiovascular Diseases 1967; 10:64 – 96. Stock KW, Jacob AL, Proske M et al. Treatment of malignant obstruction of the superior vena cava with the self-expanding Wallstent. Thorax 1995; 50:1151 – 6. Torma T. Malignant tumours of the spine and spinal extradural space: a study based on 250 histologically verified cases. Acta Chirurgica Scandinavica 1957; 225:1 – 138. Trump DL. Serious hyponatremia in patients with cancer: management with demeclocycline. Cancer 1981; 47:2908 – 12. Ushio Y, Posner T, Kim JH et al. Treatment of experimental spinal cord compression caused by extradural neoplasms. Journal of Neurosurgery 1977; 47:380 – 90. Vaeth JM & Meyer J. Cancer and the elderly. In JM Vaeth & J Meyer (eds) Frontiers of Radiation Therapy in Oncology 1985, vol 20; Karger, Basel, New York. Waldron RP, Donova IA, Drumm J et al. Emergency presentation and mortality from colorectal cancer in the elderly. The British Journal of Surgery 1986; 73:214 – 16. Warrell TP, Israel R, Frisone M et al. Gallium nitrate for accurate treatment of cancer-related hypercalcemia. Annals of Internal Medicine 1988; 108:669 – 74. Wild WO & Porter RW. Metastatic epidural tumor of the spine: a study of 45 cases. Archives of Surgery 1963; 87:137 – 42. Wright RL. Malignant tumors of the spinal extradural space: results of surgical treatment. Annals of Surgery 1963; 157:227 – 31. Yancik R. Old age as the context for the presentation and treatment of cancer. In R Yancik & PP Carbone (eds) Perspectives on Prevention and Treatment of Cancer in the Elderly 1983, p 95; Raven Press, New York. Yarboro JW & Bornstein RS. Oncologic Emergencies 1981; Grune and Stratton, New York. Yarboro JW, Bornstein RS & Mastrangelo MJ. Oncologic emergencies. Seminars in Oncology 1978; 5:123 – 231. Yoh CB, Hubaytar RT, Ford JM et al. Treatment of massive hemorrhage in pulmonary tuberculosis. The Journal of Thoracic and Cardiovascular Surgery 1967; 54:503 – 10. Zusman J, Brown BM & Nesbit ME. Hyperphosphatemia, hyperphosphaturia, and hypocalcemia in acute lymphoblastic leukemia. The New England Journal of Medicine 1973; 289:1135 – 40.

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Breast Cancer in the Elderly Robert E. Mansel and Anurag Srivastava Wales College of Medicine, Cardiff University, Cardiff, UK

THE PRESENTATION Diagnosis of breast cancer in the elderly is made by the discovery of a lump in 60–80% women. Since screening is applied less rigorously to elderly patients, the majority of women present with a palpable lump. Some studies reveal that the stage at presentation is more advanced in the elderly women (Goodwin et al., 1986; Homes and Hearne, 1981). A patient care evaluation survey was conducted by Commission on Cancer of the American College of Surgeons for 1983 and 1990 (Busch et al., 1996). They surveyed all states of United States including Puerto Rico and Canada and studied 17 029 women in 1983 and 24 004 women in 1990. Twenty percent of women in 1983 and 23% in 1990 were 75 years of age or older. The survey included 2000 hospitals (25 patients from each). The percentage of cancers detected by physicians’ examination decreased in the younger group from 27% in 1983 to 21% in 1990, whereas in the elderly, the corresponding figures were 41% and 34% respectively. Veronesi’s group from Milan reported various features of presentation and choice of therapy in the elderly (Gennari et al., 2004). They studied 2999 postmenopausal patients referred for surgery at the European Institute of Oncology, Milan, Italy, from 1997 to 2002. The patients were grouped according to age: young postmenopausal (YPM age 50–64 years, n = 2052), older postmenopausal (OPM age 65–74, n = 801), and elderly postmenopausal (EPM age ≥75, n = 146). EPM patients had larger tumors compared with YPM patients (pT4: 6.7 vs 2.4%) and more nodal involvement (lymph node positivity: 62.5 vs 51.3%). EPM patients showed a higher degree of estrogen and progesterone receptor expression, less peritumoral vascular invasion and less human epidermal growth factor receptor-2 (HER-2)/neu expression than YPM patients. Although, comorbidities were more often recorded for elderly patients (72% EPM vs 45% YPM), it did not influence surgical choices which were similar across groups (breast conservation: 73.9, 76.9, and 72.9%, respectively). No systemic

therapy was recommended for 19.1% of the EPM compared with 5.4 and 4.7% of the two other groups. In women over 70 years, estrogen receptor positive tumors are more common, range 69 to 95% compared with all tumors, range 53 to 72% (Busch et al., 1996). Pathologically infiltrating ductal carcinoma accounts for 77 to 85% of all tumors in the elderly women as compared to 68% in younger women. There is an increase in the proportion of papillary and mucinous carcinoma with advancing age. Whereas the number of lobular carcinoma in situ, comedo, medullary, and inflammatory carcinoma decreases with advancing age, the prevalence of ductal carcinoma in situ (DCIS) increases until 75 years, after which it declines (Rosen et al., 1985; Law et al., 1996). In summary, elderly women generally present with large palpable estrogen receptor positive, infiltrating ductal carcinoma with a positive lymph node (Law et al., 1996).

STAGE OF PRESENTATION Age and delay – there is generally a delay in the diagnosis of breast cancer in elderly women. In a study by Berg and Robbins (1961), the diagnosis was delayed by more than 6 months in 28% of women under 70 years of age compared to 42% delay in women above the age of 70. Similarly, Devitt (1970) observed a delay of more than 6 months in diagnosis in 35% of women above the age of 70, compared to 28% below the age of 70. The tumor is generally advanced in elderly group as shown in Table 1.

COMORBIDITY: THE MAIN REASON TO JUSTIFY UNDERTREATMENT Women suffering from heart disease, obstructive airway disease, stroke, or other major incapacitating illnesses receive inadequate diagnostic and therapeutic attention.


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Table 1 TNM Stage with age at presentation

Age(yrs) >80 >80 >75

I

II

III

IV

Reference

52% 25% 53%

18% 49% 22%

6% 15% 12%

24% 10% 13%

Robin and Lee (1985) Davis et al. (1985) Host (1986)

TNM, tumor nodes metastases.

Nicolucci et al. (1993) analyzed the data on 1724 women treated in 63 general hospitals in Italy. A comorbidity index was computed from individual disease value (IDV) and functional status (FS). IDV summates the severity and presence of specific complications for each disease suffered on a scale of 0–3, with 0 = full recovery and 3 = life-threatening disease. FS from signs and symptoms of 12 system categories evaluated the impact of all conditions, whether diagnosed or not, on patients’ health status. The study showed higher proportions of inadequate diagnosis and therapy in the elderly group. The quality of care was assessed by a score based on observed degree of compliance with standard care. The median value of overall diagnostic and staging score was 60%. About one-third of surgical operations were inappropriate; 24% of cases with stage I-II disease had unnecessary Halsted mastectomy, and breast conservation in smaller tumors of ≤2 cm was underutilized. The presence of one or more coexistent diseases was associated with failure to undergo axillary dissection and lower utilization of conservative surgery. Newschaffer et al., 1996 from the Virginia Cancer Centre evaluated 2252 women with breast cancer (without metastasis). In the group of women above 85 years, the odds of being treated surgically were one-third of those women in 66–74 years age-group. The odds of getting breastconserving surgery with radiotherapy (RT) were 0.55. Even after adjusting for comorbidity, the odds ratio remained the same. Ganz et al. (2003) examined health-related quality of life (QoL) of a cohort of older women with breast cancer. They used standardized QoL measures in a group of 691 women of 65 and above who were interviewed 3 months after surgery and twice in the following year. Physical and mental health scores declined significantly in the follow-up year, independent of age. However, a cancer-specific psychosocial instrument showed improvement in the scores. Better 3-month physical and mental scores and better emotional support predicted more favorable self-perceived health, 15 months after surgery. The authors concluded that significant decline occurs in the physical and mental health of older women in 15 months after surgery, whereas cancer-specific QoL measure improved over time. Alvan Feinstein, a famous clinical epidemiologist from Yale, has said that the failure to classify and analyze comorbid disease has led to many difficulties in medical statistics (Feinstein, 1970). There are four reasons for measuring comorbidity correctly: (1) to be able to correct for confounding thus improving internal validity of the study, (2) to be able to identify effect modification, (3) the desire to use comorbidity as a predictor of outcome, and (4) to construct a

comprehensive single comorbid scale that is valid, to improve the statistical efficiency. de Groot et al. (2003) have recently reviewed various comorbidity indices. The following indices have been applied for patients with breast cancer: “Charlson Index” – this is the most extensively studied method and includes 19 diseases which are weighted on the basis of strength of association with mortality. The “disease count index” simply counts the coexisting diseases but lacks a consistent definition and weighting for different diseases. The “Kaplan index” uses the type and severity of comorbid condition, for example, types are classified vascular (hypertension, cardiac disease, peripheral vascular disease) and nonvascular (lung, liver, bone, and renal disease). It has good predictive validity for mortality. It may be worthwhile for all the agencies involved in breast cancer research to adopt one of the above indices and record it prospectively.

SCREENING IN THE ELDERLY Presently, all women in the United Kingdom between age 50 and 65 are being offered breast cancer screening. Although those above 65 are eligible, they have not been called routinely. Till recently, those already on the regular screening were not recalled after they reached the age of 65. The NHS Breast Cancer screening Programme in the UK, 2005 has screened more than 14 million women and has detected over 80 000 cancers. The NHS Breast Screening Programme is saving at least 300 lives per year. This figure is set to rise to 1250 by 2010. By 2010, the effect of the screening program, combined with improvements in treatment and other factors (including cohort effects), could result in up to a halving of the breast cancer death rate in women aged 55–69 from that seen in 1990. The program has now expanded to invite women between 65 and 70. Thus, from Table 2 it can be seen that with increasing age the number of cancers detected goes up. In order to enhance the rate of breast examination by doctors in women above 65 years and to increase compliance with mammography, Herman et al. (1995) conducted a randomized clinical trials (RCT) at the Metro Health Medical Center Cleveland, Ohio. All house staff in Internal Medicine were asked to fill a questionnaire about their attitude toward prevention of breast cancer in elderly people after providing some basic information (Monograph and a lecture). In one arm (controls), no specific interventions were offered. In the next group (education), nurses provided educational leaflets to patients attending the clinics. In the third group (prevention), nurses filled the request forms and Table 2 Result of UK breast cancer screening – 2004 review NHS Breast Cancer screening Programme in the UK, 2005

Age 50 – 64 65 – 69

Cancer detected per 1000 women screened 7.6 20.6

BREAST CANCER IN THE ELDERLY Table 3 Rates of examination and mammography by intervention

Group Control (n = 192) Education (n = 183) Prevention (n = 165)

Breast exam (%)

Mammography (%)

18 22 32

18 31 36

facilitated women to undergo mammography. Their results are given in the Table 3: The study suggests that encouragement and education of older women by motivated doctors and nurses improves compliance. Chen et al. (1995) reported the mortality rate of women aged 65–74 screened in the Swedish 2-county trial – 77 080 women were randomized to undergo screening every 33 months and 55 985 women served as controls. Of the screened group, 21 925 were in the age-group 65–74. In the control arm, 15 344 women belonged to the agegroup 65–74 years. The relative breast cancer mortality in the screened group was 0.68, demonstrating a survival advantage in the elderly population.

RISK FACTORS IN ELDERLY Age: With advancing age, the risk of developing breast cancer rises. In a cohort of National Surgical Adjuvant Breast and Bowel Project’s Breast cancer prevention trial of USA, the presence of nonproliferative lower category benign breast disease (LCBBD) has been found to increase the risk of invasive breast cancer. The overall relative risk (RR) of breast cancer was 1.6 for LCBBD, compared to women without any LCBBD. This risk increased to 1.95 (95% confidence interval (CI) 1.29–2.93) among women aged 50 and over (Wang et al., 2004). Hormone replacement therapy (HRT) has been identified as a risk factor for breast cancer. The impact of HRT on the incidence and death due to breast cancer in the United Kingdom was assessed through a study on 1 million women (Million Women Study Collaborators, 2003). In this prospective cohort of 1 084 110 women aged 50–64, current users of HRT were found to have a higher risk of developing breast cancer than nonusers (RR = 1.66; 95% CI 1.58–1.75). The risk was highest for combined estrogen-progestogen (RR = 2; 95% CI 1.88–2.12) than for estrogen alone (RR = 1.3; 95% CI 1.2–1.4) and for tibolone (RR = 1.45; 95% CI 1.25–1.68) compared to those who never used. There was a dose response relationship of increasing risk of cancer, with increasing duration of HRT usage, the highest being with combined estrogen + progestogen used for 10 years or more (RR = 2.31; 95% CI 2.08–2.56). The Danish Nurses Cohort study (Stahlberg et al., 2004) provided data on 10 874 nurses (aged 45 years and above). Of these, 244 women developed breast cancer. After adjusting for confounding, increased risk was found with current use of estrogens (RR = 1.96; 95% CI 1.16–3.35), for combined use of estrogen + progesterone (RR = 2.7; 95% CI

1533

1.96–3.73), for current use of Tibolone (RR = 4.27; 95% CI 1.74–10.51), compared to never ever use of HRT. In current users of combined HRT with progestins, continuous combined use has higher risk (RR = 4.16; 95% CI 2.56–6.75) than cyclical combined use (RR = 1.94; 95% CI 1.26–3).

Natural History of Breast Cancer in the Elderly It has long since been thought that breast cancer in the elderly is rather indolent and a biologically less aggressive disease. Singh et al. (2004) studied the metastatic proclivity as indicated by the virulence (defined as the rate of appearance of distant metastasis) and metastagenecity (defined as the ultimate likelihood of developing distant metastasis). These authors examined 2136 women who underwent mastectomy without systemic adjuvant therapy at the University of Chicago Hospitals between 1927 and 1987. The median follow-up period was 12 years. Distant diseasefree survival(DDFS) was determined and virulence (V) and metastagenecity (M) were obtained from log linear plots of DDFS. No significant difference was observed between size of primary tumor in age-group 70 years. Significantly, fewer women above 70 years presented with positive nodes. In women with negative nodes, the DDFS was higher among age 40–70 years, compared with those among age over 70. However, no significant difference was observed in the DDFS in the node positive group in any of the age categories. The 10-year DDFS for age 40–70 was 33% and for women >70 it was 38%. Among the node negative women, V was 3% per year for age 40–70 years, as well as for age >70 years and M was 0.2 for age 40–70 years and 0.35 for age >70 years. In women with positive nodes, both V (11% per year vs 10% per year) and M (0.7 vs 0.65) were similar in both age-groups. These authors concluded that there was no evidence that breast cancer was more indolent in the elderly. Therefore, similar diagnostic and therapeutic efforts should be made in the elderly as in the younger women, the only modification made on the basis of comorbidity.

TREATMENT OF OPERABLE DISEASE The optimum treatment of breast cancer in the elderly is not yet well established. It is reasonable to apply the principles of therapy largely learned from studies in the younger cohort of women, viz. breast-conserving wide tumor excision and axillary dissection for smaller lesions, mastectomy for the larger tumors, tamoxifen for estrogen receptor (ER)-positive lesions and chemotherapy for node positive or >1 cm tumors and radiotherapy for locally advanced lesions. Unlike the treatment of younger women, which is based on sound high-level evidence from meta-analyses of large RCTs, the therapy for the elderly is not evidence based, as there is paucity of large RCTs. The women over 65 years have been excluded from many trials. In order to fill up this lacuna

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MEDICINE IN OLD AGE

in knowledge, two European Organization for Research and Treatment of Cancer (EORTC) trials were set up. In Britain, a CRC trial and a trial at Nottingham were conducted to answer the question of what would be the best therapy for the elderly. The results of these trials are summarized below. Moreover, a decision analysis has also been performed by (Punglia et al., 2003). Truong et al. (2004) have reported an overview of literature on breast-conserving therapy (BCT) in elderly women with early breast cancer. They found a paucity of prospective data and numerous retrospective series of diverse treatments with conflicting results. Their observation supports BCT + postoperative RT as the standard of care for the elderly. Crowe et al. (1994) reported the outcome of modified radical mastectomy (MRM) in a group of 1353 women (age range 22–75). The hazard ratio for death were similar in all the three age-groups (65). This data demonstrates that older women achieve similar results as younger ones, provided they are treated adequately. Among cooperative group clinical trials sponsored by the National Cancer Institute for early-stage breast cancer, women of 65 years and above constitute only 18% of participants, although they constitute 49% of eligible pool of all newly diagnosed cases. Physicians have been incriminated as the key barrier to enrolling older women in trials (Kemeny et al., 2003). The Cancer Research UK Breast Cancer Trial Group (Fennessy et al., 2004) conducted a RCT for women over 70 years of age with operable breast cancer. Of 455 patients, from 27 hospitals in the United Kingdom, 225 were randomized to surgery + tamoxifen and 230 to receive tamoxifen alone. The analysis was based on a median follow-up of 12 years. The local control was better achieved when surgery was combined with tamoxifen. Fifty-seven patients randomized to surgery and 141 to tamoxifen alone progressed. The hazard ratio (HR) for local progression for tamoxifen as compared to mastectomy was 17.24; 95% CI 6.4–47.6 and for tamoxifen compared to BCT, 5.99; 95% CI 4.12–8.7. The risk of local progression was greater in the BCT arm compared to mastectomy (HR = 2.98; 95% CI 1.06–8.39). The 5 year risk of local progression was 8% after mastectomy, 18% after breast conservation and 64% in women who had tamoxifen alone. The 10 year survival was 37.7% for surgery + tamoxifen and 28.8% for tamoxifen alone. Primary tamoxifen therapy is inferior to mastectomy and breast-conserving surgery in achieving local control. Among patients randomized to surgery + tamoxifen, the risk of local progression was greater in those who had breast conservation than in those who had a mastectomy (Fennessy et al., 2004). A strong consensus prevails that by the time the breast tumor is palpable, dissemination has already occurred and local treatment can only provide local control. Surgery cannot influence development of metastases. Data from mature randomized trials challenges this belief. Thus, local treatment offers more than local control and may prevent the spread of breast cancer from residual cancer left behind after surgery.

ROLE OF RADIOTHERAPY In a study of 558 women aged ≥50 years, by the University of Pennsylvania, who had been treated with breast conservation and RT, for stage I and II breast cancer, there were 173 women who were aged ≥65years. Treatment included complete gross excision of tumor, pathological axillary lymph node staging and breast irradiation. Women ≥65 years and those between 50–64 years, were found to have large T2 lesions (43% vs 34%; p = 0.05), ER negativity (9% vs 16%; p = 0.13). The proportion of axillary node positivity (24%) as well as the mortality rates due to breast cancer at 10 years (13%) was similar in elderly patients and those in the 50–64 age-group. The overall survival at 10 years (77% vs 85%; p = 0.14), local failure (13% vs 12%; p = 0.6) and freedom from distant metastasis (83% vs 78%; p = 0.45) were similar. The study revealed that breast cancer in the elderly is not an indolent disease and has many aggressive prognostic factors. Moreover, breast-conserving surgery and RT achieves good local control and a survival comparable to women below 65 years (Solin et al., 1995). In a decision analysis of a hypothetical cohort, by a Markov model including postmenopausal women with ERpositive T1 tumors (≤2 cm), Punglia et al. (2003) from Harvard Medical School, computed the benefits of adding RT to conservative breast surgery and tamoxifen versus BCT + tamoxifen (tam.) alone. The modeled recurrence free survival benefit of radiation was 3.35 years for women of 50 years and 0.61 years for women at 80. A 50 year old was less likely to die from breast cancer when treated with RT + tam. than with tam. alone (relative risk reduction, RRR = 54%). An 80 year old had a RRR = 42% when RT was added to tamoxifen. Compared with the untreated group, the adjusted hazard ratio of breast cancer mortality was 0.4 for tamoxifen alone (95%CI 0.2–0.7), 0.4 for BCT alone (95%CI 0.1–1.4), 0.2 for mastectomy alone (95% CI 0.1–0.7) and 0.1 for BCT + adjuvant therapy (95%CI 0.03–0.4). It is thought by some that in a selected group of elderly women, radiation could be avoided. Gruenberger et al. (1998) from University of Vienna evaluated the need of RT in a retrospective review of 356 women above 60 years, treated by quadrantectomy + axillary dissection followed or not followed by adjuvant radiation. Among node negative, ER-positive cases, there was no benefit of RT as locoregional recurrence rate was 3% with or without radiation. In this subgroup (ER positive, node negative women), adjuvant tamoxifen reduced LR to 2% with or without radiation. These authors suggest that elderly women aged 60 or above with a T1, ER positive, node negative tumor, may be spared the toxicity of RT when treated by conservation surgery, axillary dissection, and tamoxifen. Milan Trials of Breast conservation: Prof. Veronesi of Milan Institute has been a great proponent of breast conservation. He initially developed the technique of quadrantectomy plus radiotherapy (QUART) and later reduced the extent of resection to only lumpectomy. The results of the Milan trials were published in a meta-analysis of data from 1973

BREAST CANCER IN THE ELDERLY

patients treated in three consecutive randomized trials by four different radiosurgical procedures: Halsted mastectomy, QUART, lumpectomy plus RT, and quadrantectomy without RT (Veronesi et al., 1995). Median follow-up for all patients was 82 months. The annual rates of local recurrence was 0.2 for patients treated with Halsted mastectomy and 0.46 for QUART, 2.45 for lumpectomy plus radiotherapy and 3.28 for quadrantectomy without RT. The local recurrences were much higher in patients under 45 years of age as compared to women over 55 years. Overall survival was identical in the four groups of patients. This study indicated that in elderly patients, lumpectomy and RT is a satisfactory option.

ADJUVANT ENDOCRINE THERAPY Since the majority of tumors in the postmenopausal women are ER positive, hormonal manipulation by antiestrogen molecules or aromatase inhibitors is used with advantage in over 60% of cases. Crivellari et al. (2003) reported the results of International Breast Cancer Study Group Trial IV conducted in many centers from the United States, Australia, Sweden, Switzerland, Italy, and Slovenia. From 1978 to 1981, 349 women 66 to 80 years of age with pathologically involved nodes after total mastectomy and axillary clearance were randomly assigned to receive 12 months of tamoxifen (20 mg daily) plus prednisolone (7.5 mg daily) (T + P) or no adjuvant therapy. At 21 years, median follow-up T + P prolonged the disease-free survival and overall survival – 15-year DFS 10 versus 19% in control; hazard ratio 0.71; 95% CI 0.58–0.86. The therapy was also superior in controlling breast cancer recurrences. The long-term use of tamoxifen is associated with increased hazard of thrombotic episodes and endometrial proliferation. In an RCT (Rutqvist and Mattsson, 1993) of adjuvant tamoxifen (tamoxifen 40 mg daily for 2–5 years) versus no adjuvant therapy among 2365 postmenopausal women with early breast cancer in Stockholm, there was significantly reduced hospital admission due to cardiac disease. The relative hazard (tam. vs control) was 0.68 (95% CI 0.48–0.97; p = 0.03). Comparing 5- versus 2-year therapy, there was grater protection from cardiac disease with longer use of tamoxifen (relative hazard = 0.37, 95% CI 0.15–0.92, p = 0.03). The results from meta-analysis of RCTs on early breast cancer have been published by the (Early Breast Cancer Trialists’ Collaborative Group (EBCTCG), 2005). For ER-positive disease only, allocation to about 5 years of adjuvant tamoxifen reduces the annual breast cancer death rate by 31% (SE 3), largely irrespective of the use of chemotherapy and of age (1 cm on the head and neck; location on the genitals, lips, ears, site of prior radiation or scar; tumor with poorly defined clinical borders; and tumor occurring in an immunosuppresed host (Miller, 2000). For patients with a prior SCC, the 3-year cumulative risk for another SCC is 18% (Marcil and Stern, 2000). Annual follow-up examinations for at least 3 years are recommended. Patients with multiple SCCs should be seen more frequently.

Melanoma Melanoma comprises 5% of all skin cancers. It is derived from melanocytes and has the greatest potential for metastasis. The incidence of melanoma is increasing faster than any other cancer. The lifetime risk of melanoma in an individual in the United States born in 2004 is estimated at greater than 1 in 70. Older men have the highest incidence of melanoma and the highest mortality rates from melanoma. In the United States, the incidence of thick tumors (>4 mm) has continued to increase in men 60 years and older (Jemal et al., 2001). Nearly 50% of all melanoma deaths involve white men 50 years and older. Risk factors include light complexion (red-blonde hair), blistering sunburns during childhood, tendency to tan poorly and sunburn easily, and a positive family history. Additional risk factors in the middle-aged population include age greater than 50 years, male sex, and history of actinic keratoses or nonmelanoma skin cancer. There are three clinical and histologic subtypes of melanoma: nodular (15%), superficial spreading (70%), and lentigo maligna melanoma (15%). The latter usually evolve after many years from a variegate, gradually enlarging macule on the face and neck of the elderly. The other types arise most commonly on the trunk or legs. The primary lesion is a brown to black macule, papule, plaque, or nodule

Figure 22 Superficial spreading melanoma demonstrating a nodular area likely to represent deep invasion

with one or more of the following features: asymmetry, border irregularity, color variegation, and diameter greater than 6 mm (Figure 22). Patients may notice an increase in size of a pigmented lesion and bleeding. The differential diagnosis includes solar lentigo, seborrheic keratosis, dysplastic nevus, and pigmented BCC. If possible, suspected lesions should be excised with 1–2 mm margin of normal skin down to the subcutaneous fat. Melanoma is treated by surgical excision with margins determined by histological tumor thickness (Breslow depth). (Balch et al., 2001) Tumor thickness and presence or absence of histologic ulceration are the most important prognostic factors (Balch et al., 2001). Patients with thin melanomas (90% five-year survival rate), whereas those with thick tumors (>4 mm) have a 50% five-year survival rate. Evaluation of nodal involvement with sentinel lymph node biopsy provides regional lymph node staging information for patients at high risk for metastatic melanoma (primary melanomas >1.0 mm in depth, and for tumors ≤1 mm when histological ulceration is present) (Perrott et al., 2003). Newly diagnosed and established melanoma patients require periodic complete skin examinations including mucosal sites, genitals, buttocks, palms and soles, lymph nodes, and palpation for hepatosplenomegaly. They should also be instructed on how to perform monthly self-skin exams. Frequency of follow-up, laboratory tests, and imaging studies depend on the stage of disease.

CUTANEOUS MANIFESTATIONS OF INTERNAL MALIGNANCY There is a variety of skin signs associated with internal malignancy. Although uncommon, these findings with subsequent diagnostic testing may help one to discover an otherwise occult malignancy. Some cutaneous markers for malignancy are listed in Table 5.

SKIN DISORDERS IN THE ELDERLY

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Table 5 Cutaneous manifestations of internal malignancy

Skin sign

Physical findings

Associated malignancies

Metastases

≥1 cm firm nodule(s) on the scalp, flesh-colored to pink to black Erythematous scaly plaques on the ears, nose, cheeks, hand, feet and knees. Hyperkeratosis of the palms & soles Unilateral erythematous sharply defined plaque of the nipple and areola. Unresponsive to potent topical steroids Unexplained itching not associated with dry skin

Breast, lung, genitourinary

Bazex syndrome

Paget’s disease

Generalized pruritus

Dermatomyositis

Swelling of the face & eyelids with a pink to violaceous hue. Flat-topped violaceous papules over the PIP and DIP joints. Proximal muscle weakness

Erythema gyratum repens

Wavy erythematous plaques with fine peripheral scale in a concentric pattern (wood grain appearance). Lesions migrate over the skin surface Erythematous patches or plaques with exfoliative scale covering ≥90% of total body surface area Dry fish-like scale involving the extremities

Erythroderma Acquired ichthyosis Acanthosis nigricans

Hyperpigmented velvety plaques involving the flexures (axilla, groin, neck)

Upper respiratory & digestive tracts

Breast

Hodgkin’s disease Leukemia/ lymphoma Mycosis fungoides Lungs

Gastrointestinal Breast Lung, breast, stomach, other

Lymphoma, leukemia, Sezary syndrome Lymphoma, multiple myeloma, Lung, breast, cervical cancer Stomach Other gastrointestinal or genitourinary

REFERENCES KEY POINTS • Successful management of dermatophyte infections (tinea pedis, onychomycosis) requires adequate patient education, correction of underlying predisposing factors, and prophylactic measures against recurrence. • Inflammatory disorders are chronic, but can be effectively controlled with a routine skin care regimen (application of moisturizer, sunscreen) and topical therapies. • Benign lesions may be biopsied or removed if they become irritated or cosmetically undesirable. • Recommendations for skin cancer prevention include regular sun avoidance, daily application of sunscreen, long-sleeve shirts, and broad-brimmed hats. • Patient education, early detection, and adequate monitoring are the keys to timely diagnosis of skin cancer.

KEY REFERENCES • Elewski BE, Leyden J, Rinaldi MG & Atillasoy E. Archives of Internal Medicine 2002; 162:2133 – 8. • Jemal A, Devesa SS, Hartge P & Tucker MA. Journal of the National Cancer Institute 2001; 93:678 – 83. • Marcil I & Stern RS. Archives of Dermatology 2000; 136:1524 – 30. • Yaar M & Gilchrest BA. In IM Freedberg, AZ Eisen, K Wolff et al. (eds) Fitzpatrick’s Dermatology in General Medicine 2003, vol 2 pp 1386 – 98; McGraw-Hill, New York.

Ahmed A & Tollefsbol T. Journal of the American Geriatrics Society 2001; 49:1105 – 9. Balch CM, Buzaid AC, Soong SJ et al. Journal of Clinical Oncology 2001; 19:3635 – 48. Campisi J. Cell 1996; 84:497 – 500. Craze M & Young M. Journal of the American Academy of Dermatology 2003; 49:S139 – 42. Dunn-Walters DK, Banerjee M & Mehr R. Biochemical Society Transactions 2003; 31:447 – 8. Elewski BE, Leyden J, Rinaldi MG & Atillasoy E. Archives of Internal Medicine 2002; 162:2133 – 8. Fisher GJ, Kang S, Varani J et al. Archives of Dermatology 2002; 138:1462 – 70. Goukassian D, Gad F, Yaar M et al. FASEB Journal 2000; 14:1325 – 34. Jack P & Brookes P. International Journal of Cancer 1980; 25:789 – 95. Jankovic V, Messaoudi I & Nikolich-Zugich J. Blood 2003; 102:3244 – 51. Jemal A, Devesa SS, Hartge P & Tucker MA. Journal of the National Cancer Institute 2001; 93:678 – 83. Jiang J, Anaraki F, Blank KJ & Murasko DM. Journal of Immunology 2003; 171:3353 – 7. Kraemer KH. In IM Freedberg AZ Eisen, K Wolff et al. (eds) Fitzpatrick’s Dermatology in General Medicine 2003, vol 2, pp 1508 – 21; McGrawHill, New York. Kurban RS & Bhawan J. The Journal of Dermatologic Surgery and Oncology 1990; 16:908 – 14. Lebwohl M & Ali S. Journal of the American Academy of Dermatology 2001; 45:649 – 61, quiz 662-4. Lebwohl M, Dinehart S, Whiting D et al. Journal of the American Academy of Dermatology 2004; 50:714 – 21. MacLaughlin J & Holick MF. The Journal of Clinical Investigation 1985; 76:1536 – 8. Marcil I & Stern RS. Archives of Dermatology 2000; 136:1524 – 30. Miller SJ. Dermatologic Surgery 2000; 26:289 – 92. Mouton CP, Bazaldua OV, Pierce B & Espino DV. American Family Physician 2001; 63:257 – 68.

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Nehlin JO, Skovgaard GL & Bohr VA. Annals of the New York Academy of Sciences 2000; 908:167 – 79. Oikawa S & Kawanishi S. FEBS Letters 1999; 453:365 – 8. Paller AS. In IM Freedberg, AZ Eisen, K Wolff et al. (eds) Fitzpatrick’s Dermatology in General Medicine, 2003, vol 2, pp 1833 – 6; McGrawHill, New York. Patrick MH. Photochemistry and Photobiology 1977; 25:357 – 72. Pelle MT. Advances in Dermatology 2003; 19:139 – 70. Perrott RE, Glass LF, Reintgen DS & Fenske NA. Journal of the American Academy of Dermatology 2003; 49:567 – 88, quiz 589-92. Piacquadio DJ, Chen DM, Farber HF et al. Archives of Dermatology 2004; 140:41 – 6. Ryan T. Micron 2004; 35:161 – 71. Savitsky K, Bar-Shira A, Gilad S et al. Science 1995; 268:1749 – 53. Sigurgeirsson B, Olafsson JH, Steinsson JB et al. Archives of Dermatology 2002; 138:353 – 7.

Singri P, West DP & Gordon KB. Archives of Dermatology 2002; 138:657 – 63. Smith ES, Fleischer AB Jr, & Feldman SR In BA Gilchrest (ed) Clinics in Geriatric Medicine 2001, vol 17, pp 631 – 41; W.B. Saunders, Philadelphia. Touma D, Yaar M, Whitehead S et al. Archives of Dermatology 2004; 140:33 – 40. Troelstra C, van Gool A, de Wit J et al. Cell 1992; 71:939 – 53. Tzaphlidou M. Micron 2004; 35:173 – 7. Weinberg JM, Koestenblatt EK, Tutrone WD et al. Journal of the American Academy of Dermatology 2003; 49:193 – 7. Wilkin J, Dahl M, Detmar M et al. Journal of the American Academy of Dermatology 2002; 46:584 – 7. Yaar M & Gilchrest BA. In IM Freedberg, AZ Eisen, K Wolff et al. (eds) Fitzpatrick’s Dermatology in General Medicine 2003, vol 2 pp 1386 – 98; McGraw-Hill, New York. Yu CE, Oshima J, Fu YH et al. Science 1996; 272:258 – 62.

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Pressure Ulceration Joseph E. Grey and Keith G. Harding University of Wales College of Medicine, Cardiff, UK

INTRODUCTION A pressure ulcer may be defined as an area of localized damage to the skin and underlying tissue caused by pressure, shear, friction or a combination of these (European Pressure Ulcer Advisory Panel). Pressure Ulcers are known by a variety of other terms including bed sore, decubitus ulcer, pressure sore, and dermal ulcer. However, these terms do not accurately reflect the nature or etiology of the wound and are thus best avoided. Pressure ulcers arise as a local breakdown of soft tissue as a result of compression between a bony prominence and an external surface. The majority of pressure ulcers develop on the lower half of the body: two-thirds of these occur around the pelvis and one-third on the lower limbs. Common sites of pressure ulceration are shown in Figure 1. Pressure ulcers are most common in the elderly population, especially those older than 70 years, up to one-third of whom will have undergone surgery for a hip fracture. A second distinct population are those with spinal cord injuries with a reported prevalence of 20–30% 1–5 years after injury. Over four hundred thousand people develop a pressure ulcer annually in the United Kingdom. Pressure ulcers most commonly arise in the hospital setting with a prevalence ranging from 3 to 14% in the acute setting. This rate varies between specialties; 2% in general surgical patients and 10% in orthopedic patients, reflecting, in part, the age differences of the two groups (Clark and Watts, 1994). The incidence in the acute setting is between 1 and 5%, though in patients who are bed- or chair-bound for more than 1 week, the incidence rises to almost 8%. Development of a new pressure ulcer is associated with a fivefold increase in length of hospital stay (Lazarus et al., 1994). In long-term facilities, the prevalence ranges from 1.5 to 25%. The prevalence of pressure ulceration in nursing homes is not appreciably higher than in the acute hospital setting. Around 20% of pressure ulcers develop at home and a further 20% in nursing homes. Pressure ulceration in an elderly

person carries a fivefold increase in mortality, with the inhospital mortality rate of 25 to 33%. By 2020, the number of people aged over 65 years in the United Kingdom will rise by 20%: The incidence of pressure ulceration will rise concomitantly. Pressure ulcers are responsible for a significant degree of morbidity, both physical and psychological. Moreover, they represent a huge financial burden, both to the individual and to society as a whole. In 1993, the cost of pressure ulcers to the NHS was estimated at between £180 and £321 million (Touche, 1993). More recent studies have shown that this cost has escalated to between £1.4 and £2.1 billion annually, equivalent to 4% of the total NHS expenditure (Bennett et al., 2004): This was believed to be a conservative estimate as the figures did not reflect the cost of associated problems such as methicillin resistant staphylococcus aureus (MRSA) infection, heel pressure ulcers associated with peripheral vascular disease and pressure ulcers in diabetics. The cost of healing a grade IV pressure ulcer was found to be ten times that of healing a grade I pressure ulcer (Bennett et al., 2004). Osteomyelitis complicating pressure ulceration significantly increases the need for hospital admission with a lengthy in-patient course and increased financial cost, mostly reflecting nursing time. Most pressure ulcers are avoidable, with the cost of preventing pressure ulceration representing a significant potential cost saving to the patient and to the health-care system. The cost to society of pressure ulceration continues to increase as a result of increased litigation. In the United States, development of a pressure ulcer in a care home or hospital may be regarded in a court of law as evidence of clinical negligence.

PATHOGENESIS The four main extrinsic factors implicated in the etiology of pressure ulceration include interface pressure (the load perpendicular to the tissue surface), shear (the load parallel


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MEDICINE IN OLD AGE Prone position

Toes

Knees

(a)

Genitalia (men)

Breasts Acromion (women) process

Cheek and ear

Supine position

Heels (b)

Sacrum Elbows Scapulae Back of head

Lateral position

Malleous

Medial and lateral condoyle

Greater trochanter

Ribs

Acromion process

Ear

(c) Figure 1 Common sites of pressure ulceration in the at-risk individual in (a) the prone position, (b) the supine position, (c) the lateral position

to the tissue surface), friction (the load acting tangentially to the tissue surface), and moisture. While direct (interface) pressure is the most important etiological factor, all four are closely interrelated. In the 1930s, Landis estimated, in healthy volunteers, that normal capillary pressure ranged from 32 mm of mercury (mmHg) on the arterial side of the circulation to 12 mmHg on the venous side (Landis, 1930). When pressure of short duration is relieved, the tissue demonstrates reactive hyperemia, reflecting increased blood flow to the area. A sustained high closing pressure in excess of 32 mmHg was postulated to lead to decreased capillary blood flow, occlusion of blood vessels and lymphatics and tissue ischemia (Figure 2). The closing pressure was revised in later work by Landis to between 45 and 50 mmHg. Pressure as low as 40 mmHg has, however, been found to cause tissue anoxia in some elderly patients (Bader and Gant, 1988). Dermal capillaries are coiled at their bases and are thus more resistant to occlusion by pressure. The subcutaneous vessels run parallel to the deep fascial planes and are more likely to be occluded by external pressure leading to tissue

damage (Bliss, 1993). Prolonged pressure may, therefore, lead to ischemic changes and pressure ulceration due to perfusion/reperfusion injury from build up of inflammatory molecules. The highest pressures occur over bony prominences at the bone/muscle interface (Figure 3). Thus, an external pressure of 50 mmHg may rise to over 200 mmHg at a bony prominence, leading, with time, to deep tissue destruction, which may not be evident on the surface of the skin. Such pressures may decrease transcutaneous oxygen tensions to almost zero. Pressures as high as 150 mmHg have been recorded from patients lying on ordinary mattresses (Lindan, 1961; Houle, 1969); regular relief from high pressures in the at-risk patient is, therefore, essential to prevent pressure ulceration. Such changes are ultimately responsible for necrosis of muscle, subcutaneous tissue, dermis and epidermis and consequent pressure ulcer formation. It will be apparent though, that high pressure of short duration will lead to more rapid tissue damage while low pressure leads to a more insidious onset of tissue damage and ulceration

PRESSURE ULCERATION

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Pathophysiology of pressure ulcers Sustained high pressure Decrease in capillary flow

Cell (and tissue) death

Oedema Ischemia, capillary thrombosis and occlusion of lymphatics

Fluid escapes into extravascular space

Increased capillary permeability Figure 2 Schematic representation of the mechanism of pressure-induced tissue damage

700

Maximum suggested pressure/time application over bony prominences

Pressure, mm Hg

600 500 400 300

Unacceptable 200 100 Acceptable 2

4

6 8 10 12 14 16 Hours of continuous pressure

18

Figure 4 Guidelines on sitting tolerance based on the magnitude of localised pressure (From Reswick J and Rogers J. Experiences at Rancho Los Amigos Hospital with Devices and Techniques to Prevent Pressure Sores. Bedsore Biomechanics. Baltimore: University Park Press) Figure 3 Conical pattern of pressure distribution over a bony prominence, illustrating the fact that seemingly low external pressure rises to a much higher pressure at the bone/muscle interface. Thus, tissue damage may be unrecognized as the skin may still be intact

(Figure 4). However, duration of pressure is also important and tissue damage may be avoided in the face of sustained pressure, which is relieved intermittently. This forms the basis of the rationale of regular turning of patients at risk of pressure ulceration, though the minimum frequency is still a matter of debate. Clinically, pressures of 70–100 mmHg have been recorded over bony prominences supported by standard NHS mattresses (Collier, 2004). Pressure-reducing mattresses reduce this pressure to between 30 and 40 mmHg (Collier, 1996). Shear force (the load parallel to the tissue surface) is generated owing to the motion of bone and subcutaneous tissue relative to the skin, which is restrained from moving due to frictional forces (Figure 5). For example, when a

seated patient slides down the chair or when the head of a bed is elevated to greater than 30◦ , the sacral skin remains fixed with respect to the support surface while the sacrum moves, and the deep fascial blood vessels are stretched and distorted. In such circumstances, the pressure required to occlude the blood vessels is greatly reduced, which reduces the rate of recovery from tissue anoxia (Schubert and Héraudj, 1994). In the elderly individual, reduced skin elastin content predisposes to the adverse effects of shear. While interface pressure is of more importance in generating tissue damage, the concomitant presence of shear increases the risk of ischemic damage. The effect of shear may be reduced through the use of vapor-permeable mattress covers, which reduce the amount of moisture. Friction, acting tangentially to the tissue surface, opposes the movement of one surface against another (Figure 6). Frictional forces may lead to the formation of intraepidermal

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RISK FACTORS Many groups, including the Tissue Viability Society (UK), the National Pressure Ulcer Advisory Panel (NPUAP) (USA) and the European Pressure Ulcer Advisory Panel, have developed guidelines and protocols on pressure ulcer prevention and treatment. The main such body in the United Kingdom is The National Institute for Clinical Excellence (NICE). NICE has developed guidelines on pressure ulcer prevention (NICE, 2003) and is also developing guidelines on the treatment of pressure ulceration. NICE has identified various risk factors associated with the development of pressure ulceration (Table 1).

