Evidence-Based Dementia Practice

Evidence-based Dementia Practice Edited by: Nawab Qizilbash MBChB, MRCP, MSc, DPhil (Oxon) Visiting Professor of Geriatric Medicine Hospital Universitario GM-Cantoblanco 280049 Madrid Spain Member of Green College Oxford University Oxford UK

Blackwell Science

Evidence-based Dementia Practice Edited by: Nawab Qizilbash MBChB, MRCP, MSc, DPhil (Oxon) Visiting Professor of Geriatric Medicine Hospital Universitario GM-Cantoblanco 280049 Madrid Spain Member of Green College Oxford University Oxford UK

Blackwell Science

© 2003 by Blackwell Science Ltd a Blackwell Publishing Company Editorial Offices: Osney Mead, Oxford OX2 0EL, UK Tel: +44 (0)1865 206206 Blackwell Science, Inc., 350 Main Street, Malden, MA 02148-5018, USA Tel: +1 781 388 8250 Blackwell Science Asia Pty, 54 University Street, Carlton South, Victoria 3053, Australia Tel: +61 (0)3 9347 0300 Blackwell Wissenschafts Verlag, Kurfürstendamm 57, 10707 Berlin, Germany Tel: +49 (0)30 32 79 060 The rights of the Authors to be identified as the Authors of this Work has been asserted in accordance with the Copyright, Designs and Patents Act 1988. 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 or otherwise, except as permitted by the UK Copyright, Designs and Patents Act 1988, without the prior permission of the publisher. First published 2002 Reprinted 2003 A catalogue record for this title is available from the British Library and the Library of Congress ISBN 0-632-05296-1 A catalogue record for this title is available from the British Library Set in Hong Kong by Graphicraft Limited Printed in Great Britain at the Alden Press, Oxford and Northampton and bound by MPG Books Ltd, Bodmin, Cornwall For further information on Blackwell Science, visit our website: www.blackwellpublishing.com

Contents

List of Contributors, xi Foreword, xv Preface, xix Section I Evidence-based Methods in Dementia Section Editors: Nawab Qizilbash and Lon S. Schneider I.1 Introduction, 3 Nawab Qizilbash I.2 Finding the Evidence, 6 Nawab Qizilbash I.3 Critical Appraisal, 12 Nawab Qizilbash I.4 Evidence-based Etiology and Harm, 14 Nawab Qizilbash I.5 Evidence-based Diagnosis, 18 Nawab Qizilbash I.6 Evidence-based Prognosis, 26 Nawab Qizilbash I.7 Evidence-based Interventions, 31 Nawab Qizilbash I.8 Evidence-based Systematic Reviews and Meta-analyses, 42 Nawab Qizilbash I.9 Evidence-based Guidelines, 60 Nawab Qizilbash I.10 Evidence-based Economic Evaluation, 64 Nawab Qizilbash

I.11

Accessing and Using the Best Evidence Efficiently in Dementia, 71 Nawab Qizilbash I.12 Evidence-based Audit: Evaluating Implementation, 74 Nawab Qizilbash Section II Diagnosis Section Editor: Helena Chui II.1 Introduction, 81 Helena Chui II.2 Practice Guidelines, 86 Helena Chui II.3 Reaching a Diagnosis of Dementia, 92 Edited by: Helena Chui II.3.1 Neuropsychological Assessment, 92 Mary C. Tierney II.3.2 Diagnostic Instruments to Assess Functional Impairment, 101 Serge Gauthier II.4 Reaching a Diagnosis of a Dementia Subtype, 106 Edited by: Helena Chui II.4.1 Clinical Criteria for Dementia Subtypes, 106 Helena Chui and Ae-Young Lee II.4.2 Clinical History and Neurological Signs, 119 Helena Chui II.4.3 Behavioral Characteristics in Diagnosis, 124 Jeffrey Cummings

iii

iv CONTENTS

II.4.4

II.4.5

II.4.6

II.4.7

II.4.8

II.4.9

II.4.10

II.5

Neuropsychological Assessment, 129 Mary C. Tierney Genetic Markers in Differential Diagnosis, 133 Haydeh Payami Utility of CT Scanning in Diagnosing Dementia, 138 Jaime Díaz-Guzman, J. María Millán, David G. Muñoz and Félix Bermejo MRI of the Medial Temporal Lobe for the Diagnosis of Alzheimer’s Disease, 154 Lisette Bosscher and Philip Scheltens Functional Imaging in Dementia, 162 William Jagust, Helena Chui and Ae-Young Lee EEG as a Diagnostic Tool in Dementia, 170 Hilkka Soininen and Juhani Partanen Cerebrospinal Fluid Biomarkers, 175 Kaj Blennow and Anders Wallin Conclusions, 194 Helena Chui

Section III Background Facts Section Editor: Timo Erkinjuntti III.1 Historical Evolution of the Concept of Dementia: a Systematic Review From 2000 BC to AD 2000, 199 Gustavo C. Román III.2 Alzheimer’s Disease, 228 Edited by: David Knopman, Karen Ritchie, Catherine Polge, Irina Alafuzoff and Hilkka Soininen III.2.1 Preamble, 228 David Knopman III.2.2 Diagnostic Considerations, 228 David Knopman III.2.3 Clinical Picture, 234 David Knopman

III.2.4 III.2.5

III.2.6 III.2.7 III.2.8 III.2.9

III.3

III.3.1 III.3.2 III.3.3 III.3.4 III.3.5 III.3.6 III.3.7 III.3.8 III.4 III.4.1 III.4.2 III.4.3 III.4.4 III.4.5 III.4.6 III.4.7 III.5

III.5.1 III.5.2

Diagnostic Tools, 237 David Knopman Epidemiology of the Dementias and Alzheimer’s Disease, 238 Karen Ritchie Risk Factors and Mortality, 240 Karen Ritchie Prevalence and Incidence, 241 Karen Ritchie and Catherine Polge Calculating Burden, 243 Karen Ritchie Neuropathology and Ethiopathogenesis of Alzheimer’s Disease, 244 Irina Alafuzoff and Hilkka Soininen Vascular Dementia, 260 Didier Leys, Elisabet Englund and Timo Erkinjuntti Introduction, 260 Diagnosis, 260 Diagnostic Criteria, 262 Epidemiology, 265 Determinants of Vascular Dementia, 268 Clinical Patterns, 273 Heterogeneity of Vascular Dementia, 275 Differential Diagnosis, 279 Lewy Body Dementia, 288 Douglas Galasko Introduction, 288 Definition and Diagnostic Criteria, 289 Clinical Picture, 290 Incidence and Prevalence, 292 Etiology, 293 Prognosis, 294 Accuracy of Diagnostic Criteria, 294 Frontotemporal Lobar Atrophies: The Pick Complex, 297 David G. Muñoz and Andrew Kertesz Introduction, 297 Clinical Features, 298

CONTENTS v

III.5.3 III.5.4 III.5.5 III.5.6 III.5.7 III.5.8 III.5.9 III.5.10 III.6 III.6.1 III.6.2 III.6.3 III.6.4 III.6.5 III.6.6 III.6.7 III.6.8 III.7

III.7.1 III.7.2

III.7.3 III.7.4 III.7.5 III.7.6 III.7.7 III.7.8 III.7.9 III.8

III.8.1 III.8.2

Basic Biology of Tau, 300 Structural Substrates, 300 Alterations in Tau Proteins and Gene, 303 Pathogenic Mechanisms in Pick Complex, 304 Incidence and Prevalence, 305 Diagnostic Tests, 305 Diagnostic Criteria and Differential Diagnosis, 306 Clinical Vignette, 307 Other Important Dementias, 312 Juha O. Rinne Introduction, 312 Parkinson’s Disease, 312 Huntington’s Disease, 316 Progressive Supranuclear Palsy, 318 Multiple System Atrophy, 319 Corticobasal Degeneration, 319 Conclusions, 320 Infectious Dementias, 320 Irina Elovaara and Irina Alafuzoff Reversible or Arrestable Dementias, 330 Lars-Olof Wahlund, Hans Basun and Gunhild Waldemar Introduction, 330 Normal Pressure Hydrocephalus and Intracranial Space-occupying Lesions, 332 Depression, 333 Drugs, 334 Thyroid, 335 Vitamin B12, 336 Folate, 336 Other Potentially Reversible Conditions, 337 Summary, 338 Mild Cognitive Impairment, 341 Alan Kluger, James Golomb and Steven H. Ferris Introduction, 341 Definition and Diagnostic Criteria, 342

III.8.3 III.8.4 III.8.5 III.8.6 III.8.7 III.8.8 III.8.9 III.8.10

Clinical Picture, 343 Diagnostic Tools, 344 Incidence, Prevalence and Burden, 345 Epidemiologic Risk Factors, 346 Prognosis, 346 Pathology/Pathogenetic Etiology, 348 Likely Subtypes of MCI, 350 Treatment of MCI, 351

Section IV Overview of Treatment and Management Section Editors: Jeffrey Kaye, Lon S. Schneider and Nawab Qizilbash IV.1 Aims of Treatment, 357 Jeffrey Kaye IV.2 Criteria for Clinical Decisions, 359 Jeffrey Kaye IV.2.1 What is the Diagnosis? 359 IV.2.2 What are the Patient’s Principal Problems? 360 IV.2.3 What is the Prognosis? 360 IV.2.4 What are the Patient and Family Expectations? 362 IV.2.5 What is the Likelihood of Treatment Benefit? 363 IV.3 Clinical Decisions in Practice, 365 Jeffrey Kaye IV.3.1 Rationale for TreatmentaAssessing the Evidence, 365 IV.3.2 From Groups to Individuals, 366 IV.3.3 The Application of Specific Treatments for Dementia, 367 IV.3.4 Caregivers in the Therapeutics of Dementia, 368 IV.3.5 Treatment of Mood Changes and Depression, 368 IV.3.6 Treatment of Behavioral Changes, 369 IV.3.7 Cognitive Therapies, 370 IV.3.8 Preventative Therapies, 370 IV.3.9 Principles of Administration, 371 IV.3.10 Monitoring Treatment Effects, 371

vi CONTENTS

IV.4

IV.4.1 IV.4.2 IV.4.3 IV.4.4 IV.4.5 IV.4.6 IV.4.7 IV.5 IV.5.1

IV.5.2

IV.5.3

IV.5.4

IV.6

IV.6.1 IV.6.2 IV.6.3 IV.6.4 IV.6.5 IV.6.6 IV.6.7 IV.6.8 IV.6.9 IV.6.10

Delivering an Integrated Treatment Plan, 373 Jeffrey Kaye Establishing a Knowledge Base and Providing Education, 373 Addressing Social and Environmental Needs, 373 Health Maintenance, 374 Behavioral Management, 374 Neurological Management, 374 Cognitive Function, 375 Prevention, 375 What is the Evidence that a Dementia Treatment Works? 376 Criteria Used by Drug Regulatory Authorities, 376 Paul Leber Criteria Used by Purchasers of Health Care Services, 387 David Millson, David Jolley and Harry Ward Dementia Trials for Cognitive Symptoms and Modification of Prognosis: Past, Present and Future, 405 Nawab Qizilbash and Lon S. Schneider Individualizing Symptomatic Therapy: n-of-1 Trials, 417 Nawab Qizilbash Non-pharmacological Techniques, 428 Robert T. Woods Introduction, 428 Reality Orientation, 430 Reminiscence Therapy, 433 Validation Therapy, 434 Memory Training, 435 Stimulation, 436 Cognitive–behavioral Therapy, 437 Behavioral Approaches, 438 Conclusion and Integration, 441 Summary of Key Points, 442

IV.7

Drugs in Development and Experimental Approaches, 447 Murat Emre

Section V Therapies for Cognitive Symptoms, Disease Modification and Prevention Section Editors: Jeffrey Kaye, Lon S. Schneider and Nawab Qizilbash V.1 Introduction to Specific Therapies for Cognitive Symptoms or Modifying Disease Prognosis, 461 Nawab Qizilbash V.2 Treatment of Alzheimer’s Disease (With or Without Cerebrovascular Disease), 467 Edited by: Lon S. Schneider V.2.1 Introduction, 467 Nawab Qizilbash V.2.2 Acetyl-L-carnitine, 468 Mary Sano and Fadi Massoud V.2.3 Antioxidant Vitamins, 471 Jeffrey Kaye V.2.4 Donepezil in the Treatment of Alzheimer’s Disease, 473 Lon S. Schneider V.2.5 Galantamine, 484 Lon S. Schneider and Jason T. Olin V.2.6 Metrifonate, 493 Lon S. Schneider V.2.7 Rivastigmine, 499 Lon S. Schneider V.2.8 Tacrine, 509 Nawab Qizilbash V.2.9 d-Cycloserine, 516 Knut Laake and Anne Rita Øksengaard V.2.10 Ginkgo Biloba, 518 Barry S. Oken V.2.11 Estrogen, 523 Fadi Massoud, Kristine Yaffe and Mary Sano V.2.12 Hydergine, 526 Lon S. Schneider and Jason T. Olin

CONTENTS vii

V.2.13 V.2.14 V.2.15 V.2.16

V.2.17 V.2.18 V.2.19

V.2.20 V.2.21

V.3 V.3.1 V.3.2 V.3.3 V.3.4 V.3.5 V.3.6 V.3.7 V.3.8 V.3.9

Idebenone, 530 Kentaro Hashimoto Nicotine, 535 Jesus López-Arrieta Nimodipine, 537 Jesus López-Arrieta Non-steroidal Anti-inflammatory Drugs, 541 John C.S. Breitner Piracetam, 546 Leon Flicker Propentofylline, 548 Kenneth Rockwood Selegiline in the Treatment of Alzheimer’s Disease, 553 Mary Sano and Fadi Maussoud Thiamine, 557 José Luís Rodríquez-Martin Summary, Practical Recommendations and Opinions on Therapies for Cognitive Symptoms and Prognosis Modification, 560 Nawab Qizilbash and Lon S. Schneider Treatment of Vascular Dementia, 589 Introduction, 589 Jeffrey Kaye Antioxidants, 589 Nawab Qizilbash Antithrombotics, 590 Helmi L. Lutsep Blood Pressure Reduction, 593 Nawab Qizilbash CDP-choline, 596 Mario Fioravanti Ginkgo Biloba, 599 Nawab Qizilbash Hydergine, 599 Nawab Qizilbash Nimodipine, 600 Nawab Qizilbash Pentoxifylline, 600 Leon Flicker

V.3.10 V.3.11 V.3.12

V.4

V.5

V.5.1 V.5.2 V.5.3 V.5.4 V.5.5 V.5.6 V.5.7 V.5.8 V.5.9 V.5.10 V.6

V.7

Piracetam, 603 Nawab Qizilbash Propentofylline, 603 Nawab Qizilbash Summary, Practical Recommendations and Conclusions, 603 Jeffrey Kaye Treatment of Lewy Body Dementia, 608 E. Jane Byrne Treatment of Reversible or Arrestable Dementias, 615 Perminder Sachdev, Julian Trollor and Jeffrey C.L. Looi Introduction, 615 Infections of the Central Nervous System, 616 Traumatic Brain Injury and Dementia Pugilistica, 620 Alcohol-related Dementia, 620 Cerebral Hypoxia/Anoxia, 621 Tumors and Malignancy, 627 Vitamin Deficiencies, 628 Metabolic Causes, 628 Chronic Disease, 630 Conclusion, 631 Treatment of Age-associated Memory Impairment, 639 Keith Wesnes and Tony Ward Prevention of Dementia, 654 Anthony F. Jorm

Section VI Treating Non-cognitive Problems Section Editor: Pierre Tariot VI.A A Problem-oriented Approach to Common Psychiatric Problems, 669 Edited by: Pierre Tariot VI.1 Introduction, 671 Pierre Tariot VI.2 Classes of PsychotropicsaOverview of Evidence from Clinical Trials, 675

viii CONTENTS

VI.2.1

VI.2.2

VI.2.3 VI.2.4 VI.2.5

VI.3 VI.3.1

VI.3.2

VI.3.3 VI.3.4 VI.3.5 VI.4

VI.B

VI.5 VI.5.1

VI.5.2

Conventional Antipsychotics, 675 Brian A. Lawlor and Gregory Swanwick Atypical Antipsychotics, 677 Brian A. Lawlor and Gregory Swanwick Anxiolytics, 678 Louise Carrier Anticonvulsants, 682 Pierre Tariot Other Classes of Psychotropics in Dementia, 686 Pierre Tariot Problems, 695 Depressive Features in Dementia, 695 D.P. Devanand, Gregory H. Pelton and Steven P. Roose Psychosis, 698 Brian A. Lawlor and Gregory Swanwick Agitation, 705 Pierre Tariot Hypersexuality, 707 Joan M. Swearer Sleep Disturbance, 711 Joan M. Swearer Summary, Practical Recommendations and Opinions, 720 Pierre Tariot A Problem-oriented Approach to Common Medical Problems, 723 Edited by: Nawab Qizilbash and Jesus López-Arrieta Common Medical Problems, 725 Introduction, 725 Nawab Qizilbash and Jesus López-Arrieta Delirium, 728 Nawab Qizilbash and Jesus López-Arrieta

VI.5.3

VI.5.4

VI.5.5

VI.5.6

VI.5.7

Seizures, 730 Nawab Qizilbash and Jesus López-Arrieta Mobility, Falls and Fractures, 731 Nawab Qizilbash and Jesus López-Arrieta Feeding Problems and Weight Loss, 733 Nawab Qizilbash and Jesus López-Arrieta Incontinence, 734 Mark Castleden and Stephen Evans Death, 739 Nawab Qizilbash and Jesus López-Arrieta

Section VII Social, Ethical and Health Services Issues Section Editor: Henry Brodaty VII.1 Social and Ethical Issues, 747 Stephen G. Post VII.1.1 Respect and Care for the Person with Dementia, 747 VII.1.2 Diagnostic Truth-telling and Precedent Autonomy, 748 VII.1.3 Research Ethics and Informed Consent, 748 VII.1.4 Quality of Life, Morbidity Protraction, and Cognitive Enhancing Drugs, 750 VII.1.5 Dying Well in Advanced Dementia: The Ethics of Nutrition and Hydration, 751 VII.2 Driving, 755 Desmond O’Neill VII.3 Care-giver Interventions, 764 Alisa Green and Henry Brodaty VII.4 Genetic Counseling, 795 A. Dessa Sadovnick VII.5 Nursing Home Care for Patients with Dementia, 801 Ira R. Katz, Catherine J. Datto and Melissa Katz-Snellgrove

CONTENTS ix

VII.6

VII.6.1 VII.6.2 VII.6.3 VII.6.4 VII.6.5 VII.7

VII.7.1 VII.7.2 VII.7.3 VII.7.4 VII.8 VII.8.1

Organization of Care, 811 Michael S. Dennis and James Lindesay Introduction, 811 Determining Population Needs, and Service Planning, 812 Individual Components of a Dementia Service, 813 Monitoring and Evaluating Services, 824 Conclusions and Future Research Priorities, 825 Memory Clinicsaa Guide to Implementation and Evaluation, 828 Roger Bullock and Nawab Qizilbash Background, 828 Summary of Rationale for Establishing a Memory Clinic, 829 Setting up a Memory Clinic, 829 The Future Development of the Memory Clinic, 837 Health Economics, 844 Alastair M. Gray Introduction, 844

VII.8.2 VII.8.3 VII.8.4 VII.8.5 VII.8.6 VII.8.7

Methods, 845 Cost Analyses and Cost-of-Illness Studies, 845 Diagnosis, 848 Evaluations of Care and Treatment, 849 Economic Evaluation of Drug Interventions, 850 Conclusions, 852 Appendices Appendix I: Diagnostic Criteria for Common Dementias, 855 Nawab Qizilbash Appendix II: Dementia Rating Scales, 859 Roger Bullock Appendix III: National Alzheimer’s Disease and Dementia Associations and Societies, 870 Nawab Qizilbash Abbreviations, 875 Index, 879

List of Contributors

Editor Nawab Qizilbash MBChB, MRCP, MSc, DPhil (Oxon) Visiting Professor of Geriatric Medicine, Hospital Universitario, GM-Cantoblanco, 280049 Madrid, Spain and Director, Clinical Epidemiology and Evidence-based Medicine, GlaxoSmithKline, Harlow CM19 5AW, UK

Section Editors

Contributors Irina Alafuzoff MD, PhD Kuopio University Department of Neuroscience and Neurology/Section of Neuropathology, Kuopio University Hospital/Department of Pathology, PO Box 1627, FIN-70211 Kuopio, Finland

Hans Basun MD, PhD Associate Professor, AstraZeneca, S-151 85 Sodertalje, Sweden

Henry Brodaty AO, MB, BS, MD, FRACP, FRANZCP

Félix Bermejo PMD, PhD

Academic Department of Psychogeriatrics, University of New South Wales, Prince of Wales Hospital, Randwick, Sydney, New South Wales 2031, Australia

Chief Neurologist, Hospital Universitario ‘Doce de Octubre’, 28041 Madrid, Spain

Helena Chui MD MacCarron Professor of Neurology, University of Southern California Keck School of Medicine, Rancho Los Amigos National Rehabilitation Center, 8000 Annex West, 7601 East Imperial Highway, Downey, California 90242, USA

Timo Erkinjuntti MD, PhD Memory Research Unit, Department of Clinical Neurosciences, Helsinki University Central Hospital, PO Box 300, 00029 HYKS, Finland Jeffrey Kaye MD Professor of Neurology, Director, Aging and Alzheimer’s Disease Center, Oregon Health Sciences University and Portland Veterans Affairs Center, Mail Code CR-131, 3181 SW Sam Jackson Park Road, Portland OR 97201, USA

Lon S. Schneider MD Professor of Psychiatry, Neurology and Gerontology, University of Southern California Keck School of Medicine, 1975 Zonal Ave, Los Angeles, CA 90033, USA

Pierre Tariot MD Department of Psychiatry, Munroe Community Hospital, 435 East Henrietta Road, Rochester, NY 14620, USA

Kaj Blennow Institute of Clinical Neurosciences, Universitetssjukhusset, 41345 Göteborg, Sweden

Lisette Bosscher VU Medical Centre, PO Box 7057, 1007 MD Amsterdam, The Netherlands

John C.S. Breitner MD, MPH Professor and Chairman, Department of Mental Hygiene, Bloomberg School of Public Health, Johns Hopkins University, Room 850, 624 N. Broadway, Baltimore, MD 21205, USA Roger Bullock MA, MRCPsych Kingshill Research Centre, Victoria Hospital, Okus Road, Swindon SN1 4HZ, UK

E. Jane Byrne Senior Lecturer/Honorary Consultant Psychiatrist, Department of Old Age Psychiatry, The University of Manchester, Withington Hospital, West Didsbury, Manchester M20 8LR, UK

Louise Carrier MD, FRCPC Assistant Professor of Psychiatry, Psychogeriatric Community Services of Ottawa, 75 Bruyere, Ottawa ON, K1H 5C8, Canada

xi

xii LIST OF CONTRIBUTORS

Mark Castleden

Douglas Galasko MD

Quiet Waters, 5 Elmside, Budleigh Salterton, Devon EX9 6RP, UK

Department of Neurosciences, University of California, San Diego, 3350 La Jolla Village Drive, San Diego, CA 92161, USA

Jeffrey Cummings Augustus Rose Professor of Neurology, Professor of Psychiatry and Biobehavioral Sciences, UCLA School of Medicine, 710 Westwood Plaza, Los Angeles, California 90095-1769, USA

Serge Gauthier FRCPC Director, MSA Alzheimer’s Disease Research Unit, McGill Centre for Studies In Aging, 6825 Lasalle Boulevarvd, Verdun, Quebec H4H 1R3, Canada

Catherine J. Datto MD

James Golomb MD

Section of Geriatric Psychiatry, University of Pennsylvania, 3600 Market Street, Room 758, Philadelphia, PA 19104, USA

Department of Neurology and the William and Sylvia Silberstein Aging and Dementia Research Center, NYU School of Medicine, New York, USA

Michael S. Dennis MB, BCh, MRCPsych Senior Lecturer and Honarary Consultant Psychiatrist for the Elderly, Division of Psychiatry for the Elderly, University of Leicester, Leicester General Hospital, Gwendolen Road, Leicester LE5 4PW, UK

Alistair M. Gray PhD Health Economics Research Centre, Department of Public Health, University of Oxford, Institute of Health Sciences, Oxford OX3 7LF, UK

D.P. Devanand MD Professor of Clinical Psychiatry & Neurology, College of Physicians & Surgeons, Columbia University, 722 West 168th Street, New York, NY 10032, USA

Alisa Green PhD (Psych) Hons Academic Department for Old Age Psychiatry, Prince of Wales Hospital, Randwick 2031, New South Wales, Australia

Jaime Díaz-Guzman MD, PhD

ChiefaDepartment of Internal Medicine, Yao Municipal Hospital, 2-1-55 Minami Taishido, Yao City, Osaka 581-056, Japan

Neurologist, S. Neurologíca Hospital Universitario ‘Doce de Octubre’, 28041 Madrid, Spain

Irina Elovaara MD, PhD Department of Neurology, Tampere University Hospital, University of Kuopio and Kuopio University Hospital, PL 1777, 70211 Kuipo, Finland

Kentaro Hashimoto

William Jagust MD Professor and Chair, Department of Neurology, University of California, Davis, 4860 Y Street, Sacramento, California 95817, USA

Murat Emre MD Professor of Neurology, Department of Neurology, Behavioural Neurology and Movement Disorders Unit, Istanbul Medical School, 34390 Capa, Istanbul, Turkey

David Jolley

Elisabet Englund

Professor and Director, Centre for Mental Health Research, Australian National University, Canberra 0200, Australia

Associate Professor, Department of Pathology, Division of Neuropathology, Lund University Hospital, S-221 85 Lund, Sweden

Professor of Old-age Psychiatry and Medical Director, Wolverhampton Healthcare Trust, Wolverhampton, UK

Anthony F. Jorm PhD, DSc

Ira Katz MD, PhD

Stephen Evans MB, ChB, MRCP

University of Pennsylvania, Department of Psychiatry, 3535 Market St, Room 3001, Philadelphia, PA 19104, USA

Consultant Physician, Leicester General Hospital, Gwendolen Road, Leicester LE5 4PW, UK

Melissa Katz-Snellgrove MSW

Steven H. Ferris PhD The Department of Psychiatry and the William and Sylvia Silberstein Aging and Dementia Research Center, NYU School of Medicine, 550 First Avenue, New York, NY 10016, USA

Mario Fioravanti Professor of Clinical Psychology, Department of Psychiatric Science and Psychological Medicine, University of Rome, ‘La Sapienza’, P. Le A. Moro 5, 00185 Rome, Italy

Leon Flicker Professor of Geriatric Medicine, University of Western Australia, Royal Perth Hospital, Box X2213, Perth, WA 6847, Australia

Section of Geriatric Psychiatry, University of Pennsylvania, 3535 Market Street, Room 3001, Philadelphia, PA 19104, USA

Andrew Kertesz Clinical Neurological Sciences, University of Western Ontario, 1151 Richmond Street, London, Ontario N6A 5B8, Canada

Alan Kluger PhD Professor, Department of Psychiatry, Lehman College/City University of New York, 250 Bedford Park Boulevard West, Bronx, NY 10468, USA David Knopman MD Professor of Neurology, Mayo Medical School, Mayo Clinic Rochester, MN 55905, USA

LIST OF CONTRIBUTORS xiii

Knut Laake MD Professor, Department of Geriatric Medicine, Ullevaal Hospital, N-0407 Oslo, Norway Brian A. Lawlor Department of Psychiatry of the Elderly, St James’s Hospital, Dublin 8, Ireland

Anne Rita Øksengaard Department of Geriatric Medicine, Ullevaal University Hospital, 0407 Oslo, Norway

Jason T. Olin PhD

Paul Leber MD Neuro-Pharm Group, LLC, 11090 Smoketree Rd, Potomac, MD 20854, USA

Chief, Geriatric Psychopharmacology Program, Adult and Geriatric Treatment and Preventive Interventions Research Branch, National Institute of Mental Health, 6001 Executive Boulevard, Room 7160 MSC 9635, Bethesda, MD 208929635, USA

Ae-Young Lee MD Department of Neurology, Chungnam National University, Medical College and Hospital, 640 Daesa-dong, Joong-ku, Taejon, 301-040, Korea

Desmond O’Neill MD FRCPI Associate Professor, Department of Medical Gerontology, Trinity Centre for Health Sciences, Adelaide and Meath Hospital, Dublin 24, Ireland

Didier Leys Research Group on Cognitive Decline in Degenerative and Vascular Disorders (MENRT, EA 2691), Stroke Department, Roger Salengro Hospital, F-59037 Lille, France

James Lindesay Professor of Psychiatry for the Elderly, University of Leicester, Leicester General Hospital, Leicester LE5 4PW, UK

Jeffrey C.L. Looi MBBS, FRANZCP, MFPOA Staff Specialist in Aged Care Psychiatry, St George Hospital, Kogarah; Cojoint Lecturer in Psychiatry and Community Medicine, University of New South Wales; and Research Fellow, Neurposychiatric Institute, Prince of Wales Hospital, Randwick, NSW, Australia

Juhani Partanen MD, PhD University and University Hospital of Kuopio, Department of Clinical Neurophysiology, PO Box 1777, FIN-70211 Kuopio, Finland

Haydeh Payami PhD Professor of Genetics and Neurology, Oregon Health Sciences University, 3181 SW Sam Jackson Park Road, CR131, Portland, OR 97201, USA

Gregory H. Pelton MD

Jesus López-Arrieta

Department of Biological Psychiatry, New York State Psychiatric Institute, College of Physicians and Surgeons of Columbia University, 1051 Riverside Drive, New York, NY 10032, USA

ChairmanaMemory Clinic, Geriatric Department, Hospital de Cantoblanco, Madrid 28049, Spain

Catherine Polge

Helmi L. Lutsep MD Associate Director and Associate Professor, Department of Neurology, Oregon Stroke Centre, Department of Neurology, Oregon Health Sciences University, 3181 SW Sam Jackson Park Rd, CR131 Portland, OR 97201, USA

Fadi Massoud MD FRCPC Department of Neurology, Columbia University, College of Physicians and Surgeons, New York, USA

J. María Millán MD, PhD Neuroradiologist, Hospital Universitario ‘Doce de Octubre’, 28041 Madrid, Spain

David Millson MD, PhD, FFPM Professor of Medicines Management, Keele University, Staffordshire ST5 5BG, UK

David G. Muñoz MD, FRCPC Servicio de Neurología, Hospital Universitario ‘Doce de Octubre’, 28041 Madrid, Spain

INSERM-E9930, Hôpital La Colombière, Pavillon 42, BP 34493, 34093 Montpellier, Cedex 5, France

Stephen G. Post PhD Centre for Biomedical Ethics, School of Medicine, Case Western Reserve University, Cleveland, OH 44106-4976, USA Juha O. Rinne MD Professor of Neurotransmission, Turku PET Centre, University of Turku, FIN-20521 Turku, Finland

Karen Ritchie EMI 9930-INSERM Epidenmiology of Nervous System Pathologies, Hopital La Colombière, 39 Avenue Charles Flahaut, BP 34493, 34093, Montpellier, Cedex 5, France

Kenneth Rockwood Professor of Geriatric Medicine, Dalhousie University, Halifax, Nova Scotia B3H 2E1, Canada

Barry S. Oken

José Luís Rodríquez-Martin

Professor, Departments of Neurology and Behavioral Neuroscience, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97201, USA

Centro Cochrane Iberoamericano, Servei d’Epidemiologia Clinica i Salut Publica, Hospital de la Santa Creu i Sant Pau, C/Sant Antoni Ma Claret, 171, (08041) Barcelona, Spain

xiv LIST OF CONTRIBUTORS

Gustavo C. Román MD, FACP, FRSM (Lond) Professor of Medicine /Neurology, The University of Texas Health Sciences Centre at San Antonio, 7703 Floyd Curl Drive, San Antonio, Texas 78284-7883, USA Steven P. Roose

Mary C. Tierney PhD, CPsych Senior Scientist, Director Geriatric Research, STE. A145, Sunnybrook and Women’s College Health Sciences Centre, University of Toronto, 2075 Bayview Ave, Toronto, ON M4N 3M5, Canada

College of Physicians and Surgeons, Columbia University, 722W 168th St, New York 10032, USA

Julian Trollor FRANZCP Staff Specialist, Neuropsychiatric Institute, The Prince of Wales Hospital, Randwick, NSW 2031, Australia

Perminder Sachdev MD, PhD, FRANZCP Professor of Neuropsychiatry and Director, University of New South Wales, Neuropsychiatric Institute, Prince of Wales Hospital, Randwick NSW 2031, Australia

Lars-Olof Wahlund MD, PhD Professor, NEUROTEC, Section of Geriatric Medicine, Karolinska Institutet, B-84 Huddinge University Hospital, SE-1486 Huddinge, Sweden

A. Dessa Sadovnik PhD G920 Detwiller, Koerner Pavilion, Vancouver Hospital and Health Sciences CentreaUBC, 2211 Wesbrook Mall, Vancouver, British Columbia V6T 2B5, Canada

Gunhild Waldemar MD, DMSc Professor, Memory Disorders Research Unit, Department of Neurology, Copenhagen University Hospital, Rigshospitalet, 9 Blegdamsvej, DK-2100 Copenhagen, Denmark

Mary Sano PhD Department of Neurology, Columbia University, Segievsky Centre, P&S Box 16, 630 West 168th St, New York 10032, USA

Anders Wallin

Philip Scheltens MD, PhD Professor of Cognitive Neurology, VU Medical Centre, PO Box 7057, 1007 MB Amsterdam, The Netherlands

Hilkka Soininen MD, PhD Department of Neurology, Kuopio University Hospital, PO Box 1777, 70211 Kuopio, Finland Gregory Swanwick MD, MRCPI, MRCPsych Department of Psychiatry of Old Age, Adelaide and Meath Hospital, Dublin, Tallaght, Dublin 24, Ireland

Joan M. Swearer PhD Associate Professor, Departments of Neurology and Psychiatry, University of Massachusetts Memorial Health Care, University Campus, 55 Lake Avenue North, Worcester, MA 01655, USA

Institute of Clinical Neuroscience, Goteborg University, Sahlgrenska University Hospital, Molndal, SE-431 80, Sweden

Harry Ward Health Economist, Department of Medicines Management, Keele University, Staffordshire ST5 5BG, UK

Tony Ward BSc, MSc, PhD, CPsychol, AFBPsS Associate Professor and Consultant Neuropsychologist, University of the West Indies, Mona, Kingston 7, Jamaica Keith Wesnes Professor and Chief Executive, Cognitive Drug Research Ltd, CDR House, 24 Portman Road, Reading RG30 1EA, UK

Robert T. Woods Professor of Clinical Psychology of Older People, Dementia Services Development Centre Wales, University of Wales Bangor, Hollyhead Road, Bangor, Gwynedd LL57 2PX, UK

Kristine Yaffe MD Departments of Psychiatry, Neurology, and Epidemiology, University of California, San Fransisco, CA 94143, USA

Foreword

This volume represents a significant milestone in the modern history of diagnosis and interventions for dementia. The unique contribution of this volume is due to the extraordinary effort of the editors to present only well-validated practical information and the remarkable assembly of opinion leaders in clinical research as contributors. Although dementia was first formally described nearly one hundred years ago, it remained a poorly understood disorder until recently. Throughout the history of the disease, the concept of ‘senility’ shaped medical opinion. The prevailing clinical wisdom accepted, without any proof, the de facto axiom that dementia is an inevitable consequence of aging. The insistence on validation of clinical practices in geriatric medicine and the systematic efforts to critically evaluate all diagnostic and treatment approaches in dementia is a relatively recent phenomenon. Nearly all of the current information on dementia has been acquired since the 1970s. The attempts to establish diagnostic criteria, standardize assessment algorithms, validate clinical measurement instruments and search for valid biological markers began less than twenty-five years ago. In the last three decades, the dramatic advances in scientific knowledge on the neurobiology of aging and neurodegenerative disorders propelled dementia from obscurity to the forefront of modern biomedical studies. The task of translating basic scientific knowledge into practical clinical applications, particularly in the realms of differential diagnosis and effective interventions for dementia, has proved to be a difficult challenge. Historically, at the virtual ‘zero mile marker’ of the modern era of dementia

research, the barriers to technology-transfer stemmed not only from the lack of essential pieces of validated knowledge on etiology, risk factors, and putative therapeutic targets, but also due to the paucity of well-trained clinical investigators, diagnostic criteria, validated assessment instruments, clinical databases, facilities and well-characterized research participants. In order to develop evidencebased dementia practice it was necessary to build, from the ground up, piece-by-piece, a broadspectrum program consisting of human resources, clinical infrastructures and a rich body of scientific knowledge. Starting with limited resources, in 1978, the National Institute on Aging (NIA) and National Institutes of Health (NIH) launched a modest initiative to support basic and clinical research in the neurobiology of aging and dementia. As a result of these initial investments in research and infrastructure, remarkable improvements were achieved into the accuracy of the clinical diagnosis and the availability of effective interventions. Since the late 1980s the procedures for clinical assessment have steadily advanced beyond the stage of diagnosing exclusively by a ‘process of exclusion’ towards well-validated algorithms for identifying the positive clinical phenotypes of the disease. At some clinical research facilities the improvements in differential diagnosis have advanced to such sophistication that a high degree of accuracy, based on autopsy confirmation, can be attained in assessing dementia exclusively by clinical evaluation. While systematic efforts to improve the reliability and accuracy of clinical diagnosis will continue, advances in the molecular neurobiology will

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ultimately provide the urgently needed biological markers of the disease. Some of the essential rate-limiting factors (or rate enhancing factors) that have impeded (or facilitated) the pace of technology-transfer have been the ready availability of: (a) a ‘critical-mass’ of basic and clinical investigators working as multidisciplinary teams, (b) a body of validated basic and clinical knowledge (databases) derived from different disciplines, and (c) infrastructure and resources for research and clinical studies. In the early years, research on dementia was particularly hampered by the lack of appropriately trained people, ideas/data and the prerequisite infrastructure for clinical studies. It was very difficult, if not impossible, to diagnose properly or to conduct multi-site collaborative clinical studies. There was no consensus on diagnostic criteria; no standardized assessment instruments; no expertise to plan and conduct clinical trials; no facilities for longitudinal clinical studies; and no brain tissue from well-characterized patients for molecular studies. In the absence of such programs (infrastructure) as the Alzheimer’s Disease Research Centers (ADRC) and the Alzheimer’s Disease Clinical Studies (Consortium for Clinical Trials), advances in developing new treatments would not have been possible. Despite the vast improvement, the field still faces a great number of serious impediments to progress in translating basic science discoveries into effective treatments for dementia. Some of the yet-tobe-faced critical challenges for evidence-based clinical practice are outlined here. Problem one: Investigators from two different planets inhabit the world of dementia. Each group recognizes the disease by different sets of phenotypes: molecular/neuropathological vs. behavioral/ clinical phenotypes. One of the most difficult challenges for evidence-based clinical practice in dementia is to account for the functional relationships between the full spectrum of the behavioral changes (clinical symptoms) and the underlying biological mechanisms of dementia. Presently, the precise relationships between the clinical manifestations and neurobiological phenotypes of the diseases are not well defined. The information on the neuropathology of the disease is a static snap-shot

obtained at the end of a long degenerative process. Although clinical information could be obtained more readily in longitudinal studies, even these data are obtained in the later stages of the disease when some of the aberrant behavioral signs start to appear. Presently, there is little or no information on the very earliest molecular changes in the brain underlying the behaviors of individuals at risk or the person with the disease during the preclinical stages. These problems are largely due to the lack of appropriate technologies for non-invasive longitudinal observations and the means for early detection of the disease. No doubt, these hurdles will be conquered as accurate biological markers of the disease, including improved imaging techniques, and more sensitive behavioral assessment instruments become available. Problem two: The breadth and depth of the fundamental knowledge ultimately determines how quickly practical applications will emerge in any area of science. The slow progress in the early history of dementia was due to the lack of fundamental information on the normal human brain and neurobiology of the diseases. Gradually over the years, research on dementia gained momentum, and evidence-based clinical practice matured; essentially in parallel with advances in biology, genetics, biochemistry, pharmacology and neuroscience. Some of the early studies on the neurochemistry of the disease led to the discovery of a link between memory loss (a clinical symptom of the disease) and specific biochemical deficits in the brain and the formulation of the ‘cholinergic hypothesis’ of dementia, which became an important precursor for the development of treatment strategies currently in use. Recent advances in molecular biology of amyloid and tau proteins, the primary neuropathologic markers of Alzheimer’s disease, have begun to unravel the mechanisms of synthesis, trafficking and accumulation of these abnormal proteins in the brain. Research in this area has begun to produce promising leads about the role of these proteins in neural functions/dysfunctions and the means to correct these molecular mischiefs. Although the advances in neurobiology of the disease have generated a number of ideas, the precise etiology of the disease is still not known. Theories

FOREWORD xvii

on dementia have yet to be validated by crucial experiments designed to demonstrate the functional relationship(s) between the molecular aberrations and the clinical manifestations (phenotypes) of the disease. Evidence-based dementia practice needs to account for not only the lack of validation for the (presumed) causal links between the biology and behavior but also the very poor explanations for the heterogeneity of phenotypes, which may influence differential diagnosis and adverse events/ responses to treatments. Problem three: The need for an appropriate and valid model of the disease is a major handicap to developing effective disease-modifying agents and other interventions for the disease. The primary drawback of the current models of the disease is the lack of complete expression of all relevant behavioral phenotypes. One of the most serious flaws of these models is the degree of abstraction from the reality of a complex integrated physiological system i.e., the human brain. In order to understand the dynamic nature of processes, in emergent behaviors such as clinical symptoms, involving multiple complex interactions among several different systems, it is necessary to use or develop other more appropriate modeling/simulation approaches for the study of ‘complex systems’. The limitations of current transgenic modeling strategies may not pose any serious problems for drug development if the presumed (yet to be validated) relationships between the neuropathological phenotype (e.g., amyloid or tau) and the behavioral/ clinical phenotype (e.g., cognitive loss) of the disease are proven to be linear. The current modeling systems may prove to be perfectly adequate if the strategy of reducing the brain amyloid load, e.g., via vaccine or some other means, will also result in improving the symptoms of the disease; in such an event the causal relationship between brain pathology and clinical symptoms will be accepted. On the other hand if the vaccine succeeds only in reducing the brain amyloid with negligible effects on behavior, the vaccine will become an interesting laboratory reagent for experimental work. In the absence of any validation, evidence-based dementia practice should acknowledge the strong possibility that the presumed relationships between clinical/behavioral symptoms of the dis-

ease and the molecular changes in the brain are nonlinear; thus, representing much more complex systems than those being modeled by the current ‘transgenic modeling systems’. While considerable advances have been made in the development of animal models, especially in transgenic mice carrying variant forms of genes shown to be involved in dementia, in silico models in the future may become useful adjuncts to the transgenic animals and other models that are being used in drug research. Problem four: Several converging lines of evidence suggest that the neurodegenerative processes of dementia starts several years before the first clinical phenotypes are detected. The precise duration of the pre-clinical period and the details of the early molecular events are not known. The uncertainty about symptom-free early stages of the disease stems from the lack of well validated tools or technologies for detection to observe the very early degenerative processes. In addition, the increasing awareness that delaying cognitive impairments has far greater significance for the economics of public health than short-duration symptomatic relief in the later stages, has shifted the focus of public policy and drug discovery initiatives toward prevention, early detection and disease modification. This growing interest in prevention has revealed the necessity for surrogate markers of progression or a validated index of efficacy for neuroprotective agents in asymptomatic patients. In spite of these difficulties the prospect for developing useful techniques, e.g., advances in neuroimaging technologies for longitudinal measurements or early detection of neurodegenerative changes, appears very promising. Problem five: There is a growing consensus that validated biological markers of the disease will complement clinical approaches. However, prior to adoption in routine clinical use, any putative biomarker must not only detect a fundamental biological process in the disease, but should also be validated in an adequately powered study with neuropathologically confirmed cases. The ideal marker should have sensitivity greater than 80 percent for detecting disease and specificity also greater than 80 percent for distinguishing other dementias. The marker should be reliable,

xviii FOREWORD

reproducible, non-invasive, simple to perform, and inexpensive. In addition, a putative biomarker should have confirmation by at least two independent studies conducted by qualified investigators with the results published in peer-reviewed journals. Currently, none of the putative biochemical markers have been validated in adequately powered investigations.

Conclusion: This volume, Evidence-based Dementia Practice, has established a much needed standard to ensure the highest quality of care for dementia patients. The innovative structure and the future plans for this volume will allow quick incorporation of new discoveries and help to maintain the currency of information as a useful reference in a dynamic and rapidly evolving field. Zaven S. Khachaturian, PhD Potomac, MD, USA 18 January, 2002

Preface

Aims Few books take an explicit evidence-based approach to the diagnosis and management of dementia, and there are few books taking a practical and problem-orientated approach. This book takes an evidence-based approach to practical problems in dementia: our intention is to fill the gap and provide readers with the latest and best information available to enable them to answer their practical problems or to satisfy their inquisitiveness. We hope that they will dip into this book whenever they have a problem with which they are unsure, to refresh themselves or as an easy way to keep abreast of the latest evidence (and by visiting the update website of this book at www.ebdementia.info). The book is not intended to be read at one sitting but should be kept nearby for easy reference. The era of therapeutic nihilism has ended in dementia with the emergence of therapies for symptomatic treatment, those that may delay the course of the disease, that may prevent the onset of dementia, and new methods to manage symptoms. An explosion of therapies is becoming available, additionally, many new diagnostic tests are emerging designed to help make the diagnosis of dementia earlier and distinguish between the various dementias. Becoming overwhelmed by the volume of data on the diagnosis and management of dementia is a danger for busy professionals. Therefore, this book is designed to collect information on dementia, distil that which is relevant and reliable, and present it in a format that is useful to clinicians managing and treating people with dementia. This book is

designed to bring the latest and best practical evidence on new and existing ways to diagnose and manage dementia, linked to the problems encountered by clinicians and others who deal with the day-to-day care of these patients. Space is also given to provide a good detailed review of important descriptive aspects of important dementias, ranging from epidemiology to pathology. We feel well placed to edit such a book being practising clinicians involved in the care of patients and in research into the evaluation of diagnostic tests and therapies, and other aspects of dementia.

Editors Nawab Qizilbash is Visiting Professor of Geriatric Medicine, Hospital Universitario GMCantoblanco, Madrid. Formerly Honorary Consultant Physician and Honorary Senior Research Fellow at the Oxford Memory Clinic, Radcliffe Infirmary, Oxford University, UK, he founded the Oxford Memory Clinic and the UK Dementia Research Group. He was the founder and first coordinating editor of the Cochrane Dementia Group. He has been involved in developing systematic reviews in dementia and individual-patient meta-analysis in dementia and epidemiology. He remains a member of Green College, Oxford University. His employment is now as Director, Clinical Epidemiology and Evidence-based Medicine at GlaxoSmithKline, UK and Spain. All views expressed in this book are personal and do not necessarily reflect any or all opinions of GlaxoSmithKline. Lon Schneider is Professor of Psychiatry and Gerontology in Los Angeles, USA. He was a

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member of the Board of Directors of the American Association for Geriatric Psychiatry and serves on the editorial boards of the International Journal of Geriatric Psychiatry, the American Journal of Geriatric Psychiatry and the Journal of Geriatric Psychiatry and Neurology. Helena Chui is Professor of Neurology at the University of Southern California, Los Angeles, USA, and a member of the Alzheimer’s Disease Research Centers with an interest in the neuropathologies of Alzheimer’s disease and vascular dementia. Pierre Tariot is Professor of Psychiatry and Medicine at the University of Rochester, USA, with interests in behavior and clinical trials. Henry Brodaty is Professor of Psychogeriatrics at the University of New South Wales, Sydney, Australia. He was a founding member and president of the Alzheimer’s Association (Australia). He is the Chair of Alzheimer’s Disease International, 2002. His particular interests include interventions to help family care givers, behavioral complications and ethical issues in dementia. Jeffrey Kaye is Professor of Neurology and Director of Geriatric Neurology at Oregon Health and Science University and the Portland Veterans Affairs Medical Center, Portland, Oregon, USA. He directs the Aging and Alzheimer Disease Center at the University. He was among the first editors of the Cochrane Dementia Group. He has a special interest in the dementias of the oldest old and assessment of treatment outcomes. Timo Erkinjuntti is Professor of Neurology at the University of Helsinki with particular interests in vascular dementia, brain imaging and the diagnosis of memory disorders and dementia. He is a member of the editorial advisory boards of Alzheimer’s Disease and Associated Disorders, Psychogeriatrics, and Stroke. He also serves on the European Task Force on Age-related White Matter Disorders (Past Chairman), International Working Group on Harmonisation of Dementia Drug Guidelines, and the Alzheimer’s Disease International Medical Scientific Advisory Panel.

General approach The theme of this book is to bring the latest and

best available evidence, summarized in a form that is easy to grasp, to help solve the common practical problems that are encountered in patients with dementia. The two approaches are, therefore, ‘problem-orientated’ and ‘evidence-based’. Discussion of the diagnosis and management is from the standpoint of the likely manner in which patients present. For example: Is it a memory problem? What sort of memory problem is it? Is it dementia? What type of dementia is it? What has caused it? What can be done? Can it be reversed? How can it be treated? How can the patient and carer be supported in the short and long term? How can any deterioration be prevented? How can dementia services be better organized? Can the onset of dementia be prevented? These problems are tackled in a practical way using an evidencedbased approach relying on the latest and most reliable information. The problems are addressed by the best available evidence, taken, where possible, from high quality meta-analyses and systematic reviews which have attempted to summarize the totality of the available information. These references are cited in preference to individual publications to minimize possible selection biases of the authors. When evidence is absent or unreliable, this is discussed. Where circumstances require advice in the face of inadequate evidence, the contributors provide consensus positions and personal advice. This approach would be best served by a wide variety of people in different settings who have practical experience of dealing with problems on a dayto-day basis and are inclined towards ‘evidencebased’ medicine. The contributors to this book are such people. The role of the editors has been to ensure that the book is of a consistently high standard with smooth overlaps between the sections and chapters, and to seek out suitable knowledgeable contributors who would conform to the aims of the book. The contributors have been selected from the disciplines and areas involved in the care of people with dementia (geriatrics, neurology, psychiatry, psychology, public health and health economics). Identification of important and practical areas has and will be a chief function of the editors. Keeping abreast of developments likely to impact

PREFACE xxi

on clinical practice and ensuring updates will be fulfilled by the accompanying website (www. ebdementia.info).

Scope Section I describes the evidence-based approach to dementia. It reviews the steps needed to practice evidence-based medicine and provides the tools to implement evidence-based practice. Section II describes the process of reaching a diagnosis, in various levels of detail. It is designed to be problem-orientated, practical and based on the latest and best evidence. As in practice, it starts with history-taking and proceeds to physical examination, neuropsychological testing, laboratory investigations and neuro-imaging. Section III provides a background to the various dementias. It follows a traditional format in consisting of a classical description of each dementia, i.e. definition, pathology, clinical picture, epidemiology, etiology, and prognosis. However, a critical appraisal of the evidence is presented. The aim of this section is not to be encyclopedic but to cover important aspects and to be up to date. Comprehensive books and monographs exist for many of the individual dementias, especially the rare forms. Nevertheless, the section provides more than would be required by all but the most expert in any particular type of dementia. Sections IV–VI deal with the problems and management of patients with dementia. Section IV describes an overview of the general practical and ethical issues involved in the management of patients with dementia and provides a guide to subsequent sections. It also provides chapters on the evaluation of interventions from regulatory guidelines, purchasers of health services, and from advocates of pragmatic trials. Evaluation of non-pharmacological techniques and their practical application is covered. Finally, a chapter on novel drug mechanisms and potential future drugs and trials are described. Section V reviews the individual therapies specific to the type of dementiaaAlzheimer’s disease, vascular dementia, Lewy body dementia, fronto-temporal dementias, reversible or arrestable dementias and age-associated memory impairment.

Therapies currently used around the world are given emphasis, and those therapies likely to be approved and used in the near future are also discussed. It ends with a review of the current and potential scope for preventing dementia. Section VI describes the treatment and management of non-cognitive behaviors. Therapies and interventions currently used around the world are given emphasis, and those therapies likely to be approved and used in the near future are also discussed. Guidelines on the prescribing of drugs currently used are provided in detail. Treatment and management of common medical problems is also discussed in detail. Section VII deals with the organization of services, including guidance on setting up a memory clinic service, ethical issues, management of carers, driving, problems encountered in nursing homes and health economic issues related to the care of people with dementia. Finally, for easy reference, appendices provide the operational diagnostic criteria commonly used to define the major dementias (Appendix I). Appendix II describes scales commonly used in clinical practice and clinical trials, and practical advice on their usefulness. Appendix III lists the contact details of dementia and Alzheimer’s disease societies and associations around the world. Summaries with key points are provided at the start of chapters. Practice points, maxims and algorithms pepper the text to provide readily available key points. Diagrams, figures and tables are used to make the text more readable. Short descriptions of cases are used to illustrate points where helpful. Recent systematic reviews, guidelines and classic publications of important work are cited in preference to other publications. Other references can be found on the website for the reader who wishes greater detail. The website will be updated at least every twelve months with major or important new findings to ensure that it remains current, authoritative and practically useful at all times. To ease searching, updates and additions will be clearly identified and graded for importance. Information, as you are aware, can become outof-date as soon as a book hits the bookshop shelf. This is compounded by the rapid progress in dis-

xxii PREFACE

covery and understanding in the field of dementia. The Editors have done their best to include the most up-to-date material in the book but are obviously restricted by the fact that it is print on paper. To go some way towards addressing this issue, www.ebdementia.info has been developed, a companion resource that we hope you will find extremely useful. Although the entire book cannot be found on the site, we have included material that is not found in the book such as additional tables, search strategies and current developments in both clinical practice and scientific research. The site will be updated periodically and maintained by the Editors.

Readership This book is primarily intended for clinicians and others who treat and manage patients with dementia: geriatricians, neurologists, psychiatrists, psychologists, primary care physicians and general internal physicians. However, as it provides practical guidance about many aspects of the problems associated with dementia, ranging from drug

therapy to the organization of services and from prevention to psychological therapy, nurses, therapists, social workers, care managers, managers of health services, and carers of patients will find the book useful and easy to use. Being a practical book based on the latest evidence and keeping up-to-date with important new findings, it is has relevance for an international readership. Indeed, the editors are based in Australia, Finland, Spain, UK and the USA, with contributors from countries spanning all continents.

Disclaimer Although every effort has been made to ensure that drug doses and other information are presented accurately in this publication, the ultimate responsibility rests with the prescribing physician. Neither the publishers nor the authors can be held responsible for any consequences arising from the use of information contained herein. Any product mentioned in this publication should be used in accordance with the prescribing information prepared by the manufacturers. Nawab Qizilbash Lon Schneider Helena Chui Pierre Tariot Henry Brodaty Jeffrey Kaye Timo Erkinjuntti

SECT ION I

Evidence-based Methods in Dementia Edited by: Nawab Qizilbash and Lon S. Schneider

I.1

Introduction

Nawab Qizilbash

Key points • Evidence-based medicine is the practice of medicine, based on the best external clinical evidence, integrated with local clinical expertise and circumstances. • The systemic elements that evidence-based medicine applies to key aspects of the interpretation of evidence represents an improvement over that which it replaces. • The influence of evidence-based medicine in the practice of dementia will depend on the quality of available evidence. With the new millennium, the study of dementia is increasingly becoming an analytical discipline, in addition to being a descriptive one. Advances in etiology, new diagnostic techniques and the development of different therapeutic strategies and medicines for the treatment, care and prevention of the dementias herald a new era. As yet, many of these new developments and the rapidly expanding understanding and modification of pathophysiological processes, await translation into clinical practice about diagnosis, treatment and care. Demonstration of important benefits to patients is increasingly required before new treatments and diagnostic techniques are accepted as worthwhile. The acceptance by regulatory authorities of surrogate endpoints to approve drug licences has been questioned, based on the unreliability of several used by the US Food and Drug Administration, such as cardiac dysrhythmias and cardiac function (Fleming & DeMets 1996). For new medicines, the

criterion of more clinical good than harm must be met. For new diagnostic techniques, improvement in diagnostic certainty with practical and important beneficial consequences is needed. In addition, there is increasing recognition that the results of studies do not necessarily apply to the type of patients that are seen by clinicians because of differences in patient characteristics, co-morbidities, co-therapies, severity of disease, compliance, local circumstances and patient preferences, which may differ sufficiently from those in the trial situation to attentuate or change the benefit to risk ratio. The drive for more clinically relevant evidence is fueled by the large variations in practice that cannot be explained by variations in disease prevalence, burden, risk factors or differing types of patients. The pressure to contain costs and the increasing demands for greater diagnostic procedures, treatments and packages of care also fuel the demand for solid evidence to support clinical decisions. Such demands may actually lead to retaining treatments and diagnostic techniques that are worthwhile, as well as abandoning those that are not. Evidence-based medicine is the conscious, judicious and explicit use of the best available evidence to help make decisions about the care of individual patients (Sackett et al. 1996). As professionals concerned with dementia patients, at the individual or population level, our decisions and actions should be based on the best available evidence. Evidencebased dementia practice (the application of evidence-based medicine to the practice of dementia) integrates the expertise of the individual clinician with the best available evidence obtained from good and systematic clinical research. It builds on and

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4 CHAPTER I.1

reinforces clinical skills, expertise and judgement and does not replace them. Evidence-based dementia practice is designed to make the practitioner a better one and provide optimal care for patients and their families. Clinical expertise is the proficiency and judgement collected over many years through experience, practice and formal clinical education. It is reflected in the ability to make diagnoses and provide optimal care, correctly and efficiently for patients and their families, taking into consideration their preferences and circumstances. This process cannot be converted into a ‘cook book’ of easy recipes. The best external evidence refers to the information culled from well-designed, valid, reliable and clinically relevant studies relating to diagnosis, treatment and prognosis. The evidence-based approach also embraces studies of etiology and prevalence and incidence, as well as basic sciences and psychology. Good medicine requires objectively gathered external evidence and clinical expertise. External evidence without expertise may be inappropriately applied. Clinical expertise without external evidence carries risks for the patient through the use of procedures and treatments that have subsequently been shown to be ineffective, suboptimal or harmful. Hence, evidence-based dementia practice necessarily requires lifelong, self-directed learning for all those who manage, care or make decisions related to patients with dementia. Evidence-based dementia practice is the application of evidence-based medicine to dementia, similar to its application in several disciplines such as evidence-based cardiology, evidence-based surgery, evidence-based nursing, etc. Where the focus of the decision is the population or community rather than the individual, then the discipline is termed evidence-based public health. All of these terms fall under the rubric of evidence-based health care. Where the focus is to purchase or provide the best mix of health care to maximize the health of a particular group of patients or geographical population, the term ‘evidence-based purchasing’ is used. Evidence-based dementia practice may not provide the cheapest option and is geared to provide the most efficient practice so as to maximize the quality and quantity of life for dementia patients.

In some instances, carrying out evidence-based dementia practice may increase costs by accepting a new more expensive therapy or diagnostic test, while in many instances, by abandoning therapies or diagnostic procedures that are not of proven benefit to patients, costs may be reduced or allowed to be redistributed. Where practices differ, approaches may be used to determine the best pattern of care for the maximum number of patients within a population. Cost-effectiveness arguments are being increasingly used to decide how much money and resources particular services receive in relation to medical conditions. The issues of responsibility to the individual patient and to dementia patients as a group, and to the local and national population, also need to be seen in the context of effectiveness and, where appropriate, cost-effectiveness. Evidence-based medicine (and its application to dementia) is not designed to be an ivory tower discipline. It can be practised within the context of a busy general internal medicine department in a district general hospital, providing care for the local population (Ellis et al. 1995). However, in psychiatry it may not be utilized as often (Summers & Kehoe 1996), and how widely evidence-based medicine is practised in dementia is unknown, though the wide variations in use of diagnostic tests, treatments and forms of care (gleaned from many chapters in this book) suggest that it may be low. The therapies reviewed later in this book are those which are used in different countries around the world, and attest to this variation. Busy clinicians and colleagues who are involved with patients with dementia and their families, but who can only dedicate small amounts of their scarce time for study and to remain up-to-date, need material that is valid, reliable, relevant, selective, efficient and easily assimilated in order to practise evidencebased medicine. This information needs to be unbiased, appraised and incorporated into the best evidence that can be used to help patients. However, it is not just information about interventions, diagnosis and prognosis that is needed, but the synthesis of this information. The rigorous appraisal of valid, objective and appropriate evidence of the best clinical research is what this book is all about. The contributors to this book seek to identify and appraise all relevant and

INTRODUCTION 5

available clinical research related to a topic, to distil the essence of best practice and care; to foster more uniformity of care, where appropriate, so that best care becomes standard care; and to identify clinical areas that require more definitive evidence and clinical research, rather than dwell on anecdotes. This book also will help to keep readers up-to-date in important areas that are clinically and scientifically important. Evidence-based medicine is a process and its limitations are largely dependent on the nature of the problems and evidence and its application. In a complex disease such as dementia, what is clear is that evidence-based medicine is only a partial solution to the problems faced by practitioners. Nevertheless, it is better than that which it replaces: it helps to keep us up-to-date; it opens decision making to patients and their care givers; it helps to remove bad and wasteful practices and it helps to improve our reading habits by forcing us to seek out the best evidence efficiently and to ask questions, while remaining sceptical about easy answers. However, the complexity of dementia medicine means that many areas are and will remain gray zones of uncertainty with incomplete and inadequate knowledge, and the notion that everything we do can be reliably evidence-based is a forlorn hope. Therefore, we should not allow the best to become the ‘enemy of the good’: be aware that the robustness of data needed to change decisions is subjective and not a precise science; easy-to-prove hypotheses should not replace hard-to-prove hypotheses that are more relevant; and realise that most metaanalyses dealing with non-binary data, unless based on individual data, may be untrustworthy (Qizilbash & Schneider 2000). Furthermore, studies to help decide how to treat patients, how to judge responses and what to do in cases of inadequate response to therapy are difficult to conduct. As evidence-based dementia practice is increasingly implemented, the areas to which it can and cannot substantially contribute and help advance will become clearer. However, the simple process that it promotes (rigorous searching for all relevant evidence, its critical appraisal and application) should brook no argument. Evidence-based dementia practice offers limited help to the practitioner in many areas where evidence about risks and benefits is poor,

except to provide updates of practically relevant studies that may have an impact on practice. This book, by the explicit demonstration of what is known and what is not known or insufficiently known, makes discussion and argument explicit, as well as providing directions for future clinical research. As well as indicating what should be done, this book indicates which interventions currently used may not be useful, and may be associated more with harm than good. In so doing, evidencebased dementia practice should promote better research by highlighting the problems and limitations of current clinical evidence. Where the evidence may never be much better, or is currently inadequate, the ‘art’ of medicineawith its reliance on experience, analogy and extrapolation (acknowledging limitations)awill be promoted. Hence, the contributors to this book provide their expert ‘opinion’, experience and personal practice in these important murky areas of imperfect knowledge. This is in contrast to other more limited evidence-based sources such as the Cochrane Dementia and Cognitive Impairment Group systematic reviews that provide little guidance to practitioners dealing with patients in areas where the evidence is inadequate. This section outlines the principles of the acquisition, appraisal and applicability of information from different types of research, to help answer questions that confront people who deal with patients with dementia.

References Ellis, J., Mulligan, I., Rowe, J. & Sackett, D.L. (1995) Inpatient general medicine is evidence based. Lancet 346, 407–410. Fleming, T.R. & DeMets, D.L. (1996) Surrogate endpoints in clinical trials: are we being misled? Annals of Internal Medicine 125, 605–613. Qizilbash, N. & Schneider, L. (2000) Can meta-analysis be trusted in dementia? Conference of the Alzheimer’s Disease and Related Disorders Association. Washington, July 2000. Sackett, D., Rosenberg, W.M.C., Gray, J.A.M. et al. (1996) Evidence-based medicine: what it is and what it isn’t. British Medical Journal 313, 169–171. Summers, A. & Kehoe, R.F. (1996) Is psychiatric treatment evidence-based? Lancet 347, 409–410.

I.2

Finding the Evidence

Nawab Qizilbash

Key points Finding relevant evidence efficiently about diagnosis, prognosis, treatment and care, etiology and harm requires the following: • Formulating the question in sufficient detail. • Identifying the appropriate research study designs. • Selecting a method for searching the relevant information.

Evidence-based dementia practice represents the practical application of scientific methodology to answer questions raised by problems in patients with dementia and cognitive decline, questions from patients and carers and from our own curiosity, and research questions. Therefore, the ability to answer these questions quickly and efficiently, with minimal effort and time is a necessary skill for all good time-pressured health professionals. The steps to finding an answer are: 1 Formulating the question as precisely as possible and converting it into a form that allows it to be capable of being answered. 2 Finding the evidence. 3 Critical appraisal of the information retrieved. 4 Applying the information to the local situation. 5 Evaluating the effectiveness of its implementation. This process is conceptually easy; the difficulty is in implementing it during the overcrowded day of health professionals. This section covers the first two steps: defining the question and finding the evidence. The other steps are covered in subsequent chapters.

6

Formulating the question Precise definition of the question is essential to hunt for potentially relevant evidence. If this stage is done poorly, then time may be wasted and the necessary information may not be found. Questions are varied and those related to making decisions for patients could be: • What is the likelihood that my patient with a Mini Mental Status Examination (MMSE) of 23 has dementia? • Does my patient with a clinical diagnosis of mild probable Alzheimer’s disease (AD) need a single photon emission computerized tomography (SPECT) scan in addition to a computerized tomography (CT) scan that is normal? • What does treatment with a cholinesterase inhibitor have to offer my 83-year-old patient with mild AD? • What is the prognosis of a 67-year-old patient with AD? These questions are important but not sufficiently focused to begin searching for potentially relevant information. To make information capable of being hunted effectively, questions need to be built on four foundations: 1 The patient or the problem. 2 The exposure. 3 The comparison. 4 The outcome. Table I.2.1 outlines the components of questions addressed by evidence-based medicine for making decisions about patients. What has been the degree of prescribing cholinesterase inhibitors by clinicians and why have these

Table I.2.1 Examples of types of questions about dementia patients and how to break them up to find relevant evidence. Patient/problem

Exposure

Comparison

Outcome

Treatment

In an 83-year-old man with AD

does treatment with donepezil

compared with no treatment

lead to improved functional performance and for how long?

Harm

In a patient with mild AD and a smoking history

is treatment with rivastigmine

compared with no treatment

a possible cause of his weight loss?

Diagnosis

In a patient with clinically diagnosed probable moderate AD

will a temporal lobe view computerized scan

compared to diagnosis made clinically and a routine computerized scan

materially change the posterior probability of the diagnosis being probable AD?

Prognosis

In a 67-year-old man with mild AD

who has additional cerebrovascular disease

compared with the average patient with AD and no cerebrovascular disease

what is his prognosis for survival over the next 5 years?

Etiology

In an elderly patient with AD

is his cigarette smoking

compared with non-smokers

likely to be a cause of his AD?

FINDING THE EVIDENCE 7

8 CHAPTER I.2

Observational trials

Qualitative

Prevalence

Quantitative survey

Or

Quantitative

Cohort studies

Case-control studies

Experimental studies

Uncontrolled

Controlled

Randomized controlled trials

Non-randomized controlled trials

Fig. I.2.1 Study designs available to address research questions.

clinicians prescribed them requires answers from quantitative evidence and qualitative research. These two types of evidence represent a fundamental division of research designs. Hence, the importance of defining the question precisely. Once the question has been formulated, the next step is to identify what type of information needs to be found. Most important is the choice of study design that may harbor the relevant information. Several are available and each has its strengths and weaknesses (Fig. I.2.1). In answering some questions such as ‘what functional problems are expressed by patients with AD?’, good qualitative, survey and prospective studies with functional assessment instruments are research designs that are all likely to be useful. 1 Questions about treatment and diagnosis require the assessment of experimental studies. 2 Questions about prognosis or natural history require cohort or case–control studies. 3 Questions about the distribution or prevalence of characteristics or problems require surveys. 4 Questions about the harms from therapy and etiology may require the evaluation of cohort, case–control and experimental studies, ecological (between population) studies, and other types of evidence (such as spontaneous reporting of adverse events or case reports).

Searching for the evidence Having decided the research designs to pursue, the information sources available are: 1 Personal experience and knowledge. However, the drawbacks are that this information may be patchy, out-of-date or incorrect (Smith 1996).

2 Consultation with colleagues. This may be quick, relevant to local conditions and unlikely to raise very unconventional solutions. However, it may be biased, out-of-date and based on what has always been done. 3 Books. These are always out-of-date for interventions in dementia. 4 Journals. There are many sources to search of variable quality. See the search and selection strategies for each chapter in this book and on the website to glimpse the time and effort required to search the literature to find good quality studies, and the poor yield from such efforts. 5 Electronic sources. These include online journals and the Cochrane library. 6 Internet websites. There are many sources, of variable quality, to search. 7 Hybrid print/internet books, of which this is the first in dementia (the first as far as we are aware). See Chapter I.11 for details about these sources of information. It is more efficient to start with summaries that others have already compiled, with reviews and practice guidelines, rather than searching and appraising the original research papers yourself. This book represents one source of evidence-based, upto-date (with its accompanying website), systematic narrative reviews (incorporating information from meta-analyses and guidelines) that have been compiled by practising clinicians, who also offer guidance where robust data are lacking. Where no reviews or guidelines exist, it is necessary to consult the original research articles. To reach the relevant information, either appropriately summarized or the original research articles, efficient retrieval strategies are required. It is

FINDING THE EVIDENCE 9

important to note that there is no perfect search strategy and each will have a trade-off between sensitivity (finding all relevant articles) and specificity (finding only the relevant articles). Therefore, to reach all sources of the relevant information (complete sensitivity), it may be necessary to wade

through many irrelevant articles (poor specificity). However, practical and good search strategies have been developed to detect good quality articles (Haynes et al. 1994) (see Table I.2.2 for searching strategies for Medline). Many electronic libraries have upgraded their search engines to faciliate

Table I.2.2 Search strategies for detecting ‘sound’ articles on Medline (Haynes et al. 1994; Wilczynski et al. 1994). Type of study

Search strategy

Treatment Best single term

Clinical trial pt

Combination of terms with best specificity

Placebo tw or double tw and blind tw

Combination of terms with best sensitivity

Randomized controlled trial pt or random tw or drug therapy (as a subheading of the subject) or therapeutic use (as a subheading of the subject)

Diagnosis Best single term

Explode diagnosis

Combination of terms with best specificity

Explode ‘sensitivity and specificity’ or predictive tw and value tw

Combination of terms with best sensitivity

Explode ‘sensitivity and specificity’ or explode diagnosis (as a subheading of the subject) or sensitivity tw or specificity tw or diagnostic use (as a subheading of the subject)

Prognosis Best single term

Explode cohort studies

Combination of terms with best specificity

Prognosis or survival analysis

Combination of terms with best sensitivity

Incidence or explode mortality or follow-up studies or prognosis tw or predict tw or course tw or mortality (as a subheading of the subject)

Etiology or cause Best single term

Risk tw

Combination of terms with best specificity

Cohort studies or case–control studies

Combination of terms with best sensitivity

Explode cohort studies or explode risk or odds tw and ratio tw or case tw and control tw

pt, publication type; sh, subject heading; tw, text word. This strategy applies specifically to Medline. Similar strategies exist for other electronic databases.

Sensitivity

Specificity

0.99

0.74

0.92

0.73

0.92

0.73

0.82

0.70

10 CHAPTER I.2

Table I.2.3 Minimum criteria for appraising study validity. Criteria Type of study

Primary

Secondary

Tertiary

Therapy

Random allocation of patients to comparison groups

Loss to follow-up small compared with number of adverse events

—

Diagnosis

Comparison groups, of which at least one is free of the target disorder

Objective or reproducible diagnostic standard applied to all subjects

Independent interpretation of the test and diagnostic standard

Prognosis

All subjects initially free of the outcome of interest

Loss to follow-up small compared with number of adverse outcomes

—

Etiology

Clearly identified comparison groups for assessing risk of exposure and outcome

Observers blind to outcome with respect to exposure (except for objective outcomes such as death or institutionalization)

—

Review

Explicit criteria for selecting articles

Description of methods, with source of original research articles and search strategy

—

searching. The website for each chapter carries detailed search strategies used by chapter authors on Medline and other electronic databases. Although appraisal of studies related to the type of research design is covered in detail in subsequent chapters, simple checks can be used before conducting detailed appraisal: 1 Is the date of the information such that it is still relevant?

2 Who produced the information? Is it a respectable and independent source? 3 Is there a consistency of results and conclusions from different studies and from different types of study designs? 4 Grading information. Table I.2.3 provides the minimal criteria for screening good quality studies of different designs (Oxman et al. 1993). The main grading system for interventions used in this book,

Table I.2.4 Grading recommendations and evidence for interventions. Grade A: ‘High’ quality evidence with minimal potential for bias 1 Extremely reliable, often requiring large-scale randomized evidence from a single trial or a systematic review 2 Moderately reliable, from moderate-scale randomized evidence from a single trial or a systematic review 3 Questionably reliable, often small-scale randomized evidence from a single trial or a systematic review 4 Evidence from a single unplanned analysis of the aforementioned types of studies 5 High quality large series of ‘N-of-1 trials’ where evidence from levels 1–4 is absent Grade B: ‘Moderate’ quality evidence with moderate potential for bias 6 Evidence that is quasi-randomized or randomized with important sources of potential bias, e.g. lack of double-blinding when crucial, cross-over study with possibility of important carryover effect, numerous drop-outs 7 High quality non-randomized prospective or case–control study of groups with and without interventions 8 High quality case series Grade C: ‘Poor’ quality evidence with substantial potential for bias 9 Evidence from poor quality non-randomized prospective, case–control and case series studies 10 Opinions not based on the above levels of evidence (hypotheses, laboratory data, animal data, ‘experts’) Recommendations for interventions: Grades A, B, C Quality of evidence: Levels 1–10

FINDING THE EVIDENCE 11

Table I.2.5 Grading for areas with a paucity of randomized

trials. Criteria

Score*

Study design Randomized controlled trial Non-randomized, but comparable groups Non-randomized, non-comparable groups

2 1 0

Patients Use of standardized diagnostic criteria All patients accounted for/withdrawals noted

2 1

Outcomes Well validated, reliable care giver measures Well validated, reliable patient measures Service utilization ‘Blind’ ratings†

1 1 1 1

Results/conclusions Statistical significance considered Adjustment for multiple comparisons Evidence of sufficient power Follow-up assessment 6 months or beyond Clinical significance

1 1 1 1 1

*Good quality > 7; poor quality < 5. †Blind ratings include outcome measures that are verifiable independent of the assessor (e.g. death or institutionalization of the patient), self-completed outcome measures (by the study participant) or measures completed by an assessor who was blind to the group allocation of the subjects.

based on the potential for systematic bias and random error, provides a hierarchy of evidence which is shown in Table I.2.4. A grading system has been devised by Dennis and Lindsay (Chapter VII.6) for areas where interventions are not randomized (Table I.2.5); it remains to be validated but has been found to be useful.

References Haynes, R.B., Haynes, R.B., Wilczynski, N., McKibbon, K.A., Walker, C.J. & Sinclair, J.C. (1994) Developing optimal search strategies for detecting clinically sound studies in MEDLINE. Journal of the American Medical Informatics Association 1, 447–458. Oxman, A.D., Sackett, D.L. & Guyatt, G.H. (1993) User’s guide to the medical literature. 1. How to get started. Journal of the American Medical Association 270, 2093–2095. Smith, R. (1996) What clinical information do doctors need? British Medical Journal 313, 1062–1068. Wilczynski, N., Walker, C.J., McKibbon, K.A. & Haynes, R.B. (1994) Assessment of methodological search filters in MEDLINE. Proceedings of the Annual Symposium on Computer Applications in Medicial Care 17, 601–605.

I.3

Critical Appraisal

Nawab Qizilbash

Key points Clinical appraisal for the purpose of translating information into practice requires assessment of: • Internal validity—is the study sufficiently free of bias? • Magnitude of the results and their precision. • External validity—how applicable are the results to the patients beyond the study?

The following chapters provide a guide of how to appraise and apply the results of different types of studies that have an impact on diagnosis, management and care of patients with dementia. It will be apparent that few perfect studies exist. A requirement for the absence of any flaws in a study would lead to complete nihilism. What is important is that a study asks an important question and addresses it validly and reliably. It is necessary that there are a lack of flaws that can potentially bias the validity of a study to an important degree such that the conclusions would be radically changed. Also needed is sufficient reliability from a study, either alone or in combination. Again, absolute reliability is not required, rather a degree of reliability that does not importantly affect the conclusions. For example, Richard Peto, who devised one form of the odds ratio (known as the Peto odds ratio) as a measure of relative risk for associations of binary data in meta-analyses of trials, often uses the term ‘typical’ odds ratio to infer that the effect is ‘more or less’ of the magnitude

12

calculated (Yusuf et al. 1985). Although many scales have been devised to score the quality of different types of study designs, few are validated. Those scales which are validated are often pretty limited in their sensitivity and specificity (Jadad et al. 1996). Often common-sense application of good epidemiological principles provides as good a, or better, guide. Although scores have been used in parts of this book, the application of common-sense guides have been used more. A high score on the Jadad scale does not necessarily imply a good trial, as will be seen in many of the chapters in the management sections (V, VI, VII). However, poor scores on this scale do reflect poor methodology or the impracticality of conducting better studies. Certain minimum requirements (differing for different study designs) have been applied to choosing studies for inclusion in the systematic reviews within the chapters of this book, where studies of varying quality exist. These minimum guides will apply to studies to be reviewed in the updates for the website. Where only studies with sources of substantial bias exist, these minimum criteria have not been applied and whatever was available has been reviewed, with a caveat about potential bias. There are large tracts of terrain in dementia where this situation holds. Critical appraisal also cautions against viewing studies in isolation; they need to be assessed in a wider context, both with other quantitative evidence (including good meta-analyses) and qualitative information. Hence, the internal validity of a study needs to be viewed alongside its external validity (or generalizability or relevance to patients outside the study). On occasions, a study

CRITICAL APPRAISAL 13

with large potential sources of bias and imprecision may be adequate if it is consistent with a substantial body of other types of evidence. However, on many occasions where a study has good internal validity, its applicability to individual patients may remain uncertain. Sometimes it is possible to make extrapolations based on the assumption of the lack of unanticipated qualitative interactions for drug therapy and the constancy of benefits and harms across subgroups. However, in appropriate cases application of the findings may only be possible through individual controlled trials in individual patients. In the face of inadequately valid, reliable and clinically relevant evidence, the burden will fall (appropriately) on the clinician to provide the best

plan of management. This will involve using clinical experience, expertise and insights together with the preferences of the patient, and the resources available in the local setting from health and social services.

References Jadad, A., Moore, R.A., Carroll, D. et al. (1996) Assessing the quality of randomised clinical trials: is blinding necessary? Controlled Clinical Trials 17, 1–12. Yusuf, S., Collins, R., Peto, R. et al. (1985) Beta blockade during and after myocardial infarction: an overview of the randomized trials. Progress in Cardiovascular Diseases 27, 336–371.

I.4

Evidence-based Etiology and Harm

Nawab Qizilbash

Key points • Evidence about the etiology and harm from interventions is usually derived from more than one study research design. • Trial evidence is often not available to evaluate etiological factors. • Assessment of cause-and-effect etiological relationships (and rare adverse effects of interventions) is a judgement based on the synthesis of several criteria.

Questions about etiology and harm are addressed by several common research designs. Etiology relates to the causes of disease. For example, is smoking (an external exposure) a cause of Alzheimer’s disease (AD), whereby individuals who smoke may be more likely to develop AD than non-smokers? Does high blood pressure (an internal characteristic) or the apolipoprotein E4 (ApoE4) allele (a genetic trait) cause AD? Questions about harm relate to adverse events produced by drugs or other interventions. Questions about etiology and harm from drugs are addressed by observational studies (cohort, case–control and cross-population studies) and experimental studies. Nevertheless, all sources of evidence need to be examined to address questions of cause and effect, because judgements about causal inference are not decided just through statistical association. Hill (1965) developed the following criteria by which to judge causal inference: 1 Strength of association. 2 Consistency.

14

3 Specificity. 4 Temporal relationship. 5 Biological gradient (dose response). 6 Biological plausibility. 7 Coherence (how well the arguments as a whole stand up to questioning). 8 Experimental evidence (often unavailable). 9 Analogy (similar effects with related exposures). The case–control study is the most commonly used and involve individuals who have the outcome of interestaan adverse event (considered to be drug related) or a condition such as ADaand a comparison group of individuals who do not have the outcome of interest. Both groups are investigated in an identical manner for the assessment of potential risk factors, such as hypertension or the use of certain drugs. The advantages of this design are that it is relatively quick (the outcome of interest is already present) and cheap. The disadvantages arise from the potential for bias: in selecting appropriate controls, assessment of exposures between cases and controls, and the outcome altering the exposure. For example, smoking habits may change with onset of AD or other dementias, so case–control studies of smoking and AD may be discovering an effect of the dementia rather than its cause, unless smoking before the likely ‘onset’ of dementia can be assessed (Graves et al. 1990) (Chapter V.7). The induction period for AD and many other dementiasathe time from onset of the exposure (cause or etiology) until the initation of the disease process (pathogenesis, the mechanism by which the causal factor produces the disease) is unknown. The latency period (the period between the induction and detection of disease) for AD and

ETIOLOGY AND HARM 15

many other dementias is also unknown. However, both are likely to be lengthy. The cohort study overcomes some of the problems associated with case–control studies. Individuals who do not possess the outcome of interest are identified and the frequency of the outcome of interest occurring in those who have been exposed to the suspected exposure (or drug) are compared with those who are unexposed. Post-marketing surveillance studies are often a type of cohort study. The disadvantages are of practicalityaif the outcome of interest is rare or takes a long time developaand high cost. Ecological studies (between-population surveys) are a study design in which different populations are compared for the frequency or incidence of the outcome of interest and exposures. Although wider differences in exposures may be assessed, confounders may be difficult to identify and measure. Although it may be impossible for practical or ethical reasons to randomize potentially harmful exposures, reversal of the suspected exposure may be possible in randomized trials. The trial of supplemental vitamin E in AD can be viewed as such as a test for the lack of anti-oxidants contributing to AD (Sano et al. 1997). Although trials may provide strong supporting evidence they are not essential to determine causation; trials address whether removal or reduction of the exposure can reverse the effects over a relatively short period of time (e.g. 5 years is a lengthy period for a trial), while epidemiology can assess exposures over decades. For example, a randomized trial has never been conducted to examine the link between smoking and lung cancer. Moreover, such a trial, of several years’ duration would be negative because of the long induction and latency periods involved (Doll & Peto 1980). A further type of study design that is used to monitor prescribed drugs is spontaneous reporting for adverse outcomes. However, as the numerator is unreliable (it may be underreported, except for serious adverse events, or overreported depending on the degree of monitoring, awareness and sales) and the denominator is often not known, they are essentially qualitative studies. Hence, this type of study serves to provide signals of rare outcomes or for drugs that increase by many fold the risk of non-rare adverse outcomes.

With this basic description of the study designs available for addressing questions about etiology and harm, critical appraisal can begin (Levine et al. 1994).

Are the study results valid? 1 Were the comparison groups sufficiently similar? The controls should arise from the same population as the cases and be similar to the cases except for having the outcome of interest. Choosing appropriate controls is critical for case–control studies. Several sources of potential bias exist (Lasky & Stolley 1994): 2 Selection bias. Were study participants different from those who chose not to participate? For example, if people believe that head injury leads to AD, then more individuals with a history of head injury may decide to participate in a study specifically set out to test this association. Individuals who refuse to participate may be different from individuals who do, and they are often sicker. 3 Diagnostic bias. Diagnostic bias is a problem for non-population-based case–control studies. Hospital cases or those arising from specialist centers have been through some kind of referral process (self or external), which is often difficult to define, so they are not likely to be representative of the disease at large. Finding a proper comparison group in this situation may be difficult. 4 Survival bias. Those individuals who are available for study may be different from those who have not survived, and certain exposures may be related to survival. This is particularly a problem for cases of dementia that are not ‘new’ (incident cases) or in the later stages of the disease. 5 Information bias. Was information about exposures and outcomes sought in an unbiased way in the comparison groups? Information bias arises from differential assessment of the exposures and outcomes in the comparison groups. Cases, by virtue of having a disease, will be more motivated in recalling information about possible exposures. In dementia, where a family member is often called upon to provide historical information, differential recall may be even greater. Non-differential bias may occur when the ability to recall exposures occurs equally in cases and controls. This leads to

16 CHAPTER I.4

underestimation of the association, but not systematic bias. Information bias may also occur in cohort studies where knowledge of the exposure influences the assessment of the outcome. This may occur with the early diagnosis of early dementia or mild cognitive impairment, where there is more room for subjectivity. 6 Follow-up bias. Was follow-up sufficiently long and complete? Those not available for assessment during the follow-up in cohort studies and trials may be different to those who complete the study protocol (see Chapter I.6 for more details). 7 Was there a temporal relationship between cause and effect? Only cohort studies, experimental designs and prospective case–control studies can address this issue reliably. 8 Was there evidence of a dose response? An increase in risk with greater exposure levels or duration of exposure is supportive evidence of a causal link.

What were the results? 1 What was the strength of the association between the exposure and the outcome? In cohort studies and trials, the strength of the association of the exposure (or drug) and the outcome is best described by the risk ratio or rate ratioaboth termed relative risk. The relative risk is the risk of the adverse outcome in the exposed group divided by the risk of the adverse outcome in the unexposed group (see Chapter I.7 for details). However, for case–control studies, because the outcome is already determined, the odds ratio is used. This describes the odds of exposure in cases divided by the odds of exposure in controls. Only in circumstances of common diseases (with a prevalence greater than about 10%) and for odds ratios more extreme than about 4 or 0.25, is there a substantial difference between odds ratios and relative risk. This may, therefore, occur with studies of AD and dementia in people over 75 years of age. 2 How precise was the estimated strength of the association? As described in Chapter I.7, this is evaluated by the confidence interval. 3 Were important confounders adequately controlled for? Randomization is principally designed to deal with known and unknown confounders, i.e. those they are related to both the outcome and exposure (therapy). Non-randomized trials and

observational studies must adjust (or stratify in the design) for known potential confounders in the analysis. However, this can only be done if information is collected about them during the study. 4 Was there any evidence of effect modification? Were the risks (medically, not statistically) significantly different in different types of subjects, e.g. age, sex, ethnicity, etc.? If so, then a pooled stratified overall risk cannot be validly computed as the risk is highly dependent on being a member of the specific subgroups, whose risks should be provided separately.

Are the results applicable to my practice? Before addressing this question, it is worth considering if the study was specifically designed to test the hypothesis, or whether the hypothesis arose from analysis of the data. If the latter, then the hypothesis should be considered ‘new’ and in need of confirmation, either from new studies or from a systematic review of other studies. 1 Have sufficient of the principles to determine causation been metaespecially consistency of results from different studies and different types of study designs? 2 Is there evidence that different types of population differ in their risk (e.g. by age, sex, ethnicity, etc.)? 3 Are the results applicable to my patient? Again, given clear and consistent results, you need to ask if your patient and the exposure to which he or she has been subjected are sufficiently dissimilar to those in the studies to ignore the findings. 4 What is the magnitude of the risk? Although relative risks and odds ratios may appear impressive, it is important to calculate the absolute increase in harm or the number of exposures needed to harm (Chapter I.7). This puts the risks into context and also examines how much the risks could be reduced by the removal of the exposure (or drug), assuming that all of the risk can be removed by avoiding the exposure completely. Or there may be a threshold level of exposure below which risk is not elevated. 5 Should the exposure be removed? This question needs to balance the risks and benefits of removing the exposure (or drug) completely or partly with

ETIOLOGY AND HARM 17

the risks and benefits of continuing the exposure (or drug) at the present level. Hence patient (and carer) preferences may also be important. If alternatives are available (e.g. other drugs), then this assessment is fairly easy. The risks and benefits of continuing, stopping or reducing the exposure (or drug) depend on the magnitude of the excess risk, the importance of the benefits being derived by the drug (which may be lost by its removal), the time delay in removal of the risk, and whether there are any threshold levels, so that benefits can be maintained while much or all of the excess risk is removed. For example, the risk of respiratory difficulties in AD patients taking metrifonate of about 1/100 (Chapter V.2.6), appears to be sufficient to prevent its approval for this indication, given the modest benefits observed with cholinesterase inhibitors and the availability of alternatives. Meanwhile, although liver enzyme rises are frequently observed with tacrine (one withdrawn for every four treated; Qizilbash et al. 1998), because they are not lifethreatening they can be monitored closely and action can be taken according to their severity. Hence, tacrine was approved and prescribed as there was no alternative available. (See Chapter V.7 for a systematic review of suspected exposures

that may cause dementia and be potentially modifiable.)

References Doll, R. & Peto, R. (1980) The Causes of Cancer. Oxford University Press, Oxford. Graves, A.B., White, E., Koespell, T. et al. (1990) A case control study of Alzheimer’s disease. Annals of Neurology 28, 766–774. Hill, A.B. (1965) The environment and disease: association or causation? Proceedings of the Royal Society of Medicine 58, 295–300. Lasky, T. & Stolley, P.D. (1994) Selection of cases and controls. Epidemiologic Reviews 16, 6–17. Levine, M., Walter, S., Lee, H., Haines, T., Holbrook, A. & Moyer, V. for the Evidence-Based Medicine Working Group (1994) Users’ guides to the medical literature. IV. How to use an article about harm. Journal of the American Medical Association 271, 1615–1619. Qizilbash, N., Whitehead, A., Higgins, J., Wilcock, G., Schneider, L. & Farlow, M. On behalf of the Dementia Trialists’ Collaboration. (1998) Cholinesterase inhibitors for Alzheimer disease: a meta-analysis of the tacrine trials. Journal of the American Medical Association 280, 1777–1782. Sano, M., Ernesto, C., Thomas, R.G. et al. (1997) A controlled trial of selegiline, alpha tocopherol, or both as treatment for Alzheimer’s disease. New England Journal of Medicine 336, 1216–1222.

I.5

Evidence-based Diagnosis

Nawab Qizilbash

Key points • Diagnostic tests are rarely perfect. • Clinical assessment remains the most influential ingredient of diagnosis in dementia. • Few diagnostic tests in dementia (after the histology and structural imaging) profoundly affect the diagnosis formed by clinical impression. • The practice setting where the diagnostic test is carried out may have a profound influence on its performance. • The benefits (and risks) to patients of many diagnostic tests in dementia remain unclear. Good diagnosis is vital to good patient management and effective health care. The proliferation of medical technology means that clinicians are faced with choosing from an increasing number of diagnostic tests, each with advantages and disadvantages. The cost and health implications of ordering tests means that the rationale, ‘it would be nice to know or have more information’ is no longer acceptable and such tests should be ordered only when they significantly contribute to the diagnosis or therapeutic work-up of a patient. The incremental value and cost of the additional information obtained become key questions. Diagnostic tests are rarely perfect, therefore the ability to evaluate articles about diagnostic tests and, where relevant, apply the results to the management of individual patients becomes an essential skill. This section presents the principles of evaluating and applying diagnostic tests; the application of these principles with modifications for dementia

18

are described in Section II. A discussion of the questions needed to appropriately apply a diagnostic test to individual patients is given below. The three basic questions are (Jaeschke et al. (1994a,b): 1 Was the study sufficiently valid? 2 What were the results of the study? 3 Are the results applicable to my patients?

Was the study sufficiently valid? This question requires consideration of how the patients were assembled and how the diagnostic test and appropriate reference (‘gold standard’) test were applied.

Is the reference test acceptable? The accuracy of the diagnostic test being validated is best compared against those who definitely have the disease or disorder, i.e. the ‘truth’. Therefore, if the reference test is not acceptable to you in providing a sufficiently accurate diagnosis of the disease (or if a reference test was not used at all), the study is unlikely to be sufficiently valid. The ideal reference test for the presence of a disease is one that uses biopsy, autopsy or surgery. For Alzheimer’s disease (AD) the reference standard is histology. Where no absolute ‘gold’ standard exists, a set of criteria may be accepted as the reference standard, e.g. the Diagnostic and Statistical Manual (DSM), NINCDS-AIREN or International Classification of Diseases (ICD) criteria for the diagnosis of vascular dementia. The ideal reference standard for the absence of disease is a benign clinical course in the absence of intervention.

DIAGNOSIS 19

Was there an independent (‘blind’) assessment? The results of both the test being validated and the reference test should be interpreted independently and without knowledge of the results of the other test, to avoid ascertainment bias. The more the interpretation of the test results are capable of being influenced by knowledge of the results of the other test, the greater the importance of an independent assessment. Differential knowledge of information about the patient’s clinical or ancillary examination by those interpreting the tests may also bias the independent assessment. In dementia it may not be possible for the independent assessors to be completely blinded to this information. The test being validated should not be used to contribute to the reference standard test.

Was an appropriate spectrum of patients included? Most tests can distinguish between severely affected and healthy individuals. To be helpful, a test needs to distinguish the target disease from other states (including non-diseased or normality) with which it may be confused. Therefore, its value will be established in a study of patients closely resembling those in your practice. This patient range may vary between specialists in geriatrics, neurologists and psychiatrists and between general practitioners and hospital specialists. Ideally, the test should be evaluated in a broad spectrum of patients both with and without the target disease, with a range of severity and with a variety of other conditions that are commonly confused with the target disease. Patients with commonly associated co-morbid conditions may produce false positive or false negative results. Failure to include a broad spectrum of patients may lead to falsely promising results (Ransohoff & Feinstein 1978).

Were both tests applied to all patients? The properties of the test to be validated will be distorted if the results of the test in question influence the decision to undergo confirmation by the reference test, often called ‘verification’ bias. Where this

is unavoidable, perhaps because of the risks of the reference test, those not receiving both tests should be followed up and the analysis should include them. In dementia, adequate follow-up may require observation for several years to determine clinically meaningful outcomes. Where both tests are not applied, the probable effect needs to be assessed. If a relatively small proportion of individuals did not receive both tests and the characteristics of these individuals are similar to those receiving both tests, any bias is not likely to materially alter the overall results and not differ systematically in that subgroup.

Were patients recruited consecutively or randomly? If individuals are selectively chosen, although they may contain a wide spectrum of the target disease, the test to be validated may not perform as well as in a wider, not so selective group. What is essential is that the nature of this selection process is described adequately. Apart from greater generalizability of the results, the advantage of individuals recruited consecutively or randomly is the greater applicability of the pretest probabilities from the study to other settings.

How good were the results? A good diagnostic test has high discriminatory power, i.e. produces different results for people with and without the target disease. To be practically useful, the discriminatory power should significantly influence your confidence in the diagnosis for the purposes of decisions about treatment, management or prognosis for the patients in your practice. Ideally, confidence in a diagnosis should be 100%, and where this exists after history taking and examination (e.g. death or severe dementia with a clear and detailed history), a diagnostic test is of no value. Where clinical expertise is a poor guide to the diagnosis, the utility of a good test becomes important. Thus, the level of confidence in a diagnosis based on clinical expertise and findings is important and is termed the ‘pretest probability’. Being based on clinical expertise and experience, the types of patients encountered and the work

20 CHAPTER I.5

Table I.5.1 Table of the four possible results (a–d) from

comparing a diagnostic test to be validated and a reference (‘gold’) test. Reference (‘gold’) standard

Likelihood ratio for a negative result = 1 − sensitivity/specificity Predictive value of a positive result = a/a + b False alarm rate = b/a + b

Test

Disease present

Disease absent

Predictive value of a negative result = d/c + d

Test positive Test negative

a [true (+)] c [false (–)]

b [false (+)] d [true (–)]

False reassurance rate = c/c + d Prevalence of the diagnosis in the study population =

setting, the pretest probability for a given diagnosis will vary between and within countries and between generalists and specialists. In short, the diagnostic confidence in a diagnosis depends on the level of clinical expertise (taking into consideration patient type and setting) and the best objective evidence: Clinical expertise/knowledge + best objective evidence = diagnostic confidence. This may be rephrased as: Pretest probability (or odds) × likelihood ratio = post-test probability (or odds). Therefore, the two main questions to ask about the results of the study are: 1 Can data on the likelihood ratios be obtained? 2 What was the pretest probability of disease? To put these important, and other less important, properties of diagnostic testing into perspective, Table I.5.1 shows the results from a comparison of a diagnostic test to be validated and a reference test.

Properties of the diagnostic test Where a–d are defined as in Table I.5.1: Accuracy = a + d/a + b + c + d Sensitivity = a/a + c False positive rate = b/b + d Specificity = d/b + d

(a + c) (a + b + c + d)

• Accuracy is the number of individuals correctly diagnosed positive and negative but has the disadvantage of offering no information about false positives or false negatives. • Sensitivity is the probability of finding an abnormal result in individuals with the target disease. • Conversely, the false positive rate is the probability of diagnosing an abnormal result in an individual without the target disease. • Specificity is the probability of finding a normal result in individuals without the target disease. • Conversely, the false negative rate is the probability of diagnosing a normal result in an individual with the target disease.

Calculation of confidence in the diagnosis after testing Pretest odds = prevalence/1 − prevalence Post-test odds (for a positive test result) = pretest odds × likelihood ratio (for a positive test result) Post-test probability (for a positive test result) = post-test odds/post-test odds + 1 Post-test odds (for a negative test result) = pretest odds × likelihood ratio (for a negative test result) Post-test probability (for a negative test result) = post-test odds/post-test odds + 1

False negative rate = c/a + c

What is the pretest probability of disease in the study?

Likelihood ratio for a positive test result = sensitivity/1 − specificity

Before any test is ordered, there is a clinical assessment of the patient with cognitive impairment.

DIAGNOSIS 21

This provides a working differential diagnosis to which approximate probabilities are informally attached (often subconsciously). If AD is at the top of the differential diagnosis list, a test cannot prove that AD is actually present (bar a brain biopsy), but serves to modify the pretest probability of AD and produces a new (higher or lower) post-test probability. It is the likelihood ratio that determines this change in probabilities. However, in practice, it is the pretest probability that exerts the greatest influence on the diagnosis in people with cognitive impairment. In cases where a diagnosis is considered highly likely or highly unlikely, the pretest probability is unlikely to be importantly changed by any test (no matter how good a discriminator it isawith a high or low likelihood ratio), with unexpected results being attributed as false positives or false negatives. Although a careful history and examination remain the cornerstone of assessment and contribute most to the diagnostic process, it is possible to consider each piece of information from this source as a separate diagnostic test. Unfortunately, there are very little data to characterize the reliability and validity of these items of information. Expertise (accuracy and competency) is crucial here and may explain much of the variability in estimates of pretest probabilities. A further complication in providing the diagnostic properties of clinical items is that they are not evaluated in isolation but in clusters. An important influence on the pretest probability is the setting of the patients. In specialist centers the pretest probability is usually much higher than in primary care because of the selective filter of referral. This is an important contrast between diagnosis and screening. In specialist centers, higher predictive values will be obtained as the prevalence of the target disease is higher in their population of patients, although the discriminatory power of the specialist and generalist may not be very different. Hence, the pretest probability of the study population, assessed by the prevalence of the disease in that population, is important in evaluating the discriminatory power of the test under evaluation.

What is the likelihood ratio? The likelihood ratio summarizes the discriminat-

ory power of a diagnostic test and indicates the degree by which the pretest probability will be increased or decreased. A likelihood ratio greater than 1 increases the probability that the disease is present, and a likelihood ratio of less than 1 diminishes the probability that disease is present. The likelihood ratio (+, for a positive test result) is defined as: Probability of a positive result in a person with the target disease/probability of a positive result in a person without the target disease. This is equivalent to: Ratio of true positive/false positive = sensitivity/(100% − specificity) The liklihood ratio (–, for a negative test result) is defined as: Probability of a negative result in a person with the target disease/probability of a negative result in a person without the target disease. This is equivalent to: Ratio of false negative/true negative = (100% − sensitivity)/specificity Practical guidelines are: Likelihood ratio = 1; the post-test probability will be equal to the pretest probability and hence the test is of no value. Likelihood ratio = > 10 or < 0.1; will often make conclusive changes to the pretest probability. Unfortunately, such extreme values are rare. Likelihood ratio = 5–10 or 0.1–0.2; produce moderate shifts in the pretest probability. Likelihood ratio = 2–5 or 0.5–0.2; have a small (but sometimes important) impact on the pretest probability. Likelihood ratio = 1–2 or 0.5–1.0; alter pretest probabilities to a small (and rarely important) degree.

Did the test help confidence in the diagnosis? This requires calculation of the post-test probability. This can be done as outlined above or, more easily, by using an adapted nomogram by Fagan (1975) displayed in Fig. I.5.1:

22 CHAPTER I.5

0.1

99

1.0

95

0.8

0.2 0.5

2 5 10 20 30 40 50 60 70 80 90

1000 500 200 100 50 20 10 5 2 1

90 80 70 60 50 40 30 0.5 0.2 0.1 0.05 0.02 0.01 0.005 0.002 0.001

0.6 TPR

1

0.4

20 10

DECO MMSE Iowa

0.2

5 2

0.0 0.0

0.2

0.4

1 0.5

95

0.6

0.8

1.0

FPR Fig. I.5.2 ROC curves for each of three screching tests. Adapted from Ritchie and Fuhrer (1996).

0.2 99 Pretest probability (%)

Likelihood ratio

0.1 Post-test probability (%)

Fig. I.5.1 A nomogram for applying likelihood ratios. Adapted from Fagan (1975).

tial diagnosis list. An experienced clinician is likely to have a higher pretest probability for the most likely diagnosis. Sensitivity and specificity

1 Anchor a ruler on the appropriate level of the pretest probability line. 2 Swing the ruler through the appropriate value on the likelihood ratio line. 3 The post-test probability is calculated by finding the intercept of the ruler on the post-test probability line. As the likelihood ratio and pretest probabilities are point estimates, it is helpful to plausibly vary the pretest probability and the likelihood ratio (based on the confidence interval). Although confidence intervals for likelihood ratios, sensitivity and specificity are not often reported in articles of diagnostic performance in dementia, many of the tables in Section II of this book (and the website) have provided them as a ready source. It is also helpful to have in mind the levels of post-test probability that are required for a positive test result and for a negative test result. In the absence of other considerations, the pretest probability needs to be brought down below 50% by a negative result to reject the favored disease in the differen-

These two terms are more commonly used than likelihood ratios but are more limited because of the following reasons. 1 They cannot be used directly to calculate post-test probabilities. 2 They require results to be dichotomous, i.e. yes/no or present/absent. 3 Where results are not dichotomous but ordinal (e.g. low/medium/high) or continuous, they have to be forced in to dichotomous categories (e.g. low and medium/high or low/medium and high) and recalculated for each cut-off. In this way useful information is lost or requires constructing receiveroperating characteristic (ROC) curvesaso named because they were originally developed in detecting signals by radar operators. ROC curves are graphs where the vertical axis represents the true positive rate (sensitivity) for different cut-offs and the horizontal axis represents the false positive rate (1 – specificity) for the same cut-offs, and the values generated by using the cut-offs are plotted. An ROC curve can be used to formally compare the

DIAGNOSIS 23

value of different tests by assessing the area under each curve ( Fig. I.5.2). The diagonal line represents points where the true positive and false positive rates are equal. The curve that deviates further away from the diagonal line represents a better test, as it means that there are more true positives than false positives. If the ‘cost’ of a false negative result is the same as a false positive result, the best cut-off represents the point that maximizes the sum of the true positive (sensitivity) and true negative (specificity) rates, and lies nearest to the left tophand corner (a point in which there are 100% true positives and 100% true negatives). Clearly, the closer both sensitivity and specificity are to 100% the better the discrimination of the test. The lower these values, the more false positives and false negatives will arise. For practical purposes, a negative result from a test with high sensitivity effectively excludes the disease, as false negatives are rare. A positive result from a test with high specificity effectively assures the diagnosis as false positives are rare.

Are the results applicable to my patients? This requires answers to the following questions.

Can the test be used in my local setting? The test must, of course, be available and affordable. Can similar results be reproduced in your setting? Poor reproducibility may arise from technical problems in performing the test or in its interpretation. Data on reproducibility should be provided, especially where expertise is required. If reproducibility in the study was mediocre with frequent disagreements between observers, yet the test retained good discrimination, it is robust and capable of being applied to your local setting. If reproducibility is high and observer disagreement is low, either the test is simple and unmistakable or was done by highly skilled people. If the level of skill required is not available in your setting, the test may not perform as well as in the study. Some tests based on symptoms and signs have less discrimination in general practice than in tertiary care. The properties of a test may also change with a different mix of disease severity or a different distribution of competing or co-morbid conditions.

Likelihood ratios will be further from 1 with more severe disease or if few individuals who do not have the target disease have competing conditions. Likelihood ratios will be closer to 1 for disease of milder severity or where more people without the target disease have competing conditions. Therefore, if your practice is similar to that of the study and your patient meets the study inclusion and exclusion criteria, the results are clearly applicable. If not, judgement is needed. A pertinent question is: ‘Are there compelling reasons to consider that your practice and patient are so dissimilar to that of the study that its results cannot be generalized to your practice?’ Clearly, the more dissimilar your circumstances are to those of the study, the less confidence you will have that the study results will apply. Similarly, if the confidence intervals embrace values that do not markedly change the post-test results, one can have more reliance in the results. The issue of generalizability and applicability may be resolved by finding several studies in different circumstances or, better still, a systematic review of such studies, as carried out in Section II of this book.

Can you estimate your patient’s pretest probability? This can be estimated from the following sources: 1 Personal experience is an important guide for those with enough experience, often tempered by experience of the last case seen, the most dramatic or embarrassing case, or by whether you are an expert or generalist. 2 The study itself, if the setting and patients are sufficiently similar to your own and the patients in the study were recruited consecutively or randomly. 3 Practice data may be available from your records for certain important diagnoses. 4 Clinical speculation in which a sensible range of pretest probabilities are applied to determine the range of post-test probabilities.

Will the results affect clinical management? It is helpful to consider at least two decision ‘thresholds’: 1 The ‘diagnostic (or test) threshold’, where there is a probability or band of probabilities below

24 CHAPTER I.5

which a diagnosis is dismissed on the basis of a negative result and further testing stops. 2 The ‘treatment threshold’, where there is a probability or band of probabilities above which a diagnosis is confirmed by a positive test result leading to no further tests and the initiation of a treatment or management plan. Where the probability lies between these two thresholds, further testing is warranted. These thresholds depend on the risks and benefits attached to the consequences of arriving at correct and incorrect diagnoses in terms of treatment, management and prognosis. If the danger of missing a disease is high, the post-test probability needs to be very low before stopping further testing. If the risks of therapy or management (e.g. telling a patient that they have dementia) are high, a high post-test probability is needed to be certain of the diagnosis. Several diagnostic tests may be needed before a decision threshold is crossed. In this case, after each diagnostic test the post-test probability becomes the pretest probability for the next test. However, as subsequent tests are not independent of the results of the preceding test, the post-test probability at the end of the diagnostic process needs to clearly cross the decision threshold. If two tests are clearly related, application of the second test will not add much to the information furnished by the first test. For example, once the result of a computerized tomography (CT) scan to identify ischemic cerebrovascular disease as a cause or contributing factor to dementia has been determined, functional imaging is not likely to add further useful information (see Chapter II.4.6).

useful test adds information that leads to a change in management that is ultimately beneficial to the patient, or their family. As Section II demonstrates, evidence for the usefulness of many diagnostic tests is limited.

Will the patient benefit?

The future

The consequences of diagnostic testing range from reassurance when the diagnosis has been excluded, to labelling and possible further awful tests and prognostic news if the tests reach a firm positive diagnosis. Of particular relevance are the available therapeutic and management options and their risks. For cognitive impairment, tests may be accurate and influence the management of the patient, but their impact on outcome may be uncertain. For example, what is the impact on outcome of the use of magnetic resonance imaging (MRI) over CT? A

The validity of new diagnostic tests can also be evaluated in a randomized comparison (trial) with the reference test. Clinical outcomes in individuals allocated and managed on the basis of the reference test and the test under evaluation are compared. This method evaluates the efficiency of a whole management policy based on the new diagnostic test. Of course, such an approach requires the disease to be responsive to treatment and the availability of objective and meaningful outcome measures of efficacy and harm.

Is the patient willing to undertake the test? Every test has its drawbacks and the patient and family need to be involved whenever possible about the advantages and disadvantages, including the limited validity of the test. Clinical experience provides clear examples of patients with cognitive impairment who are unwilling or unable to undergo some imaging tests that require prolonged collaboration.

Time and sequence of testing To avoid unnecessary risk, cost or inconvenience, tests are often conducted sequentially; testing stops in those who pass certain diagnostic or treatment ‘thresholds’. Testing in this way increases specificity but decreases sensitivity, as the missed cases do not increase with subsequent tests. A further diagnostic tool is ‘time’, especially in cases of early possible dementia or mild cognitive impairment. The sensitivity of the clinical findings or diagnostic test will remain the same but the specificity and pretest probability will increase, as some of those without the target disease will have got better or will have been given another diagnosis, e.g. depression. Hence the discrimination (likelihood ratio) of the test (clinical history, examination or subsequent diagnostic test) will increase.

DIAGNOSIS 25

The diagnostic performance and practical usefulness of specific diagnostic tests are discussed in Section II.

References Fagan, T.J. (1975) Nomogram for Bayes theorem. New England Journal of Medicine 293 (5), 257. Jaeschke, R., Guyatt, G.H. & Sackett, D.L. for The Evidence-based Medicine Working Group. (1994a) Users’ guides to the medical literature. III. How to use an article about a diagnostic test. A. Are the results of the

study valid? Journal of the American Medical Association 271, 389–391. Jaeschke, R., Guyatt, G.H. & Sackett, D.L. for The Evidence-based Medicine Working Group. (1994b) Users’ guides to the medical literature. III. How to use an article about a diagnostic test. B. What were the results and how will they help me in caring for my patients? Journal of the American Medical Association 271, 703–707. Ransohoff, D.F. & Feinstein, A.R. (1978). Problems of spectrum and bias in evaluating the efficacy of diagnostic tests. New England Journal of Medicine 299 (17), 926–930. Ritchie, K. & Fuhrer, R. (1996) A comparative study of the performance of screening tests for senile dementia using receiver operating characteristics analysis. Journal of Clinical Epidemiology 45 (6), 627–637.

I.6

Evidence-based Prognosis

Nawab Qizilbash

Key points • Prognosis refers to the occurrence of possible clinical outcomes. • Prognostic factors are characteristics of particular patients that can more accurately predict clinical outcomes. • A prognostic model is a collection of prognostic factors to predict clinical outcomes. • Caution is needed as prediction in individual patients, based on studies of groups of patients, remains imprecise. • Few prognostic models in dementia are clinically useful. • Many prognostic studies would benefit from collaborative pooling of core common data with other studies. Prognosis refers to the occurrence of possible outcomes of a disease and hence requires knowledge about the course of the disease, ideally from biological onset although often this is only known from the time since diagnosis. For dementia, outcomes may be death, institutionalization, levels of dependency, behavioral disorders or softer outcomes such as reaching given levels of cognition, function, mood or desirable outcomes such as survival and no deterioration. Prognostic factors are characteristics of particular patients that can more accurately predict certain possible outcomes than by lumping all patients together. For example, patients with extrapyramidal signs may have a worse prognosis for institutionalization than patients without extrapyramidal signs

26

(Stern et al. 1997). In dementia prognostic factors can be demographic (e.g. age, sex, etc.), dementiaspecific (e.g. presence of behavioral problems or stage), co-morbid (e.g. other accompanying illnesses, such as stroke, heart disease, etc.) and factors external to the patients, such as carer support. Clearly, prognostic factors need not cause the outcomes, but are merely associated with them. For example, lack of carer support predicts a higher rate of institutionalization, but does not ‘cause’ institutionalization. Prognostic factors are characteristics which predict outcomes once a disease has developed, while risk factors are associated with the development of the disease. Apolipoprotein E4 (ApoE4) is known to increase the development of Alzheimer’s disease (AD) and predicts a poorer prognosis after diagnosis (Chapter II.4.4). In this example, ApoE4 is both a risk factor and a prognostic factor but there are examples of characteristics that are discrepant. For example, higher blood pressure is a risk factor for vascular dementia but low blood pressure may predict a worse prognosis for patients with this dementia (Skoog et al. 1996). This may be similar to the case in stroke in which high blood pressure predicts stroke, but low blood pressure may predict a higher stroke rate from coexisting vascular disease (Qizilbash & Evans 2000). As it is not possible or ethical to randomize patients to prognostic factors, their evaluation is based on observational cohort studies. Cohort studies in dementia follow one or more groups of defined dementia patients who have not yet suffered the outcome of interest (e.g. being placed in a nursing home) and record the number of patients who are admitted or not

PROGNOSIS 27

Table I.6.1 Questions to be considered when using an

evidence-based approach to evaluate prognosis studies (adapted from Lapacis et al. 1994). Were the study results valid? Was there a well-defined sample of patients? Were the patients recruited to the study at similar times in the course of the disease? Were the patients representative of the patient group? Was follow-up sufficiently long and complete? Were objective and unbiased outcome criteria used? Was there adjustment for important prognostic factors? What were the results? How frequent or probable was the outcome event(s) in a specified period of time? How precise were the estimates of the probability of the event? Can the results be applied to your particular patient(s)? Were the study patients similar to your own? Will the results influence selection or avoidance of therapy? Are the results useful for reassuring or counseling patients?

admitted to a nursing home over a defined period. An ideal prognostic study in dementia has a well-defined sample of dementia patients who are representative of the larger population of similar dementia patients to whom the results will apply. Also, the outcomes of interest should ideally be selected so that they can be assessed in an unbiased manner with valid and objective criteria. Trials do not provide representative cohorts as the patients who are enrolled are selected by strict inclusion and exclusion criteria. Nevertheless, they do provide one selected source of prognostic data. Where the outcomes are rare or require long follow-up (e.g. institutionalization in probable AD patients with early stage disease), the less preferred case–control study can be employed. ‘Cases’ might consist of dementia patients who have suffered the outcome of interest (e.g. institutionalization) and compared with dementia patients who had not yet suffered the outcome of interest (i.e. not institutionalized). However, case–control studies are more prone to bias, especially in selecting cases and comparable controls and also in the differential accuracy of recalling or collecting previous information on potential prognostic factors. Following the standard evidence-based approach

to evaluating studies, the questions in Table I.6.1 should be posed.

Were the study results valid? 1 Was there a well-defined sample of patients? There should be a description to specify the criteria used to establish the type of dementia (e.g. AD, dementia with Lewy bodies, etc.), any other characteristics to be studied for follow-up (e.g. aged more than 75 years) and where and how the patients were chosen for the study. Patients from special centers will often have more severe patients (with worse prognosis) than those from nonspecialist centers. Therefore, it is important to establish the next question. 2 Were the patients at the same point in the course of their dementia at the study start? A clear description of the stage of disease is needed when patients enter the study. Duration of dementia since onset is also often associated with outcome and should be reported. However, duration of dementia is very dependent on the time it took for the diagnosis to be made and hence may be variable. Studying patients late in the disease may miss determining prognostic factors that predict good outcomes, hence prognostic status should aim to include new or recently diagnosed patients, if possible, but it clearly depends to what purpose the results will be used. Such advice would not apply if the aim were to study prognostic factors for death in nursing home patients with dementia. 3 Were the patients representative? The results of the study will be used to help predict prognosis in similar patients not in the study. Therefore, the types of dementia patients in the study should reflect the population of dementia patients to which the study results will be applied. The greatest generalizations apply to population-based or community samples. Due to many factors, referral centers differ in the types of dementia patients they see, hence the population to which the results should apply are less clear. 4 Was follow-up sufficiently long? A knowledge of the clinical course of the particular types of dementia patients for the outcomes of interest will provide the answer to this question. Clearly, follow-up must be long enough for the outcomes of interest to occur.

28 CHAPTER I.6

As age is associated with prognosis for many diseases, adjustment for age is often made in such comparisons. When comparisons with groups external to the study population are made, adjustments should also be made for differences that can influence outcome, such as age, sex and socioeconomic class. Comparisons can also be made within the study group. The study group is divided into subgroups based on separate prognostic factors (e.g. stage of dementia), and the frequency of the outcome (e.g. death) in the prognostic factor subgroups can be compared. Again, adjustment is made in both subgroups for other important factors related to the outcome, such as age.

What were the results? 1 How probable are the outcomes over time? Questions of the type: ‘What are the chances that my relative will be dead in 5 years?’ can be answered. A simple answer can be provided by the overall results of the study. For example, in the study by Walsh et al. (1990), 50% of patients with dementia had died 5 years after presenting to a clinic. A more refined answer examines the significant prognostic factors found in the study, and

Survival (%)

100

Patients with hip fracture (n = 97)

80 60 40 20 0 100

Survival (%)

5 Was follow-up complete? Lack of follow-up of patients may bias the results as those patients whose fate is unknown may be different to those who remain to the end of the study or are censored when they reach the outcome of interest. There will almost always be some loss to follow-up (except perhaps for death)athe important question revolves around how much loss to follow-up seriously biases the results. In general, the larger the number whose outcome is unknown, the greater the threat to the validity of the results. Sensitivity (‘what if’) analyses can help to decide if the results are robust to the extreme scenarios of assuming that the missing data are all unfavorable or all favorable. For example, assume that 30% of the patients with AD are institutionalized during a long followup period. If 5% of patients lost to follow-up were all institutionalized, the institutionalization rate could be as high as 35%, which would not change the clinical implications of the study. If the institutionalization rate were 5% and all of the 5% of patients lost to follow-up were institutionalized, the new institutionalization rate of 10% (a doubling) could have very different implications. In circumstances where sensitivity analyses produce important changes in the results, examination of the baseline characteristics of the lost patients and those who remained in the study should be carefully compared. 6 Were objective and unbiased outcome criteria used? Outcomes can vary in their objectivity and ease of measurement. Death is objective, easily assessed and permanent. At the other extreme, quality of life is subjective, difficult to measure and varies. Therefore outcomes should be defined and assessed in an unbiased way so that assessors cannot assign better or worse outcomes to patients on the basis of different prognostic factors. For unequivocal events such as death and institutionalization, blinding is not necessary; for many other events or outcomes requiring judgements, such as staging of disease or functioning, blinding to potential prognostic factors should be employed where possible. 7 Was there adjustment for important prognostic variables? The prognosis for the entire study group can be compared with a group which does not have the criteria for entry into the study. Examples can include the general population or other dementias.

Patients with pneumonia (n = 119)

80 60 40 20 0

Cognitively intact group End-stage dementia group 30

60 90 120 150 180 Time from admission (days)

210

Fig. I.6.1 Kaplan–Meier survival curves for patients with hip fracture and pneumonia (Morrison & Sui 2000).

PROGNOSIS 29

matches them to the particular patient, to help tailor the overall figure of 50% risk, either down or up, to the particular patient. The chances of the outcome with time may change, and the only way of answering this is to examine a graph of the outcome with time, plotted on Kaplan– Meier graphs (Fig. I.6.1). The gradients in the graph will provide evidence of whether and how the chance of the particular outcome changes with time. 2 How precise are the results? A study using a sample of patients to estimate prognostic risk is unlikely to find exactly the same results as another study using similar patients. Therefore, the precision of the estimate for a study is needed so that we can see the likely range within which the true risk lies. The narrower this range, the more helpful the result; the wider the range, the less helpful the results. This uncertainty or imprecision is best estimated with 95% confidence intervals. For example, in the study by Walsh et al. (1990), survival after 5 years was 50%, with a 95% confidence interval ranging from approximately 40% to 60%. This means that there is 95% certainty that the true prognosis could be as low as 40% or as high as 60%. In the same study, the relative risk associated with the prognostic factor (behavioral problem) was 1.5 with a confidence interval of 1.0–2.5. This means that a patient with behavioral problems is 50% more likely to die than a patient without behavioral problems. However, the risk could be up to 250% higher or as low as 0% higher (relative risk 1.0), meaning that there is some, but not good, evidence from this study alone that behavioral symptoms influence the prognosis of death.

Are the results applicable to my patients? This requires clarification of several issues. 1 Were the prognostic factors confirmed in an independent group of patients? Experience has taught that prognostic factors found in one study are often not as powerful when tested in other studies (Wyatt & Altman 1995). Therefore, validation of the prognostic factors in another independent group of similar patients helps the generalization of the study results. 2 Were the study patients similar to your patient(s)? The closer your patient(s) matches those of the

study, the more applicable the results will be for you. 3 Will the results importantly influence your decision for therapy or intervention? Knowledge of the clinical course and its probability over time can help you judge whether treatment or intervention should be offered. Only vitamin E and selegiline have shown some evidence of delaying important clinical milestones (Chapter V2.21). Cholinesterone inhibitors demonstrate consistent symptomatic benefits on cognition and clinical global impairment for up to 1 year (Chapter V.2.21). The prognosis for your particular patient, given the stage in the disease, may help in the decision to assess the risks, benefit and costs of these therapies. 4 Will the results influence what you tell the patient and carers? A result of uniformly bad prognosis provides clinicians with a starting place for discussing future plans for legal wills, power of attorney, place of residence and what to expect towards the end of life. However, precision of when the timing of bad outcomes occur in any individual patient may be poor, even though for a group it may be quite precise. This uncertainty should always be borne in mind.

Prognostic models Prognostic models are a collection of variables used to predict clinical outcomes. They are more than the use of single items such as age, sex, smoking, etc. To be useful these models need to be credible, accurate, generalizable and clinically effective (Wyatt & Altman 1995). Credibility requires that all clinically relevant data have been included in the model; the data can be obtained reliably and easily; arbitrary categorization of continuous variables is avoided in the model; and it should be simple to calculate in clinical practice. Accuracy requires low false negative (failure to predict the outcome) and low false positive (predicts the outcome when it will not happen) rates. Generalizability requires that the model can be applied to other patients seen in clinical practice: the model is confirmed in another dataset; the definition of the data items are in widespread use; and the cohort at initiation of the study is described so that clinicians can apply the model to appropriate patients. Finally,

30 CHAPTER I.6

evidence of clinical effectiveness, as tested through controlled trials, is needed. In some areas other than dementia, trials of computerized decision support has shown a beneficial impact on clinical practice or patient outcome (Johnston et al. 1994). In the field of dementia (and many other diseases) the features of prognostic model usability are lacking from studies (see website for details). A computerized disease memory clinic registry pooling a core minimum dataset from many clinics would help to fill this significant gap (see Chapter VII.7.4).

References Fletcher, R.H., Fletcher, S.W. & Wagner, E.H. (1996) Clinical Epidemiology. The Essentials. Williams & Wilkins, Baltimore. Johnston M.E., Langton, K.B., Haynes, R.B., Matthieu, D. (1994). A critical appraisal of research on the effects of computer-based decision support systems on clinician

performance and patient outcomes. Annals of Internal Medicine 120, 135–142. Lapacis, A., Wells, G., Richardson, W.S. & Tugwell, P. for the Evidence-Based Medicine Working Group (1994) Users’ guides to the medical literature. V. How to use an article about prognosis. Journal of the American Medical Association 272 (3), 234–237. Morrison, R.S. & Sui, A.L. (2000) Survival in end-stage dementia following acute illness. Journal of the American Medical Association 284, 47–52. Qizilbash, N. & Evans, J.E. (2000) The prevention of stroke. In: Oxford Textbook of Geratric Medicine, 2nd edn (Evans, J.E., Franklin Williams, T. & Wilcock, G., eds), pp. 455–462. Oxford University Press, Oxford. Skoog, I., Lernfelt, B., Landahl, S. et al. (1996) A 15-year longitudinal study of blood pressure and dementia. Lancet 347, 1141–1145. Stern, Y., Tang, M.X., Albert, M.S. et al. (1997) Predicting time to nursing home care and death in individuals with Alzheimer disease. Journal of the American Medical Association 227, 806–812. Walsh, J.S., Welch, G. & Larson, E.B. (1990) Survival of outpatients with Alzheimer-type dementia. Annals of Internal Medicine 113, 429–434. Wyatt, J.C. & Altman, D.G. (1995) Commentary: prognostic models: clinically useful or quickly forgotten? British Medical Journal 311, 1539–1541.

I.7

Evidence-based Interventions

Nawab Qizilbash

Key points • Well-conducted and repooled, double-blind, randomized controlled trials represent the ‘gold standard’ research design for judging the benefits and harms of interventions. • Limited generalizability of trial results in dementia require clinical judgement in their application to patients who are different from those in the trial. • Absolute measures of benefit and harm (such as risk difference or number needed to treat) are more relevant to clinical practice than relative measures such as relative risk, odds ratios or hazard ratios. • Clinically meaningful outcomes and relevant duration of treatment are important aspects in translating the results of trials to clinical practice in dementia. • Where randomization is not possible or ethical, non-randomized intervention studies or n-of-1 trials are needed.

Therapeutic interventions are aimed at reducing symptoms and curing disease. Preventive interventions are focused on reducing the risk of disease or its complications. Data about the effects of therapeutic and preventive interventions, both benefits and harms, come from several sources of evidencea ranging from studies with little potential for systematic bias and minimal random error, such as well-designed large-scale randomized controlled trials (‘mega-trials’), through controlled but non-

randomized cohort and case–control studies, all the way to opinions based on laboratory evidence or theory. Although randomized controlled trials may have high internal validity (i.e. reflect the truth) they may have poor external validity (i.e. they reflect the truth in only a small proportion of patients, with limited generalization of the findings to other settings). Therefore, non-randomized designs have been proposed in situations where randomized trials cannot be conducted or where issues of generalizability are important (Black 1996). A classification for this book has been devised, and used in Sections V, VI and VII dealing with interventions, that judges the evidence from different sources based on the potential for systematic bias and on random error (Table I.7.1). In contrast to the Cochrane Collaboration (1996) and the US Agency for Health Care Policy and Research (1992) we are not convinced that, at least in dementia, evidence from one large, well-conducted randomized controlled trial necessarily represents a lower level of evidence than that obtained from a meta-analysis of randomized controlled trials. Although randomized trials are widespread in dementia, there are ethical and practical problems in conducting such studies for several types of interventions in dementiaaespecially non-pharmacological, psychosocial, and patient management interventions (Chapter IV.6). The American Psychological Association (Chambless et al. 1996) has also proposed criteria for identifying empirically validated treatments for non-pharmacological interventions (Table I.7.2). Although a helpful development, these criteria are not precise and have potential for much bias and random error and therefore require

31

32 CHAPTER I.7

Table I.7.1 Grading recommendations and evidence for interventions. Grade A: ‘High’ quality evidence with minimal potential for bias 1 Extremely reliable, often requiring large-scale randomized evidence from a single trial or a systematic review 2 Moderately reliable, from moderate-scale randomized evidence from a single trial or a systematic review 3 Questionably reliable, often small-scale randomized evidence from a single trial or a systematic review 4 Evidence from a single unplanned analysis of the aforementioned types of studies 5 High quality series of ‘n-of-1’ trials where evidence from levels 1–4 is absent Grade B: ‘Moderate’ quality evidence with moderate potential for bias 6 Evidence that is quasi-randomized or randomized with important sources of potential bias, e.g. lack of double blinding when crucial, cross-over study with possibility of carry-over effect, numerous drop-outs 7 High quality non-randomized prospective or case–control study of groups with and without interventions 8 High quality case series Grade C: ‘Poor’ quality evidence with substantial potential for bias 9 Evidence from poor quality non-randomized prospective, case–control and case series studies 10 Opinions not based on the above levels of evidence (hypotheses, laboratory data, animal data, ‘experts’) Recommendations for interventions: Grades A, B and C Quality of evidence: Levels 1–10

Table I.7.2 Criteria for empirically validated treatments

(Chambless et al. 1996). Well-established treatments I. At least two good group design experiments demonstrating efficacy in one or more of the following ways: (a) Superior to pill or psychological placebo or to another treatment (b) Equivalent to an already established treatment in studies with adequate statistical power (about 30 per group) or II. A large series of single case design experiments (n > 9) demonstrating efficacy. These studies must have: (a) Used good experimental designs and (b) Compared the intervention to another treatment as in IA Further clarificarion for both I and II: III. Experiments must be conducted with treatment manuals IV. Characteristics of the patients must be specified V. Effects must be demonstrated by at least two different investigators Probably efficacious treatments I. Two experiments showing the treatment is more effective than a waiting-list control group or II. One or more experiments meeting the well-established treatment criteria I, III and IV, but not V or III. A small series of single case experiments (n > 9) otherwise meeting well-established treatment criteria II, III and IV

further elaboration. For example, the assertion that equivalency can be demonstrated in a sample of 30 per group seems overly optimistic. Large and clear effects may not require randomized evidence (e.g. penicillin in pneumococcal pneumonia, insulin in type I diabetes), and yet would constitute ‘high’ quality evidence. Such evidence, unfortunately, is rare in dementia. Apart from level 1 evidence, all other levels of evidence may require consistency and coherence from non-randomized studies and experimental data for greater confidence. For example, cigarette smoking is considered to be a cause of lung cancer because of the consistency and coherence of many types of studies in spite of the lack of randomized studies to test the association. There is consensus that the randomized controlled trial is the best method to determine the value of an intervention. The fundamental idea of a clinical trial is to compare groups of patients who differ only with respect to their treatment. The randomized controlled trial compares outcomes in the group of individuals subjected to the test intervention with a comparable group of individuals who receive the control intervention. The controlled intervention may consist of no treatment, a placebo, an

INTERVENTIONS 33

Table I.7.3 Major sources of bias and the available remedies in randomized and non-randomized studies. Available remedies in non-randomized studies

Major sources of bias

Available remedies in randomized trials

Increase participation by: Relaxing exclusion criteria Having multiple centers Simple consent procedures

Patient selection bias (Limited type of patients, limiting generalizability)

Increase participation by: Relaxing exclusion criteria Having multiple centers Pragmatic design Simple consent procedures

Adjustment for known prognostic factors

Allocation bias (Through confounding)

Randomization ± stratification or minimization on key prognostic factors

Adjustment in the analysis

Treatment bias (Differential management of the intervention groups)

Double blinding with placebo

Blinding of assessors, if possible

Assessment bias (Differential assessment of subjective outcome measures)

Blinding of assessors, if double blinding not possible

Ensure complete follow-up by simple follow-up procedures. Request protocol violators to return for a final or the last scheduled visit

Attrition or follow-up bias (Non-completers may be different in response to efficacy and harms from completers)

Ensure complete follow-up by simple follow-up procedures. Request protocol violators to return for a final or the last scheduled visit

Use intention-to-treat analysis Pre-specify subgroup analyses Ensure adequate numbers of events to avoid false negative results

Analysis bias

Use intention-to-treat analysis Pre-specify subgroup analyses Ensure adequate numbers of events to avoid false negative results

Assess results from other relevant studies

Study selection bias (Not assessing the study in the context of all the relevant evidence available)

Assess results from other similar trials

established treatment considered to be the best or standard practice, or another intervention. Details of trial methodology are described by Pocock (1984) and aspects of trials in the elderly by Qizilbash (1996). If the intervention groups differ in ways other than the interventions administered, the comparison of the treatment effect may become biased. If biases can be identified then it may be possible to allow for their effects in the analysis, but where they are unknown they cannot be dealt with. The major kinds of bias that may arise and proposed solutions for both randomized and non-randomized studies are depicted in Table I.7.3. As individuals differ in their prognosis, often for unknown reasons, it is important to ensure a balance of the known and, more importantly,

unknown prognostic factors in the intervention groups. The most reliable way to achieve this aim is through randomization, which is considered an essential minimum (though not sufficient) requirement to ensure that this systematic source of bias (allocation bias) is kept to a minimum. Other methods of allocation such as alternate allocation, day of the week or date of birth may allow the entry of bias, as may the lack of any attempt to have impartial allocation, as in non-randomized studies (Chalmers et al. 1989). Allocation bias is most easily evaluated by comparing patient characteristics at baseline in the two groups. This tests whether the randomization process was successful. For example, in the trial of vitamin E and selegiline, doubts were raised over randomization as the groups had different Mini Mental Status Examina-

34 CHAPTER I.7

tion (MMSE) scores at baseline (Sano et al. 1997). This trial did not use randomization with minimization to reduce such an imbalance occurring, which because of its small size may have arisen by the play of chance. In such instances of imbalance in important prognostic factors, adjustment is required in the analysis (Sano et al. 1997). Blinding is necessary to avoid bias from the patient and assessor. The patient and clinician (and separate assessor) may be affected by knowledge of which intervention the patient has received. This may translate, consciously or unconsciously, into differences in the provision of ancillary care, treatments and in the assessment of outcomes between patients receiving the different interventions. Therefore, if the patient and clinician (and separate assessor) can be kept blind to which treatment the patient is receiving (‘double blindness’), this minimizes treatment, care and assessment bias. Where only the patients are unaware of which intervention they receive, the trial is termed ‘single blind’. In many areas of dementia, especially for psychosocial interventions, it is often very difficult to conduct double-blind studies. In such circumstances the assessor should be kept blind to which intervention the patient is receiving, if at all possible, and/or less subjective endpoints should be assessed where possible. Where endpoints are reasonably objective, such as death, nursing home placement or unequivocal levels of dependency, blindness may be a lesser issue. Placebos (inert dummy tablets) are necessary to ensure a study is kept double blind. Placebos are also needed to allow for the well-known fact that part of the treatment effect may be derived solely due to the knowledge or belief that the patient has taken a treatment, the so-called ‘placebo effect’. As well as finding benefits from placebo, side effects are also reported; therefore assessment of harm from treatment is best conducted with a placebo comparison. Attrition bias, resulting from non-completion of the trial protocol can be a serious source of bias. Some consider that trials which have a drop-out rate of greater than 20% should be viewed with caution. Nevertheless, the absolute degree of attrition is not as important as the reasons for the losses in the intervention groups. If more patients in the

treatment group drop out because of side effects or lack of efficacy than in the control group, then not including these patients in the analysis will produce an unfairly favorable impression of the treatment effect. For this reason, all patients randomized to a trial should be analysed, according to the group to which they were allocated; this is called an ‘intentionto-treat’ analysis. Analysis of only those who complete the trial should be considered only after an intention-to-treat analysis has been conducted. Differential timing of the dropouts between the groups may also be important, especially where intention-to-treat analysis with last observation carried forward methods are being employed. Analysis bias can occur when subgroups or nonprimary outcomes are analysed which were not specified before the data were examined. Finally, selection bias occurs because only a small proportion of potentially eligible patients are included in the trial because of strict inclusion/ exclusion criteria. Scales have been devised to rate the quality of trials, primarily based on randomization, blinding and follow-up. One that has been validated has been used in this book in Sections V, VI and VII on interventions (Jadad et al. 1996). The limitations of this scale are that it identifies studies with much potential for bias, but it is not terribly helpful for identifying good studies. Extensive checklists are also available (Gardner et al. 1989; Grant 1989; Reisch et al. 1989). The above scheme of major potential sources of bias in studies of treatment or prevention provides a rationale for their appraisal. The basic questions that need to be asked about the validity of the study should be considered under the following headings (Guyatt et al. 1993; Guyatt et al. 1994): • Was the study sufficiently valid? • What were the results? • Are the results applicable to my patients?

Was the study sufficiently valid? 1 Was randomization used to allocate patients to the intervention groups? 2 Were all patients accounted for at the end of the study? 3 Was follow-up complete?

INTERVENTIONS 35

4 Were all patients analysed according to the groups to which they were randomized? 5 How blind was the study? 6 Were the intervention groups similar at baseline, especially for important known prognostic variables? 7 Were the intervention groups managed in a similar fashion during the trial? No study is perfect and the biases need to be placed in the context of the size of the treatment effects. Although the focus has been on randomized studies, which are rarely perfect, non-randomized studies may also offer opportunities for sufficiently reliable evaluation of interventions where randomization is unethical or impractical. The greater potential for bias and confounding needs to be acknowledged but there appear to be no systematic comparisons of randomized and non-randomized studies in dementia. The few examples of such comparisons in other fields, suggest that the magnitude of the effects (and the variation between studies) in randomized and non-randomized studies may be similar if the subjects have similar characteristics, if there is adjustment for differences in known baseline prognostic factors and where treatment effects are large (CASS Principal Investigators and Associates 1984; Paradise et al. 1984; Hlatky et al. 1988; Horwitz et al. 1990). This provides a complementary approach for further quality research in the evaluation of effectiveness of interventions in dementia where randomization cannot be carried out, especially for many psychosocial patient management interventions.

What were the results? What was the best estimate of the size of the treatment effect? If the outcome measure is binary (‘all or nothing’), such as nursing home placement or not, then the most common measure of the magnitude of the treatment effect is relative risk. The greater the relative risk and the greater the absolute relative risk reduction, the more efficacious is the treatment. The odds ratio (and hazard ratio) may be used instead of the relative risk but can be viewed and interpreted in the same way as relative risk.

First, we need to define risk itself, using one of two methods. Risk (of an outcome) can be assessed through calculating a proportion or the odds. An example is data from the vitamin E trial (Sano et al. 1997) (Table I.7.4): • Proportion institutionalized with vitamin E: 22/85 (i.e. 22 patients are institutionalized for every 85 patients who received vitamin E). • Proportion institutionalized with placebo: 33/84 (i.e. 33 patients are institutionalized for every 84 patients who received placebo). • Odds of being institutionalized with vitamin E: 22/(85–22) (i.e. 22 patients are institutionalized for every 63 who receive vitamin E and are not institutionalized). • Odds of being institutionalized with placebo: 33/(84–33) (i.e. 33 patients are institutionalized for every 51 who receive placebo and are not institutionalized). The risk ratio (or relative risk) is the ratio of the proportion of those with the outcome (institutionalization) in the treated (vitamin E) group divided by the proportion of those with the outcome (institutionalization) in the control (placebo) group: Relative risk =

22/85 33/84

= 0.69

The odds ratio is the ratio of the odds in each group: Odds ratio =

22/(85 − 22) 33/(84 − 33)

= 0.54

In this example, the odds ratio is very different to the relative risk, because the outcomes are common. In general, when the outcomes occur in greater than about 10% of subjects, the odds ratio

Table I.7.4 From Sano et al. (1997).

Vitamin E Placebo

Institutionalized*

Not institutionalized*

Total

22 33

63 51

85 84

*Ignoring drop-outs.

36 CHAPTER I.7

should not be used. The relative risk is much preferred in evaluating trials. The ‘hazard ratio’ can be interpreted as a relative risk which takes into account the differing lengths of time that subjects are in a trial.

How precise was the best estimate of the size of the treatment effect? If the same trial had been conducted many times, the figures for the proportion having the event in the active and control groups would not be identical each time. Therefore, a confidence interval is calculated which provides a range of values within which we have a certain confidence (e.g. 95% certainty) that the true value of the treatment effect lies. The wider the confidence interval, the less certain we are that the figure produced by the study is close to the real value. The tighter the confidence interval, the more certain we are that the effect size from the study is close to the real value. If the lower end of the confidence interval does not overlap with 1, this means that the effect seen from treatment in the study is very unlikely to have occurred if the treatment had been no different from the control intervention. This is known as significance testing and is accompanied by P values. The P value (traditionally quoted at P = 0.05) provides the probability of observing a result as extreme as the one obtained from the study, under

the assumption that the two treatments do not differ. Therefore, P = 0.05 means that the result could have arisen by chance in five out of 100 repeated trials, assuming no difference between treatments groups (the ‘null hypothesis’). As this is unlikely, such a remote probability is taken as proof that the assumption of no difference is wrong, and that the alternative assumption of a real difference between the treatment groups is accepted. However, it must be accepted that this conclusion could be wrong in 5% (one in 20) of such situations. If this level of risk of being wrong is unacceptable, then more stringent values can be chosen, such as P = 0.01 or P = 0.001. When the outcome is continuous, or may be treated as continuous although it is really ordinal, such as Alzheimer’s Disease Assessment ScaleaCognitive (ADAS-Cog) or MMSE, then the measure of the treatment effect is the difference in means. The difference in means can be calculated from the means at the end of the treatment period for the active and control groups, or, more sensitively, from the mean change (from baseline to end of the treatment period) for the active and control groups. The interpretation of the confidence interval is similar to that for relative risk, except that statistical significance requires the confidence interval not to encroach on a mean difference of zero. Tables I.7.5 and I.7.6 depict these concepts.

Table I.7.5 Clinical global impression of change. Odds of improvement on tacrine compared with placebo.

Study

Final dose (mg/day)

No. of patients, tacrine/placebo 373/72

Farlow et al.

39

Davis et al.

62

96/110

Foster et al.

65

39/41

Forette et al.

66

68/53

Knapp et al.

135

381/170

Pooled

Estimates with 95% confidence intervals

957/446

1.58 (1.18−2.11) 0.5

1.0 Odds ratio

Treatment worse

1.5

2.0

Treatment better

3.0

4.0

INTERVENTIONS 37

Table I.7.6 Change in MMSE cognitive score for tacrine compared with placebo during 12 weeks. Results are based on

standardized rates of change. The final dose is the average final daily dosage of all patients randomized to tacrine in each study.

Study

Final dose, (mg/day)

No. of patients, tacrine/placebo 391/77

Farlow et al.

39

Maltby et al.

56

19/20

Davis et al.

62

103/111

Molloy et al.

64

16/6

Foster et al.

65

40/41

Forette et al.

66

68/53

Wood & Castleden

70

76/75

Gauthier et al.

71

20/25

Wilcock et al.

82

42/43

Chatellier & Lacomblez

91

34/33

Ahlin et al.

94

9/6

Knapp et al.

135

466/180

Pooled

Estimates with 95% confidence intervals

0.62 (SE, 0.2)

1284/670

−4

−2

0 Tacrine-placebo

Treatment worse

2

4

6

Treatment better

SE, standard error.

Are the results applicable to my patients? Before addressing applicability, it is important to search for other similar studies and put the results in the context of the totality of the valid evidence. Apart from mega-trials, more than one similar study should be available to assess the constancy of the findings, unless the results were really spectacular. For example, the study of vitamin E and selegiline by Sano et al. (1997), is the only one upon which to base treatment decisions (Table I.7.6), yet many questions remain about the reliability of the findings (Drachman & Leber 1997). This is akin to the regulatory agencies requesting positive results from two good trials (or very robust results from just one trial, P < 0.00125; Fisher 1999) before approval is granted for drugs. Although your patient may not be identical to those in the study, the important question to ask is whether there are good reasons why the treatment effect should not apply to your patient. The less your patient resembles those in the trial for important demographic, clinical and prognostic charac-

teristics at baseline, the more doubtful become the results of the study to your patient. There may be a temptation to look at subgroups to evaluate those who appeared to have benefited to a similar or greater degree than the overall effect, and those who fared substantially worse than the overall effect. Unfortunately, subgroup analyses, unless limited and prespecified in the protocol, are extremely unreliable (Peto 1987). The Second International Study of Infarct Survival (ISIS-2) Collaborative Group (1988) presented the results of the effects by subgroup based on astrological birth sign. Aspirin was beneficial overall for people of all astrological signs except for Libra and Gemini, for whom there was apparent harm. This spurious result was from a randomized trial of almost 18 000 patients. The size of trials to detect overall effects on average is difficult enough to achieve in dementia (Chapter IV5.3), so the possibility of reliably detecting effects in subgroups (with fewer patients) must be even slimmer in these already undersized trials. The method of statistical analysis is important in interpreting subgroup

38 CHAPTER I.7

findings. The number of comparisons (in the protocol) should be provided in the publication and not just those that were positive. A simple conservative method divides the P value by the number of comparisons to arrive at the adjusted P value. However, more rigorous analysis requires first the examination of interaction (i.e. are the subgroups significantly different from each other and from the overall effect?) followed by adjustment for multiple testing. With appropriate analysis, it is unlikely that statistically significant subgroups will emerge. Subgroup analysis should be viewed with great scepticism and used to confirm consistency between subgroups or to identify large treatment differences between subgroups. Exceptions may be those patients who can be identified to be at low risk of developing future adverse outcomes; they may have little to gain (Rothwell 1995). For example, various subgroups of patients (older and younger, milder and more severe) and various subgroups of outcomes were suggested to fare better or worse than the overall results in the individual tacrine trials. However, an individual patient data metaanalysis with nearly 2000 patients could find no convincing evidence to support these subgroup hypotheses (Qizilbash et al. 1998). Applying a rigorous statistical approach (or perhaps even the simple approach of dividing the P value by the number of comparisons) may have avoided concluding that acetyl carnitine may be beneficial in AD patients with younger onset (Chapter V.2.2). Other questions that need to be asked in assessing subgroups are: 1 Is the magnitude of the difference in the subgroup clinically important? 2 Was the difference consistent across studies? 3 Were the subgroups ranked in order of plausibility? 4 Were there good biological hypotheses before the trial to support the subgroup findings? 5 Were the subgroups defined before the study began? If subgroups are to be produced, they need to be defined by baseline characteristics such as those that cannot be affected by the therapy (e.g. age and sex) and those related to the disease (e.g. staging of disease, mixed dementia, etc.). Subgroups can also be defined by the types of outcome. However,

subgroups defined after randomization and who may be potentially affected by treatment, such as responders and compliers, can be extremely misleading as the results may be due not to the treatment but to the innate characteristics of the patients that led to particular outcomes, because of prognosis or side effects. When is your patient too different to the trial patients for you to decide that the results do not apply? For prevention of adverse events, principles from other areas of medicine can be found (Glasziou & Irig 1995). Benefits generally increase with risk from the adverse outcome (e.g. greater reduction in ischemic stroke risk in those at risk of developing ischemic stroke). Harm or the rate of adverse events other than that being specifically prevented, generally remain comparatively fixed across patient groups (e.g. hemorrhagic stroke). Hence the net benefit may be calculated as: Net benefit = risk × relative risk reduction − harm. The following assumptions need checking before accepting this approach to individualizing therapy: 1 That there is a constant relative risk reduction across subgroups. This may be different in situations of different intensity of intervention, timing of intervention, concomitant therapy or disease, and where there are both negative and positive effects on the outcome. Note that the absolute risk reduction is not constant. 2 That the absolute level of harm is fixed across subgroups of differing risk for the adverse outcome. 3 That the risk of the adverse outcome to be prevented does indeed increase in subgroups at higher risk of the outcome. This information is usually obtained from good prognostic studies. The final part of this approach requires the patient to make a relative evaluation of the benefits and harms. For example, how many adverse events or side effects are equivalent to the adverse outcome to be prevented? A patient with vascular dementia and unilateral severe carotid stenosis, without a history of clinical stroke or transient ischameic attack, may need to consider carotid endarterectomy, in the belief that it may reduce the risk of further cognitive decline and future ischemic stroke. What risk of post-surgical stroke might they accept?

INTERVENTIONS 39

These principles may apply to the primary prevention of dementia but, except for rare instances such as those cited above, are unlikely to be relevant for slowing disease progression or for symptomatic therapies. For symptomatic therapy, ‘n-of-1’ trials (Chapter IV.5.4) are required, and for progression of disease trials really large sample sizes are needed to help identify subgroups who may benefit to different degrees (Chapter IV.5.3).

1000 800 600 400 300

350 250

200 150 120 90 70 50

Are the outcomes clinically important? Benefits can be considered important if they affect clinically important outcomes as opposed to surrogate or intermediate endpoints, whose relevance for patients or carers is difficult to describe. Thus, the relevance of changes in ADAS-Cog in cholinesterase-inhibitor trials is unclear (Qizilbash et al. 1998). Meanwhile the benefits of reduction in nursing home placements are unequivocal. Other clinically important outcomes are the harms of treatment and tolerability to treatment. They can be gauged from the adverse effects and the number of withdrawals from the study. Withdrawals occur for several reasons, one of which is intolerability to the intervention and the manner of its administration within the study.

700 500

100 80 60 40

0.1

30 0.2

0.3 0.5 1 2

15

15

25 17 12

10

3 7

20

5 10

7 5

4 3

20

2

30 50 100 80 60

70 90 70

100

1

50 40 30

35 25

Are the benefits worth the harms, inconvenience and cost? Given a clinically relevant outcome, the size of the benefit is important. In particular, it needs to be judged in relation to side effects, inconvenience and cost. Although relative risk (or benefit) of an intervention may appear impressive, absolute risk (or benefit) differences between the intervention groups reflect best the gain to be obtained by individual patients. One method of expressing this gain is the ‘number needed to treat’ (NNT), which is simply the reciprocal of the absolute risk difference and can be calculated easily from a nomogram (Chatellier et al. 1996) (Fig. I.7.1). Again confidence intervals are required to express the degree of imprecision about the point estimate from the study and can be calculated (Altman 1998). For example, 40 patients would need to be treated with tacrine for one patient to benefit by a moderate or

20 15 12 9 7

10 8 6

5 4 3

2.5

2 1.5 1 0.7

0.8 0.6

0.5 Absolute risk in the absence of treatment (%)

Relative risk reduction (%)

Number needed to treat

Fig. I.7.1 Nomogram for calculating the number needed to

treat.

8 6

40 CHAPTER I.7

marked degree on the clinical global scale, but this figure could be as high as 125 or as low as 23 (Qizilbash et al. 1998). Although in trials of prevention the NNT requires the relative risk reduction to be constant for all levels of risk (otherwise regression techniques are required) and that results should not be used outside the period of the studies, for symptomatic therapies in dementia where patients are similar to those in the trial, NNTs provide a useful measure to assess benefits and risks. If the study demographic and prognostic factors for the outcomes apply to your patient and the effect size is sufficiently large, this provides a good enough reason to generalize to your patient. If the rate of adverse events is large this may outweigh the benefits in low risk patients. If the adverse event rate is high and the benefits are small one may wish to wait for trials in patients similar to yours. If the adverse event rate could be higher in your patient because of other conditions or other therapies, this consideration may outweigh any benefit in low risk patients. A clinically important NNT depends on the burden of the suffering measured from morbidity and outcome, the cost and difficulty of the intervention, and the cost of not treating the condition. It also depends on the number needed to harm. Thus, the clinician remains faced with the ‘art’ of weighing up the various sources of evidence combined with patient and carer preferences and local circumstances, to decide upon the provision of treatment for individual patients.

References Altman, D. (1998) Confidence intervals for the number needed to treat. British Medical Journal 317, 1309–1312. Black, N. (1996) Why we need observational studies to evaluate the effectiveness of healthcare. British Medical Journal 312, 1215–1218. CASS Principal Investigators and Associates. (1984) Coronary Artery Surgery Study (CASS): randomised trial of coronary artery bypass surgery. Comparability of entry characteristics and survival in randomised patients and nonrandomised patients meeting randomisation criteria. Journal of the American College of Cardiology 3, 114–128. Chalmers, T.C., Celano, P., Sacks, H.S. & Smith, H. Jr. (1989) Bias in treatment assignment in controlled clinical

trials. New England Journal of Medicine 309, 1358–1361. Chambless, D.L., Sanderson, W.C., Shoham, V. et al. (1996) An update on empirically validated therapies. Clinical Psychologist 49 (2), 5–18. Chatellier, G., Zapletal, E., Lemaitre, D., Menard, J. & Degoulet, P. (1996) The number needed to treat: a clinically useful nomogram in its proper context. British Medical Journal 312, 426–429. Cochrane Collaboration (1996) Cochrane Library. Update Software, Oxford. Drachman, D.A. & Leber, P. (1997) Treatment of Alzheimers diseaseasearching for a breakthrough, settling for less. [Editorial] New England Journal of Medicine 336 (17), 1245–1247. Fisher, L.D. (1999) One large, well-designed, multicenter study as an alternative to the usual FDA paradigm. Drug Information Journal 33, 265–271. Gardner, M.J., Machin, D. & Campbell, M.J. (1989) Use of checklists in assessing the statistical content of medical studies. In: Statistics with Confidence (Gardner, M.J. & Altman, G., eds), pp. 101–108. British Medical Journal, London. Glasziou, P.P. & Irig, L.M. (1995) An evidence-based approach to individualising treatment. British Medical Journal 311, 1356–1359. Grant, A. (1989) Reporting controlled trials. British Journal of Obstetrics and Gynaecology 96, 397–400. Guyatt, G.H., Sackett, D.L. & Cook, D.J. for the EvidenceBased Medicine Working Group (1993) User’s guide to the medical literature. II. How to use an article about therapy or prevention. A. Are the results of the study valid? Journal of the American Medical Association 270, 2598–2601. Guyatt, G.H., Sackett, D.L. & Cook, D.J. for the EvidenceBased Medicine Working Group (1994) User’s guide to the medical literature. II. How to use an article about therapy or prevention. B. What were the results and how will they help me in caring for my patients? The evidence. Journal of the American Medical Association 271, 59–63. Hlatky, M.A., Califf, R.M., Harrell, F.E. et al. (1988) Comparison of predictions based on observational data with the results of randomised trails of coronary artery bypass surgery. Journal of the American College of Cardiology 11, 237–245. Horwitz, R.I., Viscoli, C.M., Clemens, J.D. & Sadock, R.T. (1990) Developing improved observational methods for evaluating therapeutic effectiveness. American Journal of Medicine 89, 630–638. Jadad, A., Moore, R.A., Carroll, D. et al. (1996) Assessing the quality of randomised clinical trials: is blinding necessary? Controlled Clinical Trials 17, 1–12. Paradise, J.L., Bluestone, C.D., Bachman, R.Z. et al. (1984) Efficacy of tonsillectomy for recurrent throat infection in severely affected children. Results of parallel randomised and nonrandomised clinical trials. New England Journal of Medicine 310, 674–683. Peto, R. (1987) Why do we need systematic overviews of randomised trials? Statistics in Medicine 6, 233–234.

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Pocock, S.J. (1984) Clinical Trials. A Practical Approach. Wiley, Chichester. Qizilbash, N. (1996) Clinical trials and meta-analysis. In: Epidemiology of Old Age (Ibrahim, S. & Kalache, A., eds), pp. 67–77. British Medical Journal, London. Qizilbash, N., Whitehead, A., Higgins, J., Wilcock, G., Schneider, L., Farlow, M. On behalf of the Dementia Trialists’ Collaboration (1998) Cholinesterase inhibition for Alzheimer disease: a meta-analysis of the tacrine trials. Journal of the American Medical Association 280, 1777–1782. Reisch, J.S., Tyson, J.E. & Mize, S.G. (1989) Aid to the evaluation of therapeutic studies. Paediatrics 84, 815–827.

Rothwell, P.M. (1995) Can overall results of clinical trials be applied to all patients? Lancet 345, 1616–1619. Sano, M., Ernesto, C., Thomas, R. et al. (1997) A controlled trial of selegiline, alpha-tocopherol, or both as a treatment for Alzheimer’s disease. New England Journal of Medicine 336, 1216–1222. Second International Study of Infarct Survival (ISIS-2) Collaborative Group (1988) Randomised trial of intravenous streptokinase, oral aspirin, both or neither among 17 187 patients with suspected acute myocardial infarction. Lancet ii, 349–360. US Agency Health Care Policy and Research (1992). Acute Pain Management Operative or Medical Procedures Trauma. Agency for Health Care Policy and Research Publications, Rockville, MD. (AHCPR Pub 92-0038).

Evidence-based Systematic Reviews and Meta-analyses

I.8

Nawab Qizilbash

Key points • Well-conducted individual-patient metaanalyses are trustworthy and should be used to guide practice, when based on sufficient data. • Meta-analyses based on published outcome data that are non-binary are inherently untrustworthy or add little to what is already known when individual trial results are similar. • ‘Narrative’ systematic reviews are required for outcome data that is non-binary, which incorporate meta-analyses but also review all the relevant valid evidence in context. • Meta-analyses of drugs in dementia that have not been approved through the current regulatory procedures are unlikely to provide sufficiently valid or reliable data for practice. • Meta-analyses of non-pharmacological interventions that are not adequately controlled and sufficiently blinded are unlikely to add useful precision to the results of individual trials.

Where data do not provide clear answers from sufficiently similar studies that are at variance with each other in the magnitude of effect sizes, lack of statistical significance or identification of subgroups, systematic reviews and meta-analyses may help to provide a better summary of the data. The systematic review attempts to summarize the totality of the relevant and valid evidence by reducing bias, increasing precision and helping to increase generalization. Indeed, studies of health care require relevant data to have both minimal bias (in

42

relation to the treatment effect) and to increase precision to diminish false negative results. Another benefit of systematic reviews is to examine and explain the consistency or lack of consistency of results among different studies. A systematic review is a collation of primary research studies that contains explicit objectives and methods and is conducted according to explicit or reproducible methods. The elements of a systematic review are: • Formulation of the problem/question. • Study identification: a documented (good) search strategy. • Study selection and critical appraisal: applying ‘quality’ inclusion criteria to selected studies. • Data abstraction: may be qualitative data, i.e. descriptive. • Data synthesis: may be descriptive where data are not synthesizable or are descriptive. Statistical pooling of data, combined with the preceding steps, represents meta-analysis. • Main results. • Conclusions: including implications for practice and/or research. Although systematic reviews and meta-analyses can be conducted for different types of studies, this chapter focuses on trials, as the synthesis of diagnostic and epidemiological studies is fraught with more problems. The quantitative synthesis of data (meta-analysis) from the primary studies provides a summary estimate of the overall weighted, average effect with its confidence intervals and can be tested for statistical significance. Patients in one trial are compared only with other patients in the same trial and patients are not compared or mixed

SYSTEMATIC REVIEWS 43

between trials (Peto 1987). This important principle is basic to all meta-analysis, even when dealing with individual-patient data. Patients are not analysed as though all subjects had in fact been in a single large study. The fundamental issue in pooling studies is how similar or different are the included studies. Studies need to be sufficiently similar in their designs, patients, interventions, outcomes and analyses to make for meaningful pooling. Pooling of studies which differ sufficiently in these aspects may introduce important bias. A major difference between a traditional review and a systematic review is the systematic nature in which studies are chosen and appriased. Traditional reviews are written by experts in the field who use differing and often subjective criteria to decide what studies to include and what weight to give them, and hence the conclusions are often very diverse depending on the reviewer. Publication and selection bias is a major concern of traditional reviews. If treatment produced a dramatic effect, it is likely that we would know about it. Therefore, it can be assumed that most treatments in dementia that have so far been tested produce, at best, moderate or modest benefits. Therefore, moderate biases in the methodology of the primary research and systematic review process can not be permitted. The greater precision of pooling only makes sense if the biases are small compared to the treatment effects; a tighter confidence interval around a biased point estimate is of no help whatsoever. Therefore, a ‘systematic’ review process that introduces moderate biases may serve to further confuse rather than enlighten. Systematic reviews and meta-analyses are in the ascendency. They are being increasingly used in medicine and, more recently, in dementia to make decisions about treatment, management and care, and to guide future research. They appear to have a crucial role in reimbursement decisions; organizations such as the UK National Institute of Clinical Excellence (NICE) are guided by systematic review (www.nice.org.uk). The first meta-analysis in medicine appeared in 1977 (Chalmers et al. 1977), and since then there has been burgeoning growth of this methodology (Conn 1997). In dementia, meta-analysis has been propelled by the Cochrane Dementia and Cognitive Group (Table I.8.1).

Meta-analysis appears at the head of some classification systems to assign levels of evidence (Cochrane Review Handbook 1998) and some advocate their inclusion or mention in the discussion sections of all papers relating to trials (Clarke & Chalmers 1998). Meta-analysis, the statistical synthesis of the data in a systematic review, is being used to estimate the best effects of an intervention and to decide on statistical significance and precision through confidence intervals. Yet there are substantial and growing concerns about its use. It is known that the results of meta-analyses and subsequent large single trials may not agree (LeLorier et al. 1997). It is also known that individual-patient data meta-analyses are the gold standard for metaanalyses, and are more reliable than those using data abstracted from publications and more likely to withstand the test of time (Antiplatelet Trialist’s Collaboration 1994; Clark & Godwin 1998; Early Breast Cancer Trialists’ Collaborative Group 1988). The comparability of these methods in dementia has not been systematically evaulated and reported, although systematic reviews and meta-analyses are being increasingly produced in the field of dementia. Disturbingly, a recent comparison of an individual-patient data meta-analysis and a Cochrane Dementia and Cognitive Impairment Group systematic review of tacrine showed that all the unconfounded, randomized, double-blind placebocontrolled trials, produced strikingly different results (Qizilbash et al. 1998, 2000). This is the only well-conducted individual-patient data metaanalysis that the author is aware of in dementia. Examples in other fields also exist of meta-analyses of the same trials (thereby excluding selection bias) using grouped data and individual-patient data producing disturbingly dissimilar results with binary data where time to event is an important consideration, e.g. the use of ovarian ablation in breast cancer (Clark & Godwin 1998). Reasons for the disparity in the two meta-analyses of tacrine led the author of this chapter to conclude that systematic reviews in dementia based on published or grouped ordinal or continuous data are potentially untrustworthy in rejecting the null hypothesis of no effect or in describing the magnitude of the treatment effect, and need to be inter-

Table I.8.1 Important sources of potential bias in the Cochrane reviews of dementia. Selegiline (Birks et al. 1998) Exclusion bias: Maximum number of patients used in any analysis was 315 out of a potential 833 valid patients (38%). Biggest study (Sano et al. 1997) was not pooled Design: Pooling studies with very different durations of treatment Patients: Pooling mild and severe patients Outcomes: Several scales pooled that measured very different domains of cognitive function Treatment: Fairly standard across studies Analyses: All analyses were completer’s analyses and not ITT Heterogeneous studies were pooled. No mention of testing for heterogeneity Many analyses performed with no correction for multiple testing Recommendations: For practice: For research: Comment: The pooled results are unreliable and may be severely biased Any individual-patient data meta-analysis needs to include the vast majority of the valid data No NNT or NNH provided to guide practice See Chapter V.2.19 for a narrative systematic review Update: Most recent amendment August 1998 Donepezil (Birks et al. 1999) Exclusion bias: 818 out of 1920 (42%) patients were excluded from the pooled analyses Design: Pooling studies with very different durations of treatment: 12 weeks and 24 weeks Patients: No source of potential bias Outcomes: No source of potential bias Treatment: No source of potential bias Analyses: No source of potential bias. These analyses are likely to be less sensitive than analyses using individual patient data which can use multi-level models with repeat measurement data Recommendations: For practice—none given, perhaps as the authors were not clinicians For research—longer trials with more clinically meaningful endpoints in more representative patient populations Comment: The results of the individual trials were so similar and positive that nothing new came out of this systematic review that was not already known Subgroups of patients were not investigated The effect sizes from the meta-analysis may have sacrificed bias for precision by pooling effects at 12 and 24 weeks. Therefore, the larger trials may be more trustworthy than this review for determining effect sizes Individual-patient data meta-analysis needs to be performed to add anything to inspecting the individual trials in this situation with such high homogeneity No NNT or NNH provided to guide practice See Chapter V.2.4 for a narrative systematic review Update: Most recent amendment August 1998 DHEA (Huppert et al. 1998) Exclusion bias: The four included studies comprised 168 subjects. Excluded subjects comprised 56 (25%) in three studies Design: Different types of studies—randomized controlled trials and matched groups. Studies with very different durations of treatment—less than 2 weeks up to 3 months. Data from all treatment phases of cross over trials eligible for inclusion Patients: Pooling very different populations—dementia or any type of cognitive impairment mentioned in methods section. In the table of included studies none had a diagnosis and, therefore, were normal individuals Outcomes: Several scales pooled that measured very different domains of cognitive function Treatment: DHEA vs. placebo; DHEA vs. other drug; DHEA vs. no treatment Analyses: Unclear what was done Recommendations: For practice—none given For research—longer and larger trials with validated psychological measures Comment: There is clear heterogeneity in the methods of this systematic review as well as the trials included The results and conclusions of this review are unreliable No mention of DHEA being used widely for its supposed benefits in vascular disease. Update: Most recent amendment August 1998 Depression trials (also) to be added to the review Aspirin for VaD (Williams et al. 1999) Exclusion bias: Not applicable—only one study eligible Design: Non-randomized study was included although eligibility criteria stated that randomization was required. Single blind Patients: Not applicable—only one study eligible Outcomes: Not applicable—only one study eligible Treatment: Control without placebo Analyses: Dropouts were replaced in the original trial and number of dropouts unclear. No ITT analysis Recommendations: For practice—none given For research—randomized double blind placebo controlled trial for cognition and other outcomes (though problems of such a trial were acknowledged)—see Chapter V.3.3 for fuller discussion Comment: Is a meta-analysis of one trial a meta-analysis? The results of the ‘meta-analysis’ are unreliable See Chapter V.3.3 for a narrative systematic review of antithrombotics in VaD Update : Most recent amendment February 1999 DHEA, dihydroepiandrosterone; ITT, intention to treat; NNH, number needed to harm; NNT, number needed to treat; VaD, vascular dementia.

SYSTEMATIC REVIEWS 45

preted extremely carefully. The main sources of important potential bias were: 1 Exclusion bias due to only a small proportion of the relevant and valid data being used in the meta-analysis. That the review was ‘systematic’ in its methods of study identification, selection, applying quality criteria for inclusion and use of a pre-specified analysis plan, is no reassurance against the introduction of bias, when so many of the studies and data cannot be used because the reporting was inadequate for pooling in the original publications. 2 Pooling data from studies with different designs: different patients, interventions, durations and outcomes. 3 Limited intention-to-treat analyses, because of the non-binary nature of most of the outcomes, with reliance on a completor’s analysis, may introduce bias (Schulz et al. 1995). 4 Inability to use multilevel models from repeated measures to analyse the data will reduce the precision of the estimates. 5 Subgroup analyses were not possible. 6 Pooling studies with very different results. Different study results may have arisen because of differences in design, patients, manner in which the interventions were administered, outcomes and analysis. Unless the reason for the heterogeneity in the results can be found and adjusted for, some people suggest that it is inappropriate to pool the data from such a collection of studies (Thompson & Pocock 1991). The use of so-called ‘random effect models’ does not overcome this problemait is the equivalent of saying that three pears and four apples equal seven pear-apples. Richard Peto, for example, believes that random effect models are inappropriate because of the assumptions involved (Peto 1987). 7 Pooling results from different scales. New guidelines to improve the quality of metaanalyses (Moher et al. 1999) are unlikely to help with many of these problems. Other potential problems are: 1 Inability to adjust for differences in important covariates at baseline. 2 Publication bias (Weber et al. 1998). 3 Duplication of reports, often in favor of more positive studies (Tramer et al. 1997).

4 Play of chance in observing differences from comparisons that were not pre-specified. Critical appraisal is as necessary to systematic review as it is to an individual trial, and it is disappointing that no validated scoring system exists for grading the quality of systematic reviews. Cochrane reviews are considered to be of higher quality than other meta-analyses based on criteria used by members of the Cochrane Collaboration (Jadad et al. 1998; Jadad et al. 2000; Schwarzer et al. 1999) and are increasingly preferred to other reviews by doctors in other fields (McDonald et al. 1999). However, non-Cochrane meta-analyses have been more influencial in changing practice than Cochrane Dementia and Cognitive Impairment Group reviews (e.g. Antiplatelet Trialist’s Collaboration 1994; Early Breast Cancer Trialists’ Collaborative Group 1988). Given the trend to additionally publish Cochrane reviews in traditional journals their influence, through wider readership and implementation, may increase and form a benchmark for other reviews. Therefore, a review of the Cochrane Dementia and Cognitive Impairment Group systematic reviews in demen-tia was undertaken (Qizilbash & Schneider 2000). Appendix I.8.1 (p. 49) reviews each individual systematic review of the Cochrane Dementia and Cognitive Impairment Group, in terms of important sources of potential bias, a commentary on the context, and provides the main results, conclusions and recommendations of each review Table I.8.1). As the Cochrane Dementia and Cognitive Impairment Group updates its systematic reviews, the website of this book will also be updated to take account of any important changes. It can be seen from Appendix I.8.1 that issue 4 (2000) of the Cochrane Library has systematic reviews in dementia that all harbor important sources of bias. One of the most disconcerting problems is the degree of potential exclusion bias, which overshadows the concern with publication bias. Also, in clear cases of efficacy, such as with donepezil, a systematic review is not needed to demonstrate that the drug is efficacious as the trials are so homogenous. Moreover the Cochrane Dementia and Cognitive Impairment Group’s systematic review of donepezil cannot be relied upon to provide improved unbiased point estimates, the subgroup analyses do not tell us anything that we

46 CHAPTER I.8

did not know before, nor does it give information on how to use the medication, as none of the authors were clinicians involved in the care of individual patients (Birks & Melzer 2000). Experience as the founder of the Cochrane Dementia and Cognitive Impairment Group has led the author of this chapter to the view that what is required for trustworthy results and conclusions are individual-patient data meta-analyses. Where systematic reviews in dementia are from relatively small and diverse trials with mostly non-binary data and where an individual-patient data metaanalysis does not exist, the ‘narrative’ systematic review of the individual trials should be given more weight. In such cases, individual trials may be as, if not more, reliable than a systematic review (Bailer 1997; Flather et al. 1997). For tacrine, the comparison of the largest trial (Knapp et al. 1994) with the Cochrane Dementia and Cognitive Impairment Group review and with the individual-patient data meta-analysis suggests that the largest trial was more trustworthy than the Cochrane Dementia and Cognitive Impairment Group review in agreeing with the individual-patient data meta-analysis. If individual-patient data are not available for meta-analysis of non-binary data, the best that can be done is a ‘narrative’ systematic review, in which all relevant trials on a particular specific topic are discussed by comparing and contrasting the trial designs, patients, interventions, outcomes, analyses and results. This will also better help to guide future trial design (Chapter IV.5.3). Many of the chapters in this book attempt to take this approach and are written by experts knowledgeable in various aspects of dementia, from diagnosis to treatment to epidemiology and pathology. They also use previous meta-analyses within their ‘narrative’ systematic review, bearing in mind their limitations. For example, the chapter reviewing tacrine in Alzheimer’s disease, does not use the Cochrane Dementia and Cognitive Impairment Group review of tacrine (Qizilbash et al. 2000) but relies totally on the individual-patient data metaanalysis of tacrine (Qizilbash et al. 1998), which was co-written with input from investigators of all the included trials. Cochrane reviews, by contrast, are written by people who have often not had involvement in the original trials. The Cochrane

Dementia and Cognitive Impairment Group review of hydergine (Olin et al. 2000) does not really add anything to the earlier meta-analysis of hydergine published by the same authors (Schneider et al. 1994). The systematic narrative review of rivastigmine in this book (Chapter V.2.7) is helpful to practising clinicians and provides the number needed to treat (NNT), which are absent from the Cochrane Dementia and Cognitive Impairment Group systematic review of rivastigmine. It is not too extreme to say that judging by the results of the 21 reviews completed by the Cochrane Dementia and Cognitive Impairment group (in the Cochrane Library, 2000, issue 4) and the systematic narrative reviews contained in this book, it is unlikely that any new important information will emerge from attempting to pool grouped data from publications of interventions that are already in existence, because of the many problems mentioned above and the impossibility of acquiring individual-patient data from old or poorly analysed trials. It is highly likely that all judgements from these efforts will continue to state that either there is no convincing evidence of benefit (or harm) or that more data are needed. What is really needed are new data from larger and well-conducted randomized controlled trials, which can then be pooled using individual-patient data, as is currently taking place with some of the recently approved drugs. This is the major challenge that faces the evalution of interventions in dementia today, and yet the means of answering the important questions reliably is already well established in other areas of medicine (Chapter IV.5.3). Although the website accompanying this book will be updated with important new information from Cochrane reviews in dementia, it is unlikely that much will significantly change, especially the conclusions. Several of the Cochrane dementia reviews mention updates with individual patient data. However, given the complexity of conducting individual patient meta-analyses, it is likely that they will be published in mainstream journals and also funded and conducted outside of the Cochrane Dementia and Cognitive Impairment Group, as was done with the tacrine individual patient metaanalysis (Qizilbash et al. 1998). Also, it would appear that the individual patient data from trials

SYSTEMATIC REVIEWS 47

conducted by companies and submitted to regulatory authorities for licensing would provide the optimum place for the assessment of what drugs actually do. Drugs are approved and provided with certain labeling claims based on the data. Metaanalyses conducted by certain regulatory authorities, though not published, provide evidence that is wholly consistent with information on the label. Therefore, meta-analyses conducted by the Cochrane Dementia and Cognitive Impairment Group and other groups, without individual patient data, will be far inferior in addressing questions answerable from the data to those conducted internally by regulatory authorities. The issue is that these trials are not collecting the most relevant endpoints, but it does not take a meta-analysis to establish this omission. Another issue that has been raised is that the meta-analyses conducted by the regulatory authorities should be made public and accessible so that issues for which no unique solution exists, such as dealing with dropouts, can be discussed in a public debate. The magnitude of the benefits for various outcomes could also be produced. Regulatory authorities use several methods to explore the influence of dropouts: intention to treat (ITT) with last observation carried forward, completer’s analysis, ITT with retriever dropouts, modeling dropouts with remaining placebo decline, assessing dropouts at varying times during the trial to evaluate if there is differential withdrawal from the treatment and control groups. None of these issues can be addressed by the Cochrane dementia reviews without access to individual patient data, nor in any up-dates. Finally, Cochrane dementia reviews often provide little practical guidance for clinicians in the absence of perfect evidenceathis may be because some of the reviews are conducted wholly by people who are not clinicians.

Conclusions Well-conducted individual-patient data metaanalyses are the only type of meta-analyses that are trustworthy in dementia, where most outcomes are non-binary in nature. Meta-analyses based on published or grouped non-binary data in dementia are inherently untrustworthy. The introduction of moderate bias due to the methods used in conduct-

ing meta-analyses with grouped or published data is not worth the increased precision. Indeed metaanalyses may actually produce more confusion and error by giving spurious precision to results that appear different due to bias, especially subgroup analyses. If individual-patient data are not available for meta-analysis of non-binary data, the best that can be done is a ‘narrative’ systematic review, in which all relevant trials on a particular specific topic are discussed by comparing and contrasting the designs, patients, interventions, outcomes, analyses and results. This assessment will also better help guide future trials. Many of the chapters in this book attempt to take this approach and are written by experts who are knowledgeable in various aspects of dementia, ranging from treatment to diagnosis to epidemiology. They also use meta-analyses or other systematic reviews, bearing in mind their limitations. Furthermore, the deficiences of each Cochrane Dementia and Cognitive Impairment Group systematic review are tabulated in Appendix I.8.1 and will be updated on the website should there be significant changes to the review. However, the value of older pharmacological and non-pharmacological therapies is in great doubt, indicating that their benefits are not self-evident and hence, at best, are moderate, necessitating minimal bias in the conduct of a meta-analysis. Given the inherent problems of past trials (Chapter IV.5.3) and the problems in collating the raw data from them, it is likely that all old pharmacological therapies used in dementia or cognitive impairment which have not secured regulatory approval under modern guidelines, will never be reliably evaluated with meta-analysis, unless individual-patient data are made available, and this is very unlikely, except in rare cases. The use of older therapies is also diminishing rapidly as new drugs are approved under modern regulatory guidelines. Therefore, it may be more efficient to now draw a line and say that there is no robust evidence (nor is any likely to appear from old data) to recommend the use of older pharmacological therapies for dementia or cognitive impairment, and that they should instead be replaced with newer approved therapies with proven efficacy and good safety profiles. Efforts should be concentrated on designing and conducting trials which can reliably

48 CHAPTER I.8

answer important questions which are not being addressed under the current regulatory approval system (Chapter IV.5.3). This conclusion applies as much, if not more, to many non-pharmacological interventions in dementia. Meta-analyses not based on individual patient data in dementia are only likely to help the researcher, and not the practitioner. A 2-day Drug Information Agency workshop on Large Simple Trials in Neuroscience, chaired by Robert Temple (FDA), Stuart Pocock (London School of Hygiene) and Nawab Qizilbash (Oxford) in April 2001, discussed this topic for dementia, depression and schizophrenia. A summary of the proceedings of this workshop will be provided on the website of this book.