Acute Illness

Figure 5 Shear force

Pressure Ulceration is more common in immobile patients who develop pyrexia (Bar and Pathy, 1998). This leads to an increased metabolic rate and increased demand for oxygen by the compromised tissues, making pressure ulceration more likely. Acute illness also leads to general metabolic disturbance which is further compromised by, for example, poor nutrition and drug therapy, which may lead to reduced tolerance of pressure and, in patients with established pressure ulceration, to impaired healing. The precise extent to which such systemic conditions increase the risk of developing pressure damage and difficulties in healing remain to be quantified.

Limited Mobility/Immobility Figure 6 Friction force

blisters, which in turn lead to superficial skin erosions, initiating or accelerating pressure ulceration. Such forces occur, for example, when a patient is dragged across a bedsheet, pulling the sheet under the patient, sliding transfer from bed to chair, or as a result of ill-fitting prosthetic devices or footwear. Friction reduces the amount of pressure required for ulceration to occur. It must be emphasized that pressure damage reflects a complex interplay of these three forces, each playing a greater or lesser role depending on the situation pertaining at that time and also affected by the presence of moisture. While moisture, by itself, does not cause pressure ulceration, an excessively moist environment caused by, for example, perspiration, urinary or fecal incontinence or excessive wound drainage enhances the deleterious effects of pressure, friction, and shear. It also causes maceration of the skin, which compounds these factors. Friction and moisture are important factors leading to superficial skin breakdown and produce the greatest effects in areas of high pressure: The effects of friction are increased up to fivefold in the presence of moisture. Pressure and shear forces exert their effects on deeper structures (Hall, 1984; Herman and Rothman, 1989).

Immobility (the inability to reposition without assistance) or limited mobility are probably the major factors leading to pressure ulcer formation and may occur for a variety of reasons. These include paralysis (the inability to move due to loss of motor nerve function) due to neurological problems such as stroke and spinal cord injury, which lead to hemi-, para- or quadriplegia. Paralysis also leads to decreased muscle bulk and reduction of subcutaneous tissue, which, in turn, predisposes to pressure ulceration. Physical illness, including arthritis and orthopedic problems, leads to difficulty in changing position due, for example, to pain as well as joint deformity and lack of strength. The elderly are

Table 1 Risk factors for pressure ulceration

Acute illness Extremes of age Level of consciousness Malnutrition/dehydration Limited mobility/immobility History of pressure damage Sensory impairment Severe chronic or terminal disease Vascular disease

PRESSURE ULCERATION

particularly prone to such problems. Obesity may lead to reduced mobility. One of the commonest reasons for immobility in the elderly is fracture of the neck of femur. Fractured neck of femur has been shown in a cross-sectional study to be a risk factor for the development of a pressure ulcer (Scheckler and Peterson, 1986). Between 50 and 60% of patients with fracture of the femur develop a pressure ulcer, most of which develop within five days to two weeks of admission and occupying 20% of orthopedic beds (Versluysen, 1985, 1986). Being bed- or chair-bound significantly increases the risk of pressure ulceration; appropriate pressure-relieving surfaces should be provided. Individuals with increased limb tone (spasticity) may benefit from interventions such as physiotherapy, muscle relaxants, nerve block, or surgery. The number of nocturnal movements is correlated with development of pressure ulcers. One study has shown that 90% of ulceration in older patients occurred in those who have less than 20 spontaneous movements per night: No pressure ulcers were recorded in those patients with more than 50 movements per night (Exton-Smith and Sherwin, 1961). Reduced nocturnal mobility is associated with use of sedative medication and a high-pressure ulcer risk score (Barbenel et al., 1986). Other risk factors, which have been found to increase the incidence of pressure ulceration in the immobile patient, include dry skin, a preexisting grade I pressure ulcer (nonblanchable erythema of intact skin) and fecal incontinence (Allman et al., 1995). In patients with spinal cord injuries who develop pressure ulcers, the serum albumin, prealbumin and cellular adhesion molecules (which have a role in immunity and wound healing) have been shown to be lower than those without injuries (Cruse et al., 2000).

Impact of Age Age alone is not an independent risk factor for pressure ulcer development. The fact that the frequency of pressure ulcer rises with age is a consequence of the comorbidities associated with advancing age (Allman et al., 1995). The effects of all such risk factors should be minimized through their optimal management. The elderly are more likely to have underlying chronic disease, which may be severe, contribute to immobility, increase the risk of pressure ulceration and may impair healing. As many as 70% of patients with pressure ulcers are over 70 years of age (Barbenel et al., 1977). Individuals between 70 and 75 years of age have double the incidence of pressure ulcers compared with 55–69 yearolds. The greatest incidence of pressure ulcers occurs in the 80–84-year age-group (Ek and Bowman, 1982). More than two-thirds of the elderly with pressure ulcers are female (Nyquist and Hawthorn, 1987). Age-related susceptibility to skin breakdown in the face of other comorbidities may occur owing to loss of dermal vessels, thinned epidermis, flattening of the dermo-epidermal junction, decreased elastin content and increased skin permeability (Carter and Balin, 1983). Significant risk factors for

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the development of pressure ulcers in the chronically sick patient include cerebrovascular accident (CVA), impaired nutritional intake, being bed- or chair-bound and having fecal incontinence (Berlowitz and Wilking, 1989). The incidence of fracture of the neck of femur increases with age and is a significant risk factor for pressure ulcer development.

Severe Chronic or Terminal Illness Chronic and terminal illnesses are, by nature, more common with increasing age. In hospitals, the main focus of treatment is the underlying illness, and the prevention and treatment of pressure ulcers may be seen as a lower priority. Caution should be exercised in the use of drugs used in such diseases: Drugs such as sedatives and analgesics may lead to immobility, while antihypertensives may cause alteration of skin blood flow (Kanj et al., 1998). Diabetes is a major cause of morbidity and may be associated with pressure ulcer formation. Diabetics are at risk of vascular disease, which may lead to reduced tissue perfusion. Diabetic sensory neuropathy impairs the ability to sense and react to pressure, pain, and temperature. Autonomic and motor neuropathy lead to dry skin, which cracks easily, and to altered foot architecture, which itself predisposes to diabetic foot ulceration as a result of altered foot pressure. Chronic respiratory disease such as chronic obstructive pulmonary disease (COPD) may lead to decreased tissue oxygenation and thus tissue that is more prone to pressure damage. Chronic cardiovascular disease and peripheral edema may also predispose to pressure ulceration. Inadequate circulation due, for example, to cardiovascular or peripheral vascular disease will lead to poor tissue oxygenation and may predispose to pressure ulcer formation. Anemia, similarly, leads to reduced oxygenation and increased susceptibility to pressure damage: Pragmatically, the hemoglobin should, if possible, be maintained above 10 g dl−1 . Individuals with terminal illness are at high risk of pressure ulceration. Prevalence of pressure ulcers in such patients ranges from 37 to 50% (Hatcliffe and Dawe, 1996) and reflect the severity of the underlying disease. While most pressure ulcers are avoidable, they may reflect the multisystem failure that often accompanies terminal illness. In these cases, aggressive preventative measures may be inappropriate; patient comfort and dignity should be of prime concern.

Vascular Disease Peripheral vascular disease is particularly associated with smoking and diabetes. It leads to reduced blood perfusion and increased risk of pressure ulceration: The heels, feet, and toes are at particular risk (Figure 7).

Malnutrition and Dehydration Attention to nutrition is critical in the prevention and management of pressure ulcers. There is a correlation between

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MEDICINE IN OLD AGE

however, this may prove difficult to maintain in many patients. Serum Albumin concentration is often used to assess the degree of nutrition. A concentration of less than 35 g l−1 is generally taken as a reflection of poor nutrition and a risk factor for the development of pressure ulcers. It should be remembered that this is at best a crude surrogate for degree of nutrition as the half-life of albumin is relatively long (of the order of 21 days) and hypoalbuminemia may be encountered in a variety of acute illnesses. Serum prealbumin, transferrin and lymphocyte count may be better markers of (mal) nutrition. Other measures of nutritional status predictive of pressure ulcer formation include decreased body weight, reduced triceps, skin-fold thickness, and lymphocytopenia (Allman et al., 1995).

Figure 7 Heel pressure ulcer

the degree of malnutrition and the extent and severity of pressure ulceration (Allman et al., 1986). In addition, malnutrition retards the healing of established pressure ulcers (Herman and Rothman, 1989). Malnutrition (protein-energy), impaired oral intake, and the development of pressure ulceration are closely interrelated. The relative risk of pressure ulcer development in high-risk malnourished patients is more than double that of patients with normal nutritional status (Thomas et al., 1996). Two-thirds of severely malnourished nursing home residents were found in one study to have pressure ulcers, compared with none in mild to moderately malnourished residents (Pinchcofsky-Devin and Kaminski, 1986). Furthermore, malnutrition is associated with increased mortality in nursing home residents (Bourdel-Marchasson et al., 2000). Studies on the prevention of pressure ulceration through nutritional intervention are inconclusive (Mathus-Vliegen, 2004). However, it is generally accepted that, in order to prevent pressure ulceration in undernourished and malnourished patients, an energy intake of 35 kcal per kg body weight is required. 1.5 g kg−1 of protein and 1 ml per kcal per day fluid intake with the addition of the recommended daily allowance of micronutrient should be provided (though there are no good data on the amount or type) (EPUAP; Chernoff et al., 1990; Breslow et al., 1993; Mathus-Vliegen, 2004). In individuals with established pressure ulceration, the nutritional demands may be greater. Patients at high risk and those with established pressure ulceration should be assessed and reviewed by a dietician. Provision of adequate nutrition may involve supplementary feeding, either assisted or enteral (via a nasogastric or PEG tube), though there may be a degree of morbidity associated, including diarrhea, incontinence, and limited mobility while attached to the feed – in themselves risk factors for pressure ulcer formation. Supplementation with high protein dietary supplements for 15 days to older, critically ill patients has shown a reduction in pressure ulcer development (Bourdel-Marchasson et al., 2000). Practically,

Sensory Problems Sensory deficits give rise to altered ability to perceive the pain and discomfort associated with persistent local pressure, leading to reduced repositioning. Such deficits occur in individuals with neurological problems such as neuropathies (e.g. diabetic), which especially predispose to heel ulceration. Medical or psychological conditions may lead to altered conscious levels with resultant decrease in mobility. Medication is an especially common cause of altered conscious levels; these include sedatives, analgesics, and anesthetics. The effects of sensory loss in patients with stroke or spinal cord injury may be compounded by motor deficits or increased tone (spasticity), which limit mobility and the ability to reposition.

RISK ASSESSMENT There are a plethora of pressure ulcer risk assessment scales in use, though there is little evidence that any one is superior to another or that their use has led to a reduction in pressure ulcer incidence (Whitfield et al., 2000). The scales attempt to stratify the risk according to the number of known risk factors present, in order that preventive measures are instituted. They are designed for use in individuals who are bed- or chairbound or who have limited ability to reposition themselves. Some are more comprehensive than others. They all contain a core of basic components (Table 2). Table 2 Components of risk assessment scales

Age Mobility Activity Level of consciousness Nutrition Continence Skin status Illness severity

PRESSURE ULCERATION

However, some of the grading of the risk factors is subjective and observer dependent (Healey, 1996). This may be reflected in the low sensitivity (ability of the tool to correctly identify those patients who will develop a pressure ulcer) and specificity (ability of the tool to correctly identify those patients who will not develop a pressure ulcer) that the assessment scales exhibit. When using a risk assessment scale, it is judicious to consider whether it is valid, reliable, applicable to the patient group being assessed, subjective or objective, user friendly, and useful (Collier, 2004). It should be self evident that risk assessment scales are of use only if the at-risk patient identified receives appropriate intervention. NICE has, echoing advice from the Department of Health (Essence of Care) in the United Kingdom, made suggestions on the use of pressure ulcer assessment scales (Table 3). In Europe, the commonest scales used are Waterlow, Norton, and Braden. Others used include Gosnell and Knoll. The Table 3 Points to be considered when choosing support surface

Identified level of risk Skin assessment Comfort General health state Lifestyle and abilities Critical care needs Acceptability of the pressure-relieving equipment to patient and/or carer

Table 4 Waterlow risk assessment scale

Copyright 1991 Waterlow J.

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Waterlow scale is commonly used in the United Kingdom (Table 4).

Prevention of Pressure Ulcers Since direct pressure, shear forces, friction, and moisture are prerequisites for the development of pressure ulceration, pressure relief or redistribution should be the mainstay of any preventive strategy. Prevention may reduce the incidence of pressure ulceration by up to 50% (Anderson et al., 1983; Seiler, 1985). Pressure ulcer prevention is further aided by the recognition that patients with limited or no mobility are at risk. Patients, carers, and health-care workers should be educated in this respect and also in recognizing early signs of pressure damage. While risk assessment tools will aid in this respect, they are no substitute for good clinical care and observation. At-risk patients should have daily evaluations of the skin, concentrating particularly on the common at-risk areas, especially the bony prominences, including the sacral, ischial, trochanteric, and heel areas (Ayello, 1992). The skin should be kept clean and well hydrated (DeLisa and Mikulic 1985). Excess moisture should be minimized and may require the use of barrier creams or sprays and the use of absorbent pads for fecal and/or urinary incontinence. The skin over bony

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prominences should not be massaged deeply, as this may cause, rather than prevent, damage (Ek et al., 1985, 1987). In individuals not at risk of pressure ulceration, pressure relief or redistribution is an automatic, frequent, and usually reflex reaction to pressure, while in bed or seated. Individuals who are unwell or immobile turn much less frequently. These at-risk individuals should be repositioned regularly. While there are no firm data on frequency of repositioning, current practice suggests that a minimum 2-hourly repositioning schedule should be instituted, alternating the individual between lying on their back and then alternate sides (Knox et al., 1994). When positioned on the side, the individual’s back should be angled at 30◦ with respect to the support surface in order to minimize pressure over the greater trochanter and lateral malleolus (Seiler and Stahelin, 1985). Direct (“kissing”) contact of the bony prominences such as knees and ankles should be avoided through judicious use of cushions and foam wedges. “Doughnut” cushions should be avoided as they may lead to, rather than prevent, ulceration, possibly as a result of reduction of blood flow to the area of tissue which herniates through the center of the “doughnut” (Allman, 1989a,b). Friction and shear forces should be minimized; abolition of these forces is neither possible nor desirable, else the patient would slip off the support surface! While repositioning, the individual should be lifted, rather than dragged across the bed or out of a wheelchair. The support surface should be kept clean and free of any debris (e.g. food), which may exacerbate any pressure damage. Shear damage may be diminished by keeping the head of the bed at 30◦ or less, thus preventing undue pressure on the sacrum, ischial tuberosities, and heels. A variety of heel (Figure 8) and elbow protectors are in use (e.g. sheepskin) but evidence on their efficacy is lacking.

(a)

Pressure-relieving Devices There is a bewildering array of pressure-relieving and pressure-reducing support surfaces available. These include beds, mattresses, mattress overlays, cushions, chairs, and wheelchairs. There is, however, very little good-quality data supporting the use of particular pieces of equipment (RycroftMalone and Duff, 2000; Rithalia, 2004a). Furthermore, there appears to be a deal of uncertainty as to what the equipment actually achieves (Collins, 2004). There is also potential conflict in trying to combine a piece of equipment that is liked by the patient, meets the treatment objective, and is suitable for a particular care setting (Fletcher, 1995). NICE in the United Kingdom has, in its guidelines, stated that pressure-relieving devices should be based on cost considerations as well as an overall assessment of the individual. They further state that holistic assessment should include the points listed in Table 3 and should not be based solely on scores derived from risk assessment scales (NICE). However, much clinical practice in identifying the patient at risk of pressure ulcers and provision of the appropriate

(b)

Figure 8 Repose Bootee, heel protector

pressure-relieving surface continues to be dependent on the risk assessment scales. Indeed, the Waterlow scale, for example, links a risk score to a particular intervention (Watts and Clark, 1993; Winman and Clark, 1997). Moreover, many pressure ulcer prevention protocols and manufacturers of pressure-relieving surfaces imply that there are reliable cutoff points for identifying appropriate surfaces dependent on the degree of risk determined by the risk assessment scale.

PRESSURE ULCERATION

NICE guidelines advocate the use of the terms “vulnerable to pressure ulcers” and “at elevated risk of pressure ulcers” in recognition of the limitations of risk assessment scales (NICE). The implementation of holistic prevention programs, including provision of support surfaces, use of risk assessment tools, repositioning schedules, nutrition, and education programs have all resulted in reductions in pressure ulcer incidence (Xakellis et al., 1998; Lyder et al., 2002). This highlights the fact that good care is essential in both prevention and treatment of pressure ulcers. All prevention strategies require staff education. There should be a written pressure ulcer prevention and treatment policy. There should also be a multidisciplinary approach to prevention and treatment strategies including doctors, nurses, dieticians, physiotherapists, occupational therapists, speech and language therapists, housekeeping staff, catering, and supplies officers.

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Figure 9 Standard hospital mattress

Mattresses NICE guidelines recognize that there is little good-quality data on what support surface should be used in a particular circumstance. They suggest, as a minimum provision, that those individuals vulnerable to pressure ulcers should be placed on a high-specification (though low-tech) foam mattress with pressure-relieving properties. The guidelines further advise that alternating pressure or other high pressurerelieving systems should be considered in the following circumstances: 1. as a first-line preventive strategy for people at elevated risk (based on holistic assessment); 2. when the individual’s previous history of pressure ulcer prevention and/or clinical condition indicates that they are best cared for on a high-tech device; 3. when a low-tech device has failed. Support surfaces may be broadly divided into those that provide pressure reduction and those that provide pressure relief. Pressure-reducing systems produce the effect by increasing the surface area in contact with the support surface brackets (pressure = force/area). This is often the reason cited for nursing the patients in bed rather than in a chair, sitting for long periods (Gebhardt and Bliss, 1994). Pressure-relieving systems sequentially remove the source of pressure from parts of the body, usually by alternately inflating and deflating cells within mattress or mattress overlays. Support systems are more commonly classified as static or dynamic systems. Static systems are generally, but not exclusively, nonpowered, low-tech devices of which the hospital mattress is the most basic example (Figure 9). They commonly comprise a sandwich of different densities of foam or other surfaces which are profiled (Collins, 2004). Other examples of static, pressure-reducing services include foam overlays and water-, gel- and air-filled devices designed to be placed over a standard mattress.

Figure 10 “Repose” mattress overlay

Comparative studies of some overlays have shown that they are no better than good-quality foam mattresses (Medical Devices Agency, 1994). However, a randomized, controlled, prospective trial comparing a low cost, lowpressure inflatable mattress (“Repose”, Figure 10) designed to be placed on a standard hospital mattress showed no difference when compared to a high-tech dynamic support mattress and patients at high risk of pressure ulceration indicating that certain low-tech static pressurerelieving systems can be as effective as high-tech pressure-relieving systems in treating certain patient groups (Price et al., 1999). Static systems (Figure 11) are generally suitable for those individuals able to adopt a variety of positions. The system should not be able to “bottom out”, that is, the mattress (or overlay) or any part of it providing less than 2.5 cm of support. The surfaces are appropriate for patients at low risk of pressure ulcer development.

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Figure 12 Dynamic mattress

Figure 11 Static mattress

Dynamic support surfaces (Figure 12) may be either pressure-reducing or pressure-relieving devices. They are generally powered and high tech in nature. They are available as mattresses, mattress overlays and whole-bed systems. Low air-loss (pressure-reducing) mattresses have air pumped into the cells making up the mattress, some of which escapes via tiny holes in proportion to the weight placed upon it. Each cell deflates slightly, conforming to and supporting the body evenly. Care should be taken not to let the system “bottom out” (Young and Cotter, 1990; Phillips, 1999). It has been postulated that pressure-relieving devices may be useful in preventing tissue ischemia via their cyclical “zero pressure” areas (Russ and Motta, 1991). Dynamic pressure-relieving surfaces are also powered high-tech devices. The pressure relief is generally facilitated by alternately inflating and deflating cells, so that one set of cells cyclically supports the body. The body is, therefore, relieved of pressure when a set of cells deflates. Usually, the two or three cells under the head of the patient are static, thus promoting patient comfort. Cell layers, sizes, shapes, and cell cycles vary between mattresses, depending on the

manufacturer. Some dynamic systems adopt a static mode which is useful when carrying out certain procedures, for example, in the event of power failure or when transferring the patient from area to area. Table 5 lists the characteristics of different types of mattresses (Kanj et al., 1998; Lyder, 2003). Air-fluidized systems (pressure reducing) are filled with small silicone-coated beads through which air is pumped on a continuous basis, providing a dynamic surface (Figure 13). The patient’s pressure points are, therefore, constantly moving. The dry particles are able to absorb fluid, which are then removed from the system, thus helping to prevent maceration and decrease the effect of moisture on the various forms of pressure. Dynamic support surfaces are indicated for patients at elevated risk of developing a pressure ulcer, those patients with pressure ulcers who are unable to be nursed completely off the pressure ulcers, those with very large or multiple ulcers, and those with ulcers which are not healing. In the United States, the center for Medicare and Medicaid to services has divided support services into three categories based upon reimbursement costs (Lyder, 2003).

Table 5 Selected characteristics for classes of support surfaces

Performance characteristics Increased support area Low moisture retention Reduced heat accumulation Shear reduction Pressure reduction Dynamic Cost per day From Bergstrom et al., 1994.

Air-fluidized (high air loss)

Low-air loss

Alternating air (dynamic)

Static flotation (air or water)

Foam

Standard hospital mattress

Yes Yes Yes

Yes Yes Yes

Yes No No

Yes No No

Yes No No

No No No

Yes Yes Yes High

? Yes Yes High

Yes Yes Yes Moderate

Yes Yes No Low

No Yes No Low

No No No Low

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Figure 13 Air-fluidized mattress

Group 1 – Static support surfaces not requiring electricity. Group 2 – Dynamic surfaces powered by electricity or pump including alternating and low air-loss mattresses. Group 3 – Air-fluidized beds.

Figure 14 Ideal sitting position

While such devices have been shown to reduce the incidence of pressure ulceration, there is no data to show that one particular type is better than another (Rithalia, 2004b). Furthermore, there is no evidence that high-tech pressurerelieving mattresses and overlays are more effective than high specification (low-tech) mattresses and overlays (NICE; Price et al., 1999).

Seating An often-neglected area of pressure-relieving support surfaces is seating, including both chairs and cushions. Again, however, there is a paucity of clinical evidence that one seat or cushion (from the enormous array of both that are available) is better than another. Suitable seating is essential to prevent pressure damage and to maintain a balanced, symmetrical seating posture (Collins, 2004). The provision of adequate seating in an acute hospital is generally very poor. A “one size fits all” approach seems to have been adopted with little thought given to providing pressure relief or reduction. All too often the seating is in poor condition (Versluysen, 1986). There is very little access to pressure-relieving cushions. In the person’s own home and care homes, the elderly and disabled are often expected to sit for long periods in unsuitable chairs. Ideally, provision of seating, including pressure-relieving cushions, should promote good sitting balance (Figure 14) and provide comfort by taking into account the individual’s postural alignment, weight distribution, balance and stability and pressure relief or redistribution factors. The pelvis provides the interface between the seat and or cushion and the rest of the body. The main points of contact between the pelvis and seat are the ischial tuberosities, the tissue over which, not surprisingly, is the area particularly prone to pressure ulceration. In people without mobility problems, sitting is a dynamic process, the individuals changing their

Figure 15 Posterior pelvic tilt

position when they become uncomfortable and thus relieving pressure, particularly over the ischial tuberosities. Elderly, immobile, and disabled individuals often have a poor sitting posture, leading to what is known as posterior pelvic tilt (Figure 15). This may arise as a result of gravity, an unsupportive or inappropriate chair or wheelchair and poor trunk control, amongst other factors. Since the pelvis rotates posteriorly, the sacrum becomes more at risk of pressure damage. In addition, the ischial tuberosities slide forward, increasing shear and friction forces with a concomitant increase in the risk of pressure ulceration. A further consequence of the body slipping forward is that the heels become prone to further shear and frictional pressure, increasing the risk of pressure ulceration. If the seat of the chair sags, the pelvis may tilt laterally (Figure 16), leading to increased risk of pressure ulceration

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Cushion type

Suitability

Benefits/drawbacks

Static

Low- to high-risk individuals

• Supports ischial tuberosities • Thighs supported and isolated • Inexpensive, lightweight, many variations • Bottoms out with time • High interface pressures • Difficult to clean • Wears readily • Some flammable

Air filled Gel filled Fluid filled

Low- to high-risk individuals

• Pressure redistribution and reduction • Good stability • Absorbs dynamic movements • Good for wheelchairs • Air filled – lightweight and cleanable • Dependent on correct inflation • Liable to puncture • More difficult transfers • Fluid filled – heavy

Dynamic

High-risk individuals • Pressure relieving Individuals with • Increase sitting tolerance pressure ulcers • Varying inflation • Mechanical breakdown • Leaks • Regular battery charging

Figure 16 Lateral pelvic tilt

over one ischial tuberosity (as most of the body weight is supported through this tuberosity) as well as the ipsilateral greater trochanter. While turning schedules for people nursed in bed are well established, scant attention has been paid to repositioning schedules for at-risk individuals sitting in chairs or wheelchairs. Again, there is little data on the optimum frequency of posture change: if possible, the person should be encouraged to shift position every 15–30 minutes. If they are unable to do this independently, they should be repositioned at least hourly. The immobile and ill elderly person is more at risk of pressure ulceration when seated, as they often have reduced muscle bulk around the pelvis, with reduced skin elasticity. This leads to higher pressures around the ischial tuberosities. Pressure-relieving cushions may help reduce the risk of pressure damage in these individuals. Wheelchair users in the United Kingdom with postural problems and who are at risk of pressure ulceration, are entitled to be assessed for and provided with a suitable cushion or seating system (Collins, 2004). The wide range pressure-relieving cushions available reflects, in part, a degree of lack of evidence of efficacy (Bar and Pathy, 1998). However, studies have shown that cushions markedly reduce interface pressure, shear and friction forces (Palmieri et al., 1984). In addition, cushions provide support and stability for the pelvis and enable the individuals to maintain their balance when reaching for things (Fletcher, 1995). Cushions should enhance the ability to transfer either independently or with assistance and should be comfortable (Bennett et al., 1981). The cushion choice is dependent on the degree of pressure relief needed, lifestyle factors, postural stability, continence (bladder and/or bowel) and cost. The cushion should also be compatible with the chair or wheelchair (Garber et al., 1996, 2000). When choosing an armchair, attention should be paid to the seat base, cushion, backrest (with or without recline) and armrests.

Cushions, like mattresses and mattress overlays, may be classified as either static or dynamic (Figure 17). The static cushions are used mainly for pressure ulcer prevention, while dynamic cushions are used for individuals at elevated risk of pressure ulceration and those with established pressure ulcers. Table 6 illustrates the advantages and disadvantages of a range of cushions.

MANAGEMENT OF ESTABLISHED PRESSURE ULCERATION The management of established pressure ulcers has much in common with their prevention. The aim of treatment of pressure ulceration is to provide adequate pressure relief and further protection of vulnerable areas, prevent progression, and facilitate rapid healing within a multidisciplinary, holistic approach to the individual. Apart from treating the pressure ulcer, attention should focus on treatment of any underlying diseases, especially those that may adversely affect wound healing and mobility. Review of medication should ensure that there is no inappropriate sedation (which could lead to immobility). Similar nutritional regimes should be instituted in patients with pressure ulcers as for those at risk of pressure ulceration.

Pressure Relief The type of pressure relief for individuals with pressure ulcers is dependent on their needs. If the individual is

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many dynamic mattresses is their expense, which is felt by some to be excessive compared to their benefits (Lubin and Powell, 1991; Kanj et al., 1998).

Pressure Ulcer Classification

(a)

(b)

(c)

(d)

(e) Figure 17 Pressure-relieving cushions

able to be nursed off the pressure ulcer, a static support surface accompanied by a regular turning schedule may be appropriate (Hanan and Scheele, 1991). Should it not be possible to nurse the patient off the ulcer and if the pressure ulcer demonstrates no evidence of healing or deteriorates on a static surface, a dynamic support system should be employed (Table 5). Some studies in both long- and short-term care settings have demonstrated that dynamic mattresses promote healing of pressure ulcers compared to static foam mattresses, regardless of the size and depth of pressure ulcer (Allman et al., 1987; Ferrell et al., 1993). The major drawback of

There are several classification schemes for established pressure ulceration. The European Pressure Ulcer Advisory Panel (EPUAP) has developed a simple to use, four-grade classification of pressure ulcers, reflecting increasing severity of pressure damage (Table 7, Figure 18). There is no “ideal” classification system; for example, grade 1 ulceration may go unnoticed in people with darkly pigmented skin. Clinicians should also beware the pressure ulcer covered with eschar: Such wounds cannot be accurately graded until the eschar has been removed. Undermining and sinuses commonly occur and affect grading as well as healing potential. With moist wound healing techniques and optimal management of other medical conditions and nutrition, most grade 2 ulcers will heal after two weeks’ treatment: Grades 3 and 4 ulcers take an average of 6 weeks to 3 months to heal (65% grade 2, 14% grade 3 and 0% grade 4 over a 6-week follow-up period) (Xakellis and Chrischilles, 1992; Xakellis and Frantz, 1996, Xakellis et al., 1998). Generally, grades 1, 2, and 3 pressure ulcers are most amenable to local therapy, whereas grade 4 ulcers may require surgical repair (Kanj et al., 1998). It has been suggested, however, that if there is not a 30% reduction in the area of a deep pressure ulcer after 2 weeks of treatment, the wound will be unlikely to heal in any reasonable period of time without reevaluation of treatment modalities (van Rijswijk, 1993). Tools have been developed in an attempt to assess the healing of pressure ulcers. Two that have been evaluated include (1) the pressure sore status tool (PSST) (r 17 lyder) which is made up of 13 wound characteristics (e.g. edema, depth, size, exudate, etc.) and can be used to assess any chronic wound and (2) the pressure ulcer scale for healing (PUSH) tool (Stotts et al., 2001) which is similar to the PSST, comprising only three wound characteristics (length and width of the ulcer, exudate amount, and tissue type); it also takes less time to complete than the PSST. These tools, however, are not widely used. Photography of the pressure ulcer, made much easier with the advent of digital technology, is a key part of Table 7 Pressure Ulcer Classification

Grade 1:

Grade 2:

Grade 3:

Grade 4:

Nonblanchable erythema of intact skin. Discoloration of the skin, warmth, induration or hardness may also be used as indicators, particularly on individuals with darker skin Partial-thickness skin loss involving epidermis, dermis, or both. The ulcer is superficial and presents clinically as an abrasion or blister Full-thickness skin loss involving damage to or necrosis of subcutaneous tissue that may extend down to, but not through, underlying fascia Extensive destruction, tissue necrosis, or damage to muscle, bone or supporting structures with or without full thickness skin loss.

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the assessment process. However, consistent methodology is essential. Documenting the distance from which the photo was taken is important in order to obtain an accurate representation of the actual size of the ulcer (Lyder, 2003). Patient identification, date, and location should be recorded on the photo.

Local Wound Management A key measure in effective management of pressure ulcers is comprehensive evaluation of the wound and surrounding skin (Table 8). Other causes of skin ulceration should be excluded, including ischemia, vasculitis, radiation injury, and pyoderma gangrenosum: A detailed history and careful examination should help distinguish these.

Wound Debridement Moist necrotic tissue is yellow or gray (Figure 19): dry necrotic tissue is thick, hard, leathery and black (eschar) (Maklebust and Sieggreen, 2001). In the presence of necrotic tissue, wound healing is usually impossible. Removal of necrotic tissue, eschar, and debris is essential, both to facilitate wound healing and to accurately stage a pressure ulcer. While the use of debridement is largely based on expert opinion (Vowden, 2004), there is evidence that debridement stimulates healing by removing the necrotic tissue that impedes healing (Brem and Lyder, 2004). Chronic wound exudate has high levels of proinflammatory cytokines, which keep the wound in the inflammatory stage (Harris et al., 1995; Schultz and Mast, 1998). There are also high levels of matrix metalloproteinases

Grade I pressure ulcer

(a)

(e) Grade II pressure ulcer

(b)

(f)

Figure 18 (a – h) Diagrammatic representations and pictures of the four grades of pressure ulcers

PRESSURE ULCERATION Grade III pressure ulcer

(c)

(g) Grade IV pressure ulcer

(d)

Figure 18 (Continued)

(h)

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(MMPs), which destroy or alter the newly formed wound matrix (Grinnell and Zhu, 1996). Debridement and wound cleansing helps to remove the exudate and stimulate wound healing. Necrotic wounds are also associated with high levels of bacterial contamination. A direct correlation between high bacterial levels in wound tissues and delay in healing has been documented in pressure ulcers (Stotts and Hunt, 1997). Eschar (Figure 20), devitalized and infected tissue may be removed by sharp, autolytic, enzymatic, or surgical debridement. Simple sharp debridement (Figure 21) at the Table 8 Wound characteristics

Size Depth Wound bed Undermining Amount and type of exudates Surrounding skin

Figure 19 Moist necrotic tissue

Figure 20 Wound covered with eschar

Figure 21 Sharp debridement

bedside or in the treatment room using a scalpel, scissors or curette is useful when dealing with thick eschar and extensive areas of devitalized tissue. Prior treatment with local or block anesthetic may be required. Debrided tissue may be sent for microbiological or histological analysis. Minor bleeding usually accompanies sharp debridement, resulting in the release of cytokines, which may stimulate the wound healing process (Dräger and Winter, 1999). Commercially prepared enzymatic debriding agents may be available in some countries and used for those individuals with uninfected ulcers. They include streptokinase, streptodornase, fibrinolysin and deoxyribonuclease, sutilans, collagenase, and papain. Depending on the type, these debriding agents digest collagens (native and denatured), fibrinous material and nucleoproteins (Berger, 1993). They are usually delivered as an ointment onto the surface of the necrotic tissue. They should be avoided in wounds with exposed tendons. They have the potential for contact sensitization. They are not very effective on hard eschar or large amounts of necrotic material. It has been shown, however, in a randomized controlled study, that cheaper, amorphous Hydrogels (which promote autolytic debridement; see below) may be just as effective in debridement as enzyme preparations (Martin et al., 1996). Maggots are increasingly being used to debride chronic wounds (Sherman et al., 2000; Thomas et al., 1998) and may be considered a form of enzymatic debridement, though the mouth parts of the maggot also cause some mechanical irritation which is believed to aid wound healing. Such larval therapy makes use of the larvae of several species of fly, one of the commonest being the Green Bottle (Lucilia sericata). The larvae secrete an enzymatic liquor which selectively digests necrotic tissue and nonviable tissue: The digested products are then absorbed by the maggots. The liquor also contains cytokines, antiseptic substances, and proteases. The maggots have also been shown to ingest and kill bacteria (Fleischmann, 2004). Between 100 and 200 sterile maggots are used to debride wounds and are left in place for two to three days.

PRESSURE ULCERATION

Mechanical debridement is still commonly used in some countries. The most common method is the wet to dry technique, usually using woven cotton gauze. This is soaked in saline and allowed to dry out and become adherent to the wound surface. However, this method can lead to damage of healthy viable tissue when the dressing is removed and should be avoided (Kanj et al., 1998). Hydrotherapy and wound irrigation have been used to debride wounds, but evidence is limited (Palmier and Trial, 2004). Autolytic debridement occurs in all wounds and is the body’s own way of clearing necrotic tissue and debris from the area by the activity of the native enzymes within the ulcer (Thomas et al., 1999). The process relies on leucocytic activity and endogenous proteolytic enzymes. Bacterial proteases also contribute to the process (Baharestani, 1999). The intrinsic process is slow and further delayed by aging, malnutrition, and chronic disease (Himel 1995). Autolytic debridement may be promoted through the maintenance of a moist wound environment and is enhanced by the use of modern dressings, which are either moisture retentive or which hydrate the devitalized tissue. Frequent wound cleansing to eliminate the partially degraded tissue fragments is a necessary part of effective autolytic debridement. Several studies have shown that autolytic debridement is effective in digesting nonmobile tissue and more selective and less traumatic than mechanical techniques (Mulder et al., 1993; Flanagan, 1995, Bale et al., 1998, Colin et al., 1996). Autolytic debridement is painless; easy to use; able to be combined with other forms of debridement; suitable for most wounds and patients; cost-effective; and widely available (Vowden, 2004; Mulder, 1995).

Wound Cleansing This has been defined as “a process, which removes less adherent inflammatory molecules (such as cytokines and MMPs) from the wound surfaces and renders the wound less conducive to microbial growth” (Gardner and Frantz, 2004). The EPUAP in Europe and the American NPUAP have developed guidelines for cleansing pressure ulcers (Table 9). Although not isotonic, and since contact with the wound is brief, tap water suitable for drinking may be used to cleanse pressure ulcers. While sterile saline (0.91% sodium chloride) is more commonly used, it is more expensive and some studies have shown that there is a lower wound infection rate in wounds irrigated with tap water compared with wounds irrigated with sterile saline (Angeras et al., 1992). Antiseptics have long been used in an attempt to kill bacteria within a wound. However, they are also toxic to nonbacterial cells found in the wound such as fibroblasts and macrophages. In addition, they may have limited effect on bacteria within wound tissue (Ayello, 2004). In general, antiseptics should not be routinely used and when they are, it should be for a limited period only. Systemic antibiotics should be used if the wound is infected. Topical antimicrobial treatments demonstrated to enhance wound bed preparation without inhibiting the wound healing

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Table 9 EPUAP and AHCPR guidelines for cleansing pressure ulcers (Bergstrom et al., 1994; Fletcher, 2001)

European Pressure Ulcers Advisory Panel: 1. Cleanse wounds as necessary with tap water or with water, which is suitable for drinking, or with saline (strength of evidence = C). 2. Use minimal mechanical force when cleansing or irrigating the ulcer. Showering is appropriate. Irrigation can be useful for cleaning a cavity ulcer (C). 3. Antiseptics should not routinely be used to clean wounds but may be considered when bacterial load needs to be controlled after clinical assessment. Ideally, antiseptics should only be used for a limited period of time until the wound is clean and surrounding inflammation reduced (C). Agency for Health Care Policy and Research (AHCPR): 1. Cleanse wounds initially and at each dressing change (strength of evidence = C). 2. Use minimal mechanical force when cleansing the ulcer with gauze, cloth or sponges (C). 3. Do not clean ulcer wounds with skin cleansers or antiseptic agents (e.g. povidone iodine, iodophor, sodium hypochlorite solution (Dakin’s solution), hydrogen peroxide, acetic acid) (B). 4. Use normal saline for cleansing most pressure ulcers (C).

process include iodine-based dressings (e.g. Iodosorb) and noncrystalline silver-based dressings (for example, Acticoat (Smith and nephew); Actisorb 220 (Johnson and Johnson) and Aquacel Ag (Convatec)): the latter reported to minimize the potential of fungal infection (Johnson, 1991; Wright et al., 1999; Thomas and McCubbin, 2003). Silver compounds may be of use to treat wounds that have developed a bio-film, which is produced by some bacteria (Ziegler et al., 2004). Cadexomer iodine and silver compounds have been shown to reduce the bacterial burden. Wound irrigation is sometimes employed to help cleanse and debride a pressure ulcer. This ranges from use of saline filled syringes to pulsatile, battery-operated irrigation systems. The EPUAP and American Agency for Health Care Policy and Research, AHCPR (Bergstrom et al., 1994; Fletcher, 2001), recommend 4–50 psi as safe and effective irrigation pressures (the health-care professional carrying out wound irrigation should ensure that they and the patient are protected from splashback and splatter). Frequent showering with large amounts of water helps reduce the bacterial burden on the wound surface and provides psychological benefits to the patient (Bauer et al., 2000). The shower should not be aimed directly at the wound, rather directed above it, so that the water irrigates the wound without too much force (Ayello, 2004).

Dressings Dressings play a major role in the treatment of pressure ulcers. The occlusion that dressings provide promotes moist wound healing, facilitates re-epithelialization, reduces associated pain, enhances autolytic debridement and provides a barrier to bacteria (Leipziger et al., 1985; Alvarez et al., 1989; Friedman and Su, 1984, Mertz et al., 1985). There are estimated to be more than 300 different dressings marketed for pressure ulcer care (Lyder, 2003). The major dressing classification and their uses are identified in Table 10.