References Antiplatelet Trialist’s Collaboration (1994) Collaborative overview of randomised trials of antiplatelet therapy. Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. British Medical Journal 308, 81–106. Bailer, J.C. (1997) The promise and problems of metaanalysis. New England Journal of Medicine 337 (8), 559. Birks, J.S. & Melzer, D. (2000) Donepezil for mild and moderate Alzheimer’s disease (Cochrane Review). In: Cochrane Library, issue 4. Update Software, Oxford. Birks, J. & Flicker, L. (2000) Selegiline for Alzheimer’s disease (Cochrane Review). In: Cochrane Library, issue 4. Update Software, Oxford. Chalmers, T.C., Matta, R.J., Smith, H. Jr & Kunzler, A.M. (1977) Evidence favoring the use of anticoagulants in the hospital phase of acute myocardial infarction. New England Journal of Medicine 297, 1091–1096. Clark, M. & Godwin, J. (1998) Systematic reviews using individual patient data: a map for the minefields? Annals of Oncology 9, 827–833. Clarke, M. & Chalmers, I. (1998) Discussion sections in reports of controlled trials published in general medical journals: islands in search of continents? Journal of the American Medical Association 280 (3), 280–282. Cochrane Review Handbook (1998) In: Cochrane Library, issue 4. Update Software, Oxford. Conn, H.O. (1997) Intepretation of data from multiple trials: a critical review. Journal of Internal Medicine 241 (3), 177–183. Early Breast Cancer Trialist’s Collaborative Group (1988) Effects of adjuvant tamoxifen and of cytoxic therapy on mortality in early breast cancer: an overview of 61 randomised trials among 28 896 women. New England Journal of Medicine 319, 1681–1692.

Fioravanti, M. & Yanagi, M. (2000) Cytidinediphosphocholine for cognitive and behavioural disturbances associated with chronic cerebral disorders in the elderly (Cochrane Review). In: Cochrane Library, issue 4. Update Software, Oxford. Flather, M., Farkouh, M.E., Pogue, J.M. & Yusuf, S. (1997) Strengths and limitations of meta-analysis: larger studies may be more reliable. Controlled Clinical Trials 18 (16), 568–579 (with discussion 661–666). Flicker, L. & Evans, J.G. (2000) Piracetam for dementia and cognitive impairment (Cochrane Review). In: Cochrane Library, issue 4. Update Software, Oxford. Higgins, J.P.T. & Flicker, L. (2000) Lecithin for dementia and cognitive impairment (Cochrane Review). In: Cochrane Library, issue 4. Update Software, Oxford. Huppert, F.A., Van Niekerk, J.K. & Herbert, J. (2000) Dehydroepiandrosterone (DHEA) supplementation for cognition and well-being (Cochrane Review). In: Cochrane Library, issue 4. Update Software, Oxford. Jadad, A., Cook, D., Jones, A. et al. (1998) Methodology and reports of systematice reviews and meta-analyses: a comparison of Cochrane reviews with articles published in paper-based journals. Journal of the American Medical Association 280 (3), 278–280. Jadad, A.R., Moher. M., Browman, G.P. et al. (2000) Systematic reviews and meta-analyses on treatment of asthma: critical evaluation. British Medical Journal 320, 537–540 Kirchner, V., Kelly, C.A. & Harvey, R.J. (2000) Thioridazine for dementia (Cochrane Review). In: Cochrane Library, issue 4. Update Software, Oxford. Knapp, M.J., Knopman, D.S., Solomon, P.R., Pendlebury, W.W., Davis, C.S. & Gracon, S.I. for the Tacrine Study Group (1994) Controlled trials of high-dose tacrine in patients with Alzheimer’s disease. Journal of the American Medical Association 271, 985–991. Koger, S.M. & Brotons, M. (2000) Music therapy for dementia symptoms (Cochrane Review). In: Cochrane Library, issue 4. Update Software, Oxford. LeLorier, J., Gregoire, G., Benhaddad, A., Lapierre, J. & Derderian, F. (1997) Discrepancies between metaanalyses and subsequent large randomized, controlled trials. New England Journal of Medicine, 337 (8), 536. Lopez-Arrieta, J.M., Rodriguez-Martin, J.L., Sanz, F. (2000) Nicotine for Alzheimer’s disease (Cochrane Review). In: Cochrane Library, issue 4. Update Software, Oxford. McDonald, J.W.D., Mahon, J., Zarnke, K., Feagan, B., Simms, L. & Tucker, W. (1999) A randomized trial of the preference of gastroenterologists for a Cochrane review versus traditional reviews. B33. The VII Cochrane Colloquium, Rome. Moher, D., Cook, D.J., Eastwood, S., Olkin, I., Rennie, D. & Stroup, D.F. for the QUOROM Group (1999) Improving the quality of reports of meta-analyses of randomised controlled trials: the QUOROM statement. Lancet 354, 1896–1900. Neal, M. & Briggs, M. (2000) Validation therapy for dementia (Cochrane Review). In: Cochrane Library, issue 4. Update Software, Oxford.

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Olin, J., Schneider, L., Novit, A. & Luczak, S. Hydergine for dementia (Cochrane Review). In: Cochrane Library, issue 4. Update Software, Oxford. Price, J.D., Hermans, D.G. & Grimley Evans, J.G. (2000) Subjective barriers to prevent wandering of cognitively impaired people. (Cochrane Review). In: Cochrane Library, issue 4. Update Software, Oxford. Qizilbash, N., Lopez-Arrieta, J.L. & Birks, J. (2000) Nimodipine for primary degenerative, mixed and vascular dementia (Cochrane Review). In: Cochrane Library, issue 4. Update Software, Oxford. Qizilbash, N., Birks, J., Lopez-Arrieta, J., Lewington, S. & Szeto, S. (2000) Tacrine in Alzheimer’s disease (Cochrane Review). In: Cochrane Library, issue 4. Update Software, Oxford. Qizilbash, N., Whitehead, A., Higgins, J., Wilcock, G., Schneider, L. & Farlow, M. on behalf of the Dementia Trialists’ Collaboration (1998) Cholinesterase inhibition for Alzheimer’s disease: meta-analysis of 12 trials of tacrine with 1984 patients. Journal of the American Medical Association 280, 1777–1782. Qizilbash, N. & Schneider, L. (2000) Can meta-analysis be trusted in dementia? Seventh Conference of the Alzheimer’s Disease and Related Disorders Assocation. Washington, July 2000. Peto, R. (1987) Why do we need systematic overviews of randomized trials? Statistics in Medicine 6, 233–240. Rodriguez-Martin, J.L., Lopez-Arrieta, J.M. & Qizilbash, N. (2000) Thiamine for Alzheimer’s disease (Cochrane Review). In: Cochrane Library, issue 4. Update Software, Oxford. Schulz, K.F., Chalmers, I., Hayes, R.J. & Altman, D.G. (1995) Empirical evidence of bias. Dimensions of methodological quality associated with estimates of treatment effects in controlled trials Journal of the American Medical Association 273 (5), 408–412. Sano, M., Ernesto, C., Thomas, R.G. et al. (1997) A controlled trial of selegiline, alpha tocopherol, or both as treatment for Alzheimer’s disease. New England Journal of Medicine 336, 1216–1222. Schwarzer, G., Egger, M., Tallon, D., Sterne, J. & Antes, G. (1999) A comparison of Cochrane reviews with metaanalyses published in high impact journals. B50. The VII Cochrane Colloquium, Rome. Schneider, L.S., Olin, J.T. (1994) Overview of clinical trials of hydergine in dementia. Archives of Neurology 51 (8), 787–798. Spector, A., Orrell, M., Davies, S. & Woods, R.T. (2000a) Reality orientation for dementia (Cochrane Review). In: Cochrane Library, issue 4. Update Software, Oxford. Spector, A., Orrell, M., Davies, S. & Woods, R.T. (2000b) Reminscence therapy for dementia (Cochrane Review). In: Cochrane Library, issue 4. Update Software, Oxford. Thompson, C., Briggs, M. (2000) Support for carers of people with Alzheimer’s type dementia. (Cochrane Review). In: Cochrane Library, issue 4. Update Software, Oxford. Thompson, S.G. & Pocock, S.J. (1991) Can meta-analyses be trusted? Lancet 338, 1127–1130.

Tramer, M.R., Reynolds, D.J., Moore, R.A. & McQuay, H.J. (1997) Impact of covert duplicate publication on meta-analysis: a case study. British Medical Journal 315 (7109), 635–640. Weber, E., Callaham, M., Wears, R., Barton, C. & Young, G. (1998) Unpublished research from a medical specialty meeting: why investigators fail to publish. Journal of the American Medical Association 280 (3), 257–259. Williams, P.S., Spector, A., Orrell, M. & Rands, G. (2000) Aspirin for vascular dementia (Cochrane Review). In: Cochrane Library, issue 3. Update Software, Oxford.

Appendix I.8.1 Cochrane Dementia and Cognitive Impairment Group Reviews Cochrane dementia reviews: main results, conclusions and recommendations and important sources of potential bias (updated on website).

Drug interventions Tacrine for AD (Qizilbash et al. 2000) Exclusion bias: 13 out of 18 trials were excluded from the pooled analyses Design bias: Pooling studies with very different durations of treatmenta6 weeks and 6 months Patient bias: No source of potential bias Outcome bias: Specific primary and secondary outcomes were not pre-specified in the protocol. Treatment bias: No source of potential bias Analytic bias: Inadequate accounting for loss to follow-up that could introduce potential bias. ITT analyses could not be performed for pooling These analyses are likely to be less sensitive than analyses using individual-patient data which can use multilevel models with repeat measurement data Main results and conclusions: results compatible with no improvement, no change or harm from treatment Inconclusive evidence for changes on overall clinical improvement, behavioral disturbance and Mini Mental Status Examination (MMSE). Statistically significant benefit on ADAS-Cog Odds ratio for withdrawal 5.7 (95% confidence interval [CI] 4.1–7.9) Review limited by inadequacies of published data suitable for pooling

50 CHAPTER I.8

Recommendations: • For practice: not recommended • For research: longer trials needed with more clinically meaningful endpoints in more representative patient populations Comment: The results of the individual trials were dissimilar but this systematic review could only highlight the side effects and issues for further research, and could not help to provide better information than that which already existed Subgroups of patients could not be investigated The effect sizes from the meta-analysis may have sacrificed bias for precision by pooling effects at different durations; therefore, the larger trials may be more trustworthy than this review for determining effect sizes Individual patient data meta-analysis needed to be performed to add anything to inspecting the individual trials in this situation. This was done (including use of the first treatment period in crossover trials) and published in the Journal of the American Medical Association (Qizilbash et al. 1998), and came to disturbingly different conclusions to this review No NNT or NNH provided to guide practice See Chapter V.2.8 for a narrative systematic review and Chapter V.2.21 for comparison with other cholinesterase inhibitors Update: Most recent amendment November 1998

Selegiline for AD (Birks & Flicker 2000) Exclusion bias: Maximum number of patients used in any analysis was 315 patients out of a potential 833 valid patients (38%). Biggest study not pooled (Sano et al. 1997) Design bias: Pooling studies with very different durations of treatment Patient bias: Pooling mild and severe patients Outcome bias: No specific primary and secondary outcomes were specified. Several scales pooled which measured very different domains of cognitive function Treatment bias: Pretty standard across studies

Analytic bias: All analyses were completer’s analysis and not ITT Heterogeneous studies were pooled; no mention of testing for heterogeneity Many analyses performed, with no correction for multiple testing Main results and conclusions: Benefits on memory function and behavior No benefit on global ratings Few withdrawal from adverse effects Review limited by inadequacies of published data suitable for pooling Recommendations: • For practice: not recommended • For research: trials in AD using standardized cognitive scales, clinician impression of global change, dependency and care giver quality of life Comment: The pooled results are unreliable and may be severely biased Any individual patient data meta-analysis needs to include the vast majority of the valid data No NNT or NNH provided to guide practice See Chapter V.2.19 for a narrative systematic review and Chapter V2.21 for long-term effects and clinical guidance Update: Most recent amendment August 1998

Donepezil for AD (Birks & Melzer 2000) Exclusion bias: 1 out 8 trials were excluded from the pooled analyses Design bias: None (analyses separated by duration) Patient bias: No source of potential bias Outcome bias: Specific primary and secondary outcomes were not prespecified in the protocol Treatment bias: None (analyses separated by dose) Analytic bias: Inadequate accounting for loss to follow-up that could introduce potential bias These analyses are likely to be less sensitive than analyses using individual patient data which can use multilevel models with repeat measurement data Main results and conclusions: Benefits on cognition and clinical global change Inconclusive evidence for function, patient quality of life

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Withdrawal from adverse effects was higher with a higher dose of 10 mg/day Review limited by inadequacies of published data suitable for pooling Recommendations: • For practice: none provided • For research: longer trials needed in more representative patients with more clinically meaningful endpoints Comment: The results of the individual trials were so similar and positive that the quantitative analysis added little to what had been concluded by regulatory authorities (FDA, EMEA and others) and stated in the product label Subgroups of patients were not investigated Calls for patient quality of life outcome measures are premature and likely to be unrealistic Meta-analysis limited by lack of available data. The larger trials may be more trustworthy than this meta-analysis review for determining effect sizes With such high homogeneity, individual patient data meta-analysis needs to be performed to add anything to inspecting the individual trials in this situation No NNT or NNH provided to guide practice See Chapter V.2.4 for a narrative systematic review and Chapter V.2.21 for comparison with other cholinesterase inhibitors and clinical guidance Update: Most recent amendment August 2000

DHEA supplementation for cognition and well-being (Huppert et al. 2000) Exclusion bias: Four studies comprised 168 subjects; excluded subjects comprised 56 (25%) in three of the studies Design bias: Different types of studiesarandomized controlled trials and matched groups. Studies with very different durations of treatmentaless than 2 weeks to 3 months. Data from all treatment phases of cross-over trials eligible for inclusion Patient bias: Pooling very different populationsa dementia or any type of cognitive impairment mentioned in methods section. In the table of included

studies some subjects had no diagnosis, and, therefore, were normal individuals Outcome bias: Several scales were pooled that measured very different domains of cognitive function Treatment bias: DHEA vs. placebo; DHEA vs. other drug; DHEA vs. no treatment Analytic bias: Unclear what was done Main results and conclusions: Benefits on wellbeing in a 3 month study only No benefits on cognition or libido Absence of significant side-effects mentioned (no figures provided) Recommendations: • For practice: none given • For research: longer and larger trials needed with validated psychological measures Comment: There is clear heterogeneity in the methods of this systematic review as well as in the trials included The results and conclusions of this review are unreliable There is no mention of DHEA being used widely for its supposed benefits in vascular disease Update: Most recent amendment August 1998. Depression trials (also) to be added to the review

Aspirin for VaD (Williams et al. 2000) Exclusion bias: Not applicableano study eligible Design bias: None Patient bias: None Outcome bias: None Treatment bias: None Analytic bias: None Main results and conclusions: Withdrawal from adverse effects Review limited by inadequacies of published data suitable for pooling Recommendations: • For practice: none given • For research: randomized double-blind placebocontrolled trial for cognition and other outcomes (though problems of such a trial were acknowledged). See Chapters V.3.2 and V.3.12 for fuller discussion

52 CHAPTER I.8

Comment: Is a systemic review of no trials a systemic review? See Chapters V3.2 and V3.12 for a narrative systematic review of antithrombotics in VaD Update: Most recent amendment August 2000

Vitamin E for AD (Birks & Flicker 2000) Exclusion bias: Not applicableaonly one study eligible Design bias: None Patient bias: Not applicableaonly one study eligible Outcome bias: Not applicableaonly one study eligible Treatment bias: None Analytic bias: Completer’s analysis only No allowance for time to event Main results and conclusions: Benefits on the primary combined endpoint Excess of falls Withdrawal from adverse effects small Review limited by inadequacies of published data suitable for pooling Recommendations: • For practice: insufficient evidence. No advice given • For research: more trials Comment: Is a meta-analysis of one trial a metaanalysis? This is really just an assessment/commentary of one trial, which was done in the New England Journal of Medicine editorial (Drachmann & Leber 1997) The results of the ‘meta-analysis’ are unreliable See Chapters V.2.3 and V.2.21 for a narrative systematic review and clinical guidance Update: Most recent amendment August 2000

Piracetam for dementia or cognitive impairment (Flicker & Evans 2000) Exclusion bias: Maximum of six out of 26 trials were excluded in any one pooled analysis

Design bias: Pooling studies with very different durations of treatmenta12 weeks and 1 year Patient bias: Wide variety of diagnoses of cognitive decline used: AD, VaD, mixed dementia and cognitive decline Outcome bias: Specific primary and secondary outcomes were not pre-specified in the protocol. Widely different scales within each outcome domain were pooled Treatment bias: Ten-fold difference in doses in the different trials (2.4 g/day to 24 g/day) Analytic bias: Inadequate accounting for loss to follow-up that could introduce potential bias ITT analysis could not be conducted Studies with heterogenous results were pooled Multiple comparisons not pre-specified and allowed for These analyses are likely to be less sensitive than analyses using individual patient data which can use multilevel models with repeat measurement data Main results and conclusions: Benefits on global impression of changeaodds ratio of 3.5 (95%CI, 1.01–9.3) Inconclusive evidence on cognition or other measures Withdrawal from adverse effects not reported Review limited by inadequacies of published data suitable for pooling Recommendations: • For practice: not recommended • For research: another trial with modern diagnostic criteria of AD or VaD using ADAS-Cog and Clinician Global Impression of Change as primary measures, and dependency and care giver quality of life, lasting at least 6 months Comment: The individual trials were so different and the meta-analysis was so limited that nothing could be confidently concluded Subgroups of patients were not investigated The effect sizes from the meta-analysis may have sacrificed bias for precision; therefore, the larger trials may be more trustworthy than this review for determining effect sizes Individual patient data meta-analysis needs to be performed to add anything to inspecting the individual trials in this situation with such high clinical and statistical heterogeneity No NNT or NNH provided to guide practice

SYSTEMATIC REVIEWS 53

See Chapter V.2.17 for a narrative systematic review that provides the same conclusion. Update: Most recent amendment October 1998

Cytidinediphosphocholine for cognitive and behavioral disturbances associated with chronic cerebral disorders in the elderly (Fioravanti & Yanagi 2000) Exclusion bias: Maximum of eight out of 12 trials were used for any pooled analyses; many pooled analyses used far fewer Design bias: Pooling studies with very different durations of treatmenta20 days and 3 months Patient bias: Various diagnosesaincluding primary dementia, ‘subjective memory complaints’ and ‘unspecified cognitive impairment’, as well as primary dementia and chronic cerebrovascular disorders Outcome bias: Specific primary and secondary outcomes were not pre-specified in the protocol. Different memory scales were pooled Treatment bias: Ten-fold difference in dose (100 mg/day and 1000 mg/day) Analytic bias: Inadequate accounting for loss to follow-up that could introduce potential bias ITT analysis not possible Post-hoc removal of studies that were different from pooling Pooling of studies with heterogeneous results These analyses are likely to be less sensitive than analyses using individual patient data which can use multilevel models with repeat measurement data Inappropriate use of Peto odds ratio for a risk ratio of 8.89 for clinical global change Main results and conclusions: Benefits on clinical global impression, memory and behavior No benefits on attention Withdrawal from adverse effects were significantly less from the drug than from placebo Review limited by duration of studies Recommendations: • For practice: none given • For research: longer trials with current diagnostic criteria

Comment: The results and designs of the individual trials were so different that pooling is not appropriate Subgroups of patients could not be investigated The effect sizes from the meta-analysis may have sacrificed bias for precision by pooling effects at different durations and with different diagnoses; therefore, the larger trials may be more trustworthy than this review for determining effect sizes That withdrawal from adverse effects were significantly less from the drug than from placebo highlights the unreliability of the meta-analysis Individual patient data meta-analysis needs to be performed to add anything to inspecting the individual trials in this situation with such high homogeneity No NNT or NNH provided to guide practice See Chapter V.3.5 for a narrative systematic review Update: Most recent amendment August 2000

Hydergine for dementia (Olin et al. 2000) Exclusion bias: Maximum of 12 out of 19 trials were used for pooled analyses. However, very many other valid trials were excluded because of inadequate published data for pooling Design bias: Pooling studies with very different durations of treatmentaless than 10 weeks and greater than 23 weeks One trial included was confounded with multivitamins and potassium Patient bias: Various diagnosesaprimary dementia, AD, VaD, cerebral deterioration, cerebral insufficiency Outcome bias: Different comprehensive rating, global function scales and neuropsychological tests were pooled Treatment bias: Different doses (1.5–7.5 mg/day) and some trials had changing doses Analytic bias: Inadequate accounting for loss to follow-up that could introduce potential bias ITT analysis was not possible Pooling of studies with heterogeneous results These analyses are likely to be less sensitive than analyses using individual patient data which can use

54 CHAPTER I.8

multilevel models with repeat measurement data Main results and conclusions: Benefits on global and comprehensive ratings associated with younger age No benefits on attention Withdrawal from adverse effects not reported Review limited by inadequacies of published data suitable for pooling Recommendations: • For practice: benefits to at 4.5–9 mg/day, with possibly greater benefits to younger subjects and inpatients • For research: longer trials with current diagnostic criteria using higher doses (9 mg/day) Comment: Results similar to a systematic review conducted by same principal authors several years previously (Schneider & Olin 1994). See Chapter V.2.12 for a narrative systematic review The results and designs of the individual trials were so different that pooling is not appropriate The many subgroups investigated could not be reliably assessed due to the small numbers of patients available The effect sizes from the meta-analysis may have sacrificed bias for precision by pooling effects at different durations and with different diagnoses; therefore, the larger trials may be more trustworthy than this review for determining effect sizes Individual patient data meta-analysis needs to be performed to add anything to inspecting the individual trials in this situation with such high heterogeneity No NNT or NNH provided to guide practice See Chapter V.3.5 for a narrative systematic review Update: Most recent amendment July 1999

Lecithin for dementia and cognitive impairment (Higgins & Flicker 2000) Exclusion bias: Maximum of three out of 12 trials were used for pooled analysis Design bias: Pooling studies with very different durations of treatmenta1 week to 2 years One trial included was confounded with multivitamins and potassium Patient bias: Various severities of AD

Outcome bias: Different scales within the domains assessed were pooled Treatment bias: Different doses (1–25 g/day) Analytic bias: Inadequate accounting for loss to follow-up that could introduce potential bias ITT analysis not possible Pooling of studies with heterogeneous results These analyses are likely to be less sensitive than analyses using individual patient data which can use multilevel models with repeat measurement data Main results and conclusions: No benefits found on any outcome Withdrawal from adverse effects were six-fold greater in the treated group (95%CI 1.5–24) Review limited by inadequacies of published data suitable for pooling Recommendations: • For practice: no evidence to support use • For research: little priority for future research Comment: The results and designs of the individual trials were so different that pooling is not appropriate The effect sizes from the meta-analysis may have sacrificed bias for precision by pooling effects at different durations and with different diagnoses; therefore, the larger trials may be more trustworthy than this review for determining effect sizes Individual patient data meta-analysis needs to be performed to add anything to inspecting the individual trials in this situation with such high homogeneity Update: Most recent amendment May 1998

Nimodipine for primary degenerative, mixed and VaD (Qizilbash et al. 2000) Exclusion bias: Maximum of two out of 10 trials were used for pooled analysis Design bias: Pooling studies with very different durations of treatmenta4 weeks to 6 months Patient bias: Various categories of dementiaaAD, vascular and mixed dementia Outcome bias: Different scales within the domains assessed

SYSTEMATIC REVIEWS 55

Treatment bias: None (all pooled trials used 90 mg/day) Analytic bias: Inadequate accounting for loss to follow-up that could introduce potential bias ITT analysis not possible These analyses are likely to be less sensitive than analyses using individual patient data which can use multilevel models with repeat measurement data Main results and conclusions: Inconclusive evidence on overall clinical improvement, MMSE and Wechsler memory scale No other benefits found on any outcome Withdrawal from adverse effects not reported Review limited by inadequacies of published data suitable for pooling Recommendations: • For practice: not recommended • For research: large, long-term trials with modern diagnostic criteria using standard measures of cognition and more clinically meaningful measures Comment: The results and designs of the individual trials were so different that pooling is not appropriate The effect sizes from the meta-analysis may have sacrificed bias for precision by pooling effects at different durations and with different diagnoses; therefore, the larger trials may be more trustworthy than this review for determining effect sizes Individual patient data meta-analysis needs to be performed to add anything to inspecting the individual trials in this situation with such high homogeneity Update: Most recent amendment November 1999

Nicotine for AD (Lopez-Arrieta et al. 2000) Exclusion bias: None (no appropriate trials were found) Design bias: None Patient bias: None Outcome bias: None Treatment bias: None Analytic bias: None Main results and conclusions: No information available

Recommendations: • For practice: no evidence to support use • For research: at least 6-month trials in AD with outcomes of cognition, function, institutionalization and mortality Comment: Two trials awaiting review from 1995 and 1996 unlikly to change conclusions unless they have substantial data. See Chapter V.2.14 for a narrative systematic review, in which these two trials are included Update: Most recent amendment August 2000 suspended the review

Rivastigmine for AD (Birks & Melzer 2000) Exclusion bias: None Design bias: None Patient bias: None Outcome bias: Specific primary and secondary outcomes not pre-specified in the protocol Treatment bias: None Analytic bias: Inadequate accounting for loss to follow-up that could introduce potential bias Pooling with fixed effects analysis in presence of statistically significant heterogeneity Assumptions used for data not availableae.g. standard errors from one trial applied to two other trials without this information Many analyses conducted that were not pre-specified These analyses are likely to be less sensitive than analyses using individual patient data which can use multilevel models with repeat measurement data Main results and conclusions: Benefits on cognition, clinical global improvement and function No benefits on behavior Withdrawal from adverse effects higher on drug Review limited by inadequacies of published data suitable for pooling Recommendations: • For practice: none given • For research: further research on dosage to minimize adverse effects. Longer term trials with clinically significant endpoints and linked to costutility analyses

56 CHAPTER I.8

Comment: Main results and conclusions of available data were similar to those produced by the regulatory authorities (FDA, EMEA and others) and the UK NICE, and stated in the product label ITT analyses had data that were last observation carried forward, though this was discussed as not occurring in the text Subgroups of patients were not investigated The effect sizes from the meta-analysis may have sacrificed bias for precision by pooling effects at 12 and 24 weeks; therefore, the larger trials may be more trustworthy than this review for determining effect sizes Individual patient data meta-analysis needs to be performed to add anything to inspecting the individual trials in this situation No NNT or NNH provided to guide practice See Chapter V.2.7 for a narrative systematic review and Chapter V.2.21 for comparison with other cholinesterase inhibitors See Chapter V.2 for a narrative systemic review and Chapter V.2.21 for comparison with other cholinesterase inhibitors and clinical guidance Update: Most recent amendment August 2000

Thiamine for AD (Rodriguez-Martin et al. 2000) Exclusion bias: Maximum of one out of three trials were used for ‘pooled’ analysis Design bias: None (only one trial used for ‘pooling’) Patient bias: None Outcome bias: None Treatment bias: None Analytic bias: Inadequate accounting for loss to follow-up that could introduce potential bias ITT analysis not possible These analyses are likely to be less sensitive than analyses using individual patient data which can use multilevel models with repeat measurement data Main results and conclusions: Unreliable trend for placebo to be non-significantly better on cognition No data on other outcomes Withdrawal from adverse effects not reported Review limited by inadequacies of published data suitable for pooling

Recommendations: • For practice: not recommended • For research: low priority for future trials Comment: Futher trials unlikly to change conclusions unless they have substantial data. See Chapter V.2.20 for a narrative systematic review, with any new data included Update: Most recent amendment August 2000 suspended the review

Thioridazine for dementia (Kirchner et al. 2000) Exclusion bias: Maximum of seven out of 10 trials were used for pooled analyses Design bias: Pooling studies with different durations of treatmenta3 to 8 weeks Patient bias: Various diagnosesaAD, unspecified and VaD Outcome bias: Specific primary and secondary outcomes were not pre-specified in the protocol. Different scales within each domain were pooled Treatment bias: Different doses (10–200 mg/day) Analytic bias: Inadequate accounting for loss to follow-up that could introduce potential bias ITT analysis not possible Pooling of studies with heterogeneous results These analyses are likely to be less sensitive than analyses using individual patient data which can use multilevel models with repeat measurement data Main results and conclusions: Benefits on anxiety No benefits on other outcomes Withdrawal from adverse effects not calculated but reported as not significantly higher for the drug Review limited by inadequacies of published data suitable for pooling Recommendations: • For practice: use not supported • For research: longer trials with current diagnostic criteria Comment: The results and designs of the individual trials were so different that pooling is not appropriate

SYSTEMATIC REVIEWS 57

Subgroups using different comparators with thioridazine further reduced the the power of the pooled analyses The effect sizes from the meta-analysis may have sacrificed bias for precision by pooling effects at different durations and with different diagnoses; therefore, the larger trials may be more trustworthy than this review for determining effect sizes Individual patient data meta-analysis needs to be performed to add anything to inspecting the individual trials in this situation with such high heterogeneity No NNT or NNH provided to guide practice See Chapters VI.2.1 and VI.3.2 for the evidence and use of thiorizadine in a clinical context Update: Most recent amendment August 1998

Non-drug interventions Validation therapy for dementia (Neal & Briggs 2000) Exclusion bias: Maximum of two out of three trials were used in any pooled analysis Design bias: Pooling studies with very different control interventions Patient bias: Variety of severities and diagnoses of cognitive decline usedaAD and other forms of cognitive impairment Outcome bias: Different scales within each outcome domain were pooled Treatment bias: Lack of blindness may bias results in favour of the test intervention Analytic bias: Inadequate accounting for loss to follow-up that could introduce potential bias ITT analysis could not be conducted Studies with heterogenous results were pooled Multiple comparisons not pre-specified These analyses are likely to be less sensitive than analyses using individual patient data which can use multilevel models with repeat measurement data Main results and conclusions: No benefits on cognition or behavior, though non-statistically significant trends observed in favour of treatment Withdrawal from adverse effects not reported

Review limited by inadequacies of published data suitable for pooling Recommendations: • For practice: not given • For research: trial with randomization, adequate control group, appropriate stage of dementia and standardized outcome tools Comment: The individual trials were so different and the meta-analysis was so limited that little could be confidently concluded Subgroups provided unreliable analyses The effect sizes from the meta-analysis may have sacrificed bias for precision; therefore the individual trials may be more trustworthy than this review for determining effect sizes Individual patient data meta-analysis needs to be performed to add anything to inspecting the individual trials in this situation No NNT or NNH provided to guide practice See Chapter IV.6 for a narrative systematic review that provides the evidence in context and gives clinical guidance Update: Most recent amendment February 1999

Reality orientation for dementia (Spector et al. 2000a) Exclusion bias: Maximum of six out of eight trials were used in any pooled analysis Design bias: Pooling studies with very different control interventions and durations (four to 20 weeks) Patient bias: Variety of diagnoses of cognitive decline used, with inclusion of patients unlikley to have dementia Outcome bias: Different scales within each outcome domain were pooled Treatment bias: Lack of double-blindness may bias results in favour of the test intervention for the soft outcomes assessed Analytic bias: Inadequate accounting for loss to follow-up that could introduce potential bias ITT analysis could not be conducted Studies with heterogenous results were pooled Multiple comparisons not pre-specified These analyses are likely to be less sensitive than analyses using individual patient data which

58 CHAPTER I.8

can use multilevel models with repeat measurement data Main results and conclusions: Benefits on cognition and behavior Withdrawal from adverse effects not reported Review limited by inadequacies of published data suitable for pooling Recommendations: • For practice: recommended as part of dementia care • For research: trials using randomization and double-blinding Comment: The individual trials were so different and the meta-analysis was so limited that little could be confidently concluded Subgroups provided unreliable analyses The effect sizes from the meta-analysis may have sacrificed bias for precision; therefore the individual trials may be more trustworthy than this review for determining effect sizes Individual patient data meta-analysis needs to be performed to add anything to inspecting the individual trials in this situation No NNT or NNH provided to guide practice See Chapter IV.6 for a narrative systematic review that provides the evidence in context and gives clinical guidance Update: Most recent amendment February 1998

Reminiscence therapy for dementia (Spector et al. 2000b) Exclusion bias: Maximum of one (10 patients compared) out of two (30 patients available) trials were used in any ‘pooled’ analysis Design bias: None (only one study ‘pooled’) Patient bias: None Outcome bias: None Treatment bias: Lack of double-blindness may bias results in favour of the test intervention for the soft outcomes assessed Analytic bias: None Main results and conclusions: Non-significant favourable trend for behavior No benefit for cognition No/few withdrawals from protocol

Review limited by inadequacies of published data suitable for pooling Recommendations: • For practice: no guidance provided • For research: randomized controlled trials in conjunction with qualitative studies Comment: See Chapter IV.6 for a narrative systematic review that provides the evidence in context and gives clinical guidance Update: Most recent amendment April 1998

Music therapy for dementia symptoms (Koger & Brotons 2000) Exclusion bias: None (no studies suitable) Design bias: None Patient bias: None Outcome bias: None Treatment bias: None Analytic bias: None Main results and conclusions: No results Need for trials! Recommendations: • For practice: not recommended but discontinuation of music therapy unwarranted • For research: randomized controlled trials Comment: A systematic review of no trials See Chapter IV.6 for a narrative systematic review that provides the evidence in context and gives clinical guidance Update: Most recent amendment May 2000

Subjective barriers to prevent wandering of cognitively impaired people (Price et al. 2000) Exclusion bias: None (no studies suitable) Design bias: None Patient bias: None Outcome bias: None Treatment bias: None Analytic bias: None Main results and conclusions: No results Need for trials!

SYSTEMATIC REVIEWS 59

Recommendations: • For practice: not recommended. If used, should be part of a wider management plan • For research: randomized controlled trials Comment: A systematic review of no trials See Chapter VII.5 for a narrative systematic review that provides the evidence in context and gives clinical guidance Update: Most recent amendment September 2000

Support for carers of people with Alzheimer’s type dementia (Thompson & Brigg 2000) Exclusion bias: Maximum of two out of six trials were used in any ‘pooled’ analysis Design bias: Very different durations Patient bias: Different severities of disease Outcome bias: Very different outcomes used Treatment bias: Lack of double-blindness may bias results in favour of the test intervention for the soft outcomes assessed

Analytic bias: Lack of allowance for loss to follow up Not pre-specified analyses Main results and conclusions: Little evidence to conclude anything Withdrawals from protocol unknown Review limited by inadequacies of published data suitable for pooling Recommendations: • For practice: no guidance provided • For research: randomized controlled trials Comment: See Chapter VII.3 for a narrative systematic review that provides the evidence in context and gives clinical guidance Update: Most recent amendment May 1998 AD, Alzheimer’s disease; ADAS-Cog, Alzheimer’s Disease Assessment ScaleaCognitive; DHEA, dihydroepiandrosterone; EMEA, European Medicine Evaluation Agency; FDA, Food and Drug Administration; ITT, intention-to-treat analysis; MMSE, Mini Mental Status Examination; NICE, National Institute for Clinical Excellence; NNH, number needed to harm; NNT, number needed to treat; VaD, vascular dementia.

I.9

Evidence-based Guidelines

Nawab Qizilbash

Key points • Clinical guidelines represent systematically agreed statements to help health care practitioners and patients in making health care decisions. • Guidelines differ from systematic reviews by involving a range of perspectives. • Recommendations in guidelines should be reproducible among experts in the field. • Guidelines should be up to date and incorporate new important, practical information.

‘Guideline’ is defined in The Concise Oxford Dictionary as ‘directing principle’, and ‘clinical’ is defined as ‘at the sick-bed’. Guidelines have been written for many years. The focus of many earlier guidelines was the organizational framework within which clinical interventions were provided, rather than the interventions themselves. Most were based on informal consensus (e.g. the UK College of Occupational Therapists 1990). By contrast, clinical guidelines represent systematically developed statements to help health care professionals and patients (and carers) in making appropriate health care decisions for specific clinical conditions (Mann 1996). They attempt to synthesize validly and reliably the vast volume of evidence so that it can be easily used in clinical practice. They attempt to cover all important aspects that bear on clinical decisions. They refine clinical questions and try to balance benefits and risks in their recommendations in an explicit manner. In reality, they are qualitative judgements about the relative

60

importance of various results, economic as well as clinical. Therefore, the appraisal of clinical guidelines requires rigorous evaluation of the manner in which they were constructed, as well the scientific evidence on which there are based. Clinical guidelines should produce systematically developed recommendations for specific clinical interventions, whose features are that: 1 They are based on the best available evidence, i.e. an explicit systematic review process to search, select, evaluate and synthesize evidence of the effectiveness of intervention (diagnosis, treatment, prevention and care). When evidence is absent, of poor quality or conflicting, the views of experts and patients (and carers) are used to produce a consensus. 2 They provide an explicit link between recommendations and supporting evidence, as do many of the chapters in this book on diagnosis (Section II) and management (Sections V, VI and VII). 3 They deal with specific clinical interventions for specific patient groups. 4 They take a systematic approach about who should be involved in drawing up the guideline recommendations. Patient perspectives are sought and all professionals who may be involved should be included. Guidelines differ from systematic reviews in that there is interpretation of the final results of the review into recommendations for clinical practice that take into account a range of perspectives. Guidelines differ from decision analysis in being less quantitative. Guidelines should: 1 Make clear recommendations. 2 Discuss the evidence in terms of clinical applicability for particular patient groups.

GUIDELINES 61

3 Provide one of a number of formats to facilitate the implementation of research findings into clinical practice. 4 Provide a resource of information to patients (and carers), as well as professionals, thereby helping to facilitate decisions through properly informed choice and consent. Guidelines may increase or decrease health care costs (Scottish Intercollegiate Guideline Network 1999). If widely implemented, they should reduce variations in practice. National decisions should be made locally with respect for local circumstances. Clinical autonomy should remain with the clinician, as there will always be patients who differ for reasons of coexisting diseases, concomitant therapy, social factors and patient preference. The adoption of guidelines without consideration of its applicability to a particular patient could be seen as a negligent act. Guidelines can have several purposes: 1 To assist in clinical decision-making, through, for example, the use of clinical algorithms. 2 The evaluation of clinical practice through audits to review the use of resources and quality of care delivered. 3 To establish limits to medical choice through reimbursement and recertification of health care professionals. They can be aimed at different types professionals and at different levels, e.g. primary care physicians or specialists in tertiary centres. The following discussion of the appraisal of guidelines and their applicability is largely based on articles by Grimshaw and Russell (1993) Hayward et al. (1995) and Wilson et al. (1995).

Are the guideline recommendations valid? 1 Were all the important alternatives and outcomes clearly discussed? One needs to know what was not recommended (and why) to appreciate why the chosen recommendation is best. 2 Was a valid and explicit process used to identify, select, appraise and synthesize the various types of evidence available? The appraisal of treatment, prevention, diagnostic methods and prognosis, and systematic reviews and meta-analyses, and applic-

ability to individual patients, discussed earlier in this section are all relevant. Only three sets of recent (1997–2000) evidencebased guidelines in the treatment of dementia were found by this author after an extensive search of Medline, webengine (Lycos), Centre for reviews and Dissemination (http://144.32.228.3/scripts/ WEBC.EXE/nhscrd/restart) and the US government National Guideline Clearing-house website for guidelines (http://www.guideline.gov) with the key words ‘guideline and alzheimer or dementia’. The three evidence-based guidelines were: American Psychiatric Association 1997; Eccles et al. 1998; and Scottish Intercollegiate Guideline Network 1999). Therefore, in the sections on management (Sections V, VI and VII) these guidelines have been preferentially cited. 3 Was a valid and explicit process used to weigh the relative values of different outcomes (various types of benefits and harms)? This refers to the members of the guidelines group, their competing interests and backgrounds, as well as the methods used to assign relative values. 4 Have the recommendations been checked by other experts? The validity of the consensus development process may be poor if the reproducibility of consensus was poor in developing a guideline. For example, the reproducibility of consensus for two similar clinical problems by three groups of doctors was poor (Huttin 1997). Many of the recommendations from the evidence-based guidelines produced by one professional guideline group (Eccles et al. 1998), that has produced guidelines in several disease areas, were contested by several experts in dementia (Eastley et al. 1999; Marshall 1999; Matthews et al. 1999; Tapsfield & Jelley 1999). 5 Have the guidelines incorporated important new data? Given the time taken to develop guidelines this may be an important issue in areas of rapid progress in dementia, especially diagnosis and treatment. For example, the American Psychiatric Association (1997) and the North of England guidelines (Eccles et al. 1998) provide no help for the newer approved agents, rivastigmine and galanthamine. 6 Do the guidelines lead to the health gains (and costs) predicted? This is the real test of validity and, of course, the most difficult to evaluate.

62 CHAPTER I.9

What are the recommendations? Are the recommendations clinically important and practical? This depends on answers to the following questions. 1 What is the strength of the recommendation? Several schemes are available to rate the level of evidence and grade recommendations (Canadian Task Force on the Periodic Health Examination 1979; Cochrane Collaboration 1996). The scheme used in this book (Chapter I.7) has been adopted. In contrast to the US Agency for Health Care Policy and Research (US Department of Health and Human Services et al. 1992) this author is unconvinced that, at least in dementia, evidence from one randomized controlled trial necessarily represents a lower level of evidence than that obtained from a meta-analysis of randomized controlled trials, given that only one well-conducted individualpatient data meta-analysis yet exists in dementia (Qizilbash et al. 1998; see Chapter I.7). Nevertheless, it should be borne in mind that the strength of the level of evidence for an intervention (for determining benefit) can be undermined by side effects, inconvenience and cost. 2 What is the effect of allowing for uncertainty? ‘What if’ sensitivity analysis should be done for the major key factors in the evidence used to make recommendations. These analyses become increasingly necessary with decreasing levels of robust evidence.

Are the guidelines applicable to your practice? 1 Are the guideline recommendations similar to those produced by other valid evidence-based methods? Other sources of evidence-based material about the clinical issue should be sought to ensure that there is sufficient agreement about the recommendations. 2 Are the recommendations applicable to your particular patient? Guidelines should provide a description of the types of patient to whom the recommendations apply and in what circumstances they may not. Again, the relevant question is, ‘is your patient sufficiently different or have different value preferences for the benefits, harms, incon-

venience (and costs) of treatment to those discussed in the guidelines’? 3 Can I test whether the guideline recommendations have been useful to my patient? Explicit criteria should be stated against which the use of the guidelines can be evaluated through clinical audit.

Conclusions Clinical guidelines will be used increasingly in dementia. For example, the Italian health service has recently decided that the the use of donepezil, rivastigmine and galanthamine will be reimbursed only if guidelines set by them are followed. Guideline recommendations need to be appraised rigorously, so that only trustworthy ones are implemented. Given the infancy of guideline development in dementia, more than one guideline and other high quality evidence-based sources of practical evidence should be referred to before recommendations are implemented. Many of the chapters in this book represent a systematic and rigorously appraised resource, with the added clinical experience of the author of the chapter, which will be kept up to date on the website. Guideline developers may wish to use these narrative systematic reviews as another source of material to form the basis for some of their recommendations. Readers may wish to use the evidence-based practical recommendations in this book on diagnosis and management, as a crosscheck, in their evaluation of guidelines in dementia. A detailed, practical and easily accessible source of information on guideline development can be found at the Scottish Intercollegiate Guideline Network website at http://www.sign.ac.uk.

References American Psychiatric Association (1997) Practice Guideline for the Treatment of Patients with Alzheimer’s Disease and Other Dementias of Late Life. American Psychiatric Press, Washington. Canadian Task Force on the Periodic Health Examination (1979) The periodic health examination. Canadian Medical Association Journal 41, 1193–1254. Cochrane Collaboration (1996) Cochrane Library. Update Software, Oxford.

GUIDELINES 63

Eastley, R., Haworth, J., Wilcock, G. & Sharp, D. (1999) Guidelines should cover differential diagnosis. British Medical Journal 318, 731. Eccles, M., Clarke, J., Livingston, M., Freemantle, N. & Mason, J. (1998). North of England evidence based guidelines development project: guideline for the primary care management of dementia. British Medical Journal 317, 802–808. Grimshaw, J. & Russell, I. (1993) Achieving health gains through clinical guidelines. 1: Developing scientifically valid guidelines. Quality Health Care 2, 243–248. Hayward, R.S.A., Wilson, M.C., Tunis, S.R. Bass, E.B. & Guyatt, G.H. for the Evidence-Based Medicine Working Group (1995) Users’ guides to the medical literature. VIII. How to use clinical practice guidelines. A. Are the recommendations valid? Journal of the American Medical Association 274, 570–574. Huttin, C. (1997) The use of clinical guidelines to prove medical practice: main issues of the United States. International Journal of Quality Health Care 9 (3), 207–214. Mann, T. (1996) Clinical Guidelines: Using Clinical Guidelines to Improve Patient Care Within the NHS. Department of Health, London. Marshall, T. (1999) Such guidelines should consider all relevant effective treatments. British Medical Journal 318, 731. Matthews, H., Wilkinson, D. & Holmes, C. (1999) Some recommendations given are not based directly on evidence cited. British Medical Journal 318, 731. Qizilbash, N., Whitehead, A., Higgins, J., Wilcock, G.,

Schneider, L., & Farlow, M., on behalf of the Dementia Trialists’ Collaboration (1998) Cholinesterase inhibition for Alzheimer’s disease: meta-analysis of 12 trials of tacrine with 1984 patients. Journal of the American Medical Association 280, 1777–1782. Scottish Intercollegiate Guideline Network (1999) Website at http://www.sign.ac.uk. Tapsfield, W.G. & Jelley, D.M. (1999) GPs may want to continue prescribing donepezil for patients. British Medical Journal 318, 731. UK College of Occupational Therapists (1990) Guidelines for Documentation. College of Occupational Therapists, London. US Department of Health and Human Services, Public Health Service & Agency Health Care Policy and Research (1992) Acute Pain Management. Operative or Medical Procedures and Trauma. AHCPR Publication No. 92–0038. Agency for Health Care Policy and Research Publications, Rockville, MD. Walsh, S.H., Easter, R.N., Anderson, G.M. & Logan, E.G. (1990) Assessing the clinical effectiveness of preventive manoeuvres: analytic principles and systematic methods in review evidence and developing clinical practice recommendations. Journal of Clinical Epidemiology 43, 891–895. Wilson, M.C., Hayward, R.S.A., Tunis, S.R. Bass, E.B. & Guyatt, G.H. for the Evidence-Based Medicine Working Group (1995) Users’ guides to the medical literature. VIII. How to use clinical practice guidelines. B. What are the recommendations? Will they help me care for my patients? Journal of the American Medical Association 274, 1630–1632.

Evidence-based Economic Evaluation

I.10

Nawab Qizilbash

Key points • Cost-effectiveness and cost utility are the two types of economic evaluations used in assessing interventions in dementia. • Reproducibility of such analyses is of key importance. • Use of clinically meaningful endpoints within pragmatic trials is a necessary requirement for trustworthy economic analyses in dementia. • There may be severely limited generalizability of results to other cultures and societies. • Economic evaluations of interventions in dementia are currently untrustworthy for contributing to decisions about resource distribution. Ever increasing demands from an ageing population, new technologies and knowledge, increasing expectations from patients and their families, increasing expectations from health care professionals to apply new technologies for their patients, and health care costs rising faster than general

inflation mean that demands for spending resources on health care will increase. These increasing demands on limited budgets allocated by governments, health insurers and providers of health care are resulting in increasing pressures to spend even more wisely on health care. The widespread demand for recently approved drugs (e.g. donepezil, rivastigmine and galanthamine) and the knowledge that other medications will follow has created fervent interest in the implications for health care resources. To help ensure that money is spent where it can maximize health gain (i.e. value for money), economic evaluations are being employed. The fundamental aim of economic evaluation is to assess the difference in health benefits produced by one intervention over others, and relate any difference to the respective costs of the interventions. The situations in which economic evaluations are useful are depicted in Table I.10.1. This is represented graphically in Figure I.10.1. and the cost-effectiveness ratio limit is the level below which a purchaser is prepared to buy a better intervention.

Table I.10.1 Cost-effectiveness of interventions. Cost of new intervention compared to control intervention

Effectiveness of new intervention compared to control intervention More

Same

Less

More

Evaluation needed

Reject*

Reject*

Same

Adopt*

Evaluation needed

Reject*

Less

Adopt*

Adopt*

Evaluation needed?

*Assumes existing evidence of costs and effects of existing options are sufficiently robust.

64

ECONOMIC EVALUATION 65

Test treatment Cost-effectiveness ratio limit more costly (variable)

Comparison treatment dominates

Test treatment more effective but more expensive

Test treatment less effective

Test treatment more effective

Test treatment less effective but cheaper

Fig. I.10.1 Cost-effectiveness axis.

Another major health economic activity is to quantify the costs of a particular illness. Both cost of illness studies and comparative economic evaluations of interventions in dementia are described in detail in Chapter VII.8. However, this chapter focuses exclusively on the appraisal of economic evaluation of interventions, be they pharmacological or non-pharmacological. Economic evaluations are being used by reimbursement agencies such as the newly created National Institute for Clinical Excellence (NICE) to decide whether the UK National Health Service will reimburse certain licensed antidementia drugs and, in the USA, whether Managed Care organizations will provide these drugs in their health plans. The Australian and Canadian governments have used economic evaluation in a formal way to approve subsidization of licensed drugs for several years (Henry & Johannesson 1992; Canadian Coordinating Office for Health Technology Assessment 1994). By contrast the regulatory agencies such as the US Foods and Drugs Administration (FDA) and the European Medicines Evaluation Agency (EMEA) do not incorporate economic evaluation for authorizing licences (Chapter IV.5.1). Individual clinicians and other professionals make decisions about individual patients with dementia and their families. However, clinicians and other professionals are increasingly involved in making decisions and policies about groups of patients with

Test treatment dominates

Test treatment less costly

dementia. They are also being asked to formulate policies about the distribution of resources within their services. For example, with the introduction of the antidementia drugs donepezil, rivastigmine and galanthamine, some health authorities in the UK have not increased the budget to psychogeriatric services, so forcing clinical teams to choose between spending limited resources on drugs or other services. Clinicians are increasingly required to convince others that the benefits of the new interventions they use are worth the costs. Hence the basic methodology of cost-effectiveness and cost-utility analyses needs to be understood and the limitations of these methods can be used to help counter flawed evidence which argues against the use of new drugs and other interventions in dementia. This chapter guides the reader in appraising economic evaluations about interventions and, importantly, the many pitfalls and uncertainties which exist in health economic analysis. Economic evaluation is a set of formal quantitative methods to capture the outcomes and costs of alternate intervention strategies. The purpose is to make explicit the measurement of costs and the value assigned to benefits. The four basic types of economic evaluations used to assess interventions are classified on the basis of the outcomes employed (Table I.10.2): 1 Cost minimization is the comparison of costs of alternative interventions when the outcomes are

66 CHAPTER I.10

assumed to be equal or similar, and the control intervention has been established. The evaluation is simply to choose the cheaper option. This is used little as it is often not known whether the outcomes are the same, particularly in dementia. 2 Cost-effectiveness is appropriate when the health outcomes are measured in common physical units, such as death or disability, or years gained or increased function, or points on cognitive scales (e.g. Mini Mental Status Examination (MMSE)/ Alzheimer’s Disease Assessment ScaleaCognitive (ADAS-Cog)). 3 Cost utility is an extension of cost-effectiveness, where different types of health outcomes are weighted according to assigned values of ‘quality of life’ to produce a composite of both the physical measurement and the value assigned to it, e.g. qualityadjusted life years (QALYS) or disability-adjusted life years. The quality adjustment assigns a lower value to states of physical or emotional health that are less than a state of perfect or full health. Such an analysis is potentially appropriate in dementia, where different types of outcomes are produced, e.g. cognitive, function or behavioral impairment, or where increased survival may be bought at the expense of reduced quality of life by increasing time in a dependent state. This situation could conceivably apply to vitamin E and selegiline given to moderate to severe patients with Alzheimer’s disease (AD) (Sano et al. 1997). Unfortunately, quality of life is extremely difficult, if not impossible, to measure accurately in patients with dementia or even by proxies. Table I.10.2 Types of economic analysis by the types of

outcome employed. Type of economic analysis Cost minimization Cost-effectiveness

Cost-utility Cost-benefit

Type of outcome involved None (outcomes are assumed to be equivalent) Physical units (e.g. MMSE, functional scale, dependency, nursing home placement) Physical units are valued (e.g QALYS) Money (outcomes are valued in monetary termsadollars, etc.)

MMSE, Mini Mental Status Examination; QALYs, qualityadjusted life years.

4 Cost–benefit analyses value health outcomes in monetary terms, often based on the concept of ‘willingness to pay’. This type of analysis is little used in medicine, as it has a bias towards the wealthy who may be willing to pay more than poorer people.

Evaluation of economic studies Were the results valid? A number of checklists are available to appraise economic evaluations, although they seem to have had no effect on the quality of economic evaluation submitted or published in two weekly medical journals (Jefferson et al. 1998). The criteria used by the Canadian authorities to decide approval and reimbursement are available on a website (http://www.ccohta.ca). Several checklists have been drawn on to compile a list of questions pertinent to economic appraisal (Canadian Coordinating Office for Health Technology Assessment 1994; Drummond et al. 1997a,b; Gold et al. 1996; O’Brien et al. 1997). • Was a well-defined question posed in an answerable form? • Was an appropriate perspective used (i.e. society, purchaser, clinician, patient, care giver)? • Was a comprehensive description of the competing alternative options provided (i.e. who did what, to whom, why and in what quantity)? • Was the effectiveness of the programs or services established? • Were all the important and relevant costs and outcomes identified? • Were costs and outcomes measured accurately in appropriate units (e.g. hours of doctors’ time, number of clinic visits, lost work days, years of life gained, etc.)? • Were costs and outcomes valued credibly? • Were costs and outcomes adjusted for differential timing (i.e. costs and benefits arising in the future are worth less than costs and benefits today)? • Was an incremental analysis of costs and outcomes of the options performed? • Was allowance made for uncertainty in the estimates of costs and outcomes? • Did the presentation and discussion of results include all issues of concern to users?

ECONOMIC EVALUATION 67

• Were good statistical practices used? • Were averages provided, with confidence intervals? • How were right-sided censured cost data dealt with? For dementia, other details and issues need to be addressed before the results of an economic evaluation can be considered as valid and applicable: • Could differences in practices significantly alter the costs? • Would values and preferences differ across cultures and over time? • Was sufficient allowance made for the trial procedures not reflecting real life practice? • Was the imprecision in the use of surrogates (e.g. MMSE for institutionalization) modeled in the evaluation? • How much uncertainty was present in the data used from outside the trial (e.g. meta-analysis)? • How dependent are the results on the comparator used? • Are alternatives available? As the systematic review of economic evaluation of drugs (and other interventions) in Chapter VII.8 clearly demonstrates, there are huge variations in the results from analysis of the same question carried out by different health economists. One fundamental problem is the use of many scales whose clinical meaning is unclear and hence the value placed upon them is also uncertain. This problem is further aggravated for cost–utility analyses (e.g. which facilitate comparisons across disease areas with widely differing health impacts) as the problems of quality of life measurement in patients with dementia (Salek et al. 1998; Walker et al. 1998) make quality-adjusted analyses wholly unreliable. Nor can this be easily remedied by recourse to general population samples to assign values to health states in dementia from current trials. For example, how should a four-point improvement in the ADAS-Cog score over a short period of time, followed by decline be valued? How should a clinical global improvement for a short period of time, followed by decline be valued? How should a ‘symptomatic’ delay of some 6 months in cognitive decline, with no evidence of impact on the prognosis of major endpoints such as dependency or nursing home placement, be valued? However, without using some generic form of outcome

measure how should a given level of deterioration in function be evaluated against a given level of improvement or deterioration in behavior or when comparing treatments across diseases? Hence, until clear, unambiguous and meaningful outcomes such as nursing home placement and dependency are reliably measured in trials, costeffectiveness and cost-utility studies will continue to be potentially misleading and untrustworthy. Extrapolation of short term effects on the MMSE or ADAS-Cog scales over 1 year to impacts on nursing home placements is fraught with uncertainty. Levo-dopa therapy for Parkinson’s disease provides a cautionary analogy; l-dopa helps symptoms but the symptomatic effect wears off after a few years. There is little evidence that l-dopa delays progression of disease and it is unclear whether it influences medium- or long-term prognosis (Poewe & Wenning 1998; Hely et al. 1999).

Where were the results? After asking if the results were valid, questions about the results themselves need to be addressed. What were the incremental costs and outcomes of each alternative intervention? One interpretation of the incremental cost-effectiveness ratio is that it is a ratio of the extra cost that must be paid in order to gain an additional unit of health benefit. Do the incremental costs and outcomes differ between patient groups? Unfortunately, this issue is not easy to address because of the play of chance affecting subgroups (Chapter I.7). How certain or reliable are the results? One method to assess the precision in the estimate is to determine the width of the confidence intervals, and if that is very wide, this provides evidence of substantial uncertainty. Unfortunately, sample sizes for economic analyses may need to be very large, running into the thousands (Sturm et al. 1999). Even with confidence intervals sufficiently tight not to alter a decision, sensitivity (‘what if’) analyses need to be run to allow for methodological uncertainties. These should be both univariate and multivariate sensitivity analyses, where more than just one of the major drivers of the cost-effectiveness ratio is altered. Multivariate sensitivity analyses will never produce tighter confidence intervals

68 CHAPTER I.10

than univariate sensitivity analyses, yet they are rarely reported, although they are more likely to represent the true uncertainty in the estimates by using the ‘newer’ intervention in preference to the control intervention. If this approach seems too extreme, probabilistic sensitivity analyses using repeated sampling with Monte Carlo simulations should, at least, be used (Manning et al. 1996).

Are the results applicable to my service? Given the many uncertainties in economic evaluations, one should request more than one economic evaluation before attempting to generalize beyond the trial. This is akin to drug regulatory authorities requiring two trials with safe, beneficial and statistically significant results. If there are two economic analyses from two trials with similar results or one economic analysis from one large trial with highly statistically significant results (i.e. P < 0.00125; Fisher 1999), then the following questions should be asked. 1 Are the additional benefits worth the additional costs? This question may have different answers depending on the perspective of the respondent. A wealthy patient may be willing to pay a very high price for even a trivial non-clinically significant health gain. Where opportunity costs are involved (i.e. spending money on one activity will deprive another activity) for decision-makers working within some framework of equity and medical need, the issue is difficult. Firstly, comparison of costeffectiveness ratios on QALYS across different diseases with different data, methods and assumptions is fraught with difficulty (Drummond et al. 1997a). Secondly, replacement of an established treatment that had never been economically evaluated with a new treatment also throws up problems. One approach is to decide if the benefits are ‘clinically’ significant. However, the reality may be that if the increased costs are very high, then it may be impracticable to adopt the new intervention, no matter how cost-effective it isaa common situation for developing countries. 2 Are the health outcomes applicable to your patients? As with the assessment of trials, this will depend on how similar your patients are to those in the trials and whether the clinical practices in the

study are similar to those used in your practice. Another approach is to ask whether your patients and practice are sufficiently similar to those in the trial as a whole, or in any subgroup, for you to apply the results to your patients with confidence.

Are the costs likely to be similar? The costs used in published studies may not be relevant because practice patterns may vary in ways that affect the consumption of resources and local prices may differ. Also, relative prices may not be the same, i.e. different cultures vary in the relative value they place on health compared to other commodities. Lastly, methods of producing costeffectiveness analyses may differ, so that in a country less industrialized than the USA, for example, the opportunity costs of the resources may be higher. For example, shifting costs from basic sanitation to dementia treatment may have a more profound effect in a developing country than in a developed one.

Conclusions The critical appraisal of economic evaluations suggests that, except in clearcut cases, the analyses are subject to numerous methodological problems and uncertainties, especially in dementia. This can be summarized graphically in Figure I.10.2, where the wide confidence intervals of uncertainty do not help in making the decision whether or not to buy a cholinesterase inhibitor. Indeed, it can be seen that the uncertainty is much greater for costs than for effects. The weight given to quantitative evidence should be in proportion to its relevance, validity and reliability. If this criterion is adopted, few, if any, published economic evaluations in dementia should be used to decide which interventions should be adopted or dropped. This was the conclusion of the 2000 UK NICE evaluation (www.nice.org.uk). The Scottish Intercollegiate Guidelines Network, who produce practice guidelines for Scotland, exclude economic evaluations from their guidelines (http://www.sign.ac.uk/criteria.htm). Until large pragmatic trials with clinically meaningful endpoints are reported, the economic evaluation of drugs for cognitive symptoms, disease modification or preven-

ECONOMIC EVALUATION 69

CI therapy more costly

Cost-effectiveness ratio limit for CI

CI therapy more effective

CI therapy less effective

Fig. I. 10.2 Cost-effectiveness of

cholinesterase inhibitors in AD compared with placebo.

tion remains a minefield of uncertainty. Nobody can deny that the maximum health gain should be sought from precious resources aimed at health. However as a field in its infancy, many methodological difficulties need to be overcome before economic evaluations should be formally incorporated in decision-making in dementia. Without resolution of the many problems the value of their input into the decision-making process for the management of patients with dementia appears limited.

Acknowledgements I would like to thank Jonathan Karnon of Brunel University, UK, for helpful comments.

References Canadian Coordinating Office for Health Technology Assessment (1994) Guidelines for Economic Evaluations of Pharmaceuticals. http://www.ccohta.ca. Drummond, M.F., O’Brien, B., Stoddart, G.L. & Torrance, G.W. (1997a) Methods for the Economic Evaluation of Health Care Programmes, 2nd edn. Oxford University Press, Oxford. Drummond, M.F., Richardson, W.S., O’Brien, B.J., Levine, M. & Heyland, D. for the Evidence-Based Medicine Working Group (1997b) Users’ guides to the medical literature. XIII. How to use an article on economic

CI therapy less costly

analysis of clinical practice. A. Are the results of the study valid? Journal of the American Medical Association 277, 1552–1557. Fisher, L.D. (1999) One large, well-designed, multicenter study as an alternative to the usual FDA paradigm. Drug Information Journal 33, 265–271. Gold, M.R., Siegel, J.C., Russell, L.B. & Weinstein, M.C. (1996) Cost-effectiveness in Health and Medicine. Oxford University Press, Oxford. Hely, M.A., Morris, J.G.L., Traficante, R., Reid, W.G.J., O’Sullivan, J. & Williamson, P.M. (1999) The Sydney multicentre study of Parkinson’s disease: progression and mortality at 10 years. Journal of Neurology, Neurosurgery and Psychiatry 67, 300–307. Henry, D.A. & Johannesson, M. (1992) Economic analysis as an aid to subsidization decisions. Pharmacoeconomics 1, 54–67. Jefferson, T., Smith, R., Yee, Y., Drummond, M., Pratt, M. & Gale, R. (1998) Evaluating the BMJ guidelines for economic submissions: prospective audit of economic submissions to BMJ and The Lancet. Journal of the American Medical Association 280, 275–277. Manning, W.G., Fryback, D.G. & Weinstein, M.C. (1996) Reflecting uncertainty in cost-effectiveness analysis. In: Cost-Effectiveness in Health and Medicine (Gold, M.R., Siegel, J.C., Russell, L.B. & Weinstein, M.C., eds), pp. 247–275. Oxford University Press, Oxford. O’Brien, B.J., Heyland, D., Richardson, W.S., Levine, M., Drummond, M.F. for the Evidence-Based Medicine Working Group (1997) Users’ guides to the medical literature. XIII. How to use an article on economic analysis of clinical practice. B. What are the results and will they help me in caring for my patients? Journal of the American Medical Association 277, 1802–1806. Poewe, W.H. & Wenning, G.K. (1998) The natural history of Parkinson’s disease. Annals of Neurology 44 (Suppl. 1), S1–S9.

70 CHAPTER I.10

Salek, S.S., Walker, M.D. & Bayer, A.J. (1998) A review of quality of life in Alzheimer’s disease. Pharmacoeconomics 14 (6), 613–627. Sano, M., Ernesto, C., Thomas, R. et al. (1997) A controlled trial of selegiline, alpha tocopherol, or both as treatment for Alzheimer’s disease. New England Journal of Medicine 336, 1216–1222.

Sturm, R., Unutzer, J. & Katon, W. (1999) Effectiveness research and implications for study design: sample size and statistical power. General Hospital Psychiatry 21 (4), 274–283. Walker, M.D., Salek, S.S. & Bayer, A.J. (1998) A review of quality of life in Alzheimer’s disease. Pharmacoeconomics 14 (5), 499–530.

Accessing and Using the Best Evidence Efficiently in Dementia

I.11

Nawab Qizilbash

Key point For practitioners and researchers, hybrid print–internet books may represent the best means to acquire clinically relevant information that is valid, independent and balanced, up-todate, can be accessed rapidly, and efficiently reviewed within the context of other relevant information. Busy clinicians and other people who deal with the management of individual or groups of patients with cognitive decline do not have much time to search for good quality sources of information about the problems and questions related to their patients. Researchers also need quick and efficient access to quality sources of information about cognitive decline. Although the needs of these groups differ, they are not mutually exclusive and a good clinician is also often a good researcher. Carers are also increasingly wanting to access sources of data that are available to doctors and other professionals. Practitioners and researchers need information sources that provide relevant, valid, independent and balanced, up-to-date material that can be accessed rapidly and efficiently with minimal effort (Smith 1996). In addition, the professional who deals with individual or groups of patients (and carers) also needs authoritative guidance based on practical experience, where the level of evidence is less than perfect. This chapter reviews sources of information that practitioners and researchers (and well informed carers) can now access.

Books Traditionally, books on shelves provide the most familiar and rapid access to information. They are useful for the basics of practice that do not change quickly, such as anatomy, pathophysiology, the classic presentations of cases, helping to broaden differential diagnoses, historical aspects of a disease, practical suggestions in patient management and side effects of interventions. However, they cannot be relied upon to remain up-to-date and are rarely explicit about the quality and balance of evidence from which conclusions are drawn or recommendations are given. Even with extensive indices, searching for information where more than one keyword is needed is not easy. All the books currently available on dementia perfectly fit this description. In addition, many of the books on dementia are not problem-orientated and give little practical guidance to the reader–clinician, other health professional or researcher. Few current books on dementia are evidence-based and they are all out-of-date, especially for topics about diagnosis and treatment.

Bibliographical sources Many electronic databases of citations and abstracts of the medical literature exist. Few can rival Medline, the most commonly used, which is a multipurpose database containing most important citations to clinical studies and also many non-clinical articles. The rival to Medline is Embase, which is also a general purpose database of citations, and may be more comprehensive for non-clinical studies. Two

71

72 CHAPTER I.11

specialized databases are important for the field of cognitive decline: (i) Psychlit, which is a database specializing in studies related to psychology and psychiatry; and (ii) the Cochrane Controlled Trials Register, which contains citations and abstracts to all studies related to controlled interventions in any field of health care of any description. It is arguably the best single source of trials, as it has studies discovered by hand searching of journals and gray literature in many fields, including dementia, by a vast network of people around the world (Cochrane Library 1999). The reason for the development of the Cochrane Controlled Trials Register was the poor performance of traditional databases such as Medline and Embase in picking up all relevant studies related to interventions, even with the best designed search strategies (Chalmers et al. 1992). These deficiencies remain for non-controlled studies, which are not covered by the Cochrane Controlled Trials Register. Using the last issue of the 1999 Cochrane Library, 2871 citations referring to trials alone were found by using the keywords ‘dementia’ or ‘Alzheimer’. A search of the electronic journals library ‘Current Contents’ for just 1 year (1999) produced 6518 citations with the keywords ‘dementia’ or ‘Alzheimer’. Unfortunately, only about 1% of these journal articles may be sound (Smith 1991). Hence, the task of finding good balanced evidence is both difficult and awesome, from this source alone, without reference to critical summaries.

Dementia journals There are many journals which deal with dementia, and the number increases yearly. As the field straddles the main disciplines of geriatrics, neurology, psychology and psychiatry, as well as more peripheral areas such as social care, occupational therapy, speech therapy, health economics, public policy and others, it becomes difficult for even the dedicated researcher to scan these sources to obtain valid and reliable information. Moreover, the quality of studies is variable and hence time is expended sorting the ‘wheat from the chaff’. There are a few journals which try to provide this serviceaEvidence-Based Medicine, Evidence-Based Practice, Evidence-Based Nursing and EvidenceBased Mental Healthabut they do not cover the

field of dementia well, and do not provide practical guidance within the overall pattern of diagnosis or care of a patient.

Cochrane Library This electronic source would seem to be an important source to obtain valid, reliable, relevant, easily accessible and helpful information to practice evidence-based dementia medicine with patients. Unfortunately, most of the reviews from the Cochrane Dementia and Cognitive Impairment Group (Cochrane Library 2000) do not provide such information to guide the management of patients with dementia. The reason is that meta-analysis not based on individual-patient data is potentially misleading in the field of dementia, as most of the outcomes measured are not of a binary nature but are continuous or ordinal (Chapter I.8). There are important flaws in all the reviews of the Cochrane Dementia and Cognitive Impairment Group, often caused by limitations in the published original trials used in the meta-analyses. The systematic reviews are also difficult to read, are long, have much redundant material, and provide little practical help to the practising clinician or researcherathe review of piracetam is 60 pages long (see Chapter I.8). They are often written by people who do not have involvement in the care of individual patients with dementia (Birks & Melzer 2000). The rigidity of the standardized methodology employed means that valid studies (with data that are not presented in a format capable of pooling) are not given adequate, if any, weight. Therefore, the reviews are based on only a fraction of the data contained in the individual trials and suffer from ‘exclusion’ bias.

Existing internet sources There is an explosion of sources on the internet for dementia other than on-line journals. Finding these by search engines may make the enormity of the task more manageable, but it remains sizeable. In January 2000, a search of dementia or Alzheimer with the internet search engine, Yahoo, found 110 websites. The search engine Altavista found 43 520 websites with references to dementia

USING BEST EVIDENCE 73

or Alzheimer. The quality of the sources is very variable and often difficult to judge and web instruments to assess and rate the quality of health information on the internet may be unreliable (Jadad & Gagliardi 1998). The independence of the source is also at times difficult to assess. Many sites are commercial in nature, offering products and recruiting patients for trials that may influence the balance of their views. Few are evidence-based, up-to-date or provide guidance for professionals in the management and care of patients.

rapidly accessible and already appraised source of details of the evidence that underlie the statements made in the print book; the carer may access other websites (such as the Alzheimer Associations) via hypertext links. Regular updates will mean that this book will always remain relevant. We hope that the reader without time to search the vast, diverse material of variable quality can, by using this book, devote more time to practising evidence-based dementia efficiently with his or her patients, conducting research, teaching and self-learning.

Hybrid print/internet books The new genre of print/internet book aims to fulfil many of the needs of practitioners and researchers and possess all the advantages of the various vehicles of information described above and hence provide relevant, valid, independent and balanced, up-to-date material that can be accessed rapidly and efficiently with minimal effort. Furthermore, this particular book will also contain material that can be copied from the website so as to be useful for clinical use, such as diagnostic criteria, and provide hypertext links to other websites that have been recommended by the expert contributors of this book for practitioners, carers and researchers. Busy professionals dealing with patients can largely rely on the book. The researcher and more interested reader with time available can find a

References Birks, J.S. & Melzer, D. (2000) Donepezil for mild and moderate Alzheimer’s disease (Cochrane Review). In: Cochrane Library, issue 4. Update Software, Oxford. Chalmers, I., Dickersin, K. & Chalmers, T. (1992) Getting to grips with Archie Cochrane’s agenda. British Medical Journal 305, 786–787. Cochrane Library (1999) Cochrance Library, issue 4. Update Software, Oxford. Jadad, A. & Gagliardi, A. (1998) Rating health information on the internet. Navigating to knowledge or to Babel? Journal of the American Medical Association 279, 611–614. Smith, R. (1991) Where is the wisdom…? British Medical Journal 303, 798–799. Smith, R. (1996) What clinician information do doctors need? British Medical Journal 313, 1062–1068.

Evidence-based Audit: Evaluating Implementation

I.12

Nawab Qizilbash

Key points • Evaluation of evidence-based dementia practice is important in modern medical practice. • Evidence-based audit is one method of evaluation and can be practised by most clinical services. • Collaborative pooling of common core data would enormously enhance the value of audit.

Evidence-based dementia practice is about bringing the best evidence to help solve practical problems of patients with dementia, and their carers. Evaluation is needed of the implementation of evidence-based dementia practice to assess whether patients are better off as a result of this process. Unfortunately, formal evaluation to assess the effects on outcomes is difficult. First, the effects of changes in the education and implementation of professional practice is difficult to assess in any area of medicine (Oxman et al. 1995). Second, as this book demonstrates, the clinically meaningful value of most treatments is unclear based, at best, on a few thousand patients in rigorously randomized and not so rigorous studies. Hence, within a given memory clinic or service dealing with even several hundred new patients seen annually, it will be difficult to reliably evaluate the effects of interventions on outcomes. As Chapter VII.6 on the organization of dementia services points out, more rigorous evaluation of services is needed. This requires multicenter randomized and non-randomized trials. The evaluation of the effectiveness of therapies in routine clinical

74

practice that have been shown to be efficacious in the often narrow and artificial conditions of preregistration trials requires large, multicenter, pragmatic, randomized and non-randomized studies (Chapter IV.5.3). Diagnostic tests would also be helped by this kind of approach to evaluation. These kinds of pragmatic studies require collaboration and pooling of data from many centersaone feasible methodology to help this process is described in Chapter VII.7.4. Until well-designed effectiveness trials are conducted, and it is difficult to cite any from the reviews in this book, the evaluation of the outcomes of care affected by evidence-based dementia practice will remain elusive. Nihilism, however, is not the answer. The most efficacious treatment administered poorly and in inadequate circumstances may produce more harm than good. Therefore, the process of care (and implementation of the process of evidence-based dementia practice) needs evaluation, and this is feasible. This process is termed clinical audit and the purpose of this chapter is to provide a step-bystep approach, sufficient to establish audit as an effective tool with which to practice evidence based dementia medicine. It is useful to draw a distinction between audit and research: audit is designed to assess how close actual practice is to best practice or agreed standards, while research aims to establish what the best practice should be. Clinical audit is a process which seeks to improve the quality and outcomes of patient care through structured peer review in which practice and results are measured against agreed standards and modified accordingly (NHS Executive 1996). This definition allows many activities:

EVIDENCE-BASED AUDIT 75

Choose a clinical topic

Critical appraisal of all relevant evidence

Evaluate current practice

Implement changes

Make appropriate changes

Fig. I.12.1 Evidence-based clinical audit cycle.

Assess compliance with guidelines/standards

1 Methods to adopt the best practice by agreeing and implementing explicit recommendations of evidence-based dementia practice, leading to changes in management. This is the subject of this chapter. 2 Outcomes before and after changes in practice to evaluate their impact on clinical outcomesasee above. 3 Surveys of current practice. 4 The identification of problems of quality. Figure I.12.1 outlines the main stages of the evidence-based clinical audit cycle. The process is essentially similar to the traditional clinical audit cycle but with the focus on the explicit and systematic use of the best available evidence to guide the process. Evidence-based clinical audit needs to pay attention to the process of implementing the best external evidence. Hence, local management systems and the organizational environment may also need to change, to allow practitioners to effectively practice evidence-based dementia practice. The practical process of evidence-based clinical audit consists of: 1 Identifying a topic. This may be based on activities that include one or more of the following features: (a) common; (b) interesting; (c) unpopular or problematic;

Agree guidelines/protocols

Set standards

Implement guidelines/protocols Compare practice with standard

(d) high risk; (e) areas of new research or development; (f) where clear minimum standards or norms of care exist. 2 Setting objectives for the clinical audit project. These may initially be broad but should relate to processes to improve, enhance, ensure or change practice to further the practice of evidence-based dementia practice. 3 Finding relevant evidenceadiscussed in Chapters I.2 and I.11. 4 Critical appraisal of the evidence (Chapters I.3–I.11). 5 Applying the best evidence to the local setting. This book is one source (incorporating appropriate guideline recommendations) of this best evidence, and discusses its application to various situations that have been encountered by the many expert contributors. Other sources are guidelines from various sources: American Psychiatric Association, American Association of Neurology (both of which have several members contributing to this book), Scottish Intercollegiate Guideline Network, etc. 6 Agreeing evidence-based dementia practice. As this book demonstrates, there are few explicit statements of the best clinical practice that can withstand critical scrutiny for important bias or relevance. Most statements that would brook no argument

76 CHAPTER I.12

are based on good clinical care and common-sense principles, rather than robust evidence. Hence the recommendations in this book and in guidelines need discussion in the local setting. Nevertheless, as the systematic narrative reviews in this book demonstrate, there is variation in the use of diagnostic tests and interventions. While some of this variation may be justified, much of it is probably not. Therefore, these variations could become one basis for agreeing evidence-based dementia practice. The option of doing nothing may not be a choice if the topic is an important area of practice. Where good quality research is virtually absent, clinical expertise, both local and from regional centers of excellence, must be drawn upon, accepting that this is the best available information.

Implementing evidence-based dementia practice Management systems, environmental conditions and attitudes influence the implementation of evidence-based dementia practice. It is clear that improving clinical or professional practice is notoriously difficult (Grol 1992; Oxman et al. 1995). Therefore various implementation strategies may be needed (Oxman et al. 1995), and include: 1 Mechanisms for involvement of all persons who can both help and hinder the implementation of the audit process (Robertson et al. 1996). One important feature is that confidentiality is maintained for individual patients and professionals when reports are made of the audit findings. This requires agreeing who will have access to the audit findings. 2 Training and feedback (Oxman et al. 1995). 3 Peer review (Grol 1994). 4 The promotion of recommendations or standards by recognized opinion leaders (Turner 1991). 5 Clear roles and responsibilities to specific team members (Festinger 1954). 6 Involving respected outsiders or managers (Janis 1982).

Assessing compliance with evidence-based dementia practice protocols This assessment serves two main purposes: 1 The extent to which evidence-based dementia

practice has been implemented in day-to-day clinical practice. 2 The identification of reasons for non-compliance ato help increase compliance or provide exclusions to the protocol. The requirements for evaluating compliance are: 1 Assessment of how to measure the level of compliance. Clinical audit is based on devising measurable criteria against which valid, reliable and quantitative assessment of the performance of individuals or groups for specific clinical situations can be made. It involves defining a target figure and judging actual practice against the target. 2 Instruments used for measurement: this requires the definition of what to collect, where to collect it and who will collect the data. If outcome indicators are also to be used, the most commonly used ones are: (a) mortality; (b) morbidity (disability days, bed days, admissions, etc.); (c) subjective health indicators (e.g. quality of life, satisfaction with care); (d) direct measures of health and social functioning (those relevant to dementia could be cognitive, functional and behavioral, global assessments or carer burden); and (e) measures of unmet need. The agreed protocol, norms or standard of best evidence-based dementia practice must be converted into characteristics that can be measured. There are four components to audit assessment instruments (also known as indicators): (a) the aspect of care measured and the degree of evidence that would satisfy peers that a particular aspect or feature of care is being provided (known as audit criteria); (b) the proportion of cases which are expected to meet the standardathis may vary from 100% to 0%, or lie in between these extremes depending on the audit criterion; (c) definition of acceptable exceptions; and (d) instructions and a protocol for data collection. 3 Sample selection. Since the findings of audit are not necessarily generalizable to patients outside the sample, large numbers are not usually needed. Between 20 and 100 cases is normal. If changes over time are being assessed, sample sizes can be

EVIDENCE-BASED AUDIT 77

calculated that will detect a clinically significant change with certain significance levels and power (Altman 1991). These sample sizes are relatively large. 4 Method of data collection, e.g. by an interviewer, by the patient (or carer) or by routinely collected information. Electronic recording of these kind of data will greatly facilitate this process and that of analysisasee Chapter VII.7.4. 5 Method of analysis. There needs to be agreement about what level of compliance or deviation is considered clinically significant. Any deviation may be considered significant, if expected compliance is considered absolute. Changes in compliance over time can be made using tests for continuous or categorical data (Altman 1991). Alternatively, trends of compliance over time can be observed, although this may require several runs of the audit cycle. The analysis can be through: (a) descriptive statistics; (b) inferential statistics, in which hypotheses are tested, including whether changes occur over time; (c) spot checks (on data, records, practice, patients) over a short period of time, e.g. 1 day, at regular intervals or irregularly and, perhaps, unannounced; and (d) individual goal achievement and resolution of problems. This normally relates to the setting of predetermined goals based on individual patient needs or problems. The goals are then monitored and reassessed, after treatment has been instituted, periodically over an appropriate period of time. 6 Attributing change to audit. Even if improvement is demonstrated, it is difficult to definitely attribute this to the audit process, though the nature of the aspect of care and the degree and rapidity of change can help in making this judgement. Nevertheless, it is the improvement itself that is important, not precisely what caused it. However, identifying what actions are required to produce improvements is important.

Feedback of findings The feedback of findings should be made to all interested parties who have participated in the audit process and to colleagues, and the method of

feedback should be agreed before the data are collected. The purpose of feedback is to identify where improvements are needed and the actions that may be required to achieve the improvements. Individual professionals whose practice may be found to be unsatisfactory should not generally be mentioned in reports, unless agreement was secured at the onset. Attention needs to be paid to the type of information used for feedback and in what form it will be distributed. How the information will be used following feedback also needs discussion.

Agreeing and implementing changes The shortfalls in care need discussion with peers, and priorities may need to be set for which changes are the most important, as well as the speed of change that can be made. This process requires participation of all those involved in the aspect of care affected (and those who can hinder its implementation). Considering why interventions failed to bring about the desired changes can provide important information for the future. An action plan is required after the needed changes have been agreed.

Conclusions Evidence-based clinical audit is an important tool to assess whether evidence-based dementia practice is being practised and to implement any shortfalls. Practical examples that may be appropriate as audit topics for evidence-based dementia practice are: • The use of psychotropic drugs in patients with dementia. • The use of benzodiazepines in patients with cognitive impairment. • The use of drugs in dementia patients that are not indicated for dementia. • The added practical usefulness of single photon emission computerized tomography (SPECT) in routine practice for diagnosis. • The use of physical restraints in nursing homes. • The use of cholinesterase inhibitors. More conventional topics for clinical audit are suggested in Chapter VII.6 and in Riordan & Mockler (1997).

78 CHAPTER I.12

References Altman, D. (1991) Practical Statistics for Medical Research. Chapman & Hall, London. Festinger, L. (1954) A theory of social comparison processes. Human Relations 7, 117–140. Grol, R. (1992) Implementing guidelines in general practice care. Quality Health Care 1, 184–191. Grol, R. (1994) Quality improvement by peer review in primary care: a practical guide. Quality Health Care 3, 147–152. Janis, I.L. (1982) Group Think: Psychological Studies of Policy Decisions and Fiascos. Houghton Mifflin, Boston. NHS Executive (1996) Clinical Audit in the NHS. Using

Clinical Audit in the NHS: a Position Statement. Department of Health, London. Oxman, A., Thomson, M.A., Davis, D.A. & Haynes, R.B. (1995) No magic bullets: a systematic review of 102 trials of interventions to improve professional practice. Canadian Medical Association Journal 153 (10), 1423–1431. Riordan, J. & Mockler, D. (1997) Clinical Audit in Mental Health. Towards a Multidisciplinary Approach. John Wiley, Chichester. Robertson, N., Baker, R. & Hearnshaw, H. (1996) Changing the clinical behaviour of doctors: a psychological framework. Quality Health Care 5, 51–54. Turner, J.C. (1991). Social Influence. Open University Press, Milton Keynes.

SECT ION II

Diagnosis Edited by: Helena Chui

II.1

Introduction

Helena Chui

There are two kinds of questions one might ask when making a diagnosis of dementia. First, what kind of tests should be ordered (e.g. What should one look for in the medical history and physical examination? What is the best mental status test? When should a computerized tomography (CT) or magnetic resonance imaging (MRI) scan be ordered?) Second, how good are these tests? How much value do they add? Several guidelines and many textbooks are available which outline the kind of evaluation that should be undertakenawhen to order which test. Most of these documents are based on the ‘consensus’ opinion of academic specialists. More recently, attempts have been made to stratify recommendations based on the strength of evidence. In Chapter II.2, we review both consensus and evidence-based guidelines related to the diagnostic process. The main objectives of Section II focus on the second type of question: How good is a ‘test’ for making a diagnosis? (NB ‘tests’ are defined broadly to include clinical criteria, individual signs and symptoms, and laboratory studies.) We examine their value for two types of diagnoses: (i) the diagnosis of dementia (Chapter II.3), and (ii) the diagnosis of dementia subtype (Chapter II.4). In order to address these questions, we adopt an evidence-based approach (Jaeschke et al. 1994a; Jaeschke et al. 1994b; Oxman et al. 1994; Friedland et al. 1998). The ideal evidence-based review includes the following steps: Step 1 Systematic review of the literature (including an explicit search strategy). Step 2 Assessment of study validity.

Step 3 Summary of test performance (e.g. likelihood ratio, positive predictive value, negative predictive value, sensitivity or specificity). Step 4 Determination of incremental value (i.e. change between pre- and post-test probability). Step 5 Assessment of clinical significance (i.e. a test’s impact on clinical decision-making). Step 6 Assessment of cost-effectiveness. The evidence-based approach differs from the conventional review process. The latter also includes a literature search and analysis. However, conventional reviews lack a uniform and rigorous strategy for judging study quality and for rating test utility (e.g. test performance, incremental value, clinical significance or cost-effectiveness).

Study validity and summary of test performance (steps 2–3) Evidenced-based methods are relatively new to the field of dementia. Few studies address the issues outlined in steps 4–6. Therefore, for the present edition of this book, steps 1–3 were considered necessary and sufficient for inclusion as evidence. A valid study required: 1 Appropriate comparison groups, at least one of which was free of the target disorder. 2 A clear description of the spectrum of patients and controls, allowing judgement of the relevance of the results to clinical practice. 3 An independent and blind comparison of the test result with an appropriate reference (‘gold’) standard. 4 Presentation of data that enabled the calculation of a likelihood ratio (LR).

81

82 CHAPTER II.1

Table II.1.1 Class of evidence.

Table II.1.2 Modification of the class of evidence when using a surrogate reference standard (Chapter II.4).

Class

Study design

Spectrum of cases

IA IB IIA IIB

Prospective Prospective Retrospective Retrospective

Broad Narrow Broad Narrow

Description of comparison groups Studies were further qualified based on study design and the spectrum of cases: class I (prospective) vs. class II (retrospective); type A (broad spectrum of patients and controls) vs. type B (narrow spectrum of patients and controls). A prospective design decreases the likelihood of work-up bias (i.e. where the decision to perform the reference standard is influenced by the test result), hence the higher class I rating (Table II.1.1).

Independent and blind comparison of the test result with an appropriate reference (‘gold’) standard Studies were often excluded, if the authors did not explicitly affirm that the test and the reference standard were applied independently of each other. As a matter of natural history, the clinician is usually blind to pathology results. But special efforts must be made to keep the neuropathologist blind to the clinical findings. Other studies were excluded because identical features were contained in the ‘test’ and the reference standard. For example, a study comparing behavioral profiles in patients with frontotemporal dementia (FTD) vs. Alzheimer’s disease (AD) failed this criterion, if the diagnosis of FTD included behavioral features. A study comparing risk factors in AD vs. multi-infarct dementia (MID) failed, if risk factors were used to make a diagnosis of MID. A study of the usefulness of a neuropsychological test for dementia failed, if those tests were also available to the clinician making a diagnosis of dementia. A reference standard may be appropriate for one type of study, but not for another. For detecting cases with dementia, established clinical criteria (e.g. DSM-IV, Diagnostic and Statistical Manual,

Reference standard

Strength of evidence

Pathologically confirmed diagnosis Clinical diagnosis

Class I or Class II class 1 or class 2

Fourth edition) (American Psychiatric Association 1994) serve as an adequate gold standard (Chapter II.3). Yet for identifying specific subtypes of dementia (e.g. AD), clinical criteria are far less satisfactory (Chapter II.4). Here, autopsy-confirmed diagnoses are preferred. For example, against a neuropathological gold standard, NINCDS-ADRDA (National Institute of Neurological and Communicative Diseases/Alzheimer’s Disease and Related Disorders Association) and DSMI-III-R criteria for AD are sensitive (93%), but not very specific (55%) (Mayeux et al. 1998). These limitations should be recognized when using clinical criteria as a surrogate gold standard. In Chapter II.4, we designate studies using pathologically confirmed diagnoses as Class I or Class II evidence. Studies using clinical diagnoses as the gold standard are downgraded and designated class 1 or class 2 (see Table II.1.4). Each author searched for Class I or Class II evidence. However, if such studies are not available, class 1 and class 2 evidence were reviewed (e.g. MRI and electroencephalogram (EEG) studies) (Table II.1.2).

Presentation of data that enabled the calculation of an LR The likelihood ration (LR) is defined as the number of persons with the test result Ω who have the disease divided by the number of persons with the test result Ω who do not have the disease. LR (Ω) = number with disease and test result Ω /number without disease and test result Ω. For those types of tests that yield a positive or negative result, positive predictive value (PPV), negative predictive value (NPV), sensitivity (SN) and specificity (SP) are also provided (see Section I.5 for definitions). The LR can also be given for a positive (LR+) or negative test (LR−).

INTRODUCTION 83

LR (+) = sensitivity/1 − specificity, LR (−) = 1 − sensitivity/specificity. Receiver-operating characteristic (ROC) curves plot the sensitivity (y-axis) vs. (1 − specificity [x − axis]) as a function of the cut-point used to define a positive test (see Fig. I.5.2); corresponding LRs can be calculated for each cut-point. A commonly used cut-point occurs where sensitivity and specificity are simultaneously maximized (the so-called H value found at the highest leftmost point of the curve). However, this point does not necessarily correspond to the ideal LR for clinical decisionmaking.

of the Alzheimer type) are estimated using prevalence data from epidemiological surveys in the industrialized nations (e.g. USA, Europe, Japan). For dementia, age is the most important determinant of pretest probability. Table II.1.3 show pretest probabilities and corresponding odds values stratified by age derived from a meta-analysis (Jorm et al. 1987). In a refinement of this process, pretest probability could also be stratified by family history, gender, ethnicity, education and severity of dementia (Rocca et al. 1986). Acceptable post-test probabilities for ‘ruling in’ or ‘ruling out’ a disease are considered to be ≤ 90% and ≤ 10%, respectively.

Clinical significance (step 5) and cost-effectiveness (step 6)

Incremental value (step 4) The incremental value of a test is reflected in the change between pre- and post-test probabilities (Gibbons 1998; Mayeux 1998). The likelihood of disease following testing (post-test probability) can be calculated from the pretest probability and LR (NB the pretest probability is converted to an odds value and multiplied by the LR; alternatively, these values can be read from a nomogram; Fagan 1975; Chapter I.5, see Fig. I.5.1). • LRs > 10 or < 0.1 generate large and often conclusive changes from pretest to post-test probability. • LRs between 5 and 10 or 0.1 and 0.2 generate moderate shifts in pretest to post-test probability. • LRs between 2 and 5 or 0.2 and 0.5 generate small (but sometimes important) changes in probability. • LRs between 1 and 2 or 0.5 and 1.0 alter the probability to a small (and rarely important) degree. The pretest probability of dementia (or dementia

Table II.1.3 Pretest probabilities based on age. Age (years)

Probability of dementia

Odds

60–64 65–69 70–74 75–79 80–84 85–89 90–95

0.7 1.4 2.8 5.6 10.5 20.8 38.6

0.007 0.014 0.029 0.059 0.117 0.263 0.629

Clinical significance of a test is understood in relation to decision-making or treatment thresholds. A diagnostic test is clinically significant if it moves a significant number of patients from an ‘uncertain’ pre-test probability to an ‘acceptably certain’ post-test probability. The post-test probability may be plotted graphically as a function of the pre-test probability. For a given LR, incremental value is greatest for those patients with an intermediate pre-test probability. Little value is added for patients who have a very low or very high probability to start with (Chapter I.5). Another measure of clinical significance is whether a test moves a significant number of patients across a treatment vs. no treatment threshold. Here, a high LR may still be of limited utility because the test results move very few patients across a treatment threshold. It could be argued that a highly accurate test for AD would have little clinical significance for treatment, given the absence at the present time of an effective treatment. Finally, are the results applicable to my patients? Were the LRs determined in a similar group of patients, in terms of disease severity and competing diagnoses? LR values tend to be higher for persons with more severe disease, no co-morbidities, or in speciality memory clinics (compare to primary care setting or community surveys). By pooling results across a broader spectrum of patients, metaanalyses may provide variable LRs stratified by severity of dementia or clinical setting. These data

84 CHAPTER II.1

would be valuable in clinical practice where a wide spectrum of patients may be seen. At step 6, the cost of a test is considered in relation to its clinical significance. How much will it cost to move one person across a diagnostic or treatment threshold? How does this compare to the cost of not performing the test? In the field of dementia, we have only begun to grapple with these types of questions.

Table II.1.4 ‘Tests’ reaching a diagnosis of dementia. Mental state exam Neuropsychological exam Instrumental activities of daily living Activities of daily living

Table II.1.5 ‘Tests’ for reaching a diagnosis of dementia

subtype.

Organization of Section II

Clinical criteria

Chapter II.2: Practice guidelines

Symptoms (clinical history) Temporal course Behavioral symptoms Signs (clinical examination) Focal neurological signs Extrapyramidal signs Gait disturbance Neuropsychological tests Blood tests: genetic testing, ApoE genotype Structural imaging: CT/MRI Functional imaging: SPECT/PET Electrophysiological studies: EEG Cerebrospinal fluid and other biomarkers

In this chapter, we review published guidelines for the evaluation and diagnosis of dementia. These include guidelines developed by expert consensus, as well as those based more recently on an evidence-based review of the literature. Here the reader will find a synopsis of current recommendations for clinical practice.

Chapter II.3: Diagnosis of dementiab how accurate and useful are neuropsychological tests and activities of daily living questionnaires? A diagnosis of dementia requires: (i) disturbance in two or more of the following domains: learning and retaining new information (secondary memory), language, visual–spatial synthesis, or executive function; (ii) evidence for impairment of daily functioning which represents a decline from a previously higher level of performance in everyday affairs; and (iii) absence of delirium. In Chapter II.3, we consider the most reliable and accurate methods of determining whether an individual is suffering from a dementia or is functioning within normal limits for age. We review methods to assess cognitive ability and activities of daily living (Table II.1.4). In this chapter we use widely accepted definitions of dementia published in the DSM (Diagnostic and Statistical Manual) (American Psychiatric Association 1994), ICD (International Classification of Disease) (World Health Organization 1993) and the NINCDS-ADRDA criteria (National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer Disease

ApoE, apolipoprotein E; CT, computerized tomography; EEG, electroencephalogram; MRI, magnetic resonance imaging; PET, positron emission tomography; SPECT, single photon emission computerized tomography.

and Related Disorders Association) (McKhann et al. 1984). During the past several years, the focus of research has shifted to the earlier detection of mild cognitive impairment (MCI) preceding the development of full-blown dementia. These studies are covered in Section III.8 of this book. Since the ideal time for intervention is sooner rather than later, future updates on earlier diagnosis are anticipated.

Chapter II.4: Diagnosis of dementia subtypebhow accurate and useful are clinical criteria, clinical signs and symptoms, and diagnostic tests? With the exception of relatively rare autosomal dominant causes of dementia, there are no specific biological markers for the most common forms of dementia. Hence, academic neurologists and

INTRODUCTION 85

psychiatrists have taken a pragmatic approach to classification and diagnosis. Disorders are grouped according to clinical and pathological phenotype, based upon features that can be physically observed. Clinical and pathological criteria are developed which list typical phenotypic features. Pathological findings have been adopted as the reference or ‘gold standard’ by which the accuracy of clinical diagnosis is measured. The most common clinicopathological entities are known as Alzheimer’s disease (AD), vascular dementia (VaD), dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD). These are the four subtypes of dementia that are systematically reviewed in Chapter II.4. These and other types of dementia are also covered in Section III. The kinds of ‘tests’ evaluated in this chapter are summarized in Table II.1.5.

References American Psychiatric Association (1994) Diagnostic and Statistical Manual of Mental Disorders, 4th edn. American Psychiatric Association, Washington, DC. Fagan, T.J. (1975) Nomogram for Bayes theorem. New England Journal of Medicine 293, 257. Friedland, D.J., Go, A.S., Davoren, J.B. et al. (1998) Evidence-based Medicine. A Framework for Clinical Practice. Appleton & Lange, Stanford. Gibbons, R.J. (1998) Obtaining incremental information from diagnostic tests. In: Evidence Based Cardiology

(Yusef, S., Cairns, J.A. Camm, A.J. et al., eds), pp. 39–53. BMJ Books, London. Jaeschke, R., Guyatt, G. & Sackett, D.L. for the EvidenceBased Medicine Working Group (1994a) Users’ guide to the medical literature. III. How to use an article about a diagnostic test. A. Are the results of the study valid? Journal of the American Medical Association 271, 389–391. Jaeschke, R., Guyatt, G.H. & Sackett, D. for the EvidenceBased Medicine Working Group (1994b) Users’ guide to the medical literature. III. How to use an article about a diagnostic test. B. What are the results and will they help me in caring for my patients? Journal of the American Medical Association 271, 703–707. Jorm, A.F., Korten, A.E. & Henderson, A.S. (1987) The prevalence of dementia: a quantitative integration of the literature. Acta Psychiatrica Scandinavica 76, 465–479. Mayeux, R. (1998) Evaluation and use of diagnostic tests in Alzheimer’s disease. Neurobiology of Aging 19, 139–143. Mayeux, R., Saunder, A.M., Shea, S. et al. (1998) Utility of the apolipoprotein E genotype in the diagnosis of Alzheimer’s disease. New England Journal of Medicine 338, 506–511. McKhann, G., Drachman, D., Folstein, M., Katzman, R., Price, D. & Stadlan, E. (1984) Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of the Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 34, 939–944. Oxman, A.D., Cook, D.J. & Guyatt, G.H. (1994) Users’ guide to the medical literature. VI. How to use an overview. Journal of the American Medical Association 272, 1367–1371. Rocca, W.A., Amaducci, L.A. & Schoenberg, B.S. (1986) Epidemiology of clinically diagnosed Alzheimer disease. Annals of Neurology 19, 415–424. World Health Organization (1993) International Classification of Diseases, 10th edn. World Health Organization, Geneva.

II.2

Practice Guidelines

Helena Chui

Background Clinical guidelines have been published for the evaluation of patients with dementia. These guidelines address: (i) what aspects of the evaluation should be ordered routinely; and (ii) what tests should be ordered under special circumstances. Initially, the practices of experts were discussed and codified at consensus conferences. Shifts have begun recently to base recommendations on strength of evidence, as well as expert opinion.

Consensus guidelinesdexpert opinion In 1987, the National Institutes of Health (NIH) convened a consensus development conference (cosponsored by the National Institute on Aging, the National Institute of Neurological and Communicative Disorders and Stroke, and the National Institute of Mental Health, see Appendix II.2.1). An expert panel emphasized that the accurate diagnosis of dementia hinges upon a careful clinical evaluation by a knowledgeable physician: ‘A laboratory test, whether chemical, biological, imaging, or psychological should never be used as a substitute for the physician’s time, expertise, and clinical judgement’ (National Institutes of Health 1987). The clinical evaluation should be focused on obtaining a chronology of symptoms, a description of functional and behavioral changes, the focal findings in the neurological examination, and a brief mental status exam. The basic laboratory work-up should include: a complete blood count, electrolytes, syphilis serology, thyroid functions, vitamin B12 and folate, urinalysis, chest X-ray and electrocardiogram.

86

Three indications (i.e. suspected mass lesion, presence of focal signs, dementia of brief duration) were mentioned for an optional CT scan of the brain. MRI, SPECT, PET, EEG and lumbar puncture were considered controversial and not required for typical cases. The importance of continuing clinical observation beyond the initial assessment was underscored. In 1997, a consensus statement was developed jointly by the American Association for Geriatric Psychiatry, the Alzheimer’s Association, and the American Geriatrics Society (Small et al. 1997). The informant interview and the office-based clinical assessment were identified as the most important diagnostic tools. With few exceptions, the objectives and methods of the basic clinical and laboratory work-up were similar to those described in the NIH consensus statement, published a decade previously. However, folate, urinalysis, chest X-ray and electrocardiogram had been dropped from the basic laboratory evaluation. Imaging studies were still considered optional, but recommended by many clinicians and experts. A non-contrast head CT scan was considered adequate in most instances. MRI was recommended for vascular dementia, with caution against overinterpreting the clinical significance of deep white matter changes. Guidelines designed for primary care practitioners were published by the US Department of Veterans Affairs/Unversity Health-System Consortium (1997) and the American Medical Association (1999). The American Medical Association recommends neurological history and examination and certain laboratory studies in all patients. Neuroimaging studies are recommended in patients with symptoms

PRACTICE GUIDELINES 87

of short duration, other neurological signs/symptoms (e.g. seizures, headache, abnormal motor examination) or for patients aged under 60 years. Special laboratory studies (e.g. human immunodeficiency virus, erythrocyte sedimentation rate, syphilis serology), neuropsychological testing and lumbar puncture are recommended in selected patients. PET or SPECT are rarely recommended, but may possibly be used to corroborate the diagnosis of frontal lobe dementia.

Evidenced-based practice parameters Recently, attempts have been made to differentiate levels of recommendations based on the strength of evidence. In 1996, the Agency for Health Care Policy and Research (AHCPR) published clinical practice guidelines directed at the recognition and initial assessment of Alzheimer’s disease and related dementias (Costa et al. 1996). These guidelines were intended to assist the health care provider in detecting dementias in their early stages, rather than to assist with differential diagnosis. The recommendations were prepared in two versions: one for health care providers and another for consumers. Three levels of evidence were defined. Strong evidence (class A) was defined as evidence from case–control studies that compared patients who had dementia with control subjects who did not have dementia but who did have co-morbid or interfering conditions (i.e. a broad spectrum of patients and controls). Suggestive evidence (class B) was defined as the same type of case–control evidence as class A, but involving a smaller number of studies or a less consistent pattern of findings. Expert opinion (class C) was defined as evidence from clinical experience described in the literature or derived from the consensus of panel members. Triggering symptoms A list of symptoms (class C evidence) was identified as a trigger for an initial dementia assessment. These include cognitive difficulties (e.g. in learning and retaining new information, handling complex tasks, reasoning, spatial ability and orientation, or language) or changes in behavior.

Initial assessment In the presence of any of the above symptoms, an initial multifaceted assessment is recommended (class B). Two specific ‘tests’ are recommended based on class A evidence; most of the other recommendations are based on expert opinion. Initial assessment should include administration of: (i) a functional activities questionnaire (class A); and (ii) a mental status test (class A). In selecting a mental status test, visual, perceptual and motor impairment should be assessed and considered (class B). In interpreting the results of the mental status test, confounding factors such as age, educational level and cultural influences should be assessed and considered (class B). A focused medical, family, social, cultural and medication history, as well as a detailed description of the chief complaint, should be obtained from the patient and reliable informant (class C). Recommendations If both functional and mental status tests are normal and no other concerns are raised from the clinical assessment, reassurance and reassessment in 6–12 months should be suggested. If other concerns are raised, or if either functional or mental status tests are abnormal, further clinical (e.g. neurological, psychiatric, neuropsychological) evaluation should be made (class C). Neuropsychological testing (class C) is recommended when: 1 The mental state is normal but the functional questionnaire is abnormal and the patient has more than a high school education or an occupation suggesting high premorbid intelligence. 2 The mental state is abnormal but the functional questionnaire is normal, or the patient has (i) little formal education; (ii) evidence of long-standing low intelligence; (iii) inadequate command of English; (iv) is of a minority racial or ethnic background; (v) shows impairment in only one area of cognitive functioning; or (vi) has cognitive impairment of less than 6 months’ duration. In 1994, the Quality Standards Subcommittee of the American Academy of Neurology (AAN) published the Practice Parameters for Diagnosis and

88 CHAPTER II.2

Evaluation of Dementia (1994). These guidelines were based on a systematic review of the literature (Corey-Bloom et al. 1995) and address the diagnosis of dementia, as well as the diagnosis of dementia subtype. The practice parameters are stratified according to three levels of certainty: standards (strong certainty), guidelines (moderate certainty) and options (unclear certainty) (Fig. II.2.1). The neurological history and examination (including the mental status examination) were recommended as standards. Certain laboratory tests were suggested as guidelines. Other tests, including neuropsychology and imaging, were suggested as options. Unfortunately, the definitions for strength of evidence were adopted from clinical trials (e.g. Class I evidence is provided by one or more well-designed randomized control clinical trials.), which are not suitable for evaluating the value of a diagnostic test. Thus, the practice parameters are currently undergoing revision, using more appropriate measures of test performance (e.g. positive predictive value, negative predictive value, sensitivity, specificity, likelihood ratio).

Evidence The frequency of abnormal diagnostic test results deemed relevant to the diagnosis or management of dementia has been reported in several previous studies. In 200 outpatients evaluated for dementia, Larson et al. (1988) considered 3–10% of laboratory findings to be of therapeutic importance. Depending upon the referral sample, 1–20% of CT head scans have shown abnormalities amenable to treatment, including surgical intervention (e.g. subdural hematoma, normal pressure hydrocephalus or tumor) (for review see Roberts & Caird 1990). Several investigators have proposed strategies to improve the diagnostic yield of the more expensive neuroimaging studies (Simon & Lubin 1985; Martin et al. 1987; Larson et al. 1988). One study (Chui & Zhang 1997) has systematically addressed the utility of the AAN practice parameters (American Academy of Neurology 1994). This study examined the added value of laboratory, neuropsychological and imaging studies for clinical diagnosis and managementabeyond

the standard neurological history and examination. The records of 119 consecutive patients, who had been referred to a university-affiliated memory clinic, were reviewed. Laboratory testing changed the diagnosis of dementia in 9% of cases and influenced patient management in 12.6%. In a subset of 70 cases, neuropsychological testing changed the dementia diagnosis in 11.4% and influenced patient management in 1.4%. Neuroimaging (CT or MRI) changed the diagnosis of dementia in 19.3% and influenced patient management in 15.1%. Based on this relatively small, retrospective, clinicbased study, it appears that meaningful clinical information is obtained from approximately one in five neuroimaging studies and one in 10 laboratory or neuropsychological studies. To improve cost-effectiveness, guidelines for selective use of neuroimaging studies are desirable. Based on a review of the literature, the AAN Quality Standard Subcommittee suggested that imaging studies are indicated when patients: (i) are less than 60 years of age; (ii) show a non-insidious course; (iii) have focal signs or symptoms; and (iv) have a gait disturbance. Clinical judgement was used to identify cases where neuroimaging influenced diagnosis or management. In comparison with clinical judgement, the indicators for selective imaging proved to be 79% sensitive, but only 47% specific (positive likelihood ratio = 1.5; negative likelihood ratio = 2.2) (Chui & Zhang 1997). Sensitivity was limited by six false negative cases, which included four patients with silent infarcts, one with severe temporal atrophy (suggesting the possibility of Pick’s disease) and one with disproportionate enlargement of the ventricles (raising the possibility of normal pressure hydrocephalus). Specificity was limited by 42 false positive cases, where the presence of an indicator would have led to neuroimagingabut where no specific abnormality other than atrophy or mild leukoaraiosis would have been found. In clinical practice, it is more important to err on the side of greater sensitivity than specificity: it is preferable to overscan, than to underscan and miss something treatable. Although the errors resulting from application of the AAN indicators fall in the preferred direction, the data suggest they are not very good in predicting a clinically meaningful imaging study.

PRACTICE GUIDELINES 89

History Physical exam Neurological exam Mental status exam

Follow-up evaluation

Not demented

Standards

Cognitive decline affecting multiple cognitive domains?

No

Suspected

Neuropsychological testing

Yes Diagnosis and treatment

Delirium or depression?

Yes

EEG No Cognitive impairment not meeting criteria for dementia

No

Functional decline? Yes

Dementia

Yes CBC, SMA-7, LFT TFT, (T4, TSH), B12, syphilis serology

Diagnosis and treatment

No

Guidelines

Normal?

Yes

Alzheimer’s disease

+ PMH + ROS + Exam ?

No

Yes

ESR, HIV, U/A CXR, tox screen, 24° heavy metals

No

Early onset, non-insidious, focal signs/sxs, abnormal gait, ?

Yes

No

Onset < 50, rapid unsual hydrocephalus, CNS infection/vasculitis, immunosuppression, Syphilis ser, cancer met, ?

Yes

CT MRI

No

CJD, seizures, tox/met. encephalophy, encphalitis, ?

No

Yes

LP

Yes

EEG

Options

Fig. II.2.1 Practice parameters for diagnosis and evaluation of dementia (adapted from American Academy of

Neurology 1994).

Research?

SPECT PET

90 CHAPTER II.2

Conclusions and recommendations For the most part, official recommendations for the evaluation and diagnosis of dementia have been based on expert opinion. Two guidelines published during the past 5 years have taken the first steps involved in an evidenced-based review of the literature. These guidelines conducted a systematic review of the literature and evaluated the strength of evidence based on study design. However, none

have systematically analysed test performance (e.g. likelihood ratio, positive predictive value, negative predictive value, sensitivity, specificity), incremental value (i.e. change between pre- and post-test probability), assessment of clinical significance (i.e. a test’s impact on clinical decision-making) or assessment of cost-effectiveness. In this section, we take the next step in an evidence-based review and take a critical look at test performance.

Appendix II.2.1 NIH consensus recommendations for the evaluation of dementia (National Institutes of Health 1987) The initial clinical evaluation of dementia should include: 1 Chronology of symptoms. 2 Family history. 3 Behavioral and functional changes. 4 Physical examination. 5 Mental status test. Basic laboratory tests should include: 1 Complete blood count. 2 Electrolyte panel. 3 Metabolic panel. 4 Thyroid function tests. 5 Vitamin B12 and folate levels. 6 Tests for syphilis and possibly human immunodeficiency antibodies. 7 Urinalysis. 8 Electrocardiogram. 9 Chest X-ray. Ancillary tests include: 1 CT scan of the brain without contrast when: (i) the history suggests a possible mass; (ii) in the presence of focal neurological signs; and (iii) dementia is of brief duration. 2 Discontinuation of all unnecessary medications. 3 Electroencephalography when consciousness is altered or seizures are suspected. 4 Psychiatric assessment when depression is suspected. 5 Inpatient hospitalization if: (i) the history is

unclear; (ii) the patient is suicidal; (iii) acute deterioration has occurred without apparent cause; and (iv) if the social situation precludes adequate observation. 6 Neuropsychological evaluation is appropriate: (i) to obtain a baseline against which to measure change when the diagnosis is in doubt; (ii) before and following treatment; (iii) in cases of exceptionally bright individuals suspected of early dementia; (iv) in cases of ambiguous imaging findings that require elucidation; (v) to help distinguish dementia from depression or delirium; or (vi) for information about the extent and nature of impairment following focal or multifocal brain injury. 7 Speech and language analysis may be helpful to: (i) distinguish aphasia from dementia; and (ii) improve patient communication. The following were considered controversial at the time: 1 MRI. 2 PET and SPECT. 3 Lumbar puncture. 4 Event-related potentials. 5 Brain biopsy. 6 Biological markers. 7 Molecular markers for Huntington’s and Alzheimer’s disease. 8 Carotid ultrasound.

PRACTICE GUIDELINES 91

References American Academy of Neurology (1994) Practice parameters for diagnosis and evaluation of dementia (summary statement). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 44, 2203–2206. American Medical Association (1999) Diagnosis, Management and Treatment of Dementia: a Practical Guide for Primary Care Physicians. American Medical Association, Chicago. Chui, H. & Zhang, Q. (1997) Evaluation of dementia: a systematic study of the usefulness of the American Academy of Neurology’s practice parameters. Neurology 49, 925–935. Corey-Bloom, J., Thal, L.J., Galasko, D. et al. (1995) Diagnosis and evaluation of dementia. Neurology 45, 211–218. Costa, P.T., Williams, T.F., Albert, M.S. et al. (1996) Alzheimer Disease and Related Dementias: Early Recognition and Initial Assessment. Guideline Technical Report No. 19. AHCPR Publication No. 97–0703. US Agency for Health Care Policy and Research, Rockville, MD. Larson, E.B., Reifler, B.V., Sumi, S.M., Canfield, C.G. & Chinn, N.M. (1988) Diagnostic tests in the evaluation of dementia: a prospective study of 200 elderly outpatients. Archives of Internal Medicine 146, 1917–1922.

Martin, D.C., Miller, J., Kapoor, W., Karpf, M. & Boller, F. (1987) Clinical prediction rules for computed tomographic scanning in senile dementia. Archives of Internal Medicine 147, 77–80. National Institutes of Health (1987) National Institutes of Health Consensus Development Conference Statement, Vol. 6, No. 11, 6–8 July 1987. Differential diagnosis of dementing diseases. Alzheimer Disease and Associated Disorders 2 (1), 4–15. Roberts, M.A. & Caird, R.F. (1990) The contribution of computerized tomography to the differential diagnosis of confusion in elderly patients. Age and Ageing 19, 50–56. Simon, D.G. & Lubin, M.F. (1985) Cost effectiveness of computerized tomography and magnetic resonance imaging in dementia. Medical Decision Making 5, 335–354. Small, G.W., Rabins, P.V., Barry, P.P. et al. (1997) Diagnosis and treatment of Alzheimer disease and related disorders. Consensus statement of the American Association for Geriatric Psychiatry, the Alzheimer’s Association, and the American Geriatrics Society. Journal of the American Medical Association 278, 1363–1371. US Department of Veterans Affairs/University HealthSystem Consortium. (1997) Dementia Identification and Assessment. Guidelines for Primary Care Practitioners. University Health-System Consortium, Oak Brook, IL.

II.3

Reaching a Diagnosis of Dementia

Edited by: Helena Chui

II.3.1

Neuropsychological Assessment

Mary C. Tierney

One of the first decisions clinical neuropsychologists must make in the assessment of older, possibly cognitively impaired, patients is whether they meet the criteria for dementia. To do this, neuropsychologists rely on normative data provided in test manuals, compendiums (e.g. Spreen & Strauss 1998) and published research to determine which tests, and respective cut-off scores, best classify their patients as normal, cognitively impaired or demented. The question explored in this chapter is: ‘From an evidence-based perspective, which neuropsychological tests or test batteries have diagnostic validity in making these classifications?’

Search strategy and study validation Search strategy Studies were selected for inclusion in this chapter if they compared the neuropsychological test performance of a group of participants with dementia to a group that did not have dementia. We included studies whose dementia groups were composed of participants with either multiple dementia etiologies or a single dementia etiology (e.g. Alzheimer’s disease, AD). Studies that included comparisons of more than one dementia group are reviewed in Section II.4.4. Searches were conducted in PsychInfo and Medline including those from 1980 to date. The keywords used in the search of PsychInfo were: dement* or alzheimer*, sensitivity and neuropsychol*. This search was repeated except that

92

neuropsychol* was substituted with each of the following terms: california verbal learning, boston naming test, rey, auditory verbal learning test, controlled oral, oral fluency, verbal fluency, delayed recall, buschke, mini mental state, WAIS, Wisconsin card, wechsler and trail. The keywords for Medline were: alzheimer disease, dementia, cogniti*, memory, benign senescent forgetfulness, decline, impairment, sensitivity and specificity, diagnostic errors, neuropsychological tests or psychometrics. While the international literature was searched, only those articles written in English were requested. A thorough review of the references from A Compendium of Neuropsychological Tests (Spreen & Strauss 1998) was also completed. Titles and abstracts were reviewed for relevancy to this chapter. If there was any evidence that the article was relevant, it was retrieved for further assessment. Seventy-two articles were retrieved on this basis. Each article was independently reviewed and classified by at least two research psychologists with expertise in neuropsychological assessment. Articles for which a consensus classification could not be made were reviewed by a third psychologist with expertise in biostatistics. This process derived a consensus classification for every article. Fourteen studies were included in this chapter because they met the four criteria outlined in Chapter II.1.

Study validation Reference or gold standard studies were not

REACHING A DIAGNOSIS 93

included in this chapter if they failed to use clinical gold standard reference criteria for dementia, which included the dementia criteria of DSM-III-R (American Psychiatric Association 1987), DSM-IV (American Psychiatric Association 1994), ICD-9 (International Classification of Diseases), ICD-10 or NINCDS-ADRDA (McKhann et al. 1984). Thus memory impairment had to be considered as essential for the diagnosis of dementia, in addition to at least one other area of cognitive decline. If the dementia comparison group comprised people with AD only, these studies were included if they used the NINCDS-ADRDA criteria for AD. We required strict adherence to these criteria and did not include studies that made modifications to them. Although the ideal means of diagnostic confirmation is neuropathological, no studies in this review used neuropathological criteria as the gold standard, although several refer to autopsy confirmation of the diagnoses in some of the participants. The limitation with the use of clinical criteria as the reference standard is that neuropsychological tests must be used in conjunction with other assessments to determine whether an individual patient meets these clinical criteria for dementia. Thus the neuropsychological tests under investigation for diagnostic accuracy are compared against a reference standard classification which was probably based on neuropsychological tests whose diagnostic accuracy had not been established in this evidencebased manner. Unfortunately, in many of the articles reviewed, the investigators did not describe the cognitive tests used to make the clinical diagnosis although this was not considered to be a reason to exclude the article from this chapter. Independent blind validation The major reason studies did meet criteria for this chapter was because investigators did not keep the test validation process separate from the diagnostic process. Studies were excluded from this chapter if the tests under investigation were used to classify participants into the diagnostic groups. Unless the investigators stated that their tests under evaluation were not part of the diagnostic process, we did not include the study in this chapter.

Likelihood ratios Many well-designed studies were not reviewed because the authors did not provide data to calculate likelihood ratios (LRs). Following the guide provided by Jaeschke et al. (1994b), an LR for a test positive individual (LR+) of > 10 was defined as large (i.e. would generate a large change from pretest to post-test probability), an LR+ of > 5–10 was defined as moderate, an LR+ of > 2–5 was small and a LR+ of 1–2 was unimportant. Comparison groups The criterion that at least one comparison group must not meet diagnostic criteria for the target disorder was met in two ways in the studies included in this chapter. The first, and ideal, way was to ensure that diagnostic evaluations were conducted on participants in both the dementia and control groups. However, only one-third of the studies in this chapter followed this approach. In the second, less desirable, way investigators recruited participants for the control group from sources where they expected higher functioning individuals and then screened them to ensure they were normal well-functioning elderly people without subjecting them to a diagnostic evaluation. For example, some studies recruited community-dwelling control group participants through media solicitations or seniors groups and then asked questions to ensure that they were healthy and did not have any medical conditions likely to affect the brain. Dementia participants, on the other hand, often were recruited from dementia clinics and only these individuals received a thorough diagnostic work-up. This approach, although cost saving, is less desirable because it is not as thorough in its evaluation of the control group.

Classification of studies All the studies that met these four criteria were classified as either class I or class II; studies were classified as class I if the design was prospective or class II if the design was retrospective. Studies were then classified as class IA or class IIA if they included an appropriate spectrum of participants to whom

94 CHAPTER II.3

the diagnostic test would be applied in clinical practice and if there was not a work-up bias. A narrow spectrum of participants and/or a work-up bias led to the classification of studies as class IB or class IIB. Prospective and retrospective designs We have defined a prospective study as one in which all the rules of data collection, sampling procedures, inclusion and exclusion criteria, and future statistical analyses and their interpretations were documented and shared amongst investigators. In addition, the date of acquisition of the first data point in real time had to occur subsequent to agreement on all of the above. Unless sufficient details were provided, the study was judged to be retrospective. Appropriate spectrum of participants Jaeschke et al. (1994a) make the point that the pragmatic value of a test can only be established in a study that resembles clinical practice. The clinical neuropsychologist must identify those who have cognitive loss due to an underlying dementia and differentiate them from those with cognitive, affective or medical problems that may mimic dementia. Therefore, a study was judged to have an appropriate spectrum of participants if it included those with a high, medium and low suspicion of dementia based on the diagnostic reference standard. For example, studies that included only high-functioning control participants compared to dementia patients were judged to have a narrow spectrum because these comparisons do not resemble clinical practice. Work-up bias A work-up bias refers to a situation in which the results of the diagnostic test have influenced the decision to subject participants to the reference standard. For example, an investigation examining the diagnostic classification accuracy of the MMSE, which also used the MMSE to determine who received a diagnostic work-up, was considered to have a work-up bias.

Evidence Class IA Studies meeting criteria for this chapter were classified as class IA if their design was prospective, there was an appropriate spectrum of persons with and without the suspected condition, and there was no work-up bias. All studies in this section and subsequent sections are presented alphabetically by order of the name of the first author. Two studies met these criteria. The first was a cross-sectional, prospective study conducted by Incalzi et al. (1995). This study included a broad range of elderly patients who were admitted to the same hospital in Italy for minor surgery (two control samples) or to the neurology or geriatric wards (dementia sample). All participants were screened to determine whether they met DSM-IIIR criteria for dementia. The dementia sample was further screened to select those who met NINCDSADRDA criteria for AD. The investigators excluded very impaired patients, thereby including only patients with mild to moderate levels of the disease. The neuropsychological tests that accounted for discrimination among the groups were five subtests of the Rey Auditory Verbal Learning Test (RAVLT) (forgetting, immediate recall, delayed recall, false positive recognition, and middle of the list serial position effect) and the Wechsler Adult Intelligence Scale, revised (WAIS-R) Digit Span backwards. We combined the discriminant function analyses results of their two elderly control groups to derive sensitivity, specificity and LRs. As can be seen in Table II.3.1, the LR is 8.1, representing a moderate shift in pre- to post-test probability. Although the investigators report that misclassified AD patients were better educated, unfortunately neither education nor age was entered in the discriminant function analyses as covariates. The second study in this class was a prospective longitudinal study by Tierney et al. (1996). Family physicians referred their patients to this study if they were concerned about their patients’ memory loss. All subjects were screened to ensure they did not meet DSM-III-R criteria for dementia upon entry to the study. Eligible subjects were first administered a battery of neuropsychological tests

REACHING A DIAGNOSIS 95

Table II.3.1 Studies evaluating diagnostic accuracy of neuropsychological tests comparing a dementia group with a non-demented control group. Dementia group

Control group*

Clinical criteria

Study design

Incalzi et al. (1995)

AD

Nondementia

DSM, NINCDS

P

RAVLT, WAIS-R Digit Span

81

90

8.1

IA

Tierney et al. (1996)

AD†

Nondementia

DSM, NINCDS

P

RAVLT (delayed recall), WMS Mental Control

76

94

12.7

IA

Buschke et al. (1999)

Mixed and AD

Normals

DSM, NINCDS

P

MIS: Dementia vs. NC

80

96

20.0

IB (w/u bias)

87

96

22.0

Grut et al. (1993)

Mixed

Nondementia

DSM

P

MMSE

96

78

4.3

IB (w/u bias)

Heun & Jennssen (1998)

Mixed

Nondementia

DSM

P

Animal and first name fluency

84

81

4.4

IB (selection bias)

WLL (immediate recall) TMT Labyrinth

82 81 88

77 71 60

3.6 2.8 2.2

MMSE

84

90

8.4

Benton Orientation, Retention and Verbal Fluency

74

90

7.4

90

92

11.3

IB

94

93

13.4

IIB

74

93

10.6

100

93

14.3

76 92

96 96

19.0 23.0

Author

Test

AD vs. NC

Ritchie & Fuhrer (1992)

Mixed

Normals

DSM

P

Welsh et al. (1991; 1992)

AD

Normals

NINCDS

P

DWR (delayed recall)

Bondi et al. (1993)

AD

Normals

NINCDS

R

Modified WCST: AD vs. NC (no. categories) Mild AD vs. NC (no. perseverative errors)

Monsch et al. (1992)

AD

Normals

DSM, NINCDS

R

Animal fluency: All groups Supermarket fluency: Mild AD vs. NC AD vs. NC

Sensitivity

Specificity

LR+

Class

IB (selection bias)

IIB

Monsch et al. (1995a)

AD

Normals

DSM, NINCDS

R

DRS

97

99

97.0

IIB

Knopman & Ryberg (1989)

AD

Normals

NINCDS

R

DWR (delayed recall)

89

98

44.5

IIB

Leopold & Borson (1997)

Mixed

Normals

NINCDS for AD; IVD for vascular dementia

R

Spelling test WORLD

85

87

6.5

IIB

Monsch et al. (1995b)

AD

Normals

DSM, NINCDS

R

MMSE

74

98

37.0

IIB

Solomon et al. (1998)

AD

Normals

NINCDS

R

Neurocognitive Screen: enhanced cued recall; Benton Temporal Orientation, animal fluency, clock drawing

92

96

23.0

IIB

LR+, likelihood ratio for the positive test; R, retrospective; P, prospective, w/u, work-up. *A study has a narrow spectrum of participants if the control groups are composed of normals. †These tests classified participants 2 years before the onset of AD in one group.

96 CHAPTER II.3

and then followed for 2 years. After 2 years, all subjects were given another diagnostic work-up for dementia (DSM-III-R) and AD (NINCDS-ADRDA). Logistic regression analyses revealed that two of the tests administered at baseline, the RAVLT delayed recall and the mental control subtest of the Wechsler Memory Scale (WMS), showed classification accuracy as robust as the larger battery of tests. The LR was 12.7, representing a large shift from pre- to post-test probability.

Class IB Studies classified as class IB were otherwise the same as those classified as class IA except that in these studies the test was applied to either a narrow spectrum of participants with and without the suspected condition or there was a work-up bias. Buschke et al. (1999), in a cross-sectional prospective study, examined the effectiveness of the Memory Impairment Screen (MIS), a four-item cued recall task. Their sample included volunteers who were part of the Einstein Aging Study and those recruited from health care lists. Normal controls (NCs) were those who met cut-off scores on two brief cognitive screening tests and were not suspected by the testers of having cognitive problems. Those who did not meet these criteria then received a complete diagnostic work-up for dementia. This study suffers from a work-up bias in that one criterion, which determined whether participants received a dementia assessment, was suspicion of cognitive impairment by the testers and one of the tests administered by the testers was the MIS. This study would have been improved if all participants had undergone a diagnostic work-up for dementia. Furthermore, an important comparison group is virtually ignored in this study, i.e. the group who were worked-up for dementia but who were not found to meet the criteria. Inclusion of this group would have resulted in an appropriate spectrum of participants for clinical practice. Based on a MIS cut-off score of 3/4 (i.e. scores of less than 4 indicate impairment), the LRs for the comparisons between all dementia cases and NCs (20.0), and between the AD cases and NCs (22.0), were large. Grut et al. (1993) examined the diagnostic accur-

acy of the Mini Mental Status Examination (MMSE) for participants with dementia and a control group without dementia. Their sample included all the inhabitants of a region in Sweden who agreed to participate. A work-up bias was present in that performance as the MMSE determined whether a diagnostic evaluation was completed. In the study, the investigators calculated the classification accuracy of the MMSE by extrapolating from their sample who underwent diagnostic evaluation to their larger sample who were screened with the MMSE. Rather than use their figures, which were based on extrapolations from nonrandom sample selection, we recalculated sensitivity and specificity based only on those individuals who underwent diagnostic evaluation. Based on a cut-off score of 23/24 (i.e. scores of less than 24 indicate impairment) on the MMSE, the LR was 4.4, representing a small shift in pretest to post-test probability. Heun & Jennssen (1998) conducted an epidemiological study of the elderly general population in Germany. All participants received the same diagnostic work-up for dementia, which did not include radiological or laboratory tests. Their sample included 287 people, 37 of whom met the criteria for dementia. The authors acknowledge that their sample of convenience was not representative of the general population, but was a younger, healthier sample. Four of their diagnostic tests were assessed independently of their diagnostic assessment: the Word List Learning (WLL) Test, Animal Fluency, Trail Making Test (TMT) and Labyrinth Test. Based on receiver-operating characteristic (ROC) curves, the best cut-off values, which optimized sensitivity and specificity, were selected individually for each test. LRs for the first three tests (ranging from 2.8 to 4.4) represented small shifts in pre- to post-test probability. The LR for the Labyrinth Test (2.2) was too small to represent a meaningful shift in pretest to post-test probability of dementia. Ritchie and Fuhrer (1992) examined the diagnostic accuracy of a French version of the MMSE and the Benton Orientation, Retention and Verbal Fluency Tests in distinguishing between demented and non-demented cases. All participants received

REACHING A DIAGNOSIS 97

the same work-up for dementia. Compliance issues resulted in a selection bias: most of the dementia cases resided in institutions and the non-demented cases resided in the community. The LR for the MMSE at a cut-off of 23/24 was moderate (8.4). Set at the same specificity level for the MMSE (90%), the LR for the Benton tests was also moderate (7.4). The diagnostic accuracy of the test battery of the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD), in distinguishing between a group of patients with mild AD and NCs, was evaluated by Welsh et al. (1991, 1992). The screening of the NCs was not described. The delayed recall subtest of a 10-word list was the only test contributing to differences between groups. The LR was large (11.3).

Class IIA Studies were classified as IIA if the design was retrospective, there was an appropriate spectrum of persons with and without the suspected condition, and there was no work-up bias. No studies met these criteria.

Class IIB The same criteria were applied to class IIB studies as were applied to class IIA except that in these studies the test was applied to either a narrow spectrum of people with and without dementia or there was a work-up bias. Three of the seven studies in this section, i.e. Bondi et al. (1993), Monsch et al. (1992) and Monsch et al. (1995a), included patients and NCs from an existing database. AD patients were from an Alzheimer disease research centre (ADRC) and the NC group comprised spouses of patients and volunteers recruited from newspaper advertisements. All studies used ROC curves to derive cut-off scores providing optimal sensitivity and specificity. Bondi et al. (1993) examined the diagnostic accuracy of three subscales from a modified Wisconsin Card Sort Task (WCST). Large LRs were obtained with two subscales: number of categories attained (13.4) and number of perseverative errors (10.6). The diagnostic accuracy of the Dementia Rating

Scale (DRS) was examined by Monsch et al. (1995a). A very large LR was obtained (97.0) with a cut-off score of 129. This cut-off score is higher than that reported in the test manual (i.e. 124). However, the validity of this higher cut-off score in clinical practice should be determined in a study with an appropriate spectrum of participants. Monsch et al. (1992) examined the accuracy of category and letter verbal fluency measures in another sample from the Alzheimer disease research centre (ADRC) database. The AD group was very impaired, even the subsample of ‘mild’ AD patients (> 17 on the MMSE or > 114 on the DRS) included moderately impaired people. Their results indicate that fluency measures in which exemplars of higher order categories must be provided (i.e. animals, fruits, vegetables and supermarket items), contributed significantly to the regression model. Large LRs were found for distinctions between both the mild AD vs. NCs and the AD vs. NCs (ranging from 14.3 to 23.0). Knopman and Ryberg (1989) found that the 10item Delayed Word Recall (DWR) Test had a very large LR of 44.5 in a narrow spectrum of normal community-dwelling control participants and probable AD patients. Over 82% of the AD patients were selected from an AD outpatient clinic. Discriminant function analysis was used and a cut-off score of 2/3 was established. The reliability of their version of the DWR Test has not been well established. Leopold and Borson (1997) examined patients consecutively referred to a neuropsychology service who were undergoing evaluation for possible dementia or depression and who subsequently met the diagnostic criteria for dementia. These patients were compared with a control group of spouses of patients from another clinic. There was no description of the screening procedure for the controls to ensure that they were dementia-free. These two groups were compared on their ability to spell ‘world’ forwards, backwards and in alphabetical order. Multivariate analyses with age and education serving as covariates were not done despite the presence of group differences on these variables. Based on optimal sensitivity and specificity, a cutoff score of 2/3 resulted in a moderate LR (6.5).

98 CHAPTER II.3

Monsch et al. (1995b) examined the accuracy of the MMSE in a group of Swiss patients who were referred to an outpatient referral centre for a diagnostic assessment for dementia. Patients who met criteria for AD were included. The NC group was composed of paid volunteers from an adult education program and referred patients who were extensively screened and found to be cognitively normal. ROC curves were generated to determine optimal cut-off scores. Using a cut-off score of 25/26 the LR was very large (37.0), but the application of these findings to the clinical setting is limited given the narrow spectrum of participants. The 7-Minute Neurocognitive Screening battery was evaluated by Solomon et al. (1998) in a narrow spectrum of participants: outpatient memory clinic referrals found to have AD and communitydwelling volunteers. The battery consisted of an enhanced cued recall test, the Benton Temporal Orientation Test, category fluency, and a clock drawing test. Using logistic regression analyses, a large LR was found (23.0) for the combined battery of tests. The relative contribution of each test in the battery was not examined.

Conclusions Tables II.3.2 and II.3.3 describe the neuropsychological tests or test batteries that were found to generate at least a moderate change (LR > 5) in pretest to post-test probabilities of dementia (or AD). We were conservative and included only those tests with at least a moderate LR due to the design problems encountered in the majority of studies reviewed. Table II.3.2 describes those tests that accurately classified AD vs. non-AD participants and Table II.3.3 describes those tests that accurately classified dementia vs. non-dementia participants.

Clinical significance It should be noted that the application of the above tests in the clinical setting is limited because, apart from two studies (Incalzi et al. 1995; Tierney et al. 1996), investigators have not included in their control groups people who are representative of

the spectrum of patients who are seen in clinical practice. Normal high-functioning individuals, who comprised the comparison groups in most of these studies, are unlikely to be part of the spectrum of participants to whom the diagnostic tests will be applied in the clinical setting. Also, comparisons between NCs and dementia cases are likely to produce much larger LRs than comparisons with non-demented people who may have cognitive, affective or medical problems. For this reason, before the recommended cut-off scores found when comparing normal controls to dementia cases can be applied in the clinical setting, these findings must be replicated with an appropriate spectrum of participants. The two studies that used an appropriate spectrum of participants (Incalzi et al. 1995; Tierney et al. 1996) reported moderate to large LRs in the cross-sectional and predictive classification of AD and non-demented controls. Several subtests of the RAVLT, the WAIS-R Digit Span backwards and the WMS mental control subtest were found to contribute to this distinction. While Incalzi et al. (1995) did not provide cut-off scores, Tierney et al. (1996) provided a formula based on their regression coefficients for the application of their findings to the clinical setting. When a battery of two or more tests (and covariates) are found to have acceptable classification accuracy, this is a useful approach as it informs clinicians as to how they may apply the results of these tests to their patients.

Recommendations Recommendations for practice Screening for dementia in the medical office The two test batteries found to have respectable LRs in an appropriate spectrum of patients, require approximately 15–20 min to administer as well as training in their proper administration and scoring. As a result, they may not be appropriate as a firstline screening tool for the medical practitioner. As can be seen in Tables II.3.2 and II.3.3, several brief test batteries and individual tests were found useful in distinguishing between patients with dementia

REACHING A DIAGNOSIS 99

Table II.3.2 Neuropsychological tests and test batteries that distinguished between patients with AD and those without dementia with likelihood ratios of the positive test (LR+) > 5. Author Test batteries RAVLT (15-word list recall) immediate and delayed recall, false positive recognition, serial position order and WAIS-R Digit Span backwards RAVLT delayed recall and WMS Mental Control Neurocognitive Screen, which included enhanced cued recall, Benton Temporal Orientation Test, animal fluency and clock drawing

Incalzi et al. (1995)

Individual tests Memory Impairment Screen (4-word cued recall) CERAD delayed recall (10 words) MMSE (American version) Delayed Word Recall (10 words) Wisconsin Card Sort (number of categories and perseverative errors) Animal fluency Supermarket fluency Dementia Rating Scale

LR+

Class

8.1

IA

Tierney et al. (1996) Solomon et al. (1998)

12.7 23.0

IA IIB

Buschke et al. (1999) Welsh et al. (1991, 1992) Monsch et al. (1995b) Knopman and Ryberg (1989) Bondi et al. (1993) Monsch et al. (1992) Monsch et al. (1992) Monsch et al. (1995a)

22.0 11.3 37.0 44.5 13.4 and 10.6 14.3 23.0 and 19.0 97.0

IIB IIB IIB IIB IIB IIB IIB IIB

Table II.3.3 Neuropsychological tests and test batteries that distinguished between patients with dementia of unspecified aetiology and those without dementia with likelihood ratios of the positive test (LR+) > 5. Author Test batteries Benton Orientation, Retention and Fluency tests

Ritchie and Fuhrer (1992)

Individual tests Memory Impairment Screen (4-word cued recall) MMSE (French version) WORLD spelling test

Buschke et al. (1999) Ritchie and Fuhrer (1992) Leopold and Borson (1997)

(either those specific for AD or for dementia of unspecified etiology) and NC participants. These include the Neurocognitive Screening battery, the MIS, the MMSE, animal fluency, supermarket fluency and the WORLD spelling test. However, because normal-functioning older people were included in the comparison groups, the cut-off scores recommended by the investigators may be too high and, if used, may result in the identification of cognitively impaired non-demented people as being demented. One strategy may be to lower the cut-off scores on these brief screening measures, and if one’s patient

LR+

Class

7.4

IB

20.0 8.4 6.5

IB IB IIB

is identified as test-positive for dementia on these tests, a more detailed diagnostic work-up, including neuropsychological assessment, may be requested. When should the practitioner refer the patient for more detailed neuropsychological testing? A more detailed neuropsychological assessment will provide information on a broader range of cognitive abilities and affective functioning than can be obtained from a brief cognitive screenainformation that is critical to the diagnostic process. A referral

100 CHAPTER II.3

for this more detailed assessment is appropriate for individuals who are test-positive (i.e. fall below cut-off scores) on cognitive screening tests as described above. However, given the limitations of these studies with regards to the inclusion of an appropriate spectrum of patients and the failure of many investigators to covary the effects of age and education, test-negative patients who present with other clinical indications of cognitive impairment may also benefit from more detailed neuropsychological assessment. The latter is particularly relevant for patients who are better educated. A more detailed assessment may provide information regarding the extent to which depression, anxiety or other emotional states contribute to cognitive problems. Furthermore, although many of the neuropsychological tests commonly used in the assessment of dementia have not undergone evidence-based evaluation, standardized neuropsychological tests can be interpreted diagnostically by comparing the patient’s performance with normalfunctioning age-, sex- and education-matched people. Guidelines, such as those provided by the NINCDS-ADRDA criteria (i.e. a score falling below the fifth percentile or more than 1.5 standard deviations below normal is considered abnormal), can be used to interpret the patient’s test results. A more detailed neuropsychological assessment can provide a profile of cognitive strengths and weaknesses that can be used for developing therapeutic approaches and discharge planning. Also, because a detailed assessment taps a broader range of function it can be used to measure change over time as a result of a progressive disorder or the effectiveness of a variety of therapeutic interventions. An example plotting pre- and post-test probabilities for a cognitive test Let us consider the application of the LRs and how this knowledge might be applied in the clinical setting. We will illustrate the application with the test battery consisting of the RAVLT delayed recall and the WMS mental control subtest. The LR+ of this test battery was 12.7. If our patient tested positively for AD on this test battery but had a low probability for AD before we knew the test results

(pretest probability), we can calculate this patient’s post-test probability. If we set the low pretest probability to 0.05, using the nonogram for interpreting diagnostic test results as presented in Jaeschke et al. (1994b), this patient’s post-test probability would increase to 0.39. If our test-positive patient had an intermediate probability for AD (0.50) based on family history, behavioral reports and other referral information, then this patient’s post-test probability would increase substantially to 0.92. However, if a test-positive patient came to us with a very high probability of AD (0.90) then the patient’s post-test probability would not change a great deal (0.99). Based on the criteria described in the introduction, Chapter II.1, the greatest incremental value of this test battery would occur only with patients who have intermediate pretest probabilities for dementia.

Recommendations for research Several studies that compared patients with dementia and NCs found large LR+s. Therefore, replication of these promising findings with an appropriate spectrum of patients is recommended to establish their validity in the clinical setting and to develop appropriate cut-off scores. Despite the fact that an appropriate spectrum of patients was not used in these studies, their findings provide a direction for future research. Future studies should be designed to include these and similar potentially useful tests in a single study. Examining the accuracy of only one test provides limited information, whereas inclusion of many potentially useful tests in a multivariate regression model allows us to determine the combined effect of all the tests, as well as the individual contribution of each test. With this information we can determine the optimal combination and number of tests required for optimal classification. It is of interest to note that several of the tests that distinguished AD from non-AD control groups also distinguished participants with dementias of several etiologies from NCs. One explanation for this is that these groups of patients with dementia were largely composed of AD participants. Systematic exploration of this can only be achieved if

REACHING A DIAGNOSIS 101

investigators complete differential diagnoses of all participants in their mixed dementia groups. More evidence-based studies are needed to evaluate the role of neuropsychological tests in the accurate prediction of dementia in people suspected of memory impairment. Tierney et al. (1996) found that tests of memory and attention produced a large change from pre- to post-test probability of AD over a 2-year period, but evidence-based studies are needed to replicate these findings and to examine whether neuropsychological tests can produce similar changes in pre- to post-test probability of developing dementia, regardless of etiology. No studies could be found that examined the classification accuracy of tests in the diagnosis of cognitive impairment vs. normal ageing. One of the major obstacles to research in this area is the absence of acceptable reference or diagnostic standards for cognitive impairment against which the classification accuracy can be evaluated. Several criteria have been proposed but their validity has not been established to date (Crook et al. 1995; Petersen et al. 1999). Further work on the develop-

ment of ‘gold’ standard reference criteria is clearly needed in this area. Finally, journals should develop stricter editorial policies requiring investigators to indicate whether their research design is prospective or retrospective and to justify this. Retrospective studies may be subject to unknown selective factors influencing the original data and the current availability of subjects. For example, in a retrospective study based on patients who were referred to a dementia clinic, decisions to administer a particular test or to see a particular patient are not up to the investigators. Possible selective factors thus may limit the external validity of any conclusions about dementia.

Acknowledgements The author wishes to thank Dr Nancy Fisher and Dr John Paul Szalai for their assistance with the reviews and analyses of the articles. Their expertise in neuropsychological assessment, research design and statistical analyses added considerably to the substance and conclusions of this chapter.

Diagnostic Instruments to Assess Functional Impairment II.3.2

Serge Gauthier

Decline in functional abilities is a major component of the dementia syndrome. The definition of dementia in the International Classification of Diseases, 10th revision (ICD-10) (World Health Organization 1992) requires cognitive impairment sufficient to impair personal activities of daily living (ADL). The Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) (American Psychiatric Association 1994) also requires cognitive deficits sufficiently severe to cause impairment in occupational or social functioning, which must represent a decline from a higher level of functioning. These definitions are valid for primary degenerative dementias such as Alzheimer’s disease (AD) as well as vascular dementia (VaD), on the condition that functional disability in VaD is due to cognitive deficits and not to physical handicaps

produced by stroke (Chui et al. 1992; Roman et al. 1993). This chapter addresses the diagnostic usefulness of ADL scales in early stages of dementia. The following two questions are posed. First, using the definition of dementia outlined in the Diagnostic and Statistical Manual as the referent standard, how accurate are instruments to assess ADL in making a diagnosis of dementia? Second, how useful are instruments to assess ADL for differentiating the subtype of dementia? Two other major uses for ADL scales are not covered in this chapter. ADL scales have become primary outcome measures for pharmaceutical drug trials (Gauthier et al. 1997, 1999). ADL scales may also be used to predict patient and care giver needs (Carswell & Eastwood 1993). The reader is referred

102 CHAPTER II.3

to other Sections of this book for discussion of these topics.

Background There are a number of excellent reviews on the selection of ADL scales in dementia (Applegate et al. 1990; Gélinas & Auer 1999), which must take into account the fact that complex instrumental activities of daily living (IADL) are affected first in dementia, whereas personal or basic ADL are affected last. The stage of dementia under study will thus determine to a great extent which scale to use. ADL scales are completed by self-report, by informant report or by direct observation. There is debate as to which is the most reliable (Myers et al. 1993), but for practical purposes the most widely used approach is by interview of a reliable informant. The functional history taken from an informant must take into account the potential biases of that informant (who may minimize or exaggerate functional difficulties), the potential lack of opportunity to perform certain tasks, the lack of interest from depression, or the loss of initiative and planning ability from early dementia. Some ADL scales are generic for a number of physical and cognitive disabilities, others are dementia-specific: the latter are preferable as per the definitions cited previously. Some scales include a mixture of cognitive and behavioral items, most are ADL-specific: the latter are preferred in clinical drug trial research where measurable improvement in individual symptomatic domains is required (Whitehouse 1998). Some scales contain a number of IADL items that can be irrelevant because of gender and/or cultural biases, some tend to be more gender neutral. Finally, some scales are simple ‘can/cannot do’, whereas others explore the hierarchy of ‘initiation, sequence and completion’ of a given task. Examination of the commonly used ADL scales in dementia (Table II.3.4) shows that many have in common a number of ADL items (Table II.3.5), which are present in the 1984 revision of the functional activities questionnaire (FAQ) of Pfeffer et al. (1982) which could thus be used as a complement to the clinician’s semistructured interview with patient and informant for purposes of early diagnosis of dementia.

Table II.3.4 Common ADL scales used at different stages of dementia. Mild (predominantly instrumental tasks) Alzheimer Disease Cooperative Study ADL scale Functional activities questionnaire (FAQ) Instrumental activities of daily living (IADL) scale Progressive deterioration scale (PDS) Mild to moderate (balance of instrumental and self-care tasks) Cleveland scale for ADL Disability assessment for dementia (DAD) Modified interview for deterioration in daily living activities in dementia (IDDD) Nurses’ observation scale for geriatric patients (NOSGER) Moderate to severe (predominantly self-care tasks) Barthel index D-scale in severe dementia Katz ADL scale Rapid disability rating scale 2 (RDRS-2)

Table II.3.5 Commonly assessed instrumental ADL items in early dementia. Handling personal finances Keeping appointments Playing games of skill (such as bridge) or working on a hobby Preparing a meal Shopping Travelling by public transport or driving a car Using household appliances Using the telephone

Search strategy For the first question in this chapter, inclusion criteria were: (i) DSM or NINCDS-ADRDA criteria for dementia were used as a referent standard; (ii) the ADL scale was used as the diagnostic test; (iii) there was independent determination of the diagnostic test and referent standard; and (iv) the likelihood ratio could be calculated. For the second question in this chapter, the inclusion criteria were: (i) the clinical diagnosis of dementia subtype using published criteria (NINCDS-ADRDA for AD, McKeith criteria for dementia with Lewy bodies, etc.); (ii) the ADL scale was used as the diagnostic test; (iii) the clinical criteria and ADL scale were applied independently of each other; and (iv) the likelihood ratio could be calculated.

REACHING A DIAGNOSIS 103

Evidence

Recommendations for practice

Only one study was identified which assessed the utility of ADL instruments as an independent diagnostic test for dementia (Pfeffer et al. 1982). Lay informants completed a questionnaire for independence in daily activities for 195 persons living in a stable retirement community. The diagnosis of dementia was made using two independent neurologists. Using a cut-off score of 9, the Pfeffer IADL instrument was 85% sensitive and 81% specific (LR+ = 4.5) for a diagnosis of dementia. There are little data published on which specific ADL tasks are the most sensitive and specific to help clinicians diagnose dementia in its earlier stages, beyond the well-recognized fact that complex occupational tasks such as work or hobbies are altered at a stage when cognitive deficits are still mild, whereas simple overlearned tasks are preserved until later stages of dementia. Decreased interest and abilities in complex hobbies such as card games and crossword puzzles, using household equipment such as a microwave oven, and managing financial transactions are commonly reported by care givers in early stages of dementia. In the case of screening elderly populations for functional impairment potentially related to dementia, the Old Americans Resources and Services Procedures (Fillenbaum 1988) has been shown to be reliable in the setting of large-scale population studies such as the Canadian Study of Health and Aging (Ostbye et al. 1997). However, no sensitivity or specificity data were reported. In the literature, ADL scales are commonly used as an outcome measure to monitor the severity and progression of dementia, rather than as a diagnostic tool. For long-term follow-up, a more global instrument such as the Clinical Dementia Rating (CDR) which incorporates the six domains of memory, orientation, judgement and problem-solving, community affairs, home and hobbies, and personal care, has demonstrated reliability in quantifying progression over periods of a year or more (Berg et al. 1988). No studies could be identified that address the utility of ADL scales for the diagnosis of dementia subtype.

In conclusion, functional assessment is part of the diagnostic process in early dementia. A semistructured history with a reliable informant is the most practical approach, going over functional items relevant to the individual under examination in terms of gender, culture and past experience. Different ADL scales can be used, their selection being based on specific needs, from screening in an elderly population to the work-up of individuals with early cognitive complaints to the long-term follow-up of patients with progressive dementia. For the most part, ADL instruments have been used to substantiate the diagnosis of dementia. Because the ADL data and diagnosis are thus comingled, it comes as no surprise that there is very little evidence assessing their utility as independent diagnostic tests. A single study (Pfeffer et al. 1982) showed an LR = 4.5, which is comparable to many neuropsychological tests for dementia. No evidence is available upon which to base a recommendation regarding the most sensitive or specific instrument. No evidence is available indicating that ADL scales are helpful in the differential diagnosis of dementia subtype.

References American Psychiatric Association (1987) Diagnostic and Statistical Manual of Mental Disorders, 3rd edn, Revised. American Psychiatric Association, Washington, DC. American Psychiatric Association (1994) Diagnostic and Statistical Manual of Mental Disorders, 4th edn. American Psychiatric Association, Washington, DC. Applegate,W.B., Blass, J.P. & Williams, T.F. (1990) Instruments for the functional assessment of older patients. New England Journal of Medicine 322, 1207–1214. Berg, L., Miller, J.P., Storandt, M. et al. (1988) Mild senile dementia of the Alzheimer type: 2. Longitudinal assessment. Annals of Neurology 23, 477–484. Bondi, M., Monsch, A., Butters, N. & Salmon, D. (1993) Utility of a modified version of the Wisconsin Card Sorting Test in the detection of dementia of the Alzheimer type. Clinical Neuropsychology 7, 161–170.

104 CHAPTER II.3

Buschke, H., Kuslansky, G., Katz, M., Stewart, W., Sliwinski, M. & Lipton, R. (1999) Screening for dementia with the Memory Impairment Screen. Neurology 52, 231–238. Carswell, A. & Eastwood, R. (1993) Activities of daily living, cognitive impairment and social function in community residents with Alzheimer’s disease. Canadian Journal of Occupational Therapy 60, 130–136. Chui, H.C., Victoroff, J.L., Margolin, D., Jagust, W., Shankle, R. & Katzman, R. (1992) Criteria for the diagnosis of ischemic vascular dementia proposed by the State of California Alzheimer’s Disease Diagnostic and Treatment Centers. Neurology 42, 473–480. Crook, T., Bartus, R., Ferris, S., Whitehouse, P., Cohen, G. & Gershon, S. (1995) Age-associated memory impairment: proposed diagnostic criteria and measures of clinical changeareport of a National Institute of Mental Health Work Group. Developmental Neuropsychology 2, 261–276. Fillenbaum, G.G. (1988) Multidimensional Functional Assessment of Older Adults: the Duke Older Americans Resources and Services Procedures. Lawrence Erlbaum Associates, Hillsdale, NJ. Gauthier, S., Bodick, N., Erzigkeit, E. et al. (1997) Activities of daily living as an outcome measure in clinical trials of dementia drugs. Alzheimer Disease and Associated Disorders 11 (Suppl. 3), 6–7. Gauthier, S., Rockwood, K., Gélinas, I. et al. (1999) Outcome measures for the study of activities of daily living in vascular dementia. Alzheimer Disease and Associated Disorders 13 (Suppl. 3), 1–5. Gélinas, I. & Auer, S. (1999) Functional autonomy. In: Clinical Diagnosis and Management of Alzheimer’s Disease (Gauthier, S., ed.), pp. 213–226. Martin Dunitz, London. Grut, M., Fratiglioni, L., Viitanen, M. & Winblad, B. (1993) Accuracy of the Mini-Mental Status Examination as a screening test for dementia in a Swedish elderly population. Acta Neurologica Scandinavica 87, 312–317. Heun, P. & Jennssen, F. (1998) The validity of psychometric instruments for detection of dementia in the elderly population. International Journal of Geriatric Psychiatry 13, 368–380. Incalzi, R.A., Capparella, O., Gemma, A., Marra, C. & Carbonin, P. (1995) Effects of aging and of Alzheimer’s disease on verbal memory. Journal of Clinical and Experimental Neuropsychology 17, 580–589. Jaeschke, R., Guyatt, G. & Sackett, D.L. (1994a) Users’ guides to the medical literature. III. How to use an article about a diagnostic test. A. Are the results of the study valid? Journal of the American Medical Association 271, 389–391. Jaeschke, R., Guyatt, G. & Sackett, D.L. (1994b) Users’ guides to the medical literature. III. How to use an article about a diagnostic test. B. What are the results and will they help me in caring for my patients? Journal of the American Medical Association 271, 703–707. Knopman, D. & Ryberg, S. (1989) A verbal memory

test with high predictive accuracy for dementia of the Alzheimer type. Archives of Neurology 46, 141–145. Leopold, N. & Borson, A. (1997) An alphabetical ‘WORLD’: a new version of an old test. Neurology 49, 1521–1524. McKhann, G., Drachman, D., Folstein, M., Katzman, R., Price, D. & Stadlan, E. (1984) Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of the Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 34, 939–944. Monsch, A., Bondi, M., Butters, N., Salmon, D., Katzman, R. & Thal, L. (1992) Comparisons of verbal fluency tasks in the detection of dementia of the Alzheimer type. Archives of Neurology 49, 1253–1258. Monsch, A., Bondi, M., Salmon, D. et al. (1995a) Clinical validity of the Mattis Dementia Rating Scale in detecting dementia of the Alzheimer type. Archives of Neurology 52, 899–904. Monsch, A., Foldi, N., Ermimi-Funfschilling, D. et al. (1995b) Improving the diagnostic accuracy of the MiniMental State Examination. Acta Neurologica Scandinavica 92, 145–150. Myers, A.M., Holliday, P.J. & Harvey, K.A. (1993) Functional performance measures: are they superior to self-assessment? Journal of Gerontology 48, M196–M206. Ostbye, T., Tyas, S., McDowell, I. & Koval, J. (1997) Reported activities of daily living: agreement between elderly subjects with and without dementia and their caregivers. Age and Aging 26, 99–106. Petersen, R., Smith, G., Waring, S., Ivnik, R., Tangalos, E. & Kokmen, E. (1999) Mild cognitive impairment: clinical characterization and outcome. Archives of Neurology 56, 303–308. Pfeffer, R.I., Kurosaki, T.T., Harrah, C.H., Chance, J.M. & Filos, S. (1982) Measurements of functional activities in older adults in the community. Journal of Gerontoloy 37, 323–329. Ritchie, K. & Fuhrer, R. (1992) A comparative study of the performance of screening tests for senile dementia using receiver operating characteristics analysis. Journal of Clinical Epidemiology 45, 627–637. Roman, G.C., Tatemichi, T.K., Erkinjuntti, T. et al. (1993) Vascular dementia: diagnostic criteria for research studies. Report of the NINDS-AIREN International Workshop. Neurology 43, 250–260. Solomon, P., Hirschoff, A., Kelly, B. et al. (1998) A 7 minute neurocognitive screening battery highly sensitive to Alzheimer’s disease. Archives of Neurology 55, 349–355. Spreen, O. & Strauss, E. (1998) A Compendium of Neuropsychological Tests: Administration, Norms, and Commentary, 2nd edn. Oxford University Press, New York. Tierney, M.C., Szalai, J.P., Snow, W.G. et al. (1996) Prediction of probable Alzheimer’s disease in memoryimpaired patients: a prospective longitudinal study. Neurology 46, 661–665.

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Welsh, K., Butters, N., Hughes, J., Mohs, R. & Heyman, A. (1991) Detection of abnormal memory decline in mild cases of Alzheimer’s disease using CERAD neuropsychological measures. Archives of Neurology 48, 278–281. Welsh, K., Butters, N., Hughes, J., Mohs, R. & Heyman, A. (1992) Detection and staging of dementia in Alzheimer’s disease: use of the neuropsychological measures developed for the Consortium to Establish

a Registry for Alzheimer’s Disease. Archives of Neurology 49, 448–452. Whitehouse, P. (1998) Regulatory issues in anti-dementia drug development. In: Pharmacotherapy of Alzheimer’s Disease (Gauthier, S., ed.), pp 57–74. Martin Dunitz, London. World Health Organization (1992) The ICD-10 Classification of Mental and Behavioral Disorders. World Health Organization, Geneva.

Reaching a Diagnosis of a Dementia Subtype II.4

Edited by: Helena Chui

II.4.1

Clinical Criteria for Dementia Subtypes

Helena Chui and Ae-Young Lee

With the exception of relatively rare autosomal dominant causes of dementia (e.g. presenilin and amyloid protein precursor gene mutations), there are no specific biological markers for the most common subtypes of dementia. Without specific markers to depend on, academic neurologists and psychiatrists have taken a pragmatic approach to diagnosis. Diagnostic criteria have been proposed to improve the reliability and accuracy of clinical diagnosis. These criteria comprise a list of typical clinical features that increase the likelihood that a specific disorder is present. Atypical features that decrease the likelihood or exclude the diagnosis are also described. Reliability of clinical diagnosis is assessed by comparing the diagnosis reached by one clinician with that reached by another. The test of validity, i.e. ‘accuracy’ is operationally defined by comparing how well the clinical diagnosis compares to a ‘gold’ or reference standard. For most forms of dementia (e.g. Alzheimer’s disease (AD), Parkinson’s disease (PD)), microscopic features are deemed the most specific defining characteristics, and pathological findings are used as the ‘gold’ standard. However, pathological findings may not be wholly specific either, occurring to some extent in elderly persons who are cognitively normal. Hence, academicians have suggested the most reasonable but, none the less, arbitrary cut-points in defining the ‘gold’ standard. Unfortunately, limitations of the reference standard may also cloud the accuracy of the clinical diagnosis.

106

Against this backdrop, the question posed in this section is: ‘How accurate and useful are clinical criteria for some of the most common or better recognized forms of dementia, namely AD, vascular dementia (VaD), dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD)?’ For each entity, we: 1 Describe the most commonly used clinical and pathological criteria. 2 Report the reliability of the criteria. 3 Summarize the available class I and II evidence, by tabulating the sensitivity, specificity and LRs for the clinical criteria, using the pathological classification as the ‘gold’ standard. 4 Conclude with a statement about the usefulness of current criteria based on the currently available evidence.

Alzheimer’s disease Background Clinical criteria NINCDS-ADRDA criteria for probable AD require evidence of progressive dementia, no disturbance of consciousness, an onset between the ages of 40 and 90 years, and the absence of systemic disorders or other brain diseases that in and of themselves could account for the progressive deficits in memory and cognition (McKhann et al. 1984). A diagnosis of possible AD is made:

DIAGNOSIS OF A DEMENTIA SUBTYPE 107

1 in the presence of variations in onset, presentation or clinical course; 2 in the presence of a second systemic or brain disorder sufficient to produce the dementia, but not considered to be the cause of dementia; and 3 in research studies when a single, gradually progressive severe cognitive deficit is identified. A fair to moderate level of interrater reliability has been demonstrated for these clinical criteria (Kukull et al. 1990a; Lopez et al. 1990; Blacker et al. 1994; [kappa score for interrater reliability, κ = 0.51]). The American Psychiatric Association has published several versions of diagnostic criteria for dementia of the Alzheimer type (DAT): DSM-III (American Psychiatric Association 1980), DSMIII-R (American Psychiatric Association 1987) and DSM-IV (American Psychiatric Association 1994). Most autopsy studies have used DSM-III-R criteria, which require evidence of: 1 dementia; 2 insidious onset with a generally progressive deteriorating course; and 3 exclusion of all other specific causes of dementia by history, physical examination and laboratory tests. DSM-IV criteria for DAT are now in clinical use. They are similar to DSM-III-R, but combine previously separate criteria for dementia and for AD into a single category. The DSM-IV criteria require: 1 Development of multiple cognitive deficits manifested by (a) memory impairment and (b) one or more other cognitive disturbances; 2 The cognitive deficits each cause significant impairment in social or occupational function and represent a significant decline; 3 The course is characterized by gradual onset and continuing cognitive decline; 4 The cognitive deficits are not due to (a) other central nervous system conditions that cause progressive deficits in memory and cognition (b) systemic conditions that are known to cause dementia or (c) substance-induced conditions; 5 The deficits do not occur exclusively during the course of a delirium; and 6 The disturbance is not better accounted for by another axis I disorder.

The accuracy of these criteria is still untested: few DAT cases clinically diagnosed using DSM-IV criteria have been examined by autopsy. Pathological criteria Widespread dissemination of neurofibrillary tangles (NFT) and neuritic plaques (NP) throughout the cerebral cortex are recognized as the pathological hallmarks of AD. By themselves, these histological lesions are not specific for ADaoccurring to some extent in cognitively and functionally intact individuals (Price & Morris 1999). Several pathological definitions of AD have been adopted, based either on the severity of the NFT or NP. The progressive spread of NFT from transentorhinal to limbic to isocortex has been divided into six stages, commonly known as Braak and Braak stages (Braak et al. 1993)athe more advanced isocortical stages (V–VI) are often chosen to operationally define AD (National Institute on AgingaReagan Institute criteria 1997). Reflecting an alternative focus, consensus criteria developed in the US are based upon the severity of senile plaques (SP) and, more recently, specifically upon the number of NP. The National Institutes of Health/American Association of Retired Persons (NIH/AARP) Work Group criteria use age-adjusted numbers of SP to define AD (Khachaturian 1985). The revised CERAD criteria propose various levels of AD probability (i.e. none, possible, probable and definite) based upon an age-adjusted semiquantitative rating of NP (Mirra et al. 1991). Agreement among the NIH/AARP and CERAD criteria has been examined (Nagy et al. 1995): a comparable classification of autopsy cases results when positive NIH/AARP criteria are compared to the combined CERAD categories of possible, probable and definite AD. The NIA-Reagan Institute guidelines (1997) suggest that CERAD ratings and Braak and Braak stages are comparable, although this has not been formally tested to our knowledge.

Search strategy and study validation For the diagnosis of AD, we arbitrarily selected those studies using:

108 CHAPTER II.4

Table II.4.1 Clinicopathological correlations in AD (Class I and Class II evidence). Pathological criteria

Study

Sample (n)

P/R

I

Clinical criteria

Galasko et al. (1994) Class IB

170 convenience clinical diagnoses: 137 AD (111 pr AD, 26 ps AD); 19 mixed; 4 PD; 2 at risk for AD; 8 non-AD

P

Y-P

NINCDS pr/ps AD+ Pr AD Pr AD

NIH/AARP (AD+)

675 convenience hospital autopsy diagnoses: 400 AD, 146 MID, 21 mixed, 108 PD + other

R

DSM-III-R NINCDS AD plus

NIH/AARP AD+

Jellinger et al. (1990) Class IIB

Y-P

Pure AD

PPV

NPV

SS

SP

LR+

0.88

0.63

0.98

0.21

1.2

0.93 0.60

0.27 0.68

0.71 0.78

0.67 0.47

2.1 1.5

0.88

0.56

0.85

0.62

2.2

AD, Alzheimer’s disease; I, independence between clinical diagnosis and pathological diagnosis; LR+, positive likelihood ratio; MID, multi-infarct dementia; NPV, negative predictive value; P, prospective study; PD, Parkinson disease; PPV, positive predictive value; pr, probable; ps, possible; R, retrospective study; SS, sensitivity; SP, specificity; Y-P, yesapathological diagnosis.

1 NINCDS-ADRDA or DSM criteria for the clinical diagnosis; and 2 Braak and Braak staging, NIH/AARP or CERAD pathological criteria as the reference standard (Table II.4.1). These criteria are used worldwide. Except for the Braak and Braak stages, they were developed as part of a consensus process among academicians. In general, the positive predictive value (PPV), negative predictive value (NPV), sensitivity, specificity and positive likelihood ratio (LR) reported in Tables II.4.1 and II.4.2 are derived using as the reference standard either cases with AD alone (pure AD) or combined with other disorders (AD plus or AD+). When the data were available, we also report values for subsets of diagnoses. Table II.4.1 gives a short list of studies meeting all the selection criteria outlined in the introduction (Chapter II.1). Prospective studies are listed first (Class I), followed by retrospective studies (Class II). A prospective study design potentially reduces selection and work-up biases. However, few prospective studies provided the autopsy rate or assessed comparability between the autopsied vs. non-autopsied cases. In general, communitybased studies (type A) have fewer selection biases and encompass a broader spectrum of cases compared to convenience samples (type B), which

may comprise selected, typical, or more severely demented cases. Results from type A studies may be more generalizable. We identified additional studies (see Table II.4.2) that met validation criteria, except for the absence of an explicit statement certifying that neuropathological assessment and diagnosis were performed ‘blind’ to the clinical findings. Sometimes the description of methods indicated that the clinician was ‘blind’ to the neuropathological findings. However, this is expected as a matter of natural history and is not sufficient to ensure independence of clinical and pathological diagnoses. We chose to separate, but not to exclude these studies, as they represent the current best state of the evidence. We arbitrarily excluded studies that used pathological definitions other than Braak and Braak, NIH/AARP or CERAD criteria. For the most part these studies antedated the publication of the consensus guidelines. We also excluded studies that did not include non-AD dementias as a comparison group. Such studies are often cited in support of the ‘accuracy’ of the clinical diagnosis of AD, but only indicate sensitivity (usually high > 90%), without providing information about specificity, PPV, NPV or LRs. These studies are tabulated and referenced on the accompanying website.

DIAGNOSIS OF A DEMENTIA SUBTYPE 109

Evidence Class I and Class II evidence Only two studies were identified that met all of the criteria for Class I or Class II evidence, including independent neuropathological diagnosis (Jellinger et al. 1990; Galasko et al. 1994). Both were goodsized convenience samples (total n = 170 + 675; total = 845)aone prospective, the other retrospective. In both studies, the NIH/AARP criteria for a diagnosis of AD were used as the reference standard. In both studies, the positive LR for a diagnosis of AD was small (1.2–2.2). The clinical diagnosis of AD was fairly sensitive but non-specific. The LR did not differ significantly for several variations in the diagnostic categories. The LRs for a clinical diagnosis of probable or probable plus possible AD vs. a reference pathological diagnosis of pure or mixed AD were all small. Studies without explicit mention of independent pathological assessment, but otherwise meeting criteria for class I and class II evidence Nine studies, describing eight cohorts, were identified that, strictly speaking, failed the Class I and Class II criterion for independent clinical and pathological assessment. However, we would have little to report if these studies were excluded entirely (total sample size = 2735; note that two papers report cases from a single cohort: Nagy et al. 1998; 1999). Eighty-two percent of the cases in Table II.4.2 derive from a single retrospective multicenter study of 2188 cases autopsied at one of 26 NIAfunded AD centres (Mayeux et al. 1998). Although several clinical criteria were accepted, NINCDSADRDA criteria were used for 78% of the cases. The LR for a clinical diagnosis of AD (probable or possible) was = 2.1 (sensitivity = 93%, specificity = 55%). These data suggest that a diagnosis of AD is seldom missed, but that even at academic research centers a large proportion of non-AD cases are labelled incorrectly as AD. The addition of information about apolipoprotein E (ApoE) genotype (i.e. presence or absence of an ε4 allele) increased the overall specificity from 55% to 84%, although the sensitivity decreased.

The prospective community-based Oxford Project to Investigate Memory and Ageing (OPTIMA) is described in two papers (Nagy et al. 1998; 1999). Although the clinical diagnoses were made without access to the neuropathological findings, and quantitative assessments of histological lesions were made blind to the clinical information (Nagy et al. 1998), neither paper explicitly states that the neuropathologists were blind to the clinical data when making the pathological diagnoses. In one paper, the NIH/AARP and CERAD criteria are used as the gold standard (Nagy et al. 1998); while in the other paper, Braak and Braak stages are used (Nagy et al. 1999). The combined diagnosis of probable or possible AD by NINCDS-ADRDA criteria proved to be sensitive, but not very specific (LR = 2.0 [NIH/ AARP]; LR = 2.3 [CERAD]; LR = 1.5 [Braak and Braak])aa pattern reminiscent of the experience at US academic centers (Galasko et al. 1994; Mayeux et al. 1998). On the other hand, a diagnosis of probable AD by NINCDS-ADRDA criteria or of DAT by DMS-III-R showed the reverse pattern. They were not very sensitive (33–43%), but were highly specific (94–100%) resulting in a larger positive LR (LR = 5.5–5.8). One of the largest LRs is derived from a relatively small Finnish convenience sample of 53 dementia subjects and 11 normal controls (Kosunen et al. 1996). The LR for a generic diagnosis of AD (i.e. clinical AD+ vs. pathological AD+) was 8.8. Even larger LRs are obtained for an NINCDS-ADRDA diagnosis of probable AD vs: 1 probable or definite CERAD (LR = 12); or 2 definite CERAD (LR = 19.2). These data suggest that the recognition of typical cases of AD (i.e. probable AD) is very good, but atypical or mixed cases (possible AD) remain problematic. These data also show that the stratification of pathological diagnoses based on level of probability (i.e. definite, probable, possible), as well as for clinical diagnosis (i.e. probable, possible), increases the accuracy of diagnosis for typical cases. Diagnostic accuracy appears to improve slightly using a consensus process. Blacker et al. (1994) observed improvement in specificity from 72% to 84%, between pre- and post-consensus conference (the LR improved slightly from 4.5 to 5.2). In this

Study

Sample (n)

P/ R

I

Clinical criteria

Pathological criteria

PPV

NPV

SS

SP

LR+

Kosunen et al. (1996)

64 convenience: 35 AD (28 pr AD, 7 ps AD), 10 VaD; 6 mixed; 2 AD + LB; 11 controls

P AR = 53%

N

NINCDS (pr/ps AD+) NINCDS (pr AD) NINCDS (pr AD)

CERAD (ps, pr, D AD) CERAD (pr, D AD) CERAD (D AD)

0.98 0.96 0.96

0.48 0.50 0.96

0.79 0.60 0.77

0.91 0.95 0.96

8.8 12.0 19.2

Nagy et al. (1998)

73 community-based OPTIMA study: 57 AD (19 pr AD, 38 ps AD); 7 other dementia, 9 control

P

N C only

DSM-III-R (DAT)

CERAD (D/pr AD) NIH/AARP (AD) CERAD (D/pr AD) NIH/AARP (AD) CERAD (D/pr AD) NIH/AARP (AD)

0.95 0.95 1.0 1.0 0.88 0.82

0.31 0.39 0.50 0.50 0.69 0.75

0.33 0.35 0.43 0.37 0.91 0.92

0.94 0.94 1.0 1.0 0.61 0.55

5.5 5.8 Large Large 2.3 2.0

Holmes et al. (1999)

80 referral registry: 58 AD (38 pr AD [72%]; 20 ps AD); 7 pr VaD; 1 ps VaD; 3 mixed; 2 DLB; 2 DLB+

P

N C only

NINCDS (retrospective) 80% CT

CERAD (not subdivided by pr, ps, D)

0.92

0.17

0.50

0.70

1.7

Lim et al. (1999)

134 autopsy from population-based Group Health Cooperative: 86 pr AD, 14 ps AD, 34 other

P AR = 32%

N C only

NINCDS (pr/ps AD) NINCDS (pr AD)

CERAD (D/pr AD)

0.81 0.80

0.59 0.59

0.85 0.83

0.50 0.55

1.7 1.8

Nagy et al. (1999)

86 community-based OPTIMA study clinical diagnoses: 69 AD (23 pr AD, 46 ps AD); 9 other dementias; 8 normal

P AR = NA

N C only

NINCDS (pr/ps AD)

B&B V–VI B&B V–VI

0.55

1.00

1.00

0.35

1.5

0.77

0.67

0.48

0.90

4.8

NINCDS (pr AD) NINCDS (pr/ps AD)

DSM-III-R

110 CHAPTER II.4

Table II.4.2 Clinicopathological correlations in AD (studies with no mention of blinded assessment by neuropathologist).

62 convenience (clinic): 27 AD, 12 mixed, 4 other, 19 control

R

N C only

DSM-III NINCDS (pr/ps AD)

NIH/AARP (AD+)

0.86 0.82

0.67 0.84

0.76 0.92

0.80 0.65

3.8 2.6

Blacker et al. (1994)

59 convenience: 36 AD, 23 non-AD (retrospective diagnosis)

R

N C only

NINCDS Preconsensus Conference (CC) (pr/ps AD) Post-CC (pr/ps AD) Post-CC (pr AD) Post-CC (pr/ps AD) Post-CC (pr AD)

NIH/AARP (used for 82% of cases) (AD+)

0.85

0.72

0.81

0.72

4.5

0.92 0.91 0.78 0.87

0.70 0.47 0.96 0.75

0.83 0.52 0.97 0.69

0.84 0.89 0.73 0.90

5.2 4.7 3.6 6.9

NINCDS (pr/ps AD+) NINCDS (pr AD) NINCDS (pr AD)

NIH/AARP CERAD (AD+) AD+ Pure AD

0.82

0.52

0.89

0.37

1.4

0.86 0.57

0.38 0.72

0.66 0.75

0.65 0.54

1.9 1.6

NINCDS (used 78%) (pr/ps AD)

NIH/AARP CERAD (AD)

0.90

0.64

0.93

0.55

Victoroff et al. (1995)

Mayeux et al. (1998)

196 convenience (clinic) clinical diagnoses: 140 AD (116 pr AD [71%], 24 ps AD); 11 VaD; 19 mixed; 7 PD; 19 other

R

2118 convenience autopsy diagnoses: 1833 AD (84%); 355 non-AD

R

N

N

Pure AD

2.1

AD, Alzheimer’s disease; AR, autopsy rate; B&B, Braak and Braak; C, clinician blind; CT, computerized tomography; D, definite; DAT, dementia of the Alzheimer type; DLB, dementia with Lewy bodies; I, independence between clinical diagnosis and pathological diagnosis; LB, Lewy bodies; LR+, positive likelihood ratio; N, no explicit statement regarding independence; NA, not available; NPV, negative predictive value; P, prospective study; PPV, positive predictive value; pr, probable; ps, possible; R, retrospective study; SP, specificity; SS, sensitivity; VaD, vascular dementia.

DIAGNOSIS OF A DEMENTIA SUBTYPE 111

Kukull et al. (1990a)

112 CHAPTER II.4

study, unlike Nagy et al. (1998), the LR was smaller for probable AD compared to combined probable or possible AD: although specificity increased as expected for a diagnosis of probable AD, sensitivity dropped even more. The LR increased (as noted by Kosunen et al. 1996) for the diagnosis of pathologically pure vs. mixed cases. It is not clear that the relatively small improvement in specificity associated with the consensus process is cost-effective. The pattern of LRs derived from a multicenter retrospective study of 196 autopsy cases (Victoroff et al. 1995) is virtually identical to the prospective study described by Galasko et al. (1994) (note: 35 cases may have been shared between the two studies). The LR for a diagnosis of clinical AD plus vs. pathological ADis small (LR = 1.4; high sensitivity, but low specificity). The LR for probable AD was slightly larger (LR = 1.9) and decreased for pathologically pure AD (LR = 1.6). Overall, the LRs were small.

Conclusions and recommendations There is considerable room for improvement in the clinical diagnosis of AD. The mean LR+ for a combined diagnosis of NINCDS-ADRDA probable and possible AD is 2.9 (10 studies, s.d. = 2.4). A slightly higher LR+ = 4.4 is obtained for a diagnosis of NINCDS-ADRDA probable AD, but the standard deviation is large (four studies, s.d. = 5.0). The most consistent LR+ of 4.8 was obtained for a DSM-III diagnosis of DAT (three studies, s.d. = 1.0).