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Table 10 Dressings suitable for pressure ulcers

Dressing type

Pressure ulcer grade

Semipermeable film

1 Minimally exuding 2

Promote moist environment Adheres to healthy skin but not to wound Allows visual checks May be left in place for several days No cushioning Not for infected or heavily exuding wounds

Foams

Low to moderately exuding, noninfected 2–3

Degree of cushioning May be left in place 2 – 3 days Needs secondary dressing

Hydrogels

Low to moderately exuding 2 – 4

Supplies moisture to low exuding wounds Useful for cavities and sinuses May be left in place for several days Needs secondary dressing May cause maceration

Hydrocolloids

Low to moderately exuding 3 – 4

Absorbable Conformable Good in “difficult areas” – heel, elbow, sacrum May be left in place for several days May cause maceration

Hydrofibres

Moderate to Highly exuding 2 – 4

Useful in cavities, sinuses, undermining wounds Highly absorbent Nonadherent May be left in place for several days Needs secondary dressing

Alginates

Moderate to Highly exuding 2 – 4

Useful in cavities, sinuses, undermining wounds Highly absorbent Needs secondary dressing Needs to be changed daily

Advantages/disadvantages

Semipermeable (polyurethane) films are thin, transparent, nonabsorbent and coated on one side with hypoallergenic adhesive. They are suitable for grade 1 and minimally exuding grade 2 pressure ulcers. They are applied directly to the wound. Hydrogels are insoluble polymers with hydrophilic sites containing more than 80% water and are available as an amorphous gel or translucent sheet. They are semitransparent and absorbent. They are nonadherent and dry out easily. They require a secondary dressing. They feel cool and soothing when applied to the wound. They are suitable for low to moderately exuding grades 2–4 ulcers. They are also suitable for wounds not spontaneously exuding, providing a moist environment. Hydrocolloids are adherent, conformable, absorbent dressings: pastes and granules are also available and are especially suited to deeper wounds. Their conformability makes them suitable for use on “difficult” areas of the body including the

sacrum, heels, and elbows. They can be left in place for several days. They are suitable for low to moderately exuding grades 3 and 4 ulcers. As they liquefy, Hydrocolloids form a yellowish gel-like material with a characteristic odor, which may, in the unwary, be mistaken for infection. They may stimulate excess granulation. They should be used with care if muscle, tendon, or bone is exposed. Hydrocolloids may be used on a range of wound beds, from ulcers that are infected to those that are epithelialising. Alginates are polymers, which are derived from seaweed, either as calcium or sodium alginate. They are particularly useful in cavities, sinuses, and undermining grade 4 ulcers and moderately to highly exuding grades 2–4 ulcers. They are also suitable for sloughy and granulating wounds. They require a secondary dressing. They are hemostatic and useful for wounds that bleed. Hydrofibre dressings are a form of hydrocolloid. They are highly absorbent and form a cohesive gel through interaction with wound exudates, thereby also maintaining a moist wound environment. They may be used on sloughy to granulating wounds. Hydrofibres are nonadherent and may be left in place for several days. They require a secondary dressing. They are used in similar situations as alginate dressings. There are a plethora of other wounds dressings available. Their use should be guided by the characteristics of the wound, for example, site, size, depth, undermining, stage, drainage, surrounding skin involvement, wound infection, sinuses, underlying osteomyelitis, and so no. Dressing availability, cost, and ease of application may also need to be considered (Mulder and LaPan 1988; Eaglstein, 2001).

Infection It is important to realize that all pressure ulcers will be colonized with bacteria. This does not, however, equate with infection. Wound cultures from pressure ulcer swabs are polymicrobial. Aerobic bacteria include, Staphylococcus aureus, Staphylococcus epidermis, β-hemolytic streptococcus Group A, Escherichia coli, Pseudomonas aeruginosa, Proteus mirabilis, Providentia stuartii, Serratia marcescens, Enterococcus species, Enterobacter species, and Acenetobacter species (Parish and Witkowski, 1989; Witkowski and Parish, 2000). Anaerobic organisms may also be present. Even when heavily colonized, most pressure ulcers eventually go on to heal (Mertz and Eaglestein, 1984; Dagher et al., 1987; Hutchinson, 1989). Colonized wounds lack the signs of infection, which may include all or any of the features listed in Table 11. Table 11 Signs of pressure ulcer infection

Warmth Redness Pain Swelling Odor Increased wound exudate – serous, sero-sanguinous, purulent Contact bleeding

PRESSURE ULCERATION

When a pressure sore is infected, there is invasion of previously healthy tissue by microorganisms. A bacterial load of greater than 106 bacteria per gram of tissue has been found to impair wound healing (Sapico et al., 1986; Parish and Witkowski, 1989; Witkowski and Parish, 2000). Infection is usually accompanied by at least some of the signs listed in Table 11. However, some of the signs may be attenuated or absent in patients with, for example, decreased sensation, abnormal neurological function or disturbed immunological response such as may occur in an elderly patient or patient with spinal cord injury. Cellulitis may complicate pressure ulcer infection as a result of spread of infection to surrounding tissue. Bacteremia is a further serious complication of infected pressure ulcers. Bacteremia may lead to sepsis, endocarditis and death, with mortality rates between 50 and 70% (Sugarman et al., 1982). Approximately one-quarter to one-third of nonhealing pressure ulcers are associated with underlying osteomyelitis arising through direct extension from an infected pressure ulcer or blood dissemination (Sugarman, 1987; Allman, 1989a,b). Systemic treatment of an infected pressure ulcer and/or accompanying cellulitis, bacteremia, or osteomyelitis should be guided by culture and sensitivity of the organism(s). It may be prudent to start broad-spectrum antibiotic therapy while awaiting the results of tissue culture and sensitivity or blood cultures. However, swab results may not accurately reflect deep tissue cultures, which themselves may vary from one part of the ulcer to another (Kanj et al., 1998). Curettage of the ulcer base following debridement is more reliable than swab samples (Sapico et al., 1984; Lipsky et al., 1990). Ulcer biopsy, if possible, will yield better tissue cultures (Daltrey et al., 1981). Common pathogenic organisms include S. aureus, Bacteroides species, and gramnegative rods (Brown and Smith, 1999). A malodorous wound may be a sign of infection with anaerobes or Bacteroides fragilis (a facultative anaerobe). Gross tissue necrosis is usually caused by a combination of aerobic and anaerobic bacteria (Kanj et al., 1998). Treatment should initially be with parenteral antibiotics. Diagnosis of osteomyelitis and identification of the responsible pathogen is similarly fraught with difficulty. The traditional investigation of X-ray changes, elevated erythrocyte sedimentation rate and leucocytosis has a specificity of 33% and sensitivity of 60% (Darouiche et al., 1994; Brown and Smith, 1999). More sensitive investigations include bone scans and MRI or CT scanning (Figure 22). Bone scans may be difficult to interpret, as the soft tissue inflammation from an infected wound is associated with a high falsepositive rate. If the bone scan is abnormal, bone biopsy and culture may be necessary to determine infection and to identify the causative organism. A negative bone scan, however, makes osteomyelitis unlikely (Sugarman, 1987). MRI is now considered the investigation of choice for osteomyelitis (Sugarman, 1985). There is no consensus as to the duration of antibiotic treatment of osteomyelitis. Initial parenteral administration of antibiotics followed by oral antibiotics for a minimum of four to eight weeks is usual. Treatment may

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Figure 22 Bone scan of osteomyelitis underlying pressure ulcer of left hip

be monitored by measuring inflammatory markers such as ESR and CRP. Surgical debridement of the bone may be necessary. Sinus tracks may occur as a result of pressure ulceration. They occur in both superficial and deep ulcers and may extend to joint space and cause osteomyelitis. The sinuses may communicate with other structures including viscera (e.g. bowel and bladder). A sinogram or MRI may be necessary to delineate the extent and communication of these sinuses. Other complications of pressure ulcers include squamous cell carcinoma (which may metastasize), with an estimated incident of 0.5%. Septic arthritis, amyloidosis, endocarditis, meningitis, and pseudoaneurysm formation may occur rarely.

Surgical Treatment of Pressure Ulcers Surgical reconstruction may be appropriate treatment for some grade 3 and 4 pressure ulcers and may reduce healing times. An average healing time of 13 weeks has been demonstrated for grade 3 pressure ulcers if treated by skin grafting, and five weeks for those treated with musculocutaneous flaps (Brandeis et al., 1990). It has been suggested that surgery is the preferred method of treatment when the rate of healing with conservative management is less than 40% (Siegler and Lavisso-Mourey, 1991). Surgical treatment of pressure ulcers is usually reserved for those patients whose health outcomes and quality of life would significantly be improved by such intervention. There is, by extension, a definite place for palliative care for some patients with pressure ulcers whose medical and nutritional status is severely compromised, with control of symptoms rather than healing being the priority. Successful reconstructive surgery is predicated on the optimization of the individual’s medical and nutritional status. Surgery to close the defects is of long duration, with a potential for significant blood loss: postoperative immobilization is also protracted.

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Adequate pre-and postoperative nutrition is essential to facilitate wound healing. Patients should give up or refrain from smoking as this hinders wound healing and may increase the risk of flap failure (Read, 1984). Spasticity leading to contractions may need to be addressed prior to surgery for pressure ulceration, as these may interfere with the pressure relief necessary postoperatively (Haher et al., 1983). Exposure to feces and urine should be avoided and fecal or urinary diversion may be necessary in the preoperative planning process, especially in the paralyzed or neurologically compromised patient (Ferrell et al., 1993; Brown and Smith, 1999). There are various methods of surgical reconstruction of pressure ulcers largely dictated by their location and size of the defect. Primary closure with sutures is rarely of benefit and has high recurrence rates (Lewis, 1989). Skin grafts, similarly, are seldom used as they do not provide any padding and only provide a superficial barrier. Additionally, they exhibit “poor take” over exposed bone (Granick et al., 1994). Musculocutaneous and fasciocutaneous flaps are the most widely used method for reconstructing pressure ulcers. A fascial or muscular unit, the overlying skin and their blood supply, in a pedicle of tissue, is used to fill the defect made by the pressure ulcer (after debridement of devitalized tissue). Such flaps are, as a consequence of their preserved blood supply, able to withstand pressure and shear trauma. They are also particularly useful when treating pressure ulcers complicated by osteomyelitis by bringing highly vascularized muscle into the area of infection, which has been removed at the time of surgery (Daniel et al., 1979; Mathes et al., 1993; Bruck et al., 1991; Anthony et al., 1992). Other flaps used include axial flaps – a vascularized segment of skin and subcutaneous tissue is raised and rotated into the defect; microvascular flaps – tissue with a single arteriovenous pedicle is raised, the vessels transected, and anastamosed to recipient vessels adjacent to the pressure ulcer defect; free flaps – muscle flaps where the original blood supply is disconnected and reconnected to vessels at the tissue defect site – rarely used, chiefly since less complicated options are usually available (Kostako-glu et al., 1993). Postoperatively, patients require immobilization, remaining in bed with vigilant pressure relief. A low air-loss mattress or an air-fluidized bed may be necessary. Immobilization for 2 to 4 weeks is usual. Flap viability must closely be monitored. Postoperative complications include hematoma (most common, therefore, meticulous intraoperative hemostasis is necessary), wound infection, flap necrosis, dehiscence, seroma, and infection.

VAC Therapy Vacuum assisted closure (VAC) therapy is one of many synonyms in use for topical negative pressure therapy (TNP); though the term VAC is widely used in the United Kingdom (Figure 23). The technique has found an increasing role in the treatment of chronic wounds with large amounts of exudates, such as pressure ulcers (Philbeck et al., 1999). The VAC dressing is open pored (polyurethane or polyvinyl chloride), shaped to fit the wound and sealed within it using a semiocclusive dressing. A negative pressure is delivered across the wound bed via a drainage tube embedded within the foam and connected to a negative pressure device (Banwell, 1999). The negative pressure promotes granulation tissue formation (Morykwas et al., 1997). This may be facilitated by reducing tissue edema directly, by removing fluid, or indirectly by eliminating factors that promote edema, thus preventing microvascular compromise (Morykwas et al., 1997, 1999). Reduced edema may, however, reflect increase in local blood flow (Thomas and Banwell, 2004). Removal of fluid has also been postulated to remove factors inhibitory to wound healing (Banwell, 1999). Furthermore, TNP has been shown to reduce bacterial colonization of wounds both experimentally and clinically (Mullner et al., 1997; Morykwas et al., 1997; Obdeijn et al., 1999; Giovanni et al., 2001), which may further enhance wound healing. Several studies have demonstrated the efficacy of VAC therapy in the treatment of pressure ulcers (Baynham et al., 1999; Azad and Nishikawa, 2002; Coggrave et al., 2002). Dressings may only need to be changed twice weekly, thus reducing patient discomfort and cost (Schneider et al., 1998). The duration of VAC therapy depends on clinical improvement, patient compliance, and resources. VAC therapy has been advocated by some in the treatment of pressure ulcers complicated by underlying osteomyelitis (Ford et al., 2002), while others feel that osteomyelitis is a contraindication to its use (Lyder, 2003); other relative contraindications

Adjunctive Therapies Adjunctive therapies are increasingly being employed in an attempt to heal pressure ulcers. Some of these are very effective and are becoming part of the armoury of standard treatment. Yet others are experimental or in the research stage.

Figure 23 VAC therapy on sacral pressure ulcer

PRESSURE ULCERATION

include application over an open joint; peritoneal or pleural space; in patients with a coagulopathy; over a tumor, though it may be considered as part of palliative wound control (Banwell, 1999).

Physical Modalities Many physical therapies have been used to treat pressure ulcers. However, the therapeutic efficacy of hyperbaric oxygen, infrared, UV, low energy and laser irradiation, and ultrasonography has little evidence to support their use in the treatment of pressure ulceration (Bello and Phillips, 2000). Radiant heat (Normotherapy) is thought to increase blood flow and promote fibroblast and other factors associated with pressure ulcer healing (Xia et al., 2000; Kloth et al., 2000): Further evaluation with controlled trials is required. Electrical stimulation has been recommended by the Agency for Health Care Research (USA) for stages 2 to 4 pressure ulcers which have not responded to conventional therapy (Ovington, 1999). The basis of the therapy is founded on the observation that when tissue is damaged, a current of injury is generated that may trigger biological repair (Weiss et al., 1990). Electrical stimulation has been shown to enhance wound healing in human and animal models: This is thought to affect the migration, proliferation, and functional capacity of fibroblasts, neutrophils, and macrophages; promote collagen and DNA synthesis and increase the number of receptor sites for specific growth factors (Falanga et al., 1997; Gentzkow et al., 1993; Kloth and McCulloch, 1996; Baker et al., 1996). However, it has been postulated that it is in fact the occlusive dressing used which may enhance wound healing by providing the moist environment necessary to maintain endogenous current flow (Jaffe and Vanable, 1984).

Larval Therapy Sterile larvae (maggots, Figure 24) were first used as a treatment for infected or chronic wounds in the early twentieth century. Over recent years, there has been a resurgence of interest in their use for the debridement of a variety of infected or necrotic acute and chronic wounds including pressure ulcers. Two species of larvae are commonly used: Lucilia species and Phaenicia species. While they often have a significant effect on sloughy and infected wounds, their exact mechanism of action is not fully understood. Maggots have been shown to ingest and kill some bacteria and studies have also shown that larval secretions kill or inhibit the growth of a number of bacterial species including S. aureus (including MRSA) and Streptococcus. Furthermore, the metabolic activity of the maggots increases wound pH, preventing the growth of such bacteria (Thomas and Jones, 1998). The digestive juices of the larvae contain growth factors, antiseptic substances, and enzymes such as proteases (Fleischmann, 2004). Fibroblast growth stimulating factor

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has been demonstrated in the hemolymph and alimentary secretions of larvae (Prete, 1997). The presence of larvae or their metabolites may stimulate cytokine production by wound macrophages, thus stimulating the wound-healing process (Thomas and Jones, 1998). Larvae secrete powerful proteases, mainly of the serine class, which break down dead tissue, which is used for sustenance by the larvae (Young et al., 1996). Despite promising reports and widespread use, there are as yet, no large randomized, controlled trials to support the use of larvae in the treatment of pressure ulcers.

Growth Factors Growth factors are secreted regulatory proteins that control survival, growth, differentiation, and effector function of tissue cells. They require a receptor, which may not be constitutive, to exert their effect. A large number of growth factors have been described and characterized. Since wound healing is an inflammatory process, much research has been carried out to determine whether they may be useful clinically in the treatment of chronic wounds including pressure ulcers. Initial promise, however, has not translated into clinical reality to any great extent. Platelet-derived growth factor (PDGF) is one of the first growth factors released in acute wounds and as such has been investigated as a potential therapy to promote healing of chronic wounds. PDGF is a dimeric glycoprotein, released predominantly by platelet alpha granules. Topically applied recombinant PDGF-BB (rh PDGF-BB) has been shown in various small trials to produce a statistically significant reduction in pressure ulcer volume in the treatment group (Mustoe et al., 1994). Other trials have shown an improvement in the rate of re-epithelialization of pressure ulcers with exogenously applied PDGF-BB (Robson, 1991; Cox, 1993). The trials highlighted the importance of simple good basic care in the treatment of pressure ulcers. A further small, placebo controlled, double-blind study using recombinant basic fibroblast growth factor (rh bFGF) in patients with chronic grades 3 and 4 pressure ulcers demonstrated no difference in the percentage volume reduction between different arms of the study. The volume reduction compared to baseline in the actively treated group was, however, significant (Robson et al., 1992a,b). Drawbacks of such trials are that they tend to be small and of short duration; large randomized, controlled trials are needed. It is perhaps not surprising that growth factors have not proved the panacea in the healing of chronic wounds. Growth factors are present at different stages of healing and exert their effects depending on the wound microenvironment at a particular time and presence, or absence, of other growth factors. In addition, there is a balance between growth factors and enzymes responsible for their activation and degradation, which also vary at different stages in the wound healing cascade. Ideally, a diagnostic test to ascertain which of the wounds are deficient in specific growth factors is needed:

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(a)

(c)

(d) (b) Figure 24 Debridement of heel pressure ulcer with Larval therapy (a) Pre-treatment, (b) 3 days post larval therapy, (c) 7 days post larval therapy, (d) Healed pressure ulcer (Pictures courtesy of Dr S Thomas, Zoobiotic Ltd.)

Then, perhaps, the promise of exogenously applied growth factors will be fulfilled.

but no large trials have been undertaken. It is an area that merits further study.

Tissue Engineering

Other Therapies

Tissue engineered “skin equivalents” have been developed to treat both acute and chronic wounds: They are formed by growing allogeneic cells in a synthetic matrix in vitro. The “skin equivalents” may be categorized as (1) those containing epidermal elements alone; (2) those comprising dermal elements, and (3) composite grafts containing both epidermal and dermal elements (Phillips, 1998). Most of the allogeneic cells are derived from neonatal foreskins and are seeded into a variety of collagen gels or bioabsorbable meshes. Much work has been carried out into their use on chronic wounds such as venous leg ulcers and diabetic foot ulcers with good effect. There have been some promising small trials using “skin equivalents” to treat pressure ulcers,

Many other therapies for the treatment of pressure ulcers have been investigated. Topical agents include honey, sugar, vitamins, zinc, magnesium, gold, phenytoin, yeast extract, insulin, and aloe vera gel. Light therapy and ultrasound have also been tried (Kanj et al., 1998). All require further evaluation and large-scale trials to establish their efficacy.

KEY POINTS • Pressure ulcers are common, especially in the elderly patient.

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• Pressure ulcers are caused by direct pressure, friction and shear forces, individually or often acting in concert with each other: Moisture exacerbates the effects of pressure, friction and shear. • At-risk individuals should have regular risk assessments: Risk assessment scales are not a substitute for clinical judgment. • The effects of risk factors should be minimized through optimal management. • Adequate pressure relief is essential in the prevention and treatment of pressure ulcers. • Accurate pressure ulcer grading assists in the choice of treatment, dressings, and adjunctive therapies.

KEY REFERENCES • European Pressure Ulcer Advisory Panel (EPUAP). Pressure Ulcer Prevention and Treatment Guidelines, www.epuap.org. • National Institute for Clinical Excellence. Pressure Ulcer Risk Management and Prevention (Guideline B) 2003; NICE, London, www.nice.org.uk. • National Pressure Ulcer Advisory Panel (NPUAP, USA). Pressure Ulcer Prevention and Treatment Guidelines, www.npuap.org.

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Gardner SE & Frantz RA. Wound bioburden. In S Baranoski & EA Ayello (eds) Wound Care Essentials: Practice Principles 2004, pp 91 – 116; Lippinkott Williams & Wilkins, Springhouse. Gebhardt KS & Bliss MR. Preventing pressure ulcers in orthopaedic patients – s prolonged chair nursing detrimental? Journal of Tissue Viability 1994; 4:51 – 4. Gentzkow GD, Alon G, Taler GA et al. Healing of refractory stage III and IV pressure ulcers by a new electrical stimulation device. Wounds 1993; 5:160 – 72. Giovanni UM, Demaria R & Teot L. Benefits of negative pressure therapy in infected surgical wounds after cardiovascular surgery. Wounds 2001; 132:82 – 7. Granick MS, Eisner AN & Solomon MK. Surgical management of decubitus ulcers. Clinics in Dermatology 1994; 12:71 – 9. Grinnell F & Zhu M. Fibronectin degradation in chronic wounds depends on the relative levels of elastase, alpha1-proteinase inhibitor, and alpha2-macroglobulin. The Journal of Investigative Dermatology 1996; 106:335 – 41. Haher JN, Haher TR, Devlin VJ et al. The release of flexure contractures as a prerequisite for the treatment of pressure sores in multiple sclerosis: a report of 10 cases. Annals of Plastic Surgery 1983; 11:246 – 9. Hall DA. The Biomedical Basis of Gerontology 1984; John Wright, Guildford. Hanan K & Scheele L. Albumin vs. weight as a predictor of nutritional status and pressure ulcer development. Ostomy/Wound Management 1991; 33:22 – 7. Harris IR, Yee KC, Walters CE et al. Cytokine and protease levels in healing and non-healing chronic venous leg ulcers. Experimental Dermatology 1995; 4:342 – 9. Hatcliffe S & Dawe R. Monitoring pressure sores in a palliative care setting. International Journal of Palliative Nursing 1996; 2:182 – 6. Healey F. Classification of pressure sores: 2. British Journal of Nursing 1996; 5(9):567 – 8, 570, 572 – 4. Herman LE & Rothman KF. Prevention, care and treatment of pressure (decubitus) ulcers in intensive care unit patients. Journal of Intensive Care Medicine 1989; 4:117 – 23. Himel H. Wound healing: focus on the chronic wound. Wounds 1995; 7:70A – 7A. Houle RJ. Evaluation of seat devices designed to prevent ischaemic ulcers in paraplegic patients. Archives of Physical Medicine and Rehabilitation 1969; 50:587 – 94. Hutchinson JJ. Prevalence of wound infection and occlusive dressings; a collective survey of reported research. Wounds 1989; 1:124 – 33. Jaffe LF & Vanable JW Jr. Electric fields and wound healing. Clinics in Dermatology 1984; 2:34 – 44. Johnson A. A combative healer with no ill-effect. Iodosorb in the treatment of infected wounds. Professional Nurse 1991; 7:60, 62, 64. Kanj LF, Wilking SV & Phillips TJ. Pressure ulcers. Journal of the American Academy of Dermatology 1998; 38:517 – 36. Kloth LC, Berman JE, Dumit-Minkel S et al. Effects of a normal normothermic dressing on pressure ulcer healing. Advances in Skin and Wound Care 2000; 13:69 – 74. Kloth LC & McCulloch JM. Promotion of wound healing with electrical stimulation. Advances in Wound Care 1996; 9:42 – 5. Knox DM, Anderson TM & Anderson PS. Effects of different turn intervals on skin of healthy older adults. Advances in Wound Care 1994; 7(1):48 – 52, 54 – 6. Kostako-glu N, Keocik A, Ozymilaz F & Safak T. Expansion of fascial flaps: histopathologic changes and clinical benefits. Plastic and Reconstructive Surgery 1993; 91:72 – 9. Landis T. Micro-injection studies of blood pressure in human skin. Heart 1930; 15:209 – 28. Lazarus GS, Cooper DM, Knighton DR et al. Definitions and guidelines for assessment of wounds and evaluation of healing. Archives of Dermatology 1994; 130:489 – 93. Leipziger LS, Glushko V, DiBernardo B et al. Dermal wound repair: role of collagen matrix implants and synthetic polymer dressings. Journal of the American Academy of Dermatology 1985; 12:409 – 19. Lewis VL Jr. Tensor fasciae latae VY retroposition flap. Plastic and Reconstructive Surgery 1989; 84:1016 – 7.

PRESSURE ULCERATION Lindan O. Etiology of decubitus ulcers; an experimental study. Archives of Physical Medicine and Rehabilitation 1961; 42:774 – 83. Lipsky BA, Percoraro RE & Wheat LS. The diabetic foot: soft tissue and bone infection. Infectious Disease Clinics of North America 1990; 4:409 – 39. Lubin BS & Powell T. Pressure sores and specialty beds: cost containment and ensurance of quality care. Journal of ET Nursing 1991; 18:190 – 7. Lyder CH. Pressure ulcer prevention and management. The Journal of the American Medical 2003; 289:223 – 6. Lyder CH, Shannon R, Empleo-Frazier O et al. A comprehensive program to prevent pressure ulcers in long-term care: exploring costs and outcomes. Ostomy/Wound Management 2002; 48:52 – 62. Maklebust J, Sieggreen M. Pressure Ulcer: Guidelines for Prevention and Management 2001, 3rd edn, Springhouse. Martin SJ, Corrado OJ & Kay EA. Enzymatic debridement for necrotic wounds. Journal of Wound Care 1996; 5:310 – 1. Mathes SJ, Feng LJ & Hunk TK. Coverage of the infected wound. Annals of Surgery 1993; 198:420 – 9. Mathus-Vliegen EM. Old age, malnutrition, and pressure sores: an ill-fated alliance. The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences 2004; 59(4):355 – 60. Medical Devices Agency. Static Mattress Overlays: Evaluation P52 1994; DoH. Mertz PM & Eaglestein WH. The effect of semi-occlusive dressing on the microbial population in superficial wounds. Archives of Surgery 1984; 119:287 – 9. Mertz PM, Marshall DA & Eaglestein WH. Occlusive wound dressings to prevent bacterial invasion and wound infection. Journal of the American Academy of Dermatology 1985; 12:662 – 8. Morykwas MJ, Argenta LC, Shelton – rown EI & McGuirt W. Vacuum – assisted closure: a new method for wound control and treatment: animal studies and basic foundation. Annals of Plastic Surgery 1997; 38:553 – 62. Morykwas MJ, David LR, Schneider AM et al. Use of sub-atmospheric pressure to prevent progression of partial – thickness burns in a swine model. The Journal of Burn Care and Rehabilitation 1999; 201:15 – 21. Mulder GD. Cost-effective managed care: gel versus wet-to-dry for debridement. Ostomy/Wound Management 1995; 41:68 – 70, 72, 74 passim. Mulder GD & LaPan M. Decubitus ulcers: update on new approaches to treatment. Geriatrics 1988; 43:37 – 9, 44 – 5, 49 – 50. Mulder GD, Romanko KP, Sealey J & Andrews K. Controlled randomised study of a hypertonic gel for the debridement of dry eschar in chronic wounds. Wounds 1993; 5:112 – 5. Mullner T, Mrkonjic L, Kwasny O & Vecsei V. The use of negative pressure to promote the healing of tissue defects: a clinical trial using the vacuum sealing technique. British Journal of Plastic Surgery 1997; 50:194 – 9. Mustoe TA, Cutler NR, Allman RM et al. A phase II study to evaluate recombinant platelet-derived growth factor-BB in the treatment of stage 3 and 4 pressure ulcers. Archives of Surgery 1994; 129:213 – 9. National Institute for Clinical Excellence. Pressure Ulcer Risk Management and Prevention (Guideline B) 2003; NICE, London, www.nice.org.uk. Nyquist R & Hawthorn PJ. The prevalence of pressure sores within an area health authority. Journal of Advanced Nursing 1987; 12(2):183 – 7. Obdeijn MC, de-Lange MY, Lichtendahl DH & de Boer WJ. Vacuumassisted closure in the treatment of poststernotomy mediastinitis post op. The Annals of Thoracic Surgery 1999; 686:2358 – 60. Ovington LG. Dressings and adjunctive therapies: AHCPR guidelines revisited. Ostomy/Wound Manage 1999; 45(suppl 1A):94 – 106. Palmier S & Trial C. Uses of high-pressure water jets in wound debridement. In L Teot, PE Banwell & UE Ziegler (eds) Surgery in Wounds 2004; Springer, Berlin. Palmieri l, Haelen T & Cochran GVB. A comparison of sitting pressures on wheelchair cushions measured by air cell transducers and miniature electronic transducers. Bulletin of Prosthetics Research 1984; 17:5 – 8. Parish LC & Witkowski JA. The infected decubitus ulcer. International Journal of Dermatology 1989; 28:643 – 7. Philbeck TE Jr, Whittington KT, Millsap MH et al. The clinical and cost – effectiveness of externally applied negative pressure wound therapy

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in the treatment of wounds in home health care medicare patients. Ostomy/Wound Manage 1999; 45:41 – 50. Phillips TJ. New skin for old. Developments in biological skin substitutes. Archives of Dermatology 1998; 134:344 – 9. Phillips L. Providing correct pressure-relieving devices for optimum outcome. British Journal of Nursing 1999; 8(21):1447 – 52. Pinchcofsky-Devin GD & Kaminski MV Jr. Correlation of pressure sores and nutritional status. Journal of the American Geriatrics Society 1986; 34(6):435 – 40. Prete P. Growth effects of Phaenicia sericata larval extracts on fibroblasts: mechanism for wound healing by maggot therapy. Life Sciences 1997; 60:505 – 10. Price P, Bale S, Newcombe R & Harding K. Challenging the pressure sore paradigm. Journal of Wound Care 1999; 8(4):187 – 90. Read RC. Presidential address: systemic effects on smoking. American Journal of Surgery 1984; 148:706 – 11. Rithalia SV. Evaluation of alternating pressure air mattresses: one laboratory-based strategy. Journal of Tissue Viability 2004a; 14(2):51 – 8. Rithalia SV. Evaluation of alternating-pressure air mattresses: How to do it. In M Clark (ed) Pressure Ulcers: Recent Advances in Tissue Viability 2004b; Quay books, Salisbury. Robson MC. Growth factors and wound healing: part 2. Role in normal and chronic would healing. American Journal of Surgery 1991; 166:74 – 81. Robson MC, Phillips LG, Lawrence WT et al. The safety and effect of topically applied recombinant basic fibroblast growth factor on healing of chronic pressure sores. Annals of Surgery 1992a; 216:401 – 6. Robson MC, Phillips LG, Thomason A et al. Platelet-derived growth factor BB for the treatment of chronic pressure ulcers. Lancet 1992b; 339:23 – 5. Russ GH & Motta GJ. Eliminating pressure: is less than 32 mmHg enough for wound healing? Ostomy/Wound Management 1991; 34:60 – 3. Rycroft-Malone J & Duff L. Pressure ulcer guidelines. Nursing Standard 2000; 14(40):31. Sapico FL, Ginunas VJ, Thornhill – Joynes M et al. Quantitative microbiology of pressure sores in different stages of healing. Diagnostic Microbiology and Infectious Disease 1986; 5:31 – 8. Sapico FL, Witter JL, Canawati HN et al. The infected foot of the diabetic patient: quantitative microbiology and analysis of clinical features. Reviews of Infectious Diseases 1984; 6:S171 – S6. Schneider AM, Morykwas MJ & Argenta LC. A new and reliable method of securing skin graph to the difficult recipient bed. Plastic and Reconstructive Surgery 1998; 1024:1195 – 8. Schubert V & Héraudj J. The effects or pressure and shear on skin microcirculation in elderly stroke patients lying in supine or semi-recumbent positions. Age and Ageing 1994; 23:405 – 50. Schultz GS & Mast BA. Molecular analysis of the environment of healing and chronic wounds: cytokines, proteases and growth factors. Wounds 1998; 10(suppl F):1F – 11F. Seiler WO. Decubitus ulcers: preventive techniques for the elderly patient. Geriatrics 1985; 40:53 – 60. Seiler WO & Stahelin HB. Decubitus ulcers: preventive techniques for the elderly patient. Geriatrics 1985; 40(7):53 – 60. Scheckler WE & Peterson PJ. Infections and infection control among residents of eight rural Wisconsin nursing homes. Archives of Internal Medicine 1986; 146(10):1981 – 4. Sherman RA, Hall MJ & Thomas S. Medicinal maggots: an ancient remedy for some contemporary afflictions. Annual Review of Entomology 2000; 45:55 – 81. Siegler EL & Lavisso-Mourey R. Management of stage III pressure ulcers in moderately demented nursing home residents. Journal of General Internal Medicine 1991; 6:507 – 13. Stotts NA & Hunt TK. Pressure ulcers. Managing bacterial colonization and infection. Clinics in Geriatric Medicine 1997; 13:565 – 73. Stotts NA, Rodeheaver GT, Thomas DR et al. An instrument to measure healing in pressure ulcers: development and validation of the pressure ulcer scale for healing (PUSH). The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences 2001; 56:M795 – 9. Sugarman B. Infection and pressure sores. Archives of Physical Medicine and Rehabilitation 1985; 66:177 – 9. Sugarman B. Pressure sore and underlying bone infection. Archives of Internal Medicine 1987; 147:553 – 5.

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Sugarman B, Brown D & Musher D. Fever and infection in spinal cord injury patients. The Journal of the American Medical 1982; 248:66 – 70. Thomas S, Andrews A & Jones M. The use of larval therapy in wound management. Journal of Wound Care 1998; 7:521 – 4. Thomas GPL & Banwell PE. Topical negative – pressure therapy in wound management. In L Teot, TE Banwell & UE Ziegler (eds) Surgery in Wounds 2004; Springer, Berlin. Thomas DR, Goode PS, Tarquine PH & Allman RM. Hospital-acquired pressure ulcers and risk of death. Journal of the American Geriatrics Society 1996; 44(12):1435 – 40. Thomas AM, Harding KG & Moore K. The structure and composition of chronic wound eschar. Journal of Wound Care 1999; 8:285 – 7. Thomas S & Jones M. The use of larval therapy in wound management. Journal of Wound Care 1998; 7:521 – 4. Thomas S & McCubbin P. A comparison of the antimicrobial effects of four silver-containing dressings on three organisms. Journal of Wound Care 2003; 12:101 – 7. Touche R. The Cost of Pressure Sores. Report to Department of Health 1993; Department of Health, London. van Rijswijk L. Full-thickness pressure ulcers: patient and wound healing characteristics. Decubitus 1993; 6:16 – 21. Versluysen M. Pressure sores in elderly patients. The epidemiology related to hip operations. The Journal of Bone and Joint Surgery 1985; 67:10 – 3. Versluysen M. How elderly patients with femoral fracture develop pressure sores in hospital. British Medical Journal 1986; 292:1311 – 3. Vowden P. Autolytic debridement. In L Teot, PE Banwell & UE Ziegler (eds) Surgery in Wounds 2004; Springer, Berlin. Watts S & Clark M. Pressure Ulcer Prevention: A Review of Policy Documents. Final Report to the Department of Health 1993; University of Surrey. Weiss DS, Kirsner R & Eaglstein WH. Electrical stimulation and wound healing. Archives of Dermatology 1990; 126:222 – 5. Whitfield MD, Kaltenthaler EC, Akehurst RL et al. How effective are prevention strategies in reducing the prevalence of pressure ulcers? Journal of Wound Care 2000; 9(6):261 – 6. Winman G & Clark MA. A randomised, stratified survey of the current use of an alternating pressure air mattress within the national health service. Journal of Tissue Viability 1997; 7:84 – 90. Witkowski JA & Parish LC. The decubitus ulcer: skin failure and destructive behavior. International Journal of Dermatology 2000; 39:894 – 6. Wright JB, Lam K, Hansen D & Burrell RE. Efficacy of topical silver against fungal burn wound pathogens. American Journal of Infection Control 1999; 27:344 – 50. Xakellis GC & Chrischilles EA. Hydrocolloid versus saline-gauze dressings in treating pressure ulcers: a cost-effectiveness analysis. Archives of Physical Medicine and Rehabilitation 1992; 73:463 – 9.

Xakellis GC & Frantz R. The cost of healing pressure ulcers across multiple health care settings. Advances in Wound Care 1996; 9:18 – 22. Xakellis GC Jr, Frantz RA, Lewis A & Harvey P. Cost-effectiveness of an intensive pressure ulcer prevention protocol in long-term care. Advances in Wound Care 1998; 11(1):22 – 9. Xia Z, Sato A, Hughes MA & Cherry GW. Stimulation of fibroblast growth in vitro by intermittent radiant warming. Wound Repair and Regeneration 2000; 8:138 – 44. Young J & Cotter D. Pressure sores: do mattresses work? Lancet 1990; 336:182 – 3. Young AR, Mesusen MT & Bowles VM. Characterisation of ES products involved in wound initiation by Lucilia cuprina larvae. International Journal for Parasitology 1996; 26:254 – 2. Ziegler UE, Dietz UA & Schmidt K. Wound-bed preparation – promotion of granulation tissue. In L Teot, PE Banwell & UE Ziegler (eds) Surgery in Wounds 2004; Springer, Berlin.

FURTHER READING Ayello EA, Mezey M & Amella EJ. Educational assessment and teaching of older clients with pressure ulcers. Clinics in Geriatric Medicine 1997; 13(3):483 – 96. Bates-Jensen BM. The pressure sore status tool a few thousand assessments later. Advances in Wound Care 1997; 10:65 – 73. Daechsel D & Conine TA. Special mattresses: effectiveness in preventing decubitus ulcers in chronic neurologic patients. Archives of Physical Medicine and Rehabilitation 1985; 66(4):246 – 8. Galpin JE, Chow AW, Bever AS et al. Sepsis associated with decubitus ulcers. The American Journal of Medicine 1976; 61:346 – 50. Gorse GJ & Messner RL. Improved pressure sore healing with hydrocolloid dressings. Archives of Dermatology 1987; 123:766 – 71. Graham A. The use of growth factors in clinical practice. Journal of Wound Care 1998; 7:464 – 466. Leigh IH & Bennett G. Pressure ulcers: prevalence, etiology, and treatment modalities. A review. American Journal of Surgery 1994; 167:25S – 30S. Pearson A, Francis K, Hodgkinson B & Curry G. Prevalence and treatment of pressure ulcers in northern New South Wales. The Australian Journal of Rural Health 2000; 8:103 – 10. Pressure ulcers: The management of pressure ulcers in primary and secondary care, NICE , 2005; www.NICE.org.uk. Sugarman M, Hawes M, Musher DM et al. Osteomyelitis beneath pressure sore. Archives of Internal Medicine 1983; 143:683 – 8.

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Perioperative and Postoperative Medical Assessment D. Gwyn Seymour University of Aberdeen, Aberdeen, UK

INTRODUCTION Over the past 25 years, almost all surgical specialities have seen a dramatic increase in admissions of elderly and very elderly patients. The numbers being referred have been over and above that which would have been expected from demographic change alone and the rate of increase has usually been faster than the rise in surgical activity seen in younger adults, particularly in regard to elective procedures. Trends for two operations having a major effect on quality of life are shown in Figures 1 and 2. It seems that old people themselves, and their lay and professional advisers, are increasingly willing to consider surgery in old age. On the other hand, the idea that there are individuals who are “too old for surgery” is still very pervasive. There is concern that rates of surgery may be suboptimal, especially for higher technology interventions such as coronary surgery (Wood and Bain, 2001), and there is also evidence that elderly patients in lower socioeconomic groups have lower rates of surgery than their contemporaries in higher socioeconomic groups (Seymour and Garthwaite, 1999). This chapter discusses the approach that needs to be taken in elderly patients in the immediate preoperative and postoperative period, concentrating on the medical aspects of assessment. However, it must not be forgotten that the fundamental aim of a preoperative assessment is the same whatever the patient’s age: there is a need to estimate whether the likely benefits of the surgical procedure in that particular individual will outweigh the likely risks. The chapter begins with a discussion of the relationship between old age and postoperative morbidity and mortality. This is followed by a brief discussion of the causes and consequences of emergency surgery in older people. Consideration is then given to the major organ systems that are of particular relevance in the medical assessment of the older surgical patient, and pointers are given to active research

areas that are likely to affect practice in the near future. The problems of surgical diagnosis, strategies for the management of individual surgical conditions, and details of the technical aspects of surgery and anesthesia are not considered here, but have been reviewed by Crosby et al. (1992) and in a recent multiauthor book by Rosenthal et al. (2001). Additionally, a policy document on “Anaesthesia and Peri-operative Care of the Elderly” has been produced by a Working Party of the Association of Anaesthetists of Great Britain and Ireland (2001). Finally, the recent (Scottish Intercollegiate Guidelines Network, 2004) Guideline on Postoperative Management in Adults, while not confined to the older surgical patient, is of considerable relevance to older people as they make up a major proportion of patients who develop problems following surgery. The SIGN (Scottish Intercollegiate Guidelines Network) Guidelines are intended for use by nonspecialists in the early postoperative period, giving advice on early detection and management of common problems, and, equally importantly, indicating when more specialist help should be sought.

AGE AND POSTOPERATIVE OUTCOME Where age is the only risk factor studied, most statistical analyses in adult patients show a positive correlation between age and the rate of adverse postoperative outcome, and a simple interpretation would be that surgery should be discouraged in extreme old age. However, there are a number of flaws in this simplistic analysis. Firstly, there is the assumption that the outcome in an elderly individual can be predicted with accuracy from the “average” outcome of patients of the same age. As shown in the following, age as a risk factor for predicting adverse outcome in individual surgical patients lacks both sensitivity and specificity. Secondly, mortality figures do not tell us about the balance of risk and


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MEDICINE IN OLD AGE Elective Cataract Surgery, Scotland 1980−2000 4000

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Figure 1 Elective Cataract Surgery, Scotland 1980 – 2000. On the basis of data supplied by the Information and Statistics Division of NHS Scotland

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Figure 2 Elective Hip Replacement Surgery, Scotland 1980 – 2000. On the basis of data supplied by the Information and Statistics Division of NHS Scotland

benefits in individual patients. For example, in extreme circumstances, such as a ruptured aortic aneurysm, the mortality rate for nonoperative therapy is nearly 100% and so a postoperative mortality rate of 25–40% might be highly acceptable. Thirdly, outcome data related to broad surgical categories of disease do not take into account the tendency for more serious pathology to occur with advancing age. For example, young adults admitted urgently with abdominal pain tend to have conditions such as uncomplicated appendicitis or nonspecific abdominal pain, where mortality rates are low. As patients get older, an “acute abdomen” often turns out to be because of a perforated viscus, carcinoma, vascular events,

or other major pathology which have a much higher rate of mortality and morbidity (de Dombal, 1991). It is also wrong to assume that a positive correlation between age and postoperative adverse outcome indicates that the adverse outcome is a direct result of the aging process. In fact, there is little evidence that age in the absence of disease is a major risk factor for postoperative morbidity and mortality. This assertion is supported by several lines of evidence. For instance, a study from the United States, which used the Medisgroups system to grade the severity of preoperative medical problems of general surgical patients aged 65 years and over, found no relationship between age

PERIOPERATIVE AND POSTOPERATIVE MEDICAL ASSESSMENT

and outcome, once the preoperative status had been taken into account (Dunlop et al., 1993). Similarly, the APACHE III (Acure Physiology and Chronic Health Evaluation) prognostic system, which has been applied widely in intensive care units, indicated that around 47% of the variability in mortality was associated with the severity of illness, 6% with a type of disease, while only 3% appeared to be attributable to age (Knaus et al., 1991). Thus, the great body of evidence suggests that the major factor in the association between age and adverse postoperative outcome comes about not as a result of aging itself, but through a secondary association with age-associated disease (Lubin, 1993; Seymour, 1999).