LR values of this magnitude (between 2 and 5) generate small (but sometimes important) changes in pre- to post-test probability (Jaeschke et al. 1994a). No clinical protocol was identified that possessed both high sensitivity and specificity (Table II.4.3). Application of various clinical criteria lead to a trade-off between sensitivity and specificity. A diagnosis of either probable or possible AD is 90% sensitive, but only 56% specific (slightly better than chance). It has a fair PPV (84%), but a low NPV (66%). It does not offer much additional value over the simple diagnosis of dementia. On the other hand, both NINCDS-ADRDA criteria for probable AD or DSM-III-R criteria for DAT are less sensitive (53–65%), but more specific (76–88%). They have good PPVs (86–91%) but very poor NPVs (45–58%). These criteria are suitable for research purposes, where the desire is to identify typical or highly probable cases. They are unsatisfactory for clinical practice or for epidemiological studies of AD where the need is to diagnose individual cases either with or without the disease with equal accuracy. Using these criteria, the clinician cannot reliably reassure a patient that they do not have AD. The research investigator who wishes to ensure that patients classified as having AD are more likely to have AD, should choose DSM-III-R criteria for DAT or NINCDS-ADRDA criteria for probable AD (e.g. when testing a new biological marker, in the absence of neuropathological diagnosis). Whereas the investigator who wishes to include the greatest

Table II.4.3 Accuracy of the clinical diagnosis of AD: summary of Class I and II evidence (including studies with no mention of blinded assessment by neuropathologist). No. of studies

PPV: mean (sd)

NPV: mean (sd)

Sensitivity: mean (sd)

Specificity: mean (sd)

LR+: mean (sd)

10

0.84 (0.11)

0.66 (0.16)

0.90 (0.07)

0.56 (0.22)

2.9 (2.4)

NINCDS/ADRDA (probable AD)

5

0.91 (0.08)

0.45 (0.12)

0.65 (0.15)

0.76 (0.20)

4.4 (5.0)*

DSM-III (dementia of the Alzheimer type)

3

0.86 (0.09)

0.58 (0.16)

0.53 (0.21)

0.88 (0.07)

4.8 (1.0)

Criteria NINCDS/ADRDA (probable or possible AD)

AD, Alzheimer’s disease; NPV, negative predictive value; LR+, positive likelihood ratio; PPV, positive predictive value; sd, standard deviation. *Only able to calculate LR for four of the five studies.

DIAGNOSIS OF A DEMENTIA SUBTYPE 113

number of AD cases, allowing the inclusion of some non-AD cases, should choose NINCDS criteria for probable or possible AD. Clinical criteria for AD are suitable for certain types of researchawhere typical cases are desired abut remain unsatisfactory for clinical practice or epidemiological studies, where the evidence suggests they are not much more reliable than a diagnosis of dementia. The pathological criteria chosen for the reference standard affect the LR. Larger LR result against the pathological diagnosis of probable or definite AD (CERAD)awhere NP pathology is abundant. This finding is not surprisingait is easier to diagnose more severe cases of AD. On the other hand, LRs tend to decrease when making a diagnosis of pure AD, without concomitant vascular or Lewy body pathology. Improved criteria are needed for the diagnosis of non-AD dementias, alone or in combination with AD. Since no single diagnostic protocol is satisfactory, consideration should be given to the application of serial tests. For example, one might first apply a criterion that is highly sensitive but not very specific, followed by a second test that is not very sensitive but highly specific. The study by Mayeux et al. (1998) provides one example, where NINCDS-ADRDA criteria for probable and possible AD were applied first, followed by ApoE genotype. This strategy increases overall specificity and could be helpful in identifying groups at highest risk.

Vascular dementia Background Clinical diagnosis The diagnosis of VaD is problematic. For nearly two decades (1975–92), the Hachinski Ischemic Score (HIS) (Hachinski et al. 1975) and DSM-III have served as the two mainstays for the diagnosis of multi-infarct dementia (MID). During this era, vascular dementia has been conceptualized as a ‘matter of strokes large and small’ (Fisher 1968).

The HIS assigns 1 or 2 points for 13 clinical features that are associated with ischemic stroke (maximum score = 18). A cut-off score ≥ 7 points is used for a diagnosis of MID. The DSM-III-R (American Psychiatric Association 1987) requires four conditions for diagnosis: 1 dementia by DSM-III-R criteria; 2 stepwise deteriorating course and patchy distribution of deficits; 3 focal neurological signs and symptoms; and 4 evidence from the history, physical examination or laboratory tests of significant cerebrovascular disease that is judged to be etiologically related to the disturbance. Most autopsy data for VaD come from studies that used the HIS or DSM-III, or DSM-III-R, criteria to make a clinical diagnosis of MID. The last decade has witnessed a proliferation of diagnostic criteria for VaD: Alzheimer Disease Diagnostic and Treatment Centers (ADDTC) (Chui et al. 1992), National Institute of Neurological Disorders and StrokeaAssociation Internationale pour la Recherche et l’Enseignement en Neurosciences (NINCDS-AIREN) (Román et al. 1993), ICD-10 and DSM-IV. Two developments appear to have driven this flurry of activity: 1 the widespread use of neuroimaging studies; and 2 increased funding and research for AD and related dementias. Computerized tomography (since the early 1970s) and especially MRI (since the early 1980s) have proven to be highly sensitive for detecting ischemic lesionsamany of which may be clinically silent (i.e. no history of focal neurological deficit or stroke). Imaging studies have broadened the concept of VaD to include subclinical, as well as clinically manifest, ischemic brain injury. ADDTC and NINCDS-AIREN criteria venture to suggest how data from neuroimaging studies should be utilized for diagnosis. The new criteria for VaD grew in the shadow of a spotlight trained primarily on AD. The diagnosis of cases with mixed AD and VaD is recognized as particularly problematic. Improved methods are sought to determine whether ischemic lesions evident on neuroimaging studies contribute meaningfully to a progressive dementia. ADDTC and NINCDSAIREN criteria suggest that ischemic lesions should

114 CHAPTER II.4

Table II.4.4 Clinicopathological correlations in VaD (Class I and II evidence).

Study

Sample (n)

P/R

I?

Clinical criteria

Erkinjuntti et al. (1988) (Class IB)

37 hospital: 5 AD, 27 MID, 5 other dementias

P AR = 16%

Y

Jellinger et al. (1990) Class IIB

675 convenience hospital autopsy diagnoses: 400 AD, 146 MID, 21 mixed, 108 PD + other

R

Moroney et al. (1997) (Class IIB)

312 from six centers; autopsy diagnoses: 165 AD, 109 MID, 38 mixed

R

Gold et al. (1997) (Class IIB)

113 hospital

R (retro clin dx)

Pathological criteria

VaD

PPV

NPV

SS

SP

LR+

DSM-III

Presence of multiple ischemic lesions in cortical or subcortical areas (or both), without AD-type changes

MID MID + MIX

0.89 0.96

0.56 0.85

0.68 0.92

0.83 0.92

4.0 11.5

Y

DSM-III-R

1. One or more large cerebral infarcts or extensive cortical granular atrophy 2. Diffuse or multiple focal white matter damage with small disseminated infarcts or lacunes 3. Multiple small lesions or lacunes in basal ganglia or mixed cortical and subcortical vascular lesions

MID MID + MIX, PD

0.57 0.79

0.96 0.95

0.80 0.84

0.89 0.93

7.3 12.0

Y

HIS (MID > 7) HIS (MIX = 5–6)

Multiple ischemic lesions in cortex or subcortical regions without marked AD changes

MID MID + MIX MID + MIX

0.61

0.94

0.84

0.82

4.6

0.69

0.88

0.83

0.76

3.5

Multiple macroscopic and microscopic cortical infarcts or lacunar state, which involved the hippocampus and three or more neocortical areas except the primary and secondary visual cortex

MID MID + MIX MID MID + MIX MID MID + MIX

0.68 0.96 0.61 0.92 0.49 0.92

0.71 0.34 0.77 0.39 0.76 0.45

0.43 0.30 0.58 0.43 0.63 0.58

0.88 0.97 0.79 0.91 0.64 0.88

6.2 10.1 2.7 4.8 1.7 4.8

Y

HIS > 7 NINDS-AIREN (possible VaD) ADDTC (possible IVD)

AD, Alzheimer’s disease; AR, autopsy rate; dx, diagnosis; clin, clinical; HIS, Hachinki Ischemic Score; LR+, positive likelihood ratio; MID, multi-infarct dementia; NPV, negative predictive value; PPV, positive predictive value; R, retrospective; retro, retrospective; SP, specificity; SS, sensitivity; VaD, vascular dementia; Y,

DIAGNOSIS OF A DEMENTIA SUBTYPE 115

be rated differentially, with greater weight being given to those with a clearly defined temporal relation to the onset or progression of dementia. DSM-IV and ICD-10 criteria leave the relationship between ischemic lesions and dementia to the judgement of the individual practitioner. Notably, all criteria for VaD revolve around the phenotype of dementia. Dementia is a consistent manifestation of AD. Dementia, however, may be a late, secondary, and non-specific manifestation of ischemic brain injury due to cerebrovascular disease (CVD). Thus, we should consider that while ‘dementia’ may be a suitable clinical construct for AD, it may be diversionary for the diagnosis and treatment of CVD. In any case, the newer criteria are not interchangeable and lead to discrepant classification of patients (Wetterling et al. 1996; Verhey et al. 1996; Chui et al. 2000). DSM-IV criteria are the most liberal and the NINDS-AIREN the most conservative. ICD-10 and ADDTC criteria fall in between. One study indicates that the HIS is more reliable than any of the newer criteria (Chui et al. 2000). Very few autopsy data are available to assess the accuracy of the newer criteria.

1987). Gold et al. (1997) defined VaD by the presence of infarcts in parietal, temporal or frontal lobes aarbitrarily excluding purely subcortical infarcts. A pathological diagnosis of Binswanger’s subcortical arteriosclerotic encephalopathy has been made in the presence of severe white matter changes with demyelination and axonal loss plus severe and widespread changes of arteriosclerosis (Joachim et al. 1988). Unfortunately, where there is no clearly defined reference standard, there can be little clearly defined evidence.

Pathological diagnosis

Evidence

As VaD is currently conceptualized, its pathological diagnosis is also problematicanot because it is difficult to make a pathological diagnosis of cerebrovasular injury, but because it is difficult to determine post-mortem whether a vascular lesion was causal, contributory or coincidental to the dementia. No consensus has been reached about how to make a pathological diagnosis of VaD. Typically, there is a requirement for vascular lesions, often of a certain size or volume, in the absence of degenerative lesions (Tomlinson et al. 1970; Alafuzoff et al. 1987; Tierney et al. 1988). Joachim et al. (1988) considered strokes to have contributed to the clinical dementia if they were sufficiently remote or larger in size than the lacune, or if the vascular lesions involved the hippocampus, amygdala, thalamus or basal forebrain. In another schema, softening in the hippocampus and serum proteins in the perivascular parenchyma were additional requirements for a diagnosis of VaD (Alafuzoff et al.

Search strategy and study validation The following criteria were required for inclusion as Class I or II evidence: 1 clearly specified clinical criteria for MID or VaD; 2 a minimum sample size of 25 subjects with VaD; 3 independence of the clinical and pathological diagnoses; and 4 the ability to calculate the LR. Given the state of the art, we were flexible in the definition of the reference standard. If we had required clearly specified and reliable pathological criteria, virtually all studies would have been excluded.

Hachinski Ischemia Score A meta-analysis of the HIS was reported by Moroney et al. (1997). In this multicenter study, clinical and pathological data were retrospectively analysed for 312 cases (165 AD, 109 MID, 38 mixed). MID was defined by HIS ≥ 7, mixed by a score of 5–6, and AD by HIS ≤ 4. LR+ was 4.6 for a clinical diagnosis of MID (84% sensitivity, 82% specificity); LR+ was 3.5 for a diagnosis of mixed (83% sensitivity, 76% specificity). Several subsets of items were found either more commonly in MID than AD, or explained a significant portion of the variance in a logistic regression (Chapter II.4.2). A slightly larger LR of 6.2–10.1 was reported by Gold et al. (1997), with similar specificity (88– 97%), but far lower sensitivity (30–43%). It is difficult to understand the source of these differences because the methods of making pathological diagnoses in the two studies were not comparable.

116 CHAPTER II.4

DSM-III criteria In a larger retrospective study of 677 autopsied cases, a LR+ of 7.3–12.0 was reported for a DSM-III diagnosis of MID ( Jellinger et al. 1990). These cases were compiled from three different hospitals. Apart from citing DSM-III criteria, little detail is provided about the reliability of the clinical diagnosis. Similar LR values (4.0–11.5) were reported in a much smaller study of 27 MID, five AD and five other dementias (Erkinjuntti et al. 1988). In this study, all of the clinical diagnoses were made by the same neurologist, but the number of non-MID cases was small. Based on this limited data, the LR associated with DSM-III criteria for MID would generate moderate shifts in pre- to post-test probability. ADDTC criteria Only one autopsy study (Gold et al. 1997) has addressed the accuracy of the ADDTC criteria for possible ischemic vascular dementia (IVD), not probable IVD. However, the clinical diagnoses were applied retrospectively and neuroimaging studies, which are required for the application of ADDTC criteria, were unavailable in 80% of patients. The pathological definition of VaD arbitrarily excluded cases with vascular lesions confined to subcortical structures. In this study, the LR ranged from 1.7 to 4.8. Both sensitivity (58–63%) and specificity (64– 88%) were low. NINDS-AIREN criteria The accuracy of the NINDS-AIREN criteria for possible VaD were also addressed by Gold et al. (1997). A diagnosis of possible VaD (but not probable VaD) is allowed in the absence of imaging studies. In this study, the NINDS-AIREN and ADDTC criteria performed virtually identically: LR = 1.7–4.8; low sensitivity (43–58%) and higher specificity (79–91%). We identified only one other autopsy study where the NINDS-AIREN criteria were used (Holmes et al. 1999). It was excluded, however, because the number of VaD cases was too small (n = 8). Thus, there are no adequate Class I or Class II studies which address the accuracy of the newer VaD criteria.

Conclusions and recommendations Against a floating gold standard for the pathological diagnosis of vascular dementia, the positive likelihood ratios (LR+) associated with a clinical diagnosis of multi-infarct dementia falls in the 2–5 range for the HIS and 5–10 for the DSM-III or DSM-III-R criteria. In the absence of a reliable and agreed reference standard, evidence regarding the clinical diagnosis of VaD must be viewed with caution. None the less, the available data show that the LRs associated with the HIS fall in the 2–5 range, where small but sometimes important changes can be expected between pre- and post-test probability (these values are similar to those found for the NINCDS-ADRDA and DSM-III diagnoses of AD). Based on only two studies, the DSM-III criteria for MID perform even better. Here the LRs fall in the range of 5–10, where moderate shifts can be expected between pre- and post-test probability. The slightly higher LR for MID vs. AD may be attributed to the greater specificity afforded by clinical findings (e.g., focal neurological signs and neuroimaging abnormalities) for the diagnosis of ischemic brain injury. At the present time, there are limited data regarding the accuracy of the ADDTC or NINDS-AIREN criteria. The distinction between pure MID and mixed AD/MID remains elusive (in our review of the literature they have been grouped together). High priority should be given in the research community toward reaching a consensus about the diagnosis of VaD or CVD, either alone or in combination with AD.

Dementia with Lewy bodies Background Clinical criteria Consensus criteria have been recently developed for the clinical diagnosis of dementia with Lewy bodies (DLB) (McKeith et al. 1996). First, there must be evidence of progressive cognitive decline

DIAGNOSIS OF A DEMENTIA SUBTYPE 117

of sufficient magnitude to interfere with normal social and occupational function. Predominant or persistent memory impairment may not necessarily occur in the early stages. Rather, deficits in attention, executive and visual–spatial ability may be more prominent. Two of the following core features are essential for a diagnosis of probable DLB (only one is essential for possible DLB): 1 fluctuating cognition with pronounced variations in attention and alertness; 2 recurrent visual hallucinations that are typically well-formed and detailed; or 3 spontaneous motor features of parkinsonism. In a small retrospective autopsy study (n = 24) Mega et al. (1996) reported moderate interrater reliability for ascertainment of hallucinations (κ = 0.59) and extrapyramidal signs (κ = 0.46–0.68), but only fair agreement for fluctuating cognitive performance (κ = 0.25); interrater reliability for the overall diagnosis was not reported. Pathological criteria Consensus guidelines for the pathological evaluation and scoring of cortical Lewy bodies (0–10) have also been established (McKeith et al. 1996). Three subcategories of DLB are defined based on the regional distribution of LB: neocortical, limbic (transitional) or brainstem predominant.

Search strategy and study validation The Medline search of the literature identified four clinicopathological studies of DLB. None, however, met the criteria for Class I or II evidence, namely: 1 clearly defined clinical criteria and pathological criteria for DLB; 2 independence between the clinical and pathological diagnoses; and 3 a sample size of more than 25 cases. A pathological–clinical correlation study with a very large LR+ (17–25) was excluded (McKeith et al. 1994). Earlier Newcastle criteria for senile dementia of the Lewy body type (SDLT) (McKeith et al. 1992) were applied retrospectively and without knowledge of the pathological diagnoses. However, there is no assurance that the original autopsy cases

were selected without knowledge of the clinical findings. In addition, the sample studied was highly selected (20 SDLT, 21 DAT, nine MID). The large LRs are promising, but need to be confirmed using the new consensus criteria for DLB in a more representative sample. A multicenter retrospective study of 105 autopsy cases (Litvan et al. 1998) was also excluded. In this study clinical criteria for a diagnosis of DLB were not defined a priori, but left to the judgement of the neurologists. This study examined the accuracy of a clinical diagnosis of DLB (n = 14) and Parkinson’s disease (n = 15) vs. a variety of other cases with movement disorders (n = 76) (e.g. progressive supranuclear palsy, corticobasal degeneration, multisystems atrophy). Because of the large number of non-DLB cases which could artificially increase specificity (81%), PPV and sensitivity were chosen as the primary outcome measures but were found to be low (48% and 54%, respectively). Thus, senior movement disorder specialists frequently missed the diagnosis of DLB. Two studies using consensus criteria for DLB were excluded because of inadequate sample size. In a retrospective autopsy study (Mega et al. 1996), no cases received a clinical diagnosis of DLB and only four cases had cortical Lewy bodies. Also, in a community-based autopsy study (Holmes et al. 1999), only four cases received clinical diagnoses of DLB (two pure DLB, two DLB+); Lewy bodies were found in 11 cases on pathological exam. Multicenter studies may be required to accumulate sufficient sample size.

Evidence As mentioned above, no studies addressing the accuracy of the consensus criteria for DLB and qualifying as Class I or II evidence were identified.

Conclusions and recommendations Consensus criteria for the clinical and pathological diagnosis of DLB have been recently promulgated. At this time, no evidenced-based recommendations can be made regarding their reliability or accuracy. They cannot be recommended for clinical use: additional research is needed.

118 CHAPTER II.4

Frontotemporal dementia Background

does not establish the number of core features required for diagnosis, which will theoretically reduce inter-rater reliability. Interrater reliability of these guidelines has not been published.

Clinical criteria Guidelines for a diagnosis of FTD are provided in both the Diagnostic and Statistic Manual and ICD10. According to DSM-IV, FTD is characterized by changes in personality early in the clinical course, including deterioration of social skills, emotional blunting and behavioral disinhibition. Amnesia, apraxia and other features of dementia may follow later. According to ICD-10, there is: 1 progressive dementia; 2 predominance of frontal lobe features with euphoria, emotional blunting, worsening social behavior, disinhibition and either apathy or restlessness; and 3 behavioral manifestations which commonly precede frank memory impairment. The Lund and Manchester Groups (Brun et al. 1994) list a large number of features that are considered to be core, supportive, exclusionary and relatively exclusionary for the clinical diagnosis of frontotemporal dementia. Core behavioral symptoms include: 1 insidious onset and slow progression; 2 early loss of personal awareness; 3 early loss of social awareness; 4 early signs of disinhibition; 5 mental rigidity and inflexibility; 6 hyperorality; 7 stereotyped and perseverative behavior; 8 utilization behavior; 9 distractibility and impersistence; and 10 early loss of insight. Core affective features include: 1 depression and anxiety; 2 hypochondriasis; 3 emotional unconcern; and 4 inertia. Core speech disorders include: 1 a progressive reduction of speech; 2 stereotypy; 3 echolalia and perseveration; and 4 late mutism. Notably, spatial orientation and praxis are preserved. Unfortunately, the consensus statement

Pathological criteria The recent formulation accepts, under the behavioral rubric of FTD, two types of histological changes which predominantly affect the frontotemporal lobes. The most common pathology includes neuronal loss, microvacuolation and mild to moderate astrocytosis in the outer cortical layers of the frontal lobe (i.e. frontal lobe degeneration). This can be distinguished from the intense astrocytic gliosis, and often inflated neurones and intraneuronal inclusions, associated with classic Pick disease. At times, degeneration of motor neurones is associated with the frontal lobe degeneration type of FTD. The characteristic gross and microscopic features of the frontal lobe degeneration type and Pick-type of FTD are described in the Lund and Manchester Consensus Statement (Brun et al. 1994). No formal criteria, however, were established.

Search strategy and study validation The Medline search of the literature identified three clinicopathological studies of FTD (Gustafson & Nilsson 1982; Barber et al. 1995; Varma et al. 1999), but none met the criteria for Class I or II evidence: 1 clearly defined clinical criteria and pathological criteria for DLB; 2 independence between the clinical and pathological diagnoses; and 3 a sample size of more than 25 cases. The studies by Barber and Varma draw on the same cases from the Manchester Royal Infirmary. Barber analyses the results of a retrospective informant questionnaire, whereas Varma looked at neuropsychological impairments in specific cognitive domains. Neither tested consensus criteria.

Evidence No clinicopathological studies were identified that meet the criteria for Class I or II evidence.

DIAGNOSIS OF A DEMENTIA SUBTYPE 119

Conclusions and recommendations Consensus criteria for the clinical and pathological diagnosis of FTD have been recently promulgated.

II.4.2

At this time, no evidenced-based recommendations can be made regarding their reliability or accuracy. Thus, they cannot be recommended for clinical use; additional research is needed.

Clinical History and Neurological Signs

Helena Chui

In this Section, we ask the following question: ‘How useful are individual features of the clinical history and neurological examination in differentiating Alzheimer’s disease (AD), other types of dementia and normal ageing’? Changes in behavior and mental status are reviewed in Chapters II.4.3 and II.4.4.

Background Clinical history Nature of symptom onset and progression In neurodegenerative disorders (e.g. AD, dementia with Lewy bodies (DLB), frontotemporal dementia (FTD)) the onset of cognitive impairment is gradual and its progression insidious. According to conventional teaching, this contrasts with sudden onset and stepwise decline in multi-infarct dementia (MID), the most commonly recognized form of vascular dementia (VaD), where each step is attributed to a new completed stroke. In fact, however, the spectrum of VaD is broader and its course more variable. Relatives of patients clinically diagnosed with VaD report abrupt onset in 46%, stepwise progression in 50%, abrupt onset and stepwise deterioration in 34%, and insidious onset and uniformly progressive course in 29% (Fischer et al. 1990). The pattern of gradual onset and progression suggests the presence of a concomitant neurodegenerative disorder (such as AD), but is also consistent with progressive ischemia of the deep white matter in the Binswanger subtype of vascular dementia (Olszewski 1962). Thus, while sudden onset of symptoms is more common in VaD, insidious onset and progressive decline may be seen in vascular as well as neurodegenerative dementias.

Risk factors No particular medical or environmental risk factor seems to distinguish among various subtypes of neurodegenerative dementias. On the other hand, a number of conditions are clearly associated with increased risk of stroke, and hence also VaD. These so-called vascular risk factors include hypertension, diabetes mellitus, hyperlipidemia, atrial fibrillation, cigarette smoking and heavy alcohol consumption. A vast literature covers associations between vascular risk factors and stroke (see Sacco et al. 1999 for review). A smaller database examines associations between vascular risk factors and VaD (Tatemichi et al. 1993; Skoog 1998; Gorelick et al. 1999). In this chapter, we focus on the value of vascular risk factors for differentiating VaD from other forms of dementia, particularly AD (Gorelick et al. 1994; Moroney et al. 1997). Bear in mind that if vascular risk factors are used to make a diagnosis of VaDafor example, the Hachinski Ischemic Score (HIS) (Hachinski et al. 1975) and DSM-III-R or DSM-IV (American Psychiatric Association 1987, 1994)athey cannot subsequently be examined as a dependent variables in group comparisons of risk. Family history In taking a family history from a patient with dementia, it is common to discover another first degree relative with dementia, stroke and sometimes with Parkinson’s disease (PD). These discoveries by themselves do not add much to the diagnosis of dementia or its subtypes. However, a family history with multiple members affected by dementia may be highly significant, particularly if the pattern is consistent with autosomal dominant inheritance

120 CHAPTER II.4

(where 50% of family members who live to the age of risk express the disease). Such a family history suggests the likelihood of a gene mutation with high penetrance (e.g. amyloid precursor protein (APP), presenilin 1 and presenilin 2 in AD; chromosome 17 in frontotemporal dementia; cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) in vascular dementia; or α-synuclein in PD). The role of genetic testing in the diagnosis of dementia is covered in Chapter II.4.5.

Neurological examination Cranial nerves The examination of the cranial nerves is generally normal in the setting of neurodegenerative dementia. An exception occurs in progressive supranuclear palsy (PSP). In this rare Parkinson-plus syndrome, volitional saccadic eye movements are progressively lost, while slow eye movements generated in response to oculocephalic stimulation (Doll’s eyes) are preserved. Cranial nerve findings frequently accompany brainstem strokes, but in the US such patients are more likely to be followed by stroke rather than dementia programs. Hypophonic dysarthria accompanies parkinsonian syndromes, such as PD, DLB, or multi-systems atrophy. Ataxic dysarthria accompanies cerebellar degenerations. Focal motor or sensory signs The term ‘focal neurologic sign’ is commonly used to describe weakness or sensory loss ascribed to dysfunction of the central nervous system. This type of weakness is usually accompanied by other ‘upper motor neurone signs’, including extensor plantar response (Babinski or Chaddock sign), hyperreflexia or spasticity. The pattern of sensory loss (e.g. homonymous hemianopia or somatosensory loss on one side of the body) suggests dysfunction in one cerebral hemisphere or a unilateral ascending sensory tract. Focal neurological signs are commonly seen in VaD; indeed they are required by several diagnostic criteria. Focal signs may also appear in spongiform encephalopathies (e.g. Creutzfeldt–Jakob disease).

Upper and lower motor neurone signs may accompany some forms of FTD. In contrast, primary motor and sensory function are relatively spared in degenerative dementias such as AD and DLB. Extrapyramidal signs Extrapyramidal signs refer to a group of neurological findings that are ascribed to dysfunction of the basal ganglia. They may be remembered by using the mneumonic TRAP and include: tremor, rigidity, akinesia and postural changes. Although extrapyramidal signs are cardinal features of idiopathic PD, they may also accompany other degenerative dementiasaespecially DLB, PSP, and corticobasal degeneration, but also late state AD and FTD. In AD, bradykinesia and rigidity are most common, while tremor is rare (Mölsa et al. 1984; Chen et al. 1991). Six years after symptom onset, 50% of subjects with AD manifest some extrapyramidal signs (Chen et al. 1991). In the advanced stages of dementia, other factors (such as paratonic rigidity or contractures) may increase the resistance to range of motion (Franssen et al. 1991). Thus, in the late stages of dementia, increased tone loses its utility for differentiating etiology. Gait disturbance There are multiple causes of gait disturbance in the elderly. Distinguishing those due to central nervous system dysfunction vs. peripheral or musculoskeletal disorder may be difficult. Slowness and unsteadiness are non-specific, whereas a parkinsonian or apraxic gait (poor initiation, small-stepped festinating gait, decreased arm swing, turning of the whole body en bloc) is more specific. Parkinsonian gait occurs relatively early in the course of dementia in PD and DLB, and late in the course of AD. In VaD, large or small strategic infarctions are associated with a spastic hemiparetic gait, whereas multiple small lacunar infarctions in the basal ganglia and deep white matter are associated with parkinsonian gait (so-called atherosclerotic or lower body parkinsonism). Thus, parkinsonian gait disturbance occurs early in PD and DLB, variably in the course of VaD, and late in the course of AD and FTD.

DIAGNOSIS OF A DEMENTIA SUBTYPE 121

Pathological reflexes Some ‘primitive’ reflexes such as snout are seen in elderly person regardless of whether they have dementia or are cognitively intact (Koller et al. 1982). A snout reflex refers to transient puckering of the lips when the philtrum above the lip is tapped lightly. By contrast, grasp and sucking reflexes are rarely seen in cognitively normal elderly persons, but may occur in a variety of dementing diseases (Galasko et al. 1990; Kosunen et al. 1996). A grasp reflex refers to involuntary closure of the hand when the palm is stroked lightly. Grasp reflexes appear when the premotor cortex is damaged. More sustained sucking movements of the lips may occur in response to oral tactile stimulation or to a visually perceived approaching object. Sucking reflexes appear when there is severe frontal lobe dysfunction. The palmomental reflex refers to contraction of the ipsilateral mentalis chin muscles when the palm overlying the opponens pollicis is scratched. The glabellar reflex (Myerson’s sign) refers to failure to extinguish eye blinking in response to successive tapping of the forehead. Palmomental and glabellar reflexes are characteristically associated with PD, but may be seen in other disorders of the basal ganglia, as well as AD. Among patients with AD, the prevalence of snout, suck and grasp reflexes increases with the severity of dementia (Huff & Growdon 1986; Bakchine et al. 1989; Franssen et al. 1991). On the other hand, palmomental and glabellar reflexes are associated with with extrapyramidal signs, but not with severity of dementia. Myoclonus Myoclonus refers to one or a series of shock-like contractions of a group of muscles of variable regularity, synchrony and symmetry. Isolated myoclonus is normally experienced at the onset of sleep. Myoclonus in response to sensory stimulation (e.g. auditory startle) is characteristic of spongiform encephalopathy (Creutzfeldt–Jakob disease). In cross-sectional studies, myoclonic jerks have been observed in approximately 5–10% of patients with AD (Chui et al. 1985; Chen et al.

1991), particularly those with presenile onset. Prevalence of myoclonus increases with time and is associated with an increased risk of seizures. Alternating hand sequences Tests of reciprocoal motor coordination were developed and popularized by Luria (Luria 1969; Christensen 1979). Alternating between opening and closing of the hands (one hand fisted, the other flat) is mediated by bilateral premotor cortices connected via the corpus callosum. This is a simple test of motor association cortex. Impairment is encountered in AD and other degenerative dementias. Apraxia The Diagnostic and Statistical Manual (DSM-III-R and DSM-IV; American Psychiatric Association. 1987, 1994) suggests that apraxia is a common symptom in dementia. In clinical practice, however, it is not a very useful sign. First, ideomotor apraxia does not become obvious until the moderate stages of AD (usually when there are difficulties with dressing). This is also the case for reflective apraxia (the ability to imitate meaningless gestures) (Bakchine et al. 1989). Thus apraxia is not useful for differentiating early stages of dementia from normal ageing. Second, it is difficult for the general practitioner to reliably identify apraxia when aphasia and other cognitive deficits are also present, as is usually encountered in AD. An exception occurs in corticobasal degeneration. In this rare neurodegenerative disorder, apraxia develops early in the course of dementia and may be more prominent than recent memory loss.

Search strategy and study validation In order to assess the utility of individual signs and symptoms for differential diagnosis, we searched the literature for odds ratios (ORs) between two comparison groups: AD vs. normal ageing, other dementia vs. normal ageing and AD vs. non-AD dementia. Inclusion criteria were: (i) a reliably defined clinical sign or symptom; (ii) a reliably defined clinical group;

122 CHAPTER II.4

(iii) independence in determining the presence or absence of the clinical sign and diagnostic group; and (iv) the ability to calculate an OR. Most of the studies were found by hand search. If the dementia diagnosis was established by autopsy, we classified the study as Class I or II; if the diagnosis was based on clinical criteria, we classified the study as class 1 or class 2.

Evidence AD vs. normal ageing In a community study of healthy elderly subjects, subtle changes in speed of finger tapping and ambulation predicted the development of cognitive impairment 3 years later (Camicioli et al. 1998). Talking while walking apparently slows speed of ambulation more among AD patients than normal elderly control subjects (ORs not provided) (Camicioli et al. 1997). These studies suggest that AD may accentuate motor slowing associated with normal ageing. In a study of 476 individuals drawn as a randomized stratified sample from community-dwelling elderly persons (class 1b), hypomimia of the face together with akinesia of the limbs was 4.5 times more likely (95%CI 2.4–8.6) among those diagnosed with probable AD compared to those diagnosed as cognitively normal or with possible AD (Funkenstein et al. 1993). Inability to alternate hand positions (i.e. one hand fisted and the other flat) was 8.0 times (95%CI 4.0–15.9) more likely. Shuffling gait or impaired turning were 1.7 times (95%CI 0.9–3.2) more likely to be observed. The combined signs were 4.1 times (95%CI 1.9–8.9) more likely in AD. The frequency of neurological abnormalities among patients with AD vs. normal controls has been reported from several university convenience samples. The results of two studies are described below; although there are assurances that the examinations were conducted independently of the clinical diagnoses, they do not meet criteria for class 1 or 2 evidence. Huff et al. (1987) observed a higher prevalence of several neurological findings among 95 patients with mild to moderate AD (mean MMSE = 20.9 ± 5.3) vs. 87 controls. These

included: primitive reflexes (54.7% vs. 9.2%, OR = 5.2); anosmia (20.2% vs. 3.5%, OR = 5.0); and astereognosia and agraphesthesia (22.1% vs. 1.2%, OR = 4.8). Similarly, Galasko et al. (1990) compared 135 mild to moderately demented patients with AD (mean MMSE = 17.1 ± 6.4) vs. 91 nondemented elderly individuals. Several neurological signs were more frequent in AD than controls. These included: rigidity (14% vs. 0%, OR = 30.8); agraphesthesia (13% vs. 1%, OR = 17.8); stooped posture (16% vs. 1%, OR = 13.0); glabellar reflex (27% vs. 4%, OR = 8.2); grasp reflex (17% vs. 4%, OR = 4.6); and snout reflex (46% vs. 24%, OR = 3.5). The values reported in these two studies cannot be applied to the differentiation of early AD from normal ageing, because the comparisons were not stratified by severity of dementia. Galasko et al. (1990) concluded that although abnormal neurological findings occur regularly in AD, they are too infrequent early in its course to serve as useful diagnostic markers.

MID vs. AD Using autopsy-confirmed cases, Moroney et al. (1997) (Class IIB) examined the frequency of individual items in the HIS (Hachinski et al. 1975) to distinguish three groups of patients (165 AD, 109 MID, 38 mixed AD/MID). They found that MID was more likely to be associated with stepwise deterioration (OR = 6.1), fluctuating course (OR = 7.6), history of hypertension (OR = 4.3), history of stroke (OR = 4.3) and focal neurological symptoms (OR = 4.4), while the absence of these features was associated with AD (Table II.4.5). Stepwise deterioration and emotional incontinence helped to distinguish MID vs. mixed, while fluctuating course and history of stroke helped to differentiate mixed from AD. Risk factors Demographic, medical and other epidemiological factors were compared among hospital-based African-American patients with AD (n = 113) and VaD (n = 79) (class 1b) (Gorelick et al. 1994). Data were obtained via structured interviews of proxy informants. Diagnosis of VaD was based on a

DIAGNOSIS OF A DEMENTIA SUBTYPE 123

Table II.4.5 Odds ratios (95% confidence intervals) based on logistic regression analyses (Moroney et al. 1997). MID vs.

AD vs.

Item

AD

Mixed

AD/mixed

Mixed

MID/mixed

Abrupt onset Stepwise deterioration Fluctuating course Nocturnal confusion Preservation of personality Depression Somatic complaints Emotional incontinence History of hypertension History of stroke Associated atherosclerosis Focal neurological symptoms Focal neurological signs

– 6.1 (2.5–14.7)‡ 7.6 (3.2–18.5)‡ – – – – – 4.3 (1.8–10.2)† 4.3 (1.5–12.5)† – 4.4 (1.6–12.5)† –

– 4.0 (1.7–9.1)† – – – – – 3.4 (1.2–10.0)* – – – – –

2.6 (1.2–5.5)* 6.2 (3.1–12.8)‡ – – 2.4 (1.1–4.9)* – 3.0 (1.2–10.0)* – – – 2.1 (1.0–4.3)* 3.1 (1.5–6.5)† –

– – 0.2 (0.1–0.5)† – – – – – – 0.1 (0.0–0.2)‡ – – –

– 0.3 (0.1–0.7)† 0.2 (0.1–0.5)‡ – – – – – 0.5 (0.2–0.9)* 0.1 (0.0–0.2)‡ – – –

*P < 0.05; †P < 0.01; ‡P < 0.001.

Table II.4.6 Comparison of risk factors in Alzheimer’s disease (AD) and vascular dementia (VaD)apercentages and number with risk factor/number in study (Gorelick et al. 1994). Odds ratio > 1.0 favoring VaD. Risk factor

AD (%) (n of n)

VaD (%) (n of n)

Odds ratio

Hypertension Diabetes mellitus Myocardial infarction Angina pectoris Atrial fibrillation Hip fracture Prescribed medication Family history of AD, Parkinson’s disease or dementia

49.5 (54/109) 12.6 (14/111) 5.5 (6/109) 9.3 (10/108) 1.9 (2/108) 8.1 (9/111) 73.0 (81/111) 27.6 (29/105)

76.6 (59/77) 37.2 (29/78) 12.8 (10/78) 17.1 (13/76) 8.0 (6/75) 1.3 (1/79) 92.4 (73/79) 12.3 (9/73)

3.3* 4.1* 2.5 2.0 4.6* 0.15* 4.5* 0.37*

*P < 0.05.

history of stroke, focal neurological findings and evidence of a stroke lesion on CT or MRI; risk factors were not used for the diagnosis. Hypertension, diabetes mellitus, atrial fibrillation and prescribed medication were reported significantly more frequently in VaD. Hip fracture and family history of AD, PD or other dementia were reported more often in AD (Table II.4.6).

DLB vs. AD and DLB vs. PD Extrapyramidal signs are expected to be relatively greater in DLB, variable in VaD, and less in AD or

FTD. However the variability within and between each type of disorder limits the cross-sectional utility of extrapyramidal signs for differential diagnosis. For example, no significant differences were found in the frequency of tremor, increased muscle tone or bradykinesia in a retrospective comparison of 58 patients with autopsy-confirmed AD vs. 24 patients with the Lewy body variant of AD (Class IIB) (Weiner et al. 1996). Worsening of these signs following exposure to neuroleptics (i.e. neuroleptic sensitivity) was found more frequently in the Lewy body variant group (n = 4/4) than AD (n = 5/13), but the number of cases was small.

124 CHAPTER II.4

A comparison of DLB (n = 31) with PD (n = 34) showed rest tremor to be more common in PD and myoclonus to be more common in DLB (Louis et al. 1997). No differences were noted in the frequency of rigidity, bradykinesia, dystonia or gaze palsies. The occurrence of any one of four atypical features (i.e. myoclonus, absence of rest tremor, no response to levodopa or no perceived need to treat with levodopa) was 10 times more likely in DLB than in PD (OR = 10.3; 95%CI 2.6– 41.1). Thus, the constellation of signs and their response to dopaminergic agents appears to differ in DLB vs. PD.

Conclusions and recommendations

factors are reported more commonly in VaD than AD, but insidious onset and slowly progressive decline may be seen in vascular, as well as degenerative, dementias. • Focal neurological signs occur more frequently in MID than AD. Subtle but also abnormal motor and reflex findings occur regularly in AD, but have not been shown to be reliable for diagnosis, particularly early in the disease course. • Mild extrapyramidal signs may be seen in several different types of neurodegenerative and ischemic vascular disorders. Based on a cross-sectional examination, it is difficult to use these signs by themselves for differential diagnosis. Differences in the pattern and severity of such signs are worthy of longitudinal study.

• Sudden onset of symptoms and vascular risk

II.4.3

Behavioral Characteristics in Diagnosis

Jeffrey Cummings

Neuropsychiatric symptoms, emotional disorders and behavioral alterations are ubiquitous among patients with dementia syndromes. Neuropsychiatric abnormalities, however, are neither necessary nor sufficient for the identification of a dementing disorder. The fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) (American Psychiatric Association 1994) identifies dementia as a syndrome with memory impairment and disturbance of at least one other cognitive function. Subcategories of the dementia syndrome consisting of patients with dementia plus delusions or dementia plus depressed mood are recognized in the official nomenclature, but such behavioral changes are not required. Similarly, the tenth edition of the Classification of Mental and Behavioural Disorders of the International Classification of Diseases (ICD-10) (World Health Organization 1992) describes dementia as a chronic and progressive disease of the brain with disturbances in multiple higher cortical functions. The definition notes that impairments of cognitive function are commonly accompanied and occasionally preceded by deterioration in emotion control,

social behavior or motivation; however, these are not required for identification of a dementia syndrome. Subcategories of dementia identified are dementia with other symptoms predominantly delusional, predominantly hallucinatory, predominantly depressive, or with other mixed symptoms. Thus, both major classification systems recognize that behavioral symptoms may accompany dementia syndromes, but neither system requires the presence of neuropsychiatric symptoms or behavioral alterations for the diagnosis of dementia. Neuropsychiatric symptoms can be identified and quantified using a variety of checklists, inventories and rating scales. A checklist approach can be used to determine if patients meet DSM-IV or ICD-10 criteria for dementia with behavioral disturbances. Additional codes can be used to further characterize the neuropsychiatric symptoms as delusions, hallucinations, mood disorders, personality changes or sleep disturbances due to specific neurological disorders (such as Alzheimer’s disease, AD). Rating scales can be used to rate individual symptoms or multidimensional instruments can be employed to provide a profile of behavioral changes. The

DIAGNOSIS OF A DEMENTIA SUBTYPE 125

Cohen-Mansfield Agitation Inventory (CohenMansfield & Deutsch 1996) and the Cornell Scale for Depression in Dementia (Alexopoulos et al. 1988) are tools commonly used to assess agitation and depression, respectively, in patients with dementia. The Behave-AD (Reisberg et al. 1987) and the Neuropsychiatric Inventory (NPI) (Cummings et al. 1994) are instruments providing multi-dimensional symptom profiles. No neuropsychiatric symptom, emotional disorder or behavioral disturbance is completely pathognomonic of a specific dementing disorder. However, with increased attention to the neuropsychiatric symptoms of patients with cognitive impairment, highly characteristic behavioral changes have been identified. Notably, visual hallucinations are one of the primary symptoms of dementia with Lewy bodies (DLB) and frontally-mediated behavioral changes are recognized as early characteristic features of the frontotemporal dementias (FTDs). The common behavioral changes of the major dementing disorders are described below with an emphasis on comparative studies addressing the potential diagnostic utility of neuropsychiatric symptoms and behavioral disorders. A literature search was undertaken for the specific purpose of quantifying the accuracy of behavioral features for making a diagnosis of dementia subtype.

Search strategy and study validation To be included in this evidenced-based review, the following criteria were required. First, published pathological or clinical criteria were used to define the referent standard (i.e. dementia subtype). In keeping with conventions used throughout this section, pathological criteria were required for Class I or II evidence; clinical criteria sufficed for class 1 or 2 evidence. Second, the behavioral features and diagnosis of dementia were made independently of each other. Third, a likelihood ratio (LR) could be calculated. Very few studies meeting all three criteria and using clinical diagnoses as the reference standard (class 1 or 2) were found and none based on autopsy-confirmed patients (Class I or II) were identified.

Alzheimer’s disease Background A wide spectrum of neuropsychiatric symptoms is evident among patients with AD. Cross-sectional studies show that delusions are present in 15–40% of patients, whereas hallucinations are present in 10–30% (Swearer et al. 1988; Burns et al. 1990b,c; Mendez et al. 1990; Cooper et al. 1991; Mega et al. 1996). Agitation is a common behavior occurring in 40–70% of patients, while assaultiveness or aggression occur in 15–30% (Swearer et al. 1988; Burns et al. 1990b; Mega et al. 1996; Chemerinski et al. 1998). Apathy and irritability are very common, and are reported in 22–70% of patients (Teri et al. 1989; Burns et al. 1990a; Mega et al. 1996). Estimates of the reports of depression have varied widely among studies with 50–85% of patients identified as suffering from depressive mood disorders (Merriam et al. 1988; Teri et al. 1992; Mega et al. 1996). Studies comparing AD to normal controls are reviewed first, followed by those comparing AD to other subtypes of dementia.

Evidence Relatively few studies have compared psychiatric symptoms of AD with normal controls. Mega et al. (1996) using the NPI (class 2b) (Cummings et al. 1994) found that normal controls had scorable behaviors on only three of 10 inventory itemsa dysphoria, disinhibition and irritabilityaand in all cases the inventory scores were significantly higher for AD patients than controls. Likewise, Kumar et al. (1988) found irritability, paranoia, depression and critical behavior to be more common among patients with AD than among healthy control subjects. AD patients also reported diminished frequency of sexual relationships, hallucinations, illusions, confabulations and assaultive behavior, but the reports of these symptoms were sufficiently uncommon in this sample so that they did not distinguish the patients from the controls. Thus, behavioral disturbances are common in AD and some can distinguish patients with AD from groups of normal controls.

126 CHAPTER II.4

No pathognomonic or unique neuropsychiatric symptoms have been identified that distinguish AD from other dementia syndromes. The differential diagnostic utility of profiles or clusters of symptoms distinguishing AD from other dementia syndromes are discussed in further detail below.

Recommendations for practice Although behavioral disturbances are more common in AD than in normal elderly persons, they cannot be relied upon for diagnosis. Furthermore, no specific profile of behavioral disturbances can be used to reliably distinguish AD from other dementing disorders. Notwithstanding its limited usefulness for diagnosis, obtaining a behavioral profile is very important in optimizing the management of patients with AD. Many behavioral symptoms can be ameliorated with pharmacological treatment or environmental interventions.

They found that the total score and the neurovegetative signs of the scale were both significantly elevated in patients with VaD compared with those with AD; subjectively experienced symptoms showed a similar trend toward greater severity in patients with VaD compared with those with AD, but the difference was not statistically significant.

Recommendations for practice Neuropsychiatric symptoms are common in VaD and the profile may differ somewhat from that of AD (particularly the elevation of depression rating scale scores), but syndrome profiles are sufficiently similar so that they cannot be used for differential diagnosis in individual patients. If dementia is present, expert opinion suggests that an MRI scan should be obtained to further evaluate the possibility of VaD.

Frontotemporal dementia

Vascular dementia

Background

Background

Frontotemporal dementia (FTD) has a distinctive behavioral profile and behavioral symptoms can be useful in identifying this disorder, although by themselves they are not completely diagnostic. The DSM-IV (American Psychiatric Association 1994) notes that the disorder is characterized clinically by changes in personality early in the course, including deterioration of social skills, emotional blunting and behavioral disinhibition. Amnesia, apraxia and other features of dementia are noted to follow later in the course. The ICD-10 (World Health Organization 1992) provides three criteria for the diagnosis of FTD (i) progressive dementia; (ii) a predominance of frontal lobe features with euphoria, emotional blunting, worsening social behavior, disinhibition and either apathy or restlessness; and (iii) behavioral manifestations preceding frank memory impairment. They note that frontal lobe features are more marked than the predominance of temporal and parietal manifestations noted in AD. The Lund and Manchester Groups (1994) described behavioral disorders and affective symptoms considered to be characteristic of FTD. These included early loss of personal awareness, early loss of social awareness, disinhibition, mental rigidity

A plethora of neuropsychiatric symptoms have been observed among patients with vascular dementia (VaD) (Cummings et al. 1987). Delusions, hallucinations, depression and personality alterations have all been reported at elevated frequencies in populations of VaD patients (Dian et al. 1990; Flynn et al. 1991; Binetti et al. 1993; Sultzer et al. 1993). Most authors found similar rates of psychosis in VaD and AD (Flynn et al. 1991; Binetti et al. 1993; Sultzer et al. 1993); however, other symptoms have greater differential diagnostic value.

Evidence Cummings et al. (1987) and Fischer et al. (1990) noted that depression was more severe in patients with VaD than in those with AD. Similarly, Sultzer found that several depression-related scale items were more common in VaD than AD, including guilt feelings, tension and somatic concern (Sultzer et al. 1993). Sultzer et al. (1993) investigated the characteristics of the Hamilton Depression Rating Scale (Hamilton 1967) in the two populations.

DIAGNOSIS OF A DEMENTIA SUBTYPE 127

and inflexibility, hyperorality, stereotyped and perserverative behavior, utilization behavior, distractability, early loss of insight, depression, anxiety, hypochondriasis, emotional unconcern and inertia.

FTD. If the behavioral profile suggests possible FTD, many experts would recommend functional and structural imaging studies to confirm this (Chapter II.4.8).

Evidence

Dementia with Lewy bodies

Miller et al. (1997), using the Lund and Manchester criteria, compared 30 patients with FTD with 30 patients with AD. A discriminate function showed that loss of personal awareness, hyperorality, stereotyped and perserverative behavior, along with progressive reduction of speech and preserved spatial orientation, differentiated FTD and AD with 100% accuracy. In this case ascertainment of behaviors was not completely independent of diagnoses. Levy et al. (1996) used the NPI to compare groups of patients with FTD and AD. They noted that patients with relatively high scores for disinhibition and apathy and relatively low scores for depression were more common in the FTD group. These three variables accurately assigned 77% of the patients with FTD and an equal number of patients with AD to the correct diagnostic category. Diagnosis and behavioral characterization were performed independently (class 2). Some behaviors are particularly characteristic in FTD and may help distinguish this disease from other conditions. Compulsive behaviors such as eating, dressing or cleaning in a repetitive and stereotyped sequence, for example, occur in 40–70% of patients with FTD and is distinctly unusual in patients with other degenerative disorders (Ames et al. 1994; Mendez et al. 1997). Even more unique is the occasional emergence of new artistic talent in the course of the degenerative process, an event virtually unique to patients with FTD (Miller et al. 1998). Thus, the behavioral characteristics of FTD can be of substantial help in distinguishing this condition from other dementia syndromes.

Background

Recommendations for practice Among the dementia subtypes reviewed in this chapter, FTD is associated with the most characteristic behavioral profile. The NPI (Cummings et al. 1994; Levy et al. 1996) provides a practical means of assessing behavioral changes common in

Dementia with Lewy bodies also has characteristic neuropsychiatric symptoms. Consensus diagnostic criteria (McKeith et al. 1996) require the presence of a dementia syndrome and two of the following three features: (i) fluctuating cognition with pronounced variations in attention and alertness; (ii) recurrent visual hallucinations that are typically well formed and detailed; or (iii) spontaneous motor features of parkinsonism. Thus, visual hallucinations are regarded as one of the core features of the disorder. Supportive features include systematized delusions, hallucinations in other modalities and neuroleptic sensitivity. Depression is also a common feature of the disorder (Weiner et al. 1996). Rapid eye movement (REM) sleep behavior disorder is characterized by episodes of complex motor activity associated with dream mentation occurring during sleep. This disorder may occur more commonly in patients with Parkinson’s disease (PD) and DLB than in other degenerative disorders (Boeve et al. 1998).

Evidence Weiner et al. (1996) compared patients with DLB and patients with AD and found that hallucinations, delusions, low energy, psychomotor retardation, weight change and diminished work interest were all more common in patients with DLB than in those with AD. Nearly significant differences included depression and paranoia, which were also more common in DLB.

Recommendations for practice The inclusion of visual hallucinations in the diagnostic criteria for DLB indicates that this neuropsychiatric symptom is a characteristic feature of the illness. However, visual hallucinations also occur

128 CHAPTER II.4

in AD, FTD and VaD, although at lower frequencies. Patients with DLB manifest particularly high frequencies of neuropsychiatric symptoms (delusions, hallucinations and mood disorders) but the behavioral and neuropsychiatric features are not sufficiently unique to be diagnostic of the disorder. Expert opinion advises that if these behavioral features are present together with mild extrapyramidal signs, the clinician should be alerted to the increased risk of neuroleptic sensitivityawhere small doses of neuroleptic may precipitate severe rigidity and immobility.

Parkinsonian syndromes with dementia Background Dementia with Lewy bodies is but one of several dementing disorders associated with progressive parkinsonism. PD, progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are other examples of neurodegenerative disorders with dementia and parkinsonism. All of these disorders exhibit neuropsychiatric disturbances. Depression is common in PD, occurring in approximately 40– 50% of patients, although the percentage reaching criteria for a major depressive episode is small (Cummings 1992; Tandberg et al. 1996). Depression is more common in patients with cognitive impairment than in those without (Tandberg et al. 1997). Delusions and hallucinations also are common in PD, and are more frequent in patients with dementia than in those with intact cognitive function (Cummings 1991; Naimark et al. 1996; Sanchez-Ramos et al. 1996). None of these neuropsychiatric features are sufficiently distinctive to be helpful in differential diagnosis.

Evidence Litvan et al. (1996) compared the neuropsychiatric features of PSP with those of AD using the NPI. PSP patients had high scores on apathy and low scores on disinhibition, dysphoria, agitation, irritability and anxiety. The combination of high apathy scores with low agitation and anxiety scores correctly distinguished PSP from AD with 85% accuracy. No LR could be calculated from the data provided.

Studies of CBD have been accomplished using the NPI. Patients demonstrated high frequencies of depression (73%) with lower frequencies of apathy, irritability, agitation, anxiety and disinhibition. The profile of neuropsychiatric abnormalities correctly distinguished CBD from PSP 85% of the time (LR+ 22.3, sensitivity 67%, specificity 97%, positive predictive value 91%) (Litvan 1998). Huntington’s disease exhibits a variety of psychiatric symptoms. Burns et al. (1990a) found irritability to be significantly more common in patients with Huntington’s disease than in those with AD (59% vs. 32%), while the groups had similar frequencies of irritability and apathy. Litvan et al. (1998) investigated the neuropsychiatric features of Huntington’s disease using the NPI and found elevated scores for apathy, agitation, anxiety, irritability, dysphoria and euphoria. Delusions were less common and hallucinations did not occur in any of the patients. The combination of elevated scores on agitation, euphoria and irritability scales was significantly more common in Huntington’s disease compared with PSP patients who had significantly more severe apathy. None of the features were pathognomonic for the illness.

Conclusions These studies show that neuropsychiatric symptoms are common in neurodegenerative and dementing disorders. Moreover, different profiles of symptoms are present in each of the illnesses. There is sufficient overlap, however, in the symptoms and symptom complexes in different disorders that they are not diagnostic of individual illnesses and cannot by themselves form the basis for secure differential diagnoses. Some behaviors are highly characteristic of individual neurological diseases: disinhibition, compulsions and the emergence of new artistic talent are substantially more common in FTD than in any other neurological diseases; similarly, visual hallucinations and REM sleep disorder are highly characteristic of DLB. Thus, careful assessment of the neuropsychiatric symptoms exhibited by dementia patients can aid in differential diagnosis even though they lack complete discriminative power.

DIAGNOSIS OF A DEMENTIA SUBTYPE 129

Acknowledgements This project was supported by a National Institute

II.4.4

on Aging, Alzheimer’s Disease Center grant (AG16570), an Alzheimer’s Disease Research Center of California grant, and the Sidell–Kagan Foundation.

Neuropsychological Assessment

Mary C. Tierney

In the assessment of older, possibly cognitively impaired, patients the clinical neuropsychologist must first determine whether the patient shows evidence of cognitive impairment or dementia. If the judgement is made that the patient meets the criteria for dementia or cognitive impairment, the next step is to determine the most likely etiology. As with a diagnosis of dementia, neuropsychologists rely on normative data provided in test manuals, compendiums (e.g. Spreen & Strauss 1998) and published research, to determine which tests, and respective cut-off scores, best classify the etiology of their patient’s dementing illness. The question explored in this chapter is: ‘From an evidence-based perspective, which neuropsychological tests or test batteries have diagnostic validity in making these etiological classifications?’.

Search strategy and study validation Searches were conducted in PsychInfo and Medline from 1980 to 1999. While the international literature was searched, only those articles written in English were requested. A thorough review of references from A Compendium of Neuropsychological Tests: Administration, Norms, and Commentary (Spreen & Strauss 1998) was also completed. Eighty-seven articles were retrieved and reviewed on this basis. From these, only four studies were included (Table II.4.7) because they met the following four criteria as outlined in Chapter II.1: 1 The use of an objective diagnostic reference (gold) standard for dementia (DSM, ICD, NINCDSADRDA) and dementia subtype (NINCDS-ADRDA criteria for Alzheimer’s disease (AD), and objective replicable criteria for other dementia subtypes). 2 Independent blind validation of the test against the diagnostic reference standard.

3 Provision of data necessary for the calculation of likelihood ratios (LRs). 4 The inclusion of at least one comparison group that did not meet the criteria for the target disorder. No studies in this review used neuropathological criteria as the gold standard, although two referred to autopsy confirmation of the diagnoses in some of the participants. Thus, in keeping with the convention used throughout this section, studies were classified as class 1 or class 2 evidence. The major reason studies were not included in this review was because they did not provide data to calculate LRs. Following the guide provided by Jaeschke et al. (1994), an LR > 10 was defined as large (i.e. would generate a large change from pretest to post-test probability), an LR > 5–10 was defined as moderate, an LR > 2–5 was small and an LR of 1–2 was unimportant. The second most frequent reason for the exclusion of studies was because the investigators did not keep the test validation process separate from the diagnostic process. If the investigators reported that a neuropsychological test battery that included their test(s) under evaluation was used to diagnose the dementia subtype or to rule out a dementia subtype, the study was not included. If it was apparent that the neuropsychological tests(s) under evaluation was used to diagnose dementia but not to differentiate between dementia subtypes, then the study was included. The criterion that at least one comparison group must not meet diagnostic criteria for the target disorder was met only if thorough diagnostic evaluations were conducted on participants in all the dementia groups under investigation and there was some demonstration that both groups were not suffering from the same dementia subtype. We did not include studies in this chapter if the

130 CHAPTER II.4

Table II.4.7 Studies evaluating diagnostic accuracy of neuropsychological tests comparing two dementia subtypes.

Author

Dementia groups

Clinical criteria

Study design

Tests

Sensitivity

Specificity LR*

Class

Tierney et al. (1987)

AD vs. other NINCDS-ADRDA; dementias objectively defined criteria

P

WMS Logical Memory and Mental Control; Trail Making Test (A); Word Fluency (letters F,A,S)

75

63

2

1a

Barr et al. (1992)

AD vs. VaD

NINCDS-ADRDA; DSM-III-R for MID

R

BNT; Hopkins Verbal Learning 81 Test (learning and response bias for related distracter items)

71

2.8

2a

NINCDS-ADRDA; Lund and Manchester Groups’ criteria for FTD

R

CERAD: MMSE, animal fluency, modified BNT, construction tests, delayed recall/trial III learning, true positive recognition; NCSE: language comprehension, calculation and abstraction

80

62

2.1

2a

R†

RAVLT delayed recall; LPGS disengagement scale

60

57

1.4

2a

Mendez et al. AD vs FTD (1996)

Tierney et al. (1996a)

AD vs. other NINCDS-ADRDA; dementias objectively defined criteria

AD, Alzheimer’s disease; BNT, Boston Naming Test; CERAD, Consortium to Establish a Registry for Alzeimher’s Disease; FTD, frontotemporal dementia; LPGS, London Psychogeriatric Scale; MID, multi-infarct dementia; NCSE, Neurocognitive Status Examination; MMSE, Mini Mental Status Examination; P, prospective; R, retrospective; RAVLT, Rey Auditory Verbal Learning Test; VaD, vascular dementia; WMS, Wechsler Memory Scale. *This is the likelihood ratio (LR) of the positive test. The AD group was always the disease ‘positive’ group in these calculations. †This study is classified as class 2A rather than class 1A because participants were added to the database after the original study (Tierney et al. 1987) was completed.

investigators compared the dementia subtypes to normal controls and not directly to another dementia subtype. Therefore, it was necessary that the article provide classification data pertaining to the direct comparison of two dementia subtypes.

Classification of studies All studies that met these four criteria were classified as either class I or class II. Studies were classified as class 1 if the design was prospective or class 2 if the design was retrospective. We defined a prospective study as one in which all the rules of data collection, sampling procedures, inclusion and exclusion criteria, and future statistical analyses and their interpretations were documented and shared amongst investigators. In addition, the date of acquisition of the first data point in real time had to occur subsequent to agreement on all of

the above. Unless sufficient details were provided, the study was judged to be retrospective. Finally, studies were classified as class 1a or class 2a if they included an appropriate spectrum of participants to whom the diagnostic test would be applied in clinical practice and if there was not a work-up bias. A work-up bias refers to a situation in which the results of the diagnostic test have influenced the decision to subject participants to the reference standard. A narrow spectrum of participants and/or a work-up bias led to the classification of studies as class 1b or class 2b. Class 1a AD vs. mixed group with other types of dementia One study was included that met criteria for class 1a. Tierney et al. (1987), in a cross-sectional, prospective

DIAGNOSIS OF A DEMENTIA SUBTYPE 131

study, compared one group of patients with a diagnosis of AD (NINCDS-ADRDA) and a group of other dementia patients, which included those with diagnoses of non-AD etiologies. Patients with a full range of dementia severity were included. The investigators examined the combined effectiveness of four neuropsychological tests in their test battery (WMS Logical Memory and Mental Control; Trail Making part A; and Oral Fluency). The investigators did not examine the accuracy of other tests in their battery as the purpose of this investigation was to replicate the earlier findings of Storandt et al. (1984). Discriminant function analyses produced a significant model; however, the LR was small at 2.03.

the MMSE than the FTD patients, although there were no differences in age or duration of illness between the two groups. Unfortunately, the investigators did not examine specific neuropsycholgical tests which represented the cognitive domains outlined by the NINCDS-ADRDA criteria, but rather recorded the presence or absence of deficits in each of the relevant cognitive domains without specifying which tests were used to do so. Therefore, their findings are not directly relevant to this chapter but it is noteworthy that the cognitive domains of primary perception and spatial ability produced LRs that would generate a moderate change in pretest to post-test probability (7.8 and 9.5, respectively).

Class 2a

AD vs. VaD

Mendez et al. (1996) compared patients with AD (NINCDS-ADRDA) to those with frontotemporal dementia (FTD). All participants were consecutive referrals to an Alzheimer Disease Center, which as the investigators acknowledge, represents a sampling bias for the FTD patients. Based on their MMSE scores, participants could be characterized as moderately to severely impaired. The patients with FTD were younger and less impaired on the MMSE than those with AD, but unfortunately neither age nor MMSE were included as covariates in the discriminant function analyses. The discriminant function analysis, which included the CERAD battery plus subtests of the Neurobehavioral Cognitive Status Examination, was significant, but the LR was small at 2.1. Although the investigators report mean differences between the groups on the various tests in the battery, they do not report the individual contribution of each of the nine tests entered into the discriminant function analyses. We do not know if some tests in the battery may have contributed more to the discrimination than others and if the classification accuracy could have been improved if the optimal combination of tests had been used. Varma et al. (1999) evaluated the NINCDSADRDA criteria in the differentiation of AD and FTD. They compared the case records of patients with pathological confirmation of either AD or FTD. AD patients were significantly more impaired on

Two comprehensive literature reviews examining neuropsychological test differentiation of vascular dementia (VaD) and AD (Almkvist 1994; Looi & Sachdev 1999) reached somewhat similar conclusions, despite using different criteria for article selection: patients with VaD had relatively better performance on tests of memory but more deficits in frontal executive abilities than patients with AD. Unfortunately, the majority of studies reported in these previous two reviews are not reviewed in this chapter because the investigators did not provide the data necessary for the calculation of LRs or because they used the neuropsycholgical test(s) under investigation to diagnose AD and VaD. One study that met the criteria for this chapter was conducted by Barr et al. (1992) which compared AD patients with patients meeting DSM-III-R criteria for multi-infarct dementia (MID). These two groups were equivalent on demographic characteristics and overall level of dementia severity as measured by the MMSE. Based on stepwise discriminant function analyses, three test scores differentiated the groups: the Boston Naming Test and two subtests of the Hopkins Verbal Learning Test (learning and response bias for related distracter items). The LR was small at 2.8. The AD group performed more poorly on the Boston Naming Test and the learning test showed more false positive responses. Thus, these findings support the conclusion from previous reviews (Almkvist 1994; Looi & Sachdev 1999)

132 CHAPTER II.4

that AD patients show greater impairment on memory and learning tests than those with VaD, but they do not support the conclusion that VaD patients show greater impairment on executive function tests. AD vs. mixed group with other types of dementia Tierney et al. (1996b) conducted a study with the same participants as described in class 1a above, but with additional participants included who were assessed subsequent to the first publication. Again, these investigators compared one group of patients with a diagnosis of AD and another group with diagnoses of non-AD subtypes of dementia. Sixteen subscores of neuropsychological tests were entered into the stepwise logistic regression analyses together with behavioral rating scores. Age, education, mental status, sex and place of residence were included in the regression analyses as covariates. Results indicated that two tests produced a significant regression model, i.e. the RAVLT Delayed Recall and the disengagement subscale of the London Psychogeriatric Scale. The LR, however, was unimportant, at 1.4.

Conclusions No neuropsychological tests or batteries in the three studies that met the criteria for this chapter were found to generate at least a moderate change (LR > 5) in pretest to post-test probability of AD. These studies compared patients with AD to those with VaD, other dementia subtypes and FTD. Given that only four studies could be identified for this chapter, there is an important need to design and conduct studies which meet the criteria for evidencebased research. In addition, studies using autopsyconfirmed diagnoses are needed, especially to identify mixed dementia cases. There are several reasons why the studies reviewed in this chapter failed to report at least moderate LRs in the classification of dementia subtypes. First, while the reference criteria for probable AD have been found to be valid in clinicopathological studies, the validity of the criteria for other dementia subtypes, including VaD and FTD, have not been established to the same extent. Thus, it is difficult to determine whether the small LRs generated by

the neuropsychological tests are due to the discriminating power of the tests themselves or to the validity of the reference criteria. Furthermore, the samples in the studies reported included moderately to severely impaired participants. The neuropsychological tests used in these studies may have been more effective in discriminating between dementia subtypes in the earlier stages of impairment and less effective in the latter stages due to floor effects. Thus, had the participants in these studies been less impaired, the results may have been more promising.

Recommendations Recommendations for practice Very limited recommendations for clinical practice can be made in light of the small LRs found in this review. Mendez et al. (1996) reported that nine tests scores generated a small change in pretest to post-test probability of AD. However, because they did not examine the classification accuracy of those tests that were found to have significant mean differences between the groups on follow-up analyses, LRs could not be calculated for these tests. Furthermore, they did not provide cut-off scores or regression coefficients that would permit the application of their findings to the clinical setting. The same limitation can be found in the studies by Barr et al. (1992) and Tierney et al. (1987). In their other study, Tierney et al. (1996b), provided the regression coefficients to calculate the probability of AD for new patients in the clinical setting, however, due to the unimportant LR (1.4) generated in this study, these findings should be replicated before their application can be recommended.

Recommendations for research Two important considerations for future research examining neuropsychological differentiation of dementia subtypes emerge from this review. First, different neuropsychological tests may be more or less effective in diagnosing the dementia subtypes at different levels of dementia severity. Therefore, it is important to equate samples on overall level of dementia severity, and to examine the effectiveness

DIAGNOSIS OF A DEMENTIA SUBTYPE 133

of a broad range of tests at different levels. Second, differential diagnosis of the dementia subtypes is often most important in the earliest stages of the disorders when treatment options are under consideration. Thus, future studies should include mildly impaired participants or participants in the preclinical stages of the disorders if the study is longitudinal to provide the most clinically relevant results.

II.4.5

Acknowledgements The author wishes to thank Dr Nancy Fisher and Dr John Paul Szalai for their assistance with the reviews and analyses of the articles. Their expertise in neuropsychological assessment, research design and statistical analyses added considerably to the substance and conclusions of this chapter.

Genetic Markers in Differential Diagnosis

Haydeh Payami

The recent discoveries of causative and susceptibility genes for Alzheimer’s disease (AD), frontotemporal dementia (FTD) and CADASIL (a hereditary form of vascular dementia, VaD) have raised the possibility of genetic testing for prediction and differential diagnosis of dementia. Genetic testing for AD is now available commercially and for research purposes (http://www.genetests.org). Widespread use of genetic testing for AD, however, may be premature. There are two critical issues to consider: 1 Is there sufficient evidence for the clinical utility of genetic testing? The evidence presented in this chapter was obtained by reviewing published data on genes and dementia. A Medline search was used to assist in the identification of datasets. 2 Does the potential benefit of genetic testing outweigh the risks? Although this chapter is devoted to evidence, it would be irresponsible to ignore the ethical issues surrounding genetic testing. Ideally, genetic testing is intended to provide early accurate diagnosis, so that the condition can be treated earlier and more effectively. In reality, our molecular genetic skills have advanced further than our ability to treat dementia. Currently, the major benefit of genetic testing is that, in some familial cases, it is useful for differential diagnosis of dementia. The only physical risk is that of a blood draw. In the absence of effective treatment, a positive test may cause prolonged anxiety and depression. A negative test does not rule out the disease and does not guarantee peace of mind. Genetic test results often have important implications for the relatives, who may or may not want to know. There is also

the concern about employment and insurance discrimination. Because of the psychological, social and financial risks, it is strongly recommended that clinicians and researchers who offer genetic testing adhere to strict confidentiality, obtain informed consent and provide formal genetic counselling before and after the test to monitor for adverse effects.

Alzheimer’s disease Evidence Four genes have been linked to AD unequivocally; they are the amyloid precursor protein (APP) gene, the presenilins (PS1 and PS2) and apolipoprotein E (ApoE). There is also a growing list of possible AD genes whose associations with the disease are currently under investigation. APP and the presenilins cause AD, whereas ApoE is a risk factor. Presence of a known pathogenic mutation in APP or the presenilins can predict AD with 95–100% certainty. Their utility, however, is limited because they are found almost exclusively in early onset familial AD kindreds, which comprise < 5% of all AD cases. ApoE on the other hand is associated with almost all forms of AD, but as a genetic test it can neither confirm nor rule out AD. APP and presenilin mutations Early onset familial AD refers to rare kindreds in which the disease strikes at unusually early ages (< 65 years) and appears to be transmitted from

134 CHAPTER II.4

affected parents to, on average, half of their children (autosomal dominant pattern). In itself a very rare form of AD, early onset familial AD is genetically heterogeneous. It involves at least three genes (APP, PS1 and PS2) on three separate chromosomes (21, 14 and 1), and many pathogenic mutations within each gene. Reportedly, not all cases of early onset familial AD are linked to one of these genes, suggesting that there may be more genes that need to be identified. APP was the first gene in which AD-causing mutations were identified (Goate et al. 1991). Aß, the major component of the amyloid plaques, is a product of APP. Seven APP mutations have been described in 20 families with different ethnic backgrounds (Levy-Lahad et al. 1998). Five of these mutations cause early onset familial AD, one causes a combination of cerebral hemorrhage and dementia, and one causes cerebral hemorrhage amyloidosis of the Dutch type. Age at onset of AD in APP mutation carriers ranges from 39 to 67 years. No one with an APP mutation has remained symptomfree past the age of 67 (Levy-Lahad et al. 1998). Penetrance (i.e. the probability that a mutation carrier will develop the disease) is essentially complete (100%) by the late sixties. PS1, a highly conserved gene with unknown function, is the most common cause of early onset familial AD (Sherrington et al. 1995). To date, more than 80 families with diverse ethnic backgrounds have been described with a pathogenic PS1 mutation. There are over 40 different PS1 mutations, each of which is sufficient to cause AD (Levy-Lahad et al. 1998). Age at onset ranges from 28 to 65 years. With the exception of one 68-yearold asymptomatic individual, every PS1 mutation carrier has developed AD before the age of 65 (Cruts & van Broeckhoven 1998). Penetrance is > 99%. The third AD gene, PS2, bears a striking homology to PS1 (Levy-Lahad et al. 1995). Only four PS2 mutations have been identified so far (Levy-Lahad et al. 1998). One is responsible for the founder effect seen in the Volga German families, the other three were each found in a single European family. Age at onset for PS2 mutations is later than that for APP or PS1, and can vary from 40 to 75 years. There are two reported cases with PS2 mutations

that have remained unaffected past the age of 80. Levy-Lahad et al. (1998) estimate the penetrance as > 95%. Apolipoprotein E The common forms of AD (i.e. early onset sporadic, late onset sporadic and late onset familial AD) are thought to be caused by a complex interaction of genes and environmental factors. ApoE is one of the genes involved. ApoE is on chromosome 19 and has three common alleles: ε4, ε3 and ε2. ε4 is associated with increased risk and earlier age at onset of AD, ε3 is neutral and ε2 may be protective. Many studies have shown a dosage effect, with ε4 homozygotes (ε4ε4) having the highest risk, followed by ε4 heterozygotes (ε3ε4). Only 2% of the population are ε4ε4 homozygous, while 25% are ε3ε4 heterozygous. A Medline search identified 69 case–control studies of ApoE and AD. Despite the differences in study designs, methods and patient populations used, almost every study found a significantly higher frequency of ε4 in AD patients than in controls. It is also clear in virtually every dataset that ε4 is neither necessary nor sufficient for the development of AD. A large portion of AD patients lack ε4, and many ε4-positive individuals live to advanced ages free of dementia. ApoE genotype modulates age at onset of dementia: ε4 carriers have on average the earliest onset, ε3 homozygotes are intermediate and ε2 carriers may have delayed onset. The genotypespecific age at onset distributions overlap considerably, such that it is not possible to predict age at onset based on ApoE genotype. Farrer et al. (1997) performed a meta-analysis, using data from 5930 AD patients and 8607 nondemented controls. They identified all published case–control studies using a Medline search, and collected the available data from 40 research centres, creating the largest study of ApoE and AD reported to date. Patients were diagnosed as having definite (i.e. autopsy confirmed) or probable AD (clinical diagnosis). The proportion of ε4-positive subjects among patients vs. controls was 59% (n = 5107) vs. 26% (n = 6262) for Caucasians, 52% (n = 235) vs. 36% (n = 240) for AfricanAmericans, 47% (n = 336) vs. 17% (n = 1977) for

DIAGNOSIS OF A DEMENTIA SUBTYPE 135

the Japanese, and 36% (n = 261) vs. 20% (n = 267) for Hispanics. Most published studies of ApoE and AD are genetic studies and do not provide sensitivity and specificity values. For the purpose of this chapter, we estimated sensitivity, specificity and positive likelihood ratios from the published raw data when available. Table II.4.8 shows the results for the study by Mayeux et al. (1998), which was specifically designed to assess the utility of ApoE in the differential diagnosis of AD (discussed further below), the meta-analysis of clinic-based case– control studies by Farrer et al. (1997) and individual population-based studies if they had a sample size of 50 or more. For every ethnic group, the positive likelihood ratio calculated from the populationbased study was lower than that calculated from the clinic-based studies. The results shown in Table II.4.8, in agreement with the collective evidence in the literature, demonstrate that the ApoE genotype alone is not sufficiently sensitive or specific for the diagnosis of AD (sensitivity range 0.23–0.59, specificity range 0.59–0.84). Few studies have examined the utility of ApoE for the differential diagnosis of dementia. Mayeux et al. (1998) reviewed the clinical and autopsy diagnosis of 2188 patients referred to one of 26 AD centres for evaluation of dementia. Using the pathological diagnosis of AD as the gold standard, they calculated the sensitivity and specificity as 93% and 55% for the clinical diagnosis, 65% and 68% for the presence of ε4, and 61% and 84% for the sequential use of clinical diagnosis and ApoE genotype. They concluded that ApoE genotype is not sufficiently sensitive or specific to be used alone for the differential diagnosis of AD in demented individuals, but it may improve the specificity of the diagnosis (increased from 55% to 84%) when used as an adjunct to clinical diagnosis. We calculated the positive likelihood ratio as 2.03 for ε4 alone, and 3.81 for the combination of clinical diagnosis and ε4. It should be noted that Mayeux et al.’s study (1998) was clinic based and, as demonstrated in Table II.4.8, likelihood ratios are usually lower for population-based studies. Several critical issues remain under investigation. There are differences between men and women and among racial groups in the prevalence of AD,

and in the strength of the association between AD and ApoE. Therefore, the predictive value of ApoE is likely to be different for men and women and for different ethnic groups. Furthermore, other genes and non-genetic factors (e.g. head injury, smoking and education) may modify the ApoE effect. Age is an important consideration. The effect of ApoE on AD risk is age dependent, but there is controversy over when it peaks and when (or if) it disappears. Finally, and possibly most critical to the use of ApoE in the differential diagnosis, is the report of the association of ε4 with non-AD dementias including VaD, Lewy body dementia and FTD. These findings have not been as well established as the association of ApoE with AD, none the less, they raise the possibility that ApoE may have a common role in age-related neurodegenerative disorders, rather than being a specific marker for AD.

Recommendations for practice APP and presenilin mutations All the pathogenic mutations in APP and the presenilins meet geneticists’ criteria for a ‘disease gene’: they segregate with the disease phenotype in pedigrees, and are absent in controls. Therefore, technically, they can be used for diagnosis, both for differential diagnosis of dementia in symptomatic individuals, and for presymptomatic predictive testing. To summarize the practical points about genetic testing with APP or presenilins: 1 Individuals with a family history of early onset AD would be candidates for genetic testing. 2 Since all of the known mutations are autosomal dominant, an offspring of an affected parent has 50% prior probability of having inherited the mutation. A blood sample will be sufficient for the genetic test to determine if an at-risk individual has inherited a mutation. To find out about the availability of specific tests check the website http://www.genetests.org. 3 A positive test result is highly informative. Persons who have a pathogenic mutation have a 95–100% chance of developing AD. However, genetic tests cannot predict age at onset. 4 A negative test result is often uninformative. Persons who do not have the pathogenic mutation

136 CHAPTER II.4

Table II.4.8 Sensitivity (SS), specificity (SP) and positive likelihood ratio (LR+) of ApoE for the diagnosis of AD*. Reference

Comments

Standard dx

Age (years)

Ethnicity

Number of subjects

SS

SP

LR+

Mayeux et al. (1998)

Clinic based Use of clinical dx and ε4 in differential dx of AD

Neuropathology

72 ± 10 at clinical dx

97% white 2% black 1% other

AD = 1643 Other dementias = 190

0.61

0.84

3.81

Mayeux et al. (1998)

Clinic based Use of ε4 alone in differential dx of AD

Neuropathology

72 ± 10 at clinical dx

97% white 2% black 1% other

AD = 1770 Other dementias = 418

0.65

0.68

2.03

Farrer et al. (1997)

Clinic based, meta-analysis, case–control

Clinical or neuropathology

40–90

Caucasian (mixed)

AD = 5107 Control = 6262

0.59

0.74

2.27

Van Duijn et al. (1994)

Population based, case–control, early onset AD

Clinical

Onset ≤ 65

Caucasian (Dutch)

AD = 175 Control = 159

0.53

0.73

1.96

Slooter et al. (1998)

Population based, case–control

Clinical

≥ 55

Caucasian (Dutch)

AD = 97 Control = 997

0.37

0.72

1.32

Skoog et al. (1998)

Population based, retrospective

Clinical

85

Caucasian (Swedish)

AD = 52 Not demented = 303

0.56

0.61

1.43

Farrer et al. (1997)

Clinic based, meta-analysis, case–control

Clinical or neuropathology

40–90

AfricanAmerian

AD = 235 Control = 240

0.52

0.64

1.44

Tang et al. (1998)

Population based, prospective

Clinical

≥ 65

AfricanAmerican

AD = 53 Not demented = 128

0.34

0.59

0.83

Farrer et al. (1997)

Clinic based, meta-analysis, case–control

Clinical or neuropathology

40–90

Hispanic

AD = 261 Control = 267

0.36

0.80

1.80

Tang et al. (1998)

Population based, prospective

Clinical

≥ 65

Hispanic

AD = 145 Not demented = 516

0.27

0.74

1.03

Farrer et al. (1997)

Clinic based, meta-analysis, case–control

Clinical or neuropathology

40–90

Japanese

AD = 336 Control = 1977

0.47

0.83

2.76

Katzman et al. (1997)

Population based

Clinical

≥ 55

Chinese

AD = 65 Control = 363

0.46

0.80

2.30

Evans et al. (1997)

Community based

Clinical

≥ 65

AD = 88 Unaffected = 490

0.23

0.84

1.44

Mullan et al. (1996)

Population based

Clinical

AD = 107 Non-AD = 248

0.55

0.73

2.04

*Only the study by Meyeux et al. (1998) was designed to assess the utility of ε4 for the differential diagnosis of AD. The remaining studies were designed to assess the strength of the genetic association between ε4 and AD, and hence did not calculate SS and SP. The values shown here were calculated using the published raw data. Individual studies are listed only if they are population based, have ≥ 50 AD cases, and provide raw genotype data on patients and controls. LR+ = SS/(1–SP), i.e. ratio of the proportion of patients with ε4 vs. the proportion of controls with ε4.

DIAGNOSIS OF A DEMENTIA SUBTYPE 137

may still have AD, caused by another mutation or other causes. 5 Genetic testing should be done with informed consent, adhere to strict confidentiality and provide genetic counselling before and after the test. Apolipoprotein E The study by Mayeux et al. (1998) has demonstrated that using the ApoE genotype as an adjunct to clinical diagnosis may increase the specificity, but not the sensitivity, for the differential diagnosis of AD in demented patients. Further research is needed to assess the applicability of this finding to the general population and to determine the predictive value of ApoE by gender, ethnicity and age. The use of ApoE as a diagnostic marker in asymptomatic individuals is not recommended. The issue has been addressed by several international committees representing the American College of Medical Genetics/American Society of Human Genetics, the Alzheimer Disease International, the United Kingdom Alzheimer Disease Genetic Consortium, and the National Institute on Aging/ Alzheimer Association. The consensus statements concured that ApoE testing should not be used to diagnose AD in symptom-free individuals. The opinions on the use of ApoE in differential diagnosis of dementia were divided (note, however, that the statements preceded the study by Mayeux et al. 1998). They cautioned against the premature introduction of genetic testing, and encouraged investigators to guard against adverse consequences on genetic privacy and psychological wellbeing of the patients and families.

Familial FTD Evidence So far, two genes have been linked to the familial form of FTD: tau on chromosome 17, and an as yet unidentified gene on chromosome 3 (Wilhelmsen 1998). Tau encodes the major component of the neurofibrillary tangles. According to a recent population-based study by Rizzu et al. (1998), 40% of all FTD is familial, and at least 40% of

familial FTD kindreds have a tau mutation. The first mutation in tau was identified in 1998. In less than a year, 10 additional mutations have been found in a collection of FTD families (Wilhelmsen 1998). More mutations are likely to emerge. The mutations are autosomal dominant and highly penetrant (although the exact estimate is not available). They segregate in families, and are absent in controls. They have not been found in sporadic FTD or in AD. The clinical expression of tau mutations is variable, ranging from behavioral changes including disinhibition and dementia to balance and motor impairment. Abnormal tau deposits in the brain are found in other neurodegenerative disorders including AD. It is not yet clear if the tau locus has an etiological role in AD and other dementing disorders (Wilhelmsen 1998; Higgins et al. 1999; Houlden et al. 1999).

Recommendations for practice Tau mutation analysis is being used for the differential diagnosis of FTD in research centres. FTD patients with a family history of FTD, where there is evidence of disinhibition or personality change prior to memory loss, are candidates for tau mutation analysis.

Hereditary VaD Evidence CADASIL (cerebral autosomal arteriopathy with subcortical infarction and leukoencephalopathy) is a hereditary disorder with an autosomal dominant inheritance. CADASIL is the first and so far the only form of VaD that has an identified gene: Notch3 on chromosome 19. Notch3 is involved in cell fate specification during early development, but its role in the pathogenesis of stroke and dementia is not known. Several mutations have been found in the gene. Joutel et al. (1997) found Notch3 mutations in 90% of CADASIL patients studied. The mutations segregated with the disease in the families, and were absent in controls. The frequency of Notch3 mutations in other forms of dementia is not known. Although the utility of this gene for diagnosis is promising, it needs further research.

138 CHAPTER II.4

Recommendations for practice Genetic testing may be useful for rare cases of VaD patients suspected to have CADASIL. Presence of a Notch3 mutation can help confirm clinically suspected CADASIL, where there is a history of stroke, migraine, seizures and confluent deep white matter changes on neuroimaging studies.

Conclusions At the beginning of this chapter we posed two questions. 1 Is there sufficient evidence for the clinical utility of genetic testing? The answer is yes. In some cases, genetic testing can be used reliably for the differential diagnosis of dementias. Disease genes, like APP, presenilins, tau and Notch3 are deterministic. They can be used for predictive testing in asymptomatic individuals, as well as for differential diagnosis in dementia patients. Risk factors like ApoE are probabilistic.

II.4.6

ApoE is therefore not useful for predictive testing, and its use in differential diagnosis is under investigation. 2 Does the potential benefit of genetic testing outweigh the risks? Until there is prevention or cure, benefits of genetic testing are limited to differential diagnosis and family planning. The risks can be psychological, social and financial. Only patients can decide if their need to know outweighs the risks. Clinicians are responsible for educating the patients and arming them with all the information they need to make an informed decision. It is critical that genetic testing is performed in strict confidence and that genetic counseling is provided to patients who wish to receive the results. Ready or not, we are fast approaching the era when genetic tests are routine and essential tools for diagnosis and for explaining ill health to patients. New disease genes and risk factors are being discovered at an unprecedented rate. This chapter will be updated frequently on the website, with the new advances in the field.

Utility Of CT Scanning in Diagnosing Dementia

Jaime Díaz-Guzman, J. María Millán, David G. Muñoz, and Félix Bermejo Key points In the evaluation of dementia: 1 Brain computed tomography (CT) scanning has modest value for the positive diagnosis of Alzheimer’s disease (AD). 2 There is wide variation in the reported likelihood ratios (LR) for the diagnosis of AD based on several measurements of brain atrophy on CT scans: positive LRs between 2 and 4 are most common and consistent with clinical practice. 3 Brain CT scanning is more efficient in ruling out structural treatable intracranial lesions, but the usual pretest probabilities are low, on the order of 3–4%. 4 Brain CT plays a critical role in the evaluation of vascular dementia (VaD). 5 More investigations are needed to study the cost-efficiency of CT scanning in patients with dementia.

CT scanning has provided researchers and clinicians alike with the first systematic non-invasive study of brain morphology in patients with dementia. Each new generation of CT scanners has provided increased diagnostic precision and enlarged the number of indications for its use (Burns 1998), although currently other techniques surpass its reliability and precision. It shares with neuropsychological tests, genetic, and other biological markers, a central role in the diagnostic evaluation of patients with cognitive impairment (Bottino & Almeida 1997; Cammer 1997). Thus, it is useful to analyse its diagnostic utility, from both in formal (technical characteristics) and operative (diagnostic value measured in terms of sensitivity, specificity, and LRs) points of view. In clinical practice, the purpose of CT scanning is to support the diagnosis of AD and to rule out structural lesions, such as subdural hematomata, tumours, hydrocephalus and infarcts (Katzman 1990). As for any other medical procedure, cost and inconvenience must be weighed

DIAGNOSIS OF A DEMENTIA SUBTYPE 139

against the real benefit to the individual patient and to the health care system (Clarfield & Larson 1990; George et al. 1997). This chapter focuses on two questions: (i) how useful is the CT scan in the diagnosis of dementia (e.g. AD vs. normal ageing, Fig. II.4.1); and (ii) how useful is a CT scan for the diagnosis of dementia subtypes (e.g. surgically correctable lesions, VaD, vs. AD)?

Background In evaluating the utility of CT scanning for diagnosis, three questions should be considered following an evidence-based systematic approach (Jaeschke et al. 1994a,b; Sackett et al. 1997): 1 Are the results of the study valid? 2 What are the results? 3 Will the results help me in caring for my patients?

(a)

(b) Fig. II.4.1 CT scans of patient with (a) Alzheimer’s disease,

and (b) tensional headache control patient. Note cortical atrophy and marked enlargement of lateral ventricles in the demented patient.

Fig. II.4.2 Fifty-six year old woman with normal pressure

hydrocephalus.

140 CHAPTER II.4

The use of CT to rule out surgically correctable dementia has been evaluated in several reports (Smith & Kiloh 1981; Beck et al. 1982; Bradshaw et al. 1983; Dietch 1983; Jellinger 1987; Martin et al. 1987; Clarfield 1988; Katzman 1990; Roberts & Caird 1990; Jagust & Eberling 1991; Chui & Zhang 1997). Surgically correctable cases of dementia represent 5–13% of those studied. However, as Larson et al. (1984) point out, only 1% of dementia cases are fully curable. For example, half of all cases of normal pressure hydrocephalus (NPH) (Fig. II.4.2) appear before age 60 and represent 2% of cases of dementia (Clarfield 1988), however, the response rate to shunt treatment is a disappointing 15% (Vanneste et al. 1992). Tumours represent 1–4% of cases of dementia; only 15% of these are relatively benign meningiomas. Chronic subdural hematomas (Fig. II.4.3) occur in only 0.4% of demented patients (Clarfield 1988), however, although the tumour or the subdural collection can be resected or evacuated (i.e. it is treatable), cognitive prognosis is poor even after surgery, especially for elderly patients (Luxon & Harrison 1979; Black 1985; Mulley 1986; Riisoen & Fossan 1986). The

sensitivity, specificity and LR of CT in the diagnosis of surgically correctable lesions is difficult to ascertain (as no large series have been reported and there are methodological problems) but they appear to be moderate to high. In diagnosing NPH, brain astrocytoma and chronic subdural hematoma in patients with cognitive impairment, positive LRs are, respectively, 2.2, 3.3–4.8 and 9.7 (Tans 1977; Caille & Guibert-Tranier 1981; Vanneste et al. 1993). The corresponding negative LR are: 0.6, 0.06–0.44, and 0.03. In other words, a normal CT scan moderately reduces the likelihood that the patient has either NPH or glioma, and greatly reduces the likelihood of a subdural collection. However, the frequency of these conditions is low. A reasonable question is, therefore, how cost-effective is widespread screening for these relatively rare surgically treatable conditions? Concerning the use of CT scans in diagnosing VaD, there are no large studies with neuropathologic confirmation of diagnosis. Data available come from several series where clinical diagnostic criteria for multi-infarct dementia were used as reference standards (overestimation bias of diagnostic test).

Fig. II.4.3 Postcontrast axial CT scan

shows an hipodense left-sided chronic subdural hemorrhage (CSDH). Note subfalcine herniation of the lateral ventricles, corticomedullary interface displacement and enhancing cortical veins streched across the CSDH.

DIAGNOSIS OF A DEMENTIA SUBTYPE 141

Sensitivity ranged from 75–89%, with a specificity close to 95%. The corresponding positive LR is 15–17.8, which clearly points to increased chances of VaD. The negative LR is 0.1–0.3, which is moderately useful in excluding VaD in the absence of infarcts (Ladurner et al. 1982; Larson et al. 1986; Erkinjuntti et al. 1987b, Erkinjuntti et al. 1987c; Aharon-Peretz et al. 1988). In differentiating VaD from AD with CT scans (Scheltens & Kittner 2000), leukoaraiosis has a positive LR of 2.0, and a negative LR of 0.4. The most common causes of dementia in the elderly are attributed to primary neurodegenerative disorders (e.g. AD, dementia with Lewy bodies, frontotemporal dementia). Studies on the utility of

Fig. II.4.4 Lateral scheme and

topogram showing two different protocols in neuroimaging of dementia. A–A′: Routine 10 mm cut parallel to canto-meathal line al temporal-lobe level. Enlarged temporal horns (arrow) are visualized. B–B′: Temporal-lobe oriented (20°-negative-angle cut). Temporal structures are observed easier than with A–A′ cuts. Hippocampal lucencies (arrowheads) may be visualized as direct extensons of perimesencephalic cisterns.

CT scanning in neurodegenerative dementias have used a variety of evaluation techniques: qualitative ratings by experienced radiologists; tissue density sampling; and linear, planimetric and volumetric measurements of various anatomical brain regions. For evaluation of dementia in elderly individuals CT is usually confined to axial plane imaging, although slight modifications in scan angle can be applied. Typical slice collimation for CT is 5–10 mm, with an axial plane matrix of 256 × 256 or greater. However, when studying dementias, a reverse angle CT plane can be used to qualitatively rate the size of the choroidal-hippocampal fissure (de Carli et al. 1992b; Giacometti et al. 1994; Becker et al. 1995) (Fig. II.4.4). Due to the limitations of the technique

142 CHAPTER II.4

Dementia (51143 articles) Diagnosis OR diagnost* (28 991 articles) Computed-tomograph* OR CT-scan* OR brain-CT OR Head-CT (2313 articles) Sensibility OR Specificity OR LR OR likelihood ratio (112 articles)

Fig. II.4.5 Evidence-outline search on

diagnostic utility of CT scan in dementia. May 2000.

(imprecise depiction of anatomic boundaries between gray and white matter or between brain and cerebrospinal fluid, and Hounsfield artifacts at interfaces of soft tissue with dense bone), MRI is preferred nowadays for quantitative studies of atrophy (see Chapter II.4.7). In addition, a more sensitive diagnosis of small infarcts, periventricular and deep white matter lesions is possible with MRI than with CT, but MRI may be less specific with respect to identifying significant cerebrovascular disease in the diagnosis of dementia (Lopez et al. 1995; Scheltens et al. 1998). This chapter provides an evidence-based review of the validity and quality of studies assessing the utility of CT in dementia patients. We examine the selection and number of patients, differential and non-differential biases, independence between patient evaluation, CT scanning, application of the gold standard, data presentation, diagnostic precision, applicability of results to clinical practice and cost-utility. Successive technical improvements in CT scanning introduce further complexity, making it difficult to ensure comparability between studies.

Search strategy and analysis procedure The systematic analyses undertaken in this chapter employ the methods proposed by Jaeschke et al.

(1994a,b) and outlined in the introduction to this section (II.1). 1 Systematic review of the literature (including explicit search strategy). 2 Assessment of study validity. 3 Summary of test performance. 4 Determination of incremental value (i.e. change in pre- and post-test probability). 5 Assessment of clinical significance (i.e. the impact of a test on clinical decision making). The databases used for literature search were Medline (1975–2000), The Cochrane Database of Systematic Reviews, ACP Journal Club 1991–98 and Evidence-Based-Medicine December 1995–98; supplemented by relevant cited references in the papers identified. The search profile is shown in Fig. II.4.5. Sensitivity for papers considered relevant was 55/112 = 49%. Corrected sensitivity in relation to original articles was 22/42 = 52%. These figures do not improve after the application of McMaster’s EBM search filters (IHS Library Medline Search Filters 2000). The search results are listed in Tables II.4.9–11. Several papers were excluded: some original articles lacked adequate methodology to produce consistent results (Huckman et al. 1975; Roberts & Caird 1976; George et al. 1986; de Leon et al. 1989a, b; Diaz et al. 1991; Kawamura et al. 1991;

DIAGNOSIS OF A DEMENTIA SUBTYPE 143

Table II.4.9 Diagnostic value of CT scanning findings in the evaluation of dementia: validity. Methods sufficiently detailed?

Author

BCRS

Appropriate spectrum

Verification bias

Brinkman (1981)

Not specified

Dementia

No or not applicable Healthy control subjects

Yes

Ford (1981)

Yes

Dementia syndrome

No or not applicable Elderly inpatients not demented

Yes

Damasio et al. (1983)

Yes

Dementia syndrome

No or not applicable Healthy control subjects

Yes

Albert et al. (1984)

Yes

AD ‘presenile’ patients

No or not applicable Age-matched healthy controls

Yes

Drayer et al. (1985)

Yes

AD patients

No or not applicable Age-matched healthy controls

Yes

Erkinjuntti et al. (1987)

Yes

AD, MID, PVD with several degrees of severity

No or not applicable

Yes

Kido et al. (1988)

Partially*

Probable AD

No or not applicable Healthy control subjects

Yes

Jayakumar et al. (1989)

Not specified

MID patients

No or not applicable Age-matched patients with mild neurological symptoms

Scarce data on CT technical aspects

de Leon et al. (1989b)

Not specified

Mild-to-severe AD; minimal age-related memory changes; volunteer controls cognitively normal

Possible

Scarce explanations

Leys et al. (1989)

Yes

Probable AD with several degrees of severity

No or not applicable Age and sex-matched controls with several neurological disorders

Yes

George et al. (1990)

Yes

AD patients, no severity specified

No or not applicable Healthy control subjects

Yes

de Carli et al. (1992b)

Yes

AD patients mildly demented

No or not applicable Control subjects

Yes

Engel & Gelber (1992)

Partially

Probable AD

Possible Other dementias, non-AD type (all patients were ambulatory)

Yes

Jobst et al. (1992a)

Yes

AD patients and adequate spectrum of various dementia syndromes

No or not applicable

Yes

Jobst et al. (1992b)

Yes

Various degrees of mental deterioration

No or not applicable Healthy control subjects

Yes

Koslow et al. (1992)

Yes

Probable AD, no severity specified

No or not applicable Healthy control subjects

Yes

de Leon et al. (1993)

Yes

Memory complaints and minimal cognitive impairmet

No or not applicable Healthy control subjects

Yes

Continued on p. 144

144 CHAPTER II.4

Table II.4.9 (cont’d)

Author

BCRS

Appropriate spectrum

Verification bias

Methods sufficiently detailed?

Buchpiguel et al. (1996)

Yes

Several dementia disorders, no severity specified; control subjects

No or not applicable

CT scan type not specified

Lavenu et al. (1997)

Yes

Probable and possible AD

No or not applicable Controls: MMD

Yes

Pasquier et al. (1997)

Yes

Very appropriate, with cases of MMD

No or not applicable

Yes

Jobst et al. (1998)

Yes

Varying degrees of mental deterioration

No or not applicable

Yes

O’Brien et al. (2000)

Yes

Probable and possible AD, PVD, DLB and depression patients

No or not applicable

Yes

BCRS, Blind Comparison Reference Standard; DLB, dementia with Lewy bodies; MID, multi-infarct dementia; MMD, miscellaneous memory disorders; PVD, probable vascular dementia patients. *In this series, subject’s age was available to CT scan raters.

Alexander et al. 1995); others were excluded from the final analysis because even if the method was appropriate in terms of validity, data presentation or statistical analysis (most often discriminant analysis) did not permit calculations of sensitivity and specificity (Jacoby & Levy et al. 1980; Soinien et al. 1982b; Gado et al. 1983; George et al. 1983; Kohlmeyer et al. 1983; Eslinger et al. 1984; Turkheimer et al. 1984; Creasey et al. 1986; Ichimiya et al. 1986; LeMay et al. 1986; Sandor et al. 1988; Kobari et al. 1990; Zubenko et al. 1990; Gorelick et al. 1992). Interesting papers on longitudinal serial studies were excluded for the same reason (Brinkman & Largen 1984; Luxemberg et al. 1987; Aylward et al. 1996).

Evidence The reader is referred to radiological textbooks for a description of the morphological features used to define brain tumours, hematomas, NPH, infarcts and white matter (Osborn 1994). The parameters used to define a ‘positive’ test for neurodegenerative dementias include several linear and volumetric measures of atrophy (see Tables II.4.10–11). Most studies investigate the diagnostic utility of CT in AD patients where AD and non-AD subjects have

been compared. In some studies normal subjects constitute the comparison group; in others different dementias were used.

Are the results of the studies valid? Primary guides Reference standard Characterization. For AD, autopsy diagnosis remains the gold standard in spite of criticisms related to age-cohort effects, selection bias, comorbility and postmortem changes (biological or related to fixation). Criteria of National Institutes of Health and American Association of Retired Persons (NIH-AARP) (Khachaturian 1985) have been replaced by those of the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD; Mirra et al. 1991) and the use of Braak stageing (Braak & Braak 1997). Only two studies in this series have utilized a necropsy-based reference standard and are indicated by upper case Class designations (e.g. Class 2A) (Jobst et al. 1992a; Jobst et al. 1998; see Table II.4.9). In the remaining papers, clinical criteria constitute the reference standard and are designated by lower case ‘class’

Table II.4.10 Diagnostic Value of CT scanning findings in the evaluation of dementia: description.

Author

Subjects

Age (range or media) in years

Brinkman (1981)

Pt: 39 C: 29

Ford (1981)

Reference standard

Parameter

60.4 ± 9.4 76.9 ± 7.3

Not clearly established

Clinical criteria; neuropsychological evaluations (WAIS, Benton)

Quantitative indexes of cerebral atrophy (AD patients vs. controls)

Pt: 41 C: 18

53–87

Geropsychiatric inpatient unit

Clinical criteria of dementia (Strub & Black 1977); arbitrary severity classification

Extent of cerebral atrophy and ventricular enlargement in demented and elderly patients

Damasio et al. (1983)

Pt: 46 C: 46

70.0 ± 6.4 74.2 ± 6.4

Pt: University data-base; C: recruited from retirement communities

Clinical diagnosis. Roth’s (1971) definition of dementia

Brain atrophy in AD patients vs. healthy elderly controls

Albert et al. (1984)

Pt: 8 C: 10

53–64 53–64

Pt: not established C: Boston V.A. outpatient clinic

Clinical diagnosis, neuropsychological tests, DRS, ADLS

Ventricular size in ‘presenile’ AD patients vs. healthy elderly patients

Drayer et al. (1985)

Pt: 60 C: 60

60.7 (51–69) Matched

Not established

Clinical diagnosis; WAIS; Halstead–Wepman aphasia screen test; MMSE; DRS

Brain atrophy in AD patients vs. healthy elderly patients

Erkinjuntti et al. (1987c)

AD: 68 MID: 79 PVD: 46

70.5 (40–96) 73.0 (48–92) 75 (53–90)

Demented patients consecutively admitted at University Department of Neurology

Cognitive testing. DSM-III criteria. Modified ischaemic score

Cortical atrophy by linear measurements

Kido et al. (1988)

Pt: 39 C: 29

63.3 ± 3.5 61.9 ± 3.9

Not established

NINCDS-ADRDA criteria; cognitive examination; MMSE (36/39 patients)

Temporal lobe atrophy in AD patients vs. controls. Subjective measurements

Jayakumar et al. (1989)

Pt: 30 C: 30

61.4 55.1

Reference center (National Institute of Mental Health and Neurosciences in Bangalore, India)

Clinical criteria for VaD (DSM-III), Hachinski’s ischaemic score (1975)

Brain vascular disease signs in VaD-MID vs. control patients

Leys et al. (1989)

Pt: 30 C: 30

63.4 ± 7.7

Not established

Cognitive scales; NINCDS-ADRDA criteria; GDS

Cerebral atrophy

George et al. (1990)

Pt: 34 C: 20

56–87 60–85

Reference center (NYUADRP) Controls: healthy spouses

AD: diagnostic criteria not specified; clinical scales (GDS, MMSE)

Temporal lobe changes and ventricular volume measurements in AD patients and controls

de Carli et al. (1992b)

Pt: 20 C: 17

66 ± 9 62 ± 8

Not established

Clinical criteria; NINCDS-ADRDA, severity evaluated with MMSE

Mean rates of enlargement for total lateral ventricular volume in diagnosis of AD. Cut point = 3.5 cm3/year

Engel & Gelber (1992)

Pt: 56 C: 44

73 ± 11 74 ± 12

Reference center (geriatric clinic)

Clinical criteria (DSM-III-R; NINCDS-ADRDA, Hachinski < 4), without ‘laboratory data’ criteria

CT abnormalities other than atrophy

Continued on p. 146

DIAGNOSIS OF A DEMENTIA SUBTYPE 145

Clinical setting

Table II.4.10 (cont’d)

Reference standard

Parameter

No provided

Recruited from general practitioners and hospital-based services

Cognitive testing (DSM-III-R, MMSE, CAMCOG)

Medial temporal lobe thickness in AD patients vs. normals

Pt: 44 C: 75

57–93 47–88

Inclusion from general practitioners and hospital services

Khachaturian criteria for AD (1985)

Khachaturian’s criteria of AD

Koslow et al. (1992)

Pt: 58 C: 59

46–89 46–78

Reference University Center

Clinical criteria (DSM-III; NINCDS-ADRDA) and clinical diagnosis

Planimetric or volumetric measures in AD patients and controls

de Leon et al. (1993)

Pt: 32

71.1 ± 9.4

AD center clinic and volunteer

Clinical criteria (CDS, NINCDS-

Prediction subsequent AD 4

C: 54

70.1 ± 8.0

controls

ADRDA, DSM-III-R), psychometric batteries

years apart

Buchpiguel et al. (1996)

Pt: 52 C: 11

Not specified 58–84

Not provided

Clinical criteria (DSM-III, NINCDS-ADRDA)

Global impression of anatomic aspects of head CT scan

Lavenu et al. (1997)

Pt: 64 + 13 Probable AD: 64 Possible AD: 137 MMD: 48

51–93 72.2 ± 7.5 1.6 ± 9.8 70.9 ± 7.5

University Memory Clinic recruitment

Clinical criteria (DSM-III-R, NINCDS-ADRDA) McKeith (1994), Lund and Manchester group (1994), Benson (1988) and Riley (1990) criteria

Medial temporal lobe atrophy

Pasquier et al. (1997)

Prob AD: 124 Poss AD: 50 MMD: 119 Anx/Depr: 19 C: 21

71.1 ± 7.7 72.7 ± 7.3 67.8 ± 8.9 60.7 ± 6.4 66.7 ± 8.5

University Outpatient Memory Disorders Clinic

Clinical criteria (DSM-III-R, NINCDS-ADRDA) McKeith (1994), Lund and Manchester group (1994), Benson (1988) and Riley (1990) criteria

Temporal lobe atrophy

Jobst et al. (1998)

AD: 80 Other Dem: 24 C: 14

56–96 53–85 53–89

Recruitment from general practice and hospital-based services (primary and tertiary referrals)

Khachaturian criteria for AD (1985)

Minimum width of the medial temporal lobe in AD patients versus other dementias and healthy controls

O’Brien (2000)

AD: 69 PVD: 25 DLB: 9 Depr: 13

80.2 ± 7.4 77.4 ± 7.9 76.1 ± 5.0 76.1 ± 5.0

Consecutive referrals to a geographically based old age psychiatry service

Clinical criteria (NINCDS-ADRDA, NINDS-AIREN, DSM-IV, consensus DLB)

Temporal lobe atrophy

Subjects

Jobst et al. (1992a)

Pt: 61 C: 18

Jobst et al. (1992b)

AD, Alzheimer’s disease; ADLS, Activities of daily living scale; Anx/Depr, anxiety–depression; C, controls; CT, computed tomography; Dem, dementia/s; Depr, depression; DLB, dementia with Lewy bodies; DRS, Dementia Rating Scale; GDS, global deterioration scale; MID, multi-infarct dementia; MMD, miscellaneous memory disorders; MMSE, Mini Mental Status Examination (Folstein); NINCDS-ADRDA, National Institute of Neurological and Communicative Disorders and Stroke and Alzheimer’s Disease and Related Disorders Association criteria for probable or possible AD (McKhann 1984); NYUADRP, New York University Aging and Dementia Research Program; Poss, Possible; Prob, probable; Pt, patients; PVD, probably vascular dementia; VA, Veterans Administration.

146 CHAPTER II.4

Age (range or media) in years

Clinical setting

Author

Table II.4.11 Diagnostic value of CT scanning findings in the evaluation of dementia: results and commentaries. Post-test probability for pretest of:

Author

Analytic measurements

Brinkman et al. (1981)

ThV-SF = 0.5 ThV = 0.5 or VBR corrected for age

Ford (1981)

Subjective classification of: acerebral atrophy aventricular enlargement

Sensibility (CI 95%)

Specificity (CI 95%)

LR+

LR–

3.2 0.3 > 15 < 0.1

Evidence class

0.1

1

10

25

50

0.3 90.6

3.1 98.9

26.1 99.9

51.4 99.9

76.1 1b 99.9

Commentary

76.9 (56.4–91.0) 96.0 (79.6–99.9)

75.8 (56.4–89.7) 99.99

Case-control not matched; mean age of the controls higher than AD; not established severity of dementia group; wide CI; poor technical quality of the CT measurements; possible non-blind CT interpretationbias over-values test accuracy

2a 92.7 (80.1–98.5) 85.4 (70.8–94.4)

88.9 (65.3–98.6) 77.8 (52.4–93.6)

8.4 3.9

0.1 0.2

0.8 0.4

7.8 7.8

48.1 30.1

73.6 56.3

89.3 79.5

Weak reference standard; retrospective; not matched patients–controls; disproportion cases/controls (2/1)

Composite formula of two measures: the bodies of LV and the IHF

78.3 (63.6–89.1)

89.1 (76.4–96.4)

7.2

0.2

0.7

6.8

44.4

70.5

87.8 2b

Weak RfSt; test accuracy calculated by multi-variant analysis (discriminant function); not feasible test in clinical practice

Albert et al. (1984)

Semi-automated computer analysis of fluid volume (ASI-II program) = 8% fluid volume on bodies of LV slice

87.5 (47.3–99.7)

90.0 (55.5–99.8)

8.8

0.1

0.9

8.1

49.3

74.5

89.7 1b

Wide CI, reference standard poorly defined; validity of semiautomated CT analysis?; difficult to perform in usual clinical setting; selection bias

Drayer et al. (1985)

Overall rating of atrophy (LV, cortical sulci, ThV)

61.7 (48.2–73.9)

90 (79.5–92.2)

6.2

0.4

0.6

5.9

40.7

67.3

86.1 1a

RfSt poorly defined; wide spectrum of patients; good adjusting system in spite of subjective rating; easy and acceptable method in usual clinical setting

Erkinjunti et al. (1987)

Visual rating distinguishing: Central atrophy amild AD vs. vascular amoderate–severe AD vs. vascular

1a 78.8 (61.1–91.0) 83.3 (68.6–93.0)

18.3 (9.5–30.4) 14.4 (7.5–24.4)

0.9 0.9

1.6 1.2

0.1 0.1

1.0 1.0

9.7 9.8

24.3 24.5

49.1 49.3

Poorly defined reference standards; qualitative (nonquantitative) measurements for atrophy available to calculate sensibility and Continued on p. 148

DIAGNOSIS OF A DEMENTIA SUBTYPE 147

Damasio et al. (1983)

Post-test probability for pretest of:

Author

Analytic measurements Thickness of the temporal cortex amild AD vs. vascular amoderate–severe AD vs. vascular WMLA avascular vs. mild AD avascular vs. moderate– severe AD

Sensibility (CI 95%)

Specificity (CI 95%)

LR+

LR–

0.1

1

10

25

50

Evidence class

specificity; very good spectrum of dementing disease; vascular vs. degenerative

60.9 (45.4–74.9) 55.0 (38.5–70.7)

32.4 (21.7–44.6) 29.9 (20.0–41.4)

0.9 0.8

1.3 1.5

0.1 0.1

0.9 0.8

8.9 8.0

22.7 20.7

46.9 44.0

57.9 (40.8–73.7) 65.5 (54.6–75.4)

95.5 (77.2–99.9) 73.9 (58.9–85.7)

12.9 2.5

0.4 0.5

1.3 0.3

11.5 2.5

58.8 21.8

81.1 45.6

92.8 71.5

Temporal horn enlarged Linear > 3 mm in temporal lobe atip aborder abody Temporal horn asymmetry Sylvian cistern rating

66.7 (49.8–80.9)

94.7 (74.0–99.9)

12.6

0.4

1.2

11.3

58.3

80.8

92.6 1b

56.4 (39.6–72.2) 100 43.6 (27.8–60.4) 100 48.7 (32.4–65.2) 100 53.8 (37.2–69.9) 82.8 (64.2–94.2) 87.2 (72.6–95.7) 82.8 (64.2–94.2)

> 15 > 15 > 15 3.1 5.1

0.4 0.5 0.5 0.6 0.2

85.0 81.4 82.9 0.3 0.5

98.3 97.8 98.0 3.1 4.9

99.8 99.8 99.8 25.8 36.0

99.9 99.9 99.9 51.0 62.8

99.9 99.9 99.9 75.8 83.5

Jayakumar et al. (1989)

Cortical or deep infarcts WMLA

93.3 (77.9–99.2) 53.3 (34.3–71.7)

9.3 8.0

0.1 0.5

0.9 0.8

8.6 7.4

50.9 46.9

75.7 72.6

90.3 1b 88.8

Leys et al. (1989)

Atrophy global index appreciation and several brain indexes

George et al. (1990)

Hippocampal lucency Temporal horn Medial atrophy Lateral atrophy Overall temporal atrophy Ventricular volume (composite linear ventricular measure)

Kido et al. (1988)

de Carli Volumetric method (LV) et al. (1992b)

90 (73.5–97.9) 93.3 (77.9–99.2)

ROC curves

Commentary

1a

Wide confidence intervals; the lack of a neuropathologic reference standard can explain a false over-value (100%) specificity of temporal lobe linear measurements for AD Easy and acceptable method in usual clinical setting (visual rating) Weak RfSt; wide confidence intervals; blind evaluation of diagnostic test respect to RfSt? Presentation data does not allow for calculation of sensibility and specificity; measurement tools seems mildly powerful

82.4 (65.5–93.2) 79.4 (62.1–91.3) 56.0 (37.9–72.8) 71.0 (52.5–85.0) 59.0 (40.7–75.4) 68.0 (49.5–82.6)

75.0 (51.0–91.3) 70.0 (45.7–88.1) 80.0 (56.3–94.3) 70.0 (45.7–88.1) 80.0 (56.3–94.3) 68.0 (64.4–96.0)

3.3 2.6 2.8 2.4 2.9 4.5

0.2 0.3 0.6 0.4 0.5 0.4

0.3 0.3 0.3 0.2 0.3 0.5

3.2 2.6 2.8 2.3 2.9 4.4

26.8 22.7 23.7 20.8 24.7 33.5

52.9 46.9 48.3 44.1 49.6 60.2

76.7 1b 72.6 73.7 70.3 74.6 81.9

Reference standard poorly defined Good methodology, however wide confidence intervals in sensibility and specificity

89.5 (66.9–98.7)

94.1 (71.3–99.9)

15.2

0.1

1.5

13.3

63.8

83.5

93.8 1b

Good methodology; wide confidence intervals

148 CHAPTER II.4

Table II.4.11 (cont’d)

CT abnormalities (ischemic, tumours…) other than atrophy in non-AD patients vs. AD

52.3 (36.7–67.5)

85.0 (73.8–93.6)

3.7

0.6

0.4

3.6

48.0

54.9

78.5 2a

Blind CT rater shows 57/60 (95%) agreement with respect to non-blind CT-rater; poor validity; retrospective and probably selection bias; the wide spectrum of dementing illness is interesting

Jobst et al. (1992a)

Average thickness of medial temporal lobe, measured at the thinnest point*

96.0 (86.5–99.5)

60.7 (40.6–78.5)

2.4

0.1

0.2

2.4

37.5

44.9

71.0 1b

Age not specified; 15% necropsy studies (blinded?) from the original cohort doesn’t allow inclusion in the sensitivity–specificity analysis of the series

Jobst et al. (1992b)

Temporal lobe-oriented CT measured at the narrowest point, corrected by the expected value to give a MoM

91.0 (78.0–97.0)

98.7 (92.8–99.9)

< 0.1

6.6

41.4

94.6

95.9

98.6 Ia

44/167 (26%) necropsy performed in the clinicallydiagnosed AD patients; it is not specified whether neuropathologist was blinded to clinico–radiological information; Pt and C not matched; laborious method for adjusting CT measures diminish daily clinical utility; severity?

Koslow et al. (1992)

ThV-SF distance (mean LR) SF Volume (mean LR) SF area (mean LR) VL abody diameter abifrontal diameter abicaudate diameter amaximum area of bodies atotal volume ThV abithalamic diameter amaximum area atotal area

77.6 (64.7–87.5)

84.8 (73.0–92.8)

5.1

0.3

0.5

4.9

36.2

63.0

83.6 1b

70.7 (57.3–81.9) 70.7 (57.3–81.9)

84.8 (73.0–92.8) 81.4 (69.1–90.3)

4.7 3.8

0.4 0.4

0.5 0.4

4.5 3.7

34.1 29.7

60.8 55.9

82.3 79.2

Good methodology, but the severity spectrum is not fully specified

81.0 (68.6–90.1) 69.0 (55.5–80.5) 69.0 (55.5–80.5) 72.4 (59.1–83.3) 70.7 (57.3–81.9)

74.6 (61.6–85.0) 71.2 (57.9–82.2) 84.8 (73.0–92.8) 72.9 (59.7–83.6) 76.3 (63.4–86.4)

3.2 2.4 3.7 2.7 3.0

0.2 0.4 0.4 0.4 0.4

0.3 0.2 0.4 0.3 0.3

3.1 2.4 3.6 2.6 2.9

26.2 21.0 29.2 22.9 24.9

51.5 44.4 55.3 47.1 49.9

76.1 70.6 78.8 72.8 74.9

72.4 (59.1–83.3) 74.1 (61.0–84.7) 69.0 (55.5–80.5)

69.5 (56.1–80.8) 76.3 (63.4–86.4) 74.6 (61.6–85.0)

2.4 3.1 2.7

0.4 0.3 0.4

0.2 0.3 0.3

2.3 3.1 2.7

20.9 25.8 23.2

44.2 51.0 47.5

70.4 75.8 73.1

de Leon et al. (1993)

HCSF Ventricle measurement

91.0 (72.0–99.0) 74.0 (51.6–89.8)

89.0 (51.8–99.7) 78.0 (40.0–97.0)

8.3 3.4

0.1 0.3

0.8 3.4

7.7 3.3

47.9 27.2

73.4 52.9

89.2 1b 77.1

Results based on discriminating function classification

Buchpiguel et al. (1996)

‘Normal’ vs. ‘abnormal’ AD vs. non-AD

82.7 (69.7–91.3) 52.9 (35.1–70.2)

63.6 (30.8) 68.9 (49.2–84.7)

2.3 1.7

0.3 0.7

0.2 0.7

2.2 1.7

20.2 15.9

43.1 36.2

69.4 1b 63.0

Disproportionate case/ control ratio: 5/1; enough follow-up; wide CI

Lavenu et al. (1997)

Medial temporal lobe thickness = 11.5 mm as indicative of atrophy aprob AD vs. (poss AD + MMD)

70

1a

78.1 (66.0–87.5)

52.0 (37.2–66.7)

1.8

0.4

0.2

1.8

16.4

37.0

63.8

Good methodology; applicable in usual clinical setting; appropriate controls with MMD

Continued on p. 150

DIAGNOSIS OF A DEMENTIA SUBTYPE 149

Engel & Golber (1992)

Table II.4.11 (cont’d)

Author

Analytic measurements aposs AD vs. MMD aprob or poss AD vs. MMD

Pasquier et al. (1997)

Medial temporal lobe thickness = 11.5 mm as indicative of atrophy aprob AD vs. (anx + control) aprob AD vs. MMD aprob or poss AD vs. MMD aposs AD vs. (anx + control)

Jobst et al. (1998)†

Temporal lobe-oriented CT measured at the narrowest point, corrected by the expected value to give a MoM

O’Brien et al. (2000)

Medial temporal lobe thickness = 11.5 mm as indicative of atrophy, distinguishing between: aprob AD vs. depression aprob AD vs. DLB aprob AD vs. PVD aDEM vs. depression

Sensibility (CI 95%) 69.2 (38.6–90.9) 76.6 (65.6–85.5)

Specificity (CI 95%) 52.0 (37.2–66.7) 55.7 (42.4–68.5)

LR+ 1.4 1.6

LR– 0.6 0.5

0.1 0.1 0.2

1 1.4 1.6

10

25

50

13.8 15.1

32.5 34.7

59.0 61.5

Evidence class

1a

83.9 (76.2–89.9)

95.0 (83.1–99.4)

16.8

0.2

1.7

14.5

80.8

84.8

94.4

83.9 (76.2–89.9) 74.1 (67.0–80.5)

50.4 (41.1–59.7) 50.4 (41.1–59.7)

1.7 1.5

0.3 0.5

0.2 0.2

1.7 1.5

15.8 14.2

36.1 33.2

62.9 59.9

50.0 (35.5–64.5)

95.0 (83.1–99.4)

0.5

1.0

9.2

52.6

77.0

91.0

85.0 (75.2–92.0)

47.4 (31.0–64.2)

0.3

0.2

1.6

15.2

35.0

61.8 Ia

10

1.6

1a

51.0 (38.4–63.0) 51.0 (38.4–63.0) 51.0 (38.4–63.0) 54.0 (44.3–64.2)

77.0 (46.2–95.0) 56.0 (21.2–86.3) 32.0 (14.9–53.5) 77.0 (46.2–95.0)

2.2 1.2 0.8 2.4

0.6 0.9 1.5 0.6

0.2 0.1 0.1 0.2

2.2 1.2 0.8 2.3

19.8 11.4 7.7 20.7

42.5 27.9 20 43.9

68.9 53.7 42.9 70.1

Commentary

Healthy controls are scarce (French law forbids the testing of radiation on volunteers), and their median age is lower than AD patients; wide spectrum of MMD; original article does not provide complete calculations for sensibility and specificity, but gives a table with all the data that are needed for the calculations Neuropathologist blinded to clinico–radiologic information? (it is not specified); patients and controls not matched; laborious method for adjusting measures diminishes utility in usual clinical setting; wide confidence intervals; sensibility and specificity only re-calculated (from the original tables in the article) for pathology-proved cases Wide confidence intervals; good methodology, correct question in clinical setting: differential diagnosis between dementia syndromes; does not include healthy control subjects

*A necropsy was performed in 10 of the 51 patients with a clinical diagnosis of AD and two in the control group, but data are insufficient to calculate sensitivity and specificity. †In this paper we have preferred to include only cases with neuropathologic comprobation, in order to classify it as IA-level of evidence. AD, Alzheimer’s disease; C, controls; C, CT, computed tomography; DRS, Mattis’ dementia rating scale; HCSF: hippocampal cerebro-spinal fluid accumulation; IHF, inter-hemispheric fissure; MMD, miscellaneous memory disorders; LR–, negative likelihood ratio; LR+, positive likelihood ratio; LV, lateral ventricles; mean LR: mean estimation in left and right sides; MMD, miscellaneous memory disorders; MoM, multiple of median; Pt, patients; RfSt, Reference standard; THV, third ventricle; ThV-SF: third ventricleaSylvian fissure ratio; VBR, ventricular-brain ratio; WMLA, white matter low attenuation.

150 CHAPTER II.4

Post-test probability for pretest of:

DIAGNOSIS OF A DEMENTIA SUBTYPE 151

designations (e.g. class 2a). In the latter group of studies cognitive tests are used to classify patients as demented, non-demented, or AD. Although widely used, the diagnostic accuracy of these tests, particularly for the diagnosis of dementia subtype, is limited (see Chapter II.4.1). Another methodological problem is the ‘exclusion of other cerebral diseases’, often using CT findings, in the major clinical diagnostic criteria for AD such as Diagnostic and Statistical Manual of Mental Disorders (DSM-III) (American Psychiatric Association 1987), or those from National Institute of Neurological and Communicative Disorders and Stroke, and the Alzheimer’s Disease and Related Disorders Association Work Group (NINCDSADRDA). Only Engel and Gelber (1992) explicitly exclude information obtained from neuroimaging from the reference standard. Thus, diagnosis of the reference standard may be contaminated by the results of the diagnostic test. Independent, blind comparison with a reference standard (BCRS) (see Table II.4.9). Only three studies failed to specify whether the interpretation of CT was performed blind to the reference standard (Brinkman et al. 1981; Jayakumar et al. 1989; de Leon et al. 1989a); two studies did so partially (Kido et al. 1988; Engel & Gelber 1992). This is a key-point in the evaluation of validity: the rater of the CT image should not have access to either clinical or reference standard information. Appropriate spectrum sample of patients to whom CT scan examination will be applied in clinical practice The largest sample of cases compare AD and normal controls. A total of 1118 cases of suspected AD and 967 controls have been evaluated (see Table II.4.10). Average age in most studies is between 60 and 80 years; several have age and sex-matched controls. Most often, patients are recruited from Memory Clinics or reference centers, thus decreasing applicability of results to the usual clinical setting of the office neurologist. Six studies did not clearly establish the source of referral (Brinkman et al. 1981; Drayer et al. 1985; Kido et al. 1988; Leys et al. 1989; de Carli et al. 1990; Buchpiguel et al. 1996). Half of the analysed cases included a spec-

trum of disease graded at least as mild, moderate, or severe; in the rest the global diagnosis of ‘probable AD’ is used or no staging of dementia severity is mentioned. The samples for VaD (n = 79, Erkinjuntti et al. 1987a; n = 25, O’Brien et al. 2000), dementia with Lewy bodies (n = 9, O’Brien et al. 2000) or other causes of dementia (n = 24, Jobst et al. 1998), are much smaller. The frequency of surgically correctable lesions clearly related to the dementing illness (e.g. subdural hematoma, NPH, meningioma) was very small (Bradshaw et al. 1983; Clarfield 1988; Engel & Gelber 1992).

Secondary guides Verification bias It is difficult to ascertain if work-up bias (verification bias) has taken place in this series, but it does not seem probable because of the nature of the test and reference standard. It is unlikely that the CT scan result would have influenced the decision to obtain the reference standard (which mostly comprised clinical criteria). Design in this series was usually prospective, avoiding this relatively common bias. Sufficient detail in describing methods to permit replication Most of the studies examined provide explicit descriptions about the technical aspects of the CT scan and the study design to permit replication (see Table II.4.10). Only three studies do not provide sufficient information on these points (de Leon et al. 1989a; Jayakumar et al. 1989; Buchpiguel et al. 1996). Table II.4.10 compares the analytical measures reported by each author, mostly linear or volumetric measures, and temporal lobe orientation.

What are the results and will they help me in caring for my patients? Data presentation in LR form None of the studies included in this review presented their data as LRs, but sufficient information was provided to allow their calculation (see

152 CHAPTER II.4

Table II.4.11). Similarly none of the papers gave the confidence intervals associated with sensitivity or specificity or indicated how CT findings would change pretest and post-test probabilities. In Table II.4.11 we include these measures. Calculations have been made with Epiinfo Program 6,04a (CDC, WHO) and Excel 2000 software, using Bayesian properties and relationships in the 2 × 2 diagnostic table (see Chapter II.1). As shown in Table II.4.11, most of the calculated LR+ fall between 2 and 5, generating small changes in probability. A few studies show LR+ between 5 and 10, generating moderate shifts in pretest to post-test probability. Limited information about history, physical examination and epidemiological data makes it difficult to estimate pretest probabilities. For that reason, we calculate incremental value based on several pretest probabilities (from 0.1% to 50%). This offers an estimation of several post-test probabilities for AD, assuming a positive finding in CT scanning. Table II.4.11 demonstrates that several studies reach LR > 15, with high post-test probabilities. In these cases, it may be serious methodological difficulties that are responsible for biases, rather than over-estimates of sensitivity and/or specificity (see Table 3, Brinkman et al. 1981; Kido et al. 1988; de Carli et al. 1992b; Jobst et al. 1992b; Pasquier et al. 1997).

Reproducibility of the test result and its interpretation in usual clinical setting Only Jobst et al. (1992a, 1998) and O’Brien et al. (2000) recruit probable AD patients from Primary Care Clinics. Most of the studies took place in Memory Clinics and referral University Centers, explaining why both prevalence and severity are high (only a few authors provide data on this topic). Complicated and combined analytic measurements on CT scans are not practical in primary care or neurology clinics. Radiologists rarely give quantitative ratings. However, visual ratings for severity of atrophy are practical and accurate (LR+ = 2–5). Recognition of infarcts in the diagnoses of vascular or multi-infarct dementia is even better (LR ≅ 10) (Erkinjuntti et al. 1987c; Jayakumar et al. 1989).

Applicability of the results to our patients Most of the articles cited in Tables II.4.9–11 studied patients and controls essentially without co-morbidity. The CT scan, like any test, may change its diagnostic properties with a different sampling of disease severity or distribution of competing conditions. If CT scans are used to investigate dementia, at the office or in the general hospital, in patients without AD but with competing conditions that also produce brain atrophy, the LRs will probably move closer to 1 and the test will appear less useful (reduced specificity). This could be an important factor limiting the specificity of the CT scan for a diagnosis of AD in primary care settings.

Will the results of CT scanning change our management? It is difficult to ascertain test and treatment thresholds based on the CT scan data dealing with AD, based on this data. Competing and complementary diagnostic tests may move diagnostic probability through decision thresholds, perhaps more reliably than CT scanning. It is difficult to determine if treatment of a structural finding from the CT scan will ultimately improve the patient’s cognitive status. Consideration of surgical risk, age, comorbidity, danger of the disease if left untreated and, possibly, medico-legal questions should be made in each case (Martin et al. 1987; Katzman 1990; Cammer 1997; George et al. 1997; Small & Leiter 1998; Foster et al. 1999). There are contradictory data about the comparative long-term prognosis of VaD vs. AD. In some reports (Mölsa et al. 1995; Aevarsson et al. 1998) patients with VaD had a worse outcome than patients with AD. Others (Ballard et al. 1996; Rockwood et al. 2000) estimated similar 5-year mortality rates for VaD and AD, ranging from 40% (community-dwelling subjects) to 70% (institutionalized sample). These studies have some biases and the role of CT scanning in these patients is unclear. Co-morbidity was only associated with an increased risk of death in AD, and poorer functional status predicted death only in VaD (AgüeroTorres et al. 1998). However, Rockwood et al. (2000) compared controls to subjects with vascular–

DIAGNOSIS OF A DEMENTIA SUBTYPE 153

cognitive impairment without dementia, and found that the rate of institutionalization and mortality in the latter group was significantly higher than in those with no cognitive impairment. Curiously, in a clinicopathological study of demented patients with AD, VaD and mixed dementia (Ettlin et al. 1989), the sensitivity of the CT scan in detecting cerebral infarcts was only 18%, while the sensitivity of the clinical features was 73%. Several problems are recognized in epidemiological research on VaD, including differences in choice of diagnostic criteria and definition of outcome. This makes it difficult to ascertain the role for CT in VaD. There are few outcome studies based on the decision to obtain or withhold CT scan (due to obvious clinical considerations). Nonetheless, it seems reasonable to assume that there is potential for prevention and treatment of VaD through more aggressive identification and treatment of vascular risk factors, modification of target blood pressure in the presence of severe leukoaraiosis, and possibly anti-platelet aggregation (Williams et al. 2000). So, cranial CT (and, of course, MRI and functional neuroimaging) may have yet a paramount role in the management of dementia (Fig. II.4.6).

Cost-effectiveness None of the authors cited in Tables II.4.9–11 address the question of cost-effectiveness. However, Foster et al. (1999) review patients in Scotland above and below the age of 65 years, and combine clinical information with epidemiological and financial data. They propose that the most costeffective screening strategy is to scan all patients but treat only subdural hematomas, gaining 178 quality-adjusted life-years (QALY) at a cost of £9000, £14 171 and £23 000 per QALY for patients aged below 65, exactly 65 and above 65 respectively, at the time of the scan. CT scanning appears cost-effective in the first group (under 65 years). This study did not address the role of CT in VaD. Due to its complexity, we have only begun to deal with VaD (Simon & Lubin 1985). As mentioned above, epidemiological data regarding prognosis of VaD are scarce (Agüero-Torres et al.

Fig. II.4.6 CT scan showing multiple cortical infarcts,

enlarged lateral ventricles and subcortical lucencies in a patient with vascular dementia.

1999) and do not yet allow answers to questions about cost-effectiveness of neuroimaging in diagnosing and treating VaD. With regard to improved cost-utility in the management of dementia, practice guidelines (see Chapter II.2) have proposed several clinical ‘indicators’ to perform neuro-imaging (i.e. symptom onset before age 60 years, non-insidious course, focal symptoms and/or signs, or abnormal gait). This approach substantially restricts the indication of neuroimaging. Chui and Zhang (1997) explored the added value of performing neuroimaging in all patient with suspected dementia (n = 119), regardless of the indications of clinical parameter. There were four cases without American Academy of Neurology (AAN)-indication for imaging amongst 41 cases (Neurology 1994) in which the CT changed diagnosis (4/41 = 9.8%). This translates to a NNS (number of patients necessary to screen) of 11 patients to discover one cause of dementia distinct from AD using a CT scan. Considering all forms of neuroimaging (MRI and/or

154 CHAPTER II.4

CT) for this purpose, the diagnosis was changed in 6/41 (14.6%) patients without indication for imaging, with NNS = 7 patients. These NNS are very acceptable and provide a rational background for the recommendations made by Corey-Bloom et al. (1995) in their AAN position paper, ‘a neuroimaging procedure should be performed once in all causes of dementia’ (Katzman 1990; Corey-Bloom et al. 1995; Knopman et al. 2001).

Conclusions In terms of positive LRs, the value of the CT scan in diagnosing AD is only modest. Our evidence-based review has shown serious validity problems at several levels. Inappropriate reference standards, selection bias, incomplete blinded evaluations, a narrow spectrum of patients and a LR+ of around 2–5 with wide confidence intervals in sensitivity and specificity were the main problems. CT scanning is capable of detecting structural lesions other than atrophy (LR+ of around 10–15 and 2–5 for vascular and non-vascular lesions, respectively). The clinician should keep in mind that the prior probability of finding surgically correctable lesions is low, and consider the subsequent diagnostic or therapeutic steps. In most cases, these would rely not only on CT findings. If the CT shows brain infarcts or significant white matter changes suggesting VaD or mixed (vascular and degenerative) dementia, appropriate cardiovascular management would be warranted. From the point of view of the cost-utility, the best yield is obtained when dementia occurs in patients younger than 65 years. Detection of cere-

brovascular disease should immediately lead us to consider hypertension and other risk factors, and to consider prophylactic treatment with antiplatelet medication. However, an assessment of various cost-effective strategies is sorely lacking in the literature. At the present time it remains reasonable to screen all patients, as recommended by practice guidelines, mostly in university centers and investigational settings. However, whilst awaiting more sophisticated studies in this field, the decision to perform neuroimaging in dementia patients should be based on the particular features (epidemiological, socio-economical, medico-legal) of each medical center.

Practice recommendations 1 Consider performing brain CT scan once in all cases of dementia, unless deemed inappropriate in your clinical setting and health system. 2 When requesting neuroimaging, emphasize to the neuro-radiologist whether your objective is to rule out treatable structural lesions, to confirm the diagnosis of degenerative disorder, or both. 3 If clinical data lead you to consider a structural lesion and CT is normal or questionable, you should consider a more sensitive test (i.e. brain MRI). 4 It may be useful for you to make a note of each CT petition, stating the pretest probability, and check it after the test. This evidence-based discipline will help you to understand the diagnostic value of tests and will make your clinical diagnosis more reliable.

MRI of the Medial Temporal Lobe for the Diagnosis of Alzheimer’s Disease II.4.7

Lisette Bosscher and Philip Scheltens

Alzheimer’s disease (AD) is the most common form of dementia over the age of 60 (Ott et al. 1995). The diagnosis of AD can be made using clinical criteria (probable AD by NINCDS-ADRDA

(McKhann et al. 1984); DSM-III-R (American Psychiatric Association 1987) ). Based on clinicopathological correlation, the accuracy of these criteria is limited, with a specificity of approximately

DIAGNOSIS OF A DEMENTIA SUBTYPE 155

0.76 to 0.88 and a sensitivity of 0.53 to 0.65 (see Chapter II.4.1 for review). Varma et al. (1999) found an even lower specificity of 0.23 when using the NINCDS-ADRDA criteria to distinguish patients with AD from those with frontotemporal dementia (FTD). Other diagnostic tests are therefore greatly needed. The following question is addressed in this chapter: ‘What is the utility of MRI atrophy of the medial temporal lobe for distinguishing: (i) AD from normal ageing, and (ii) AD from other types of dementia?’

Background The hippocampus and surrounding structures play an important role in memory function in animals and humans (Zola-Morgan et al. 1986; Squire & Zola-Morgan 1991). Several histopathological studies have suggested that histopathological changes in the medial temporal lobe structures occur early in the course of AD and are specific for AD (Hyman et al. 1984; Ball et al. 1985; Braak & Braak 1991; Bobinski et al. 1997, 1998). One of these even stated that AD is a ‘hippocampal dementia’ with neurofibrillary tangles and plaques found predominantly in this limbic structure (Ball et al. 1985). Significantly more neuronal loss has been found in the hippocampi of patients with AD compared to normal elderly people (West et al. 1994). Also the severity of AD correlates with neuronal and volume loss in parts of the hippocampus (Bobinski et al. 1998). Soon after the introduction of X-ray computerized tomography (CT) many studies were carried out to investigate its diagnostic value for AD (for review see de Carli 1990). Later, CT studies used assessments of medial temporal lobe structures with modest success (de Leon et al. 1989b, 1997; Jobst et al. 1992a; Smith 1996), but some of the results still need to be confirmed. Using MRI, it became possible to study different areas within the medial temporal lobe, such as the hippocampus proper, parahipppocampal gyrus, subiculum, entorhinal cortex and amygdala. Many have been measured using a variety of tracing techniques and anatomical boundaries. Most studies focused on the hippocampus, after publication of the study of Seab et al. (1988).

Some studies have employed linear or visual measurements (Scheltens et al. 1992, 1997; Erkinjuntti et al. 1993; O’Brien 1995; de Leon 1996; Frisoni et al. 1996; Horn 1996; Pucci et al. 1998; Barber et al. 1999). Because of their supposedly (but debatable) greater accuracy and reliability, most studies have used volumetric measures of medial temporal lobe structures (Fig. II.4.7) (Seab 1988; Kesslak 1991; Jack et al. 1992, 1997, 1998; Pearlson et al. 1992; Convit 1993; Kiliany et al. 1993; Desmond et al. 1994; Soininen et al. 1994; Laakso et al. 1995, 1996, 1998; Wilson et al. 1996; Barta 1997; Kidron 1997; Kohler 1997; Mori et al. 1997; O’Brien et al. 1997; Kohler et al. 1998; Krasuski et al. 1998; Harvey 1999; Smith et al. 1999). Comparison studies have found good correlation between these assessment techniques (Convit 1993; Desmond et al. 1994; Harvey 1999; Wahlund et al. 1999). In this chapter, we conduct an evidenced-based review of the utility of MRI assessment of medial temporal lobe atrophy (MTA) for the diagnosis of AD. We deliberately choose MRI instead of CT because of the superiority of this technique in this region, in terms of spatial resolution and absence of beam-hardening artefacts, the paucity and poor reproducibility of the published CT studies and the expected increase in availability of MRI over CT in clinical practice. We will use the term MTA as a general term, but will report mainly the results achieved by measuring or rating hippocampal atrophy and report on the other structures if measured.

Search strategy and study validation The search was conducted using the Medline database with the keywords: Alzheimer’s disease, MRI, hippocampus, volumetric-, area-, linear measurement and visual assessment. Studies were included if they used an objective clinical diagnostic reference as the gold standard, usually the NINCDS-ADRDA criteria (McKhann et al. 1984) and/or DSM-III-R or DSM-IV (American Psychiatric Association 1987, 1994), with or without follow-up. We only included studies meeting the criteria for class 1 or 2 evidence, as described in Chapter II.1, and when a

156 CHAPTER II.4

Fig. II.4.7 Medial temporal lobe on

MRI: volumetric assessment using manual tracing.

likelihood ratio (LR) could be calculated. In keeping with the conventions established in this section, only studies using neuropathologically confirmed diagnoses were considered as possible Class I or II evidence, but no such studies were found. If clinical diagnoses were used as the gold standard, the study was considered as ‘class 1 or 2’ evidence. Because the second author was involved in some of the studies reviewed, designation of the class of evidence was performed by the first author only, using a worksheet provided by the editors. The search results are listed in Tables II.4.12–15, according to the MRI analysis method. The tables include the number of subjects, scan details, parts of the medial temporal lobe studied as well as other regions of interest (ROI), sensitivity and specificity (if given or calculated from the data), correlations with neuropsychology or severity of dementia, and the class of evidence. Studies that were excluded (e.g. classified as ‘class III or IV’) can be found on the website. Studies that evaluated the diagnostic value of various MTA measurements in its relation to memory tests and apolipoprotein E (ApoE) were excluded because we found them less relevant to our aims as stated in the introduction above. Studies that addressed specifically the combination of MRI with PET or SPECT were also excluded because of

their scarcity and because they are not of immediate clinical relevance.

Evidence As can be seen in the tables the majority of studies listed here involve small and selected groups. This makes it difficult to apply the results to the large and diverse group of patients one encounters in clinical practice. From Tables II.4.12–15 it may be inferred that the number of studies meeting the inclusion criteria is also small (n = 27). The overall LR+ for the first aim (AD vs. controls) is approximately 10 and the overall LR+ for AD vs. non-AD is around 6, although the number of studies for this is small. Differences in study techniques Different techniques have been employed to assess MTA. Several studies used a qualitative method which involves a visual rating scale, usually a four or five point scale ranging from absent to severe MTA (Fig. II.4.8) (Scheltens et al. 1992, 1997; Erkinjuntti et al. 1993; Golomb et al. 1993; Horn 1996). Visual assessment correlated well with linear and volumetric measurements (Desmond et al.

Table II.4.12 Diagnostic value of hippocampal volumetry and medial temporal lobe measurements: volumetric measurements. Anatomy

Results

Other ROI

Correlation with

Class of evidence

1.5 T/4 mm slices

Coronal, perpendicular to long axis HC

SS 85%, SP 100%

Anterior temporal lobe

Not mentioned

1b

18 AD, 8C

1.5 T/5 mm slices

Coronal, perpendicular to long axis HC

SS 89%, SP 100%

Amygdala (+ HC 100% sensitive)

MMSE

1b

Ikeda et al. (1994)

6 poss. AD, 8 prob. AD, 8C

1.5 T/5 mm slices

Coronal, perpendicular to orbitomeatal line

SS 94%, SP 100%

PHG, temporal lobe

Laakso et al. (1995)

32 AD, 16 C

1.5 T/1.5– 1.8 mm slices

Coronal, perpendicular to long axis HC

SS 84%, SP 94% LR+ 14

Amygdala, frontal lobe

Laakso et al. (1996)

50 AD, 9 VaD, 12 PD, 8 PDD, 34 C

1.5 T/1.5– 2 mm slices

Coronal, perpendicular to long axis HC

Low specificity

Jack et al. (1997)

94 AD, 126 C

1.5 T/1.6 mm slices

Coronal

For fixed SP of 80%, SS 77.8–86.7%, LR+ 3.9–4.3

Convit (1997)

27 AD, 22 MCI, 27 C

1.5 T/4 mm slices

Coronal, perpendicular to long axis HC

Pantel et al. (1997)

20 AD, 10 C

1.5 T/1.25 mm slices

Laakso et al. (1998)

55 AD, 43 AAMI, 42 C, 20 YC

Pantel (1998)

Author

Subjects

Scan/slice thickness

Jack et al. (1992)

20 AD, 22 C

Lehericy et al. (1998)

1b

1b

MMSE, delayed recall

1b

PHG, amygdala

Not mentioned

1b

AD vs. MCI, SS 89%, SP 86.4%; LR+ 6.5

(MCI HC < 14%) PHG, temporal gyri, CSF

Delayed memory

1b

15° cranial to orbitomeatal line, amygdalo-hippocampal complex

SS 85%, SP 60%, LR+ 2.1

Brain, frontotemporal lobes

MMSE, GDS, BCRS

IB

1.5 T/ 1.5–2 mm slices

Coronal, perpendicular to long axis HC

SS 83.6%, SP 89.6%, LR+ 8

HC spared in AAMI

1b

22 AD, 17 VD, 13 C

1.5 T/1.25 mm slices

Coronal, 15° cranial to orbitomeatal line

AHC could not differentiate AD and VaD, no significant difference in volume is found

Krasuski et al. (1998)

13 AD, 21 C

1.5 T/5 mm slices

Coronal, perpendicular to sylvian fissure

Left HC: SS 80%, SP 90%; LR+ 8; left HC + amygdala: SS 85%, SP 95%; LR+ 17

Juottonen (1999)

30 AD, 32 C

1.5 T/2 mm slices

Frisoni (1999)

12 FTD, 30 AD, 30 C

1.5 T/2 mm slices

Coronal, perpendicular to HC + entorhinal cortex

1b

None found

1b

SS 80%, SP 91%, LR+ 8.9

Entorhinal cortex + gender SS 90%, SP 94%; LR+ 15

1b

For fixed SP of 90%, SS 80%, LR+ 8

Entorhinal cortex

2b

AAMI, age-associated memory impairment; AD, Alzheimer’s disease; AHC, anterior hippocampus; BCRS, Brief Cognitive Rating Scale; C, controls; CSF, cerebrospinal fluid; FTD, frontotemporal lobe dementia; GDS, Global Deterioration Scale; HC, hippocampus; LR+, positive likelihood ratio; MCI, mild cognitive impairment; MMSE, Mini Mental Status Examination; PD, Parkinson’s disease; PDD, Parkinson’s disease + dementia; PHG, parahippocampal gyrus; ROI, regions of interest; SP, specificity; SS, sensitivity; T, tesla; VaD, vascular dementia; YC, young controls.

DIAGNOSIS OF A DEMENTIA SUBTYPE 157

MMSE, delayed recall

158 CHAPTER II.4

0

2

4 Fig. II.4.8 Visual rating of MTA.

1

3

Table II.4.13 Diagnostic value of hippocampal volumetry and medial temporal lobe measurements: visual and linear measurements.

Anatomy

Results

Other ROI

Correlation with

Class of evidence

0.6 T/5 mm slices

Coronal, 0–4 scale

SS 81%, SP 67%, LR+ 2.5

Ventricles, reliability?

MMSE

1b

34 AD, 39 C

1.5 T/3–5 mm slices

0–4 rating scale + linear assessment

SS 41%, SP 90%, LR+ 4.1

ERC, temporal cortex, temporal horns

Frisoni (1996)

46 AD, 31 C

1.5 T/1.3 mm

Linear measurements of MTA, frontal lobe

Discriminant analysis with SP set at 95%, SS max 93% for moderate AD and 81% for mild AD

1b

de Leon (1996)

130 C, 72 MCI, 73 mild AD, 130 AD

1.5 T/6 mm slices

Axial, 0–3 rating scale Kappa 0.92

Discriminant analysis: SS 95% SP 85%, LR+ 6.3

1b

Scheltens et al. (1997)

10 AD, 41 C

0.6 T/5 mm slices

Coronal, 0–4 scale

SS 70%, SP 76%, LR+ 2.9

O’Brien et al. (1997)

77 AD, 61 depression, 44 other dementias, 40 controls

0.3 T/5.1 mm slices

Coronal, 0–3 scale, anterior hippocampal atrophy best

SS 83%, SP 80%, LR+ 4.15 for C; SP 89% vs. other dementias, LR+ 7.27

Pucci et al. (1998)

39 AD, 15 other dementias, 33 C

1 T/3 mm slices

Coronal, linear measurements of MTA

Left HC height, SS 79%, SP 69%, LR+ 2.54

None

1a

Barber et al. (1999)

28 AD, 26 DLB, 24 VaD, 26 C

1 T/5 mm slices

0–4 point visual rating scale for MTA

AD vs. controls: SS 100%, SP 96%, LR+ 25; DLB from AD: SS 38%

CAMCOG memory subscale

1a

Author

Subjects

Scheltens et al. (1992)

21 AD, 21 C

Erkinjuntti et al. (1993)

Scan/slice thickness

1b

MMSE

1b

1a

AD, Alzheimer’s disease; C, controls; CAMCOG, cognitive section of the Cambridge examination for mental disorders of the elderly; DLB, dementia with Lewy bodies; ERC, entorhinal cortex; HC, hippocampus; LR+, positive likelihood ratio; MCI, mild cognitive impairment; MMSE, Mini Mental Status Examination; MTA, medial temporal lobe atrophy; ROI, regions of interest; SP, specificity; SS, sensitivity; T, tesla; VaD, vascular dementia.

DIAGNOSIS OF A DEMENTIA SUBTYPE 159

Positive predictive value: AD vs. all others 75%. Negative predictive value: AD vs. all others 91%

160 CHAPTER II.4

Table II.4.14 Diagnostic value of hippocampal volumetry and medial temporal lobe measurements: visual and volumetric

assessment. Scan/slice thickness

Anatomy

Results

24 AD, 15 C

0.3 T/5.1 mm slices

Coronal, visual 0–3 scale and volumetry

41 AD, 36 other dementias, 66 C

1.5 T/2.8 mm slices

0–4 scale for MTA and volumetry

Author

Subjects

Desmond et al. (1994)

Wahlund et al. (2000)

Other Correlation ROI with

Class of evidence

Visual: SS 92%, SP 93%, LR+ 13.1 Volumetric: SS 83%, SP 87%, LR+ 6.4

—

1b

Visual: SS 95%, SP 96%, LR+ 24 for C; SP 85% for other dementias; LR+ 6.3 Volumetry: SS 85%, SP 95% for C; LR+ 17; SP 64%, LR+ 2.4 for other dementias

—

Not mentioned

1a

AD, Alzheimer’s disease; C, controls; LR+, positive likelihood ratio; MTA, medial temporal lobe atrophy; ROI, regions of interest; SP, specificity; SS, sensitivity; T, tesla.

Table II.4.15 Diagnostic value of hippocampal volumetry and medial temporal lobe measurements: longitudinal studies.

Author

Subjects

Jack et al. (1998a)

Visser (1999)

Scan/slice thickness

Other ROI

Correlation with

Class of evidence

Decrease in hippocampal volume 2.5 times greater in AD than in C

—

—

1b

MTA visual rating + memory tests good predictor: 96% correctly classified

—

—

1a

Anatomy

Results

24 cognitively 1.5 T/1.6 mm normal, 24 AD slices

Follow-up 1 year

45 subjects: 7 AD, 38 C

Follow-up 3 years

0.6 T/5 mm slices

AD, Alzheimer’s disease; C, controls; MTA, medial temporal lobe atrophy; ROI, regions of interest; T, tesla.

1994; Harvey et al. 1999; Wahlund et al. 1999) (see Table II.4.14), and is considerably less timeconsuming (Wahlund et al. 1999) and easily applicable in clinical practice. The downside may be a larger interrater variability (see Fig. II.4.8; Scheltens et al. 1995). Studies using visual analysis yield better results than those in which volumetric analysis was used. Of the 10 studies using visual analysis, only eight had class 1 (a or b) evidence. Volumetric studies have an aura of greater reliability and accuracy, but the data in this review do not support this notion. Probably due to the large variety in the techniques used in studying hippocampal and

other medial temporal lobe volumes, a strict and direct comparison of studies is problematic. The evidence coming from these studies was of class 1 (a or b) strength in 11 of the 19 studies reviewed. Two studies that directly compared the two methods showed results in favour of visual analysis with class 1 evidence. A variety of scanning angles and anatomical delineation parameters are used in the volumetric studies listed and this may seriously hamper direct comparisons of the results. Ikeda et al. (1994) stated that different scanning angles do not influence volume measurements. Hasboun et al. (1996) found that different acquisition methods not per-

DIAGNOSIS OF A DEMENTIA SUBTYPE 161

pendicular to the long axis of the medial temporal lobe did lead to variation in absolute values, but not in differences in comparing group averages. However, using different anatomical boundaries of structures within the medial temporal lobe may influence diagnostic results. An example is the inclusion or exclusion of the subiculum or uncus when measuring hippocampal volume. Pantel et al. (1997) and Pantel (1998) measured the amygdalohippocampal complex combining two structures that are difficult to distinguish. AD vs. normal controls Linear measurements of MTA are less timeconsuming and costly than volume measurements, and may be less susceptible to interobserver variation. Scheltens et al. (1992) compared visual and linear measurements and found significant differences in MTA between AD patients and controls only with visual assesment. Frisoni et al. (1996) found a maximum sensitivity of 81% at a specificity of 95% for differentiating moderate AD cases from controls using a compound score of linear measurements that included the temporal horn. Pucci et al. (1998) found the best discriminating parameter to be height of the left hippocampus, with a sensitivity of 79% and a specificity of 69%. In volumetric studies, higher sensitivity and specificity figures are found for differentiating AD from controls. The first studies even showed 100% accuracy, but these results were probably biased because only very small groups were studied. Later studies showed lower sensitivity and specificity figures. The use of different slice thicknesses could influence the results due to overprojection and partial volume effect (Bergin et al. 1994). Soininen et al. (1994) estimated that this could lead to an error of aproximately 30% with 3 mm slices. However, a study conducted using 1, 3 and 5 mm slices to measure hippocampal volume found no significant differences (Laakso et al. 1996). Longitudinal studies of AD vs. normal ageing Longitudinal studies (see Table II.4.15) are few, but they all show that MTA predicts AD. This is in accordance with the finding that patients with

mild AD have smaller hippocampi (Killiany et al. 1993; Lehericy et al. 1994; de Leon et al. 1996). Studies in which hippocampal volume was assessed in subjects with ‘mild cognitive impairment’ or ‘age-associated cognitive impairment’ reported significant atrophy (Soininen et al. 1994; Golomb et al. 1993, 1996). Another longitudinal study performed by Mueller et al. (1998) showed that the rate of atrophy in cognitive healthy elderly people does not increase with age which suggests that the significant atrophy found in the studies mentioned above does indeed reflect preclinical dementia. Sullivan et al. (1995) even found that there is an age-related decline of temporal lobe grey matter but not of the hippocampus in the healthy elderly. AD vs. non-AD dementia There are only a few studies in which AD patients were compared to patients with other dementias (Horn et al. 1996; Laakso et al. 1996; O’Brien et al. 1997; Pantel 1998; Pucci et al. 1998; Barber et al. 1999; Frisoni 1999; Harvey 1999; Wahlund et al. 2000). Three of these studies (Laakso et al. 1996; Pantel 1998; Harvey et al. 1999) showed no significant difference in MTA between AD patients and those with other dementias. In the other studies, a difference was found but specificity was lower for distinguishing AD from other dementias than from healthy controls. Combined use of structural and functional imaging Combining MRI with functional neuroimaging has been done for PET and SPECT imaging. Jobst et al. (1992a) had already shown that atrophy of the medial temporal lobe on CT is associated with reduced blood flow in the posterior parietotemporal cortex in patients with AD. This association has also been found by Parnetti et al. (1996) for hippocampal volume reduction measured on MRI. This combination of techniques can yield a higher accuracy for diagnosing AD. For example, a combination of SPECT assessment of regional blood flow and volumetry of several medial temporal lobe structures (entorhinal cortex, amygdala, hippocampus) yielded 100% discrimination of AD from

162 CHAPTER II.4

control subjects (Pearlson et al. 1992), but these results were not corroborated by Scheltens et al. (1997). A correlation has also been found for PET studies using fluorodeoxyglucose (FDG) for measuring the cerebral metabolic rate for glucose and MRI volumetry of the hippocampus and parahippocampal gyrus (Yamaguchi et al. 1997). The combination of structural and functional imaging is promising, but further studies are required.

Conclusions and recommendations Based on the above some conclusions can be drawn. Unfortunately the first one must be that the data are still limited, especially concerning the value of MTA in differentiating AD from other dementias and mild cognitive impairmenta probably the most relevant question for clinical

II.4.8

practice. No studies actually used postmortem data as the gold standard and sample sizes were generally small, with a few exceptions. Moreover, employment of different techniques prevents pooling of data. However, when a diagnostic marker is needed that adequately differentiates AD from normal ageing, an assessment of MTA will result in a reasonably high positive likelihood ratio. As MRI studies become increasingly common, adding coronal slices will yield valuable extra information at no extra cost or burden for the patient. In this respect, making one MRI examination during the course of a dementia evaluation can hardly be judged to be optional any more. Volumetric quantification of MTA is still confined to research settings because of the poor generalizability and agreement between centres.

Functional Imaging in Dementia

William Jagust, Helena Chui and Ae-Young Lee Background Technical background Positron emission tomography (PET) and single photon emission computed tomography (SPECT) are both nuclear medicine imaging techniques that utilize injected radioactivity to generate threedimensional images of brain function. Because of a host of differences resulting from physical and chemical characteristics of positron-emitting and single photon-emitting radionuclides, the two techniques differ in many respects. Thus, PET has been used with a far greater variety of different radiotracers than SPECT, and has inherent superiority for resolution and sensitivity. Nevertheless, SPECT is more available and has been widely applied so that considerable clinical data are reported. Despite the differences, most clinical PET studies use tracers for measuring glucose metabolism (CMRglc) such as 18F-fluorodeoxyglucose (FDG) in a non-quantitative way, and most SPECT studies use tracers for measuring blood flow in a nonquantitative way. While there are relatively little

data that directly compare PET and SPECT results, the two techniques yield comparable results in groups of dementia patients, although PET is probably more sensitive because of its greater resolution (Messa et al. 1994). When comparing results from different studies it is important to note differences in instruments (i.e. PET vs. SPECT) but also to note differences in quantitative technique. Both SPECT and PET may use semiquantitative measures (such as ratios of counts) or visual rating scales. While the former may have advantages of quantitative precision, the latter are usually more applicable to clinical settings. Results from the two methods of data analysis may differ considerably. Clinical background Initial PET studies of blood flow and oxygen metabolism demonstrated reductions in both of these physiological processes in the parietal and temporal cortices of patients with Alzheimer’s disease (AD) (Frackowiak et al. 1980). Although the underlying mechanism of these changes are still debated, they have been widely found using both PET and

Table II.4.16 Neuropathologically verified series. Sample

Diagnoses

Imaging/analysis/pattern

Pathological criteria

Prospective?

Sens

Spec

PPV

NPV

LR+

Class

Jobst et al. (1998)

118

80 AD 24 other dementia 14 controls with autopsy

SPECT Rater Parietotemporal hypoperfusion

CERAD Definite or probable

Prospective

0.89

0.6

0.81

0.74

2.2

IA

Bonte et al. (1997)

54

43 AD 2 FTD 9 non-AD

SPECT Rater Posterior superior parietal

Prospective

0.86

0.73

0.92

0.57

3.2

IA

Read et al. (1995)

27

13 AD 14 non-AD

SPECT Rater temporoparietal

Retrospective

0.85

0.64

0.69

0.82

2.4

IIA

Khachaturian

AD, Alzheimer’s disease; CERAD, Consortium to Establish a Registry for Alzheimer’s Disease; FTD, frontotemporal dementia; NPV, negative predictive value; LR+, positive likelihood ratio; PPV, positive predictive value; Sens, sensitivity; Spec, specificity; SPECT, single photon emission computed tomography.

DIAGNOSIS OF A DEMENTIA SUBTYPE 163

Reference

164 CHAPTER II.4

SPECT tracers of blood flow and metabolism (Foster et al. 1983; Johnson et al. 1990). In addition to changes in temporal and parietal cortex, posterior cingulate cortex also appears to be hypometabolic early in the disease (Minoshima et al. 1997; Ibáñez et al. 1998). Although there is a suggestion that these functional changes correlate with the distribution of neuropathology postmortem (Friedland et al. 1985; de Carli et al. 1992a), there are a paucity of data that address this subject. For the purposes of this review, based upon the existing data, we defined a ‘diagnostic’ pattern of regional cerebral blood flow (rCBF) or regional cerebral glucose metabolism (rCMRglc) in AD as showing temporal or parietal hypofunction. This could be defined as bilateral or asymmetric, with or without additional perfusion defects depending on the specific study. It is important to note that a number of studies in this review use exploratory and retroactive procedures to define diagnostic patterns, with predictable results in terms of changes in sensitivity and specificity. An example of a typical diagnostic pattern, seen in a PET CMRglc study is shown in Plate II.1, facing p. 154.

Search strategy and study validation The evidence that supports the clinical utility of SPECT and PET in the diagnosis of dementia falls into several categories. Although the classification of evidence as types I, II and III is useful, it is more instructive to evaluate the reason that studies may be classified in each category. First is the nature of the ‘gold’ standard for validation of the diagnosis. Relatively few studies using neuropathological criteria for validation have been published. A second issue regards the nature of the subjects selected. While many studies are prospective, they have often enrolled subjects who were clinically diagnosed with typical AD during life and frequently exclude subjects with complex or multi-factorial illness, and thus represent a narrow range of people with AD. In fact, studies (Class IA) that have included both autopsy validation and a wide spectrum of subjects are unusual. Another issue that is not directly relevant to classification is the nature of control groups. While many studies compare AD patients to healthy

older subjects, fewer still compare AD patients to patients with other dementias. Clinical diagnosis of AD may be quite accurate, but clinical diagnosis of other dementias (such as dementia with Lewy bodies (DLB) or vascular dementia (VaD)) has not achieved this level of accuracy. Thus, while comparisons between AD and other dementias may be more clinically important than comparisons between AD and normals, unless pathological validation is available they are far more likely to be invalid. For the purposes of this review, studies will be divided into those with neuropathological validation, those with clinical validation that compare AD and normals, and those with clinical validation that compare AD with other dementias. With regard to the comparison of AD patients to patients with other dementias, two experimental approaches have been applied. One approach is to select groups of patients that represent exemplars of each disorder, while another approach is to study an unselected serial sample of patients. Obviously the former group results in type ‘b’ studies and are generally less representative of clinical populations. Within each type of study (pathologically verified, AD vs. controls, AD vs. other dementias) we include studies rated as class I or II evidence. Class IA evidence includes prospective studies with blinded evaluation of SPECT or PET imaging. Class IB includes such studies in which a narrow representation of the disorder is included. Class IIA includes retrospective studies with blinded evaluation and a full spectrum of disease. Class IIB includes similar retrospective studies with a narrow spectrum of cases. Studies that utilized receiver-operating characteristic (ROC) curves with cut-points described post hoc were included as class II (since the data analysis is by definition retrospective), but are noted as problematic in the discussion. After the search was performed, studies that did not meet these criteria were excluded, as were many studies that reported on group differences but did not contain individual case data that permitted the calculation of sensitivity, specificity and positive likelihood ratios (LR+). The studies sampled were limited to those primarily focused on AD, as the clinical diagnosis of other dementias may be less valid and such studies are fewer in number. Thus, comparisons between AD and normals or other dementias represent the focus

DIAGNOSIS OF A DEMENTIA SUBTYPE 165

of this review, so that the primary question of interest is the utility of these techniques in the diagnosis of AD.

Evidence Neuropathologically validated samples (Table II.4.16)

A number of reports have emanated from the Oxford Project to Investigate Memory and Ageing (OPTIMA). An initial report in 1992 (Jobst et al. 1992a) mentioned 12 patients (out of the total sample of 51 patients) who had histopathological confirmation of their dementia diagnosis. All of the 11 patients with AD had both temporoparietal hypoperfusion (graded by a rater) and medial temporal lobe atrophy, while one patient had neither AD nor temporoparietal hypoperfusion. One patient was clinically diagnosed with VaD, but had AD pathologically and by SPECT. In 1998 these authors published their experience with 118 autopsyconfirmed cases, which included both dementia patients and controls ( Jobst et al. 1998). They found that 65 of 73 patients with AD and 11 of 24 patients with non-AD dementias showed temporoparietal hypoperfusion using their grading system. In addition, 4 of 14 autopsied controls showed this hypoperfusion. Thus, for the autopsy-confirmed subjects only, the sensitivity, specificity, positive predictive value and negative predictive values were relatively high (Table II.4.16). When one includes an additional 105 non-autopsied controls, values for specificity were considerably higher. Bonte et al. (1997) studied 54 patients with dementia who had autopsies and SPECT scanning interpreted by a rater. Values for sensitivity, specificity, positive predictive value and negative predictive value were quite comparable to those obtained by the OPTIMA group, although specificity was higher. In this study, patients with histological AD with Lewy bodies were considered to have AD; had they not, clearly the specificity would have been lower. In a small study of 27 subjects, 13 of whom had autopsy- or biopsy-confirmed AD, Read et al. (1995) used clinician readings of SPECT scans in comparison to pathology. They reported that SPECT predicted pathology in 92.6% of their

cases, including a group of seven patients with frontotemporal dementia (FTD) or Pick’s disease who all had frontal or frontotemporal hypoperfusion. From their data, calculation of sensitivity, specificity and positive and negative predictive values for AD was possible and produced values again similar to the other two studies noted above.

Clinically validated samples of AD vs. controls (Table II.4.17) A very large number of studies have compared patients with AD to normal ageing with generally consistent results (Table II.4.17). Representative studies will be discussed here. Johnson et al. (1990) studied 58 patients who met NINCDS-ADRDA criteria for probable AD (McKhann et al. 1984), in comparison to 15 control subjects and found that qualitative ratings of SPECT scans had high sensitivity and specificity. When only mildly demented patients (defined as those with scores of 10 or less on the Blessed Dementia Scale (Blessed et al. 1968)) were included, the sensitivity fell to 0.80. In another study by this group that compared 29 AD patients with 78 controls and used a quantitative method, sensitivity and specificity were 0.91 and 0.86, respectively (Johnson et al. 1993). A number of studies used quantitative ratios of radioactive counts with an ROC curve approach. These studies have the limitation that the ROC cut-off values were chosen post hoc. Eberling et al. (1992) studied 50 patients with probable or possible AD and 14 controls. Using an ROC curve approach with a semiquantitative ratio method of data analysis, they found that a cut-off of temporal cortex : rCBF ratio 88% below that of controls classified AD patients with a sensitivityof 0.82 and a specificity of 0.93. A higher sensitivity (0.86) could be achieved with a slightly higher cut-off of 93% of control values, but at a price of a reduced specificity (0.79). The study reported by Claus et al. (1994) recruited AD patients from a dementia clinic and controls from a community sample in Rotterdam. Using ROC curves and defining AD as a value less than 2 standard deviations below controls, the authors found a sensitivity of 0.63 and a specificity of 0.87 for temporal lobe perfusion. When specificity was set

166 CHAPTER II.4

Table II.4.17 Clinical seriesaAD vs. controls. Reference

Sample

Diagnoses

Imaging/analysis/pattern

Clinical criteria

Prospective?

Sens

Spec

PPV

NPV

LR+

Class

0.96

0.65

6.8

1b

Johnson et al. (1990)

73

58 AD 15 Controls

SPECT Rater Parietal

NINCDS-ADRDA

Prospective

0.88

0.87

Eberling et al. (1992)

64

50 AD 14 controls

SPECT Quantitative/ROC Temporal or parietal

NINCDS-ADRDA

Prospective

0.86

0.79

4.1

2b

108

48 AD 60 controls

SPECT Quantitative/ROC Temporal

NINCDS-ADRDA

Prospective

0.63

0.87

4.8

2a

VanGool et al. (1994)

86

68 AD 18 controls

SPECT Quantitative/ROC Temporoparietal

DSM-II-R and NINDS

Retrospective

0.43

0.89

3.9

2a

Minoshima et al. (1995)

59

37 AD 22 controls

PET Quantitative, z-score, ROC Parietal

NINCDS-ADRDA

Retrospective

0.95

1

Scheltens et al. (1997)

51

10 AD 19 controls 22 ‘minimal dementia’

SPECT Quantitative/ROC Temporoparietal

DSM-III-R

Prospective

0.3

0.78

Claus et al. (1994)

2b

1.4

2a

AD, Alzheimer’s disease; CERAD, Consortium to Establish a Registry for Alzheimer’s disease; NPV, negative predictive value; LR+, positive likelihood ratio; PET, positron emission tomography; PPV, positive predictive value; ROC, receiver-operating characteristic; Sens, sensitivity; Spec, specificity; SPECT, single photon emission computed tomography.

DIAGNOSIS OF A DEMENTIA SUBTYPE 167

at 0.9, sensitivity was 0.56 in moderately demented patients and 0.79 for severely demented patients. Scheltens et al. (1997) also selected subjects from a community sample. They studied a group of 41 clinically normal subjects, 22 of whom were actually classified as having ‘minimal dementia’, and 10 patients with probable AD. ROC curve analysis resulted in a very low sensitivity in separating AD patients and controls. While this study had a great advantage in selecting subjects from a community sample, the inclusion of minimal dementia patients in the normal group limits the interpretation of the data. Van Gool et al. (1995) selected 68 cases of probable AD from 120 patients presenting to a memory clinic. These patients were compared with a group of 18 controls. Using ROC analysis, they also found relatively low sensitivity for AD which was considerably poorer for older rather than younger patients. Notably, this study was biased by the fact that the investigators incorporated SPECT results in the final clinical diagnosis. Minoshima et al. (1995) studied 37 AD patients and 22 normal controls with PET using an automated method of stereotaxic surface projection and calculating Z scores for the AD patients relative to the controls. Although the study was retrospective and used a series of cut-offs that were defined post hoc, very high sensitivities and specificities were found for parietal cortex metabolism.

Clinically validated samples of AD vs. other dementias (Table II.4.18) As noted in the introductory section of this chapter, studies that compare AD to other dementias are important but may be severely limited by diagnostic accuracy when not validated pathologically. Many non-Alzheimer dementias, notably VaD and dementia related to Parkinson’s disease, may be associated with the neuropathology of AD (Boller et al. 1980; Jellinger et al. 1990), so that the issue of ‘differential diagnosis’ of these dementias may not be the appropriate question to ask. Because of this, only studies that have neuropathological validation can truly differentiate all of these types of dementias. Relatively few studies have used SPECT imaging

to evaluate substantial sample sizes using a prospective approach in unselected subjects. Holman et al. (1992) studied 132 consecutive patients referred to a nuclear medicine department with cognitive complaints. They visually rated scan patterns, and compared their interpretations to the clinical diagnosis obtained an average of 10 months later. Despite an unselected sample the study was nevertheless biased because only 113 of the initial group of subjects ultimately received a diagnosis and 14 cases were excluded because they were diagnostic dilemmas. False positives were generally accounted for by patients with Parkinson’s disease and dementia and VaD. Bergman et al. (1997) studied a group of 58 AD patients, 20 controls, 17 patients with VaD and 25 patients with cognitive impairment not meeting criteria for dementia who presented to a memory disorders clinic. Results varied depending on the pattern that was chosen as diagnostic for AD. When any temporoparietal hypoperfusion (unilateral or bilateral with or without additional findings) was chosen, sensitivity and specificity were 0.55 and 0.65, respectively. However, when only bilateral temporoparietal hypoperfusion was chosen, sensitivity was 0.21 and specificity was 0.80. In another study, Talbot et al. (1998) prospectively enrolled 363 dementia patients and imaged them with SPECT at the time of presentation. Clinical diagnoses were established over the ensuing 1–6 years, and the five most common diagnosesaAD, VaD, LBD, FTD and progressive aphasiaawere compared, with a relatively low sensitivity for AD but good specificity. The authors found that bilateral posterior hypoperfusion significantly increased the odds of AD in comparison to VaD or FTD, each with a LR of over 4. The authors noted that the utility of this technique is highly related to the particular diseases being compared, with AD vs. FTD and VaD the most useful comparison. Salmon et al. (1994) studied CMRglc with PET prospectively in 129 dementia patients and compared patterns of metabolism to clinical diagnosis. They found a sensitivity of 0.94 and a specificity of 0.53 for patterns that included temporoparietal hypometabolism, even if frontal involvement was more severe. Limiting interpretation of a ‘positive’ PET scan to scans that showed only bilateral tem-

Table II.4.18 Clinical seriesaAD vs. other dementias. Sample

Diagnoses

Imaging/analysis/pattern

Clinical criteria

Prospective?

Sens

Spec

PPV

NPV

LR+

Class

Holman et al. (1992)

113

52 AD 11 vascular 11 Parkinson’s 14 HIV dementia 2 FTD 23 other

SPECT Rater Bi-or unilateral temporoparietal

NINCDS-ADRDA

Prospective

0.81

0.75

0.74

0.82

3.2

1b

Powers et al. (1992)

39

13 AD 11 controls 15 Parkinson’s

PET Rater Bilateral temporoparietal

NINCDS-ADRDA

Retrospective

0.38

0.88

3.1

2b

Salmon et al. (1994)

129

65 AD 19 atypical (includes FTD) 13 Parkinson’s 1 PSP 8 vascular 9 mixed 4 depression 10 other

PET Rater Bilateral temporoparietal

NINCDS-ADRDA

Prospective

0.66

0.68

0.65

0.66

2.1

1a

Bergman et al. (1997)

120

58 AD 20 controls 17 vascular 25 cognitive impairment

SPECT Rater Uni-or bilateral temporoparietal

NINCDS-ADRDA

Prospective

0.55

0.65

0.58

0.6

1.6

1a

Lavenu et al. (1997)

125

77 AD 29 FTD 10 DLB 5 vascular 4 other

SPECT Rater Uni or bilateral temporoparietal

NINCDS-ADRDA

Retrospective

0.66

0.64

0.75

0.54

1.8

2a

Talbot et al. (1998)

314

132 AD 24 DLB 78 vascular 58 FTD 22 primary progressive aphasia

SPECT Rater Bilateral posterior

NINCDS-ADRDA

Prospective

0.45

0.86

0.7

0.68

3.2

1a

AD, Alzheimer’s disease; CERAD, Consortium to Establish a Registry for Alzheimer’s Disease; DLB, dementia with Lewy bodies; FTD, frontotemporal dementia; NPV, negative predictive value; LR+, likelihood ratio; PET, positron emission tomography, PPV, positive predictive value; Sens, sensitivity; Spec, specificity; SPECT, single photon emission computed tomography.

168 CHAPTER II.4

Reference

DIAGNOSIS OF A DEMENTIA SUBTYPE 169

poroparietal hypometabolism lowered sensitivity to 0.66 and raised specificity to 0.68. In addition to the usual problems associated with clinical diagnoses, this study contained a group of 19 patients with features felt to be atypical for AD. While many of these subjects probably had FTD (three were autopsy confirmed), diagnoses were uncertain in many. A large number of studies have compared clinically diagnosed patients with one another using a retrospective approach. Lavenu et al. (1997) studied patients with probable and possible AD in comparison to patients with a host of other disorders including FTD, DLB and VaD. Although they used both SPECT imaging and CT measures of medial temporal lobe thickness, independent data for SPECT were presented to permit derivation of sensitivity and specificity. Powers et al. (1992) studied 13 patients with probable AD, 11 controls and 15 patients with Parkinson’s disease using PET and 15 O water to measure rCBF. Scans were rated as positive for AD based on the presence of bilateral temporoparietal hypoperfusion. Sensitivity for AD was low.

Conclusions The optimal study of functional neuroimaging as a diagnostic test is a prospective study, enrolling an unbiased sample with regard to clinical presentation, and following all subjects to autopsy. This study has clearly not yet been done. However, the work reported by Jobst et al. (1998) and Bonte et al. (1997) comes closest. Although these samples probably suffer from some selection bias, they were acquired prospectively and validated. Sensitivity, specificity and positive and negative predictive values would seem to support the diagnostic utility of the technique. However, it is important to note that the figures reported for sensitivity and specificity are in the same range as those reported for clinical diagnoses in a recent large multicenter study (Mayeux et al. 1998). The likelihood ratios in these autopsy-validated studies are in the order of 2, which suggests that these modalities, in most clinical situations, will have minimal diagnostic impact. Interestingly, the LRs reported for SPECT and PET are in the same range as those reported

for clinical diagnosis vs. autopsy elsewhere in this volume. Although considerably more data are available in considering non-autopsy-validated studies, the conclusions are not very different. Most such studies show results for sensitivity, specificity and positive likelihood ratios in the range of clinical diagnoses. In general, studies with particularly poor diagnostic performance tend to be biased by the inclusion of patient groups that might overlap with AD pathologically, and studies showing particularly good diagnostic performance tend to be biased by high prior probability of AD. It is apparent from a review of Tables II.4.16–18 that studies that compare AD patients to controls generally show the highest LRs ratios (in the order of 4). However, studies comparing AD patients to other dementias show LRs in the range of 2–3asimilar to the autopsy-validated studies. Again, the results that are most likely to relate to clinical practice suggest that SPECT and PET imaging are not likely to be useful in most situations.

Recommendations for practice and research Despite these empirical findings, SPECT and PET have been suggested to be useful in the diagnosis of AD by the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology (AAN) (American Academy of Neurology 1996), which rated the use of SPECT as ‘established’ based on class II evidence. The Quality Standards Subcommittee of the AAN (1994) listed PET and SPECT as optional parts of the diagnostic evaluation of the demented patient. The data presented in this review do not address the question of precisely which situations may be most useful for these investigations. Thus, while an overall LR of 2 is not often helpful, there may be specific situations in which SPECT or PET imaging could be very valuable. Several studies suggest that the most useful clinical distinction is between AD and FTD. For example, a PET FDG scan of a patient with FTD is shown in Plate II.2, facing p. 154, clearly demonstrating a pattern of hypometabolism that is quite different from that seen in AD (see Plate II.1,

170 CHAPTER II.4

facing p. 154). While such images support the diagnostic utility of PET or SPECT in this situation, prospective studies with postmortem diagnostic confirmation are relatively lacking. Other dementia differentiations, such as AD vs. DLB or AD vs. ischemic vascular dementia (IVD) are not as clear. An area of great potential interest is the use of these techniques in the presymptomatic detection of patients with AD. However, very mild or early AD, from these studies, may be associated with normal scans and such studies generally show lower LRs than studies of more demented subjects. Longitudinal evaluation of mildly impaired patients will be necessary to answer this question.