AGE, EMERGENCY SURGERY, AND POSTOPERATIVE OUTCOME It has been known for many years that nonelective surgery is associated with a higher rate of postoperative problems than is elective surgery. Survival curves from a study of elderly general surgical patients in North Wales (Edwards et al., 1996) have suggested that, while both age and nonelective surgery were associated with postoperative mortality, nonelective surgery had a strong association with short- and medium-term survival, while age had a major effect on longterm postoperative survival. However, the interpretation of the association between nonelective surgery and adverse outcome in older patients is complicated by the fact that there is also a positive correlation between increasing age and the tendency to be admitted nonelectively. An excellent series of reports produced in England and Wales by the National Confidential Enquiry into Perioperative Deaths (NCEPOD) have focused attention on postoperative deaths which might have been preventable. They have pointed to deaths following emergency surgery (often carried out out-of-hours by less experienced staff on medically unstable patients) as a continuing cause for concern. The reports also show that over two-thirds of postoperative deaths occur in patients aged 71 years and over. Within Scotland, the SASM (Scottish Audit of Surgical Mortality) audits all postoperative deaths and has come to similar conclusions.

CARDIAC PROBLEMS Cardiac Surgery (see Chapter 52, Cardiac Surgery in the Elderly) In patients who are undergoing cardiac operations such as coronary artery bypass grafts or valve replacement, surgery is usually carried out under elective conditions and detailed information about cardiac status is available preoperatively. Furthermore, such patients tend to be treated postoperatively in intensive care units. Under such circumstances postoperative mortality rates tend to be gratifyingly low even in

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older patients. In the previous edition of this textbook, reference was made to a survey of patients undergoing cardiac operations in Washington DC. Even at that time, a quarter of patients were aged 70 years and over and they had a 30-day mortality of 5.3%, compared with a 2.7% 30-day mortality in patients aged 69 years or under (Katz et al., 1995). Around the same time, Unsworth-White and colleagues from St George’s Hospital in London concluded that while the risks of cardiac surgery “above 70 years of age, and certainly above 80 years of age, are appreciably higher. . . they are not prohibitive” (Unsworth-White et al., 1993), and, in common with the Washington unit, about a quarter of their cardiac patients were aged 70 and over. In the last 10 years, there have been several hundred publications on cardiac surgery in old age, and in many areas, particularly North America, it is becoming almost routine. Alexander et al. (2000), from North Carolina, reviewed hospital outcome in 67 764 patients (4743 aged 80 years and over) undergoing cardiac surgery in 22 centers involved in the National Cardiovascular Network. The overall incidence of morbidity and mortality in the octogenarians was lower than that previously reported, but remained higher than the rates encountered in younger patients. However, in octogenarians without significant comorbidity, mortality rates approached those of younger patients. While these results are encouraging, the elderly individual opting for open-heart surgery needs to be aware of the risks as well as the benefits. In an editorial giving a “cardiologist’s perspective”, Sprigings (1999) points out that the reported rate of postoperative stroke in some series of octogenarians undergoing aortic valve surgery is above 10%. As the nonsurgical treatment of severe aortic stenosis is unsatisfactory, Sprigings accepts that the decision to recommend surgery in those with severe symptoms and no other medical problems is not difficult, but there remain many other elderly cardiac patients in whom there is true uncertainty as to the right course of action. In all cardiac surgery, but particularly in conditions other than aortic stenosis, there is a widespread appreciation that the quality of life and the functional capacity as well as survival need to be taken into consideration, and cardiac surgery in old age can have major impact on the first two of these factors (Jaeger et al., 1994; Walter and Mohan, 1995; Awad et al., 1995; Olsson et al., 1996).

Noncardiac Surgery The major postoperative cardiac complications are myocardial infarction (MI) and acute heart failure. The former may be difficult to diagnose in the early postoperative period as pain can be masked by anesthesia and analgesia, and surgical trauma to muscles may make interpretation of cardiac enzyme changes difficult, although newer enzyme tests such as troponin-I and troponin-T offer the potential for enhanced specificity (Surveillance for perioperative MI, 2002). Using traditional clinical criteria, postoperative MI has been estimated to occur following 1–4% of general surgical operations in the over-65s and cardiac failure has been reported

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in 4–10%, with the mortality rate associated with postoperative myocardial infarction being around 50% (Seymour et al., 1992). The rate of postoperative cardiac complications in patients aged 75 and over is 2–3 times that of those aged 65–74 (Seymour et al., 1992). Depending on the definitions and diagnostic tests used, much higher estimates of perioperative MI rates have been reported. Thus, Badner et al. (1998) in a group of 323 patients aged 50 or over undergoing noncardiac surgery reported a 5.3% incidence of postoperative MI when the criteria were based on autopsy data, new Q waves on ECG, and creatine kinase (CK-2) levels. However, when cardiac troponin-T levels greater than 0.2 mcg l−1 were incorporated into the diagnostic criteria, the estimated rate of perioperative MI rose to 11.2% and further relaxation of ECG criteria led to an estimate of 20.7%. In day-to-day medical practice, the main need for preoperative cardiac assessment arises in the elderly patient who is undergoing noncardiac surgery. Thus, Mangano (1990) estimated that, for each patient undergoing cardiac surgery in the United States, there are up to 10 other “cardiac” patients (i.e. patients with known heart disease or two or more major cardiac risk factors) undergoing noncardiac surgery. Mangano estimates that a third of all patients aged 65 and over fall into this “cardiac” category, and a proportion of the remaining two-thirds will have occult ischemic heart disease which may reveal itself only during the perioperative period. The “cardiac assessment of the noncardiac surgical patient” has accordingly become a major focus of research in recent years. The earliest reports in this field identified a number of individual risk factors which were correlated with an increase in adverse postoperative cardiac outcomes. These included previous myocardial infarction, congestive heart failure, angina, age, hypertension, diabetes, arrhythmias, peripheral vascular disease, valvular heart disease, smoking, and previous cardiac surgery (Badner et al., 1998). Later, researchers attempted to construct multifactorial indices of cardiac risk from these individual risk factors (Goldman et al., 1977; Detsky et al., 1986), but, as recognized by their originators, there are limitations in applying these indices to individual patients (Mangano & Goldman, 1995; Mangano, 1995). A major milestone in this field was the appearance of the 1996 guidelines on perioperative cardiovascular evaluation for noncardiac surgery, issued jointly by the American College of Cardiology and the American Heart Association (AAC/AHA) (Eagle et al., 1996). These were subsequently updated in 2002 taking account of 400 or so references that had appeared between 1995 and 2000 (Eagle et al., 2002). The first point to make of both of the AAC/AHA reports is that they found relatively few randomized control trials (RCTs) on which to base their recommendations. Part of the problem is that most of the studies quantifying postoperative risks are necessarily of an observational or cohort design, although RCTs may be feasible at a later stage. Another problem with RCT studies in the field of perioperative risk reduction is that the interventions may be complex and consist of changes in practice and organization rather than simple drug interventions. However, as in most cases the field of cardiology lends itself to drug

interventions, an important development between the 1996 and 2002 AAC/AHA reports was the appearance of trials showing short- and long-term cardiac benefits of β-blockade in surgical patients (see pages 32–35 of the 2002 report), with the two publications by Poldermans et al. (1999) and Boersma et al. (2001) being particularly influential. Other important additions to be found in the 2002 AAC/AHA update are discussions of renal insufficiency, better quantification of the predictive role of preoperative functional capacity, more detailed guidance on preoperative cardiac assessment, and an assessment of the role of percutaneous coronary intervention. The fundamental three-part strategy of risk prediction used in the 1996 ACC/AHA report remained unchanged in the 2002 version. Indeed, a similar strategy is likely to be a suitable model for use in risk prediction outside the cardiovascular field. The three separate areas of risk considered are: (a) major clinical predictors of risk (b) functional capacity (c) surgery-specific risk. Within category (a), “major” clinical predictors are identified as unstable coronary syndromes, decompensated heart failure, congestive heart failure, significant arrhythmias, and severe valvular disease. In the “intermediate” clinical predictor group are found mild angina, previous myocardial infarction, compensated or stable congestive cardiac failure, diabetes, and renal insufficiency. The “minor” clinical predictors are advanced age, abnormal ECG, non-sinus rhythm, history of stroke, and uncontrolled hypertension. In respect to category (b), specialists in geriatric medicine will readily identify with the concept that age by itself in the absence of disease is not a major predictor of an adverse outcome. Similarly, they will concur with the importance of functional capacity in determining the outcome. The 1996 ACC/AHA report introduced the concept of defining functional capacity in terms of metabolic equivalents (MET levels) and this approach deserves to be more widely known both in medicine and surgery. Perioperative cardiac problems are much increased when a patient is unable to meet a four MET level of activity: this is roughly equivalent to climbing a flight of stairs, walking up a hill or walking on level ground at a speed of 4 mph or 6.4 kmph. The 2002 report has continued to champion the MET concept, and was able to incorporate a publication by Reilly et al. (1999) relating selfreported exercise tolerance to the risk of serious perioperative complications. Category (c), the third element of the ACC/AHA risk assessment, classifies surgical procedures into high, intermediate and low risk. Examples of “high” risk (cardiac risk often >5%) include emergency major operations particularly in the elderly, aortic and other major vascular surgery, peripheral vascular surgery, and procedures likely to be associated with large fluid shifts or blood loss. “Intermediate” (cardiac risk generally 90 years

2 >95 years 0 Age Figure 1 Mortality associated with surgery and anesthesia

Table 1 Mortality associated with surgery and anesthesia

Age (years)

Mortality rate

General population 60 – 69 70 – 79 >80 >90 >95

1.2% (Pedersen et al., 1990) 2.2% (Pedersen et al., 1990) 2.9% (Pedersen et al., 1990) 5.8 – 6.2% (Djokovic and Hedley-Whyte, 1979) 8.4% (Hosking et al., 1989) 13% (Djokovic and Hedley-Whyte, 1979)

Table 2 ASA grading of physical status (American Society of Anesthesiologists 1963)

Grade I II III IV V

Normal healthy patient Patient with mild systemic disease Patient with severe systemic disease Patient with severe systemic disease which presents a constant threat to life Moribund patient not expected to survive without operation

Source: Reproduced by permission of American Society of Anesthesiologists, Inc.

CARDIOVASCULAR MORBIDITY ASSOCIATED WITH SURGERY AND ANESTHESIA The age-related changes that occur within the cardiovascular system are responsible for the higher incidence of perioperative myocardial infarction, cardiac failure, and arrhythmias in this age-group. There is a reduction in the sensitivity of the parasympathetic system to changes in baroreceptor stretch, blood pressure, and heart rate. The sensitivity of the sympathetic system also declines. This diminishes the body’s ability to compensate for sudden change. There is a progressive stiffening of both the arterial and venous vessels, again reducing capacity for vasoconstriction or dilatation in the face of loss of intravascular volume. Stiffening of the myocardium occurs also, affecting diastolic relaxation and filling pressures. This may lead onto diastolic dysfunction with an increase in left atrial pressure and pulmonary congestion. Superimposed on physiological change, anesthetic

agents cause peripheral vasodilatation, with a decrease in systemic vascular resistance. As many elderly patients have a contracted intravascular volume secondary to diuretic therapy, this can mean a sudden fall in tissue perfusion pressure. Anesthetic agents are myocardial depressants, particularly in higher doses, and have the capacity to adversely affect cardiac output. Preoperative assessment is focused on identifying those risk factors that have been identified in studies as being predictive of adverse postoperative outcome (Table 3) (Goldman et al., 1977; Eagle et al., 1996). Following the initial interview, the patient’s baseline level of function is assessed. If there are no significant predictors in the history, evaluation may be safely confined to detailed physical examination and a 12-lead electrocardiogram (ECG). ECG will identify patients with left ventricular hypertrophy or ST segment depression. These patients may require further investigation with an exercise ECG, depending on the surgical procedure planned. Patients who cannot exercise because of claudication or arthritis may be assessed with a dobutamine stress echocardiograph. Coronary angiography is reserved for patients with angina at rest or unstable angina. On the basis of the results, preoperative revascularization may be warranted. Clinically detected cardiac murmurs and features of congestive cardiac failure are further evaluated using echocardiography. Preoperative valve replacement is indicated for patients with severe disease. Less severe valve lesions or those following valve surgery require prophylactic antibiotic administration. Arrhythmia detected at rest or during exercise should be treated if possible before surgery. If sinus rhythm is not achieved, rate control with anticoagulation is acceptable. Type II or type III heart block requires insertion of a temporary or permanent pacemaker. Using the information gained from the history, examination, and further investigations, the anesthetic management is aimed at maximizing myocardial perfusion through maintenance of tissue perfusion pressure and oxygenation throughout the intraoperative and postoperative period. Postoperative admission to the HDU or intensive care unit should be anticipated for elderly patients with significant cardiac symptoms, especially those undergoing abdominal or thoracic procedures. Invasive monitoring of blood pressure and central venous pressure is commenced early and continued throughout the perioperative period. Regional anesthesia provides superior analgesia postoperatively and may reduce the Table 3 Predictive factors for postoperative cardiovascular morbidity

Myocardial infarction within previous 3 months Decompensated congestive cardiac failure Arrhythmia (except premature atrial contractions) Unstable angina or angina at rest (New York Heart Association Grade IV) Uncontrolled hypertension Severe valvular disease Poor general medical condition Poor exercise capacity Diabetes mellitus History of stroke

ANESTHESIA IN OLDER PEOPLE

incidence of adverse cardiac events in certain patients, such as vascular and abdominal surgery. The institution of perioperative β-receptor blockade has been shown to reduce the risk of myocardial ischemia and is generally well tolerated by older patients (Poldermans et al., 1999). β-blockade is thought to increase the time spent in diastole, increasing filling, and increasing time for coronary artery perfusion. A combination of intravenous fluid infusion and vasopressor agents are used to maintain mean arterial blood pressure within 20% of the patient’s baseline, awake blood pressure. Episodes of hypotension must be managed promptly and oxygenation increased during the period of reduced flow. Postoperatively, the patient requires a similar level of care and monitoring. Supplemental oxygen therapy, optimum analgesia, rate control, and judicious blood transfusion will assist in maximizing myocardial oxygen supply. Particular attention should focus on the first 3 days, when myocardial infarction is most likely to occur. Many episodes of ischemia in this age-group may be silent and may not be associated with the development of Q waves on the ECG. A low index of suspicion, the presence of new ST changes, in combination with serial estimations of serum troponin T and I concentrations will assist in early diagnosis.

RESPIRATORY MORBIDITY ASSOCIATED WITH SURGERY AND ANESTHESIA The physiological changes associated with aging predispose the older patient to respiratory complications after surgery and anesthesia. A mixed obstructive/restrictive pattern develops from the decrease in total lung capacity, elastic recoil of the thorax, pulmonary parenchymal compliance, and vital capacity. Decreased compliance and muscle power mean a fall in forced expiration and reduced capacity to cough and clear secretions. Closing capacity, dead space, and residual volume increase so that the lungs of the supine patient become atelectatic. These changes do not occur in a uniform manner throughout the lungs, resulting in areas of good ventilation in combination with underventilated segments. A decrease in pulmonary blood flow combined with progressive loss of alveolar surface area diminishes the resting arterial oxygen tension from 95 ± 2 mmHg at age 20 to 73 ± 5 mmHg at 75 years. Occurring in tandem, there is an age-associated loss of central nervous system sensitivity to changes in arterial oxygen and carbon dioxide tensions. The physiological and structural changes cause an increase in ventilation/perfusion mismatch. This is exacerbated by the effect of anesthesia, in particular, general anesthesia. In addition, general anesthesia reduces reflex pulmonary hypoxic vasoconstriction. Regional anesthesia impacts less on the respiratory system as it does not necessitate intubation of the trachea, avoids the effect of intermittent positive pressure ventilation, and provides highly effective postoperative pain relief. Preoperative preparation of the patient involves a detailed history and examination in combination with functional

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assessment. Taking the patient for a walk, including two flights of stairs, during the preoperative visit provides a useful measure of the patient’s baseline physiological status. Smoking cessation for at least 8 weeks is to be recommended (Smetana, 1999). Chest physiotherapy in the 24 hours preceding surgery provides some physical benefit and facilitates instruction for deep breathing and coughing postoperatively. Patients with active pulmonary infection require more postponement of surgery and more aggressive medical treatment. The anesthetic technique should employ regional analgesia/anesthesia where possible. Short-agents such as propofol, remifentanil, sevoflurane, and atracurium are most suitable for general anesthesia. Muscle relaxants should always be reversed at the end of the procedure. Invasive monitoring may be used to advantage to guide fluid therapy as the older patient will tolerate rapid expansion of intravascular and extravascular volumes poorly due to the changes in pulmonary compliance, perfusion, and renal function. This may be continued into the postoperative period in the context of intensive care or HDU admission. Postoperatively, oxygen supplementation and chest physiotherapy should be continued for a minimum of 5 days as this is the greatest period of risk of nocturnal hypoxia and the onset of pneumonia.

CENTRAL NERVOUS SYSTEM MORBIDITY ASSOCIATED WITH SURGERY AND ANESTHESIA Elderly patients are at risk of serious central nervous system morbidity and mortality due to neuronal loss associated with aging, the presence of coincident pathology such as cerebrovascular atherosclerosis, and a reduction in neurotransmitter concentrations. This makes them less able to adapt successfully to the challenges imposed by surgery and anesthesia. The morbidity associated with anesthesia and surgery in the older patient most commonly takes the form of postoperative confusion (POC) or stroke.

Postoperative Confusion The risk factors for the development of POC are listed in Table 4. POC is associated with an increased rate of morbidity, delayed return to baseline function, and delayed discharge home from hospital. To date, there is little evidence for an overall strategy to reduce the incidence in surgical patients, but some general recommendations may be made. Consideration should be given to admitting the patient as a daycase, as elderly patients become less disorientated when in familiar surroundings with familiar carers. The preoperative assessment should highlight particular issues that could be modified or preempted, such as alcohol withdrawal depression. Hearing aids and spectacles should be left with the patient until induction of anesthesia and returned to the patient a soon as possible. Medications listed

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Table 4 Risk factors for the development of postoperative confusion

Table 5 Risk factors for postoperative stroke in the elderly

Preoperative factors Older age Depression/Anxiety Dementia Preoperative sensory deficit in hearing or vision Alcohol withdrawal/Sedative withdrawal Preoperative use of multiple medications

Preoperative factors:

Preexisting cerebrovascular disease Ischemic cardiac disease Atherosclerosis Carotid occlusion Preoperative vascular disease Hypertension Diabetes mellitus Physical inactivity

Intraoperative and postoperative factors:

Hemodynamic instability

Intraoperative factors Hypoxia Hypocarbia Hypotension

Hypoxemia

Postoperative factors Inadequate analgesia

Source: From Jin and Chung (2001) Copyright The Board of Management and Trustees of the British Journal of Anaesthesia. Reproduced by permission of Oxford University Press/British Journal of Anaesthesia.

Perioperative factors Sepsis Surgical procedure Cardiac surgery Orthopedic surgery especially joint replacement Perioperative medications Anticholinergics: Atropine, scopolamine. Glycopyrrolate to a lesser extent Barbiturates Benzodiazepines Antihistamines

in Table 3 should be avoided. Intraoperative monitoring of blood pressure, ventilation, and oxygenation requires a meticulous approach. Regional analgesic techniques should be employed where possible to reduce the use of sedating narcotics in the postoperative period. There is no difference in the incidence of POC between the intraoperative use of general anesthesia and spinal or epidural anesthesia (Chung et al., 1997). Postoperatively, if the patient is confused, they should be nursed in a quiet, dark room. Organic causes should be treated promptly. Haloperidol 0.25–2 mg orally at night may be useful. Low doses of diazepam or chlorpromazine may be used as adjuncts if the patient does not respond to simple measures. Physical restraints usually serve to antagonize the patient further and should not be used. Referral to the occupational therapy and social work departments will be necessary to assist with cognitive assessment, follow-up, and discharge planning. Long-term cognitive impairment has been documented by the International Study of Postoperative Cognitive Dysfunction (ISPOCD) (Moller et al., 1998). Ten per cent of patients were found to have cognitive deficits 3 months after surgery, with age as the only significant predictive factor.

Postoperative Stroke There have been few studies to determine the incidence of stroke occurring after surgery and anesthesia. The incidence from small retrospective studies would seem to suggest that the incidence is low –; in the order of 0.25% when a patient is undergoing noncarotid vascular surgery (Larsen et al., 1988; Sultana et al., 1997). Stroke most commonly occurs between the 5th and 26th day postoperatively. Risk factors for postoperative stroke are in Table 5 (Jin and Chung, 2001).

Patients with poorly controlled preoperative hypertension should have their surgery postponed to allow time to institute adequate pharmacological control. Patients with clinically detected carotid bruits should have further investigations and, if necessary, referral to a vascular surgeon before their intended procedure. The severity of the neurological deficit and the potential for rehabilitation after perioperative stroke varies enormously, and therapy must be directed at the individual patient.

RENAL MORBIDITY ASSOCIATED WITH SURGERY AND ANESTHESIA Renal function is known to deteriorate with age, and, therefore, greater care will be needed to maintain renal function perioperatively. Decline in numbers of the functional unit, the glomerulus with age, means that glomerular filtration rate falls from 125 ml minute−1 in the young adult to 80 ml minute−1 in the older individual. As this fall in glomerular filtration rate (GFR) is usually accompanied by a decrease in muscle mass, there is rarely an increase in serum creatinine. During the perioperative period, the kidney will be exposed to many challenges: rapid fluid shifts in the intravascular and extravascular compartments, numerous medications administered simultaneously, electrolyte changes, and acid–base abnormalities (Epstein, 1996). In the face of these challenges, the underlying loss of function becomes exposed, leading to the development of postoperative renal failure. Atherosclerosis of the vascular supply of the kidney and coincident disease due to diabetes mellitus or hypertension further complicates the situation. In addition, the elderly patient tends to be taking a greater number of prescribed medications that have the potential to interact with anesthetic agents and conditions arising during surgery, such as hypotension. Anesthetic drugs have little direct effect on renal function. Anesthetic agents reduce cardiac output with subsequent renal vasoconstriction, which may cause a fall in renal perfusion. Enflurane and isoflurane produce fluoride when metabolized, which may cause renal injury if the anesthesia is very prolonged. Sevoflurane produces a substance known as compound A at low fresh gas flows, which is nephrotoxic


if not removed by effective scavenging of waste anesthetic gases (Conzen et al., 2002). It is unusual for either of these chemical entities to present a problem in the clinical context. Management of the patient starts with a high index of suspicion. Following a detailed preoperative review, fluid and electrolyte status should be closely monitored in the pre-, intra- and postoperative periods. Nephrotoxic medications should be stopped preoperatively if possible. Medications that deplete the intravascular volume and lead to electrolyte loss should be reviewed in the context of the patient’s state of hydration and the planned surgical procedure. For example, a patient taking a loop diuretic scheduled for elective inguinal hernia repair should probably continue taking the medication, while a patient with low urinary output scheduled for emergency laparotomy for bowel obstruction should have the loop diuretic reviewed by the anesthesiologist. The dosing intervals of medications excreted by the kidney such as aminoglycosides may need to change and doses titrated to plasma levels. The development of perioperative renal failure increases the requirement for renal replacement, intensive care admission, and mortality. Acute tubular necrosis accounts for the majority of cases of renal failure. Prevention is based on optimizing the circulation preoperatively, close hemodynamic monitoring perioperatively, and maintenance of adequate perfusion pressures, including the judicious use of inotropes. Intraoperative low-dose dopamine infusion promoting renal vasodilatation and the use of mannitol as a free radical scavenger have been advocated (Kellum and Decker, 2001; Lameire et al., 2003).

PERIOPERATIVE HYPOTHERMIA Elderly patients are at a greater risk of developing perioperative hypothermia than younger patients owing to a number of factors. They have a reduced muscle mass, with a lower basal metabolic rate. This is often accompanied by reduced fat stores secondary to malnutrition. The shivering mechanism occurs later in response to cooling. In young patients, shivering begins peripherally at 1 ◦ C less the normal core temperature of 36.5 ◦ C. As patients age, this may not occur until their core temperature has fallen by 2 ◦ C. Shivering increases cellular oxygen demands by 20–30%, increasing myocardial oxygen consumption, which may be deleterious for the older patient with cardiovascular pathology. Less vasoconstriction occurs in the older patient for a given fall in temperature, meaning that more heat is lost to the environment. Surgery and anesthesia have a detrimental effect on thermoregulation. Anesthetic agents cause peripheral vasodilatation with abolition of the shivering mechanism so that patients lose the ability to compensate for cooling. The opening of major cavities such as the abdomen and thorax increases the amount of heat lost to the environment. The effect of perioperative hypothermia are listed in Table 6. Prevention of hypothermia is more efficient and cost effective than warming the patient postoperatively. Patients should

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Table 6 The effect of perioperative hypothermia

• • • • • • • • • • •

Increased cardiac morbidity Increased incidence of cardiac arrhythmias Altered platelet function Increased blood loss Increased blood viscosity – combined with vasoconstriction may cause higher incidence of deep venous thrombosis Shift of oxygen dissociation curve to left with less oxygen released by hemoglobin to the tissues Inhalation of cold gases causes reduction in protective reflexes in respiratory tract through effects on cilia motility Increased incidence of postoperative wound infection Increased incidence of postoperative decubitus ulcers Decreased drug metabolism, resulting in longer recovery times Prolonged hospitalization

be kept in a warm room with blankets during their admission to the operating department. Induction of anesthesia should take place in a similar environment. Anesthetic gases should be warmed and humidified. Intravenous fluids should be warmed. Sterile preparation of the operative site should take place using warmed sterile solutions. A warm ambient temperature of the operating room should be maintained until the patient is draped. Forced air warming blankets may be placed under the drapes. At the end of the procedure, warm blankets should be placed over the patient during their transfer to the postanesthetic care unit.

PREOPERATIVE ASSESSMENT When carrying out a preoperative assessment of the older patient, it is important to place the function of the cardiovascular and respiratory systems into the context of the whole patient. It must be remembered that patients may have mild cognitive impairment affecting their memory, or they may be embarrassed and unwilling to admit disability. Answers may be slow as information is recalled. The history may be extensive and complicated and so sufficient time should be allotted to the interview. The clinical presentation of disease may differ greatly from that in younger patients. Conditions such as hyper and hypothyroidism are notoriously difficult to diagnose in the older patient. It is best if the assessment takes place several days before the planned surgery to allow enough time for further investigations if necessary. Attendance at a preanesthetic outpatient clinic will mean the patient can meet all of the multidisciplinary team members together, providing enhanced perioperative and discharge planning. Following the interview, the anesthesiologist must review the patient’s medical chart and carry out a comprehensive physical examination. Keeping in mind the demands and implications of each surgical procedure, the anesthetic plan will then be made and discussed with the patient. The anesthesiologist should expect much variation between each elderly patient. Routine investigations based on age alone are not warranted and should be directed by the clinical evaluation (Fleisher, 2001).

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Particular issues to be addressed over the course of the assessment are: 1. The planned surgery. The surgical procedures most frequently carried out in the elderly are listed in Table 7. 2. The cognitive status of the patient. Does the patient answer questions in a coherent manner? Will they be suitable for ambulatory admission or a regional anesthetic technique? 3. The baseline function of the patient. Can they dress themselves; do the shopping, walk up a short flight of stairs? 4. Does the patient have symptoms suggestive of cardiac disease? Remember, patients may not report symptoms because of reduced mobility. 5. Does the patient have signs or symptoms of respiratory disease? Shortness of breath at rest is an important prognostic sign. 6. What are the patient’s current medications and their compliance with them? 7. Previous anesthetic experiences. 8. Vital signs on examination especially blood pressure, pulse rate, and rhythm. Meticulous attention to detail when planning the perioperative care of the patient can reduce the incidence of minor morbidity. Reduction of minor incidents may prevent escalation into life-threatening events. Table 7 Pharmacological analgesic options

Agent

Advantages

Side effects

Acetaminophen (Paracetamol)

Oral and rectal route Opioid sparing

Hepatotoxicity, do not exceed 4 g/24 hours

NSAID

Oral, rectal, and parenteral route Opioid sparing

Gastric irritation Renal toxicity Antiplatelet effects

COX-II Inhibitors

Oral and parenteral route Opioid sparing Less severe gastric irritation and renal toxicity than NSAIDs

Gastric irritation Renal toxicity

Opioids

Oral, rectal, parenteral, spinal, epidural route Profound analgesia available as short-acting and long-acting preparations

Sedation/Confusion/ Dysphoria Respiratory depression Metabolites may be toxic, for example, normeperidine Nausea/Vomiting Ileus Pruritus Urinary retention when administered into CSF/epidural space Bradycardia Hypotension especially if patient is dehydrated

NSAID, Non-steroidal Anti-Inflammatory; COX-II, Cyclo-oxygenase-II.

PAIN ASSESSMENT AND MANAGEMENT IN THE ELDERLY Pain Assessment Effective pain management in the elderly is subject to all of the usual barriers to pain management, such as fear of addiction. With the older surgical patient, there are additional problems to be overcome. The assessment of pain forms the basis of successful pain relief. It is necessary to obtain a baseline measure of pain before instituting pharmacological measures to reduce that pain. Assessment allows the treatment to be evaluated and the need for further pain relief established (Katz and Melzack, 1999). The needs of the older patient in assessing pain have not yet been fully met (Cook et al., 1999). Conventional pain scores such as the visual analogue score (VAS) have limited application in this age-group due to the prevalence of mild/moderate cognitive impairment, hearing difficulties, and poor eyesight. The older patient may differ significantly in their cultural interpretation of pain and pain relief (Severn and Dodds, 1997). Reporting of pain may be altered in this age-group because of the misperception among older patients that it is necessary for pain to follow surgery and that staff are doing all that they can to relieve it. They may also fear reporting that they have pain in case this means something has gone wrong, or that they may be seen as being “difficult”. Health-care staff may mistake patients who do not report pain for patients who do not have pain. Attempts have been made to validate other scores such as the Faces Pain Score in older adults, but at present, there is no single system suitable for all elderly patients (Wong and Baker, 1988; Herr et al., 1998). The accuracy of pain assessments may be increased by making the assessment more frequently, particularly following the administration of each analgesic dose. Another hurdle to achieving adequate pain relief is the assumption that elderly patients do not experience pain to the same extent as younger patients. There is very little evidence for this misperception (Oberle et al., 1990).

The Effect of Pain in Older Surgical Patients The consequences of pain in surgical patients include (Ballantyne et al., 1998; Rodgers et al., 2000): • sympathetic hyperactivity, producing tachycardia, myocardial ischemia, hypertension via the adrenal hormonal axis; • decreased pulmonary function with atelectasis and hypoxemia, as a result of poor cough and reduced mobility; • increased risk of deep venous thrombosis (DVT), as a result of reduced mobility; • potential development of a chronic pain state through sensitization of pain pathways;


• postoperative delirium. This is particularly the case in patients who have predisposing risk factors for delirium such as visual, hearing, or cognitive deficit; • increased length of stay. Adequate pain relief in all patients may reduce postoperative morbidity (Ballantyne et al., 1998). The preoperative assessment visit should be used as an opportunity to discuss with the patient the postoperative analgesia pertinent for their procedure, particularly when regional analgesic techniques are planned. Education and reassurance may be provided to the patient and their family, diminishing their concerns regarding addiction and side effects. Instruction may be given on the use of equipment for patient controlled analgesia (PCA), which may be reinforced later by a visit from the acute pain team.

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sympatholysis, attenuating the stress response and improving myocardial oxygenation. Regional analgesia continued into the postoperative phase provides more profound analgesia with lower doses of narcotics than intravenous opioid administration, thus minimizing the potential for sedation, respiratory depression, and ileus. It decreases the incidence of respiratory complications in patients undergoing abdominal and thoracic procedures and decreases admission rates to the intensive care unit and overall length of stay (Rodgers et al., 2000). Regional analgesia decreases the rate of postoperative deep venous thrombosis due to relative vasodilatation of the venous plexus in the lower limbs and by decreasing the time to mobilization. Continuous epidural analgesia postoperatively can cause hypotension and lower extremity motor and sensory deficits. For this reason, nursing and medical staff require training on the recognition and management of potential complications of regional analgesic techniques.

Pharmacological Management of Pain A continuous, multimodal approach to postoperative pain management is indicated for elderly patients because it minimizes potential adverse effects from high doses of any single agent. Changes in drug absorption, distribution, metabolism, and elimination may affect the eventual plasma level and effect of a given analgesic drug. Increased gastric pH and decreased gastric motility reduce or delay drug absorption. The volume of distribution of drugs changes because of an increase in total body fat and a decrease in body water. Water-soluble opiates such as morphine have a smaller volume of distribution and therefore can produce higher plasma levels. Lipid-soluble drugs, such as fentanyl, have a larger volume of distribution and can produce a prolonged duration of action in older patients (Dodds, 1995). Reduced serum albumin concentrations and other plasma proteins from chronic illness or poor nutrition will reduce drug distribution, increasing the potential for adverse affects. Concurrent medical conditions, for example, renal impairment, may reduce excretion of the drug from the body. Liver disease may reduce drug metabolism and lead to accumulation of active drug and active drug metabolites. Reduced muscle mass leads to unpredictable absorption of drugs administered by the intramuscular route (Dodds, 1995). The pharmacological analgesic options available are listed in Table 7. The key to effective pain management in patients of all ages is regular and appropriate assessment, combined with regular administration of multimodal analgesic agents.

The Role of Regional Analgesia The intraoperative use of regional anesthetic techniques either in combination with general anesthesia or alone has been shown to reduce short- and long-term cardiac and mortality in the elderly following total hip arthroplasty, vascular surgery, and abdominal surgery. It is thought to do this by

The Role of Patient Controlled Analgesia (PCA) in the Elderly Intravenous PCA has been shown to be safe in elderly patients (Egbert et al., 1990), but health-care staff frequently hesitate to prescribe it because of the concern that it may cause confusion or inadequate analgesia in the older patient. Older patients should not be automatically excluded from using PCA, either via the intravenous or the epidural route. The cognitive state and physical abilities of each patient should be assessed on an individual basis.

ETHICAL CONSIDERATIONS FOR PERIOPERATIVE CARE OF THE ELDERLY Decisions regarding surgery and anesthesia become more complicated in the older patient particularly when their ability to make a competent decision is compromised through cognitive impairment or illness. Paternalism on the part of the physician does not respect the patient’s fundamental right to autonomy. Patients must be provided with the information they require, in a suitable format, to empower them with decision-making capacity. Informed consent leading to the choice of a treatment option or informed refusal of a treatment option must be respected by all professionals. If there is concern regarding the older patient’s ability to assimilate information and decide, then further advice should be taken before deeming the patient “incompetent”. Formal assessment of mental state may be necessary. If legal incompetence is concluded, decisions about the cessation or instigation of treatment may be taken by a proxy. This is often a family member. However, it may not be valid to assume that the proxy knows the wishes of a patient as they may never have discussed issues such as withdrawal of treatment. The proxy may be appointed on a formal basis through enduring power of attorney, or the patient may

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make their wishes known through an advanced directive. The legal standing of advanced directives varies across legal jurisdictions. If there is no proxy available, doctors may make decisions about care “in the best interests” of the patient. Efforts should be made early in the patient’s admission to anticipate important decisions about medical care so that the patient may be involved as much as possible and proxy decision making is avoided. The patient’s current and potential quality of life may impact on the decision to proceed to surgery or not. Previously made decisions concerning resuscitation, often referred to as do-not-resuscitate (DNR) orders, should be revised before a patient is admitted to the operating department for surgery. The outcome of cardiac arrest differs greatly from that on the general ward, with 60% of patients surviving to hospital discharge compared with 7–17% of patients who sustain cardiopulmonary arrest on the ward (Martin et al., 1991). This because cardiac arrest in the operating theater is monitored and witnessed, whereas a patient may be arrested on the ward for a variable length of time before resuscitation efforts begin. In addition, cardiac arrest in the operating theater is often due to reversible causes such as arrhythmia, medication administration or hypovolemia, which when promptly managed, restore adequate circulation to the patient. In the light of this, a patient with a terminal process such as pancreatic cancer, with a DNR order on the ward, may have this decision reversed during the period he is in the operating theater for palliative ileostomy, if that is what the patient wishes following informed consent.

STRATEGY TO REDUCE POSTOPERATIVE MORBIDITY AND MORTALITY IN THE ELDERLY Reduction in anesthesia- and surgery-related morbidity and mortality involves a strategy that encompasses both individual organ systems and a wider view of the perioperative process (Table 8).

Preoperative Nutritional Supplementation Up to 40% of older patients admitted to hospital are malnourished (McWhirter and Pennington, 1994). Elderly patients with malnutrition are poor candidates for surgery and anesthesia, as it places them at particular risk from hypothermia, decubitus ulcers, drug overdose, local and systemic infection, anemia, and wound breakdown. The most common form of malnutrition in this age-group is proteincalorie malnutrition (Bonjour et al., 1996). Low protein intake is associated with low intakes of calcium and vitamin D, both of which are necessary in the formation of callus after fracture. Loss of muscle secondary to malnutrition increases fatigability, decreases strength, and reduces the ability to maintain adequate ventilation. The evidence from recent studies, including a Cochrane review, suggests that nutritional supplementation should be confined to those patients who are malnourished, in order to

Table 8 Summary of the anesthetic management of elderly patients

Preoperative assessment for identifying high-risk patients Careful history Physical examination Twelve-lead ECG Functional status assessment Nutrition assessment Preoperative preparation Effective control of coexisting disease Stopped smoking for 8 weeks Training in cough and lung expansion techniques Chest physiotherapy for elderly at risk of pulmonary complications Correction of malnutrition Routine precautions for major surgery Temperature monitor and control Ripple mattress DVT prophylaxis Intra-arterial pressure monitoring Hemodynamic stability Combination of anesthetic and vasopressor, β-blockers and vasodilatation Avoid fluid overload Quick recovery from anesthesia Use short-acting anesthetic agents Combine epidural anesthesia with GA for major abdominal and thoracic surgery Antagonize neuromuscular blocking drugs Postoperative period Prevent hypoxemia: supplemental oxygen, reversal of neuromuscular drugs Prevent hypothermia: keep warm perioperatively Effective postoperative pain control: regular multimodal analgesia Source: From Jin and Chung (2001) Copyright The Board of Management and Trustees of the British Journal of Anaesthesia. Reproduced by permission of Oxford University Press/British Journal of Anaesthesia.

achieve an acceptable risk-benefit ratio, where side effects to the patient are balanced against a demonstrable clinical effect (Avenell and Handoll, 2000). The evidence to date suggests that simple oral supplements are the optimum method of supplementation as oral supplementation is more cost effective, more tolerable, and psychologically more acceptable to patients than nasogastric or parenteral nutrition. It has not been extensively studied however. Simple qualitative assessment of nutritional status on admission to hospital may be carried out as part of the routine nursing assessment (Allison, 1995). Because of the prevalence of poor nutrition in older patients presenting for surgery, prompt preoperative referral to a dietician of all patients who are deemed malnourished on nursing assessment should take place. This will facilitate early institution of simple oral supplementation in the postoperative phase, with nasogastric supplementation in patients who are severely malnourished. The emphasis should be on restoring function and decreasing perioperative morbidity rather than rapid weight gain.

Prevention of Perioperative Decubitus Ulcers The older surgical patient presents a unique challenge to the perioperative care team in the prevention of pressure ulcers. It is suggested that 25% of pressure ulcers are acquired


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intraoperatively (Aronovitch, 1999). For many patients, pressure ulcers mean increased pain, longer hospital stays, and reduced quality of life. A pressure ulcer can be defined as an area of localized damage to the skin and underlying tissue, caused by a disruption in the blood supply, preventing oxygen and vital nutrients from reaching the cells (EPUAP, 1998). Schultz et al. (1999) suggested that a pressure sore beginning in the operating theater develops initially in muscle and the subcutaneous tissues before progressing outwards to the dermis and epidermis. This causes an erythematous area, which may be mistaken for a burn. This may go on to become an established pressure sore. Pressure sores occurring in surgical patients are often not attributed to their time spent in theater, as the initial damage may not be apparent until several hours or days have passed (Vermillion, 1990). The development of a pressure ulcer is considered to be largely preventable with the implementation of an effective preventive strategy (EPUAP, 1998), and the occurrence of pressure ulcers has been used as a proxy measurement of quality care. Anesthetized patients are subjected to prolonged pressure on dependent body parts as neither the position or duration of surgery can be altered. Duration of surgery is a major risk factor in pressure ulcer formation, in conjunction with the patient’s level of tissue tolerance and the support surface. Other risk factors for pressure ulcer formation have been well established (Table 9). A constellation of these features is frequently found in the older patient presenting for surgery. On the basis of the literature to date, prevention of decubitus ulcers in the perioperative period should concentrate on the following points:

• early assessment of risk factors, combined with full history and clinical examination; • meticulous attention during manual handling, particularly after the patient has been anesthetized; • caution during positioning for surgery; • specialized table mattresses such as alternating air devices or gel overlays should be used for patients at particular risk; • maintain normothermia; • maintain diastolic blood pressure above 35 mmHg; • low-dose local anesthetic infusions for regional analgesic techniques; • frequent reevaluation.

Table 9 Risk factors for the development of perioperative decubitus ulcers

The appropriateness of the surgery may need to be reviewed in older patients who, because of their preoperative baseline, are at particular risk of a poor outcome. Unnecessary surgery that exposes the patient to a high risk/low benefit ratio should not be undertaken without expert opinion and full informed consent from the patient. If possible, a less invasive surgical approach may be utilized, for example, thoracoscopic evacuation of hemothorax or laparoscopic-assisted colonic resection. These techniques result in less pain, a quicker recovery, and a shorter hospital stay.

Extrinsic Pressure Shear Friction Moisture Intrinsic Age (>40 years) Nutritional status Body mass index Comorbidity Core temperature Low diastolic pressure Low serum albumin Immobility prior to surgery Operating room factors Duration of surgery Surgical position Type of mattress Positioning devices Warming devices Epidural anesthesia/analgesia Anesthetic agents Type of surgery Extracorporeal circulation Inappropriate manual handling

The Role of Daycase Admission There is no upper age limit for daycase admission, and older patients may benefit cognitively from reduced disruption to their daily environment and routine. Prior consultation at the preoperative assessment clinic should screen patients for suitability. Patients should be medically stable and able to understand simple instructions with regard to medications and fasting. A reminder telephone call the evening before surgery is useful in encouraging compliance. Patients require a responsible companion to accompany them home and to stay overnight. It is this issue that most often causes difficulty. Community services and follow-up need to be in place before the patient leaves the hospital.