II.4.9

Future research on the issue of the utility of these techniques should be aimed at several specific questions: 1 What is the utility of SPECT or PET when used sequentially, along with the clinical diagnosis? Specifically, what sort of incremental information, over and above that achieved with clinical evaluation, do these techniques add? 2 Which are the specific diagnoses most likely to be differentiated with SPECT or PET? 3 How useful is SPECT or PET in early cases of dementia or in patients with presymptomatic AD? Can these techniques be used to increase the probability that such individuals have AD?

EEG as a Diagnostic Tool in Dementia

Hilkka Soininen and Juhani Partanen

In the differential diagnosis of dementia, clinical symptoms and signs, together with findings in CT or MRI scans, are often clear enough to suggest the right diagnosis. However, there are some important clinical settings where further tools such as electroencephalogram (EEG) (Table II.4.19) may be helpful, for example in differentiating: (i) early Alzheimer’s disease (AD) from normal ageing; (ii) early AD from depression; and (iii) AD from other causes of dementia such as frontotemporal dementia (FTD) or Creutzfeldt–Jakob disease (CJD). EEG has also been used as an aid to predict the prognosis of AD as well as to monitor the effects of drug treatment. The questions posed in this chapter are: ‘What is the utility of EEG to differentiate AD from normal ageing, and AD from other causes of dementia?’.

Background The EEG is usually recorded with scalp electrodes using the international 10/20 system. A scalp EEG primarily reflects cortical electrical activity, but there is a decrease in amplitude (more for high than low frequency components) and some smearing of the spatial sources of the electrocorticogram due to overlying structures with different impedances (e.g. cerebrospinal fluid, dura, bone, skin). The

EEG consists of electric transients, or potentials, which are mainly summed postsynaptic potentials of cortical pyramidal neurones. These transients summate when they are evoked in sufficiently large quantities with certain time, space and orientation characteristics. Spontaneous EEG rhythms, alpha (8–12 Hz), beta (> 12 Hz) and theta (4–7 Hz), as well as sleep spindles, have their principal origin in the thalamus, from which the rhythms are transferred to the cortex via thalamocortical loops (Steriade et al. 1990). Diffuse slow waves may be triggered either from the thalamus or from the cortex, while focal slow waves are usually associated with local involvement of the white matter (Gloor et al. 1977). Evoked potentials and eventrelated potentials are triggered by external stimuli or events; they are usually averaged for analysis. EEG reactions may also be studied in the form of desynchronization and synchronization responses (Pfurtscheller & Ananibar 1977; Pfurtscheller 1992). In clinical practice, a paper EEG tracing is visually inspected and the basic phenomena and possible alterations are described. Spectral analysis of the EEG may be performed after transformation of the EEG from time domain to frequency domain using, for example, the fast Fourier method (Penttilä et al. 1985). Thus the exact amplitude or power

DIAGNOSIS OF A DEMENTIA SUBTYPE 171

Table II.4.19 EEG methods in used in the differential diagnosis of AD. Paper EEG Power spectral analysis of EEG Brain mapping Functional studies Coherence analysis Microstates Sleep EEG (stage of sleep should be specified)

values of different frequency bands of EEG may be determined. Spatial information of any of these variables may be expressed in the form of a brain map, for example the distribution of alpha amplitude over the scalp. Functional studies may compare alpha activity in a relaxed awake state with eyes closed (EC) to an active looking state with eyes open (EO), which may be expressed as the EC : EO ratio (Könönen & Partanen 1993). EEG coherence describes the similarity of electric function between two or more cortical sites; 0 means no coherence and 1 means exactly similar function (Leuchter et al. 1987). Disruption of deep or cortical pathways may decrease the coherence value between two sites that normally work in concert. Sleep EEG may reveal alterations not seen in the awake state. For example rapid eye movement (REM) sleep may reveal increased slowing of temporal EEG in AD compared to healthy individuals (Petit et al. 1992). Modern techniques allow coregistration in an individual subject of given electric sources directly to their MRI scans (Gevins et al. 1999), thereby improving physiological and structural correlations. A variety of sophisticated methods greatly enhance the information available in the EEG.

AD vs. normal ageing Search strategy and study validation Numerous studies using visual assessment and later spectral power analysis and brain mapping have shown that there is slowing of the EEG in AD. Only one prospective autopsy study met strict criteria for a Class IB study (Soininen et al. 1992), by virtue of independence between the EEG diagnosis and the clinicopathological diagnosis. However, 15

studies on EEG findings of dementia fulfil class 1 criteria as they used clinical diagnoses as the reference standard. Three employed visual analysis (Rae-Grant et al. 1987; Soininen et al. 1992; Robinson et al. 1994) and 12 used spectral analysis (Brenner et al. 1986, 1989; Leuchter et al. 1987, 1993; Breslau et al. 1989; Soininen et al. 1989; Coben et al. 1990; Szelies et al. 1992; Pritchard et al. 1994; Jelic et al. 1996; Hassainia et al. 1997; Strijers et al. 1997). Moreover, there are four class 1 studies using assessment of quantitative tonic REM EEG (Petit et al. 1992, 1993; Moe et al. 1993; Hassainia et al. 1997). Many otherwise excellent studies were excluded because, while demonstrating significant differences in between group comparisons, they do not provide quantitative data for the calculation of sensitivity and specificity. Other studies were excluded because they lacked assurance that the EEG analyses were conducted independent of clinical information. Although not considered grounds for exclusion, intraobserver reliability and test–retest data were seldom given.

Evidence The degree of slowing of the EEG correlates with the severity of cognitive decline in AD (Penttilä et al. 1985). Therefore, higher sensitivity is expected in more severely demented cases. Furthermore, it is important to note that the usefulness of EEG parameters change with increasing severity of dementia (e.g. theta may be the important parameter early on, while delta becomes more important later) (Coben et al. 1985). Coben et al. (1990) studied quantitative EEG (QEEG) in AD patients with mild dementia vs. controls. Using percentage theta activity as the diagnostic criterion, sensitivity was 24% and specificity was 100%. Another study using QEEG to distinguish patients with mild to moderate AD from normal elderly subjects (Soininen et al. 1989) also found only modest sensitivity (50%), but high specificity (100%). In a population-based cohort, visual EEG resulted in a sensitivity of 67% and specificity of 84% (positive likelihood ratio, LR+ = 4.2) and QEEG in a sensitivity ranging from 67 to 44% with a specificity of 88% (LR+ = 2–3)(Strijers et al. 1997). Based on these studies, we conclude that low sensitivity restricts the use-

172 CHAPTER II.4

fulness of QEEG in early AD. In contrast, most AD patients in more advanced stages of dementia have abnormal EEGs, but at this stage the clinical diagnosis is also less in doubt. In a study of 26 patients with definite AD for whom the diagnosis was confirmed neuropathologically, 25 of 26 (96%) had an abnormal EEG (Soininen et al. 1992). The severity of the disease at the time of the EEG recording was moderate to severe. There have been several attempts to improve sensitivity and specificity of EEG as a diagnostic tool using neural net data analysis, coherence measures and sleep EEG studies. Neural net analysis does not significantly improve discriminative power (Pritchard et al. 1994). There are no data showing that coherence analysis when used alone improves sensitivity and specificity to distinguish AD patients and controls (Leuchter et al. 1987). A study by Jelic et al. (1996) suggests that a combination of temporoparietal coherence, together with alpha and theta relative power, resulted in a sensitivity of 78% and specificity of 100% to separate mild to moderate AD patients from controls. More promising results have been obtained by sleep EEG studies. Slowing of the EEG in temporal areas during REM sleep is accentuated in AD patients compared with controls (Petit et al. 1992, 1993; Moe et al. 1993; Hassainia et al. 1997). Discriminant analysis, using a ratio of slow over fast frequencies, yielded a classification rate of 90.4% (sensitivity 81.5%, specificity 100%) for REM sleep and for wakefulness the same measure resulted in correct classification of 80.8% of the AD patients and control subjects (sensitivity 66.7%, specificity 96%) (Hassainia et al. 1997). While these results are promising, they require confirmation in a prospectively designed study. Sleep recordings may not be feasible in common clinical practice.

Recommendations for practice The value of EEG in distinguishing mild AD from normal ageing is limited by low sensitivity. EEG may be of help in separating dementia from depression and AD from FTD, but additional studies are needed. Of the more sophisticated techniques, QEEG analysis during REM sleep showing EEG slowing in temporoparietal regions appears to be

the most promising. At the early stage of AD conventional EEG or QEEG does not add to information of a good neuropsychological exam.

Vascular dementia Evidence There were two class 2b studies in vascular dementia (VaD) (Soininen et al. 1982b; Robinson et al. 1994). One study showed 91% sensitivity and 71% specificity to separate VaD patients from controls (Soininen et al. 1982b). The AD patients and VaD patients could not be reliably differentiated from each other, although asymmetries were more common in VaD patients. It is noteworthy that the patients in this study had moderate to severe dementia. Robinson et al. (1994) reported conventional EEG findings in 86 patients with AD, 17 patients with mixed AD and multi-infarct dementia vs. 56 control subjects. They found a sensitivity of 87% for AD and 77% for the mixed group (vs. controls) while the specificity was 65% (LR+ = 2.5 for AD; LR+ = 2.2 for the mixed group). Attempts have been made to use measures of EEG coherence to differentiate AD from VaD (Leuchter et al. 1992). These investigators postulate predominant dysfunction of the long cortical tracts in AD and of the short regional connections involving deep thalamic loops in VaD. Using criteria based on interregional differences in coherence, 76% of the demented subjects were correctly classified. However, sensitivity and specificity cannot be calculated on the basis of the data provided.

Recommendations for practice Based on the evidence, EEG cannot be recommended as a reliable method to diagnose VaD.

FTD or frontal lobe dementia Evidence Previous studies have suggested that normal EEGs are found in FTD. There are two class 2b studies of EEGs in FTD. The study by Yener et al. (1996)

DIAGNOSIS OF A DEMENTIA SUBTYPE 173

reported QEEG findings in 26 AD, 13 FTD and 27 healthy control subjects. Using five QEEG measures with stepwise discriminant function analysis, AD was correctly separated from FTD groups; each were separated with 84.6% accuracy, and in another analysis controls were distinguished from the FTD group with 84.6% accuracy. The relative power from the temporal region in the beta-2 band, and from the parietal region in the theta and alpha and beta-2 bands were the best discriminators between AD and FTD. Sensitivity, specificity and LR could not be calculated from the data provided. Forstl et al. (1996) investigated QEEG in 10 patients with frontal lobe dementia (FLD), 10 patients with AD and 10 control subjects. The FLD patients had no pathological changes in EEG compared with controls. The AD patients and FLD patients were distinguished with a sensitivity of 70% and specificity of 90%. The AD patients had significantly more theta and delta bands than FLD patients, but in coherence there was no difference between these groups.

Recommendations for practice The EEG is often normal in FLD, but evidence derives from studies with small sample sizes.

Creutzfeldt–Jakob disease Evidence The EEG is generally considered a useful tool for the diagnosis of CJD. In a retrospective study (Class II), Bortone et al. (1994) reviewed a series of 15 CJD patients, observed in the period 1975–91. In 12 cases the diagnosis of CJD was confirmed on postmortem examination. All patients showed periodic sharp wave complexes (Fig. II.4.9). They concluded that the EEG can give essential information for the diagnosis of CJD if serial recordings are performed in different stages of the disease, and if not only the presence of periodic sharp wave complexes is considered, but also the reactivity of EEG to dynamic events such as the response

Fp2-T4 T4-O2 Fp2-C4 C4-O2 Fp1- T3 T3-O1 Fp1-C3 C3-O1 F8-Fz T4-Cz T6-Pz F7-Fz 50 mV Fig. II.4.9 An EEG with generalized

periodic complexes (about 1 Hz) in a women aged 71 years with CJD.

T3-Cz T5-Pz

1S

174 CHAPTER II.4

to external stimuli and drugs, and the level of consciousness. Another retrospective study (Steinhoff et al. 1996) assessed the sensitivity, specificity and interobserver reliability of periodic sharp wave complexes in the EEGs of patients with CJD. Sixty-eight EEGs in 29 patients with suspected CJD were analysed by two investigators: 15 patients had CJD and 14 had other rapidly progressive dementias. For periodic sharp wave complexes, blinded analysis resulted in a sensitivity and a specificity of 67% and 86%, respectively. No normal controls were included in this study. Interobserver reliability was excellent (kappa = 0.95).

Recommendations for practice CJD is a rare disorder with a rapidly fatal course. Although evidence is based on small series of patients, use of the EEG is feasible in clinical practice and the presence of periodic sharp wave complexes together with a typical clinical picture supports the diagnosis of CJD.

Dementia with Lewy bodies Evidence There were only a few reports of EEG in dementia with Lewy bodies (DLB) and none provide Class 1 or class 2 evidence of EEG changes in LBD. A retrospective study by Briel et al. (1999) reported that 17 of 19 (89%) EEG recordings were abnormal among patients with DLB confirmed at autopsy. The severity of dementia in these patients ranged from 0.5 to 2.0 on the Clinical Dementia Rating (CDR) scale. The DLB patients had even more disturbed EEGs and more temporal slow wave transients (50% vs. 18%) than 11 AD patients with a severity of 0.5–3.0 on the CDR scale. However, no control group was included in this study and no LR could be calculated.

Recommendations for practice No class 1 or class 2 data currently support the use of EEG for the diagnosis of DLB.

Depression Evidence Previous studies have suggested that EEGs could be used to separate AD from depression in which the EEG is usually normal. Brenner et al. (1989) studied 35 patients with mixed symptoms of depression and dementia, 10 patients with depressive pseudodementia, 35 patients with AD and 61 controls. They found that in mixed depression and depression alone, the EEG was more often normal, while among patients with AD or patients with mixed dementia and depression, the EEG was often abnormal. In another study, tonic REM sleep epochs from the all-night sleep EEG were investigated in 24 patients with major depression and the findings were

Table II.4.20 EEG findings in the differential diagnosis of

dementia. Class 1 evidence AD vs. normal aging Visual EEG: slowing of dominant occipital rhythm, increase in slow waves QEEG: increase of delta and theta power, decrease of alpha power, slowing of the mean and peak frequency Decreased temporoparietal coherence Accentuation of EEG slowing in temporoparietal regions in REM sleep Decreased EC : EO response Vascular dementia vs. AD Slowing of the EEG as in AD More asymmetric findings than in AD Decreased coherence Frontotemporal dementia vs. AD Normal EEG in FTD Depression vs. AD More often normal EEG in depression and depressive pseudodementia than in AD and AD with depressive symptoms Class 2 evidence DLB vs. AD More often abnormal EEG in DLB than in AD Class 3–4 evidence CJD vs. AD Presence of periodic sharp wave complexes

DIAGNOSIS OF A DEMENTIA SUBTYPE 175

compared to those obtained in 35 patients with AD and 43 control subjects (Moe et al. 1993). Diagnostic scores correctly identified 88% of patients with major depressive disorder, 89% of mild AD subjects and 100% of control subjects. The diagnostic discrimination of AD is based on the fact that AD subjects have significantly less tonic REM EEG energy in the 13–30 Hz frequency range and more in the 1–10 Hz range than control or depressed subjects. No LR could be calculated from this study.

Recommendations Although some data are promising, there are currently no class 1 or class 2 studies that support the use of EEG to differentiate depression from AD and additional studies are needed.

II.4.10

Conclusions The value of EEG in distinguishing mild AD from normal ageing is limited by low sensitivity. EEGs may be of help in separating dementia from depression and AD from FTD, but additional studies are needed. Of the more sophisticated techniques, QEEG analysis during REM sleep showing EEG slowing in temporoparietal regions appears to be the most promising. More high quality studies meeting class I or II criteria, or even class 1 or class 2 criteria, are still needed. Whether various stimulation conditions such as eyes open vs. eyes closed will improve diagnostic accuracy in early AD awaits confirmation. Table II.4.20 summarizes useful EEG findings in diagnosing different types of dementia.

Cerebrospinal Fluid Biomarkers

Kaj Blennow and Anders Wallin Background

Alzheimer’s disease (AD) is the major cause of dementia in the western world. Although hereditary forms of AD exist, the majority of AD patients have no obvious family history of AD and their disease is classified as sporadic AD. Today, several acetylcholine esterase inhibitors which may have beneficial effects on the AD symptomatology have been licensed for the treatment of AD. Drugs that may also have effects on the disease process (e.g. anti-inflammatory compounds and drugs affecting amyloid β protein (Aβ) aggregation) are currently being tested or are under development. When these types of drugs reach the clinical phase, accurate identification of AD patients will be critical. Today, the clinical diagnosis of AD is largely based on the exclusion of other dementing illnesses. A relatively high accuracy rate with regard to the clinical diagnosis of AD (80–90%) has been reported (Tierney et al. 1988; Galasko et al. 1994; Jellinger 1996). However, these reports emanate

from expert research academic centers and are often based on patients in the later stages of the disease who were followed for some years up to the confirming autopsy. The diagnostic accuracy rate is probably considerably lower in general hospitals and in the earlier stages of the disease when the symptoms are often silent or indistinct and clinical diagnosis is more difficult (see Chapter II.4 for review). This is unfortunate, as pharmaceutical therapy is probably most effective early in the course of disease, before the degenerative processes have gone too far. Thus, there is a great need for biochemical diagnostic markers (biomarkers) that could aid in the diagnosis of AD early in the course of the disease. During the last few years, cerebrospinal fluid (CSF) biomarkers for AD have gained increased attention. As the molecular pathogenesis of AD is better known than those of other dementia disorders (e.g. frontotemporal dementia (FTD) and vascular dementia (VaD)), research and development of CSF biomarkers for dementia have focused on AD.

176 CHAPTER II.4

Fig. II.4.10 Schematic drawing of

a neurone adjacent to an astrocyte and a capillary. Also shown are neurofibrillary tangles within the cytoplasm of the neurone and two senile plaques in the vicinity of the neuronal processes. Three cerebrospinal fluid (CSF) biomarkers and the pathogenic changes they reflect are indicated.

In this chapter, we review the two CSF biomarkers that have been most extensively studied by different research centers and have proved to have the highest clinical diagnostic potential, i.e. CSF-tau and CSF-Aβ42 (Fig. II.4.10). We do not review CSF markers with inconclusive test results (e.g. CSF-neurone-specific enolase and CSF-neuronal thread proteins).

Rationale for the use of CSF biomarkers for AD A biomarker for AD should have a direct relation to the central pathogenic processes of the disease. AD is characterized by neuronal and synaptic degeneration and an increased number of senile plaques (SP) and neurofibrillary tangles (NFT) compared with the number found in non-demented individuals. SP are basically composed of a central core of aggregated Aβ (Masters et al. 1985), which is a breakdown product from amyloid precursor protein (APP) (Kang et al. 1987). NFT are proteinaceous intracellular thread-like structures made up of a phosphorylated form of the microtubuleassociated protein tau, called phosphotau (Goedert 1993). The CSF is directly connected with the extracellular space of the brain. Thus, it is likely that biochemical changes in the brain are reflected in the CSF. Since AD pathology is restricted to the brain, the CSF is the obvious source of biomarkers for AD.

Clinical factors affecting the evaluation of CSF biomarkers for AD The sensitivity (i.e. the ability to identify true AD cases) and the specificity (i.e. the ability to differentiate AD from other dementias and normal ageing) should be above 80% for a useful CSF biomarker for AD (Consensus Report of the Working Group on Molecular and Biochemical Markers of Alzheimer’s Disease 1998). However, there are some factors that may render difficult the evaluation of the sensitivity and specificity of a CSF biomarker for AD. First, accurate autopsy-confirmed ‘gold’ standard diagnoses are needed to calibrate the accuracy of CSF biomarkers for AD, but this need is hardly met. New potential CSF biomarkers for AD are almost always evaluated on clinically diagnosed patients (class 1 or class 2 evidence). Although the positive predictive value (i.e. the probability that AD is present when the diagnostic criteria are met) has been relatively highaabout 85%athe negative predictive value (i.e. the probability that AD is not present when the diagnostic criteria are not met) has been considerably lower (Tierney et al. 1988; Galasko et al. 1994; Jellinger 1996) as the clinical diagnostic criteria for non-AD dementias (e.g. VaD and FTD) are less well established and have been less validated than those for AD. Neuropathological studies have also found that a high proportion (40–80%) of clinically diagnosed patients with VaD have notable concomitant AD pathology

DIAGNOSIS OF A DEMENTIA SUBTYPE 177

(Jellinger 1996; Kosunen et al. 1996). Thus, the current criteria for the clinical diagnosis of AD and other dementia disorders cannot be considered to be of ‘gold’ standard quality. Second, even if they are asymptomatic, age-matched control subjects may harbour presymptomatic AD lesions in their brains (Tomlinson & Henderson 1976; Davies et al. 1988; Price & Morris 1999), which reduces the specificity of the biochemical markers. For both of these reasons, it is difficult to get high sensitivity and specificity figures for CSF biomarkers.

Search strategy and study validation Medline searches were conducted using the key words: CSF and Alzheimer, CSF and tau, and CSF and amyloid. Most studies on CSF biomarkers have used clinical classification as the gold standard for comparison (class 1 or class 2 evidence); very few, if any, have used autopsy-confirmed diagnoses. The studies were most often performed on stored CSF samples from previously diagnosed patients and controls. Only two studies have examined the sensitivity and specificity of CSF-tau (Andreasen et al. 1999b) or the combination of CSF-tau and CSF-Aβ42 (Andreasen et al. 2001) in routine clinical practice, with the CSF samples being continuously analysed in a clinical neurochemistry laboratory.

Evidence CSF-tau protein Tau is a microtubule-associated protein located in the neuronal axons, and hyperphosphorylated tau is the main component of the NFT (Goedert 1993). There are six different isoforms of tau and several phosphorylation sites in the human brain (Goedert 1993). Current ELISA assays for CSF-tau use antibodies that detect all isoforms of tau, regardless of their phosphorylation states, and thus measure the ‘total’ CSF-tau level. The marked increase in CSF-tau in severe degenerative disorders, such as Creutzfeldt–Jakob disease (CJD) (Otto et al. 1997), as well as the transient increase in acute destructive disorders, such as stroke (Arai et al. 1995), suggests that the level of CSF-tau reflects the degree of neuronal/axonal degeneration, regardless of cause.

CSF-tau in AD An increase in CSF-(total)tau in AD has been recorded in numerous studies (for review see, for example, Andreasen et al. 1998; Galasko et al. 1998). The ability of CSF-tau to discriminate between AD and normal ageing was relatively good, above 80%, in most studies (Table II.4.21). The magnitude of the figures seems to depend mainly on the control populations and cut-off levels used. Thus, the figure was usually higher with healthy controls than with a control sample consisting of patients with mild psychiatric/neurological disorders, and higher cut-off levels usually resulted in lower sensitivity and higher specificity and vice versa. The increase in CSF-tau in AD is also found in the earlier stages of dementia (Blennow et al. 1995; Motter et al. 1995; Riemenschneider et al. 1996; Galasko et al. 1997; Andreasen et al. 1998; Kurz et al. 1998; Andreasen et al. 1999c). Thus, determination of CSF-tau may aid in the clinical diagnosis of AD early in the course of the disease, especially in differentiating AD from normal ageing and depression. This may make it easier to diagnose AD and start treatment early in the course of the disease. CSF-tau in non-AD conditions The fact that an increase in CSF-tau can be found in a variety of chronic degenerative disorders, such as CJD, and in acute destructive conditions, such as stroke, detracts from the specificity of CSF-tau. However, this does not really reduce the clinical usefulness of CSF-tau, since these disorders can usually be clinically distinguished from AD. It is more problematic that high CSF-tau levels are found in a proportion of cases of other dementias. This applies particularly to VaD, in which high CSF-tau levels have been found in a relatively high proportion of cases by some studies (Blennow et al. 1995; Andreasen et al. 1998) and only in occasional cases by other studies (Mori et al. 1995; Tato et al. 1995; Arai et al. 1998; Mecocci et al. 1998; Nishimura et al. 1998; Hulstaert et al. 1999). This discrepancy may be due to differences in patient samples, e.g. between patients admitted to psychiatric/geriatric clinics and those admitted

178 CHAPTER II.4

Table II.4.21 Studies on the combination of CSF-tau and CSF-Aβ42 as diagnostic biomarkers for AD. Disorder

No.

Sensitivity

AD Controls OND including non-AD dementia

82 60 74

90%

AD Controls OND including non-AD dementia

93 54 89

40%

AD Controls OND Non-AD dementia

150 100 84 79

85%

AD MCI Controls Depression Non-AD dementia

105 20 100 5 32

94% 75%

Specificity

LR+

Type of study

Study

4.5 1.9

Multicenter study in US (6 centers) Clinically diagnosed patients Archive CSF samples

Galasko et al. (1998)

80% 39–65%

4.0 4.0

Multicenter study in Japan (3 centers) Clinically diagnosed patients Archive CSF samples

Kanai et al. (1998)

90% 90%

6.5 6.1 2.0

International multicenter study (10 centers) Clinically diagnosed patients Archive CSF samples CSF analyses run at each research center

Hulstaert et al. (1999)

87% 86% 58%

Prospective, community-based study Clinically diagnosed patients CSF samples run continuously in routine clinical neurochemistry

Andreasen et al. (2001)

87% 100% 53%

7.2 high 2.0

AD, Alzheimer’s disease; CSF, cerebrospinal fluid; LR+, positive likelihood ratio; OND, other neurological disorders; MCI, mild cognitive impairment (these patients developed AD at follow-up).

to neurological clinics, and to differences in diagnostic criteria. The latter differences may result in patient samples with a varying proportion of patients with concomitant AD pathology. It has been suggested that VaD patients with high CSF-tau levels may constitute a subgroup with concomitant AD pathology (Andreasen et al. 1998), which implies that CSF-tau might be of use in identifying VaD cases where AD is a contributory factor to the dementia. In contrast, in patients with other types of dementia (e.g. alcoholic dementia), chronic neurological disorders (e.g. Parkinson’s disease, progressive supranuclear palsy) and psychiatric disorders (e.g. depression), elevated CSF-tau levels have been found only in occasional cases (Blennow et al. 1995; Molina et al. 1997; Ellis et al. 1998; Mitani et al. 1998; Morikawa et al. 1999; Urakami et al. 1999).

et al. 1992). However, both Aβ in AD brain tissue and secreted Aβ show heterogeneity at the N- and C-termini. The most common secreted form, Aβ40, ends at Val-40, while a longer form, Aβ42, which comprises about 10% of total Aβ, ends at Ala-42 (Vigo-Pelfrey et al. 1993). Aβ42 is the predominant form in both diffuse plaques and SP cores (for review see Dickson 1997). Current assays are specific to Aβ42, with minimal cross-reactivity against peptides ending at residues 43 or 40 (Motter et al. 1995; Vanderstichele et al. 1998). A similar decrease in Aβ42 is found in AD, regardless of whether Aβ1-42 or all N-terminally truncated peptides ending at residue 42 are measured (Tamaoka et al. 1997). Measurements of Aβ in the CSF have a potential for reflecting cerebral amyloid deposition. Hypothetically, secreted Aβ binds to aggregated Aβ in extracellular SP, with lower levels remaining in the CSF.

CSF-Aβ 42

CSF-Aβ42 in AD

Amyloid β is generated as a soluble peptide during normal cellular metabolism and is secreted into the extracellular space and biological fluids (Haass

A marked decrease in CSF-Aβ42 is found in a high percentage of patients with AD (Motter et al. 1995; Galasko et al. 1998; Andreasen et al. 1999a,

DIAGNOSIS OF A DEMENTIA SUBTYPE 179

2001; Hulstaert et al. 1999), resulting in a relatively good ability for CSF-Aβ42 to distinguish AD from normal ageing. However, the specificity of CSF-Aβ42 for the diagnosis of AD has been less extensively studied than for CSF-tau and has to be further evaluated.

Combination of CSF-tau and CSF-Aβ 42 The strategy of combining CSF-tau and CSF-Aβ42 as biomarkers for AD is appealing since the concentrations of these substances are believed to reflect two of the central pathogenic processes in the disorder, and the combination might thus result in increased sensitivity and specificity. Indeed, some large studies have shown that both sensitivity and specificity increase for the combination compared with CSF-tau or CSF-Aβ42 alone (Hulstaert et al. 1999; Andreasen et al. 1999c, 2001).

Recommendations for practice The major clinical usefulness of CSF-tau seems to be in the discrimination of AD from normal ageing. It might also be of some use in some other differential diagnoses (e.g. from depression, alcohol dementia and Parkinson’s disease). The major clinical usefulness of CSF-Aβ42 seems also to be in the discrimination of AD from normal ageing and some other differential diagnoses (e.g. depression and Parkinson’s disease). There are, however, relatively few studies examining the specificity of CSF-Aβ42 compared with a relatively large number of studies on the specificity of CSF-tau. There is also evidence that the combined use of CSF-tau and CSF-Aβ42 increases both the sensitivity and the specificity for the diagnosis of AD compared with either analysis used alone.

Conclusions and recommendations for research Much effort has focused on finding one single CSF biomarker for AD, but without success. The pathogenic specificity of the candidates leaves a great deal to be desired. For example, neuronal and synaptic degeneration is not only found in AD but also in most chronic degenerative disorders of the brain

(Masliah 1995). Similarly, Aβ deposition is not specific to AD but is also found in normal ageing, dementia pugilistica, Lewy body dementia and after acute brain trauma. Phosphorylation of tau is found in normal ageing, dementia pugilistica and progressive supranuclear palsy (Davies et al. 1988; Roberts et al. 1990b, 1994; Verny et al. 1994; McKenzie et al. 1996). Thus, since the neuropathological findings in AD are non-specific, there is little hope of ever finding a single biomarker for specific and absolute discrimination between AD and other dementia disorders. Instead, a combination assay of several CSF biomarkers may increase the sensitivity and specificity for AD (see Fig. II.4.6). Further, the accuracy of the clinical diagnosis of AD may increase if the diagnosis is based on combined information from the clinical examination, brain imaging (SPECT, CT/MRI scans) and biochemical markers. To draw a parallel, the clinical diagnosis of myocardial infarction is based on the combination of clinical symptomatology, electrocardiography and biomarkers (e.g. creatine kinase). Likewise, CSF biomarkers have potential as diagnostic aids in the most problematic differential diagnoses from AD, especially age-associated memory impairment, depressive pseudodementia, alcoholic dementia, Parkinson’s disease and VaD.

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II.5

Conclusions

Helena Chui

Three kinds of procedures form the cornerstones for the diagnosis of dementia: (i) medical history including assessment of functional activities; (ii) physical and neurological examination; and (iii) mental status examination. Agreement on this matter is found in both evidence-based guidelines published to datea by the Agency for Health Care Policy and Research (Costa et al. 1997) and the American Academy of Neurology (1994)aas well as many consensus documents. The indications for other diagnostic studies seem less clear and the decision is usually left to the judgement of the practitioner. The recent propagation of consensus statements seems to suggest that all is well in the diagnostic arena. Additional steps have been taken in this evidencebased review. The following query has been system-

atically addressed: ‘How good are the “tests” presently available to us’? The usefulness of specific symptoms, signs and tests have been evaluated using quantitative measures of test performance such as odds and likelihood ratios. Two subquestions were asked: ‘How useful is the test, first for the diagnosis of dementia (Table II.5.1) and, second, for the differential diagnosis of dementia subtype (Table II.5.2)’? An ideal test would offer a large positive likelihood ratio (LR) (i.e. > 10) that would generate large and often conclusive change in pre-test to post-test probability. This interdisciplinary evidence-based review shows only one category of tests reaching this standard. In general, the test LRs are small. Large LRs were discovered only for the mental

Table II.5.1 Reaching a diagnosis of dementia. LR 2–5 (small) Neuropsychology MMSE Buschke Memory Impairment Screen (four-word cued recall) Delayed Word Recall (10 words) CERAD Delayed Recall (10 words) Animal fluency Supermarket fluency Wisconsin Card Sort Activities of daily living Pfeffer ADL

5–10 (moderate)

> 10 (large)

8.4

37.0 22.0 44.5 11.3 14.3 19.0 and 23.0 10.0 and 13.4

4.5

ADL, activities of daily living; CERAD, Consortium to Establish a Registry for Alzheimer’s Disease; LR, Likelihood ratio; MMSE, Mini Mental Status Examination.

194

CONCLUSIONS 195

Table II.5.2 Diagnosis of dementia subtype. LR 2–5 (small) Clinical criteria (Class I and II) NINCDS-ADRDA: probable AD DSM-III: dementia of the Alzheimer type Hachinski Ischemic Score DSM-III: MID Consensus: DLB Lund and Manchester: FTD Neurological examination Behavioral features Neuropsychological evaluation (class 1 or 2) AD vs. other dementia AD vs. VaD AD vs. FTD ApoE4 for AD (Class II) Structural imaging (CT): (mostly class 1 or 2) AD vs. controls—ventricular size AD vs. controls—atrophy AD vs. other dementias—atrophy Structural imaging (MRI): medial temporal atrophy (only class 1 or 2) AD vs. normal ageing AD vs. non-AD Functional imaging: SPECT or PET (some Class I or II) Pathologically verified AD vs. non-AD Clinical AD vs. controls Clinical AD vs. non-AD Electroencephalography (mostly class 1 or 2) AD vs. normal ageing AD vs. VaD AD vs. FTD (n = 1) CJD (n = 1) CSF (only class 1 or 2) AD vs. controls

4.4 4.8 4.6

5–10 (moderate)

> 10 (large)

6.2–10.1 7.3–12.0

Not available Not available Odds ratios only Odds ratios available 1.4 and 2.0 2.8 2.1 2.3–3.8 8.2 (3–15) 6.8 (2.2–16.8) 1.4 (0.8–1.8)

10 6

2.2–3.2 1.4–6.8 1.8–3.2 2–4 2 7 4.8 4–7

AD, Alzheimer’s disease; ApoE4, apolipoprotein E4; CJD, Creutzfeldt–Jakob disease; CSF, cerebrospinal fluid; CT, computerized tomography; DLB, dementia with Lewy bodies; FTD, frontotemporal dementia; LR, likelihood ratio; MID, multi-infarct dementia; MRI, magnetic resonance imaging; PET, positron emission tomography; SPECT, single photon emission computerized tomography; VaD, vascular dementia.

status and neuropsychological examination for the purpose of making a diagnosis of the dementia syndrome. For the diagnosis of specific aetiological subtypes of dementia, great stake has been placed on consensus clinical criteria. Yet, clinicopathological correlations reveal relatively small LRs (magnitude 2–5). Such values will generate only small, but sometimes important, changes in proba-

bility. Thus, it appears that we are pretty good at making a diagnosis of dementia (telling that something is wrong), but not very good at determining its cause. For many tests used in the differential diagnosis of dementia, there are limited Class I or II autopsyconfirmed data. Based on available class 1 and 2 data, neuropsychological profiles, apolipoprotein

196 CHAPTER II.5

E genotype, structural and functional imaging, electroencecelopathy (EEG) and cerebrospinal fluid (CSF) studies do not appear to perform much better than consensus clinical criteria. While there may be specific instances where discrimination may be higher (e.g. the SPECT scan in differentiating AD from FTD or an EEG for the diagnosis of CJD), the overall results are disappointing. Novel approaches to the diagnosis of dementia are greatly needed. Although the likelihood ratios of individual tests are small, the value of combining several independent tests in series should be explored. New and specific biomarkers must be developed. As the number of individuals affected by dementia

continues to grow exponentially, there is little room for complacency about diagnosis.

References American Academy of Neurology. (1994) Practice parameters for diagnosis and evaluation of dementia (summary statement). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 44, 2203 –2206. Costa, P.T., Williams, T.F., Somerfield, M. et al. (1997) Recognition and Initial Assessment of Alzheimer’s Disease and Related Dementias. AHCPR Publication No. 97–0702. US Department of Health Care Policy and Research, Rockville, MD.

SECT ION III

Background Facts Edited by: Timo Erkinjuntti

Historical Evolution of the Concept of Dementia: a Systematic Review from 2000 BC to AD 2000 III.1

Gustavo C. Román

Introduction

Ancient era

Dementia [from the Latin dement–demens; out of one’s mind] is defined by Webster’s (1976) as, ‘1: a condition of deteriorated mentality that is characterized by marked decline from the individual’s former intellectual level and often by emotional apathyacontrasted with amentia (mental retardation). 2: madness (synonym: insanity)’. Dorland’s (1985) adds the synonyms aphrenia, aphronesia and athymia. Insanity [from the Latin insanitas; from in not, sanus sound] is defined as, ‘mental derangement or disorder . . . the term is a social and legal rather than a medical one, and indicates a condition which renders the affected person unfit to enjoy liberty of action because of the unreliability of his behaviour with concomitant danger to himself and others’. Senility [from the Latin senilitas; from sen-senex old, old man] is defined as, ‘old age; the period of life marked by the weakness and deterioration that may accompany advanced years’ (Dorland’s 1985). Likewise, senile dementia, senile psychosis, senile insanity and dotage are given as synonyms. Therefore, from its beginnings the concept of dementia has been synonymous with madness; these two words are deeply rooted in the common language of many cultures where the word dementia continues to carry the connotation of insanity, and more precisely the notion of either dementia paralytica (neurosyphilis) or dementia praecox (schizophrenia). The history of the concept of dementia may be divided into four major epochs (Table III.1.1) that cover the four millennia from 2000 bc to ad 2000.

The history of mental disease began in obscure times of human evolution with animistic, magical and sacred concepts wherein mental symptoms resulted from the external influence of supernatural forces (Roccatagliata 1986). Sacrifices to the gods, spells or amulets, and the intervention of the shaman, healer or magician counteracted these forces. Remnants of those concepts have persisted until today. According to Boller and Forbes (1998), around 2000 bc the ancient Egyptians were aware of memory alterations occurring with age. During the Pharaonic era, an accurate description of the problems of old age, including memory loss, is found in the Maxims of Ptah Hoty (9th Century bc): ‘My Sovereign master, old age, is here. Senility has descended on me; the weakness of my childhood is returned and I sleep all the time . . . My spirit is forgetful and I can no longer remember yesterday’ (quoted by Loza & Milad 1990). It is considered that this ancient period ended about 1500 bc with the development in the Greek and Roman world of a medical-sacerdotal psychiatry based on the interpretation of dreams, under the protection of gods such as Melanpos, Orpheus and Asclepios. This approach provided the background for the development of clinical psychopathology. Disease began to be treated with personal advice based on the contents of the dreams, rites that included songs, music and dance, as well as with the use of cathartic medications such as hellebore. The origin of Classic Hellenic medicine can be traced to attempts ‘to remove illness from the hands of the priests and the aegis of the gods’ (Neaman 1975).

199

200 CHAPTER III.1

Table III.1.1 Main periods in the evolution of the concept of dementia. Ancient era: from prehistoric times to the beginning of medical sacerdotal psychiatry (about 1500 BC) Classic era: from the first written mentions of dementia in the works by Greek, Roman, Byzantine and Arab writers until the end of the Middle Ages (AD 1500); this long era (3000 years) was heavily influenced by the Hippocratic–Galenical system of medicine Scientific era (1600–1900): characterized by clinical and anatomical descriptions, clinicopathological correlations, semantic agreement on the meaning of the word dementia, and first etiological studies (general paresis in neurosyphilis) Modern era (1901–2000): Clinical and pathological studies of eponymic forms of dementia, epidemiological surveys and etiological studies. The current era began in the early 1960s with ultrastructural studies, followed by pharmacological treatments in the 1970s, protein chemistry in the 1980s, and molecular biology and genetics in the 1990s (Terry et al. 1994)

Table III.1.2 Important dates in the ancient history of dementia. Date

Place and event

Ancient Era 9th Century BC

Pharaonic Egypt: Maxims of Ptah Hoty senility as second childhood

Classic Era 6th Century BC 5th Century BC 4th Century BC 3rd Century BC 2nd Century BC 1st Century BC 1st Century AD 2nd Century AD AD 131–201

Greece: Pythagoras defines senium as onset of second childhood at age 63 Greece: Sophocles writes Oedipus at Colonus at the age of 90 years emphasizing successful aging Greece: Corpus Hippocraticum: dementia is normal consequence of aging Alexandria: Erasistratus’ concept of pneuma (vital spirits) Herophilus: blood plethora causes delirium Rome: Cicero first uses senile for old age and defines senilis stultitia as senile folly or dotage Rome: Lucretius writes that with ‘the mighty force of years . . . the intellect grows dim’ Rome: Celsus first medical use of dementia (out of one’s mind) and insanity (Greek Phrenesis) Greco-Roman: Aretaeus separates mental and nervous diseases. Recognized senile mania as dotage Greco-Roman: Galen localizes seat of soul or pneuma in frontal lobes. Old age inexorably causes morosis (moronity) and the brain becomes ‘cold and hard’

Classic era The history of dementia during the Greco-Roman period has been extensively reviewed by Roccatagliata (1986), as well as by Halpert (1983), Berchtold and Cotman (1998), and Boller and Forbes (1998). The most important landmarks will be mentioned here, beginning with Hellenic medicine in the 6th Century bc (Table III.1.2).

Sixth Century BC One of the earliest figures during this period was Pythagoras of Samos (floruit circa 530 bc), the Greek philosopher and mathematician who first taught that the brain is concerned with reasoning (McHenry 1969). Pythagoras defined the senium or ‘old age’ as the period of life after 63 years of

age when the body declines, there is regression of mental capacities, and ‘the system returns to the imbecility of the first epoch of the infancy’ (Halpert 1983). Even today, dotage is defined as ‘advanced age attended by enfeebled mentality and childishness acalled also second childhood’ (Webster’s 1976). Pythagoras also noted that dying at an advanced age was exceptional: ‘The scene of mortal existence closes, after a great length of time, to which, very fortunately few of the human species arrive’ (Halpert 1983). Average life expectancy in Roman times was less than 30 years, in England in 1700 it was 35 years, by 1840 it had risen to 40–43 years and, in the 1980s it reached 76–80 years (Mahendra 1987). Currently, the fastest growing segment of the population is the oldest-old, aged 85 years and older (Brookmeyer et al. 1998). Therefore, it is likely that throughout most of the last four millennia

HISTORICAL CONCEPT OF DEMENTIA 201

senile dementia was a relatively uncommon occurrence. It was only in the last quarter of the 20th Century that senile dementia reached ‘epidemic’ proportions (Terry 1976, Katzman 1976, Plum 1979), prompting the denomination of Alzheimer’s disease as ‘the disease of the century’ (Reisberg 1983).

Fifth Century BC The life of the playwright Sophocles (c. 496–406) is an example of successful ageing: he lived almost the entire 5th Century bc in Greece and at 90 years of age wrote his play Oedipus at Colonus, where the central figure is the elderly but undefeated Oedipus Rex, blind and exiled, but with the capacity to transcend his earlier tragedies. Sophocles provided in this play a striking example of undiminished aging that culminates with Oedipus becoming a demigod. The Greeks at this timeafollowing Pythagoras abelieved that ‘the mind and its derangements were clearly located in the brain’ (Lyons 1987). Plato (c. 427–347 bc), a contemporary of Hippocrates, described man as made up of body and soul. In his Dialogues, he wrote: ‘The disorders of the soul, which depend upon the body, originate as follows: We must acknowledge disease of the mind to be a want of intelligence; and of this there are two kinds; to wit, madness and ignorance’ (Goshen 1967). Plato, however, continued to classify madness according to the influence of the deities as prophetic or Apollonian, ritualistic or Dionysian, poetic or inspired by the Muses, and erotic or caused by Aphrodite or Eros (Lyons 1987). Regarding the problems of old age, in Plato’s Republic the government was run by the elderly. Nonetheless, according to Torack (1983), in The Laws, Plato equated ‘extreme old age [with] childish wantonness’ and he believed that mental failure was inevitable in the elderly. He wrote: ‘. . . old men must beware . . . because of the weakness of the brain’ (Halpert 1983). Along the same lines, Aristotle (384–322 bc), son of a physician and a disciple of Plato, also affirmed that in old people ‘there is not much left of the acumen of the mind which helped them in their youth, nor of the faculties which served the intellect, and which some call judgement, imagination, power of reasoning and

memory . . . [old people are] gradually blunted by deterioration . . . they can hardly fulfill their function’ (Halpert 1983). Hippocrates of Cos (c. 460–377 bc), the Father of Medicine, assigned the brain a central role in all mental and vital processes (Riese 1959, Roccatagliata 1986a). On his treatise On the Sacred Disease he wrote: [From the brain] come joys, delights, laughter and sports, and sorrows, griefs, despondency, and lamentations. And by this, in an especial manner we acquire wisdom and knowledge . . . by the same organ we become mad and delirious. Senile dementia was not included in the Corpus Hippocraticum, probably because it was considered a normal part of the ageing process (Berchtold & Cotman 1998). However, Halpert (1983) has argued that paranoia in Hippocratic writings had the same meaning of what Pythagoras called imbecility and could refer to senile dementia. Following Anaximandros’ idea of an ideal number to represent the rigorous geometric symmetry of the Universe or kosmos, the Greeks believed that the number 4 represented universal harmony (Lasso de la Vega 1976). Thus, there were four basic elements in natureafire, water, air and earthaeach with primary and opposite qualities (hot, cold; dry, wet); accordingly, Hippocrates held that all body fluids were composed of varying proportions of four cardinal body fluids or humours that explained the different temperaments (blood, sanguine; black bile, melancholy; phlegm or pituita, phlegmatic; yellow bile, choleric), with one type of temperament for each age: blood in childhood, yellow bile in maturity, black bile in presenility and pituita during senility. With age the brain would become ‘dry and cold’ predisposing the elder to melancholy (melas black, chole bile) and to mental decline. Also, imbalance of these humours would produce diseases that could be cured with the discharge of the abnormal humours by blood letting, sweating, phlegm from the nose, urination, vomiting or purge (Lyons 1987). For instance, Hippocrates recommended the following treatment in Regimen: Vapour baths too are beneficial, as is the use of vomiting after them, and the food after the

202 CHAPTER III.1

vomiting should be increased at longer intervals . . . following such a regimen will make such men healthy and more intelligent. But if the fire should be mastered to a greater extent by the water in the soul, we have then cases of what are called by some ‘senseless’ people, and by others ‘grossly stupid’ . . . these persons are benefited by vapours baths followed by purging with hellebore, the diet to be the same as before (quoted by Goshen 1967). Sacred diseases ended with Hippocrates: ‘Epilepsy is a disease considered sacred because of inexperience . . . the disease is not caused by the gods’ anger.’ He also described three types of mental disorders or paranoia: phrenitis or febrile delirium, mania or non-febrile insanity, and melancholia or depression. According to Roccataglaita (1986a), with the birth of psychiatric nosology under Hippocrates, ‘for the first time in history symptoms were seen as an expression of a biological process set within a metabolic theory.’ The Hippocratic concepts of health and disease, and his classification of insanity, persisted well beyond the Middle Ages, and even permeate current notions of mental disease.

Third Century BC During the 3rd Century bc the School of Alexandria emphasized the importance of symptoms in the expression of mental disease and contributed solid concepts of neuroanatomy, pharmacology and neuropsychology. Erasistratus of Chios (c. 320– 250 bc), the father of physiology, developed the pneuma concept whereby air taken by the lungs was changed to vital spirits distributed by the blood; in the cerebral ventricles vital spirits changed to animal spirits that then spread throughout hollow nerves (McHenry 1969). Herophilus of Calcedonius (322–255 bc), the father of anatomy, concluded that acute psychoses derive from ‘alteration of blood that stagnates in the canaliculi of the brain’ (Roccatagliata 1986). This concept of blood plethora or stasis of blood in the brain was to become ‘cerebral congestion’ (Hammond 1878), a cause of disease accepted until the beginning of the 19th Century (Román 1987a), probably as a reflection of the damaging effects of arterial hypertension on the brain.

The lasting influence of Erasistratus and Herophilus resulted mainly from the commentaries written by Celsus and Galen later in the Roman period.

Second Century BC In Rome, during the 2nd Century bc, Marcus Tullius Cicero (106–43 bc), a Roman philosopher, orator and politician, wrote a well-known apologia or defense of old age in his book De Senectute: ‘The senile folly [sic esta senilis stultitia] usually called dotage, madness or delirium [quae deliratio appelair solet] is a characteristic, not of all old men, but only of those who are weak in mind and will [senium levium est]’. According to Halpert (1983), in this book the word senile was used for the first time to indicate ‘old age’. The word stultify has similar roots [from the Latin stultus; foolish] and means ‘to allege or prove (oneself or another) to be of unsound mind; to cause to appear foolish, stupid or absurdly illogical’ (Webster’s 1976). The concept of senile stultitia is found unchanged centuries later. For instance, Philip Barrow (1560– 1590) wrote: ‘If reason be lost together with the memorie, then the affect is called Fatuitas or stultitia [that is] foolishness or doltishness and both these do come of one disposition, but that is more vehement wher both are hurte’ (quoted by Hunter & Macalpine 1982), and in 1624, Vincent de Beauvais said: ‘stultitia is the absence of right and goodness in both deeds and words and is caused by ignorance’ (quoted by Neaman 1975).

First Century BC Also in Rome, during the 1st Century bc, the poet and philosopher Titus Lucretius (c. 99–55 bc), continued the notion that mental decline ‘was a natural accompaniment of advanced old age’ (McMenemey 1963). He wrote: . . . when the mighty force of years Their frame hath shaken, and their limbs collapse With blunted strength, the intellect grows dim. The tongue talks nonsense and the mind gives way And all things fail, and altogether go. (Lucretius: De Rerum Natura 3: 454; quoted by McMenemey 1963)

HISTORICAL CONCEPT OF DEMENTIA 203

First Century AD The Roman physician, medical writer and encyclopedist Aulus Cornelius Celsus (fl. ad 14–37) was the first scholar to translate Greek medical terms into Latin, providing also a synthesis of the various medical theories proposed by the Greeks and the School of Alexandria (Roccatagliata 1986b). According to Berríos (1987b) Celsus was the first to employ the words dementia and insanity (insania) as medical terms in De Medicina (1st Century ad): ‘I shall begin with insanity, and first with that form of it which is both acute and found in fever. The Greeks call it Phrenesis [phrenitis]’ (Celsus, Book III, 18, 2–3, p. 288; quoted by Berríos 1987b). Celsusafollowing Hippocratesadivided insanity into melancholia, acute febrile frenzy or phrenitis, and dementia, a persistent form of insanity following an acute febrile delirium (Roccatagliata 1986, Berríos 1987a, Mahendra 1987). Celsus wrote: ‘But insanity is really there when a continuous dementia begins [continua dementia ess incipit], when the patient, although up till then in his senses, yet entertains certain vague imaginings; the insanity becomes established when the mind becomes at the mercy of such imaginings’ (Celsus, Book III, 18, 2–3, p. 288; quoted by Berríos 1987b). Celsus wrote in Latin at a time when Greek was the language of intellectuals; therefore, his books were practically lost until the Renaissance when they were finally printed (Lyons 1987).

Second Century AD The Greek physician Aretaeus of Cappadocia (2nd Century ad) clearly differentiated between nervous diseases and mental disorders (McHenry 1969, Roccatagliata 1986c). A careful clinician, Aretaeus appears to have referred to senile dementia when he wrote that he had observed a symptomatic form of mania that ‘. . . occurs in old people suffering from loss of reason . . . it resembles the mania from mandrake or wine . . . but whilst in those cases the brain is hot . . . in the first case the brain is extremely cold’ (quoted by Roccatagliata 1986c). For Aretaeus, the centre of emotional life or thymus was in the heart and the cooling of the brain was a secondary event. The symptoms of senile

mania resembled ‘those of amentia [but] they have a brief course and the patient recovers completely’ (quoted by Roccatagliata 1986c). Aretaeus probably used the term dotage for senile dementia, as follows: ‘dotage which is the calamity of old age . . . dotage commencing with old age never intermits, but accompanies the patient until death’ (Alexander 1972). Claudius Galenus, better known as Galen of Pergamum (ad 131–201) unified the medical knowledge accumulated from the 5th Century bc to the 2nd Century ad into a comprehensive system that had a lasting influence in medicine for many centuries (Roccatagliata 1986d). He wrote over 500 works on scientific subjects. He dissected many animals but refused to dissect the human cadaver, although he accurately described the anatomy of the brain, and followed the nerves from their origins to their terminations in muscles and viscera. Galen classified quite correctly the cranial nerves but counted only seven (McHenry 1969). He wrote on muscle tone, that he felt represented a constant physiological ‘tension of the organism’ (Roccatagliata 1986). Following the teachings of Erasistratus in Alexandria, Galen believed that the frontal lobes were the seat of the soul (pneuma) and the source where the animal spirits originated. He believed that apoplexy was a result of obstruction of the cerebral ventricles by thick pituitary phlegm, blocking the action of the animal spirit. Galen used the term morosis (moronity, from the Greek moros sluggish, dull, stupid) as an overall term for both idiocy and dementia. In morosis ‘. . . the knowledge of letters and other arts is totally obliterated; indeed they can’t even remember their own names’. Galen included old age among the causes of morosis: ‘. . . on account of extreme debility in old age, some are afflicted with similar symptoms’ (Berchtold & Cotman 1998). He also wrote: ‘Old age is not natural in the same way that feeding and growing are’ (Halpert 1983). Galen believed that mental deterioration was inevitable in the elderly, and he called old age ‘a natural distemper’ causing ‘rarefaction and diminution in quantity of the animal spirits . . . coldness and humidity of the brain’ (Halpert 1983). This concept was to prevail in medicine almost until the end of the 20th Century.

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Middle Ages After the fall of Rome to the Goths in 476, Galenism reached Europe by the collaboration of Christian monastic scholars and Arab and Jewish physicians. During the Byzantine Empire, universities, libraries and medical schools declined. Christian doctrine with emphasis on the conflicts between evil and good prevailed (Roccatagliata 1986). Oribasius of Pergamum (ad 320–400) taught that delirious melancholic psychoses were not demoniac possessions and advised the use of opium to produce prolonged sleep as treatment. Paulus Aegineta (ad 625–690) also insisted that insomnia often is a consequence of sadness and that sleep ‘sedates the unquietness of the mind’ (Roccatagliata 1986). In the field of dementia one of the most important contributors during the early Middle Ages was St. Isidore of Seville (ad 556–636). Ordained bishop of Seville in 600, he wrote De Natura Rerum and the 20-volume encyclopedia Etymologiae sive Origines, whose book IV is dedicated to medicine. Bishop Isidoreaprobably for the first time in history aclearly distinguished between insania (insanity), dementia, and amentia (Neaman 1975). Furthermore, Bishop Isidore separated congenital idiocy from acquired insanity. Dementia is slow to develop and temporary in its effects, and amentia is congenital and permanent (synonymous with fatuitas, fatuity, silliness). Also, he accurately divided insanity into mania and melancholia. Mania is ‘a disordered state of mind characterized by fury and agitation, as distinguished from the depression . . . called melancholia [characterized by] disorientation, social withdrawals, and feelings of mistrust’ (quoted by Neaman 1975). Beginning in 711 with the Arab conquest of Spain, Europe would receive during the next 700 years the influence of Islamic and Greco-Roman medicine (Table III.1.3). The writings of Isaac Judaeus (Abu Ya’qub Is-hac ibn Sulayman alIsraili), a physician born in Egypt (c. 850), were translated in the 11th Century by Constantine the African, a surgeon of the famous medical school at Salerno (Italy). Following the Galenical tradition, Judaeus wrote in his Liber de Oblivione: The operation of the mind is threefold. It is fantasy, rational intellect and memory. In the

front ventricle of the brain, air is mixed and in that ventricle the animal spirit enters and makes the senses of sight, hearing, smelling, tasting, speech. From this space the animal spirit is carried to the medial ventricle where it is made pure and clearer for this is the seat of reason and intellect. The rear chamber is the seat of memory. Ali ibn Sinã (980–1038), better known as Avicenna, wrote the Canon Medicinae that continued the influence of the Hippocratic-Galenical school on medical teaching during most of the medieval period. The Rabbi Moses ben Maimonides (1135– 1204), an eminent physician born in Cordoba, Spain, described senile dementia in his Medical Aphorisms, as follows: ‘Sometimes mental confusion and forgetfulness occur purely from senility or extreme weakness’ (quoted by Torack 1983). During the Middle Ages, lack of anatomical knowledge limited the development of accurate concepts. For instance, in 1290, at the age of 80 years, the Franciscan friar Roger Bacon (1214– 1294), wrote a book entitled Methods for Preventing the Appearance of Senility. In it, Bacon wrote, quoting from Isaac Judaeus and Haly Abbas: In the posterior part of the brain occurs oblivion and memory, concerning which Haly Regalis speaks in his first theoretical treatize saying that old age is the home of forgetfulness . . . An injury to the reasoning faculty happens in the middle part of the brain. Memory is not necessarily impeded. An injury to the imagination occurs in the anterior part of the brain. Memory and judgement are not affected (quoted from Torack 1983). In the above text, Haly Regalis refers to Haly Abbas’s Dispositio Regalis (Royal Book, al-Malaki or Liber Regius). This encyclopedic book of GrecoRoman medicine was written in Arabic by Haly Abbas (Ali ibn al-Abbas), a Persian physician of the 10th Century ad; the Latin version of his book was used by physicians up to the 16th Century ad. According to Berchtold and Cotman (1998), Bacon’s ‘reference of the brain as the source of mental processes is noteworthy, because for the prior millennium and for centuries following the medieval period, the heart had predominated as the seat of human intelligence.’

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Table III.1.3 Important dates in the history of dementia during the Middle Ages and the Renaissance. Date (AD)

Place and event

600

Seville, Spain: Bishop St. Isidore writes Etymologiae Sive Origines, defines insania, dementia and amentia

800

Egypt: Isaac Judeus following Galen, describes a three-ventricle brain

1290

England: Roger Bacon at the age of 80 years wrote Methods for Preventing the Appearance of Senility

1381

France: the word demence first used

1452–1519

Italy: Leonardo da Vinci first corrects three-ventricle brain using wax mold

1543

Belgium: Flemish anatomist Andreas Vesalius publishes De Humani Corporis Fabrica

1549

Holland: Jason de Prato writes De Cerebri Morbis considered the first neurology textbook with a chapter on dementia: ‘De memoriae detrimento’

1546–1616

England: William Shakespeare describes senile dementia in his play King Lear

1592

England: first use of the word dementia

From the close of the Middle Ages, as well as during the discovery and exploration of the New World, and then during the Renaissance and the Enlightenment, medicine saw an increase in anatomical knowledge, clinical descriptions, clinicopathological correlations, and etiological studies of dementing illnesses. However, the ideas of Galenism remained strongly grafted into medical knowledge. The persistent belief that insanity was produced by excessive pressure of the pneuma (air in the brain) or the calcification of pituita led, at the end of the Middle Ages, to the popular use of trepanation of the skull for the treatment of dementia, as illustrated by Hieronymus Bosch in ‘The Extraction of the Stone of Madness’ (c. 1490) in an elderly gentleman probably afflicted by senile dementia (Fig. III.1.1). It was widely held that the brain had three ventricles, and that memory (Fig. III.1.2) was stored in the posterior ventricle, thought and judgement in the middle one, and imagination in the anterior ventricle. Impressions from vision, hearing, smell and taste would be conveyed to the anterior part of the frontal ventricle to form a sensus communis or common sense (McHenry 1969). Leonardo da Vinci (1452–1519), the 15th Century Renaissance man par excellence, continued to draw a human brain with three ventricles, until he invented the method of using wax casts of the ventricular system that provided him with the correct anatomical structure. Accurate knowledge

Fig. III.1.1 ‘The Extraction of the stone of Madness’, Hieronymus Bosch (c. 1490).

206 CHAPTER III.1

(a)

(b)

Fig. III.1.2 Illustration of brain with three ventricles. (a) Woodcut by Reisch (1512). Messages from hearing, vision, smell, and

taste converge to frontal ventricle location of sensus communis, imagination originates here and passes to middle ventriclea guarded by the vermis or ‘red worm’ (choroid plexus)afor thought and judgement, memory is located in the hind ventricle (according to McHenry 1969). (b) Drawing by Leonardo da Vinci (c. 1504) illustrating Galen’s idea of the brain with three ventricles. Using wax cast methods, da Vinci later correctly depicted the ventricular anatomy (World Health Organization).

of human anatomy, and in particular of cerebral anatomy, improved substantially with the publication of De Humani Corporis Fabrica by Vesalius (1543).

Sixteenth Century Finally, towards the 16th Century some efforts were made in medicine to escape the Greco-Roman influence. One of the pioneers was Theophrastus Bombastus von Hohenheim, better known as Paracelsus (1493–1541). Paracelsus wrote: ‘My books are not like those of other physicians copying Hippocrates and Galen. I have composed them on the basis of experiments which are the greatest

masters’ (quoted by Klawans 1982). He noticed the important role of heredity in mental retardation: ‘people who have received insanity from the mother’s womb as a heritage, such as a family which is insane or a child that has been born insane: the seed and its function may be defective, or it may be inherited from the part of the father or mother . . . lacking in the power of matter which makes and builds the brain’ (Paracelsus, Diseases that Deprive Man of his Reason, 1567) (quoted by Goshen 1967). Nonetheless, during the 16th Century some of the best descriptions of senile dementia were to be found not in medical texts but in literary works. Shakespeare (1564–1616) masterfully described King Lear’s early dementia (Kail 1986):

HISTORICAL CONCEPT OF DEMENTIA 207

You see me here, you gods, a poor old man, As full of grief as age; wretched in both!

or their names . . . this . . . commeth by some blowe, sickness, or age’ (quoted by Berríos 1987b).

And then, Does any here know me? This is not Lear. Does Lear walk thus? Speak thus? Where are his eyes? Either his notion weakens, or his discernings are lethargied. Ha! Waking? Tis not so. Who is it that can tell me who I am? The final stage of the dementia is succinctly described by Kent, King Lear’s faithful follower (III, vi, 87): . . . trouble him notahis wits are gone. Some rare comments on dementia appeared, however, in medical writings. In 1549, Iason Pratensis ( Jason de Pratis) published in Basle the first textbook of neurology, De Cerebri Morbis, which included a chapter on dementia, ‘De memoriae detrimento’ (van Gijn 1998). In 1592, Cosin used the term lethargie for ‘. . . a notable forgetfulness of all things, almost that heretofore a man hath knowen,

Scientific Era Seventeenth Century The most important names in the history of dementia during the 17th, 18th and 19th Centuries are summarized in Table III.1.4. In 1621, Robert Burton (1577–1640) wrote under the name Democritus Junior an immensely popular book called The Anatomy of Melancholy that went to five editions during the author’s life, and to a number of reprinted editions, including the latest in 1977. Burton wrote: ‘The diseases of the mind [morbus imaginationis, aut rationis laesae: diseases of the imagination, or of injured reason] which are three of four in number, frenzy, madness, melancholy, dotage and their kinds.’ He then defined dotage (dementia) with two varieties, congenital (oligophrenia) and acquired (with constant or intermittent manifestations); delirium or phrenitis (in the

Table III.1.4 Important dates in the history of dementia during the Scientific Era (17th, 18th and 19th Centuries). Date

Place and event

1872

England: Thomas Willis’ first clinical description of patients with vascular dementia in De Anima Brutorum. Uses stupidity or morosis for dementia and lists head injury, stroke, trauma, alcohol, epilepsy, and old age as causes. Improves brain anatomy

1778–84

England: William Cullen uses Amentia senilis for senile dementia

1793

Italy: Vicenzo Chiarugi following Galen, writes that hardening of the brain in the elderly, and plethora in middle aged, causes amentia and insanity, respectively

1800

France: Philippe Pinel first uses senile dementia. Uses medical statistics and longitudinal patient follow-up

1812

USA: Benjamin Rush introduces the term dementia, according to Pinel’s use

1822

France: Antoine Bayle identifies arachnoiditis in neurosyphilis

1826

France: Louis Calmeil describes general paralysis of the insane in neurosyphilis

1838

France: Esquirol separates dementia from amentia, provides first clinical and pathologic descriptions of senile dementia

1860

France: Morel and Houel confirm brain atrophy and weight loss in the elderly

1873

Middle Port, Ohio, USA: George Huntington presents his paper On Chorea

1857–76

Esmarch, Jessen, Fournier link veneral syphilis with GPI and tabes dorsalis

1913

Noguchi and Moore demonstrate Treponema pallidum in brains of GPI patients

GPI, general paralysis of the insane.

208 CHAPTER III.1

context of a febrile illness, including inflammation of the brain or its membranes); madness, and melancholy. Dotage, fatuity, or folly is a common name to all . . . it is natural or ingenite, which comes by some defect of the organs . . . as we see in our common fools; . . . or else it is acquise, an appendix or symptom of some other disease, which comes or goes. Phrenitis, which the Greeks derive from the word φρην [phrén mind], is a disease of the mind with a continual madness or dotage, which hath an acute fever annexed, or else an inflammation of the brain, or the membranes . . . of it, with an acute fever, which causeth madness and dotage . . . it differs from melancholy and madness, because their dotage is without ague. Madness, frenzy, and melancholy are confounded by Celsus, and many writers; others leave out frenzy, and make madness and melancholy but one disease, which Jason Pratensis especially labours, and that they differ . . . in quantity alone, the one being a degree to the other, and both proceeding from one cause . . . Madness is therefore defined to be a vehement dotage, or raving without a fever, far more violent than melancholy. Thomas Willis (1621–1675) was one of the leading figures of 17th Century English medicine (Fig. III.1.3). His book, Cerebri Anatome: Cui Accessit Nervorum Descriptio et Usus (1664) ‘marked the transition between medieval and modern notions of brain function’ (Feindel 1970). Willis (1664) also first coined the term ‘Neurology’ to mean ‘the Doctrine of the Nerves’, i.e. the knowledge of the cranial, spinal and autonomic nerves. In 1672, in his book De Anima Brutorum, Willis described what are probably the first accurate clinical observations of patients with vascular dementia (Robertson 1923, Hare 1959, Hierons 1967, Hughes 1991). He wrote: I have observed in many cases that when, the Brain being indisposed, they have been distemper’d with a dullness of mind and forgetfulness, and then afterwards with a stupidity and foolish-

Fig. III.1.3 Thomas Willis M.D. (1621–1675) at age 45 (by David Loggan, frontispiece from Pathologiae Cerebri, 1667).

ness, they would afterwards have fallen into a Palsie, which I oft did predict; to with, the Morbific matter being by degrees fallen down, and at length being heaped up somewhere within the Medullar Trunk (where the Marrowy Tracts are more strained than in the Streaked Body) to a stopping fulness. For according as the places obstructed are more or less large so either a universal Palsie, or an half Palsie of one side, or else some partial resolutions of members happen . . . (Thomas Willis: De Anima Brutorum, Part II, ‘Concerning the Soul of the Brutes’, Chapter 9, 1672; quoted by Hare 1959) The clinical picture that combines progressive cognitive declineafrom ‘dullness of mind and forgetfulness’ down to ‘stupidity and foolishness’a accompanied by either hemiplegia, weakness of facial, ocular movements, and tongue, sometimes with recovery or ‘partial resolution’, most likely corresponds to instances of vascular dementia. For

HISTORICAL CONCEPT OF DEMENTIA 209

many years the above paragraph was incorrectly considered to be an early description of syphilitic dementia paralytica (Robertson 1923, Hare 1959). Willis believed that the cerebral cortex was the source of ‘Imagination and Memory’; but, as mentioned above, he localized the lesions in the subcortical white matter (the ‘streaked body’ is the corpus striatum and the ‘medullar trunk’ is the medulla oblongata), even suggesting that the extent of the symptoms depends on the location and size of the brain lesion. Willis’s London Practice of Physick (published posthumously in 1684) clearly separates congenital mental retardation from acquired forms of dementia (Berríos 1987b). Following the terminology of his contemporaries (Burton 1621), instead of the word dementia Willis used the synonymous terms stupidity, morosis, and foolishness to ‘signify a defect of the intellect and judgement, yet it is not improperly reckoned among the Diseases of the head or brain’ (quoted by Berríos 1987b). Willis clearly mentions that old age can cause dementia. He wrote: For in the first place stupidity . . . is sometimes original or born with one and so it is either hereditary as when fools beget fools . . . or stupidity being born with one is as it were accidental . . . Secondly, there are more evident causes . . . some at first crafty and ingenuous become by degrees dull, and at length foolish by the mere declining of age (Thomas Willis: Practice of Physick, chapter XIII, p. 209) In addition to aging, Willis lists other causes of dementia including head injury, alcohol and opiate abuse, brain diseases, severe epilepsy, and apoplexy: . . . great strokes or bruising of the head such as happen from a fall from high place; . . . frequent drunkenness; . . . frequent use of opiates [which] very much troubles the sharpness of the mind; . . . violent and sudden passions . . . and cruel diseases of the head. This frequently happens in a great and long epilepsy . . . and further I have taken notice in many that stupidity has accompanied the palsie or has gone before . . . apoplexy.

In summary, Willis’s contributions to the anatomical and clinical knowledge of his time were unsurpassed. In addition to studying a large list of diseases, Willis provided lasting and accurate information on brain anatomy, cerebrovascular circulation, stroke, mental retardation, and the most important causes of dementia including ageing and vascular disease (Hughes 1991). Also, Willis provided for the first time clinical examples of patients with vascular dementia.

Eighteenth Century The history of dementia during the 17th and 18th Centuries has been reviewed by Berríos (1987b). The word dementia has long been used in Europe: demence in France since 1381, and dementia in English since 1592; demencia is found in a Spanish dictionary in 1791 (Berríos 1987b), although, as mentioned above, Bishop Isidore of Seville provided a definition of the Latin word dementia in his book Etymologies written around ad 600. Blancard’s (1726) Physical Dictionary gives anoea: ‘extinction of the imagination and judgement’ as equivalent to dementia. Webster’s (1976) defines anoia [from the Greek, a without, noos mind] as ‘mental deficiency, idiocy’. Berríos (1987b) also mentioned that the French Encyclopédie, edited by Diderot and d’Alembert in 1754, provided remarkably clear medical and legal definitions of dementia. In Edinburgh, William Cullen (1712–1790) coined the word neurosis and classified Amentia into Amentia senilis, Amentia congenita, and Amentia acquisita causa externa (Cullen 1778–1784). Although the word dementia was not included, according to Berríos (1987b) Cullen listed the following synonyms for amentia: amnesia, fatuitas, memoriae debilitas, morosis, oblivio, and stupiditas. Cullen (1793), however, provided a sound English definition of Amentia senilis as a medical entity (equivalent to senile dementia): ‘Imbecility of judgement, by which men either do not perceive the relation of things or forget them due to diminished perception and memory when oppressed with age’ (quoted by Torack 1983). Cullen’s classification was accepted widely in Europe; for instance, Pinel in Paris, translated his book into French (Cullen 1785).

210 CHAPTER III.1

But for the efforts to define and classify senile dementia mentioned above, Galenical views persisted during the 18th Century. For instance, in Florence, Vicenzo Chiarugi in his book On Insanity and its Classification (1793) wrote: ‘Old people lapse into true amentia ordinarily because of loss of memory and inertia of the fantasy due to a hardening of the fibers of their brain in keeping with the rest of their body’. He also believed that blood congestion was a cause of insanity: Once the disposition towards insanity is formed through a very strong plethora, although the paroxysm ends, insanity can occur again even through a much weaker plethora. It is not necessary that in all the cases the quantity of blood carried to the head be really more than the diameter of the vessels, because it seems certain that the violence of the shock and the speed with which the blood moves are sufficient, even without the plethora, to upset the fantasy and to cause delirium. Renowned physicians such as Boerhaave (1668– 1738) and von Haller (1708–1777) concluded that senile brains, when examined at postmortem, were ‘dry, hard and friable.’ Only Giovanni Battista Morgagni (1682–1771), the Italian anatomist and pathologist, concluded objectively: ‘I do not lay so much stress upon this hardness, I would have you know that in some persons whose minds had not been disordered, I did not find the cerebrum less hard’ (quoted by Torack 1983).

Nineteenth Century In 1812, the term dementia was introduced in North American medicine by Benjamin Rush (1745–1813), considered the first American psychiatrist, following the use proposed by Pinel. Rush had described earlier, at the turn of the century (1793), a case of severe senile dementia as follows: I met with an instance of a woman between 80 and 90 who exhibited the marks of a second infancy, by such total decay of her mental faculties as to lose all consciousness in discharging her alvine and urinary excretions. In this state of

the body, a disposition to sleep succeeds the wakefulness of the first stages of old age. In 1812, Rushaa traditional Galenistarecommended the following therapies to improve memory: Depleting remedies, if plethora attend, and the pulse be tense or oppressed. These should be bleeding, purges and low diet. After the reduction of the system the remedies should be blisters . . . cubebs [Java pepper], cardamom seeds, lavender and rosemary or cloves, cold bath and cold weather, and exercise (preferably a trotting horse to excite dormant ideas). The father of French psychiatry, Philippe Pinel (1745–1826) is remembered more for the myth of removing the chains from the mentally ill at Bicêtre Hospital (Weiner 1994), than for his books (Pinel 1798, 1800, 1802) and his innovative approach to the study and treatment of mental disease. Pinel was instrumental in converting the institutions for the insane from prisons to hospitals. He wrote: Public mental asylums have been considered places of confinement and isolation for dangerous patients and pariahs. Therefore, their custodians, who in most cases are inhuman and unenlightened, have taken the liberty of treating these mentally sick in a most despotic, cruel, and violent manner, though experience continually shows the happy results of a conciliating attitude, of a kind and compassionate firmness. (Pinel 1806, English translation according to Goshen 1967) He also introduced statistical analysis of hospital admissions as a means of improving patient care (Pinel 1802), and opened the Salpêtrière wards to medical students. Pinel was an excellent clinician and an immensely popular teacher; for instance, in 1802, more than 800 medical students registered for one of his classes (Weiner 1994). In 1798, he wrote Philosophic Nosography (six editions up to 1818), a system for classification of diseases originally written as a textbook for his students. In Nosographie (1798), Pinel used the terms amentia and morosis for cognitive impairment and, according to Berríos (1994), probably for the first time coined the term senile dementia [démence sénile].

HISTORICAL CONCEPT OF DEMENTIA 211

In his Treatize on Insanity (1800), he also used dementia as a separate form of insanity (a synonym of amentia and morosis) but did not separate it from congenital mental retardation. His use of senile dementia continued the Galenical view that ageing is a disease that results inexorably in ‘the slow and progressive enfeeblement of intellectual and moral faculties’ (Halpert 1983). It has been suggested that subsequent translations of the term démence sénile into other European languages led to widespread use of ‘senility’ as a medical diagnosis, synonymous with ‘senile dementia’ (Halpert 1983). In England, John Cooke (1756–1838), author of A Treatize on Nervous Diseases (1820–1821), one of the first neurology textbooks, clearly described sequelae of apoplexy causing intellectual deficits: ‘I have in several instances seen palsy terminating in childishness, or complete imbecility.’ He also provided one of the earliest descriptions of the emotional incontinence of pseudobulbar palsy resulting from stroke: Persons recovering from apoplexy appear, in many instances, to have undergone a most wonderful change as to the affections of the mind: we are informed that the wisest men and the bravest soldiers, persons of the strongest mental powers, have become so enervated as to weep like children on the slightest occasions. At the Salpêtrière Hospital in Paris, Jean Étienne Dominique Esquirol (1722–1840), Pinel’s most distinguished student continued his Maître’s struggle to give proper case to the mentally ill. Esquirol has been ‘one of the most underrated medical authors in the field of dementia’ (Boller & Forbes 1998). Pinel served as president of Esquirol’s thesis committee in 1805, and he was his chief at La Salpêtrière from 1811 to 1825 (Weiner 1994). Esquirol surveyed his Maître Pinel’s struggle to give proper care to the mentally ill. At the request of the Minister of the Interior he surveyed mental institutions in France and wrote a dramatic report (Esquirol 1819) that eventually led to the French national law of 1838, still in force today, that instituted proper departmental asylums (Weiner 1994). Esquirol used his mentor’s epidemiological methods (Fig. III.1.4)acareful clinical observation of

inpatients longitudinally over timeaand insisted on precise terminology. Esquirol’s book Des Maladies Mentales considérées sous le rapports médical, hygiénique et médico-légal (1838) [Mental Maladies, from the medical, hygienic and medico-legal viewpoints], is considered the first modern classification of mental disease. Esquirol clearly separated dementia from amentia: [Amentia or] Idiocy . . . is not a disease, but a condition in which the intellectual faculties are never manifested; or have never developed sufficiently to enable the idiot to acquire . . . knowledge. Dementia is . . . a cerebral disease characterized by an impairment of sensibility, intelligence and will [une affection cérébrale . . . charactérisée par l’affaiblissement de la sensibilité, de l’intelligence et de la volonté]. and provided the now-classical comparison: A demented man has lost the advantages he used to enjoy; he was a rich man who has become poor. The idiot, on the contrary, has always been in a state of want and misery. He further described the typical progression of senile dementia: Senile dementia results from the progress of age. There is . . . loss of sensibility along with . . . [loss of] the faculty of understanding, before reaching an extreme state of decrepitude. Senile dementia commences with feebleness of memory, particularly recent memory; attention . . . becomes impossible, the will is uncertain, the movements are slow. Esquirol provided the new classical clinicopathological studies in psychiatry, analysing the results of 66 autopsies performed under his direction at the Royal Home for the Insane at Charenton, as follows: Mortality is more common in dementia than in melancholia or mania, responding for half of the deaths. At autopsy . . . the skull of the elderly is thicker and denser . . . the arteries at the base of the brain are cartilaginous or even ossified, specially in senile dementia . . . the cerebral

212 CHAPTER III.1

(b) (a) Fig. III.1.4 (a) Title page of 1838 edition of Mental Maladies a Treatize on Insanity by Étienne Esquirol (1722–1840). (b) Illustration of the early use of hospital statisticsapioneered by Pinel: Left, survival curve by age groups (first column < 20 years of age, last column 85 and older). Right, age distribution of insane inmate population at Maison Royale des Alienés de Charenton. Notice the normal distribution with peak age from 30 to 40 years.

convolutions are atrophic, one gyrus separated from the next, [gyri are] shallow, flattened, compressed, smaller, specially in the frontal region. (Esquirol: Des Maladies Mentales, 1838, pp. 239– 242) Nonetheless, neuropathological studies of dementia lagged behind. An early reference to brain atrophy in patients with dementia is found in 1860 in the Traité des

Maladies Mentales written by Benoît Agustin Morel (1809–1873). He wrote: ‘loss in brain weightaa constant feature of dementiaais also present in ageing, and is an expression of decadency in the human species’ (quoted by Berríos 1994). This concept of cerebral atrophy with age appears to have been readily accepted. For instance, the pathology textbook written in 1862 by Charles Houel, a student of Cruveilhier in Paris, mentioned that senile brain atrophy, often found in the

HISTORICAL CONCEPT OF DEMENTIA 213

elderly, may be generalized or partial. In the first case the brain is notoriously smaller, firmer, and of decreased volume; the hemispheres are no longer in contact with the cranium, the convolutions are smaller and the sulci are wider; at the same time the ventricular cavities are enlarged and the cerebrospinal fluid is abundantly secreted to fill the empty spaces. (Houel 1862, p. 581) Among neurologists, these concepts were also readily accepted. In New York, William Alexander Hammond (1828–1900), one of the founding fathers of the American Neurological Association, in his textbook A Treatise on Diseases of the Nervous System (1871) defined senile dementia as ‘the slow and progressive enfeeblement of the intellectual and moral faculties consequent upon old age’ (p. 337). In 1888, at Queen Square in London, William Gowers (1845–1915) wrote in his Manual of Diseases of the Nervous System (1888): In old age the brain wastes, like many other organs, and becomes smaller and firmer. The amount of fluid in the ventricles and on the surface becomes increased in proportion to the lessened bulk of the brain . . . This wasting of the brain is commonly attended by no symptoms. Senile mental failure is often ascribed to it, but since it may exist in considerable degree without the slightest mental defect caution should be observed in attributing to it any mental changes that may coexist. (p. 947) Also in England, in 1894, John Hughlings Jackson (1835–1911), one of the most influential figures in neurology, wrote an article titled: ‘The Factors of Insanities’, where he illustrated his hierarchical view of the nervous system and the importance of progressive dissolution (loss of function) in the clinical manifestations and in the surfacing of primitive signs and reflexes in patients with dementia. He wrote: In every insanity there is morbid affection . . . of the highest cerebral centres; as the pathological processes produce loss of function, there is dissolution . . . reversal of evolution of the highest cerebral centres . . . Dissolution and evolution in cases of insanity vary inverselyathe shallower the dissolution the higher the range of evolution

remaining . . . The senile dement undergoes dissolution very slowly. Here the negative mental affection is greatest, is indeed total; there is dementia. . . . At the close of the 19th Century the main advance in psychiatry, in general, and in the study of the dementias in particular, had been the identification of neurosyphilis as a truly organic mental disease. Neurosyphilis Cerebral neurosyphilis [also known as dementia paralytica, general paralysis of the insane (GPI), paralysie general des alienées, folie paralytique, general paresis, progressive paralysis of the insane (PPI), and syphilitic insanity] became the first mental disease with a clear etiology. As mentioned above, early descriptions of mental decline in patients with ‘paralysis’ by Willis (1672) and Haslam (1798) most likely represent instances of vascular dementia (Hare 1959). The clinicopathological features of dementia paralytica were clearly identified during the third decade of the 19th Century by French physicians working in mental hospitals in Paris (Hare 1959), as a consequence of the purported emergence of a mutated ‘neurotropic’ strain of the syphilis agent. However, the most likely explanation is epidemiological: this was an unexpected bonus of the severe French policy of institutional confinement addressed not only to persons affected by mental disease (les alienées)aa legal term introduced in 1838 (Berríos 1987a)abut also including prostitutes, sexual offenders, vagrants, free-thinkers (les libertins) and those guilty of religious profanation (Simon 1986, Foucault 1972, Gutting 1994). According to Foucault (1972), these measures resulted in massive confinements that ‘displaced in just 6 years one percent of the population of Paris (5000–6000 people)’. The internment of a population at high risk for sexually transmitted diseases, plus the insane, resulted in geographical clusters of symptomatic neurosyphilis at Bicêtre (for males), La Salpêtrière for women (Fig. III.1.5), and Charenton (for men and women), among other institutions. Antoine Bayle (1822, 1826) first identified at

214 CHAPTER III.1

Fig. III.1.5 View of La Salpêtrière (c. 1780) in the vicinity of Paris. The foreground depicts arrival of contingent of prostitutes (filles de joie) to be interned. By 1690, the population was above 3000 people and by 1788, it reached 8000. (Drawing by Savard, engraved by Duparc. Original at Musée de l’Assistance Publique, Paris. Photo by courtesy of Assistance Publique des Hôpitaux de Paris, France.)

Charenton the presence of arachnitis chronique in 189 cases studied at postmortem between January, 1815 and July, 1823. He also noted the constant presence in these patients of ‘monomanie des grandeurs’. In 1826, Louis Florentin Calmeil (1798– 1895) described the typical clinical picture of the paralysie general des alienées as consisting of megalomania, slurred speech, dementia, urinary and fecal incontinence, and finally paralysis from ischemic strokes (ramollissements) as a result of vasculitis (Nonne 1902). The link with venereal syphilis was suggested by Esmarch and Jessen (1857) and by Fournier (1876) for tabes dorsalis. Finally, in 1913, Noguchi and Moore demonstrated the presence of Treponema pallidum in paretic brains.

Modern era

Treatise on Mental Diseases, written in 1900 by Henry John Berkley, Clinical Professor of Psychiatry at The Johns Hopkins University in Baltimore. He summarized in five groups the existing knowledge on the insanities: ‘I. Idiopathic insanities, without ascertainable alteration of the brain substance [melancholia, mania, stupor]. II. Insanities consecutive to organic lesions of the cerebral substance [syphilis, senile insanities with two varieties: presenile and senile, organic dementia [post-stroke, brain abscess, hydrocephalus, meningitis, disseminated sclerosis, tumours, trauma and insolation]; intoxications, bacterial infections, autogenic poisoning (uremia, etc.). III. Insanities of the psychical degenerate [paranoias, epilepsia, neurasthenia, histeria]. IV. States of arrested development (idiocy, cretinism, imbecility]; and, V. Childhood Psychoses.’

Twentieth Century

Cellular neuroanatomy and histopathology

With the arrival of the 20th Century the main advances in the field of dementia were achieved in the study of etiology; it was at this time that neurosyphilis, cerebrovascular disease, Alzheimer’s disease and Pick’s disease were clearly recognized as forms of dementia separate from senile dementia. These studies were made possible by technical advances in microscopy and histology (Table III.1.5). The nosology prevailing in psychiatry at the turn of the century can be found in the textbook,

The microscopic study of neural structures became possible with improvements in the quality of the compound microscope and with the development of histology techniques (McHenry 1969); the latter included appropriate tissue fixation (alcohol was used as a fixative by Vicq d’Azyr in 1786 and by Christian Reil in 1809, formaldehyde by F. Blum in 1893), paraffin embedding (introduced in 1869 by E. Klebs) and the invention of the microtome (by Bernard von Gudden in 1875).

HISTORICAL CONCEPT OF DEMENTIA 215

Table III.1.5 Important dates in the contemporary history of dementia (early 20th Century). Date

Place and event

1894

Germany: Otto Binswanger first uses the term presenile dementia; describes chronic progressive subcortical encephalitis and arteriosclerotic brain degeneration

1894

Germany: Alois Alzheimer separates arteriosclerotic brain degeneration from general paresis, describes senile cortical atrophy and dementia post-apoplexiam (1898)

1901

France: Pierre Marie describes état lacunaire Frankfurt, Germany: Auguste D admitted by Alzheimer to Hospital for the Mentally Ill and Epileptic

1902

Germany: Alois Alzheimer coined the name Binswanger’s disease

1906

Prague, Czech Republic: Arnold Pick describes sixth case of focal brain atrophy (Pick’s disease) Frankfurt, Germany: Auguste D dies, autopsy shows cerebral atrophy, small vessel arteriosclerosis

1907

Prague, Czech Republic: Oskar Fischer describes miliary or drusal necrosis (amyloid plaques) in presbyophrenia (called Fischer’s disease by Arnold Pick) Tübingen, Germany: Alzheimer reports finding neuronal loss and tangled fibrils (neurofibrillary tangles) in Auguste D’s brain, (ApoE genotype e3/ e3)

1910

Germany: Emil Kraepelin’s 8th edition of Lehrbuch published, divides senile and presenile dementia, includes atherosclerotic insanity as a senile form, Alzheimer’s disease included as presenile dementia

1911

Germany: Alzheimer reports second patient, Johann F., a plaques-only case (ApoE genotype ε3/ ε3)

1912

Germany: F.H. Lewy describes cellular inclusions in Parkinson’s disease (Lewy bodies)

1920–21

Germany: Creutzfeldt and Jakob describe spastic pseudosclerosis (CGD)

The first books on the histology of the nervous system were Observationes Anatomicae et Microscopicae de Systematis Nervosi Structura (1838) written by Robert Remak (1815–1865) at the University of Berlin, and Manual of Human Histology (1853) written by his student Rudolph Albert von Kölliker (1817–1905), in Zürich, Switzerland. In 1858, Joseph von Gerlach (1820–1891) first used carmine red to stain nervous tissues. The aniline methods of Franz Nissl (1860–1919) followed next; Nissl first used magenta red, then methylene blue, and finally toluidine blue with lasting success. Later came the gold and silver techniques of Camillo Golgi (1843–1926) and Santiago Ramón y Cajal (1852–1934) for neurones, the lithium carbonate method of Pío del Río-Hortega (1882–1945) for glia, as well as those of Carl Weigert (1845–1904) and Vittorio Marchi (1851–1908) for myelin. These, and other techniques, allowed the rapid development of cellular neuroanatomy and histopathology (Bielschowsky 1907, Nissl & Alzheimer 1914, Spielmeyer 1922).