Choice of Surgical Approach

Perioperative Audit There is an important role for perioperative audit in the care of the older surgical patient. Attendance at preoperative assessment clinics, proportion of patients cancelled for medical reasons on the morning of surgery, unplanned admission to the intensive care unit, incidence of postoperative myocardial infarction, patient satisfaction, and 30-day mortality are just a few examples of outcome measures that may provide scope for audit and implementation of change in individual surgical units.

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CONCLUSIONS Good anesthetic care of the older person involves an assiduous approach to both minor and major elements of the perioperative process. The preparation of the patient begins early and is best carried out in a multidisciplinary unit that is focused on the needs of the elderly. Most information required to plan the anesthetic may be gained from a detailed history and clinical examination of the patient. Occasionally, special investigations or preparatory procedures are required. Short-acting agents and/or regional anesthesia are recommended, providing there are no special indications for general anesthesia or contraindications to regional techniques. Provision of adequate pain relief with regular assessment and formal charting of pain scores should be adopted as routine practice. Fluid and electrolyte management should not be left to the most junior member of the team – consideration of the fluid, electrolyte, and nutritional needs of the patient should be a priority throughout the perioperative course. Oxygen supplementation should be continued routinely to reduce the incidence of hypoxemia preoperatively and postoperatively.

KEY POINTS • Advanced age is not a barrier to anesthesia and surgery. • Anesthesia should be carried out, or closely supervised, by an anesthesiologist with sufficient experience of anesthesia in elderly patients. • Adequate time must be allocated for a detailed preoperative assessment. • Invasive monitoring and regional anesthesia should be utilized liberally. • The intraoperative anesthesia care should be viewed as part of a continuum, with therapy such as oxygen supplementation, analgesia, and fluid management continued into the postoperative period.

KEY REFERENCES • Ballantyne JC, Carr DB, deFerranti S et al. The comparative effects of postoperative analgesic therapies on pulmonary outcome: cumulative meta-analyses of randomized, controlled trials. Anesthesia and Analgesia 1998; 86:598 – 612. • Jin F & Chung F. Minimizing perioperative adverse event in the elderly. British Journal of Anaesthesia 2001; 87(4):608 – 24. • Lameire NH, De Vriese AS & Vanholder R. Prevention and nondialytic treatment of acute renal failure. Current Opinion in Critical Care 2003; 9(6):481 – 90. • McWhirter JP & Pennington CR. Incidence and recognition of malnutrition in hospital. British Medical Journal 1994; 308:945 – 8. • Moller JT, Cluitmans P, Rasmussen LS et al. Long-term postoperative cognitive dysfunction in the elderly ISPOCD1 study. ISPOCD Investigators. International Study of Postoperative Cognitive Dysfunction. Lancet 1998; 351:357 – 61.

REFERENCES Allison SP. Cost-effectiveness of nutritional support in the elderly. The Proceedings of the Nutrition Society 1995; 54(3):693 – 9. American Society of Anesthesiologists. New classification of physical status. Anesthesiology 1963; 24:11. Aronovitch SA. Intraoperatively acquired pressure ulcer prevalence: a national study. Journal of Wound, Ostomy and Continence Nursing 1999; 26(3):130 – 6. Avenell A & Handoll HH. Nutritional supplementation for hip fracture aftercare in the elderly. Cochrane Database Systematic Review 2000; 4:CD001880. Ballantyne JC, Carr DB, deFerranti S et al. The comparative effects of postoperative analgesic therapies on pulmonary outcome: cumulative meta-analyses of randomized, controlled trials. Anesthesia and Analgesia 1998; 86:598 – 612. Bonjour JP, Schurch MA & Rizzoli R. Nutritional aspects of hip fractures. Bone 1996; 20:79 – 82. Chelluri L, Pinsky MR & Grenvik AN. Outcome of intensive care of the ‘oldest old’ critically ill patients. Critical Care Medicine 1992; 20:757 – 61. Chung F, Meier R, Lautenschlager E et al. General or spinal anesthesia: which is better in the elderly? Anesthesiology 1997; 67:422 – 7. Conzen PF, Kharash ED, Czerner SF et al. Low flow sevoflurane compared with low flow isoflurane anesthesia in patients with stable renal insufficiency. Anesthesiology 2002; 97(3):578 – 84. Cook AKR, Niven CA & Downs MG. Assessing the pain of people with cognitive impairment. International Journal of Geriatric Psychiatry 1999; 14:421 – 5. Crosby DL, Rees GAD & Seymour DG (eds) The Ageing Surgical Patient: Anaesthetic, Operative and Medical Management 1992; Wiley, London. Djokovic JL & Hedley-Whyte J. Prediction of outcome of surgery and anesthesia in patients over 80. Journal of the American Medical Association 1979; 242:2301 – 6. Dodds C. Anaesthetic drugs in the elderly. Pharmacology & Therapeutics 1995; 66:369 – 86. Eagle KA, Brundage BH, Chaitman BR et al., Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Committee on Perioperative Cardiovascular Evaluation for Noncardiac Surgery. Guidelines for perioperative cardiovascular evaluation for noncardiac surgery. Circulation 1996; 93:1278 – 317. Egbert AM, Parks LH, Short LM & Burnett ML. Randomized trial of postoperative patient-controlled analgesia vs. intramuscular narcotics in frail elderly men. Archives of Internal Medicine 1990; 150:1897 – 903. Epstein M. Aging and the kidney. Journal of the American Society of Nephrology 1996; 7:1106 – 22. European Pressure Ulcer Advisory Panel. A policy statement on prevention of pressure ulcers. British Journal of Nursing 1998; 7(15):888 – 90. Fleisher LA. Routine laboratory testing in the elderly: is it indicated? Anesthesia and Analgesia 2001; 93:249 – 50. General Office for National Statistics. Life Tables and Mortality Statistics 1995; Her Majesty’s Stationary Office, London. Goldman L, Calderal DL & Nussbaum SR. Multifactorial index of cardiac risk in non-cardiac surgical procedures. The New England Journal of Medicine 1977; 297:845 – 50. Hall WJ. Update in geriatrics. Annals of Internal Medicine 1997; 127:557 – 64. Herr KA, Mobilly PR, Kohout FJ & Wagenaar D. Evaluation of the faces pain scale for use with the elderly. The Clinical Journal of Pain 1998; 14(1):29 – 38. Hosking MP, Lobdell CM, Warner MA et al. Anaesthesia for patients over 90 years of age. Outcomes after regional and general anaesthetic techniques for two common surgical procedures. Anaesthesia 1989; 44:142 – 7. Jin F & Chung F. Minimizing perioperative adverse event in the elderly. British Journal of Anaesthesia 2001; 87(4):608 – 24. Katz J & Melzack R. Measurement of pain. Surgical Clinics of North America 1999; 79:231 – 52.

ANESTHESIA IN OLDER PEOPLE Kazmers A, Perkins AJ & Jacobs LA. Outcomes after abdominal aortic aneurysm repair in those >80 years of age: recent veterans affairs experience. Annals of Vascular Surgery 1998; 12:106 – 12. Kellum JA & Decker JM. Use of dopamine in acute renal failure: a metaanalysis. Critical Care Medicine 2001; 29(8):1526 – 31. Lameire NH, De Vriese AS & Vanholder R. Prevention and nondialytic treatment of acute renal failure. Current Opinion in Critical Care 2003; 9(6):481 – 90. Larsen SF, Zaric D & Boysen G. Postoperative cerebrovascular accidents in general surgery. Acta Anaesthesiologica Scandinavica 1988; 32:698 – 701. Martin RL, Soifer BE & Stevens WC. Ethical issues in anesthesia. Management of the do-not-resuscitate patient. Anesthesia and Analgesia 1991; 73:221 – 5. McWhirter JP & Pennington CR. Incidence and recognition of malnutrition in hospital. British Medical Journal 1994; 308:945 – 8. Miller R. The biology of aging and longevity. In WR Hazzard & JP Blass (eds) Principles of Geriatric Medicine and Gerontology 1998; McGrawHill, New York. Moller JT, Cluitmans P, Rasmussen LS et al. Long-term postoperative cognitive dysfunction in the elderly ISPOCD1 study. ISPOCD Investigators. International Study of Postoperative Cognitive Dysfunction. Lancet 1998; 351:357 – 61. National Confidential Enquiry into Peri-Operative Deaths. Department of Health, London, November 1999. Oberle K, Paul P & Wry J. Pain, anxiety and analgesics: a comparative study of elderly and younger surgical patients. Canadian Journal on Aging 1990; 91:13 – 22. Pedersen T, Eliasen K & Henriksen E. A prospective study of mortality associated with anaesthesia and surgery: risk indicators of mortality in hospital. Acta Anaesthesiologica Scandinavica 1990; 34:176 – 82.

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Poldermans D, Boersma E, Bax JJ et al., Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography Study Group. The effect of bisoprolol on perioperative mortality and myocardial infarction in high-risk patients undergoing vascular surgery. The New England Journal of Medicine 1999; 341(24):1789 – 94. Rodgers A, Walker N, Schug S et al. Reduction of postoperative mortality and morbidity with spinal and epidural anaesthesia: results from overview of randomized trials. British Medical Journal 2000; 321:1493, www.bmj.org. Schultz A, Bein M, Dumond K et al. Aetiology and incidence of pressure ulcers in surgical patients. AORN 1999; 70(3):434 – 9. Severn AM & Dodds C. Cognitive dysfunction may complicate assessment of pain in elderly patients. British Medical Journal 1997; 315:551. Smetana GW. Preoperative pulmonary evaluation. The New England Journal Medicine 1999; 340:937 – 44. Sultana CJ, Campbell JW, Pisanelli WS et al. Morbidity and mortality of incontinence surgery in elderly women: an analysis of medicare data. American Journal of Obstetrics and Gynecology 1997; 176:344 – 8. The Association of Anaesthetists of Great Britain and Ireland. Anaesthesia and Peri-Operative Care of the Elderly 2001; AAGBI, London. Vermillion C. OR acquired pressure sores. Decubitus 1990; 3(1):26 – 30. Wong D & Baker C. Pain in children: comparison of assessment scales. Pediatric Nursing 1988; 14(1):9 – 17.

FURTHER READING Howell SJ, Sear YM, Yeates DM et al. Risk factors for cardiovascular death after elective surgery under general anesthesia. Brit Journal of Anesthesia 1998; 80:14 – 9.

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Health Issues in the Aging Female Carolyn D. Philpot Saint Louis University School of Medicine, St Louis, MO, USA

CANCER Cancer is one of the leading causes of death in women (Levi et al., 2001). The aging female is at risk for endometrial, ovarian, breast, cervical, vulvar, and vaginal cancer. Since there is risk with increasing age, reviewing the risk factors are important to help promote a good quality of life. Proper screening, early detection, treatment, and management of comorbidities are essential.

Endometrial Cancer Endometrial cancer is the fourth most common malignancy in women after breast, colorectal, and lung cancer. Peak incidence occurs in women between 50 and 60 years of age, and the incidence appears to be climbing. The 5-year survival rate for all stages of endometrial cancer has been estimated at 65%. Risk factors include nulliparity, obesity, and prolonged use of unopposed exogenous estrogen. The most common symptom is postmenopausal vaginal bleeding. Besides a physical examination and pap smear, a pelvic ultrasonography and either a endometrial biopsy or dilation and curettage is required for diagnosis or exclusion of diagnosis of endometrial cancer. (A positive Pap test for endometrial cancer will only show in 35–50% of the cases and should not be the only determinant in diagnosis.) Optimal treatment is a hysterectomy with bilateral oophorectomy, and dissection of the retroperitoneal lymph nodes in the pelvic and para-aortic region (Geisler and Geisler, 2001). Additional treatment, such as chemotherapy, radiation or both may also be indicated for advanced stages of cancer and discussion is needed with the patient’s oncologist and geriatrician to weigh the risks with the benefits.

Ovarian Cancer After endometrial cancer, ovarian cancer is the second most common gynecological malignancy. Peak incidence occurs

in women aged between 50 and 60. Risk factors include uninterrupted ovulation (nulliparity or contraceptive usage) and inherited genetic mutations. Symptoms usually are nonspecific. Abdominal pain, abdominal distention, and gastrointestinal disturbances are complaints sometimes voiced from women with ovarian cancers, but symptoms may not develop until late in the disease process. Screening, except for high-risk patients, may include ultrasonography and tumor markers; however, it is thought to be of limited value. Ovaries are generally small and not palpable in the postmenopausal woman and if, upon physical exam, an ovary is able to be palpated, immediate evaluation is warranted since it is suggestive of ovarian cancer. Initial treatment involves surgical removal of the tumor. Chemotherapy may be considered depending on the tumor stage, the patient’s comorbidities, and benefits versus risks. Since most ovarian cancers are detected when the tumor is advanced, long-term prognosis is usually poor.

Breast Cancer Approximately 50% of all new breast cancer cases occur in women over the age of 65. The incidence of breast cancer increases up to the age of 80, levels out between the ages of 80 and 85, and then is thought to decline. It is difficult to evaluate those over 85 years owing to limited data. Risk factors for developing breast cancer may include personal or family history of breast cancer and/or colon or endometrial cancer in first-degree relatives, nulliparity or late first pregnancy at 31 years of age or older, late menopause, early menarche, abdominal obesity, estrogen replacement therapy, history of atypical hyperplasia on biopsy for benign breast disease (Chlebowski et al., 2003). Screening for breast cancer in a postmenopausal woman includes monthly self –breast examinations, an annual physical exam by a physician or other health-care provider, and a yearly, or every 2 years, mammogram. Research has shown that screening for breast cancer in women aged 50 to 70


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has improved survival by early detection. There are many doctors that feel that mortality could be reduced 25–30% if all women received proper mammographic screening. There is limited data on breast screening in woman over 70 years, but it is thought that mammography is of benefit. Since 10–20% of all breast cancers are not picked up on mammography, physical examination is also important. Less than 50% of all women 65 years or older have ever had a mammogram, and those who have had a mammogram, have obtained one on a routine basis. There has been argument among physicians against instituting routine screening for breast cancer in the elderly woman, stating that disability and shorter life expectancy may have a direct effect on the desirability and cost-effectiveness of screening. On the other hand, the life expectancy of a healthy woman in her mid-tolate 70s is approximately 10 more years, and for a healthy woman aged 85, 7 more years. Thus, screening appears to be warranted. The clinical characteristics of breast cancer are the same, despite the age of the individual. Cancer is generally suspected when breast lesions palpated feel firm or abnormalities are detected on mammography. A palpable breast mass in a postmenopausal woman requires immediate attention since most palpable masses are malignant. All breast masses in this age-group should have a biopsy whether the mass was palpated and/or detected on mammography. Prognosis is determined by the stage of the disease. Owing to lack of clinical studies, it is unclear if women over the age of 65 have the same clinical course as compared to that of younger women. The course of treatment is prompted by the stage of the disease. Until recently, many elderly women with breast cancer were not aggressively treated; however, today many older women with breast cancer are working with their oncologists and geriatricians discussing various treatment options.

Cervical Cancer Cervical cancer occurs in women of all ages but its incidence peaks in women aged 40 to 50 years (Benedet et al., 2001). Symptoms vary and hinge on the stage of the tumor. Some women may be asymptomatic, while others may show clinical signs of postmenopausal or postcoital bleeding. Routine Pap testing is the best method of screening. If the Pap test results are positive, colposcopy-directed biopsies and endocervical curettage are used to establish diagnosis. Radical hysterectomy is the recommended treatment for cervical cancer. Adjuvant radiation or chemotherapy may also be used. The combined cure rate for all cervical cancers is 50–60%.

Vulvar Cancer Vulvar cancer accounts for approximately 3–4% of all gynecological malignancies in the United States (Beller et al.,

2001a). The average age at diagnosis is 70 years, and the incidence increases with age. The most common symptoms exhibited in vulvar cancer are vulvar pruritus, pain, and a palpable vulvar lesion; however, many women are asymptomatic (Hyde et al., 2002). A discharge may be present. Histology generally reveals squamous cell carcinoma. Biopsy may be indicated for diagnosis. Treatment is generally surgical and for extensive lesions, a radical vulvectomy with unilateral or bilateral inguinal lymphadenectomy is recommended. Radiation and chemotherapy may also be considered adjuvant therapy. Prognosis for early-staged lesion are generally favorable. The 5-year survival rate is 80–90% if there is no metastasis to the lymph node and 16–30% if lymph node metastasis is present.

Vaginal Cancer Vaginal cancer is relatively rare (Beller et al., 2001b). The average age at diagnosis is 60 to 65 years. It is estimated that 95% of these lesions are squamous cell carcinomas. Vaginal bleeding or discharge is an early symptom. Pain or postcoital bleeding may be exhibited in sexually active women. Where the tumor involves the anterior vaginal wall, it may cause dysfunction with voiding, since the vaginal wall may invade into the urethra. Biopsy is indicated for diagnosis. Radiation therapy is the main choice of treatment; however, surgery and chemotherapy may be utilized in specific cases. Prognosis is dependant upon the size and location of the tumor. The 5-year survival rate for all types is estimated to be from 25–48%.

MENOPAUSE Menopause is the permanent cessation of menses as a result of ovarian aging. It is clinically diagnosed after 12 months of amenorrhea. The perimenopausal transition is defined as the time prior to the permanent cessation of menses and is identified with irregular menstrual cycles. Transitional time has been shown to vary in length from 2 to 8 years. The average age, in the United States, at which menopause occurs is 51. Early symptoms of menopause include irregular menstrual cycles, headache, fatigue, changes in mood and cognition, insomnia, and hot flashes (Table 1). Some women may experience vertigo, heart palpitations, and tachycardia. A later clinical presentation may include urinary incontinence, dry skin, breast changes, genital atrophy with dyspareunia, vaginitis, and cystitis. Early symptoms of menopause is often irregular menstrual periods. They may vary in frequency, duration, and blood flow amount. Menstrual bleeding that is unusually heavy, lasts more than 10 days, or that occurs more often than once every 3 weeks should be clinically evaluated for possible neoplasms. Another early symptom of menopause is hot flashes. About 80% of perimenopausal women report hot flashes

HEALTH ISSUES IN THE AGING FEMALE Table 1 Signs and symptoms of menopause

Irregular menstrual cycle Insomnia Hot flashes Mood swings Cognitive changes Skin changes Genitourinary atrophy Headache Fatigue Vertigo Heart palpitations/tachycardia

and up to 50% of these women may continue to have symptoms for up to 5 years. Hot flashes may also occur after surgical menopause. Research shows that short-term use of hormone replacement therapy (HRT) will help relieve severe vasomotor symptoms, but will not abolish symptoms. Women who have had bilateral salpingo oophorectomy are at high risk for cardiovascular disease. This is especially true if HRT was not initiated. Early natural menopause is also at high risk. Diagnosing menopause may be determined by elevated serum levels of follicle-stimulating hormone. Estrogen replacement therapy is the best treatment for symptoms of menopause. Duration of estrogen replacement therapy is controversial and each case should be reviewed for risk versus benefit.

Postmenopausal Vaginal Bleeding About 20–30% of postmenopausal vaginal bleeding is due to atypical adenomatous endometrial hyperplasia or endometrial cancer. It may also be caused by the use of estrogen or progesterone or by genital atrophy resulting from low estrogen levels. History taking should include past and present gynecological problems. A drug history should indicate whether any exogenous estrogens were used. A pelvic and bimanual exam should be performed to rule out any trauma, tumors, or bleeding from atrophic sites. A Pap test should also be performed to aid in diagnosis. Transvaginal ultrasonography may be useful for diagnosis. If the endometrial thickness is less than 5 mm, cancer or endometrial hyperplasia is doubtful. Endometrial thickness over 5 mm is suspicious for malignancy and further work-up is promptly warranted. Endometrial biopsy may then be indicated as well as a full fractional dilatation and curettage (D & C). If postmenopausal bleeding is found to be cancerous, then treatment should be tumor specific. If cancer is nondetected, estrogen is initiated because it may be secondary to atrophy. For those women taking exogenous hormones, the estrogen dosage may need to be decreased and progesterone increased. If bleeding continues, a more aggressive work-up is needed.

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Postmenopausal Hormone Replacement Therapy Approximately 6 million women in the United States are taking HRT. The use of estrogen ranges from relief of postmenopausal symptoms to what was assumed, until recently, long-term health benefits. Until recently, it was felt that estrogen replacement had a protective effect against cardiovascular disease. From the data collected by the Heart and Estrogen/Progestin Replacement Study Follow-up (HERS II) trial and other recent secondary prevention studies, the new recommendations are against initiating or continuing its use for the primary prevention of cardiovascular disease. The Women’s Health Initiative (WHI) study stated that estrogen and progestin therapy should not be initiated or continued for the primary prevention of coronary heart disease and was suggestive that it may stimulate breast cancer growth and hinder breast cancer diagnosis. This combination of hormone replacement also showed an increase in pulmonary embolus.

Sexual Dysfunction in the Menopausal Woman Many women have experienced a lack of interest (decreased libido) or arousal in sexual activity (sexual arousal disorder), achieving orgasm (female orgasmic disorder), or have had pain prior or during sexual activity (dyspareunia) (Gutmann, 2005; Kingsburg, 2004). When one or more of these symptoms occur, causing anguish and interference with interpersonal relationships, it is diagnosed as female sexual dysfunction (FSD). The exact prevalence is unknown; however, one survey found that more than 40% of women aged 18 to 59 alluded to having sexual dysfunction. It has also been suggested that the prevalence of FSD increases while women are going through menopause transition. Perimenopausal and postmenopausal women have repeatedly reported that they have lost an interest in sex and do not find sex “pleasurable”. Studies have shown that there is a decline in sexual functioning from early to late perimenopause. In late perimenopausal to postmenopausal women, studies reveal that there is a decrease in libido and sexual responsitivity, an increase in dyspareunia, and a decline in sexual activity. Screening questions that are useful for FSD are given in Table 2. The causes of FSD are multifactorial. Hormonal, physical, and psychosocial changes are key components of FSD. Table 2 Screening questions for female sexual dysfunction

1. Are you currently involved in a sexual relationship? With men? With women? Both? Multiple partners? 2. How often do you engage in sexual activity? Intercourse? Masturbation? 3. Do you feel that your sex drive has changed? Less? Same? Increased? 4. Do you have difficulty in obtaining an orgasm? Inability? Pain with? 5. Are you satisfied with your current sexual relations? 6. Do you have any sexual concerns that you would like to discuss?

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Hormonal Changes There is a decline of circulating androgens during the late reproductive years. Androgen deficiency is associated with a decline in libido, decline in sensitivity to sexual stimulation, and arousability. Estrogen deficiency can cause changes in the genitourinary system. Estrogen therapy, both topical and systemic, has been shown to improve vaginal atrophy, increase blood flow to the vagina and increase lubrication.

Physical Changes In addition to the hormonal changes that occur in the genitourinary system, other conditions can contribute to FDS. Limited movement or pain from arthritis may be a factor. Recent pelvic surgery or trauma is another. Some medications, such as, antihistamines, antidepressants, and blood pressure medication can lead to a decreased libido and inability to achieve orgasm.

Psychosocial Changes A woman may have concerns over the well being of her sexual partner. If she or her sexual partner is ill, or have a debilitating disease, it can have a direct impact on sexual function. Women, who live longer than men, often are without a sex partner. Not having a partner does not mean they are no longer in need of nurturing, affection, and physical contact. Depression and anxiety can contribute to FDS. Research has shown that only 14% of Americans aged 40 to 80 have been asked by their doctor if they had any sexual problems within the past 3 years. Since this number is relatively small, the physician or health-care provider needs to remember to inquire about the patient’s sexual health along with the history taking during physical exam. Data from a large survey has indicated that 68% of men and women thought their physician would be uncomfortable talking about sex, and 71% thought that if sexual problems were disclosed, nothing would be done about the problem. Only 14% out of 1384 women ever reported sexual problems to their health-care provider in a study conducted by the American Association of Retired Persons. Of those women discussing sexual problems, most confer with their gynecologist rather than their private medical doctor (PCP). It is felt that physicians do not talk about sex because of a lack of education, comfort and confidence, and lack of time and treatment options (Table 2).

OSTEOPOROSIS Osteoporosis is a major risk factor for fractures in the older population and is estimated to account for approximately

1.5 million low trauma fractures yearly (Ribeiro et al., 2000). The lifetime risk of sustaining a fracture to the spine (symptomatic), hip or distal radius in white women is approximately 40% (while only 13% in white men) aged 50 years and older. The 6-month mortality rate from a hip fracture is approximately 10–20%. Of the survivors, about 25% will require assisted or nursing home care and approximately 50% will require an assistive device to aid in their ambulation. Osteoporotic fractures are associated with annual costs in the United States ranging between 7 and 20 billion dollars. One to one-and-a-half percent of all hospital beds in Europe are occupied by patients with osteoporosis. This European figure is expected to more than double in the next 50 years. In the United States, the estimated prevalence of osteoporosis is 8 million in women and 2 million in men and the estimated related health costs exceed 14 billion dollars annually. Primary osteoporosis occurs mainly in older people aged 51 to 75 years, and can be arranged in two groups: postmenopausal osteoporosis and age-related bone loss (senescence). The incidence of primary osteoporosis is six times more common in women than in men. Women are at higher risk because they have a lower peak bone mass compared to men and have an acceleration of bone loss during menopause. Primary osteoporosis is thought to be atypical in premenopausal women, while secondary osteoporosis composes only a small amount of elderly women. (Elderly women may have a combination of both primary and secondary osteoporosis.) Age-related bone loss is complex and multifactorial. As one ages, changes occur in cortical bone, trabecular bone, and bone marrow. Studies show that there is a decline in bone mineral density after the third decade of life and continues to decline at a rate of approximately 0.5% per year. During menopause, women, however, have an accelerated bone mineral density loss at an estimated rate of 3–5%. Hormonal changes of vitamin D and reduction of calcium absorption also have an impact on aging bone. Vitamin D levels decrease with age and vitamin D deficiency in elderly people is common. Absorption rates also decline by 40%. Aging changes in skin reduce the amount of 7dehydrocholesterol, the precursor and rate of conversion of vitamin D3 . Declining renal function leads to a drop of activity of 1-α-hydroxylase, which is responsible for the activation of vitamin D3 . Lower calcium levels then occur from these changes causing activation of the calcium sensor receptor in the parathyroid gland. Parathyroid hormone is secreted, stimulating osteoclast activity, which keeps serum calcium levels in homeostasis at the price of bone mineralization. Secondary osteoporosis may also have many other conditions causing bone loss such as various endocrine and neoplastic abnormalities, gastrointestinal disease, and drug usage (Table 3). Osteoporosis has no symptoms; therefore, a thorough evaluation is critical for detection of osteoporosis. Assessment begins with a complete history alluding to its risk factors as stated in Table 4. Major risk factors for osteoporosis

HEALTH ISSUES IN THE AGING FEMALE Table 3 Secondary causes of osteoporosis

Endocrine Hyperthyroidism Cushing’s syndrome Osteomalacia Paget’s disease Primary hyperparathyroidism Gastrointestinal Malabsorption syndromes Alcoholism Neoplastic states Bone Metastases Multiple myeloma Medication Glucocorticoids Anticonvulsants Excessive thyroid hormone replacement

Table 4 Risk factors for osteoporosis

Advanced age Female gender Race (more prevalent among white, Asian, and Hispanic decent) Heredity (approximately 50 – 80% of peak bone mass is genetically determined) Small body size/weight (103 years, specific genetic variations may play a prominent role. • Centenarian offspring. Following in the footsteps of their parents. The offspring of centenarians are a valuable model for the study of environmental and genetic factors related to successful aging. • Genetic findings. Reproducible genetic associations with exceptional longevity are still rare, reflecting the likely complex nature of gene –gene and gene –environment interactions that dictate the ability to survive to extreme old age.

KEY REFERENCES • Barzilai N, Atzmon G, Schechter C et al. Unique lipoprotein phenotype and genotype in humans with exceptional longevity. JAMA 2003; 290(15):2030 – 40. • Evert J, Lawler E, Bogan H & Perls T. Morbidity profiles of centenarians: survivors, delayers, and escapers. Journals of Gerontology. Series A, Biological Sciences and Medical Sciences 2003; 58(3):232 – 7. • Hitt R, Young-Xu Y, Silver M & Perls T. Centenarians: the older you get, the healthier you have been. Lancet 1999; 354(9179):652. • Perls TT, Wilmoth J, Levenson R et al. Life-long sustained mortality advantage of siblings of centenarians. Proceedings of the National Academy of Sciences of the United States of America 2002a; 99(12):8442 – 7. • Schachter F, Faure-Delanef L, Guenot F et al. Genetic associations with human longevity at the APOE and ACE loci. Nature Genetics 1994; 6:29 – 32.

REFERENCES Andersen-Ranberg K, Vasegaard L & Jeune B. Dementia is not inevitable: a population-based study of Danish centenarians. Journals of Gerontology. Series B, Psychological Sciences and Social Sciences 2001; 56:P152 – 9. Atzmon G, Schechter C, Greiner W et al. Clinical phenotype of families with longevity. Journal of the American Geriatrics Society 2004; 52:274 – 7. Barker DJP. Mothers, Babies, and Health in Later Life 1998; Churchill Livingstone, London. Barzilai N, Atzmon G, Schechter C et al. Unique lipoprotein phenotype and genotype in humans with exceptional longevity. JAMA 2003; 290(15):2030 – 40.

CENTENARIANS Barzilai N, Gabriely I, Gabriely M et al. Offspring of centenarians have a favorable lipid profile. Journal of the American Geriatrics Society 2001; 49(1):76 – 9. Blackwell D, Hayward MD & Crimmins EM. Does childhood health affect chronic morbidity in later life? Social Science & Medicine 2001; 52:1269 – 84. Blansjaar BA, Thomassen R & van Schaick HW. Prevalence of dementia in centenarians. International Journal of Geriatric Psychiatry 2000; 15:219 – 25. Copeland JR, McCracken CF, Dewey ME et al., The MRC-ALPHA Study. Undifferentiated dementia, Alzheimer’s disease and vascular dementia: age- and gender-related incidence in Liverpool. British Journal of Psychiatry 1999; 175:433 – 8. Corder EH, Saunders AM, Strittmatter WJ et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 1993; 261(5123):921 – 3. Costa D. Understanding the twentieth century decline in chronic conditions among older men. Demography 2000; 37:53 – 72. Cutler RG. Evolution of human longevity and the genetic complexity governing aging rate. Proceedings of the National Academy of Sciences of the United States of America 1975; 72:4664 – 8. Ebly EM, Parhad IM, Hogan DB & Fung TS. Prevalence and types of dementia in the very old: results from the Canadian study of health and aging. Neurology 1994; 44(9):1593 – 600. Elford J, Whincup P & Shaper AG. Early life experience and adult cardiovascular disease: longitudinal and case-control studies. International Journal of Epidemiology 1991; 20:833 – 44. Elo I. Childhood Conditions and Adult Health: Evidence from the Health and Retirement Study 1998; Population Aging Research Center Working Papers, University of Pennsylvania, Population Aging Research Center, Philadelphia. Evans DA, Beckett LA, Field TS et al. Apolipoprotein E epsilon4 and incidence of Alzheimer disease in a community population of older persons. JAMA 1997; 277(10):822 – 4. Evans DA, Funkenstein HH, Albert MS et al. Prevalence of Alzheimer’s disease in a community population of older persons. Higher than previously reported. JAMA 1989; 262(18):2551 – 6. Evert J, Lawler E, Bogan H & Perls T. Morbidity profiles of centenarians: survivors, delayers, and escapers. Journals of Gerontology. Series A, Biological Sciences and Medical Sciences 2003; 58(3):232 – 7. Falconer D. The inheritance and liability to certain disease estimated from the incidence among relatives. Annals of Human Genetics 1965; 29:51 – 76. Farrer L & Cupples A. Determining the genetic component of a disease. In J Haines & MA Pericak-Vance (eds) Approaches to Gene Mapping in Complex Human Diseases 1998; Wiley-Liss, New York. Fontaine KR, Redden DT, Wang C et al. Years of life lost due to obesity. JAMA 2003; 289:187 – 193. Fraser GE & Shavlik DJ. Ten years of life: is it a matter of choice? Archives of Internal Medicine 2001; 161(13):1645 – 52. Fries JF. Aging, natural death, and the compression of morbidity. New England Journal of Medicine 1980; 303(3):130 – 5. Geesaman BJ, Benson E, Brewster SJ et al. Haplotype based identification of a microsomal transfer protein marker associated with human lifespan. Proceedings of the National Academy of Sciences of the United States of America 2003; 100:14115 – 20. Graves AB, Larson EB, Edland SD et al. Prevalence of dementia and its subtypes in the Japanese American population of King County, Washington state. The Kame Project. American Journal of Epidemiology 1996; 144(8):760 – 71. Gudmundsson H, Gudbjartsson DF, Frigge M et al. Inheritance of human longevity in Iceland. European Journal of Human Genetics 2000; 8(10):743 – 9. Hagberg B, Alfredson BB, Poon LW & Homma A. Cognitive functioning in centenarians: a coordinated analysis of results from three countries. Journals of Gerontology. Series B, Psychological Sciences and Social Sciences 2001; 56:P141 – 51. Hall A & Peekham CS. Infections in childhood and pregnancy as a cause of adult disease: methods and examples. British Medical Bulletin 1997; 53:10 – 23.

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Hebert LE, Scherr PA, Beckett LA et al. Age-specific incidence of Alzheimer’s disease in a community population. JAMA 1995; 273(17):1354 – 9. Herskind AM, McGue M, Holm NV et al. The heritability of human longevity: a population-based study of 2872 Danish twin pairs born 1870 – 1900. Human Genetics 1996; 97(3):319 – 23. Hitt R, Young-Xu Y, Silver M & Perls T. Centenarians: the older you get, the healthier you have been. Lancet 1999; 354(9179):652. Kerber RA, O’Brien E, Smith KR & Cawthon RM. Familial excess longevity in Utah genealogies. Journals of Gerontology. Series A, Biological Sciences and Medical Sciences 2001; 56(3):B130 – 9. Kliegel M, Moor C & Rott C. Cognitive status and development in the oldest old: a longitudinal analysis from the Heidelberg Centenarian Study. Archives of Gerontology and Geriatrics 2004; 39:143 – 56. Kuh D & Ben-Shlomo B. A Life Course Approach to Chronic Disease Epidemiology 1997; Oxford University Press, Oxford. Lee JH. Genetic evidence for cognitive reserve: variations in memory and related cognitive functions. Journal of Clinical and Experimental Neuropsychology 2003; 25(5):594 – 613. Lee CK, Klopp RG, Weindruch R & Prolla TA. Gene expression profile of aging and its retardation by caloric restriction. Science 1999; 285:1390 – 3. Ljungquist B, Berg S, Lanke J et al. The effect of genetic factors for longevity: a comparison of identical and fraternal twins in the Swedish Twin Registry. Journals of Gerontology. Series A, Biological Sciences and Medical Sciences 1998; 53(6):M441 – 6. McCarthy MI, Kruglyak L & Lander ES. Sib-pair collection strategies for complex diseases. Genetic Epidemiology 1998; 15(4):317 – 40. McGue M, Vaupel JW, Holm N & Harvald B. Longevity is moderately heritable in a sample of Danish twins born 1870 – 1880. Journal of Gerontology 1993; 48(6):B237 – 44. Mitchell BD, Hsueh WC, King TM et al. Heritability of life span in the Old Order Amish. American Journal of Medical Genetics 2001; 102:346 – 52. Mosley W & Gray R. Childhood precursors of adult morbidity and mortality in developing countries: implications for health programs. In J Gribble & S Preston (eds) The Epidemiological Transition: Policy and Planning Implications for Developing Countries 1993, pp 69 – 100; National Academy Press, Washington. Perls T & Fretts R. Why Women Live Longer Than Men 1998, pp 100 – 7; Scientific American Press. Perls TT, Wilmoth J, Levenson R et al. Life-long sustained mortality advantage of siblings of centenarians. Proceedings of the National Academy of Sciences of the United States of America 2002a; 99(12):8442 – 7. Perls T, Kunkel L & Puca A. The genetics of aging. Current Opinion in Genetics & Development 2002b; 12:362 – 9. Preston S, Elo IT, Hill ME & Rosenwaike I. The Demography of African Americans, 1930 – 1990 2003; Kluwer Academic Publisher. Preston S, Hill ME & Drevenstedt GL. Childhood conditions that predict survival to advanced ages among African Americans. Social Science & Medicine 1998; 47:1231 – 46. Puca AA, Daly MJ, Brewster SJ et al. A genome-wide scan for linkage to human exceptional longevity identifies a locus on chromosome 4. Proceedings of the National Academy of Sciences of the United States of America 2001; 98(18):10505 – 8. Ravaglia G, Forti P, De Ronchi D et al. Prevalence and severity of dementia among northern Italian centenarians. Neurology 1999; 53(2):416 – 8. Richards M & Sacker A. Lifetime antecedents of cognitive reserve. Journal of Clinical and Experimental Neuropsychology 2003; 25(5):614 – 24. Ritchie K & Kildea D. Is senile dementia “age-related” or “ageing-related”? -evidence from meta-analysis of dementia prevalence in the oldest old. The Lancet 1995; 346:931 – 4. Robine JM, Romieu I & Allard M. French centenarians and their functional health status. Presse Medicale 2003; 32:360 – 4. Scarmeas N & Stern Y. Cognitive reserve and lifestyle. Journal of Clinical and Experimental Neuropsychology 2003; 25(5):625 – 33. Schachter F. Causes, effects, and constraints in the genetics of human longevity. American Journal of Human Genetics 1998; 62(5):1008 – 14.

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Schachter F, Faure-Delanef L, Guenot F et al. Genetic associations with human longevity at the APOE and ACE loci. Nature Genetics 1994; 6:29 – 32. Silver MH, Jilinskaia E & Perls TT. Cognitive functional status of age-confirmed centenarians in a population-based study. Journal of Gerontology, Psychological Science 2001; 56B:P134 – 40. Sobel E, Louhija J, Sulkava R et al. Lack of association of apolipoprotein E allele epsilon 4 with late-onset Alzheimer’s disease among Finnish centenarians. Neurology 1995; 45:903 – 7. Stern Y. The concept of cognitive reserve: a catalyst for research. Journal of Clinical and Experimental Neuropsychology 2003; 25(5):589 – 93. Stone L. Early life conditions that predict survival to extreme old age, Paper presented at the Annual Meeting of the Population Association of America, Atlanta, 2002. Terry DF, Wilcox MA, McCormick MA & Perls TT. Cardiovascular disease delay in centenarian offspring. Journals of Gerontology. Series A, Biological Sciences and Medical Sciences 2004a; 59(4):M385 – 9. Terry DF, Wilcox M, McCormick M et al. Reduced all-cause, cardiovascular and cancer mortality in centenarian offspring. Journal of the American Geriatrics Society 2004b; 52:2074 – 76. Terry D, McCormick M, Andersen S et al. Cardiovascular disease delay in centenarian offspring: role of heat shock proteins. Annals New York Academy of Sciences 2004c; 1019:502 – 5.

Terry DF, Wilcox M, McCormick MA et al. Cardiovascular advantages among the offspring of centenarians. Journals of Gerontology. Series A, Biological Sciences and Medical Sciences 2003; 58(5):M425 – 31. Thomassen R, van Schaick HW & Blansjaar B. Prevalence of dementia over age 100. Neurology 1998; 50:283 – 6. Thomassen R, van Schaick HW & Blansjaar BA. Prevalence of dementia over age 100. Neurology 1999; 52:1717. Vita AJ, Terry RB, Hubert HB & Fries JF. Aging, health risks, and cumulative disability. New England Journal of Medicine 1998; 338(15):1035 – 41. von Strauss E, Viitanen M, De Ronchi D et al. Aging and the occurrence of dementia: findings from a population-based cohort with a large sample of nonagenarians. Archives of Neurology 1999; 56(5):587 – 92. Wechsler H, Rigotti NA, Gledhill-Hoyt J & Lee H. Increased levels of cigarette use among college students: a cause for national concern. JAMA 1998; 280:1673 – 8. Wei M, Kampert JB, Barlow CE et al. Relationship between low cardiorespiratory fitness and mortality in normal-weight, overweight, and obese men. JAMA 1999; 282:1547 – 53. Wilson R, Barnes L & Bennett D. Assessment of lifetime participation in cognitively stimulating activities. Journal of Clinical and Experimental Neuropsychology 2003; 25(5):634 – 42.

PART III


Diagnostic Interventions

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Diagnostic Imaging and Interventional Radiology J. Richard Harding St Woolos and Royal Gwent Hospitals, Newport, UK

INTRODUCTION Diagnostic imaging and interventional radiology in the elderly is little different from that of the adult population in general, but there are certain specific considerations. The problems and difficulties which can arise in diagnostic imaging and interventional radiology are not unique to the elderly; they are, however, more common in old age than in younger or middle-aged adults. Nevertheless, it is not unusual to occasionally encounter 80 or even 90 year olds who are fitter and more cooperative than some 50-year-old patients. Coupled with the increasing numbers of older people in the population at large plus the higher incidence and prevalence of many pathological conditions requiring investigation and treatment in this age-group, those difficulties which can arise assume an increasing importance; this justifies particular attention and care needed, in order to achieve a satisfactory investigation/intervention and to avoid undue distress or discomfort to the elderly patient. In particular, neoplastic disease and vascular disorders (cardiovascular, cerebrovascular, and peripheral vascular diseases) are more common in elderly patients than in younger or middle-aged patients. Requests for radiological investigation of older patients, both for in- and outpatients, are received from many sources in addition to those from departments of geriatric medicine, but the potential problems are the same. Some nongeriatric clinical specialties have a high proportion of elderly patients (e.g. urology, gynecology, and general medicine), although referral of such patients can be from almost any clinical speciality (with the notable exceptions of obstetrics and pediatrics!). A large number of elderly referrals also emanate from general practice. Appropriate choice of relevant investigation, with clear information/explanation to the patient and/or his/her relatives or carers can have a significant effect in alleviating or reducing unnecessary anguish in these patients, who are frequently

already anxious, distressed, or in pain or discomfort as a result of their condition and age. Kindness and patience can pay dividends.

GUIDELINES TO GOOD PRACTICE IN RADIOLOGICAL IMAGING The use of radiological investigations is an accepted part of medical practice, but there is no known safe radiation dose. In requesting any radiological investigation, it should be remembered that all X-rays are potentially carcinogenic and tetragenic. The patient’s interest will be best served only if the likely disadvantages of the examination (inconvenience, discomfort, the risk of radiation to those X-rayed, and the benefits which might have to be foregone when resources are committed to the X-ray examination) are less than the anticipated benefits. Man-made radiation now accounts for 15% of the total radiation burden to the population, of which 97% is due to diagnostic medical exposures. No investigation should be requested unless it can be clinically justified and its result is likely to influence patient management. Many measures, including technical features of X-ray equipment design and radiographic technique, are utilized to reduce the radiation dosage to patients from necessary radiological examinations. Some of the reasons for avoiding or reducing exposure to ionizing radiation from radiological examinations are not relevant in the elderly (e.g. avoiding radiation to the developing embryo or fetus in pregnant patients) or are of lesser significance than in younger patients (e.g. risks of mutation in germ cells), but it is, nevertheless, a sound and recommended practice to avoid unnecessary irradiation of patients and to keep that which is necessary to a minimum for the sake of the patient and the operator(s). Many elderly patients will still have a fairly long life expectancy,


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so radiation-induced cancer cannot be dismissed. There is no threshold for the induction of such effects, any ionizing radiation is theoretically dangerous and its use must be justified, that is, the potential benefit must outweigh the small risks. Requests for radiological investigation should follow the guidelines published by the Royal College of Radiologists (RCR) in the booklet Making the Best Use of a Department of Clinical Radiology: Guidelines for Doctors (3rd edn) (RCR Working Party, 2003). These guidelines are not intended to replace clinical judgement but to support it in times of doubt or difficulty. The guidelines state that a useful investigation is one in which the result – positive or negative – will alter management or add confidence to the clinician’s diagnosis. A significant number of radiological investigations do not fulfil these aims. Unnecessary investigations increase waiting time, waste limited resources (Audit Commission, 1995), lower standards, and may add unnecessarily to patient irradiation (The Ionising Radiation (Protection of Persons Undergoing Medical Evaluation or Treatment) Regulations 1988, (POPUMET); The Ionising Radiation (Medical Exposure) Regulations 2000, (IR(ME)R 2000); European Directive 97/43/Euratom (The Medical Exposures Directive). Such is the perceived risk of medical litigation that X rays are sometimes requested even when they are not considered clinically necessary by the referring doctor. If, as a result of careful clinical examination, it is decided that an X ray is not necessary for the future management of the patient and this is recorded in the patient’s notes, it is unlikely that the decision will be challenged on medicolegal grounds. The position of clinicians following the guidelines will be further strengthened because it will have the support of the RCR. Apart from the medicolegal issue, the chief causes of the wasteful use of radiology are: 1. Investigation when results are unlikely to affect patient management: because the anticipated “positive” finding is usually irrelevant, for example, degenerative spinal disease (as “ normal” as gray hairs from early middle age) or because a positive finding is so unlikely. DO I NEED IT? 2. Investigating too often: that is, before the disease could have progressed or resolved, or before the results influence treatment. DO I NEED IT NOW? 3. Repeating investigations which have already been done: for example, at another hospital, in an outpatient department, or in the accident and emergency department, or already requested by another member of the clinical team caring for the patient. HAS IT BEEN DONE ALREADY? 4. Failing to provide appropriate clinical information and questions that the radiological investigation should answer: Deficiencies may lead to the wrong radiographs being obtained (e.g. the omission of an essential view). HAVE I EXPLAINED THE PROBLEM?

5. Performing the wrong investigation: Imaging techniques are developing rapidly. It is often helpful to discuss the investigation with a radiologist before it is requested. IS THIS THE BEST INVESTIGATION? Continued use of the RCR Guidelines leads to a reduction in the number of referrals for investigations and also to a reduction in medical radiation exposure (Roberts, 1988; National Radiological Protection Board and The Royal College of Radiologists, 1990; RCR Working Party, 1991; RCR Working Party, 1992; Roberts, 1992). Nevertheless, the primary objective of the RCR Guidelines is to improve clinical practice. Such guidelines work best if they are used in conjunction with clinicoradiological dialogue and as part of the audit process. The Ionizing Radiation (POPUMET) Regulations (1988) require all concerned to reduce unnecessary exposure of patients to radiation. Health authorities, NHS trusts, and individuals using ionizing radiation must, by law, comply with these regulations. One important way of reducing radiation dose is to avoid repeating investigations unless there is a sound clinical reason to do so. Table 1 shows the effective doses delivered by different examinations, the approximate equivalent number of chest Table 1 Relative radiation doses and their equivalent natural radiation period

Effective dose (mSv)

Equivalent number of chest X rays (approx.)

Equivalent period of natural background radiation

Extremitiesa (e.g. knee) Chest (single PA film) Skull Cervical spine Dorsal spine Lumbar spine Hip Pelvis Abdomen Biliary tract

0.01 0.02 0.1 0.1 1.0 2.4 0.3 1.0 1.5 1.3

0.5 1 5 5 50 120 15 50 75 65

1.5 days 3 days 2 weeks 2 weeks 6 months 14 months 2 months 6 months 9 months 7 months

Barium studies Esophagus Stomach & duodenum Small bowel Large bowel IVU CT headb CT chest or abdomen

2.0 5.0 6.0 9.0 4.6 2.0 8.0

100 250 300 450 230 100 400

1 year 2.5 years 3 years 4.5 years 2.5 years 1 year 4 years

0.1

5

1.0 1.0 1.0 5.0 18.0

50 50 50 250 900

Examination

Radionuclide studies c Lung ventilation (81m Krypton) Lung perfusion Kidney Thyroid Bone Myocardium (201 Thallium)

2 weeks 6 months 6 months 6 months 2.5 years 9 years

Source: Reprinted from Clinical Radiology, V39, Roberts CJ, Towards the more effective use of diagnostic radiology, pp 3 – 6, Copyright 1988, with permission from The Royal College of Radiologists. a On the basis of a survey carried out in the mid-1980s. b On the basis of studies carried out in 1989. c Courtesy of Dr RA Shields, Manchester.

DIAGNOSTIC IMAGING AND INTERVENTIONAL RADIOLOGY CT Lumbar spine Barium enema Barium meal IVU Abdomen Pelvis Chest Limbs and joints Skull Thoracic spine Dental

Frequency Collective dose

0

5

10 15 Contribution (%)

20

25

Figure 1 Frequency of, and collective dose from, different radiological investigations in the United Kingdom (Reprinted from Clinical Radiology, V39, Roberts CJ, Towards the more effective use of diagnostic radiology, pp 3 – 6, Copyright 1988, with permission from The Royal College of Radiologists)

radiographs, and the equivalent period of natural background radiation. The effective dose is a weighted sum of equivalent doses (in millisieverts, mSv) to a number of body tissues, where the weighting used for the different tissues depends upon the relative risks of fatal malignancy or severe hereditary defect for low radiation doses. The effective dose is the dose of uniform whole-body irradiation which would carry the same risk of malignant disorders as the examples listed, all of which involve nonuniform irradiation. Figure 1 shows the relative frequency of X-ray examinations and their contributions to the collective population dose. The dose imparted by computed tomography (CT) is high and should be minimized. In recent studies, the contribution of CT to the collective dose from all X-ray examinations has increased to one-third and is probably still rising (National Radiological Protection Board, 1992). In many situations, potentially less harmful imaging modalities such as ultrasound or magnetic resonance imaging (MRI) can be substituted for CT.

PROBLEMS IN RADIOLOGY – GENERAL CONSIDERATIONS The problems which can arise in radiological examination of the elderly are mainly related to locomotor and communication difficulties resulting from the aging process and diseases occurring more commonly in old age. Complications which can occur in diagnostic imaging and interventional radiology relate not only to radiation but also to drugs used and procedures performed in the clinical radiology department (Ansell et al., 1996). For elderly outpatients, actually getting to the X-ray department can be difficult; such patients may be unable to use a car or public transport, or afford a taxi fare. Elderly patients may never have driven or have owned a car, or may have had to give up driving because of failing eyesight

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or musculoskeletal disabilities preventing driving or getting into or out of a car, or walking to it. Where car transport cannot be provided by a friend, relative or carer, or a taxi is unaffordable or inappropriate, the patient will be dependent upon a hospital car or the ambulance service. In cases of severe disability, ambulance transport is the only possibility. The patient may be unable to walk far and may require transfer into and out of the ambulance by wheelchair. Suitable facilities at the hospital allow wheelchair access to departments, for example, wheelchair ramps alongside small flights of steps and adequate and appropriately sited provision of passenger lifts. This is easier to achieve in modern purpose-built hospitals and radiology departments than in those housed in older (e.g. Victorian) buildings, where such access was not originally planned. Within the radiology department, the reception and waiting areas, changing cubicles, examination rooms, and toilets need adequate provision for wheelchair access. Modified changing cubicles are required, larger than normal, with extra-wide or double doors to accommodate not only the patient and wheelchair, but also a friend, relative, carer, nurse, or radiography helper for those patients who need assistance in dressing and undressing to change into an examination gown for radiographic procedures. Problems can be encountered within the X-ray examination room in moving patients on and off the examination table. Most conventional radiographic imaging tables are quite high off the ground, the tabletop being anything between 24 and 28 inches above floor level; physically getting the less mobile patient on and off such tables, whether from a standing position or from a wheelchair, can present difficulties. This can be overcome by using specially designed elevating examination tables, which rise and lower hydraulically from a minimum height of 20 inches up to a maximum of 36 inches. Transfer of a patient to and from such variable-height tables is thus considerably easier than with conventional tables, and involves a minimum of lifting of the patient; some wheelchair patients are able to move themselves on and off such tables with only a little assistance (Figure 2). An additional advantage of this type of examination table is that it has a “floating” tabletop. Once the patient is lying on the table, it is not necessary to physically move him/her for radiographic positioning, as the entire tabletop is readily mobile longitudinally and laterally on release of electronic locks operated by foot switches. Thus, the patient and the part of the body to be radiographed can be easily positioned relative to the overhead X-ray tube without moving the patient relative to the tabletop, avoiding any potential discomfort. The precise position is delineated in the usual way for radiographic exposures by means of a light-beam collimator, which illuminates with visible light the shape, size, and position of the area on the patient to be radiographed. Some types of X-ray equipment (e.g. CT scanners) use low-power laser light beams for precise patient positioning. For transferring patients on to examination tables, assistance from staff (radiographers, nurses, radiography helpers) is often required. Proper training of staff in patient-lifting techniques is essential to avoid injury to patients and staff.

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Figure 2 Elevating adjustable height, floating table top X-ray examination table

Lifting of patients without such training has the potential of back injury to the lifter and risks of the patients being dropped. Large numbers of back injuries currently occur to NHS staff as a result of lifting (Health and Safety Executive, 1992). Some hospitals and trusts have adopted “no-lifting” policies; all patient transfers and lifting being by mechanical aids – this has led to a significant reduction in the incidence of back injuries in staff (Royal College of Nursing, 1996). Mechanical lifting hoists are available for handling immobile patients. There are a variety of hoists available depending on patient’s needs, but these hoists have tended to be used only in extreme cases as they have been felt to be cumbersome and time consuming to use. Newer battery-powered lifting hoists such as the Arjo Maxilift are much more versatile and user friendly, and are helpful for transfer of wheelchair patients onto examination tables. Facilitation of transfer of patients from stretchers/trollies or inpatient beds on to examination tables can be helped using the Patslide , a large, low-friction, semiflexible plastic sheet measuring about 5-feet long by 2-feet wide, that can be used to bridge the narrow gap between stretcher and examination table. The patient is rolled partly onto his/her side, the Patslide positioned beneath the patient and a slide sheet, and the patient then rolled onto his/her back again and easily slid across it onto the examination table, because of the low coefficient of friction of the Patslide surface plus the ease of maneuver of the slide sheet (Figure 3). Many hospital beds and stretcher trollies can be adjusted in height to ease such transfers, allowing a slight downhill slope for easier movement of patients both on and off. Slide sheets

Figure 3 Placement of the Patslide to transfer a patient from an X-ray examination table onto a hospital trolley

which aid the user to turn patients and to move them up and down the bed into a sitting position easily without causing discomfort to the immobile patient and without causing undue stress to either the patient or the carer can also help in the transfer of patients from hospital bed to trolley and then onto the X-ray table. Some elderly patients are unable to stand without assistance, or to stand still enough or for long enough for erect radiographs to be obtained, for example, PA (posteroanterior) or lateral chest radiographs. These can be performed with the patient seated, using a special hydraulic examination chair with removable back and arm rests which can be left in situ except during the actual radiographic exposure (Figure 4). The seat can be raised, lowered, rotated, and locked in position with ease. There are a variety of reasons why patients may need assistance getting on and off radiographic examination tables, including: Immobility • Joint stiffness and/or pain – arthritis, including osteoarthritis, rheumatoid arthritis, gout, ankylosing spondylitis, and other erosive arthropathies • Muscle stiffness and pain – rheumatism, lumbago, and so on • Neuralgia – sciatica, and so on • Paralysis – stroke • General weakness/debility • Obesity

DIAGNOSTIC IMAGING AND INTERVENTIONAL RADIOLOGY

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is not intended to be exhaustive; it covers those examinations most frequently performed in elderly patients plus less common procedures where there are special considerations.

Plain Film Radiography

Figure 4 Use of hydraulic chair for erect chest radiographs for patients unable to stand

• Amputation • Neurological disorders – Parkinson’s disease, ataxias, multiple sclerosis • Tendency to fall – vertigo, faintness Inability to cooperate • Deafness • Blindness • Failure to comprehend or remember instructions – dementia, lack of understanding of the language of communication Unwillingness to cooperate • Dementia – Alzheimer’s disease, multi-infarct, and so on • Psychological – depression, psychiatric illness, stubbornness, pride, dignity, shame, apprehension, claustrophobia. Physiological handling of intravascular contrast media and of drugs used in radiology may be impaired in the elderly due to diminished renal and hepatic function; this must be allowed for in the choice and dosage of these agents.

IMAGING TECHNIQUES AND INTERVENTIONAL PROCEDURES – SPECIFIC PROBLEMS Various problems can arise related to specific imaging investigations or interventional procedures. The following list

The general problems previously discussed, which can make getting on and off X-ray examination tables difficult, can also cause difficulties in patient positioning and radiographic exposure. Problems can be encountered in keeping patients still for sufficient time for the radiographic exposure; in these circumstances it is helpful to keep the exposure time as short as possible to minimize movement effects. This can be achieved by use of higher kilovoltage (kV) techniques when soft tissue contrast is not critical. Since radiographic exposure depends on the mAs (milliamp.seconds) setting, the use of as high a tube current as possible within the limits of the X-ray tube capacity and the generator output will shorten the time. For most X-ray sets, however, the mAs setting is combined in one control, so exposure time cannot be separately selected. For abdominal exposures of the renal tract, kidney, ureter and bladder (KUB), the use of compression reduces the exposure, and hence the exposure time, by moving soft tissues not of interest out of the field of view. Bowel preparation can reduce the X-ray exposure for KUB radiographs by emptying the colon of feces (Hasan et al., 1996). Immobilization devices such as sandbags, retaining straps and supports, and compression bands can be helpful in preventing involuntary movements. The chest radiograph is useful in assessing heart size – clinical assessment can be misleading in the elderly patient (Mulkerrin et al., 1991). Breath holding is important to avoid movement blur in radiographic examination of the chest or abdomen; achieving this can be difficult if the patient is unable to hear or understand instructions, has a very poor memory, or is unwilling or unable to cooperate for the reasons previously discussed. Shortage of breath may present similar problems in breath holding, even in cooperative patients. Breathlessness due to cardiac failure, airways obstruction (chronic obstructive airways disease – COAD – or asthma) can present problems, but fortunately the exposure for chest radiographs is short, typically 0.01 seconds. Anxious or agitated patients may have difficulty in keeping still; careful explanation and reassurance by the radiographer are essential. Extremes of weight (i.e. gross obesity or emaciation) in some elderly patients can make correct radiographic exposure difficult. Emphysema necessitates relative underexposure of chest radiographs to avoid an overexposed “black” film. An abdomen distended by ascites or by a fecally overloaded colon from severe constipation, or the abdomen of a grossly obese patient requires relative overexposure. Exposure factors in plain film radiography are largely controlled automatically by means of automatic exposure control (AEC) ionization chambers, which are sensors that react to the amount of radiation passing through them en route to the film, terminating the exposure when sufficient; the skill of

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the radiographer is nonetheless paramount in obtaining good radiographic exposure as well as positioning. For patients who are too unwell to be moved from the ward to the department of clinical radiology, portable radiographic examinations can be performed. These will seldom be of as good quality as departmental radiographs, owing to the limited power output of the portable X-ray machine, and particular difficulties arise in positioning the patient, achieving adequate film-focus distance, and controlling exposure. Portable exposures are best confined to chest radiographs, although a reasonable quality abdominal radiograph is possible, except in obese patients. Transfer of the patient to the radiology department in his/her hospital bed is a better alternative to portable radiography; even if the patient is still radiographed in bed, as higher-quality radiographs can be obtained.

Digital Radiography In digital or “filmless” radiography, an X-ray image produced by an image intensifier is recorded digitally and stored in a computer memory, replacing the conventional X-ray film. (An image intensifier is a device for greatly enhancing the faint fluorescence of an input phosphor screen in response to radiation, by electron release and capture, causing much brighter fluorescence of an output phosphor screen viewed by a TV camera). The resulting image is viewed on a TV monitor. Hard copy can be made using a laser imager or other imaging devices (Harding and Roberts, 1996). The exposure time is usually shorter in digital radiography than in conventional radiography – this can be advantageous in patients who have difficulty in keeping still or in breath holding. Clinical Radiology Departments and hospitals generally are moving more and more towards computerised digital systems with paperless electronic requesting and reporting, and filmless PACS (picture archiving communication systems) without hard copy, and allowing simultaneous multi-site access to images by radiologists and clinicians.

Barium Studies of the Gastrointestinal Tract Barium Swallow

The cooperation of the patient in drinking adequate volumes of barium quickly enough, and at the right time, is essential for diagnostic studies of the esophagus, and particularly for rapid sequence radiography (at 2, 3, or 4 frames per second) or videoradiography of the oropharynx and upper esophagus. Elderly patients are more likely to aspirate barium into the larynx, trachea, and bronchial tree during barium swallows and meals. This can lead to aspiration pneumonia requiring physiotherapy and can be fatal (Ansell, 1987). Patients who are unable to stand can still have an erect barium swallow on an overcouch X-ray table by raising the footstep and sitting the patient on it. If there is difficulty in drinking from an ordinary cup, a feeding cup with a spout can be substituted, or the patient can drink through a large-bore

flexible straw. In extreme cases, the barium can be spooned into the patient’s mouth. Barium Meal and Barium Follow-through

An empty stomach is mandatory for barium meal and barium follow-through (upper gastrointestinal) studies. Compliance of the patient with fasting instructions is essential. Diabetic patients are best scheduled first or second in early-morning barium lists to lessen risks of hypo- or hyperglycemia. Diabetics on insulin or oral hypoglycemic therapy should withhold these agents until after eating breakfast immediately following the barium meal. Patients taking other oral medication need to withhold this because of fasting for a barium meal or follow-through; pills and capsules should be taken with a small glass of water before the barium study, notwithstanding the requirements of fasting, and this must be made clear in the patient information/instruction sheet. It is necessary to emphasize the importance of taking a small cupful of water with tablets or capsules, as these can otherwise remain in the esophagus for long periods of time without being absorbed (Evans and Roberts, 1976). In addition to being therapeutically ineffective in this situation, some medications will cause esophagitis. Orally ingested barium can subsequently cause severe constipation in susceptible elderly subjects (Ansell, 1987). This should be explained to the patient, relative, or carer, and the patient advised to eat plenty of high-fiber food, fruits, and so on after the barium meal, or to take a mild laxative. Smooth-muscle relaxants are frequently administered to patients undergoing barium meals (and barium enemas) to allow adequate gaseous distension of the stomach (or colon) in double-contrast examinations, where fine mucosal detail can be evaluated. Buscopan (hyoscine N -butyl bromide, 20 mg intravenously) is often used, but should not be given to patients suffering from cardiac arrhythmias, coronary artery disease, or closed-angle glaucoma (Fink and Aylward, 1995), all of which are more common in the elderly. Glucagon 0.5 mg i.v. may be substituted in these patients (Goei et al., 1995). An effervescent agent – sodium bicarbonate granules, powder, or tablets, sometimes with citric acid as an adjuvant – is swallowed before the barium to produce carbon dioxide gas for the doublecontrast technique. The patient must refrain from burping or belching, or a double-contrast barium meal will not be possible. A normally conducted barium meal means changing patient position from erect to prone and supine, and quite a lot of turning between prone and supine positions – patients have to be fit to undergo a barium meal! The examination can, however, be tailored with limited views and fewer changes of position in very ill patients. Barium Enema

Bowel preparation for barium enema requires several days of dietary modification/restriction and strong oral laxatives on


the day before the examination. This can make some patients unwell to the extent that outpatients will contact the radiology department requesting that the examination be cancelled or postponed; it is advisable to try to persuade these patients to attend regardless, as it is a pity to have undergone the fairly arduous preparation and then not to have the enema and, even worse, to have to undergo bowel preparation a second time. In particular, patients can feel unwell because of the bowel preparation during hot summer weather. Dehydration can occur; adequate fluid intake must be maintained. Migraine attacks may be precipitated in susceptible patients. If a large or even moderate amount of fecal residue is present in the colon, a double-contrast examination is unlikely to be diagnostic; filling defects such as polyps or tumors can be missed, and ulceration can be difficult to evaluate. It is said that the radiologist who attempts a doublecontrast barium enema on the inadequately prepared patient requires (and acquires) only a knowledge of feces! Such patients are better examined by a single-contrast technique using barium followed by water – this is far more likely to achieve a diagnostic result even without the superior mucosal detail afforded by double-contrast studies. A singlecontrast examination is also more suitable for patients who have difficulty in retaining barium – it is quicker, less uncomfortable, and patients who cannot retain air insufflated for double-contrast examinations can often retain fluid in a barium/water examination. Multiple “spot” radiographs can be obtained on 100-mm cut film (as commonly used for barium meals) taken from the output phosphor screen of an image intensifier by a camera using a similar mirror arrangement to that in single-lens reflex cameras. This allows rapid alternation between a TV camera (during fluoroscopic screening) and a spot film camera (to record hard copy). There is the advantage of a shorter exposure time than with conventional radiographic film exposure, avoiding movement blur in restless or breathless patients, plus the added advantages of shortening the examination time, as 100 mm film changing is automatic and quick, and reducing radiation exposure compared with conventional film. In patients likely to have difficulty retaining barium, the use of a balloon retention barium enema catheter can help, but patient cooperation is still required – the inflated balloon catheter can be expelled rectally by uncooperative patients. The use of smooth-muscle relaxants makes the barium enema examination less uncomfortable for the patient, in addition to improving diagnostic quality. For patients with anal strictures or fistulae, in whom a normal-sized catheter cannot be inserted, a smaller Foley bladder catheter can be substituted.

Intravenous Urography (IVU) Renal function declines in the elderly (Cox et al., 1991). Higher doses of contrast medium may be required for opacification of the renal tract. Modern low-osmolality nonionic contrast media are much more patient-friendly than the older ionic contrast media, but there are still risks of allergy

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and precipitation of cardiac failure (Holtas and Tornquist, 1987; Harding, 1996a). Renal function of patients undergoing contrast examinations may become impaired, particularly if there is pre-existing renal disease (Trewhella and Dawson, 1990). Patients with diabetes are more likely to have some degree of impairment of renal function than the normal population and are said to be at greater risk of contrast nephropathy. Metformin (glucophage) therapy for non-insulin-dependent diabetes mellitus may occasionally cause severe life-threatening lactic acidosis in patients with impaired renal function, with mortality greater than 50% (Monson, 1993; Sirtori and Pasik, 1994). The combination of metformin and X-ray contrast media may have adverse affects because contrast media impair or further impair renal function and hence metformin excretion. Significant numbers of patients attending for diagnostic and interventional radiological procedures involving contrast medium administration, such as during IVU, will be taking metformin. All patients who are to receive intravascular X-ray contrast media (whether for IVU, vascular studies, or enhancement of CT scans) should be asked if they are diabetic and, if so, whether they are receiving metformin (glucophage) therapy. The advice of The Royal College of Radiologists is that if a patient is receiving metformin therapy, the drug should be stopped for 48 hours before and 48 hours after any X-ray contrast medium examination. This should be discussed fully with the patient’s referring clinician or general practitioner (GP) – adjustment of the control of the patient’s diabetes may be needed. Renal function should be checked 48 hours after the injection of X-ray contrast medium and prior to the resumption of metformin therapy. X-ray contrast medium–enhanced procedures in emergencies should continue to be carried out without delay. However, the patient’s referring clinician or GP and the local renal physicians should be consulted. Obesity and constipation can obscure renal detail, although this can be overcome by tomography in patients able to cooperate with adequate breath-holding (tomography requires a longer exposure time than plain radiographs).

Vascular Radiology Patient cooperation in keeping very still is essential for arteriography and venography, especially when digital subtraction is utilized. Digital subtraction angiography (DSA), previously known as digital vascular imaging (DVI), is similar to digital radiography, but may be included as an “add-on” to older fluoroscopic imaging equipment, as well as being built into digital radiographic equipment. In DSA, summated TV frames early in a sequence of images during a dynamic vascular examination are subtracted pixel by pixel from later-summated TV frames, following intravascular injection of a radiographic contrast medium. This results in imaging only those structures in the field of view opacified by the contrast medium, with subtraction of overlying bony or gas-filled structures. This is analogous to

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a similar technique applied in the past using photographic subtraction of a plain radiograph taken before contrast medium injection from a later one in which the blood vessels were opacified by contrast medium. DSA is very sensitive and can satisfactorily image considerably diluted contrast medium. For example, faintly opacified arteries can be imaged following intravenous injection of contrast medium, which becomes diluted by mixing with blood during its passage through the right heart chambers, the pulmonary vascular system, and the left side of the heart before entering the systemic arterial circulation. This is a less invasive procedure than conventional arteriography and can be performed on an outpatient basis (Harding and Lenaghan, 1985). The image data may be recorded digitally, as in digital radiography, or on older systems may be recorded on magnetic recording tape in analog form. The subtraction images can be viewed dynamically on a TV monitor either as a continuous real-time image showing gradual appearance and disappearance of contrast medium in the blood vessels being studied, or as regularly upgraded static images at short time intervals. The optimal images can then be frozen for production of hard copy. Very small amounts of patient movement during DSA can be compensated for on postexamination analysis by registering the position of the early mask relative to the contrast-filled images, or even utilizing a post-opacification mask, but larger amounts of movement make the technology unusable. For abdominal angiography breath holding is essential. Vascular access for angiography by the Seldinger technique (Seldinger, 1953) requires local anesthesia to avoid excessive pain. Systemic intravenous sedation and analgesia may be needed in addition for apprehensive patients, but it must be remembered that older patients are frequently more sensitive to such agents because of diminished metabolic clearance, and a slowly administered, titrated lower dose is usually necessary, along with careful monitoring of pulse, respiration, blood pressure, and arterial oxygen saturation by pulse oximetry. If a patient is sedated to a semiconscious level, anesthetic assistance is the ideal; at the least, a trained and experienced nurse should be dedicated to the task of monitoring and caring for the patient (Skelly, 1996). For some vascular procedures, and particularly for more difficult superselective arteriography and interventional vascular procedures, such as angioplasty, stenting, or embolization, a patient may be lying on the X-ray fluoroscopy table for several hours. Many invasive vascular investigations are now being replaced by other noninvasive imaging modalities, for example, ultrasound, including Doppler and power Doppler, CT angiography, and MRI angiography.

ULTRASOUND Ultrasound scanning uses a probe operated by the piezoelectric effect to emit ultrasound of frequency 3.5–10 MHz into

the patient and receive returning echoes from internal structures, producing a real-time, gray-scale image displaying the echo intensity as a 2D image on a TV monitor. Doppler ultrasound allows flow within blood vessels to be displayed. In duplex Doppler, the 2D image and Doppler waveform are displayed simultaneously, allowing accurate placement of the sampling gate over the region of interest. Color flow Doppler assigns different colors (usually red and blue) to flow in different directions, so that adjacent arteries and veins are displayed in different colors superimposed on the monochrome ultrasound image. Abdominal and pelvic ultrasound scanning needs the patient’s cooperation in keeping still, turning into position, and breath holding including deep inspiration for examination of the liver, gallbladder, spleen, and kidneys. Adequate ultrasound examinations are more difficult to perform and interpret in obese patients, and also in very thin patients. Pelvic ultrasound for examination of the uterus, ovaries, and adnexa needs a full urinary bladder. Other ultrasound scans, for example, of the thyroid gland, breast, and testes, and arterial and venous Doppler ultrasound, do not usually present any special problems in the elderly.

NUCLEAR MEDICINE Nuclear medicine imaging or gamma camera scanning produces images from γ -rays emitted by a radionuclide injected in to the patient. The most common radionuclide used is technetium (99m Tc), which is tailored to image different structures or physiology by chelating it with compounds to target specific organs and/or physiological functions. The emitted γ -rays are detected by a gamma camera, which consists of a large lead-shielded crystal that scintillates when a γ -ray enters it. Groups of photomultiplier tubes behind the crystal detect and localize the scintillations and a computer analyzes the resulting electrical signals and reconstructs an image. Nuclear medicine demonstrates physiology rather than anatomy. Because of the requirement to keep the radiation dose to the patient as low as possible, gamma camera scans typically need long imaging periods ranging from 5 to 30 minutes, during which the patient must remain absolutely still – this can be difficult for elderly patients. Patients with orthopnea due to cardiac failure can have difficulty lying flat for nuclear medicine examinations.

COMPUTED TOMOGRAPHY Computed tomography (CT; computer-assisted tomography – CAT scanning) uses measurements of X-ray attenuation recorded by an array of detectors from a thin fan-beam of X rays. The X-ray source and detector array rotate circumferentially around the patient. This results in millions of measurements of X-ray attenuation, which can be used to


reconstruct an image of an axial slice through the patient by computer analysis using a back-projection method. Images can be reformatted in other planes, for example, coronal and sagittal, by summating information from adjacent axial slices, and 3D reconstructions are possible. The latest generation of CT scanners use helical or spiral scanning instead of planar scanning of individual axial slices, resulting in decreased scanning time and allowing better dynamic imaging of blood vessels following contrast medium injection. Patients must keep absolutely still during CT scans or image artefacts will occur. For examination of the thorax or abdomen, breath holding is necessary. It is possible to scan the entire thorax or abdomen during a single breath-hold in cooperative patients using helical scanning. CT angiography following intravenous contrast medium injection can produce diagnostic images, including 3D reconstructions, avoiding the need for conventional invasive arteriography.

MAGNETIC RESONANCE IMAGING MRI uses the principles of nuclear magnetic resonance (NMR) to produce cross-sectional images without the use of ionizing radiation. The patient is placed in a very strong magnetic field, typically 0.5–1.5 tesla (5000–15 000 gauss; cf. the earth’s magnetic field is 0.7 gauss). Radio frequency pulses are applied at the same frequency as the precession frequency of the protons (hydrogen atoms) present in the body, causing them to resonate, like tuning forks of the same frequency. Some of the protons which are aligned with the applied magnetic field will invert or “flip” as a result, and if the radio frequency pulse is long enough, the protons will all precess in phase rather than randomly. When the radio frequency pulse is removed the protons will revert to their former state; those which have inverted will return to their earlier alignment, and they will again precess randomly. This results in very small magnetic field changes which can be detected by receiving coils, amplified, and reconstructed into cross-sectional images in any plane (Harding, 1996b). Examination sequences range from less than 1 minute to more typical times of 4 to 5 minutes, depending on the pulse sequence employed. During each examination sequence, complete freedom from movement is essential to avoid artefacts. Various immobilization devices and supports can aid this, often incorporated into surface coils, which give better visualization of localized body areas such as the head, neck, or knees. MRI scanning can be a daunting experience for elderly patients, due to the confined space within the scanner and the noise generated during scanning when the magnetic field gradients are changing rapidly. For the patient, entering the aperture of the MRI scanner can be reminiscent of a coffin entering a crematorium – this certainly frightens some patients and about 5% of all patients refuse MRI scanning because of claustrophobia or fear. The noise during scanning with knocking and hammering sounds which can be similar

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to a pneumatic drill in operation, although not quite as loud, can be upsetting; ear plugs can minimize the problem, though this makes patient communication a little more difficult. Conventional headphones cannot be incorporated into ear muffs as they would be nonoperative in the high magnetic field within the scanner, tens of thousand times the strength of the earth’s magnetic field. There are various contraindications to MRI, most of which are more common than the average in elderly patients, for example, cardiac pacemakers, ferromagnetic implants such as some surgical clips, some prosthetic cardiac valve replacements, and cochlear implants.

THERMAL IMAGING Thermography is not widely utilized in the United Kingdom, but is undertaken in some centers. It has the advantages of being noninvasive and free of risks. It can be performed by a contact technique using liquid crystal detectors or with a thermal imaging camera which detects infrared (IR) radiation emitted by the patient, displayed as an image on a TV monitor. Thermal imaging is mainly used in the investigation of back pain syndromes and vascular disorders. In the author’s experience it has proved a very useful examination tool in the initial investigation of deep venous thrombosis (DVT) (Harding, 1995, and in the investigation of osteomyelitis complicating diabetic foot ulceration, where diagnostic thermographic changes occur before radiological abnomalities, enabling earlier aggressive therapy, with significant reduction in morbidity (Harding et al., 1998, 1999)).

INTERVENTIONAL RADIOLOGY Interventional procedures may be undertaken under X-ray fluoroscopic control, ultrasound, CT, or MRI guidance. The range of interventional radiological procedures is constantly increasing in scope and complexity (Watkinson and Adam, 1996; Wilkins et al., 1989; Rickards and Jones, 1989; Harding, 1993). Careful selection of patients for interventional radiological procedures is essential, jointly decided between the radiologist and referring clinician. Informed consent is essential before performing interventional radiological procedures, and is best obtained by the radiologist personally rather than by junior clinical medical staff who may not be familiar with the details of the procedure to be performed. Consent should be obtained before the patient comes to the radiology department. This gives the radiologist the opportunity to build a relationship with the patient and, although time-consuming, this is time well spent. The importance of good communication between the radiologist and the patient cannot be overstated. The radiologist can assess the apprehensions and likely reactions of the patient away from the pressures of the radiology department. The benefits and potential risks of the procedure can be

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explained under circumstances in which the patient is better able to concentrate and more likely to remember the points that have been made. It also gives the patient time to gain confidence in the radiologist, to ask questions, and to have a chance to reflect on what has been said before the procedure is performed. “Good communication is the greatest antagonist to litigation” (Oscar Craig, past President of the Royal College of Radiologists) (Allison and Allison, 1996). Deep sedation and analgesia will be required for interventional radiological procedures, and for certain patients or procedures general anesthesia will be necessary. The patient sedated for interventional radiology will require careful clinical and electromechanical monitoring. Clinical monitoring includes assessment of the level of consciousness, anxiety and/or pain, respiratory rate, depth and regularity, skin color, temperature and pulse rate, character, and regularity. Electromechanical monitoring includes pulse oximetry and blood pressure. ECG monitoring is a useful adjunct to pulse oximetry for patients at increased cardiovascular risk where myocardial ischemia and/or arrhythmia is present or may be precipitated. The elderly are particularly susceptible to both the wanted and unwanted effects of all benzodiazepine sedatives (Skelly, 1996). • Biopsy, and so on – guided biopsy, aspiration cytology, and preoperative tumor localization. • Drainage – percutaneous drainage of obstructed systems, collections, or abscesses. • Fistula creation, and so on – deliberate creation of fistulae, ostomies, or shunts. • Stricture dilatation, and so on – dilatation, stenting, or bypassing of strictures or recanalization of occlusions. • Embolization – deliberate obliteration of occlusion of vessels or aneurysms. Needle biopsy or aspiration cytology of masses under imaging guidance is used for diagnosis and staging in many parts of the body, for example, liver, pancreas, abdominal and pelvic lymph nodes, kidney, adrenal glands, spleen, retroperitoneum, lung, pleura, mediastinum, and musculoskeletal system. Preoperative breast tumor localization with a wire marker makes the surgical approach easier and more accurate. Percutaneous drainage of abscesses or collections is frequently performed, including subphrenic and other intraabdominal abscesses, intrahepatic abscesses, pyonephrosis, perinephric abscess, pelvic collections, and pancreatic cysts or pseudocysts. In the thorax, pleural, intrapulmonary, and mediastinal collections can be accurately drained under CT or ultrasound control. Vascular procedures include percutaneous transluminal angioplasty and vascular stenting for arterial stenosis or occlusion, arterial thrombolysis for acute obstruction in peripheral limb arteries and coronary arteries, aspiration thromboembolectomy, and mechanical thrombectomy and venous thrombolysis. Percutaneous transcatheter embolization is used for deliberate occlusion of aneurysms or selective occlusion of blood vessels supplying arteriovenous

malformations (AVMs) and fistulae, or varices. Emergency embolization for hemorrhage is most commonly required for gastrointestinal hemorrhage, massive hemoptysis usually from bronchial arteries, and trauma to kidney, liver, or pelvis. Pulmonary artery embolization is also occasionally performed, for hemoptysis is not responsive to bronchial (and nonbronchial systemic) embolization. Dilatation and stenting can be undertaken in superior vena cava (SVC) obstruction. Complications relating to intravascular lines and, in particular, venous catheters are not uncommon, and can usually be easily remedied in the radiology department. Foreign bodies can be retrieved from the vascular system by percutaneous catheter techniques, for example, fragments of central venous catheters, inferior vena caval filters, metallic stents, and misplaced embolization coils. Bronchial stenting for palliation of malignant tracheobronchial stenosis can be placed under a combination of direct (endoscopic) vision and radiological fluoroscopic screening. The TIPS (transjugular intrahepatic portosystemic shunt) procedure is used to create a fistula between the portal and hepatic venous systems for the relief of portal hypertension with recurring variceal bleeding. DVT can be prevented from causing pulmonary emboli by percutaneous insertion of devices into the inferior vena cava (IVC) under fluoroscopic control. IVC filters are not used in first-line prophylaxis against pulmonary embolic disease, but have a small but increasingly well-defined role in those patients who are unsuitable for conventional prophylaxis with anticoagulant therapy or who need temporary protection. In the urinary tract, interventional procedures include percutaneous nephrostomy drainage and ureteric stenting for ureteric obstruction, percutaneous dilatation of ureteral strictures, percutaneous occlusion of ureteral fistulae, and percutaneous suprapubic cystostomy and urethral stenting for bladder outlet obstruction. Percutaneous nepholithotomy for renal calculi is used occasionally in selected cases, but has been largely superseded by extracorporeal shock wave lithotripsy (ESWL). Biliary obstruction can be treated by percutaneous transhepatic biliary drainage or percutaneous cholecystostomy, which is also used for drainage of acute empyema of the gallbladder or for access for gallstone removal. Benign and malignant biliary structures can be dilated and stented percutaneously and calculi in the intrahepatic and extrahepatic tree removed. Interventional radiology may be combined with endoscopic procedures in the biliary tract. In the gastrointestinal tract, interventional radiological procedures are performed in the treatment of esophageal structure by balloon dilatation and stenting. Percutaneous gastrostomy, transgastric jejunostomy, and percutaneous jejunostomy are used for enteral nutrition therapy or gastrointestinal decompression. Radiologically guided cacostomy can be used in colonic obstruction as a temporizing measure in high-risk surgical patients. Colonic strictures following surgical anstomosis can be dilated by balloon catheter techniques.


KEY POINTS • An aging population is generally associated with multiple comorbid conditions. • Good communication and an understanding approach is essential for successful investigation and intervention. • Assessment of risk/benefit outcome is critical for successful resource utilization and clinical benefit for patients. • Specific adaptations of radiology unit and equipment to facilitate management of older disabled patients are of cardinal importance. • CT, MRI, Ultrasound, and barium studies are often essential investigations for older people, but require their cooperation.

KEY REFERENCES • DH (Department of Health). The Ionising Radiation (Medical Exposure) Regulations 2000, (IR(ME)R 2000). Department of Health, Statutory Instrument 2000 No. 1059. The Stationery Office Limited, HMSO, London, ISBN 0-11-099131-1. • European Union. European Directive 97/43/Euratom (The Medical Exposures Directive); EU, Brussels. • National Radiological Protection Board and The Royal College of Radiologists. Patient Dose Reduction in Diagnostic Radiology 1990; HMSO, London, ISBN 0-85951-327-0. • RCR Working Party. Making the Best Use of a Department of Clinical Radiology: Guidelines for Doctors 2003, 5th edn; Royal College of Radiologists, London. • Royal College of Nursing. Introducing a Safer Patient Handling Policy 1996, pp 1 – 7; Royal College of Nursing, London.

REFERENCES Allison D & Allison H. Ethics and informed consent. In A Watkinson & A Adam (eds) Interventional Radiology: A Practical Guide 1996, pp 12 – 5; Radcliffe Medical Press, Oxford. Ansell G. Alimentary tract. In G Ansell & RA Wilkins (eds) Complications in Diagnostic Imaging 1987, 2nd edn, pp 218 – 46; Blackwell Scientific Publications, Oxford. Ansell G, Bettmann MA, Kaufman JA & Wilkins RA (eds) Complications in Diagnostic Imaging and Interventional Radiology 1996, 3rd edn; Blackwell Science, Oxford. Audit Commission. Improving Your Image: How to Manage Radiology Services More Effectively 1995; HMSO, London, ISBN 0-11-8864-149. Cox JR, Macias-Nunez JF & Dowd AB. Renal disease. In MSJ Pathy (ed) Principles and Practice of Geriatric Medicine 1991, 2nd edn, pp 1159 – 77; Wiley, Chichester. DH (Department of Health). The Ionizing Radiation (Protection of Persons Undergoing Medical Examinations or Treatment – POPUMET) Regulations 1988; HMSO, London. DH (Department of Health). The Ionising Radiation (Medical Exposure) Regulations 2000, (IR(ME)R 2000). Department of Health, Statutory Instrument 2000 No. 1059. The Stationery Office Limited, HMSO, London, ISBN 0-11-099131-1.

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European Union. European Directive 97/43/Euratom (The Medical Exposures Directive); EU, Brussels. Evans KT & Roberts GM. Where do all the tablets go? Lancet 1976; 2:1237 – 9. Fink AM & Aylward GW. Buscopan and glaucoma: a survey of current practice. Clinical Radiology 1995; 50:160 – 4. Goei R, Nix M, Kessels AH & Ten Tusscher MPM. Use of antispasmodic drugs in double contrast barium enema examination: glucagon or buscopan? Clinical Radiology 1995; 50:553 – 7. Harding JR. Percutaneous antegrade ureteric stent insertion in malignant disease. Journal of the Royal Society of Medicine 1993; 86:511 – 3. Harding JR. Liquid crystal thermography in the investigation of deep venous thrombosis. In K Ammer & EFJ Ring (eds) The Thermal Image in Medicine and Biology 1995, pp 232 – 6; Uhlen Verlag, Vienna. Harding JR. The characteristics of an ideal intravascular contrast medium. RAD Magazine 1996a; 22(259):16. Harding JR. Principles of magnetic resonance imaging. In L Paine (ed) Hospital Management International 1996b, pp 203 – 4; Sterling Publications, London. Harding JR, Banerjee D, Wertheim DF et al. Infrared imaging in the longterm follow-up of osteomyelitis complicating diabetic foot ulceration. Proceedings of the Engineering in Medicine & Biology Society, Institute of Electrical & Electronic Engineers 1999; 21:1104. Harding JR & Lenaghan AE. The impact of digital subtraction angiography on a district general hospital. The British Journal of Radiology 1985; 58:814. Harding JR & Roberts SA. Laser imaging in clinical radiology. Journal of Photographic Science 1996; 44:11 – 3. Harding JR, Wertheim DF, Williams RJ et al. Infrared imaging in diabetic foot ulceration. European Journal of Thermology 1998; 8:145 – 9. Hasan AKH, Sutton D, Burne D & Menhinick S. Intravenous urography; the value of oral laxative. International Uroradiology ‘96-Program and Abstracts 1996, p 134; European Society of Uroradiology and the Society of Uroradiology. Health and Safety Executive. Manual Handling Operations Regulations 1992: Guidance on Regulations 1992; HMSO, London. Holtas S & Tornquist C. Renal complications of contrast media. In G Ansell & RA Wilkins (eds) Complications in Diagnostic Imaging 1987, 2nd edn, pp 37 – 52; Blackwell Scientific, Oxford. Mulkerrin E, Saran R, Dewar R et al. The apex cardiac beat: not a reliable clinical sign in elderly patients. Age Ageing 1991; 20:304 – 6. National Radiological Protection Board. Protection of the Patient in X-ray Computed Tomography 1992; HMSO, London, ISBN 0-85951-345-8. National Radiological Protection Board and The Royal College of Radiologists. Patient Dose Reduction in Diagnostic Radiology 1990; HMSO, London, ISBN 0-85951-327-0. RCR Working Party. A multi-centre audit of hospital referral for radiological investigation in England and Wales. British Medical Journal 1991; 303:809 – 12. RCR Working Party. Influence of the Royal College of Radiologists’ guidelines on hospital practice: a multicenter study. British Medical Journal 1992; 304:740 – 3. RCR Working Party. Making the Best Use of a Department of Clinical Radiology: Guidelines for Doctors 2003, 5th edn; Royal College of Radiologists, London. Rickards D & Jones SN. Percutaneous interventional uroradiology. The British Journal of Radiology 1989; 62:573 – 81. Roberts CJ. Towards the more effective use of diagnostic radiology: a review of the work of the RCR Working Party on the more effective use of diagnostic radiology 1976 – 1986. Clinical Radiology 1988; 39:3 – 6. Roberts CJ. The RCR multi-centre guideline study: implications for clinical practice. Clinical Radiology 1992; 45:365 – 8. Royal College of Nursing. Introducing a Safer Patient Handling Policy 1996, pp 1 – 7; Royal College of Nursing, London. Seldinger SI. Catheter replacement of the needle in percutaneous arteriography: a new technique. Acta Radiologica 1953; 39:368 – 76. Sirtori CR & Pasik C. Re-evaluation of biguanide, metformin: mechanism of action and tolerability. Pharmacological Research 1994; 30:187 – 228.

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Skelly A. Analgesia and sedation. In A Watkinson & A Adam (eds) Interventional Radiology: A Practical Guide 1996, pp 3 – 11; Radcliffe Medical Press: Oxford. Trewhella M & Dawson P. Intravascular contrast agents and renal failure. Clinical Radiology 1990; 41:373 – 5. Watkinson A & Adam A (eds) Interventional Radiology: A Practical Guide 1996; Radcliffe Medical Press, Oxford. Wilkins RA, Nunnerley HB, Allison DJ et al. The expansion of interventional radiology. Report of a survey conducted by the Royal College of Radiologists.Clinical Radiology 1989; 40:457 – 62.

FURTHER READING Gray JAM. Social and community aspects of ageing. In MSJ Pathy (ed) Principles and Practice of Geriatric Medicine 1991, 2nd edn, pp 181 – 94; Wiley, Chichester. Monson JP. Selected side-effects. II. Metformin and lactic acidosis. Prescribers’ Journal 1993; 33:170 – 3.

PART III


Infectious Disorders

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Infectious Diseases Ann R. Falsey University of Rochester School of Medicine and Dentistry, Rochester, NY, USA

INTRODUCTION It is at the extremes of age when susceptibility to infection and the complications thereafter are the greatest. With the rapid growth of the number of elderly persons in most developed countries, an understanding of the unique features of infectious diseases in the aged is essential. The many causes of increased morbidity and mortality from infections in the elderly are outlined in Table 1. Aging is associated with the presence of chronic diseases as well as declines in cellular and humoral immune function. In addition to the physiologic changes of aging, a segment of the older population lives in congregate settings such as group homes and long-term care facilities (LTCF), which present special issues related to the spread of infectious diseases. The incidence of some infections, such as influenza, decreases with advancing age, yet the morbidity is substantially higher. However, many infections increase in both frequency and severity in older age-groups (Tables 2 and 3). It is also important to recognize that the specific types of organisms affecting older persons differ from those affecting younger age-groups and that older persons may not exhibit the typical clinical manifestations of infection that are observed in healthy young adults. Infections of specific organ systems will be discussed separately in their respective articles. This article will review the epidemiology, clinical manifestations, and general approach to infections in older persons. In addition, sexually transmitted diseases (STDs), severe acute respiratory syndrome (SARS), specific problems unique to LTCF, and current recommendations for vaccination in the elderly will be discussed.

EPIDEMIOLOGY OF INFECTIONS Infections are among the most common causes of hospitalization and death in both community-dwelling and institutionalized older persons. The incidence of infection depends on the

place of residence and functional status of the groups studied. Although 95% of older adults do not live in LTCFs, specific data on infection rates in community-dwelling elderly are limited. In a 2 year prospective study of 417 independent older persons, investigators found that 224 (54%) experienced a total of 494 infections (Ruben et al., 1995). Respiratory tract, genitourinary and skin infections accounted for 53, 24, and 18% of the infections, respectively. Of note, 144 (35%) of these 417 persons were hospitalized 260 times. One hundred of the 260 admissions (38%) involved infection and, in half, infection was the primary diagnosis. In addition, hospitalized older persons have been shown to experience higher rates of nosocomial infections which are associated with a higher mortality rate (Emori et al., 1991). The number of infections occurring in nursing homes approaches that of acute-care hospitals. The demographics of nursinghome populations are very different compared to those of community-dwelling older persons. Nursing-home residents are generally 85 years or older (40%), female (71%), and white (92%) (Verghese and Berk, 1990). Single day prevalence studies yield highly variable infection rates with upper limits of 32.7% and incidence rates up to 20 infections per 100 resident-months, resulting in approximately 1.5 million nosocomial infections per year in LTCF in the United States (Smith et al., 1991). In addition to the chronic problems of respiratory, urinary tract, and skin infections, nursing homes are prone to epidemics of certain diseases, such as tuberculosis (TB), conjunctivitis, scabies, gastroenteritis, and influenza. Infection is the most common problem, necessitating transfer from nursing homes to acute-care hospitals, accounting for between 10 and 49% of all transfers.

Specific Infections Bacterial Respiratory Infections

Pneumonia is one of the most important infectious causes of morbidity and mortality in persons of any age, but it is


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Table 1 Causes of increased morbidity and mortality of infections in older persons

Immunosenescence Diminished mobility Physiologic change in organ systems Poor circulation Edema of soft tissues Weakening of respiratory muscles Depressed gag reflex Obstructive uropathy Changes in vaginal flora associated with diminished estrogen levels Comorbid diseases Cardiac Pulmonary Diabetes Malignancies Dementia Peripheral vascular disease Iatrogenic Intravenous lines Implantable cardiac devices: valves, pacemakers, defibrillators Feeding tubes Bladder catheters Congregate living

Table 2 Infections that increase in frequency with age

Pneumonia Tuberculosis Urinary tract Chronic bacterial prostatitis Herpes zoster Skin/soft tissue Contiguous focus osteomielitis Endocarditis Bacteremia Diverticulitis Cholecystitis Intrabdominal abscess Clostridium difficile diarrhea Adapted from Yoshikawa (1994).

Table 3 Increased mortality associated with infections in older persons

Infection Pneumonia Influenza SARS Pyelonephritis Bacteremia Appendicitis Cholecystitis Tuberculosis Infective endocarditis Bacterial meningitis Herpes zoster HIV

Relative risk of mortality of elderly compared to young adults 3 6 – 16 3–9 5 – 10 3 15 – 20 2–8 10 2–3 3 7 5

Adapted from Yoshikawa (1994).

in the young children and the elderly where its impact is greatest felt (see Chapter 61, Respiratory Disease in the Elderly). The incidence of pneumonia is 10 times greater

in adults over 70 years compared to persons between 20 and 29 years old (Woodhead, 1994). In addition, the likelihood of requiring hospitalization for pneumonia rises dramatically with age; from 0.54 cases per 1000 among persons aged 35 to 44, to 11.6 cases per 1000 persons over age 75 (Marrie, 1994). The incidence of community-acquired pneumonia in all adult age-groups is highest during the winter months, and is likely due to winter respiratory viruses. Pneumonia is the leading cause of nosocomial infection related deaths. In the National Nosocomial Infection Surveillance (NNIS) System study in the United States, pneumonia accounted for 18% of the infections and 48% of the deaths between 1986 and 1990 (Emori et al., 1991). The risk of nosocomial infections increases from a relatively constant rate of 10/1000 discharges for persons under age 50 to 100/1000 over age 70 (Gross et al., 1983). Other risk factors associated with nosocomial pneumonia in the elderly include neurologic disease, renal disease, dependency in activities of daily living, difficulty with oropharyngeal secretions, presence of nasogastric tubes, poor nutrition, intubation, and intensive care admission (Hanson et al., 1992; Harkness et al., 1990). Similar to the acute-care hospital, pneumonia is the second most common infection in chronic care facilities, but remains the most common cause of death (Niederman, 1993). The susceptibility to infection correlates strongly with the degree of functional impairment (Alvarez, 1990). Underdiagnosis of pneumonia is common because of nonspecific symptoms, the infrequent use of chest radiographs, and difficulty in obtaining sputum. Prevalence rates of lower respiratory tract infection in nursing homes range from 1.9 to 2.5% with incidence rates of approximately 47 per 100 resident-months (Garibaldi et al., 1981). The spectrum of pathogens that cause pneumonia in the elderly is broader than in young adults and includes nontypable Hemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus, and gram-negative bacilli. Nevertheless, S. pneumoniae remains the most common bacterial pathogen causing up to 60% of community-acquired pneumonias in the elderly (Woodhead, 1994). Lastly, the “atypical” pathogens Mycoplasma pneumoniae and Chlamydia pneumoniae are relatively uncommon in persons over age 65. Hospitalacquired pneumonia in the elderly is frequently caused by enteric gram-negative rods and accounts for as many as 60 to 80% of all cases (Niederman, 1993). The NNIS study showed that nosocomial pneumonia was due to Pseudomonas in 18%, Enterobacter sp. in 11%, Klebsiella pneumoniae in 8%, E. coli in 6%, and S. aureus in 15% of cases. Viral Respiratory Tract Infections

Rates of upper respiratory tract infections, the majority of which are caused by viruses, decline with advancing age and average one infection per year. However, the rates of infection depend in large part on the place of residence with increased rates of infection observed in seniors living in congregate settings (see Chapter 58, Epidemiology of Respiratory Infection). A recent study by Hodder et al. (1995) showed that the overall rate of respiratory infections

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was 2.5/100 person-months in community-dwelling elderly in contrast to 10.8/100 person-months in an adult daycare setting. Rates of infection in nursing homes are highly variable due to the epidemic nature of most respiratory viruses. Influenza virus is the most well recognized viral cause of serious illness in elderly persons. Although nonpandemic influenza attack rates are 20 to 30% in preschool and schoolage children and drop to 10% for older adults, complications rates are highest in the elderly (Glezen and Couch, 1978). During epidemics of influenza H3N2, hospitalization rates are approximately 6 to 15/1000 for persons over age 65 (Glezen, 1982). Lower respiratory tract involvement with influenza also increases with age, rising from 4 to 8% in under age 50 up to 73% in persons over age 70 (Betts, 2000). The risk of death from influenza increases 39-fold by the presence of chronic medical conditions such as cardiovascular disease, diabetes, renal disease, anemia or immunosuppression, and the presence of both pulmonary and cardiovascular disease raises the mortality 870-fold. Respiratory syncytial virus (RSV) is now recognized as the second most important respiratory viral pathogen in older persons with a disease burden similar to nonpandemic influenza (Thompson et al., 2003). Outbreaks of RSV in nursing homes have been described with average attack rates of 20% and rates of pneumonia ranging from 5 to 67% and death ranging from 0 to 53% (Falsey and Walsh, 2000). Although the precise incidence is unknown, recent studies indicate that RSV is a cause of excess morbidity and mortality in community-dwelling elderly as well (Zambon et al., 2001). In addition to influenza and RSV, a number of other viral pathogens such as coronaviruses, rhinoviruses, parainfluenza, and the newly described human metapneumovirus can also cause significant illness in older persons. Urinary Tract Infection

Bacteriuria is the most common bacterial infection affecting older persons (Nicolle, 1997). The prevalence of bacteriuria in community-dwelling women under age 60 is 1.3 ◦ C during infectious episodes. If fever is defined as a rectal temperature of >37.5 ◦ C, most infected nursing-home patients will have fever; therefore, authorities recommend the following guidelines for defining fever in older persons. 1. Persistent elevation of body temperature at least >1.3 ◦ C above baseline values. 2. Oral temperature of 37.2 ◦ C or greater on repeated measurement. 3. Rectal temperatures of 37.5 ◦ C or greater.

FEVER OF UNKNOWN ORIGIN Persistent fever without a known cause is a diagnostic challenge in any age-group, but it is particularly problematic in the elderly person who may not tolerate a prolonged and invasive workup. Fever of unknown origin (FUO) was originally defined by Petersdorf and Beeson as fever >38.3 ◦ C for at least 3 weeks, which remains undiagnosed after 1 week of in-hospital evaluation. The causes of FUO in the older patient differ somewhat from those in younger age-groups (Norman, 2000). Of infectious causes, intraabdominal abscess are most common followed by TB and endocarditis. Unlike younger age-groups, viral infections are relatively infrequent causes of FUO. Collagen vascular disorders, particularly temporal arteritis and polymyalgia rheumatica, are important causes of FUO in the elderly accounting for 31% of cases in one study (Knockaert et al.,

INFECTION CONTROL IN LONG-TERM CARE FACILITIES Infection prevalence rates in LTCFs range from 1.6 to 32.7 and incidence rates range from 2.7 to 9.5 infections per 1000 resident-months (Nicolle, 2000). Elderly residents of institutions are particularly vulnerable to infection because of their debilitated state, impaired mental status, and the frequent use of urinary catheters. Studies have shown that at any point in time, 8% of nursing-home patients are receiving systemic antibiotics (Nicolle et al., 2000). Frequently, workup has been inadequate, and in 25 to 75% of cases antibiotic choices are inappropriate, leading to the development of resistant organisms. The necessity of hands-on contact between residents and staff may facilitate transmission of pathogens. A unique problem in the LTCF is the wandering resident who may be incontinent or coughing and be a vector for the spread of infectious agents. Additionally, limited access to laboratory tests and X ray facilities make the diagnosis of infection more difficult. Lastly, problems with infection control may be exacerbated by the lack of accessible hand-washing facilities and private rooms, as well as communal dining and bathroom facilities. Unlike hospitals, the LTCF is a home for its residents, and infection control practices must be balanced with resident needs and comforts. Guidelines for infection control practitioners in LTCFs have been developed to assist with surveillance, diagnosis, treatment, and containment of infectious diseases in various types of facilities (Bentley et al., 2001). Hand washing is the cornerstone of any infection control program in long-term care. Unfortunately, while this is simple and effective, compliance is often poor. New alcohol gel hand sanitizers offer high antimicrobial activity and ease of use and may improve compliance. One recent study showed a 30% decrease in infections in LTCF units with gel sanitizers compared to those without them (Fendler et al., 2002).

Influenza Outbreaks of influenza virus in LTCFs are characterized by high attack rates with significant morbidity and mortality (Centers for Disease Control, 2004). Influenza virus is spread

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Table 6 Influenza chemoprophylaxis: recommended dosage for persons over age 65

Drug

Activity

Amantadine Rimantadine Zanamivir Oseltamivir

Influenza Influenza Influenza Influenza

A A A and B A and B

Route of administration

Dosage

Oral Oral Inhaled Oral

≤100 mg day−1a ≤100 mg day−1b Not approved 75 mg day−1c

a Further dose adjustment required for creatinine clearance less than 50 ml/minute. Dosing interval should be increased to every 48 to 72 hours. b Dose should be decreased with severe hepatic or renal disease (creatinine clearance less than 10 to 20 ml/minute). c Dose should be adjusted with severe real disease (creatinine clearence 10 mm of induration; however, >5 mm of induration is also considered positive in those who are in close contact with persons with infectious TB or who have chest radiographs suggestive of previous TB. Some authorities recommend PPD retesting annually or every 2 years for all residents with a negative PPD. At a minimum, nonreactors should be retested whenever a new active case of TB is diagnosed or suspected. Individuals with a positive PPD who were negative during the preceding 2 years and who have normal chest radiographs should receive isoniazid prophylaxis for 9 months under close supervision. Even for patients at advanced ages the benefits of such practice outweigh the risks. Previous recommendations included chemoprophylaxis for individuals with a positive PPD of unknown duration with certain high-risk conditions such as diabetes, renal failure, immunosuppression, chronic steroid use, and silicosis as well as those with abnormal chest radiographs. In 2000, the US Center for Disease Control and Prevention (CDC) with the American Thoracic Society revised the recommendations, such that any high-risk individual with a positive PPD should receive chemoprophylaxis regardless of age or duration of positive PPD. Residents of nursing homes are considered high risk. The decision to treat such individuals remains somewhat controversial. A high index of suspicion for active TB should be maintained by clinicians, because signs and symptoms may be atypical and the PPD negative in older persons. Employees of LTCFs are also at increased risk of infection with TB. They should have a PPD placed at the time of employment and also annually (Zevallos and Justman, 2003).

SPECIFIC INFECTIONS Sexually Transmitted Diseases Despite the perception among health-care providers that elderly adults are not at risk for STDs, many older adults remain sexually active and are at risk for STDs (Calvert, 2001). The Janus report on sexual behavior found that 69% of American men over the age of 65 and 74% of woman report some form of sexual activity at least weekly. Additionally,

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in a survey of persons between the ages of 80 to 100, 62% of men and 30% of women engaged in sexual intercourse. Because of cultural, social, and religious practices of older adults, they may be less likely to speak freely of STDs and thus, it is important for providers to be mindful of such issues. The finding of an STD in a nursing-home resident should always prompt an investigation because of concerns for elder abuse.

Human Immunodeficiency Virus Human immunodeficiency virus (HIV) is a cause of enormous morbidity and mortality worldwide. While it is predominantly a disease of younger persons, data reported to the CDC in the United States indicates that approximately 10% of Acquired Immune Deficiency syndrome (AIDS) cases are in persons >50 years (Chiao et al., 1999). Before 1989, 15% of AIDS cases in older persons were transfusion related. However, since 1996, the epidemiology of HIV in older adults has changed. Transfusion now only accounts for 2.4% of cases, whereas men who have sex with men accounts for the largest percentage at 36% and intravenous drug use (IVDU) accounts for 19%. Although IVDU is the second most common risk factor, it is significantly less than in individuals of ages between 13 and 49. Both heterosexual contact (14%) and unknown risk (26%) are significantly greater in adults over 50 years of age compared to younger age-groups. Numerous studies indicate that older age is associated with a shortened interval between time of HIV diagnosis and the development of AIDS as well as time from onset of AIDS to death (Adler et al., 1997). Hemophiliacs >55 years have a relative mortality of 4.7 after developing AIDS compared to younger counterparts. The reason for decreased survival in older AIDS patients is likely multifactorial and includes comorbidities, delay in diagnosis, and age-related immune dysfunction (Calvet, 2003). Studies by Adler et al. (1997) have demonstrated that destruction of T-cells of young and old patients progress at the same rate but older persons have an impaired ability to replace functional T-cells. Clinical presentation of AIDS in older persons is similar to that in younger adults, but diagnosis remains challenging because common medical problems associated with aging may confuse or delay workup. Thus, patients may undergo extensive workups for cerebrovascular disease, Alzheimer’s disease, malnutrition, cancer or depression before the diagnosis of HIV is even entertained. Although several studies have shown that the clinical presentation of AIDS in older patients is similar to the young and that pneumocystitis pneumonia (PCP) is the most common opportunistic infection in both groups, some differences are worth mentioning. 1996 CDC data indicates that older individuals are significantly more likely to develop wasting syndrome and HIV encephalopathy than are patients aged 13 to 49 years (Calvet, 2003). In addition, 14% of older adults develop malignancies; most commonly Kaposi’s sarcoma or non-Hodgkin’s lymphoma. HIV encephalopathy in older persons deserves special mention, given the prevalence of Alzheimer’s and

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cerebrovascular disease in this population. HIV is associated with subacute encephalitis, which leads to a subcortical dementia in contrast to Alzheimer’s disease which is a cortical disease often leading to aphasia and other manifestations of cortical dysfunction. The progression of HIV encephalopathy is expected to be relatively rapid with decline over months compared to the more slowly evolving Alzheimer’s. In addition, HIV dementia is associated with pleocytosis in the cerebrospinal fluid (CSF) in 25% of cases, whereas CSF is normal in Alzheimer’s disease. It is important to consider HIV in the workup of dementia since antiretrovirals may slow progression or improve symptoms. The treatment of HIV infection in older age has not been well studied. Most trials of antiretroviral medications have excluded persons over age 60. A recent cross-sectional survey of HIV infected individuals taking highly active antiretroviral therapy (HAART) found that persons over age 55 tolerated therapy as well as younger subjects with no significant differences in adherence rates or the need for modification of treatment because of side effects (Manfredi et al., 2003). However, older patients had lower mean drop in viremia (0.5 log10 vs 1.0 log10 ) and immune recovery was significantly slower and more blunted. Interestingly, other investigators found that compliance with HAART was better in persons >50 years compared to younger age-groups. At present, more studies of HAART in older age-groups are needed to evaluate efficacy; but age alone is not a sufficient reason to deny treatment. Prevention of HIV is critical in all age-groups. A problem unique to older age-groups is that both health-care professionals as well as patients themselves do not perceive the risk appropriately. In AIDS behavioral studies in the United States, less than 7% of subjects who were sexually active, >50 years, and who resided in cities with a high prevalence of HIV had ever had HIV testing done (Calvet, 2003). Additionally, less than 11% of older people had ever discussed HIV testing with their doctor. As a result of decreased concerns about pregnancy, older adults are also much less likely to use condoms than younger people. Clearly, STD testing and safe sex practices need to be addressed in older agegroups.

Syphilis Primary and secondary syphilis are not common in persons over age 55 accounting for only 4% of cases reported in the United States in 1997 (Calvert, 2001). Although uncommon, syphilis should be considered in any sexually active patient with an unexplained rash or a new genital ulceration. While early syphilis is not frequent, latent syphilis is primarily a problem of older age. A serum rapid plasma reagin (RPR) is typically included in a routine dementia workup. If the confirmatory specific Treponema pallidum antibody is positive, then all patients with infection for greater than 1-year duration should have a lumbar puncture performed. This includes most elderly adults with a positive RPR. It is particularly important to evaluate the CSF if any neurologic

signs or symptoms are present (including deafness), the patient has co-infection with HIV or other signs of tertiary syphilis such as aortitis or gummas. Unfortunately, there is no gold standard for the diagnosis of neurosyphilis and CSF – venereal disease research laboratories (VDRL) are positive in only 50% of cases of neurosyphilis. Thus, even mild pleocytosis or elevation of protein may indicate CNS involvement and are indications for treatment. The optimal treatment of neurosyphilis is 18 to 24 million units of intravenous penicillin for 10 to 14 days. Follow-up is required to insure a response to therapy.

Herpes Simplex Herpes Simplex virus type 2 (HSV-2) or genital herpes simplex is extremely common, affecting 22% of the adult population in the United States (Calvet, 2003). Seroprevalence for HSV-2 rises with increasing age, the highest prevalence being in previously married, black women aged 60 to 74 years. Approximately 70 to 80% of individuals with HSV-2 antibodies are not aware of their infection. Thus, HSV-2 should be kept in mind when evaluating perineal ulcers or rash even if the patient does not have a known history of genital herpes. The best method of diagnosis remains to be viral culture of early lesions. The virus is relatively hardy and grows rapidly; usually within 48 hours. However, a negative culture does not rule out the infection. Treatment includes acyclovir and the new formulations, famciclovir and valacyclovir, which offer improved oral absorption. Treatment may be initiated for primary infection to decrease symptoms or with recurrent disease to suppress outbreaks. Patients should be counseled that transmission can occur even if the patient has no symptoms, and therefore the use of condoms at all times is encouraged.

Gonorrhea Infection with Neisseria gonorrhea is uncommon in the elderly and occurs at a rate of 4/100 000 in persons 65 years and older. There is no clear evidence that gonorrhea (GC) is more severe in elderly persons compared to the young although cases of disseminated GC in the elderly have been reported (Calvet, 2003). Diagnosis is usually made by urethral or cervical culture but can also be accomplished by polymerase chain reaction (PCR). Treatment of uncomplicated GC: a single dose of Ceftriaxone 125 mg IM, Cefixime 400 mg PO or an oral quinolone. Local resistance patterns and travel should be kept in mind when selecting therapy.

Severe Acute Respiratory Syndrome (SARS) In March of 2003, the World Health Organization issued a global alert regarding a severe atypical pneumonia in China, Hong Kong, and Vietnam referred to as Severe Acute Respiratory Syndrome (SARS). A newly discovered coronavirus

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(SARS-Cov) was subsequently identified as the cause of SARS (Peiris et al., 2003). It is hypothesized that SARSCov is an animal virus, which crossed the species barrier into humans possibly from “game food” in southern China. Infected persons initially present with fever, myalgias, and rigors. Cough is common, but dyspnea and chest tightening may only present later in the illness. Unlike other common respiratory viruses, rhinorrhea and sore throat are uncommon. Diarrhea may occur in approximately 20% of cases. Laboratory findings include ground glass opacifications on chest radiographs, lymphopenia, and elevations of liver function tests. Although fever is present in over 90% of patients with SARS, afebrile cases of SARS can occur in the elderly. In one such case, an elderly adult presented with malaise and poor appetite with a hip fracture secondary to a fall but no fever. The case-fatality rate during recent outbreaks was 9.6% (range 0–40%). Advanced age is the single most important risk factor for death; patients >60 years have a case-fatality rate of 45% and the relative risk of death is 1.5 to 1.8 per each decade of life increased (Christian et al., 2004). Patients are most infectious later in the illness when symptoms progress, requiring hospitalization. Transmission is believed to be through direct or indirect contact of mucous membranes (eyes, nose, mouth) with infected secretions but spread via small particle aerosols has not been completely ruled out. Diagnosis can be made by viral culture, reverse transcriptasepolymerase chain reaction (RT-PCR) or serology; however, no test is very sensitive early in illness. Despite initial enthusiasm for high dose steroids and ribavirin, at present there is no specific therapy for SARS. Intensive work on antivirals and vaccines is ongoing.

VACCINATION Vaccination is one of the most cost-effective strategies available to reduce the morbidity and mortality associated with a number of infectious diseases. Although vaccine response rates are diminished in older persons and cost effectiveness has been debated, three vaccines are recommended for all older persons: tetanus toxoid, pneumococcal vaccine, and influenza virus vaccine.

Tetanus–diphtheria Toxoid The annual incidence of tetanus cases in developed countries is very low (Bentley, 1992). However, over 50% of the tetanus cases occur in persons over the age of 50, with 60% mortality. More than 90% of the deaths from tetanus are in persons over age 50 (Richardson and Knight, 1991). Because there is no natural immunity to tetanus, disease occurs almost exclusively in those who are inadequately or unimmunized. Since routine vaccination of school children and armed forces personnel did not begin until the 1940s, many elderly persons never received a primary series of

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tetanus toxoid immunization. In addition, the recommended booster doses every 10 years are frequently neglected in older persons. Studies from the United States, Britain, Germany, Denmark, and Sweden have shown that 45 to 80% of community-residing elderly and 30 to 50% of nursing-home residents lack immunity (Gergen et al., 1995). Although commonly associated with accidental trauma, a significant number of tetanus cases occur in the setting of chronic skin ulcers, gangrenous extremities or recent surgery (Bentley, 1992). The current vaccine contains formaldehyde-denatured tetanus toxoid and diphtheria toxin (Td), and will provide protection to diphtheria as well as tetanus. Although studies have shown that the antibody levels achieved by older adults are lower than those of young adults, protective antibody titers are present in 100% of older persons after the third dose of primary immunization. Duration of antibody may also be somewhat diminished but booster doses are highly effective at raising antibody to protective levels. Vaccination is well tolerated by older persons and the only contraindication is a history of neurological or severe hypersensitivity reactions to previous Td. The current recommendations are that all older persons who are inadequately immunized or whose history of immunization is unknown receive primary immunization with Td. Although standard recommendations are for a single Td booster every 10 years after primary immunization, some authorities feel that a single booster given at age 65 is the most cost-effective practice (Balestra and Littenberg, 1993). All older patients evaluated for wounds should be questioned regarding immunization status, and Td immunization given as appropriate. In addition, immunity status should be determined prior to elective bowel surgery and for nursing-home patients with decubitus ulcers or vascular complications.

Pneumococcal Vaccine Pneumococcal infections are an important cause of illness and death in older persons, thus making prevention of these infections by vaccination highly desirable. Approximately 30 to 50% of community-acquired pneumonias are due to Streptococcus pneumoniae (Fedson et al., 1994). At least 16 000 cases of invasive pneumococcal disease occur yearly in the United States among people over age 65. Case-fatality rates are as high as 40% for bacteremia and 55% for meningitis, despite prompt diagnosis and treatment with appropriate antibiotics (Bentley, 1992). Vaccination has become even more important with the rapid increase and global spread of antibiotic-resistant pneumococci. Pneumococcal vaccine contains purified capsular polysaccharide antigens from different serotypes of S. pneumoniae. The first vaccine, licensed in 1977, contained 14 of the 83 different serotypes. In 1983, an expanded 23-valent vaccine became available. Vaccine-associated reactions occur within 24 hours in 10 to 15% of elderly vaccinees and consist primarily of local discomfort. Fever of >100 ◦ F occurs in approximately 2% of vaccinees and usually lasts less than 24 hours. Severe local and systemic reactions have been reported more often in younger persons and

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revaccinated individuals (Bentley, 1992). Pneumococcal vaccine and influenza vaccine may be administered simultaneously at different sites without affecting immunogenicity or side effects. Most healthy young adults maintain adequate antibody levels for 5 to 6 years. Several studies suggest that, while older persons respond to pneumococcal vaccine, they may have lower peak titers and antibody levels may diminish at a more rapid rate. Early studies involving small numbers of young individuals showed high rates of local Arthus-type reactions when subjects were revaccinated. More recent data indicate that older persons who received the 14-valent vaccine may be revaccinated with the 23-valent vaccine 6 years after primary vaccination with no significant side effects and a boost of antibody levels. Much debate has been generated concerning the efficacy of pneumococcal vaccine in high-risk populations, particularly older persons. Pneumococcal vaccine was shown to be highly effective when tested in young healthy South African gold miners, a group in whom the incidence of disease is very high. However, the results of controlled trials in older persons in the United States have been inconclusive because of the small sample sizes used. Retrospective casecontrol studies have shown pneumococcal vaccine to be between 50 and 80% effective for the prevention of invasive pneumococcal disease in older persons (Fedson et al., 1994). Vaccine efficacy has been shown to decrease progressively over time and is least efficacious in very elderly persons (>85 years). Yet, in the largest case-control study published, the 5-year efficacy in immunocompetent patients aged 65 to 74 was 71%, and in those 75 to 84 years of age the 3-year efficacy was 67% (Shapiro et al., 1991). Analyses of the cost effectiveness of pneumococcal vaccine have estimated that routine vaccination of all persons over age 65 is a cost-saving procedure (Fedson et al., 1994). The most recent analysis of the effectiveness of pneumococcal vaccine involved 47 000 adults over age 65 and confirmed a significant reduction in the risk of bacteremia associated with vaccination but did not show a beneficial effect for nonbacteremic pneumonia (Jackson et al., 2004). Pneumococcal vaccine is recommended for immunocompetent persons at increased risk of pneumococcal disease for a variety of chronic illnesses such as cardiovascular disease, pulmonary disease, diabetes mellitus, cirrhosis and, alcoholism (Table 7) (Center for Disease Control and Prevention, 1997). It is also recommended for patients with CFS leaks, and for persons aged 65 or older. Revaccination should be considered for those individuals at highest risk of fatal pneumococcal disease and who received the 23-valent vaccine over 6 years ago. It should also be considered for patients who have a rapid decline in antibody titers,for example, patients with nephrotic syndrome. Revaccination is also recommended for healthy elderly persons who received vaccine before age 65 and more than 10 years has passed. Routine revaccination of elderly persons is not currently recommended (Bentley, 1992). This is because of concerns about reduced immunogenicity of repeat vaccinations with polysaccharide vaccines. A recent study from Sweden examined the effect of revaccinating elderly adults after 5 years with

Table 7 Indications for pneumococcal vaccine

Primary vaccination Over age 65 years Ages 2 – 64 years Chronic illnesses including CHF, COPD, diabetes, alcoholism, liver disease Nephrotic syndrome, CSF leaks Asplenia Immunocompromised Special ethnic groups including Native Americans and other groups with high rates of invasive pneumococcal disease Revaccination (greater than 5 years since primary vaccination) Patients with rapid decline in antibody levels Asplenia Nephrotic syndrome Renal failure or transplantation HIV Other forms of immunosuppression Over age 65 If primary vaccination took place under age 65 Vaccine status is unknown Adapted from Center for Disease Control and Prevention (1997)

pneumococcal vaccine (Torling et al., 2004). Although there was a significant increase in the mean geometric antibody concentration, levels were lower than after primary vaccination. These issues have stimulated interest in the pneumococcal conjugate vaccines in adults (Abraham-Van Parijs, 2004). While these vaccines offer the advantage of stimulating T lymphocytes and memory, they include only seven antigenic types compared to 23 in the polysaccharide vaccines.

Influenza Vaccine Influenza continues to be an important cause of excess morbidity and mortality throughout the world, especially in the elderly (Centers for Disease Control, 2004). The current vaccine contains two type A and one type B influenza virus strains representing the viruses predicted to circulate during the upcoming year. The vaccine is made from highly purified, egg-grown inactivated viruses in a trivalent preparation. Whole virus, subunits, and purified surface antigen preparations are available. Acute local reactions such as mild soreness at the vaccination site occur in approximately one-third of vaccinees. Systemic reactions, including fever, occur in less than 1% of vaccinees, and appear to be less severe in older persons. Influenza vaccine is contraindicated in persons with an anaphylactic or immediate hypersensitivity reaction to eggs. The efficacy of influenza vaccine depends on the age and immunocompetence of the subjects as well as the match of the vaccine to the epidemic strain. In placebo-controlled trials of young healthy persons, efficacy rates for reducing influenza infection ranged from 67 to 92% (Bentley, 1992). Effectiveness in other populations, especially the elderly, has been more variable with occasional reports of vaccine failure. One of the few prospective, randomized, placebocontrolled trials of influenza vaccine efficacy, from the Netherlands, demonstrated that vaccination resulted in a

INFECTIOUS DISEASES Table 8 Groups in which yearly influenza vaccination is recommended

Groups who are at increased risk for influenza-related complications Persons > age 65 Residents of nursing homes and chronic care facilities Persons with chronic cardiac or pulmonary disorders Persons who have required regular medical follow-up during the preceding year because of chronic metabolic diseases (including diabetes), renal dysfunction, hemoglobinopathies or immunosuppression Persons who can transmit influenza to high-risk groups Physicians, nurses, and other health-care personnel Employees of nursing homes with patient contact Providers of home care Household members of persons in high-risk groups

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• Signs and symptoms of infection in the elderly may be more subtle or atypical compared to young adults. • LTCF have high prevalence rates of infection. Hand washing and antibiotic control are important measures for limiting the spread of resistant organisms in these facilities. • Influenza and pneumococcal vaccine are beneficial and cost-effective methods to reduce morbidity and mortality associated with these infections in all groups of older adults.

Adapted from Centers for Disease Control (2004).

58% reduction of influenza infection in vaccines (Govaert et al., 1994). A recent three-year case-control study from the United States found influenza vaccine to be both efficacious and cost effective (Nichol et al., 1994). Although vaccine recipients had more coexisting illnesses at baseline than those who did not receive the vaccine, vaccination was associated with a reduction in yearly hospitalization rates during the 3-year period for pneumonia and influenza by 48 to 57% and for all chronic respiratory conditions by 27 to 39%. Vaccination was also associated with a 37% reduction in the rate of hospitalization for congestive heart failure (CHF) when influenza A was epidemic. In the three influenza seasons studied, vaccination was associated with decreases of 39 to 54% in mortality from all causes. While effective in all older adults, benefit from influenza vaccine is greatest in those with high-risk conditions (Hak et al., 2002). In addition, influenza vaccine is associated with a reduction in hospitalizations for cardiac disease and strokes in the elderly (Nichol et al., 2003). In LTCFs, the efficacy of influenza vaccine in preventing uncomplicated influenza infection is low (28–37%) (Centers for Disease Control, 2004). However, the efficacy in reducing complications, including hospitalization (47%), pneumonia (58%), and death (76%), is substantial. Achieving a high rate of vaccination among nursing-home residents has been shown to reduce the spread of infection in such a facility, thus preventing disease through herd immunity. A number of well-designed studies have shown influenza vaccine to be a highly cost-effective intervention and provide compelling evidence for increasing programs aimed at improving compliance with recommendations for annual influenza vaccination. Groups in whom vaccination is recommended are listed in Table 8.

KEY POINTS • Infections are a leading cause of hospitalization and death in older persons. • Susceptibility to infection in the elderly is multifactorial and includes diminished immune function, comorbid diseases, and congregate living residences.

KEY REFERENCES • Jackson LA, Neuzil KM, Yu O et al. Effectiveness of pneumococcal polysaccharide vaccine in older adults. The New England Journal of Medicine 2004; 348:1747 – 55. • Kost R & Straus S. Postherpetic neuralgia – pathogenesis treatment and prevention. The New England Journal of Medicine 1996; 335:32 – 42. • Nichol KL, Nordin J, Mullooly J et al. Influenza vaccination and reduction in hospitalizations for cardiac disease and stroke among the elderly. The New England Journal of Medicine 2003; 348:1322 – 32. • Nicolle LE. Asymptomatic bacteriuria in the elderly. Infectious Disease Clinics of North America 1997; 11(3):647 – 62. • Slotwiner-Nie PK & Brandt LJ. Infectious diarrhea in the elderly. Gastroenterology Clinics of North America 2001; 30:625 – 35.

REFERENCES Abraham-Van Parijs B. Review of pneumococcal conjugate vaccine in adults: implications on clinical development. Vaccine 2004; 22:1362 – 71. Adler WH, Padmavathi V, Chrest FJ et al. HIV infection and aging: mechanisms to explain the accelerated rate of progression in the older patient. Mechanisms of Ageing and Development 1997; 96:137 – 55. Alvarez S. Incidence and prevalence of nosocomial infections in nursing homes. In A Verghese & SL Berk (eds) Infections in Nursing Homes and Long-Term Care Facilities 1990, pp 41 – 54; Karger, New York. Arden NH. Control of influenza in the long-term-care facility: a review of established approaches and newer options. Infection Control and Hospital Epidemiology 2000; 21:59 – 64. Baldassarre JS & Kaye D. Special problems of urinary tract infection in the elderly. The Medical Clinics of North America 1991; 75:375 – 90. Balestra DJ & Littenberg B. Should adult tetanus immunization be given as a single vaccination at age 65? Journal of General Internal Medicine 1993; 8:405 – 12. Bentley DW. Vaccinations. Clinics in Geriatric Medicine 1992; 8:745 – 60. Bentley DW, Bradley SF, High F et al. Practice guideline for evaluation of fever and infection in long-term care facilities. Journal of the American Geriatrics Society 2001; 49:210 – 22. Betts R. Influenza virus. In GL Mandell, JF Bennett & R Dolin (eds) Principles and Practices of Infectious Diseases 2000, 4th edn, pp 1546 – 67; Churchill Livingston, New York. Boscia JA, Kobasa WD, Knight RA et al. Epidemiology of bacteriuria in an elderly ambulatory population. American Journal of Medicine 1986; 80:208 – 14. Bradley SF. Issues in the management of resistant bacteria in long-term care facilities. Infection Control and Hospital Epidemiology 1999; 20:362 – 6. Bradley SF. Staphylococcus aureus infections and antibiotic resistance in older adults. Clinical Infectious Diseases 2002; 34:211 – 6. Calvert H. Sexually transmitted diseases. In T Yoshikawa & DC Norman (eds) Infectious Disease in the Aging: A Clinical Handbook 2001, 1st edn, pp 313 – 22; Humana Press, Totowa.

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Calvet HM. Sexually transmitted diseases other than human immunodeficiency virus infection in older adults. Clinical Infectious Diseases 2003; 36:609 – 14. Center for Disease Control and Prevention. Prevention of pneumococcal disease: recommendations of the Advisory Committee of Immunization Practices (ACIP). Morbidity and Mortality Weekly Report 1997; 46(RR-8):1 – 24. Centers for Disease Control. Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP). Morbidity and Mortality Weekly Report 2004; 53(RR-6):1 – 40. Chiao KY, Ries KM & Sande MA. AIDS and the Elderly. Clinical Infectious Diseases 1999; 28:740 – 5. Christian MD, Poutanen SM, Loutfy MR et al. Severe acute respiratory syndrome. Clinical Infectious Diseases 2004; 38:1420 – 7. Donahue J, Choo P, Manson J & Platt R. The incidence of herpes zoster. Archives of Internal Medicine 1995; 155:1605 – 9. Durand M, Calderwood S, Weber D et al. Acute bacterial meningitis in adults. The New England Journal of Medicine 1993; 328:21 – 8. Emori TG, Banerjee SN, Culver DH et al. Nosocomial infections in elderly patients in the United States 1986 – 1990. American Journal of Medicine 1991; 91(S3B):3B-289S – 93S. Falsey AR & Walsh EE. Respiratory syncytial virus infection in adults. Clinical Microbiology Reviews 2000; 13(3):371 – 84. Fedson D, Shapiro E, LaForce F et al. Pneumococcal vaccine after 15 years of use: another view. Archives of Internal Medicine 1994; 154:2531 – 5. Fendler EJ, Ali Y, Hammond BS et al. The impact of alcohol hand sanitizer use on infection rates in an extended care facility. American Journal of Infection Control 2002; 30:226 – 33. Garibaldi RA, Brodine S & Matsumiya S. Infections among patients in nursing homes: policies prevalence and problems. The New England Journal of Medicine 1981; 30:731 – 5. Gergen P, McQuillin G, Kiely M et al. A population-based serologic survey of immunity to tetanus in the United States. The New England Journal of Medicine 1995; 332:761 – 813. Glezen WP. Serious morbidity and mortality associated with influenza epidemics. Epidemiologic Reviews 1982; 4:24 – 44. Glezen WP & Couch RB. Interpandemic influenza in the Houston area 1974 – 76. The New England Journal of Medicine 1978; 298:587 – 92. Govaert TME, Thijs CTMCN, Masurel N et al. The efficacy of influenza vaccination in elderly individuals – a randomized double-blind placebocontrolled trial. Journal of the American Medical Association 1994; 272:1661 – 5. Gross PA, Rapuano C, Adrignolo A & Shaw B. Nosocomial infections: decade-specific risk. Infection Control 1983; 4:145 – 7. Hak E, Nordin J, Wei F et al. Influence of high-risk medical conditions on the effectiveness of influenza vaccination among elderly members of 3 large managed-care organizations. Clinical Infectious Diseases 2002; 35:370 – 7. Hanson LC, Weber DJ, Rutala WA & Samsa GP. Risk factors for nosocomial pneumonia in the elderly. American Journal of Medicine 1992; 92:161 – 6. Harkness GA, Bentley DW & Roghmann KJ. Risk factors for nosocomial pneumonia in the elderly. American Journal of Medicine 1990; 89:457 – 63. Hodder SL, Ford AB, FitzGibbon PA et al. Acute respiratory illness in older community residents. Journal of the American Geriatrics Society 1995; 43:24 – 9. Jackson LA, Neuzil KM, Yu O et al. Effectiveness of pneumococcal polysaccharide vaccine in older adults. The New England Journal of Medicine 2004; 348:1747 – 55. Knockaert DC, Vanneste LJ & Boobaers HJ. Fever of unknown origin in the elderly. Journal of the American Geriatrics Society 1993; 41:1187 – 92. Kost R & Straus S. Postherpetic neuralgia – pathogenesis treatment and prevention. The New England Journal of Medicine 1996; 335:32 – 42. Manfredi R, Calza L, Cocchio D & Chiodo F. Antiretroviral treatment and advanced age: epidemiologic laboratory and clinical features in the elderly. Journal of Acquired Immune Deficiency Syndromes 2003; 33:112 – 4. Marrie TJ. Community-acquired pneumonia. Clinical Infectious Diseases 1994; 18:501 – 15.

McKinsey D, Ratts T & Bisno A. Underlying cardiac lesions in adults with infective endocarditis. American Journal of Medicine 1987; 82:681 – 8. Miller L & Choi C. Meningitis in older patients: how to diagnose and treat a deadly infection. Geriatrics 1997; 52(8):43 – 55. Mylotte JM, Tayara A & Goodnough S. Epidemiology of bloodstream infection in nursing home residents: evaluation in a large cohort from multiple homes. Clinical Infectious Diseases 2002; 35:1484 – 90. Nichol KL, Margolis KL, Wuorenma J & Von Sternberg T. The efficacy and cost effectiveness of vaccination against influenza among elderly persons living in the community. The New England Journal of Medicine 1994; 331:778 – 84. Nichol KL, Nordin J, Mullooly J et al. Influenza vaccination and reduction in hospitalizations for cardiac disease and stroke among the elderly. The New England Journal of Medicine 2003; 348:1322 – 32. Nicolle LE. Asymptomatic bacteriuria in the elderly. Infectious Disease Clinics of North America 1997; 11(3):647 – 62. Nicolle LE. Infection control in long-term care facilities. Clinical Infectious Diseases 2000; 31:752 – 6. Nicolle LE, Bentley DW, Garibaldi RA et al. Antimicrobial use in longterm-care facilities. Infection Control and Hospital Epidemiology 2000; 21:537 – 45. Niederman MS. Nosocomial pneumonia in the elderly patient chronic care facility and hospital considerations. Clinics in Chest Medicine 1993; 14:479 – 90. Norman DC. Fever in the elderly. Clinical Infectious Diseases 2000; 31:141 – 51. Peiris JSM, Yuen KY, Osterhaus AD & Stohr K. The severe acute respiratory syndrome. The New England Journal of Medicine 2003; 349:2431 – 41. Richardson J. Bacteremia in the elderly. Journal of General Internal Medicine 1993; 8(2):89 – 92. Richardson J & Knight A. The prevention of tetanus in the elderly. Archives of Internal Medicine 1991; 151:1712 – 7. Ruben FL, Dearwater SR, Norden CW et al. Clinical infections in the non-institutionalized geriatric age group: methods utilized and incidence of infections. The Pittsburgh good health study. American Journal of Epidemiology 1995; 141:145 – 57. Scheckler WE & Peterson PJ. Infections and control among residents of eight rural Wisconsin nursing homes. Archives of Internal Medicine 1986; 146:1981 – 4. Schuchat A, Robinson K, Wenger J et al. Bacterial meningitis in the United States in 1995. The New England Journal of Medicine 1997; 337(13):970 – 6. Selton-Suty C, Hoen B, Grentzinger A et al. Clinical and bacteriological characteristics of infective endocarditis in the elderly. Heart 1997; 77:260 – 3. Setia U, Serventi I & Lorenz P. Bacteremia in a long-term care facility. Archives of Internal Medicine 1984; 144:1633 – 5. Shapiro ED, Berg AT & Austrian R. Protective efficacy of polyvalent pneumococcal polysaccharide vaccine. The New England Journal of Medicine 1991; 325:1453 – 60. Slotwiner-Nie PK & Brandt LJ. Infectious diarrhea in the elderly. Gastroenterology Clinics of North America 2001; 30:625 – 35. Smith PW, Daly PB & Roccaforte JS. Current status of nosocomial infection control in extended care facilities. American Journal of Medicine 1991; 91:3B-281S – 5S. Straus S, Ostrove J, Inchauspe G et al. Varicella-zoster virus infections. Annals of Internal Medicine 1988; 108:221 – 37. Terpenning M, Buggy B & Kauffman C. Infective endocarditis: clinical features in young and elderly patients. American Journal of Medicine 1987; 83:626 – 34. Thompson WW, Shay DK, Weintraub E et al. Mortality associated with influenza and respiratory syncytial virus in the United States. Journal of the American Medical Association 2003; 289(2):179 – 86. Torling J, Hedlund J, Konradsen HB & Ortqvist A. Revaccination with the 23-valent polysaccharide vaccine in middle aged and elderly persons previously treated for pneumonia. Vaccine 2004; 22:96 – 103. Verghese A & Berk S. Introduction and epidemiologic considerations. In A Verghese & A Berk (eds) Infections in Nursing Homes and Long-Term Care Facilities 1990, 1st edn, pp 1 – 11; S Karger, Basel.

INFECTIOUS DISEASES Warren JW, Tenney JH, Hoopes JM et al. A prospective microbiologic study of bacteriuria in patients with chronic indwelling urethral catheters. Journal of Infectious Diseases 1982; 146:719 – 23. Wells AU, Fowler CC, Pegler-Ellis RB et al. Endocarditis in the 80’s in a general hospital in Auckland [New Zealand]. Quarterly Journal of Medicine 1990; 76:753 – 62. Woodhead M. Pneumonia in the elderly. The Journal of Antimicrobial Chemotherapy 1994; 34:85 – 92.

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Yoshikawa T. Infectious diseases immunity and aging. In D Powers & J Morley (eds) Aging Immunity and Infection 1994, 1st edn, pp 1 – 11; Springer Publishing Company, New York. Zambon MC, Stockton JD, Clewley JP & Fleming DM. Contribution of influenza and respiratory syncytial virus to community cases of influenzalike illness: an observational study. Lancet 2001; 358:1410 – 6. Zevallos M & Justman JE. Tuberculosis in the elderly. Clinics in Geriatric Medicine 2003; 19:121 – 38.

146

Tuberculosis Shobita Rajagopalan and Thomas T. Yoshikawa Charles R. Drew University of Medicine and Science, Los Angeles, CA, USA

INTRODUCTION In the year 2004, tuberculosis (TB) remained one of the leading infectious causes of illness and death worldwide. Estimates of morbidity and mortality from TB vary widely, but reliable sources report approximately two billion people currently infected with quiescent but viable tubercle bacilli, with two to three million deaths occurring from TB each year. In the United States, during the past two decades, the excess in morbidity reflected a changing epidemiologic pattern. Human immune deficiency virus (HIV) infection, poverty, homelessness, substance abuse, and immigration from countries with a high prevalence of TB all contributed to TB morbidity. Overburdened public health TB services were not only unable to manage the resurgence in the 1980s but were also unprepared to cope with emerging multidrug resistance. Since the mid-1990s to the present, aggressive TB control, implementation, and enhanced resources have resulted in a substantial decline in the overall incidence of TB. The geriatric population across all racial and ethnic groups and both genders are at substantial risk for Mycobacterium tuberculosis (Mtb) infection, perhaps because of both biological (compromised nutrition and immune status, underlying disease, medications, and possible racial predisposition) and socioeconomic factors (poverty, living conditions, and access to health-care). Most vulnerable are frail elderly residents of nursing homes and other long-term care facilities. Because of the highly communicable potential of Mtb, the inevitable endemic transmission between residents and from resident to staff has been demonstrated in such facilities. (For the purpose of clarity, TB infection, or latent TB, refers to contained and asymptomatic primary infection with a positive tuberculin skin test reaction, whereas TB disease indicates overt clinical manifestations of TB). The Institute of Medicine report, Ending Neglect: The Elimination of TB in the US, which was undertaken through sponsorship from the Centers for Disease Control and

Prevention (CDC), reviews the lessons learned from the neglect of TB between the late 1960s and the early 1990s and reaffirms commitment to a more realistic goal of elimination of TB in the United States (Institute of Medicine, 2000). This chapter will review the epidemiology, pathogenesis and immunologic aspects, subtle clinical characteristics, diagnosis, management and prevention of Mtb infection in community-dwelling and institutionalized aging adults, as well as highlight the updated revised guidelines for targeted tuberculin skin testing and treatment of latent TB infection (LTBI).

EPIDEMIOLOGY Developed nations including the United States and parts of Southeast Asia report an estimated 380 million persons infected with Mtb; about 80% of infected persons in Europe are 50 years of age or older (Rajagopalan, 2001). Populationbased surveys of both TB infection and TB disease reveal that the overwhelming burden of disease and the highest annual risk for infection are borne by those living in developing countries. In the United States, TB prevails among the foreign-born and minorities. From 1985 to 1992, TB incidence increased among all ethnic groups except non-Hispanic whites and Native Americans/Alaskan Natives. Among the different ethnic groups, Hispanics experienced the greatest increase in reported cases (74%) (Centers for Disease Control and Prevention, 1993). From 1992 to 2000, the overall incidence of TB in the United States declined by 45%, largely because of improved funding resources channeled into TB control programs, which allowed for the implementation of directly observed therapy (DOT). In 2000, the TB incidence ratio was 5.8 cases/100 000 population, the lowest ever recorded in this country (Centers for Disease Control and Prevention, 2002a). However, the percentage of cases among foreignborn persons increased from 27% in 1992 to 46% in 2000 (Centers for Disease Control and Prevention, 2002b).


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TB also occurs with disproportionate frequency among the elderly (Reichman and O’Day, 1978; Narain et al., 1985). Elders living in communal settings such as nursing homes or other long-term care facilities have a TB incidence rate approximately four times greater than the general population (Schultz et al., 2001). The aggregate TB incidence rate for nursing home residents is 1.8 times higher than the rate seen in community-dwelling elderly (Hutton et al., 1993). The enhanced efficiency of TB transmissibility within congregate settings such as prisons, nursing facilities (nursing homes), chronic disease facilities, and homeless shelters has raised concerns about TB infection and disease in the institutionalized elderly (Ijaz et al., 2002; Rajagopalan and Yoshikawa, 2000). Positive tuberculin reactivity associated with prolonged stay among residents of long-term care facilities for the elderly has been demonstrated, implying an increasing risk of TB infection.

by senescence (shown in murine models), other concomitant age-related diseases (diabetes mellitus, malignancy), chronic kidney disease and renal insufficiency, poor nutrition, and immunosuppressive drugs may also contribute to this increase (Yoshikawa, 1992). In the elderly, approximately 90% of TB disease cases are due to reactivation of primary infection. Persistent infection without disease may occur in 30 to 50% of individuals. Some elderly persons previously infected with Mtb may eventually eliminate the viable tubercle bacilli and revert to a negative tuberculin reactor state. These individuals are thus at risk of new infection (reinfection) with Mtb. There are therefore three subgroups of older persons potentially at risk for TB: One subgroup never exposed to TB that may develop primary TB disease, a second subgroup with persistent and latent primary infection that may reactivate, and a third subgroup that is no longer infected and consequently at risk for reinfection.

PATHOGENESIS AND IMMUNOLOGIC ASPECTS

SUBTLE CLINICAL CHARACTERISTICS

The pathogenesis of TB infection and disease begins in most cases with the inhalation of the tubercle bacilli (Adler and Rose, 1996). The usual inoculum is no more than one to three organisms, which are taken up by alveolar macrophages and carried to regional lymph nodes. Spread may occur via the lymphohematogenous route with dissemination to multiple organs. From two to eight weeks after infection, cell-mediated immunity (CMI) and delayed-type hypersensitivity (DTH) responses develop, leading to the characteristic reactive tuberculin test and to the containment of infection. Chemoattractants cause monocytes to enter the area and become transformed into histiocytes forming granulomas. Although the bacilli may persist within macrophages, additional multiplication and spread is curtailed. Healing usually follows with calcification of the infected focus. Caseous necrosis may result secondary to the immune response. Erosion into a bronchiole causes cavity formation where bacilli can multiply and spread. Solid necrosis can result from production of hydrolases from inflammatory cells causing tissue liquefaction and creating a prime medium for microbial replication, generating up to 10 billion bacilli/ml. Individuals who develop active disease either fail to contain the primary infection or develop reactivation as a result of relative or absolute immune suppression at a point remote from primary infection. This is most likely to occur in immunocompetent adults within the first 3 years after exposure. Factors related to progression of disease reflect a weakened immune status and include physiological states, for example, normal aging; associated intercurrent disease – particularly diabetes mellitus, malignancies causing primary immunosuppression or requiring toxic chemotherapy, or corticosteroid-dependant diseases such as asthma or collagen vascular disease; poor nutritional status particularly related to alcohol and drug abuse; smoking and HIV infection. Although, it is likely that the increased frequency of TB in the elderly could partly be due to CMI that is impaired

Clinicians must be aware that frail older persons with TB disease may not demonstrate the overt and characteristic clinical features of TB such as fever, night sweats, or hemoptysis. They may exhibit more subtle clinical manifestations of “failure to thrive” with anorexia, functional decline and low-grade fever, or weight loss (Perez-Guzman et al., 1999). Although, several published works have attempted to delineate clearcut differences between younger and older TB patients, such studies have provided quite variable findings. In a metaanalysis of published studies, comparing pulmonary TB in older and younger patients, evaluating the differences in the clinical, radiologic, and laboratory features of pulmonary TB, no differences were found in the prevalence of cough, sputum production, weight loss, fatigue/malaise, radiographic upper lobes lesions, positive acid-fast bacilli (AFB) in sputum, anemia or hemoglobin level, and serum aminotransferases (Perez-Guzman et al., 1999). A lower prevalence of fever, sweating, hemoptysis, cavitary disease, and positive purified protein derivative (PPD), as well as lower levels of serum albumin and blood leukocytes were noticed among older patients. In addition, the older population had a greater prevalence of dyspnea and some underlying comorbid conditions, such as cardiovascular disorders, chronic obstructive pulmonary disease, diabetes mellitus, gastrectomy history, and malignancies. This meta-analytical review identified some subtle differences in clinical presentations of older TB patients, when compared with their younger TB counterparts. However, most of these differences can be explained by the already known physiologic changes that occur during aging. The majority of older TB patients (75%) with Mtb disease manifest active disease in their lungs (Yoshikawa, 1992). Extrapulmonary TB in the elderly is similar to younger persons and may involve the meninges, bone and joint, and genitourinary systems, or disseminate in a miliary pattern (Mert et al., 2001; Kalita and Misra, 2004; Shah et al., 2001; Malaviya, 2003; Lenk and Schroeder, 2001). Infection of

TUBERCULOSIS

lymph nodes, pleura, pericardium, peritoneum, gall bladder, small and large bowel, the middle ear, and carpal tunnel have been described in the literature. Because TB can involve virtually any organ in the body, this infection must be kept in the differential diagnosis of unusual presentations of diseases, especially in the elderly. Thus, TB has been aptly described as “the great masquerader”.

DIAGNOSIS Clinicians caring for the elderly must maintain a high index of suspicion for TB when possible, in order to promptly recognize and treat infected individuals.

Tuberculin Skin Testing The Mantoux method of tuberculin skin testing using the Tween-stabilized PPD antigen is one of the diagnostic modalities readily available to screen for TB infection, despite its potential for false-negative results (Markowitz et al., 1993). In the elderly, because of the increase in anergy to cutaneous antigens, the two-step tuberculin test is suggested as part of the initial geriatric assessment to avoid overlooking potentially false-negative reactions (Tort et al., 1995). The American Geriatrics Society routinely recommends two-step tuberculin testing as part of the baseline information for all institutionalized elderly (American Geriatrics Society, 1993). The two-step tuberculin skin test involves initial intradermal placement of five tuberculin units of PPD, and the results are read at 48 to 72 hours. Patients are retested within two weeks after a negative response (induration of less than 10 mm). A positive “booster effect”, and therefore a positive tuberculin skin test reaction, is a skin test of 10 mm or more and an increase of 6 mm or more over the first skin test reaction. It is important to distinguish the booster phenomenon from a true tuberculin conversion. The booster effect occurs in a person previously infected with Mtb but who has a false-negative skin test; repeat skin test elicits a truly positive test. Conversion (not to be confused with the booster phenomenon) occurs in persons previously uninfected with Mtb and who have had a true negative tuberculin skin test, but who become infected within 2 years as demonstrated by a repeat skin test induration that is a positive 10 mm or more during this period. Several factors influence the results and interpretation of the PPD skin test. Decreased skin test reactivity is associated with waning DTH with time, disseminated TB, corticosteroids and other drugs, and other diseases as well as the elimination of TB infection. False-positive PPD results occur with cross-reactions with nontuberculous mycobacteria and in persons receiving the Bacillus Calmette-Guerin (BCG) vaccine, the latter having been administered to some foreignborn elderly persons, which has an unpredictable effect on the PPD skin test reactivity and is presumed to wane after 10 years. The use of anergy testing has been debated because of lack of a standardized protocol for selection of the number

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and type of antigens to be used, the criteria for defining positive and negative reactions, and administration and interpretation techniques (Slovis et al., 2000).

QuantiFERON-TB (QFT) Testing In 2001, the QuantiFERON-TB (QFT) test was approved by the US Food and Drug Administration (FDA) to aid in the detection of LTBI. This in vitro test measures by an enzymelinked immunosorbent assay (ELISA), the concentration of interferon-gamma (IFN-γ ) released from tuberculin PPDsensitized lymphocytes in heparinized whole blood incubated for 16 to 24 hours. Interpretation of QFT results is stratified by estimated risk for Mtb infection in a manner similar to the tuberculin skin test using different induration cut-off values as shown in Tables 1(A) and (B) (Centers for Disease Control and Prevention, 2003a). The role for QFT in targeted testing has not yet been clearly defined and may be a useful alternative to tuberculin skin testing in the future for all infected individuals including the elderly.

Chest Radiography Chest radiography is indicated in all individuals with suspected TB infection, regardless of the primary site of infection. In the elderly, 75% of all TB disease occurs in the respiratory tract and largely represents reactivation disease; 10 to 20% of cases may be as a result of primary infection (Woodring et al., 1986). Although reactivation TB disease characteristically involves the apical and posterior segments of the upper lobes of the lungs, several studies have shown that many elderly patients manifest their pulmonary infection in either the middle or lower lobes or the pleura, as well as present with interstitial, patchy, or cavitary infiltrates that may be bilateral. Primary TB can involve any lung segment, but more often tends to involve the middle or lower lobes as well as mediastinal or hilar lymph nodes. Thus, caution must be exercised in dismissing the radiographic diagnosis of pulmonary TB in the elderly because of the atypical location of the infection in the lung fields.

Laboratory Diagnosis Sputum samples must be collected from all patients, regardless of age, with pulmonary symptoms or chest radiographic changes compatible with TB disease and who have not been previously treated with antituberculous agents. In elderly patients unable to expectorate sputum, other diagnostic techniques such as sputum induction or bronchoscopy should be considered. Flexible bronchoscopy to obtain bronchial washings and to perform bronchial biopsies has been shown to be of diagnostic value for TB disease in the elderly; however, in the frail and very old patient, the risk of such a procedure must be carefully balanced against the

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Table 1A Interim recommendations for applying and interpreting QuantiFERON-TB (Centers for Disease Control and Prevention. Guidelines for using the QuantiFERON-TB test for diagnosing latent Mycobacterium tuberculosis infection. Morbidity and Mortality Weekly Report 2003a; 52 (RR02): 15 – 8)

Reason for testing

Population

Initial screening

Positive results

Evaluation

Tuberculosis (TB suspect)

Persons with symptoms of active TB

Induration ≥5 mm

Chest radiograph, smears, and cultures, regardless of test results

Increased risk for progression to active TB, if infected

Persons with recent contact with TB, changes on chest radiograph consistent with prior TB, organ transplants, or human-immunodeficiency virus infection, and those receiving immunosuppressing drugs equivalent of ≥15 mg day−1 of prednisone for ≥1 montha Persons with diabetes, silicosis, chronic renal failure, leukemia, lymphoma, carcinoma of the head, neck, or lung, and persons with weight loss of ≥10% of ideal body weight, gastrectomy, or jejunoileal bypassa Recent immigrants, injection-drug users, and residents, and employees of high-risk congregate settings (e.g. prisons, jails, homeless shelters, and certain health-care facilities)b

Tuberculin skin testing (TST) might be useful; QFT not recommended TST; QFT not recommended

Induration ≥5 mm

Chest radiograph if TST is positive; treat for LTBI after active TB disease is ruled out

Increased risk for LTBI

Other reasons for Military personnel, hospital staff, testing among and health-care workers whose persons at low risk risk of prior exposure to TB for LTBI patients is low, and US-born students at certain colleges and universities a

TST; QFT not recommended

Induration ≥10 mm

TST or QFT

Induration ≥10 mm; percentage tuberculin response ≥15 %

TST or QFT

Induration ≥15 mm; percentage tuberculin response ≥30 %

Chest radiograph if either test is positive; confirmatory TST is optional if QFT is positive; treat for LTBI after active TB disease is ruled out; LTBI treatment when only QFT is positive should be based on clinical judgment and estimated risk Chest radiograph if either test is positive; confirmatory TST if QFT is positive; treatment for LTBI (if QFT and TST are positive and after active TB disease is ruled out) on the basis of assessment of risk for drug toxicity, TB transmission, and patient preference

QFT has not been adequately evaluated among persons with these conditions; it is not recommended for such populations.

Table 1B QuantiFERON-TB testing: results and interpretation (Centers for Disease Control and Prevention. Guidelines for using the QuantiFERON-TB test for diagnosing latent Mycobacterium tuberculosis infection. Morbidity and Mortality Weekly Report 2003a; 52 (RR02): 15 – 8)

M–Na (IUmL) T–Nb (IUmL)

Avian difference (%)

Tuberculin response (%)c

≤1.5

All other response profiles

All other response profiles

≥1.5 ≥1.5

All other response profiles ≥1.5

All other response profiles ≤10

All other response profiles ≤15 ≥15 but 6 weeks treatment)

• Serology • Culture, immunohistology, and PCR of surgical material Chlamydia spp.

• Serologye • Culture, immunohistology, and PCR of surgical material

• Doxycycline • Newer fluoroquinolonesf (Long-term treatment, optimal duration unknown)

Mycoplasma spp.

• Serology • Culture, immunohistology, and PCR of surgical material

• Doxycycline • Newer fluoroquinolonesf (>12 weeks treatment)

Legionella spp.

• Blood cultures • Serology • Culture, immunohistology, and PCR of surgical material

• Macrolides plus rifampin • Newer fluoroquinolonesf (>6 months treatment)

Tropheryma whipplei (Agent of Whipple’s disease)

• Histology and PCR of surgical material

• Cotrimoxazoleg • β-lactam plus aminoglycoside (Long-term treatment, optimal duration unknown)

a

Owing to the lack of large series on IE due to these pathogens, optimal-treatment duration is mostly unknown. Treatment durations in the figure are indicative, and based on selected case reports. b According to reference (Hadjinikolaou et al., 2001). c Doxycycline 100 mg orally twice a day and hydroxychloroquine 200 mg orally 3 times a day (hydroxychloroquine levels in the serum were monitored) was significantly superior than doxycycline (Raoult et al., 1999). d Several therapeutic regimens were reported, including aminopenicillins and cephalosporins combined with aminoglycosides, doxycycline, vancomycin, and quinolones (reviewed in (Brouqui and Raoult, 2001)). e Beware of serologic cross-reaction with the more common IE pathogen Bartonella spp. f Newer fluoroquinolones are more potent than ciprofloxacin against intracellular pathogens such as Mycoplasma spp., Legionella spp., and Chlamydia spp. g Treatment of Whipple IE remains highly empirical. Successes were reported with long-term (>1 year) cotrimoxazole therapy. γ -interferon plays a protective role in intracellular infections. It was proposed as adjuvant therapy in Whipple’s disease (Dutly and Altwegg, 2001).

when antibiotics have been prescribed prior to blood cultures, or in the case of fastidious organisms such as those presented in Table 3. Although specific studies are lacking, IE due to fastidious organisms does not seem to differ in elderly and younger people (Brouqui and Raoult, 2001). Thus, except for an increased frequency of S. gallolyticus in the elderly, the microbial etiology of IE is quite comparable in older and younger patients. The prediction of a plausible pathogen depends on the patient’s underlying conditions rather than on age. For example, coagulasenegative staphylococci are more frequent on prosthetic valve than on native valves. Antibiotic-resistant staphylococci are

more frequent in health-care associated infections than in community-acquired diseases. Streptococcus gallolyticus is more prevalent in older patients and should prompt specific colon investigation, because it is suggestive of an underlying colonic neoplasia (Hoen et al., 1994; Waisberg et al., 2002).

MORTALITY Mortality has been reported as being either much higher in elderly than younger patients (up to 45% vs 10–25%,

INFECTIVE ENDOCARDITIS IN THE ELDERLY Table 4 Complications of infective endocarditis in elderly (≥65 years) and younger (1 : 800 2. Endocardial involvement – Positive echocardiogram for IE (transesophageal echo recommended in patients with prosthetic valves, patients rated as “possible” IE by clinical criteria, or complicated IE [paravalvular abscess]; transthoracic echo as first in other patients): (i) Oscillating intracardiac mass on valve or supporting structure, or in the path of regurgitant jets, or on implanted material, in the absence of an alternative anatomic explanation, or (ii) Abscess, or (iii) New partial dehiscence of prosthetic valve – New valvular regurgitation (worsening or changing of preexisting murmur not sufficient) Minor criteria 1. Predisposing cardiac condition or intravenous drug use 2. Fever: ≥38 ◦ C (100.4 ◦ F) 3. Vascular phenomena: major arterial emboli, septic pulmonary infarct, mycotic aneurysms, intracranial hemorrhage, conjonctival hemorrhage, Janeway’s lesions 4. Immunologic phenomena: glomerulonephritis, Osler nodes, Roth spots, rheumatoid factor 5. Microbiology: positive blood cultures, but not meeting major criteria as mentioned above, serologic evidence of active infection with plausible microorganismsd 6. Echocardiogram consistent with IE but not meeting the major criterion noted abovee Diagnosis Definite • Pathology or bacteriology of vegetations, major emboli or intracardiac abscess specimen, or • 2 major criteria, or • 1 major and 3 minor criteria, or • 5 minor criteria Possible f • 1 major and 1 minor criterion, or 3 minor criteria Rejected • Firm alternative diagnosis, or • Resolution of IE syndrome after ≤4 days of antibiotherapy, or • No pathologic evidence at surgery or autopsy after ≤4 days of antibiotherapy • Does not meet criteria mentioned above a

Modifications of the Duke criteria proposed by Li et al. (Li et al., 2000) are highlighted in bold in the table. The revised criteria were validated against a retrospective cohort of pathologically demonstrated and/or prospectively followed endocarditis cases. The revision was intended to increase both the diagnostic specificity (diagnostic threshold) and the sensitivity for endocarditis due to S. aureus and difficult to cultivate organisms. b Includes Haemophilus spp., Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, and Kingella Kingae. c Original Duke criteria state: “or community-acquired S. aureus or enterococci in the absence of primary focus” (Durack et al., 1994). d Excludes single positive cultures of coagulase-negative staphylococci and organisms that do not cause endocarditis. e Appears in the original Duke criteria (Durack et al., 1994), abandoned in the revised criteria (Li et al., 2000). f Original Duke criteria state: “findings consistent with IE that fall short “Definite”, but not “Rejected” (Durack et al., 1994).

the culture media, prolonging incubation (≥2 weeks), serology, agglutination, indirect fluorescence, ELISA, complement fixation, and polymerase-chain-reaction (PCR) amplification of genes that are specific for bacteria, such as the genes of the 16S ribosomal RNA (Brouqui and Raoult, 2001; Houpikian and Raoult, 2002). PCR is useful to identify bacterial DNA in tissue samples, including valves, and peripheral emboli (Goldenberger et al., 1997). It proved invaluable to detect poorly or noncultivable bacteria such as Tropheryma whipplei (Dutly and Altwegg, 2001). However, it may remain positive in spite of clinical cure even after prolonged antibiotic treatment. Thus, specific knowledge and careful interpretation is required to avoid erroneous conclusions.

Undiagnosed culture-negative IE is a problem because unusual pathogens may not respond to empirical β-lactam and aminoglycoside therapy. Table 3 lists the principal organisms of this group, and the proposed diagnostic procedures, and tentative therapy (Brouqui and Raoult, 2001).

MANAGEMENT Treatment of IE involves several medical specialists including infectious disease experts, cardiologists, cardiovascular surgeons, and sometimes neurologists. In spite of this wide interest, no large-size and/or blinded studies exist on IE treatment. Most recommended therapies are based on

1758

MEDICINE IN OLD AGE

Table 6 Suggested treatment for native valve endocarditis due to streptococci, enterococci, and HACEK microorganisms (Adapted from references (Francioli et al., 1995; Wilson et al., 1995) and (Moreillon and Que, 2004))

Antibiotic

Dosage and route

Penicillin-susceptible viridans streptococci and Streptococcus bovis: Penicillin G 6 × 2 – 3 million U day−1 IV Ceftriaxonea Penicillin G with gentamicin Ceftriaxonea with netilmicin Vancomycin

1 × 2 g day−1 day IV or IM 6 × 2 – 8 million U day−1 IV 3 × 1 mg kg−1 day−1 IV or IM 1 × 2 g day−1 IV or IM 1 × 4 mg kg−1 day−1 IV 2 × 15 mg kg−1 day−1 IV

Duration (week) 4 4 2 2 2 2 4

Intermediate penicillin-resistant (MIC 0.1 – 1 mg l−1 ) viridans streptococci and Streptococcus bovis: 4 Penicillin G with gentamicin 6 × 3 million U day−1 IV 2 3 × 1 mg kg−1 day−1 IV or IM 4 Vancomycin 2 × 15 mg kg−1 day−1 IV Enterococcus spp.b : Penicillin G with gentamicin Ampicillin with gentamicin Vancomycin with gentamicin

6 × 3 – 5 million U day−1 IV 3 × 1 mg kg−1 day−1 IV or IM 6 × 2 g day−1 IV 3 × 1 mg kg−1 day−1 IV or IM 2 × 15 mg kg−1 day−1 IV 3 × 1 mg kg−1 day−1 IV or IM

Microorganisms of the HACEK groupc : 1 × 2 g day−1 day IV or IM Ceftriaxone† Ampicillin with gentamicin 6 × 2 g day−1 IV 3 × 1 mg kg−1 day−1 IV or IM

4–6 4–6 4–6 4–6 4–6 4–6 4 4 4

Comments Preferred in patients older than 65 years or with impaired renal function Studies suggest that gentamicin 1 x/day might be adequate Recommended for β-lactam allergic patients Studies suggest that gentamicin 1 x/day might be adequate Recommended against highly resistant strains or for β-lactam allergic patients 6-weeks therapy recommended for patients with >3 months symptoms Studies suggest that gentamicin 1 x/day might be adequate Monitor drug serum levels and renal function

Studies suggest that gentamicin 1 x/day might be adequate

a Preferred for outpatient treatment. b Treatment of endocarditis due to vancomycin-resistant enterococci requires a careful assessment of susceptibility to alternative antibiotics, including the new streptogramin combination quinupristin/dalfopristin. c Includes Haemophilus spp., Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, and Kingella Kingae.

experimental works, expert opinions, or small case-control studies (Francioli et al., 1995; Wilson et al., 1995; Moreillon and Que, 2004). Bactericidal antibiotics are a cornerstone of therapy. Therapeutic schemes recommended for the most common pathogens are presented in Table 6 and Table 7 (Francioli et al., 1995; Wilson et al., 1995). High concentrations of antibiotic in the serum are desirable to ensure diffusion into the vegetations. Prolonged treatment is mandatory to kill dormant bacteria clustered in the infected foci. Outpatient and oral therapy is sometimes proposed (Rehm, 1998), but prolonged parenteral therapy is usually recommended. The choice of an optimal regimen is based on antibiotic susceptibility testing. Minimal inhibitory concentrations of the principal drugs for the infecting pathogens should be determined. Resistant pathogens and culture-negative IE may fail to respond to standard treatment and this is discussed in the following text.

Intermediately resistant streptococci may respond to standard therapy because β-lactam concentrations in the serum are much greater than the MIC for these bacteria. Peak serum levels of penicillin G, amoxicillin, or ceftriaxone are in the order of 100 mg l−1 , that is, 100–1000 times greater than the MIC of intermediately resistant streptococci (MIC = 0.1–1 mg l−1 ). Nonetheless, potentiating the β-lactam activity by combining it with an aminoglycoside is recommended in such situations. Alternative drugs must be considered against highly resistant streptococci. These include vancomycin, to which streptococci are still widely susceptible. In the future, newer quinolones with anti-gram-positive activity and quinupristin–dalfopristin may prove useful (Entenza et al., 1995; Entenza et al., 1999). Oxazolidinones are an alternative, but they are poor bactericides. Upcoming daptomycin and tigecycline require further experimental evaluation.

Penicillin-resistant Streptococci

Methicillin-resistant and Vancomycin-resistant Staphylococci

Streptococci are becoming increasingly resistant to penicillin and other β-lactams, owing to a decreased β-lactam affinity of their membrane-bound penicillin-binding proteins (PBPs). Penicillin-resistant streptococci are classified as having either intermediate resistance (MIC of 0.1–1 mg l−1 ) or high resistance (MIC over 1 mg l−1 ).

All methicillin-resistant staphylococci carry a new, lowaffinity PBP, called PBP2A that confers cross-resistance to most β-lactam drugs. In addition, methicillin-resistant staphylococci are usually resistant to most other drugs, leaving only vancomycin to treat severe infections.

INFECTIVE ENDOCARDITIS IN THE ELDERLY

1759

Table 7 Suggested treatment for native valve and prosthetic valve endocarditis due to staphylococci (Adapted with modifications from references (Wilson et al., 1995) and (Moreillon and Que, 2004))

Antibiotic

Dosage and route

Native valves Methicillin-susceptible staphylococci Flucloxacillin, or oxacillin, or nafcillin with gentamicin (optional) Cefazolin (or other first generation cephalosporins) with gentamicin (optional) Vancomycin

6 × 2 g day IV 3 × 1 mg kg−1 day−1 IV or IM 3 × 2 g day−1 IV 3 × 1 mg kg−1 day−1 IV or IM 2 × 15 mg kg−1 day−1 IV

4–6

Recommended for β-lactam allergic patients

Methicillin-resistant staphylococci Vancomycin

2 × 15 mg kg−1 day−1 IV

4–6


6 × 2 g day−1 IV 3 × 300 mg day−1 orally 3 × 1 mg kg−1 day−1 IV or IM 2 × 15 mg kg−1 day−1 IV 3 × 300 mg day−1 orally 3 × 1 mg kg−1 day−1 IV or IM

≥6 ≥6 2 ≥6 ≥6 2

Rifampin increases the hepatic metabolism of numerous drugs, including warfarin

2 × 15 mg kg−1 day−1 IV 3 × 300 mg day−1 orally 3 × 1 mg kg−1 day−1 IV or IM

≥6 ≥6 2

Prosthetic valves Methicillin-susceptible staphylococci a Flucloxacillin, or oxacillin, or nafcillin with rifampin and gentamicin Vancomycin with rifampin and gentamicin

Methicillin-resistant staphylococci Vancomycin with rifampin and gentamicin

Duration (week)

4–6 3 – 5 days 4–6 3 – 5 days

Comments

The benefit of gentamicin addition is not demonstrated Alternative for patients allergic to penicillins (not in case of immediate type penicillin hypersensitivity)


a

Rifampin plays a special role in prosthetic device infection, because it helps kill bacteria attached to foreign material. Rifampin should never be used alone, because it selects for resistance at a high frequency (ca. 10−6 ).

Yet, vancomycin-resistance is developing. S. aureus and coagulase-negative staphylococci with intermediate resistance to vancomycin have emerged worldwide. The mechanism of intermediate resistance is mediated by chromosomal mutations affecting the synthesis of the cell wall (Hiramatsu, 2001). High vancomycin-resistance had emerged 15 years ago in enterococci, and could be transferred experimentally into S. aureus (Noble et al., 1992). Recently, few highly vancomycin-resistant S. aureus were isolated in the clinics. Their vancomycin-resistant genes were also acquired from enterococci (Rep, 2002). Treatment of IE caused by vancomycin-resistant staphylococci will require new approaches. At present, a few unconventional alternatives are available, including old and new β-lactams with relatively good affinity to PBP2A (Entenza et al., 2002), quinupristin–dalfopristin combined with or without β-lactams (Entenza et al., 1995; Vouillamoz et al., 2000), antibiotic combination including cotrimoxazole (de Gorgolas et al., 1995), and maybe oxazolidinones (Jacqueline et al., 2002). Methicillin-resistant staphylococci are usually resistant to newer quinolones. Promising future drugs include daptomycin (Sakoulas et al., 2003).

Multiple-drug-resistant Enterococci These organisms are resistant to most available drugs, including vancomycin. Treatment of such bacteria relies on the combination of multiple drugs and the use of experimental antibiotics. It requires precise determination of antibiotic

susceptibilities, testing for bactericidal activity, maybe determining the serum inhibitory and bactericidal titers, and monitoring drug levels in the serum. Although aminoglycosideresistance is often present, these drugs may still synergize with cell-wall inhibitors, provided that the aminoglycosides MIC is ≤1000 mg l−1 . Streptomycin is worth testing because it may be active against enterococci that are resistant to other aminoglycosides. Salvage regimens suggested to combat highly aminoglycoside-resistant, but ampicillinsusceptible, enterococci include continuous infusion of highdose ampicillin, alone or in combination with ceftriaxone, other β-lactam combinations, or oxazolidinones. Whenever envisioned, such an approach should be based on expert opinion. As for streptococci, upcoming daptomycin, and tigecycline require further studies (Kennedy and Chambers, 1989; Lefort et al., 2003).

Culture-negative Endocarditis Table 3 summarizes the treatment of IE due to rare pathogens. Brucella spp. IE responds to ≥3 months treatment with doxycycline (100–200 mg every 12 hours) plus cotrimoxazole (960 mg every 12 hours) or rifampin (300–600 mg day−1 ) combined with or without streptomycin (16 mg kg−1 day−1 ). Surgery may be required (Hadjinikolaou et al., 2001). Cure is considered by an antibody titer returning to

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