Vascular dementia The history of vascular dementia during the 19th and 20th Centuries has been recently reviewed (Román 1999a). Two of the most distinguished figures of this period were Otto Binswanger (1852–1929) in Jena (Fig. III.1.6a) and Alois Alzheimer (1864–1915) in Frankfurt and Main (Fig. III.1.7a). The life and work of Binswanger (Schneider & Wieczorek 1991, Román 1992) and Alzheimer (Beach 1987, Berríos 1990, Berríos & Freeman 1991, Bick 1994, Weber 1997) have been amply reviewed. They were contemporary, and had common interests, having trained in Germany in pathology and neuropsychiatry. Also, before embarking in the study of cerebrovascular disease as a cause of dementia, both had previously published some of the first monographs on the neuropathology of neurosyphilis (Fig. III.1.6b), an entity that had become an exceedingly common cause of dementia in Europe at that time (Binswanger 1893, Nonne 1902, Alzheimer 1904). Based on the success of the syphilis paradigm,

216 CHAPTER III.1

(a) Fig. III.1.6 (a) Otto Binswanger (1852–1929) (National Library of Medicine, Bethesda, Maryland, USA). (b) Title page of his influential book on The Histopathology of the Cortical Disease in General Paralysis of the Insane (1893). (c) Title page of his article On the Demarcation of the General Paralysis of the Insane (3, 10 and 24 December 1894). In this article Binswanger introduced the term presenile dementia, described arteriosclerotic brain degeneration, and encephalitis subcorticalis chronica progressiva (named Binswanger’s disease by Alzheimer).

but working independently, Binswanger and Alzheimer began a series of clinicopathological correlation studies attempting to isolate additional forms of dementia (Alzheimer 1894, 1895, 1898, 1899, 1902; Binswanger 1894, 1908; Binswanger & Schazel 1917; see also Mast et al. 1995). The first results were presented in September of 1894, at the conference of German Alienists in Dresden, where Alzheimer and Binswanger described several novel forms of vascular dementia. Interestingly, it was at this meet-

(b)

ing that Binswanger (1894) used for the first time the term presenile dementia (präsenilen Demenz, Fig. III.1.6c): ‘Ich möchte dieselben unter dem Begriff der einfachen, präsenilen Demenz zusammenfassen’ (author’s emphasis). They identified four new forms of vascular dementia (reviewed by Román 1999), as follows: Arteriosclerotic brain degeneration, perivascular gliosis of the brain cortex or senile cortical atrophy (Alzheimer 1898), dementia postapoplexiam (Mast et al. 1995, Alzheimer 1898), and Binswanger’s chronic progressive subcortical encephalitis (Nissl 1920, Olszewski 1962, Schorer & Rodin 1990, Blass et al. 1991, Förstl et al. 1991, Pearce 1997). In 1902, Alzheimer coined the name Binswanger’s disease and provided additional histological details. He said:

HISTORICAL CONCEPT OF DEMENTIA 217

Binswanger-type subcortical white matter rarefaction was first reported in 1854 by Maxime Durand-Fardel [1816–1899], the father of gerontology in France, in his Traité Clinique et Pratique des Maladies des Vieillards [Clinical and Practical Treatise of Diseases of the Elderly]. Durand-Fardel described an asymptomatic condition he named atrophie interstitielle du cerveau (‘interstitial atrophy of the brain’) consisting of: an alteration of the cerebral pulp . . . [that] seems quite different from the infarct proper . . . it does not seem to be due to a change in the consistency of the brain but to a rarefaction of the pulp . . . a mere interstitial atrophy . . . If a section is performed at the centre of the changes, it can be seen that the white matter is rarefied . . . We do not know any symptom characteristic of this change.

(c)

[In 1894,] Binswanger, in addition to arteriosclerotic brain atrophy, also described a chronic diffuse subcortical encephalitis, of which he says that in it a strong arteriosclerosis of the brain arteries is also evident, so that the suggestion arises to attribute the subcortical fibre loss to nutrition disorders caused by the arteriosclerosis. Binswanger’s encephalitis subcorticalis [is], as the anatomical investigation shows, only a subform of arteriosclerotic brain atrophy. Under the microscope the cortex appears quite well preserved in most regions . . . whereas most of the white matter is lost. However, the white cores of the convolutions and the short association fibre bundles are as a rule preserved. The deeper white matter is either completely absent or very lightly stained . . . These lesions are due to a particularly severe arteriosclerosis of the long vessels of the deep white matter. (translation by Mast et al. 1995)

In 1842, Durand-Fardel also first described état criblé, the dilatation of perivascular spaces around cerebral arterioles; he suggested that this ‘sieve-like state’ was a result of vascular congestion (Román 1987a). In 1901, Pierre Marie (1853–1940), at the Hospice de Bicêtre, described a remarkably similar clinical condition, état lacunaire, emphasizing the presence of multiple lacunes. Dementia was not a salient feature, but some intellectual deficit was considered to be constant in état lacunaire (Marie 1901). In addition to lacunes, there was ventricular dilatation and lesions of the white matter having the appearance of a moth-eaten rag (aspect d’étoffe mitée), with islands of fibrillary glia (Román 1999b). Arteriosclerotic insanity The widespread dissemination of Binswanger and Alzheimer’s studies on vascular dementia depended, however, of their acceptance by Emil Kraepelin (1856–1926), perhaps the most influential psychiatrist of his time. In 1903, Kraepelin moved to his new Psychiatrischen und Nervenklinik at Neßbaumstraße in Munich and appointed Alzheimer as director of the Clinic’s Anatomisches Laboratorium; in 1904 Alzheimer habilitated himself as Privatdozent with a postdoctoral thesis (Habilitationsschrift) entitled ‘Histological study on the differential diagnosis of progressive paralysis’ (Alzheimer 1904). Kraepelin’s Nervenklinik

218 CHAPTER III.1

(a)

(b)

Fig. III.1.7 (a) Alois Alzheimer (1864–1915) (National Library of Medicine, Bethesda, Maryland, USA). (b) Dr Alzheimer’s first patient, Auguste D, in a 1902 photograph taken at Frankfurt am Main’s Hospital for the Mentally Ill and Epileptic where she was admitted because of behavioral problems (courtesy of Dr Konrad Maurer and The Lancet).

attracted a distinguished audience that included Gaetano Perusini and Francesco Bonfiglio from Italy, Hans Creutzfeldt and Alfons Jakob from Germany, Nicolás Achúcarro from Spain, as well as Salomon Carter Fuller and Smith Ely Jeliffe from the USA (Weber 1997, Hamann 1997). Walther Spielmeyer (1879–1935), who went to publish some of the most famous books on neuropathology (Spielmeyer 1911, 1922), was Alzheimer’s successor when he was offered the prestigious chair of psychiatry at the University of Breslau in Silesia (now Wrocdaw, in Poland) (Amaducci et al. 1986). Successive editions of Kraeplin’s Lehrbuch gauged the advances made in psychiatry from one edition to the next. Kraepelin’s ideas regarding taxonomy were based on essential clinical features and have thus resisted the test of time and have per-

meated into the 21st Century (Berríos & Hauser 1988). In the 1910 edition of his Lehrbuch der Psychiatrie, Kraepelin separated presenile dementia from the former group of the senile dementias (Das senile und präsenile Irresein). Among the senile dementias he included ‘arteriosclerotic insanity’ or ‘arteriosclerotic psychosis’ (Das arteriosklerotische Irresein), further dividedafollowing closely the conclusions of Alzheimer and Binswangerainto four clinicopathological variants. The chapter on Das arteriosklerotische Irresein (Kraepelin 1910) includes illustrations of arteriosclerotic brain degeneration showing multiple lacunar strokes, état criblé, and severe arteriolosclerosis; as well as senile cortical atrophy (perivascular gliosis), illustrating granular atrophy and laminar necrosis. It also provided probably the first illustration of Binswanger’s disease. It was in this same 8th edition

HISTORICAL CONCEPT OF DEMENTIA 219

of his textbook that Kraepelin (1910) first included ‘Alzheimer’s disease’ as a form of presenile dementia. Senile dementia and Alzheimer’s disease In his Lectures on Clinical Psychiatry (1913) Kraepelin confirmed his view that senile dementia was ‘an exaggeration of normal senility’ resulting from poor cerebral circulation and brain atrophy. He wrote: The very extensive loss of memory, which has only spared the inveterate impressions of a long time past, complete the picture of that morbid exaggeration of the changes seen in normal senility, which is known as senile dementia . . . The most obvious cause of such disturbances is to be found in the senile lesions of the blood-vessels, but there is no doubt that, independently of these changes, a large area of nervous cortical tissue atrophies [may be found], at any rate in morbid senile dementia. Alzheimer (1898) recognized that some cases of senile dementia may present with depression or with psychomotor agitation, as follows: Finally, one observes cases of melancholia which after a long interval of mental health recur in a second attack, in which the mental defect soon comes to the foreground and progressive senile dementia follows. One cannot draw a sharp boundary between melancholias of the involutional period which end with recovery and those which end up in senile dementia . . . Kraepelin’s delirious diseases of old age may be unique expressions of senile brain degeneration. On the basis of histological examinations I must endorse this view of Kraepelin. Interestingly, as early as 1898, Alzheimer separated clinically senile and presenile dementia. He wrote: Presenile dementia is distinguished from the common senile dementia by the pre-existing feebleness of the intellect and the early appearance of senile feeblemindedness, and from paralysis by its long slow course and the lack of characteristic physical symptoms of paralysis. (translated by Bick 1994)

Also, already in 1898, Alzheimer minimized the importance of vascular factors in senile dementia. He wrote: With regard to the fundamental anatomic origin of senile dementia, there is certainly unanimity as to the fact that atheromatous degeneration of the brain vessels is of essential importance for the development of senile brain atrophy . . . I myself earlier regarded this concept as correct. But then, I examined a case which had to be called presenile dementia in which I found severe atrophic processes on the ganglion cells, but also rather insignificant atheromatous vascular changes. Alzheimer was not referring to his now-famous first patient Auguste D, who only until 25 November 1901 was to be admitted to the Hospital for the Mentally Ill and Epileptic in Frankfurt am Main, where Alzheimer was working as a resident at the time when he wrote this review (Alzheimer 1898). Auguste D died on 8 April 1906, three years after Alzheimer had moved to Munich (Maurer et al. 1997). Alzheimer briefly reported the case at the Meeting of the South-West Germany Psychiatrists held in Tubingen on 3 and 4 November 1906 (Alzheimer 1907). The case was further studied and published in 1910 by Gaetano Perusini (Bick & Amaducci 1987, Bick et al. 1987). Modern histology studies of the brain of Auguste D confirmed the presence of numerous neurofibrillary tangles and amyloid plaques, and her ApoE genotype was ε3/ε3 (Graeber et al. 1998). In 1911, Alzheimer reported his second case, Johann F., a 56-year-old man with presenile dementia hospitalized for 3 years in Kraepelin’s clinic in Munich with a diagnosis of vascular dementia. This patient’s brain had numerous amyloid plaques but no neurofibrillary tangles, it lacked amyloid precursor protein (APP) mutations at codons 692, 693, 713, and 717; and, as in the case of Auguste D, his APOE genotype also was ε3/ε3 (Graeber et al. 1997). The controversy surrounding the autonomy of Alzheimer’s disease as a separate form of presenile dementia (identical to senile dementia) has been discussed authoritatively by Bick (1994). Briefly, Oskar Fischer (1907) in Prague had described

220 CHAPTER III.1

‘miliary or drusal necrosis of Redlich’ (drusige Nekrosen)aan old name for amyloid plaquesaas a specific finding in patients with presbyophrenia, a subtype of dementia with prominent confabulation (Berríos 1986), later called ‘Fischer’s disease’ by Pick (Amaducci et al. 1986). As mentioned above, Alzheimer (1904, 1907, 1911) and Perusini (1910, 1911) found similar structures in elderly brains. The presence of neurofibrillary tangles is considered Alzheimer’s unique contribution (Perusini 1911), but as mentioned above, his second patient was a ‘plaque-only’ case without tangles (Graeber et al. 1997). Regarding vascular lesions, when Alzheimer first examined Auguste D. (see Fig. III.1.7b) on 29 November 1901 he found that she had a left hemiparesis. He wrote: ‘Muscular strength: at the left side considerably reduced compared with the right side . . . No facial nerve differences. Patellar reflexes normal’ (Maurer et al. 1997, p. 1548). Furthermore, the autopsy, performed after Auguste’s death on 8 April 1906, reported: ‘Anatomical diagnosis: moderate hydrocephalus (external internal); cerebral atrophy; arteriosclerosis of the small cerebral vessels’ (Maurer et al. 1997, p. 1548). To Alzheimer’s credit, in 1907, when he first presented the typical neuropathological findings he recognized that ‘we are dealing with a peculiar, littleknown disease process’ not vascular in origin. Graeber et al. (1997) found no evidence of vascular lesions upon re-examination of the brain. Therefore, since 1898, Alzheimer had already recognized that senile dementia resulting in loss of brain weight and ‘widespread degeneration of ganglionic cells of the cortex’ could occur without cerebrovascular disease. In 1912, Walton, in Boston, had reached a similar conclusion. Nonetheless, Kraepelin’s term arteriosclerotic dementia incorrectly became synonymous with senile dementia, implying that cortical atrophy in the elderly resulted from ischemic–hypoxic neuronal death. In 1914, Joseph Jules Dejerine (1849–1917), a distinguished neurologist at the Salpêtrière in Paris, recognized the difficulties faced by neurologists separating vascular dementia from senile dementia and the artificial increase in frequency that would result from using Kraepelin’s term. In fact, in 1939, Arthur Noyes, a psychiatrist in

Pennsylvania, in his psychiatry textbook noted the false epidemic increase in cases of vascular dementia: Since 1912 the admission rate of arteriosclerotic psychoses to public hospitals . . . has increased more than six-fold. [This] is probably attributable to a growing tendency on the part of the hospital authorities to make a diagnosis of cerebral arteriosclerosis rather than that of senile dementia. Clinically the two conditions are often difficult to differentiate. Concurrently, Alzheimer’s disease and Pick’s disease were considered to be quite rare. Writing in 1959, in the 2nd edition of his textbook, neurologist H. Houston Merritt stated: Both Pick’s and Alzheimer’s disease are rare. Rothschild and Kasanin found 9 cases of Alzheimer’s disease in a series of 234 consecutive autopsies in a hospital for mental patients in the United States. McMenemey reported the incidence of 1.2% of Alzheimer’s disease in 487 autopsies at a mental hospital in England. Sjögren, Sjögren and Lindgren collected 80 cases from the mental hospitals in Stockholm with autopsy proof in 36 of the cases, equally divided between Pick’s and Alzheimer’s disease. The unification of presenile Alzheimer’s disease and senile dementia began to take place in the 1960s and 70s as a result of the careful correlation studies of Roth, Tomlinson and Blessed (1966) (see also, Roth 1955, Blessed et al. 1968 and Tomlinson et al. 1970) in Newcastle upon Tyne, UK, until the unification under the name ‘senile dementia of the Alzheimer type’ finally occurred towards 1976 (Katzman 1976, Plum 1979). Other forms of dementia Huntington’s chorea On 15 February 1872, George Sumner Huntington (1850–1916) read before the Meigs and Mason Academy of Medicine in Middle Port, Ohio, US, a report simply titled, On Chorea. Huntington described a disease characterized by a striking movement disorder, leading to insanity and dementia.

HISTORICAL CONCEPT OF DEMENTIA 221

The familial nature of this illness had been carefully documented by his father, Dr George Lee Huntington, and by his grandfather, Dr Abel Huntington who had practiced medicine in East Hampton, Long Island, in the State of New York, dating back to 1797 (DeJong 1970, Bruyn et al. 1974). The disease was traced to two brothers from Suffolk, England, who had migrated to Boston Bay in 1630. Some one thousand cases could be traced to this common ancestry in 300 years (Vessie 1932). Some of the cases of dancing mania or Saint Vitus dance (Chorea sancti Vidi) occurring in Germany during the 14th and 15th Centuries, and illustrated in paintings by Peter Brueghel and Hieronymous Bosch, could have been instances of Huntington’s chorea (McHenry 1969), chorea minor of Sydenham (1686), or massive hysteria. Alzheimer (1911b,c), wrote one of the first studies on the neuropathology of Huntington’s chorea.

inate substance and in the dorsal motor nucleus of the vagus, but only rarely in the substantia nigra. He wrote: ‘[These cellular inclusions] are simply findings which I up till now have found in all the cases of paralysis agitans that I have examined, but which were absent in the control cases’ (translation by Forno 1990). The interest in the substantia nigra in Parkinson’s disease resurfaced in May 1917, when Constantin von Economo (1876–1931) first described encephalitis lethargica, an infectious disease with a mortality of around 38%, which first appeared in Europe in 1915, perhaps related to the influenza epidemic. A frequent chronic sequela was postencephalitic parkinsonism, accompanied by oculogyric crises, and severe degeneration of the substantia nigra. It was no until 1961 that a form of dementia characterized by presence of Lewy bodies within cortical neurones was clearly identified. Creutzfeldt–Jakob disease

Pick’s disease and the frontotemporal dementias Arnold Pick (1851–1924) headed the school of neuropsychiatry in Prague for many years. He was immensely productive with more than 280 publications, mainly in the field of aphasia and behavioural neurology (Kertesz & Kalvach 1996). Between 1892 and 1906 he described six patients with presenile dementia and behavioral syndromes that resulted from severe, circumscribed and asymmetric focal atrophy of the brain (Pick 1892, 1901, 1904, 1906). Other than the macroscopic description of the brains (provided by Chiari), Pick gave no histological information and he felt that his cases were non-vascular in nature and the result of a localized degenerative process. Alzheimer (1911a) described ballooned neurones and the typical intranuclear inclusions, now called Pick bodies. Pick’s disease and related focal atrophies are currently classified as frontotemporal dementias (Kertesz & Muñoz 1998, Binetti et al. 1998, Levy et al. 1998).

In 1920, Hans Gerhardt Creutzfeldt reported ‘a peculiar nodule-forming disease of the nervous system’ in a young woman seen at Spielmeyer’s institute in Munich; and, a few months later, Alfons Maria Jakob (1921), in Hamburg, published three more cases of ‘spastic pseudosclerosis’, followed by two more cases later. Spielmeyer (1922) recognized the unity of the disease and called it Creutzfeldt–Jakob disease (CJD) (Kirschbaum 1968). After kuru (Gajdusek et al. 1965, 1966), this became the first form of transmissible dementia in humans (Gibbs et al. 1968), attributable to non-conventional viruses or prions. The epidemic outbreak of bovine spongiform encephalopathy (BSE) in Great Britain (1985–95) and the occurrence of an atypical variant of CJD caused by the same prion strain (Hill et al. 1997), suggest that human infection by ingestion of beef contaminated with prions may produce in humans the rare form of degenerative dementia described by Creutzfeldt and Jakob in the 1920s (see Collinge 1998).

Lewy-body dementia

Into the new century

In 1912, F.H. Lewy described the cellular inclusions named after him in patients with Parkinson’s disease, mainly in the nucleus basalis, in the innom-

Enormous progress was achieved in the study of dementia during the last quarter of the 20th Century, in large part the result of advances in

222 CHAPTER III.1

other areas of medicine, in particular epidemiology, microbiology, immunology, virology, imaging, genetics, molecular biology, neuropathology, and pharmacology. The unexpected growth of the elderly population forced the elimination of the mixed group of ‘organic brain syndromes’ and ‘arteriosclerotic senility’ of the 1960s, in order to better define and investigate individual diseases, describe their clinicopathological features, frequency and risk factors. Progress has been particularly rapid not only for the eponymic diseases named after Alzheimer, Binswanger, Pick, Lewy, Creutzfeldt and Jakob, but also for the different categories of vascular dementia where prevention appears possible, and most importantly for the AIDS-related dementia that in the last years of the 20th century replaced syphilis as the principal infectious cause of dementia. The emphasis for the future is towards the early diagnosis of dementia in the hope that new therapies will prevent the occurrence of dotage. Perhaps the paradigm needed to diagnose dementia in the near future may have to return to the most crucial and sensitive of the frontal lobe functions, the one defined by the ancients as the sensus communisa executive control function (Román & Royall 1999).

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Pinel, P. (1802) La Médecine Clinique rendue plus précise et plus exacte par l’application de l’analyse ou Recueil et résultat d’observations sur les maladies aigües, faites à la Salpêtrière. Brosson, Gabon et Cie, Paris. Plato. The Laws. Book IX. [Transl. Bury, R.G.: Manchester University Press, 1921.] Plato. Republic. [Transl. Shorey, P., Loeb Classical Library, 2 Vols: Harvard University Press, Cambridge, MA.] Plum, F. (1979) Dementia; an approaching epidemic. Nature 279, 372–373. Pratensis, I. (1549) De Cerebri Morbis. Basle. (Quoted by van Gijn 1998). Remak, R. (1838) Observationes Anatomicae et Microscopicae de Systematis Nervosi Structura. Reimerianis, Berolini. Reisberg, B. (1983) Alzheimer’s Disease. The Standard Reference. The Free Press, New York. Riese, W. (1959) A History of Neurology. MD Publications, New York. Robertson, G.M. (1923) The discovery of general paralysis. Journal of Mental Science 69, 1. Roccatagliata, G. (1986) A History of Ancient Psychiatry. Greenwood Press, New York. Roccatagliata, G. (1986a) Hippocrates and the birth of clinical psychiatry. In: A History of Ancient Psychiatry (ed. Roccatagliata, G.), pp. 161–170. Greenwood Press, New York. Roccatagliata, G. (1986b) Aulus Cornelius Celsus: the Roman Physician and psychiatry. In: A History of Ancient Psychiatry (ed. Roccatagliata, G.), pp. 181–192. Greenwood Press, New York. Roccatagliata, G. (1986c) Aretaeus of Cappadocia: the clinician of Mania. In: A History of Ancient Psychiatry (ed. Roccatagliata, G.), pp. 223–235. Greenwood Press, New York. Roccatagliata, G. (1986d) Claudius Galenus: organismicdynamic psychiatry. In: A History of Ancient Psychiatry (ed. Roccatagliata, G.), pp. 193–213. Greenwood Press, New York. Román, G.C. (1987a) Cerebral congestion. A vanished disease. Archives of Neurology 44, 444–448. Román, G.C. (1987b) Senile dementia of the Binswanger type. A vascular form of dementia in the elderly. JAMA 258, 1782–1788. Román, G.C. (1992) Historical aspects: From Alzheimer to Binswanger. In: Vascular Dementia (ed. Román, G.C.). Thieme, New York. New Issues in Neurosciences 4, 83–85. Román, G.C. (1999a) A historical review of the concept of vascular dementia: lessons from the past for the future. Alzheimer’s Disease and Associated Disorders 13 (Supplement 3), S4–S8. Román, G.C. (1999b) Vascular dementia today. Revue Neurologique (Paris) 155 (Supplement 4), 64–72. Román, G.C. & Royall, D.R. (1999) Executive control function: A rational basis for the diagnosis of vascular dementia. Alzheimer’s Disease and Associated Disorders 13 (Supplement 3), S69–S80. Roth, M. (1955) The natural history of mental disorders in old age. Journal of Mental Science 101, 281–301.

HISTORICAL CONCEPT OF DEMENTIA 227

Roth, M., Tomlinson, B.E. & Blessed, G. (1966) Correlation between scores for dementia and counts of ‘senile plaques’ in cerebral grey matter of elderly subjects. Nature 209, 109–110. Rush, B. (1793) An account of the state of mind and body in old age. In: Medical Inquiries and Observations, Vol. 2. Dobson, Philadelphia, PA. (Quoted by Torack 1983.) Rush, B. (1812) Medical Inquiries and Observations upon the Diseases of the Mind. Kimber & Richardson, Philadelphia, PA. Schneider, R. & Wieczorek, V. (1991) Otto Binswanger (1852–1929). Journal of the Neurological Sciences 103, 61–64. Schorer, C.E. & Rodin, E.A. (1990) Binswanger’s disease: a complete translation. Journal of Geriatric Psychiatry and Neurology 3, 61–66. Shakespeare, W. King Lear. [Brooke, T. & Phelps, W.L. (eds): Yale University Press, New Haven, CT, 1947.] Simon, N. (1986) La Pitié-Salpêtrière. L’Arbre à Images, Paris. Sophocles. Oedipus at Colonus. [Transl. Storr, F., Loeb Classical Library, 2 Vols: Heineman, London.] Spielmeyer, W. (1911) Technik der mikroskopischen Untersuchung des Nervensystems. Springer, Berlin. Spielmeyer, W. (1922) Histopathologie des Nervensystems. Springer, Berlin. Sydenham, T. (1686) Schedula monitoria de novae febris ingressu. G. Kettilby, London. [Transl. Greenhill as On St. Vitus’s Dance: On the Appearance of a New Fever in Schedula Monitoria, para. 19, pp. 198–200; and in The Works of Thomas Sydenham, M.D.: chapter XVI, Processus Integri, pp. 257–259: The Sydenham Society, London, 1850.] Terry, R.D. (1976) Dementia: a brief and selective review. Archives of Neurology 33, 1–4.

Terry, R.D., Katzman, R. & Bick, K.L. (1994) Alzheimer Disease. Raven Press, New York. Tomlinson, B.E., Blessed, G. & Roth, M. (1970) Observations on the brains of demented old people. Journal of Neurological Science 11, 205–242. Torack, R.M. (1983) The early history of senile dementia. In: Alzheimer’s Disease. The Standard Reference (ed. Reisberg, B.), pp. 23–28. The Free Press, New York. Vessie, P.R. (1932) On the transmission of Huntington’s chorea for 300 years. The Bures family group. Journal of Nervous and Mental Disease 76, 553–573. Walton, G.L. (1912) Arteriosclerosis probably not an important factor in the aetiology and prognosis of involution psychoses. Boston Medical and Surgical Journal 167, 834–836. Weber, M.M. (1997) Alois Alzheimer, a coworker of Emil Kraepelin. Journal of Psychiatric Research 31, 635–643. Webster’s (1976) Third New International Dictionary of the English Language Unabridged. G. & C. Merriam Co, Springfield, IL Weiner, D.B. (1994) ‘Le geste de Pinel’: The history of a psychiatric myth. In: Discovering the History of Psychiatry (eds Micale M.S. & Porter, R.), pp. 232–247. Oxford University Press, New York. Willis, T. (1664) Cerebri anatome: cui accessit nervorum descriptio et usus. Ja. Flescher, Londoni. Willis, T. (1667) Pathologiae cerebri et nervosi generis specimen. Guil. Hall, Oxford. Willis, T. (1672) De Anima Brutorum Quae Hominis Vitalis ac Sensitiva est. Ric. Davis, Oxonii. [Transl. Pordage, S. in Dr Willis’ Practice of Physick, Two Discourses Concerning the Soul of Brutes: T. Dring, C. Harper & J. Leigh, London, 1684.] Willis, T. (1684) The London Practice of Physick. [Transl. Pordage, S. In Dr Willis’ Practice of Physick, Two Discourses Concerning the Soul of Brutes. (T. Dring, C. Harper & J. Leigh.) London, 1684.]

III.2

Alzheimer’s Disease

Edited by: David Knopman, Karen Ritchie, Catherine Polge, Irina Alafuzoff and Hilkka Soininen

III.2.1

Preamble

David Knopman Key points

• The sensitivity of the clinical diagnosis of Alzheimer’s disease (AD) is > 80%, but the specificity is lower. • Most patients with early AD have little to no awareness of their deficits. Even if they do, they almost never act upon their concerns. • Deficits in learning and retaining new material are the hallmark of the memory disorder in AD. • Even though quantitative differences exist between early and late onset AD, these differences are of relatively little diagnostic value to clinicians. • The time from diagnosis to nursing home placement is approximately 3–6 years for the majority of AD patients. • Parkinsonian signs, hallucinations and delusions are associated with more rapid decline. • There are no laboratory tests that have been validated for routine diagnostic use in suspected AD. Alzheimer’s disease (AD) is the prototypical and most common dementing disorder. It is found in all

228

human populations worldwide. It typically appears in later life: while it can appear in individuals in their 30s or 40s, the vast majority of cases are over the age of 65 years. Alzheimer defined the neuropathology of the disorder in his original publication in 1907. The seminal work of Blessed, Tomlinson and Roth in 1968 identified the relationship between the neuropathological features and the cognitive disorder. Over the next decade, the biochemistry of AD began to be better understood, first with the discovery of the cholinergic deficit, and later, by the characterization of the beta-amyloid peptide. We now know of three gene mutations which are associated with a large number of the cases of autosomal dominant transmission of the disorder. One and presumably more susceptibility genes exist for the disorder. As the new millennium opens, we have several neurotransmitter-based palliative therapies for the disorder, and evidence that an antioxidant is also effective in modifying the symptomatic course of the disease. Prospects are excellent for the introduction of more potent disease- or symptom-modifying therapies in the next decade. The present chapter presents an evidence-based review of AD, covering the broad array of basic science and clinical aspects of the disease.

ALZHEIMER’S DISEASE 229

Vignette When Mr Smith was 54 years old, he developed low back pain and was treated with ibuprofen and codeine. Coincident with the use of the medications, he became paranoid and confused. He did not wish to be left alone and developed signs of depression. These symptoms developed over a period of 2 weeks. The patient himself stated that he had trouble focusing his train of thought. Two years later he saw a neurologist because of memory problems. He was still working when the neurologist saw him. The patient noted that he was having trouble with procedures that he had previously been familiar with. He had no other significant medical problems. He did not smoke, drink or have any exposure to elicit drugs. His initial mental status exam showed him to be fully orientated. Arithmetic performance was intact. Memory was not tested. The remainder of the neurological exam was normal. He retired from work about 6 months later. When another neurologist saw him 1 year later, he was having problems with orientation, construction and free recall. He scored 25 out of 30 points on the Mini Mental Status Examination (MMSE). His delayed recall performance on the auditory verbal learning test, a 15-word list learn-

III.2.2

ing task, was zero. An MR scan did not show specific changes. The diagnosis of AD was made formally, 3 years after the onset of symptoms. He was placed on Cognex and Prozac. The Cognex was discontinued within several months because of side effects. Over the next year he declined. His MMSE score fell to 17 correct out of 30. Over the following year he became completely disoriented. His MMSE was 14 at a point 2 years after the diagnosis. One year later his score had fallen to 4 correct. His wife had become unable to care for him and he entered a nursing home 6 years after the onset of symptoms, and 3 years after first seeing a neurologist. By 7 years into his symptoms, he had become mute and incontinent. He developed myoclonus and generalized seizures. He died approximately 7 years after the initial onset of symptoms. An autopsy confirmed that he had AD and no other pathology. Both neuritic plaques and neurofibrillary tangles were prominent in the frontal, temporal and parietal lobes, yielding a diagnosis of definite AD by Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) criteria and a Braak stage of V–VI. (Comment: this man’s illness, extending over 7 years was typical of AD even though the onset seemed somewhat unusual at the time.)

Diagnostic Considerations

David Knopman

Alzheimer’s disease (AD) is the most common dementing disorder. Several different diagnostic criteria for AD have been published. The two most widely used are the National Institute of Neurological and Communicative Diseases and Alzheimer’s Disease and Related Disorders Association (NINCDSADRDA) criteria (McKhann et al. 1984) and the Diagnostic and Statistical Manual (DSM) DSM-IV criteria (American Psychiatric Association 1994). Other criteria include DSM-IIIR (American Psychiatric Association 1987) and the International Classification of Diseases 10th revision (ICD-10) (World Health Organization 1992). These criteria are not interchangeable, as there are important

conceptual differences between them (Erkinjuntti et al. 1997). The specifics of these criteria are outlined in Table III.2.1. The specificity and sensitivity of the diagnosis of AD has been calculated against neuropathological findings (Table III.2.2) for some of the criteria. Three clinical–pathological correlation studies (Jobst et al. 1998; Holmes et al. 1999; Lim et al. 1999) have examined the specificity and sensitivity of the NINCDS-ADRDA criteria, and have reported somewhat disparate values for the clinical diagnosis of probable AD vs. the pathological diagnosis of ‘pure’ AD. When the diagnoses of probable and possible AD were combined, the sensitivity of pathologically

Table III.2.1 Diagnostic criteria for AD. NINCDS-ADRDA

DSM-IIIR

DSM-IV

ICD-10

Description of core syndrome

Dementia established by clinical examination and documented by (mental status) examination

Dementia

The development of multiple cognitive deficits

Dementia

Course

Progressive worsening of memory and other cognitive functions

Insidious onset and course generally progressive and deteriorating

Gradual onset and continuing cognitive decline

Insidious onset with slow deterioration

Memory disorder

Progressive worsening of memory (not further described)

Demonstrable evidence of impairment in short- and long-term memory. Impairment in short-term memory, inability to learn new information, may be indicated by inability to remember three objects after 5 min. Long-term memory impairment, inability to remember information that was known in the past, may be indicated by inability to remember past personal information or facts of common knowledge

Impaired ability to learn new information or recall previously learned information

Typically affects the registration, storage and retrieval of new information, but previously learned and familiar material may also be lost, particularly in the later stages

Other symptoms required for diagnosis

Deficits in (one) or more areas of cognition (in addition to a memory disorder); such as language (aphasia), motor skills (apraxia) and perception (agnosia)

And at least one of the following (is required): impairment in abstract thinking, impaired judgment; other disturbances of higher cortical function such as the aphasia, apraxia, agnosia and constructional difficulty, personality change

One or more of the following (is required): disturbances in executive functioning (ie, planning organization, sequencing, abstracting; aphasia (language disturbance); apraxia (impaired ability to carry out motor activities despite intact motor function); agnosia (failure to recognize objects despite intact sensory function)

Impairment of thinking and of reasoning capacity, and a reduction in the flow of ideas. The processing of information is impaired, (difficulty in attending) to more than one stimulus at a time, and (difficulty in shifting) the focus of attention from one topic to another

Behavior, effect, personality

Diagnosis is supported by altered patterns of behavior

There may also be subtle personality changes such as the development of apathy, lack of spontaneity and a quiet withdrawal from social interactions

Not discussed

See above comments about impairment of thinking, but otherwise not discussed

Functional impairment

Diagnosis is supported by impaired activities of daily living

The disturbance significantly interferes with work or usual social activities and relationships with others

The cognitive deficits each cause significant impairment in social or occupational functioning and represent a significant decline from a previous level of functioning

(Required) Declines in both memory and thinking which are sufficient to impair personal activities of daily living

Exclusions

No disturbances of consciousness; features that make the diagnosis of AD uncertain or unlikely include: sudden, apoplectic onset; focal neurological findings; and seizures or gait disturbances at the onset or very early in the course

Not occurring during the course of delirium; all other specific causes of dementia by history physical examination and laboratory tests

Other CNS conditions; systemic conditions; substance-induced conditions; not exclusively during delirium; not better accounted for by another Axis I disorder (eg. major depressive disorder, schizophrenia)

Absence of systemic or (other) brain disease which can induce a dementia; absence of a sudden, apoplectic onset, or of neurological signs such as hemiparesis occurring early in the illness

230 CHAPTER III.2

Criteria

Table III.2.2 Clinical–pathological correlations in AD. Clinical prob. AD* vs.

Prob or poss† AD vs.

Study

Origin of subject sample

Case definition clinical diagnosis to enter study

Sample size (no. of dementia patients)

% of NINCDS prob AD clinical diagnoses

AD (all) prevalence (% of total, by path criteria)

Overall diagnostic accuracy (AD+ nonAD) by path

pure path AD‡ sensitivity

pure path AD‡ specificity

pure AD pure path‡ AD path‡ sensitivity specificity

any§ any§ path AD path AD specificity sensitivity cases

Jobst et al. (1998) Holmes et al. (1999) Lim et al. (1999) Galasko et al. (1994) Wade et al. (1987) Victoroff et al. (1995) Gearing et al. (1995) Klatka et al. (1997)

Population Population Population Clinic Clinic Clinic Clinic Clinic

Dementia Dementia Dementia Dementia Dementia Dementia AD AD

104 80 123 170 65 196 106 170

38 48 64 65 60 59 100 100

77 85 76 86 74 76 93 88

66 70 75 62 70 63 – –

49 66 83 78 87 75 87 88

100 75 55 47 78 54 – –

96 – 85 93 – 86 – –

– 50 – 90 – 89 – –

– 70 – 42 – 37 – –

ALZHEIMER’S DISEASE 231

*Clinical diagnoses of probable AD by NINCDS-ADRDA criteria, except Wade et al. (1987). †Clinical diagnoses of probable or possible AD by NINCDS-ADRDA. ‡Neuropathological diagnoses of definite AD by CERAD or Khatchaturian neuropathological criteria, except Wade. §Neuropathological observation of any AD pathology regardless of abundance or relationship to diagnostic criteria.

61 – 50 32 – 41 – –

232 CHAPTER III.2

pure AD was high, but the specificity was lower. In samples of patients based on recruitment from dementia clinics, three studies (Wade et al. 1987; Galasko et al. 1994; Victoroff et al. 1995) reported similar values for sensitivity and specificity. From series that included only AD patients clinically (Gearing et al. 1995; Klatka et al. 1997), the sensitivities were reported to be in the 87–88% range.

Methodology for selection of articles cited in the sections on presentation and natural history of AD A literature review was conducted by searching Medline in the fall of 1998 in conjunction with a project sponsored by the American Academy of Neurology on the diagnosis of dementia. The search sought articles on the topic of dementia diagnosis. In addition to this search, articles in the literature from 1983 to the present and captured in the author’s personal bibliographic files were pulled and reviewed.

Memory A deficit in memory is the hallmark of the cognitive disorder in AD. More precisely it is a deficit in new learning and encoding of information (Storandt et al. 1984; Knopman & Ryberg 1989; Welsh et al. 1991; Petersen et al. 1994; Herlitz et al. 1995; Tierney et al. 1996; Grober & Kawas 1997). While the ability to retrieve information from long-term memory is eventually impaired in AD, the important diagnostic feature is the deficit in new learning. DSM-IIIR erred in requiring impairment in longterm memory; DSM-IV noted that deficits in longterm memory were not required for the diagnosis. It is sometimes referred to as ‘short-term’ memory. Operationally, recall of information after a 5-min delay is the measure of new learning in AD patients. In the majority of patients with AD, memory complaints will be the dominant set of symptoms. Memory complaints account for many of the symptoms that caregivers report (Vitaliano et al. 1986).

Orientation Presentation of AD Disturbances in recent memory function are the typical symptoms that lead to the suspicion and eventual diagnosis of AD. Patients repeat themselves in conversation, repeat the same question, or forget recent conversations (Rubin et al. 1989; Koss et al. 1993; Oppenheim 1994; Petersen et al. 1994). The symptoms may be so insidious in onset that they may be ignored or misinterpreted by family caregivers or physicians as insignificant, ‘normal aging’, or depression. Patients with AD usually ignore their own shortcomings and deny or minimize their deficits (Grut et al. 1993; Lopez et al. 1994; Starkstein et al. 1996; Seltzer et al. 1997). Loss of the ability to carry out key daily tasks such as shopping, handling money or doing chores around the house may be more powerful triggers than forgetfulness for seeking medical attention. Symptoms are typically present for 1–3 years before family members bring the patient to medical attention. Neuropsychiatric symptoms such as hallucinations, delusions, profound depression or marked irritability may be more likely to prompt an evaluation than forgetfulness itself.

Orientation is clearly impaired in patients with AD. Given the ubiquitous nature of impairment of orientation in dementia, as well as its ease of assessment, reference to orientation among the core deficits of dementia would seem warranted. To the extent that orientation is mediated by memory, attention, language, visuospatial function and even executive functions, its impairment is a proxy for dysfunction in one or more of those domains.

Language Disturbances of language function, ‘aphasia’, are frequently seen in AD. Observational studies show that dementia patients exhibit deficits in naming (Faber-Langendoen et al. 1988; Shuttleworth & Huber 1988) and word fluency at mild stages of disease (Faber-Langendoen et al. 1988; Green et al. 1990).

Visuospatial processing Disturbances of visuospatial synthesis are well recognized and may be the predominant symptom in

ALZHEIMER’S DISEASE 233

AD in some patients (Crystal et al. 1982; Hof et al. 1990; Mendez et al. 1990; Graff-Radford et al. 1993; Levine et al. 1993; Victoroff et al. 1994; Giannakopoulos et al. 1999). On occasion, the visual symptoms are the presenting ones.

Executive function Impairment of ‘executive’ functions and attention may be demonstrable neuropsychologically in early AD (Kopelman 1991; Kanne et al. 1998), and the consequences of deficits in problem solving, judgment, foresight and mental agility lead to loss of competence in daily living (Marson et al. 1995).

Loss of function From the perspective of the caregiver, a loss of ability to carry out activities necessary for independent daily living is the most important manifestation of AD. The losses include difficulties with handling money and finances, travelling independently, cooking, shopping, or using a telephone (Vitaliano et al. 1986; Green et al. 1993; Galasko et al. 1997a). These changes are often present at the time of diagnosis. For most AD definitionsaDSM-IIIR, DSMIV and ICD-10abut not NINCDS-ADRDA, loss of function is a required element of the definition of the dementia of AD.

Neuropsychiatric symptoms The DSM-IV, NINCDS-ADRDA and the ICD-10 definitions of AD fail to include changes in personality, impairment of affect and disturbances of behavior among the core symptoms of dementia, even though, empirically, these entities are common in early dementia of diverse etiologies. The spectrum of changes is protean, ranging from increased apathy and social withdrawal to disinhibition or irritability (Reisberg et al. 1987; Teri et al. 1988; Mega et al. 1996; Reichman et al. 1996; Gilley et al. 1997; Patterson et al. 1997). Recognition of the affective and behavioral symptoms of dementia should increase diagnostic sensitivity. So long as some other cognitive deficits are present, the inclusion of this domain should not reduce specificity of the diagnosis of dementia.

Non-anterograde amnesia presentations of AD On occasion, AD presents in ways other than as a disorder in which recent memory is a primary area of deficiency. Sometimes, impaired judgment, social misbehavior and other manifestations of a frontotemporal dementia may be as prominent as the memory disorder (Neary et al. 1988; Brun 1993; Miller et al. 1997). Another rare alternative presentation of AD is that of a visual disturbance, visual agnosia, that is more bothersome to the patient’s function than the memory problems. The visual agnosia manifests as impaired figure and ground perceptions, impaired reading, impaired face recognition and impaired object recognition (Crystal et al. 1982; Hof et al. 1990; Mendez et al. 1990; Graff-Radford et al. 1993; Levine et al. 1993; Victoroff et al. 1994). AD patients rarely present with anomia or expressive language deficits (Green et al. 1990).

Age of onset Historically, the distinction between a ‘presenile’ and a ‘senile’ form of AD was frequently invoked. In the past 20 years, that distinction has been largely abandoned, but the fact remains that there are some clinical features of the disease that covary with age. For example, the autosomal dominant form of AD occurs almost exclusively among those with very young age of onset. The effects of some susceptibility genes such as apolipoprotein E (ApoE), have a strong age dependence (Farrer et al. 1997). Clinically, several studies have shown that patients under age 65–70 years tend to have slightly different clinical presentations, either in terms of faster rates of progression or more language deficits at the time of diagnosis (Heston & Mastri 1982; Huff et al. 1987; Becker et al. 1988; Lawlor et al. 1994; Raskind et al. 1995). However, even if such differences are present in group analyses, age-related differences are hardly ever detectable on an individual basis (Huff et al. 1987).

Natural history The natural history of AD varies considerably from

234 CHAPTER III.2

one individual to the next, but there are some approximate values that can be applied to the different phases of the illness. The average length of time from onset of symptoms until diagnosis is 2–3 years (Knopman et al. 1988; Thal et al. 1988; Morris et al. 1989; Galasko et al. 1990; Walsh et al. 1990). The average duration of time from diagnosis to nursing home placement (a marker of severe dementia) is 3–6 years (Colerick & George 1986; Knopman et al. 1988; Brodaty et al. 1993; Severson et al. 1994; Knopman et al. 1996; Heyman et al. 1997; Scott et al. 1997; Stern et al. 1997). Alzheimer patients spend approximately 3 years in nursing homes prior to death (Welch et al. 1992). Thus, the total duration of AD is roughly 9–12 years. Mortality in AD averages less than 10% per year (Barclay et al. 1985; Martin et al. 1987; Knopman et al. 1988; Walsh et al. 1990; Evans et al. 1991; Brodaty et al. 1993; Katzman et al. 1994; Kukull et al. 1994; Bowen et al. 1996; Heyman et al. 1996). Causes of death in AD include pneumonia, sepsis and other common causes of mortality in the elderly such as cardiovascular disease and stroke (Kukull et al. 1994; Beard et al. 1996). A large number of studies have examined rate of progression of AD within the symptomatic phase using mental status examinations such as the Mini Mental Status Examination (MMSE). Across patients whose initial MMSE scores ranged from 10 to 26, the average rate of change per year is about 3 points (Katzman et al. 1988; Ortof &

III.2.3

Crystal 1989; Salmon et al. 1990; van Belle et al. 1990; Galasko et al. 1991; Schneider 1992; Morris et al. 1993; Kraemer et al. 1994). The variability is considerable as indicated by the standard deviation of ~4 about this value (van Belle et al. 1990; Morris et al. 1993; Knopman & Gracon 1994). The rate of decline obeys a curvilinear relationship to the cognitive test scores (Morris et al. 1993; Stern et al. 1994). Faster rates of decline occur in the mid-portions of the scales, and slower rates occur among milder and more severe patients. Moreover, a decline over one 6-month or 1-year period does not predict the rate of decline over a subsequent time interval (Salmon et al. 1990). There are few predictors of rate of progression, but parkinsonian signs, hallucinations and delusions have been shown to be associated with more rapid decline (Chui et al. 1994; Stern et al. 1994; Lopez et al. 1997). This set of observations is consistent with recent findings that patients with dementia and Lewy Bodies have a faster rate of decline than comparably demented AD patients (Olichney et al. 1998). Another way of conceptualizing the progression of AD is to look at the time to reach key milestones of the disease such as deteriorating to a Clinical Dementia Rating (CDR) of 3 or losing basic activities of daily living skills. In one large study of carefully diagnosed AD patients (Galasko et al. 1995), these values can be used to discuss prognostic issues with families.

Clinical Picture

David Knopman

Stages of AD (see Fig. III.2.1 and Table III.2.3) Very mild AD Between the state of normal cognitive and functional abilities and that of mild but definite dementia is a condition that is now referred to as mild cognitive impairment (MCI) (Petersen et al. 1995). Others have referred to this state as possible dementia prodrome, or very mild Alzheimer’s Disease (AD) (Rubin et al. 1989). Individuals with

MCI often have memory complaints that mirror their poor performance on tests of memory and learning, but they appear to function normally in daily affairs. MCI is often a precursor of AD, but not always (Hanninen et al. 1995; Petersen et al. 1995). Approximately 15% of MCI patients deteriorate and qualify for a diagnosis of AD per year (Petersen et al. 1995; Petersen et al. 1999). Patients with mild cognitive impairment are sometimes identified because they are discovered coincidentally to have poor performance on mental status testing.

ALZHEIMER’S DISEASE 235

Intact

Relative decline of function

Basic ADL Recent memory

Verbal/non-verbal cognition

Very impaired

Instrumental ADL Very mild

Mild

Moderate

Advanced

(a)

Very mild

Mild

Moderate

Advanced

(b)

Fig. III.2.1 Schematic view of changes in cognitive function (a), and function (b), in AD. ADL, activities of daily living.

Sometimes patients with MCI refer themselves to physicians because of concerns about their own memory. Not all MCI patients go on to develop AD. Thus, some individuals with the features of MCI have a static condition, rather than a deteriorating one. Some of these individuals presumably have had impaired memory on a life-long basis. Others may have sustained brain injuries at an earlier age that have produced static dysfunction. Thus, the category of MCI, as currently conceptualized, is heterogeneous with respect to prognosis for future decline. This stage corresponds roughly to Clinical Dementia Rating (CDR) stage 0.5 (Hughes et al. 1982) or Global Deterioration Scale (GDS) stage 2 (Reisberg et al. 1982).

Mild AD The syndrome of mild AD [which is CDR stage 1 (Hughes et al. 1982) or GDS stages 3 or 4 (Reisberg et al. 1982)] is characterized by clear-cut deficits in recent memory, deficits in at least one of the other cognitive domains and loss of functional independence. Functional loss in individuals with mild AD might take the form of difficulties with financial affairs, difficulties with geographical orientation in their own homes and other familiar places (Henderson et al. 1989), or an inability to do tasks within known jobs or around the home. Their ability to recall information from the past is often impaired only minimally at this stage of the illness. Changes in personality frequently are part of the presentation of mild AD. The spectrum of personality changes ranges from increased apathy and

social withdrawal to disinhibition or irritability (Reisberg et al. 1987; Teri et al. 1988; Mega et al. 1996; Reichman et al. 1996; Gilley et al. 1997; Patterson et al. 1997). Depression is common also, and can exacerbate cognitive deficits (Greenwald et al. 1989; Kramer & Reifler 1992; Levy et al. 1996). Paranoia and obsessions may become evident, although these are more likely to occur in later stages of the disease. Frank hallucinations and delusions occasionally occur in mild AD. On mental status examination, patients with mild AD score between 20 and 26 on the MMSE. Memory performance may be the most abnormal portion of the cognitive examination. Patients recall nothing after a short delay (Knopman & Knopman 1989; Welsh et al. 1991; Petersen et al. 1994; Buschke et al. 1997; Grober & Kawas 1997). A mild AD patient may have largely intact conversational comprehension and spontaneous speech. However, patients with mild AD and their families report difficulties finding words, that can be observed with naming tests that use less common objects (Faber-Langendoen et al. 1988; Shuttleworth et al. 1988). Abstract reasoning deficits may be detectable with more difficult tasks that require mental agility to manipulate sequential mental tasks. However, prior intellectual and occupational achievement strongly affects how well a mild AD patient will do with naming or abstract reasoning. Most patients with mild AD have some constructional difficulties. On more detailed neuropsychological testing, widespread deficits in visuospatial processing are often observed (Mendez et al. 1990; Binetti et al. 1998).

236 CHAPTER III.2

Table III.2.3 Stages of AD. Stage

CDR

GDS Recent memory

Language

Visuospatial

Executive

Behavioral

Motoric

Mild cognitive 0.5 impairment

2

Subjective memory complaints; poor performance on free recall

No observable deficits or minimal word-finding errors

No observable deficits or inconstant geographic orientation deficits

No observable deficits, or subtle declines in very high functioning persons

No changes or mild personality change; may be less energetic

None

Mild dementia 1

3–4

Frequently repeats self; forgets recent events; poor to nil free recall; usually at least one error on temporal orientation

Mild but detectable word-finding errors; intact ordinary comprehension

Geographic disorientation; mild errors in drawing or construction but gist is present

Some difficulties with money, shopping, judgement; mild errors on calculations and mental agility

No changes or mild personality change, apathy, depression, indifference, mild irritability

Some extrapyramidal features

Moderate dementia

2

5

Nil recall; very impaired recognition memory

Word-finding problems frequent; mild comprehension deficits

Cannot navigate outside home without companion; gross drawing and construction errors; some dressing difficulty

Unable to handle financial affairs or any complex decisionmaking; gross errors on calculations and mental agility

Apathy, indifference; Some extrapyramidal some patients may features or frank be very irritable, parkinsonism anxious or depressed

Severe dementia

3

6–7

Nil recall or recognition

Sparse meaningful verbal output; very impaired comprehension

Cannot find way in own residence; unable to draw or copy; unable to dress self

Severe impairment with no pretence of preserved abilities; gross deficits in toileting, personal hygiene, apathy, indifference, some patients may be very irritable, anxious, aggressive

Apathy, indifference; some patients may be very irritable, anxious or depressed

Some extrapyramidal features or frank parkinsonism; may experience seizures; myoclonus

ALZHEIMER’S DISEASE 237

The motor neurological examination is typically normal in patients with mild AD, although some subtle extrapyramidal signs may be seen (Galasko et al. 1990; Funkenstein et al. 1993; Stern et al. 1994).

Even at this stage of the illness, the motor neurological examination may be normal except for signs of mild rigidity or bradykinesia (Galasko et al. 1990; Stern et al. 1994).

Moderate AD

Severe AD

Patients with moderate AD (CDR stage 2 or GDS stage 5) not only are dependent on others for higher-level daily living activities, such as finances, shopping or transportation, but may also, on occasion, need to be reminded to bathe and to dress appropriately. Moderate AD patients may fail to recognize acquaintances that are not part of the patient’s daily retinue. Patients at this stage of AD should no longer operate motor vehicles or devices such as lawn movers, power saws or probably even stoves and ranges. Neuropsychiatric disturbances may become prominent. Delusions and hallucinations are common. Patients often begin to misrecognize their own homes as ‘home.’ Irritability and paranoia are common symptoms of moderate AD. Disrupted sleep may also occur. On mental status examinations with the MMSE, moderately severe AD patients will score between 10 and 19. Patients at this stage have word- and name-finding deficits that are obvious in conversation. Information or recent events are often almost instantly forgotten. Motor apraxia may be evident at this stage of AD (Rapcsak et al. 1989). If patients with moderate AD have reasonably competent spouse or child care givers, they can often remain in the family residence. If not, moderate AD patients may need supervised living situations. Some assistance almost always becomes needed for solo caregivers in the later stages of moderate AD.

Patients with severe AD (CDR stage 3 or GDS stages 6 and 7) need 24-h supervision. They have negligible memory for events, conversations and, unfortunately, even close family members. They have substantial word-finding difficulties. Their spontaneous speech is impoverished. They may be virtually mute, or they may use jargon-filled speech that conveys no meaningful information (Peavy et al. 1996). They need extensive assistance with bathing, dressing, eating and urination/defecation. They are more likely than milder patients to become aggressive when offered assistance with undressing or urination/defecation, although some severe patients are very docile. Despite their fragmentary cognition, severely demented patients may experience depression, anxiousness and fear. They typically score below 10 on the MMSE (Volicer et al. 1994; Peavy et al. 1996). A minority of AD patients experience generalized seizures (Romanelli et al. 1990; Mendez et al. 1994), often in the severe stage of the disease. Patients may also exhibit marked rigidity, bradykinesia, gait and balance difficulties and masked faces (Galasko et al. 1990; Clark et al. 1997). Severely demented individuals are at high risk for fatal pneumonias and other diseases that occur in debilitated persons (Evans et al. 1991; Kukull et al. 1994; Beard et al. 1996; Bowen et al. 1996).

III.2.4

Diagnostic Tools

David Knopman

The diagnosis of Alzheimer’s Disease (AD) cannot be verified with a laboratory test at present. A variety of methods have been proposed: cerebrospinal fluid (CSF) tests (de la Monte et al. 1997; Galasko et al. 1997b; Andreasen et al. 1998; Galasko et al. 1998; Kanai et al. 1998); various tests involving

the eyes (Scinto et al. 1994; Litvan & FitzGibbon 1996; Graff-Radford et al. 1997; Growdon et al. 1997; Kardon 1998); magnetic resonance neuroimaging approaches (Jack et al. 1992; Killiany et al. 1993; Fox et al. 1996; Scheltens et al. 1997; Reiman et al. 1998); and functional neuroimaging

238 CHAPTER III.2

(Powers et al. 1992; Claus et al. 1994; Jobst et al. 1994; Masterman et al. 1997; Scheltens et al. 1997; Talbot et al. 1998). To a greater or lesser degree with each proposed diagnostic test, there is either clear evidence of overlap between normal elderly and AD, or insufficient data available to prove that the procedure is useful clinically. In part, some of the failures may be a consequence of the inaccuracies of the clinical diagnosis, as discussed above, as well as the difficulties in obtaining autopsy

confirmation of the diagnosis in a large representative sample of patients. There is also a problem with determining the proper comparison group. It is not clear whether cognitively normal subjects, patients with non-AD dementias or both should be the primary ‘not-AD’ comparison. A reliable non-invasive or minimally invasive marker of the brain neuropathology of AD is sorely needed. Criteria for evaluating future diagnostic markers have recently been formulated (Consensus Report 1998).

Epidemiology of the Dementias and Alzheimer’s Disease III.2.5

Karen Ritchie Key points

Introduction

• Dementia is a generic term referring to progressive loss of cognitive functions, commonly accompanied by changes in mood, behavior and personality. The two most common forms are Alzheimer’s disease (AD) and vascular dementia (VaD), accounting for 60% and 25%, respectively, of all senile dementias. • Confirmed risk factors for AD are age, an ApoE e4 allele, vascular pathology, and a family history of dementia or vascular disorder. The principal risk factors for VaD are age and a family history of vascular pathology. Risk factors may be interactive, with the coexistence of certain factors greatly increasing risk. Average survival time from disease onset is around 8 years. Prevalence rates are seen to rise exponentially, ranging from 1.5%, between ages 65 and 69, to 44.8% in the age range 95–99. Incidence has been estimated at 1% per annum over age 60. • Dementia is one of the most important causes of disability in the elderly. Around 60% of people receiving disability benefits have dementia. Dementia creates resource demands not only for the afflicted person, but also for care givers as caring for a person with this disorder has consistently been found to increase risk for physical and mental disorder.

Classification and etiology of the dementias Dementia is a generic term referring to chronic or progressive disturbance of cortical and subcortical functions, including allocation of attentional resources, memory, reasoning, language, and visuospatial analysis. These cognitive changes are also commonly accompanied by alterations of mood, behavior and personality. The causes of dementia are numerous and may generally be divided into two principal groups: primary degenerative dementias and secondary dementias (that is, dementias which may occur in the course of another disease process) (Fig. III.2.2). The primary dementias may be further divided into cortical and subcortical dementias according to the site of the principal underlying lesions. The two most common forms of primary cortical dementia are AD and Pick’s disease. AD accounts for approximately 60% of all causes of dementia and is characterized by the appearance of amyloid plaques and neurofibrillary tangles in the frontal, temporal and parietal areas of the brain. These lesions are also observed in the brains of normal ageing people. The reason for their rapid proliferation in AD is still largely unknown. The question remains as to whether they are the cause or the

ALZHEIMER’S DISEASE 239

Primary dementias

Secondary dementias

Cortical

Sub-cortical

Vascular

Non-vascular

Alzheimer’s disease Pick’s disease

Huntington’s disease Creutzfeldt–Jakob Steele–Richardson Supra-nucear palsy

Multi-infarct dementia Lacunar dementia Binswanger dementia Hemodynamic dementia

Encephalitic Hemorrhagic Anoxia AIDS

Fig. III.2.2 Classification of the dementias.

result of the disease process. Pre-senile (before age 65 years) and senile (after age 65) forms of AD have been differentiated formally: the distinction appears to be justified in terms of differences in the probable underlying genetic risk factors and some clinical differences observed in the clinical course of the disease, the pre-senile form often taking a more rapid course. Pick’s disease accounts for only 1% of all causes of dementia and is characterized by frontal lesions giving rise to early changes in personality and social behavior. Lack of drive is common and insight is severely impaired. The subcortical dementias collectively account for 5% of all dementias and include such forms as Huntington’s chorea (a genetic disorder with onset usually between the ages of 20 and 50 years, characterized by choreic movements and dementia with apathy and disorganization, rather than memory deficits), Creutzfeldt–Jakob disease (a rapid dementia characterized by delirium and spastic rigidity resulting from glycoprotein particles without DNA or RNA, known as prions), supra-nuclear palsy or Steele–Richardson’s syndrome (a rare neurological disorder characterized by global mental deterioration, and disturbance of ocular and motor movements), some forms of Parkinson’s disease (a disease characterized by tremor and dementia, in some cases characterized by failure to recognize new stimuli and short-term memory disorder). The VaDs are the principal cause of secondary dementias (representing approximately 25% of all causes). Up until the early 1980s all VaDs were considered to be the result of multiple infarcts. Other causes have now been differentiated although their origins are still the cause of some controversy. These are senile dementia of the Binswanger type, caused by periventricular white matter lesions,

lacunar dementia, resulting from tiny infarcts, and haemodynamic dementia, attributed to hypoperfusion caused by cardiac dysrhythmias and hypotension. Given the ongoing controversy concerning subtypes of VaD they will be generally referred to in this text as the VaDs. VaD and AD may co-occur in the same individual in which case the term ‘mixed dementia’ is applied. AD and VaD are the most common forms of dementia and are thus the focus of the present review. Although AD and VaD may occur in young adults, this is relatively rare and the populations afflicted by these two disorders are almost entirely elderly. In the face of the phenomenon of population ageing, it is these two disorders which imply the greatest burden in terms of loss of human resources and health sevice spending.

Natural history of the major dementing diseases The onset of AD is insidious with longitudinal studies of homozygotic twins reporting deficits in cognitive functioning in the affected twin up to 20 years before diagnosis (Hofman et al. 1991). As intellectual deterioration is generally slow, the elderly person may continue to interact socially for several years. The first phase of the disease typically involves irregular memory lapses, particularly evident in word-finding, spatial disorientation and disorganization in everyday life. Mood disturbances, especially depression, are common, but psychotic features are rare. The second stage is marked by further deterioration in cognition and personality and focal symptoms (dysphasia, apraxia, agnosia) appear. Extrapyramidal signs are also common and extensor plantar responses may be observed. Hallucinations and delusions may also occur

240 CHAPTER III.2

and the elderly person at this stage often fails to recognize family members. In the terminal stage of the disease there is profound cognitive disorder and mutism and the elderly person becomes doubly incontinent and bedridden. Neurological signs include forced grasping, sucking reflexes, epileptic seizures, severe striatal rigidity and tremor. The onset of VaD is generally more acute than in AD and may often go unnoticed unless there has been a clear case of vascular accident. Early symptoms include headache, dizziness, syncope and tinnitus. The accompanying cognitive deficits fluctuate in severity and may be preceded by emotional

III.2.6

or personality changes. Cognitive impairment may change on an hourly basis and clouding of consciousness is common, especially towards the evening. Cerebral infarction causes abrupt episodes of hemiparesis with dysphasia or visual disturbances. Episodes are transient at first and followed by a recovery of function. As the disease progresses, an increasing number of permanent neurological deficits remain with increasing dementia, pseudobulbar palsy and a tendency to walk in very tiny steps. The cognitive deficit is patchy and highly variable in progression from one individual to another. Personality may be well preserved until late in the disease.

Risk Factors and Mortality

Karen Ritchie

Risk factors and protective factors Epidemiological studies have largely focused on risk factors for late-onset Alzheimer’s disease (AD). Of the large number of hypotheses that have been explored only old age (Jorm et al. 1987; Hofman et al. 1991; Ritchie et al. 1992), a family history of dementia (Soininen & Heinonen 1982), a history of vascular disorder (Hofman et al. 1991) and the allele ApoE e4 (Corder et al. 1994) are currently considered confirmed risk factors. Female sex (Tomlinson et al. 1970; Wade et al. 1987), a history of head injury (Mortimer et al. 1985), western rather than eastern nationality (Li et al. 1989), and, more recently, a negative relationship with the use of hormonal replacement therapy (Tang et al. 1996), have all been found to modify risk of AD. Some studies have shown significant odds ratios for environmental factors such as sleep apnea (Reynolds et al. 1985), exposure to aluminum (Martyn et al. 1989), advanced parental age (Amaducci et al. 1986), and an inverse relation with smoking (Hofman et al. 1991). However, other studies have not confirmed these original observations. While the use of analgesics as a risk factor for AD had initially been dismissed by early studies, more recent analyses suggest a possible protective effect which has been hypothesized to be a consequence of their anti-inflammatory properties (McGeer et al. 1990).

The role of socio-economic factors in AD is highly controversial. A negative correlation has consistently been found between cognitive impairment and education level, with high levels of education reducing in particular the degree of deterioration on verbal tasks (Dartigues et al. 1991; Leibovici et al. 1996). However, the relationship between these factors and AD has not been clearly established; indeed, some studies have found higher prevalence rates in people with low levels of education (Li et al. 1989; Dartigues et al. 1991). Other authors have suggested that pre-morbid intelligence and neuronal reserve capacity may be link factors affecting both socio-economic status and disease onset (Leibovici et al. 1996). There have been far fewer studies of risk factors for vascular dementia (VaD), partly because of its lesser significance in terms of prevalence and the difficulties in making an accurate diagnosis. The principal risk factors are generally considered to be age and family history (Akesson 1969; Jarvik & Matsuyama 1983). Other factors commonly showing significant odds ratios are diabetes (Meyer et al. 1988), hypertension (Wilkie & Eisdorfer 1971), cholesterol (Muckle & Roy 1985), tobacco (Wilkie & Eisdorfer 1971; Pinessi et al. 1983; Muckle & Roy 1985; Meyer et al. 1988) and alcohol use (Pinessi Meyer). Most risk factor studies have been over-simplistic in their conceptual approach. Primarily, they have failed to recognize the possibility that subtypes of

ALZHEIMER’S DISEASE 241

AD and VaD may exist such that the impact of a potentially important risk factor may have been overlooked as a result of the summing together of all cases. The possibility of the existence of subtypes in terms of both areas of the brain affected and evolution of the disorder has been raised by a number of authors (Martin 1987; World Health Organization 1970; American Psychiatric Association 1980; Gurland et al. 1983; Mckhann et al. 1984; Nilsson & Persson 1984; Barclay et al. 1985; Schoenberg et al. 1985; Preston 1986; Treves et al. 1986; Zhang et al. 1990; Burns et al. 1991; Ritchie & Touchon 1992; Roelands et al. 1994; Osuntokun et al. 1995; Ritchie & Kildea 1995; Hofman et al. 1997). Although clinical dementia subtypes such as Lewy-body dementia and frontotemporal dementia have been identified more recently, these have not been formally recognized in international classification systems. A second limitation has been the use of a univariate approach to the establishment of risk factors. That is, most studies have assumed a single underlying cause or the independent action of causes. The real situation is most likely to be far more complex, involving, for example, an interaction between genetic risk factors and one or more environmental catalysts. Studies that have examined combinations of risk factors have produced higher odds ratios (e.g. Tang et al. 1996), the greatest risk cited to date being the combination of ApoE e4 and atherosclerosis (Hofman et al. 1997).

III.2.7

Mortality and survival Survival rates for dementia cannot be estimated with any accuracy because of the difficulties of defining a precise point of time for disease onset. The clinical diagnosis is frequently made many years after families first note behavioral deterioration in the sufferer. The only information presently available is taken from estimates of survival time from either diagnosis or admission to care. It is now generally accepted that dementia shortens life significantly (Schoenberg et al. 1985; Treves et al. 1986). The average survival time from the time of diagnosis is around 8 years (Barclay et al. 1985) but there is general agreement that survival time with AD is greater than with VaD (Ferm 1974; Burns et al. 1991). Women also show longer survival with both AD and VaD than men, even when differences in life expectancy are taken into account (Barclay et al. 1985; Burns et al. 1991). It is important to note that dementia is rarely given as a cause of death although its course is irreversible. In the USA the principal cause of death given for people with AD is respiratory disorders and for people with VaD the leading cause is cardiovascular disease (Schoenberg et al. 1985). In Finland bronchopneumonia is the principal stated cause of death of persons with dementia. Death records are therefore unreliable sources of information on dementia prevalence.

Prevalence and Incidence

Karen Ritchie and Catherine Polge Prevalence

Over the past four decades, epidemiological studies have been carried out across the general population as well as clinic-based samples. Prevalence studies have been the most common, reaching over 70 studies to date. Data are now available in various parts of the world, including Africa, Australia, China, Europe, Japan, USA, the Russian Federation, Scandinavia, Latin America, India, Canada, Egypt, Korea and Singapore. Only very limited information on specific dementias has been provided in incidence as well as in prevalence studies.

Accurate estimates and international comparisons were not feasible up until the 1980s because of variability in the case-detection methods used. Most studies conducted after 1980 have used internationally recognized diagnostic criteria, notably DSM-III (Homer & Gilleard 1990), ICD-9 (World Health Organization 1970), their associated standardized assessment batteries, and the clinical directives of the US Department of Health and Human Services (McKhann et al. 1984). As a result, studies conducted after 1980 show high consistency in their reported prevalence rates, with senile dementia being estimated to affect approximately 5% of

242 CHAPTER III.2

Table III.2.4 A meta-analysis of Age (years)

Number in group

% prevalence (observed)

95% confidence intervals

% prevalence (fitted model)

65–69 70–74 75–79 80–84 85–89 90–94 95–99

1459 4740 6291 4327 4191 1388 317

1.53 3.54 6.80 13.57 22.26 31.48 44.48

1.16–2.60 3.01–4.07 6.18–7.42 12.54–14.58 21.00–23.52 29.04–33.92 36.28–52.68

1.50 3.54 7.30 13.40 22.17 33.00 44.80

the population aged over 65 years in western countries. Given the complexity and expense involved in making a provisional diagnosis of dementia, most population studies have been conducted in two phases, a screening test followed by clinical assessment of positively screened cases. This procedure is acceptable if the clinical examination is based on adequate case-finding criteria as described above, and if a representative sample of negatively screened individuals is also subject to clinical examination to adjust for errors in screening test detection. Dementia prevalence increases with age so that estimates will be to a large extent dependent on the age ranges sampled. A number of meta-analyses have been conducted which have attempted to demonstrate changes in rates with age (Preston 1986; Jorm et al. 1987; Ritchie et al. 1992). Rates of around 1.5% at age 65 are consistently found with an exponential increase in prevalence (rates doubling around every four years) and rising to around 30% over age 80. Over this age there is some evidence that prevalence rates stabilize and even diminish (Ritchie & Kildea 1995), but this may be a consequence of survival effects, and incidence studies with adequate numbers at high ages are required to confirm this observation. Table III.2.4 shows prevalence rates derived from a metaanalysis (Preston 1986) of studies using acceptable diagnostic criteria. Observed prevalence rates are given with their 95% confidence intervals. A logistic rather than an exponential model is found to fit the observed data best, giving the prevalence rates in the final column.

Incidence Incidence studies are less numerous because they

dementia prevalence rates derived from nine studies using internationally accepted diagnostic criteria (with confidence intervals), and estimates derived from a fitted logistic model.

require longitudinal observation to ascertain new onset of dementing diseases. Nevertheless, existing incidence studies have shown that dementia of all types is approximately 1% per annum in persons aged 60 years and over. Incidence rates appear to rise exponentially with age as with prevalence. There is some evidence to suggest that incidence is higher in women (Akesson 1969) although Nilsson (Nilsson & Persson 1984) has found the opposite. Disease-specific studies show higher consistency with a general trend for higher incidence of Alzheimer’s disease (AD) in women and a higher incidence of vascular dementia (VaD) in men. Very few data are available on country of residence and ethnicity; however, a higher incidence of dementia has been reported in New York than in London (Gurland et al. 1983) and the incidence of early onset AD has been reported to be higher in Israeli Jews of European and American origin compared to those of African or Asian origin (Treves et al. 1986). Changes over time in incidence are difficult to ascertain as so few studies are available and the tendency for long-term studies to introduce changes in case-finding criteria. In Europe and North America, AD is more common than VaD, according to most estimates. This contrasts with a higher prevalence of VaD in China, Japan and the Russian Federation. An important exception is a large survey conducted in Shanghai (Zhang et al. 1990) where it was found that AD accounted for 65% of all cases of dementia. In other countries of the developing world, dementia of any type seems to be rare. There is some evidence to suggest that AD is not found in Nigerians, either in community surveys or in autopsy series (Osuntokun et al. 1995).

ALZHEIMER’S DISEASE 243

III.2.8

Calculating Burden

Karen Ritchie

Dementia-free life expectancy Following the development of methods to adjust mortality rates by morbidity, increasing interest has been shown in using this and other methods to estimate years of life lost in a given state of health. Health expectancies, a population health index which estimates the number of life years lived in a given state of disease or disability, provide a simple method for examining changes in the burden of dementia which accompany changes in life-expectancy and also permit cross-cultural comparisons. Calculations of dementia-free life expectancy have now been made for France, Australia, UK, the Netherlands, Belgium and Ireland (Ferm 1974; Homer & Gilleard 1990; Ritchie et al. 1994a; Ritchie et al. 1994b; Roelands et al. 1994; Bone et al. 1995). From these calculations it has been found that the greatest number of persons with senile dementia in the countries so far studied are between 80 and 86 years of age. At every age women have a longer dementia-free life expectancy than men; however, expressing this as a proportion of total life expectancy, it can be seen that this advantage is partly lostaso although women live longer than men in all countries studied, a large proportion of

this time is lost in dementia. Life expectancy with dementia is consistently around 1 year from age 65 onwards. In terms of burden, this means that for every person in the population aged over 65 years health planners should allow for 1 year of life with dementia (see Table III.2.5).

Rates of institutionalization The proportion of dementia cases living in the community, as opposed to nursing homes, hostels or other settings, is of considerable importance, both for health economics and for services. This proportion is likely to vary considerably, as it is dictated by cultural and social conditions. Many of the studies conducted to date have been based on selected clinical series and, as such, estimates may not apply to the full range of dementia severity as it occurs in the general population. In a prevalence study conducted in Beijing (Li et al. 1989) all patients with dementia were found to be living in the community. This might be expected because homes for the aged do not exist in many developing countries. This is in marked contrast to the pattern in most developed countries, where as many as two-thirds of all cases are typically found in institutional settings (Ely et al. 1995).

Table III.2.5 Life expectancy, dementia-free life expectancy and life expectancy with dementia at the age of 65 years by sex

and country. LE at 65 years

DemFLE at 65 years

DemLE at 65 years

% DemFLE/LE

Country

Men

Women

Men

Women

Men

Women

Men

Women

France UK (Liverpool) UK (3 cities) Belgium Eire Netherlands USA Switzerland (Geneva) Switzerland (Zurich)

15.4 13.1 14.4 14.0 13.5 14.5 18.11 16.1 16.9

19.7 17.1 19.7 18.3 16.9 19.0 21.48 20.4 21.0

14.8 12.6 13.7 13.4 13.0 14.0 16.9 17.4 16.2

18.8 15.9 17.8 16.7 15.7 17.7 19.6 19.1 18.4

0.6 0.5 0.7 0.6 0.5 0.5 1.2 –1.3 0.7

0.9 1.2 1.9 1.6 1.2 1.3 1.9 1.4 2.6

96.4 96.2 94.6 95.7 96.5 96.4 93.5 93.0 96.0

95.4 93.1 89.9 91.3 93.1 93.2 91.4 93.0 88.0

DemFLE, dementia-free life expectancy; DemLE, life expectancy with dementia; LE, life expectancy.

244 CHAPTER III.2

Dementia and disability Dementia is one of the most important causes of disability in the elderly. The evolution of the senile dementias is paralleled by progressive loss of ability to participate in society and to care for oneself. Around 60% of elderly people who receive aid for disability have dementia (Harrison et al. 1990; Kay et al. 1991). A large range of physical activities are affected in people with senile dementia, principally washing, dressing and feeding oneself, moving about, and sphincter control (Ferm 1974; Harrison et al. 1990; Homer & Gilleard 1990; Kay et al. 1991; Freels et al. 1992; Ritchie et al. 1994a; Ritchie et al. 1994b; Bone et al. 1995; Ely et al. 1995). In public health terms dementia creates resource demands not only for the person with dementia but also for care givers, as it has been consistently

demonstrated that caring for a person with dementia greatly increases the care giver’s risk of physical and mental disease (Poulshock & Deimling 1984; Harrison et al. 1990; Homer & Gilleard 1990; Kay et al. 1991; Freels et al. 1992; Cahill & Shapiro 1993; Ritchie et al. 1994a; Ritchie et al. 1994b; Bone et al. 1995; Ely et al. 1995). Recent studies have also pointed out that care givers are commonly the victims of violent attacks by the person with dementia (Poulshock & Deimling 1984). It has been estimated that as many as 89% of care givers have been victims of aggression (Cahill & Shapiro 1993). A further problem, which has received relatively little attention, is that of abuse of the person with dementia. Studies conducted in Britain and the USA have attested to high rates of physical, mental and sexual abuse both in domiciliary care and in institutions (Homer & Gilleard 1990).

Neuropathology and Ethiopathogenesis of Alzheimer’s Disease III.2.9

Irina Alafuzoff and Hilkka Soininen Key point

The ethiopathogenesis of Alzheimer’s disease (AD) is still unclear. Molecular genetic studies have revealed diversity in the genetics of AD but also pointed out the possibility and/or the requirement of a variety of mechanisms (genetics, oxidative stress, toxic) in different cascade models (βA hypothesis, tauopathy) leading to a neuronal degeneration causing AD. There is no doubt about the important roles played by βA4 or mictotubule-associated protein tau in the pathophysiology of this disease. The question still remains, however, how are these two elements linked together and which other elements are of major importance in initiating, contributing to or influencing the progression of the disease? Dementia of Alzheimer’s type affects a large proportion of the increasingly ageing population. Clinical entity AD embodies a selection of pathological

phenomena from the histopathological and ethiopathogenetic points of view. As a result of this, neuropathological investigation under standardized conditions, and the evaluation of genetics and risk factors, are of utmost importance in formulating a rational basis for future therapy.

Neuropathological analysis The histopathological hallmarks of AD are neurofibrillary tangles (NFT) and senile/neuritic plaques (SP/NP) (Khachaturian 1985; Braak & Braak 1991; Mirra et al. 1991; Dickson 1997a). Other notable signs are neuronal loss (Ball 1977; Esiri & Wilcock 1984; West et al. 1994; Gomez-Isla et al. 1996), neuropil threads and glial reaction in the neocortex (Itagaki et al. 1989; Delacourte 1990; Harpin et al. 1990; Carpenter et al. 1993; Le Prince et al. 1993; Arnold et al. 1996; DiPatre & Gelman 1997; Egensperger et al. 1998; Overmyer et al. 1999a,b), granulovacuolar degeneration (GVD) (Ball & Lo 1977) and Hirano bodies (Gibson & Tomlinson

ALZHEIMER’S DISEASE 245

1977) in the hippocampus, and white matter changes (Brun et al. 1990). A major problem in using histopathology in diagnostics is that these changes are not seen exclusively in AD but also are present in unimpaired aged individuals and in many other degenerative brain disorders. Furthermore, lesions considered as hallmarks for other degenerative disorders such as Lewy bodies (LB) in Parkinson’s disease (PD) (Gearing et al. 1995; Hulette et al. 1995; Hansen 1997; Jellinger 1997; Heyman et al. 1999) and/or brain infarcts (Gorelick et al. 1996) are also seen in patients fulfilling clinical and pathological criteria for AD.

Histopathological diagnostic criteria Since 1985 several diagnostic criteria have been proposed, e.g. the Khachaturian (Khachaturian 1985), Consortium to Establish a Registry for Alzheimer’s Disease (CERAD, Mirra et al. 1991) and Braak and Braak (Braak & Braak 1991) criteria. In the Khachaturian and CERAD criteria, diagnosis is based mainly on the number of SP/NPs in the neocortex, related to the age of the patient and to the existing clinical symptoms of dementia. In Braak and Braak criteria, the diagnosis is based on a topographical staging of the appearance of NFTs. Recently a panel of neuropathologists (National Institute on Ageing and the Reagan Institute Working Group on diagnostic criteria for the neuropathological assessment of Alzheimer’s disease) proposed neuropathological criteria for AD based on both NFTs and SP/NPs (Hyman & Trojanowsky 1997). In 1997, in Neurobiology of Aging, several researchers wrote about their experiences with a variety of diagnostic criteria (Ball & Murdoch 1997; Braak & Braak 1997; Coleman 1997; Dickson 1997b; Duyckaerts & Hauw 1997; Gambetti 1997; Geddes et al. 1997; Hansen & Terry 1997; Hyman 1997; Jellinger & Bancher 1997; Mann 1997; Markesbery 1997; Mirra 1997; Perl & Purohit 1997; Powers 1997; Price 1997; Trojanowski et al. 1997; Wisniewski & Silverman 1997). In conclusion, there are still no universally accepted neuropathological criteria for AD. Moreover, there are no generally accepted histopathological diagnostic criteria for mild cognitive impairment or for the presymptomatic stage of AD. Furthermore,

the significance of lesions such as LBs and vascular pathology in AD is still a matter of debate. Lesions of interest The NFT is an intracytoplasmatic mass of thickened and tortuous fibrils. Ultrastructurally, the NFT consists of abnormal filamentous deposits (Wisniewski et al. 1976), paired helical filaments (PHF) and related straight filaments (SF). These filaments are made of the microtubule-associated protein (MAP) tau in a hyperphosphorylated state (Goedert et al. 1992; Goedert 1993). As a consequence of the major role that MAP tau plays in the pathology of AD, the disease is sometimes listed as one of tauopathies. NFTs are not easily seen in sections stained with haematoxylin and eosin (H & E) but they are revealed clearly by silver stains such as Gallyas and Bielschowsky. The fibrils are also well labelled with antiserum prepared against the whole NFT, the PHF or against various constituents of the NFT. Many degenerative brain disorders other than AD are associated with the appearance of NFT and, moreover, NFTs are also seen in aged unimpaired individuals. In 1991, Braak and Braak (Braak & Braak 1991) were able to demonstrate a characteristic distribution pattern of NFTs and neuropil threads permitting a differentiation of AD into six neuropathological stages. However, it is still unclear whether or not, in unimpaired individuals with few NFTs in the hippocampus, the number of NFTs would have increased with time and eventually induced clinical symptoms of dementia had they survived. In the ‘Kuopio brain bank’ NFTs were seen in the hippocampus of 62% of 300 unimpaired aged individuals (mean age at death 75 ± 8 yr, range 61–98) whereas neocortical NFTs were seen in only 8%. The number of NFTs has been shown to increase with the progression of the disease and has revealed a significant correlation with the severity of symptoms (Wilcock & Esiri 1982; Cummings et al. 1996; Berg et al. 1998). In conclusion, NFTs are a rather common change in the aged brain. The appearance of PHF in the neocortex in association with amyloid plaques and as NFT, however, is a distinctive feature of AD and should lead to the diagnosis of degenerative brain disorder, presumably AD, regardless of the clinical symptoms.

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While NFT is seen primarily within the pericaryon, the plaques occupy the neuropil (Dickson 1997a). In general, there are two major morphological types of plaques (Dickson et al. 1988). The senile/neuritic plaque SP/NP consists of a central core of amyloid-like material surrounded by swollen abnormal neurites whereas the diffuse non-neuritic plaque (n-NP) lacks the swollen abnormal neurites and consists of diffuse deposits of the same protein found in the central core of SP/NPs. As with NFTs, plaques are difficult to see in H & E but are readily demonstrated using the silver impregnation method (Bielschowsky, Braunmuhl, Bodian). SP/NPs and non-NPs are also visualized by labeling with antiserum prepared against various constituents of the plaque. Ultrastructurally the SP/NP comprises a central core of extracellular amyloid fibrils intermingled and surrounded by a large number of neuronal processes (Dickson 1997a). The abnormal neuronal processes contain PHFs and SFs. Glial processes are seen interspersed among the neurites (Dickson 1997a). Ultrastructurally the diffuse n-NP contains amyloid fibrils but few or no abnormal neuritic processes. It has been hypothesized that over time the n-NP’s develop into SP/NPs (Dickson 1997b). The principal component of amyloid in plaques is a small protein, βA4 (Wisniewski et al. 1994; Checler 1995), derived from the amyloid precursor protein (APP) by proteolysis. The normal function of APP, a transmembrane glycoprotein is still unclear. It is generally accepted that SP/NPs are obligatory for the diagnosis of AD (Khachaturian 1985; Mirra et al. 1991). Therefore, one should analyse several cortical regions using both silver impregnation or immunohistochemical labelling. Because of the major role of βA4 in the pathology of AD, many researchers consider AD to be one form of amyloidosis (Wisniewski et al. 1989). The plaques, and specifically the n-NPs, are common in the brains of unimpaired aged individuals. In ‘Kuopio brain bank’ material, βA4 aggregates (n-NPs and SP/NPs) were visualized in 72% of 300 unimpaired aged individuals (mean age at death 75 ± 8 yr, range 61–98) using immunohistochemical methods, whereas silver impregnation demonstrated SP/NP in the neocortex in only 9% of the brains studied. The βA4 load increases with ageing and the number of

SP/NP increases with the duration of the disease (Cummings et al. 1996; Bartoo et al. 1997). There are also reports that have failed to observe any relationship between the number of SP/NPs and the severity of dementia (Berg et al. 1998). In conclusion, plaques are a rather common change in the aged brain. The appearance of neuritic plaques in the neocortex is a distinctive feature of AD and should lead to the diagnosis of AD regardless of the clinical symptoms. The histopathological diagnosis of AD is based on finding a large number of NFT and SP/NP’s in the neocortex. This, however, does not mean that these lesions are the only ones to be seen in the affected brain tissue. Neuropil threads are easily visualized both with silver impregnation and with immunohistochemical labeling. They are seen in all AD cases and are more common with the increase in the appearance of NFTs (Braak & Braak 1991). The main constituents of neuropil threads are SFs. White matter pathology (Brun et al. 1990) and vascular pathology (Gorelick et al. 1996) in AD is still debated and no generally accepted consensus criteria are available. The major problem in evaluating the pathological events related to the white matter or vessels is the lack of a specific diagnostic marker. The concomitant finding of extensive white matter rarefaction, macroscopic and/or microscopic infarcts should be noted in the protocol. This is of special importance when patient material has to be analysed in a research setting. However, the significance of these lesions is still under critical evaluation and debate. During recent years glial pathology has been intensively investigated in AD. In the AD brain, glial fibrillary acidic protein (GFAP) expressing astrocytes have been seen in the vicinity of plaques (Dickson et al. 1988; Dickson 1997b) and diffusely in the brain tissue (Renkawek et al. 1994). Studies have shown that the number of GFAP-expressing astrocytes is significantly higher in brain tissue of AD patients compared to age-matched controls (Overmyer et al. 1999a), and that the number of astrocytes correlates significantly with the counts of NFTs and SP/NPs (Harpin et al. 1990). Whether the function of astrocytes varies with the progression of the disease or whether astrocytic function

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influences the progression of the disease is still not known. Microglia, a resident mononuclear phagocyte in the central nervous system (CNS), is the first cell to respond to various types of CNS insults. One of the cell surface markers expressed on activated microglia is the class II, major histocompatibility complex (MHC class II) antigen HLA-DR glycoprotein (Rogers et al. 1988; Mattiace et al. 1990; Tooyama et al. 1990; Sasaki & Nakazato 1992). Recent studies have shown significantly increased up-regulation of HLA-DR in brain tissue from AD patients compared to age-matched controls (Carpenter et al. 1993; Overmyer et al. 1999b). The association between SP/NPs and activated microglia has been studied in AD and results supporting (McGeer et al. 1987; Styren et al. 1990) and disputing (Ohgami et al. 1991; DiPatre & Gelman 1997) a close relationship between plaque formation and microglia have been reported. However, recent studies have shown a significant linkage between the microglial activation and NFT counts (DiPatre & Gelman 1997). Furthermore, studies have indicated that both gender and, specifically, the apolipoprotein E genotype influence the relationships between plaques, NFTs and glia (Egensperger et al. 1998; Overmyer et al. 1999b). It is still not known whether the activation rate of microglia varies with the progression of the disease or whether microglia can influence the progression of the disease. Finally, the concomitant finding of LBs should be considered. LBs are found in unimpaired age individuals as incidental findings especially in the substantia nigra. In the ‘Kuopio brain bank’ material LBs were seen in 7% of 300 aged unimpaired individuals. LBs are readily seen in H & E preparation in substantia nigra whereas their detection in cortex is facilitated by immunohistochemical techniques that label LBs with antibodies directed to their various compounds. The significance of LBs has increased since the description of Dementia with Lewy Bodies (DLB), an entity wherein the symptomatology is associated with neocortical LBs (Burkhardt et al. 1988; McKeith et al. 1996). The cytoplasmic synuclein-containing, ubiquitinated inclusions of these LBs are sometimes also seen in AD cases leading to a histopathological diagnosis

as PD/AD, AD/PD (Gearing et al. 1995; Hulette et al. 1995; Hansen 1997; Jellinger 1997). As for infarcts, LBs should always be noted (McKeith et al. 1996) specifically in a research setting, even though the significance of the concomitant finding of AD and LBD pathology is still unclear.

Résumé In conclusion, the diagnosis of AD has been and is still based on the finding of a large number of NFTs and SP/NPs in the neocortex. Many other pathological changes, not specific for AD, can also be seen in the brain tissue. In the clinical setting, semiquantitative estimation of essential AD lesions as described in CERAD criteria (Mirra et al. 1991) is sufficient for an AD diagnosis. However, concomitant findings of other lesions should be noted. In the research setting, a more detailed analysis of essential AD lesions is recommended, one of these being the morphological staging as described by Braak and Braak (Braak & Braak 1991). In research it is especially important that concomitant lesions such as infarcts and LBs are noted. In clinical research the aim in any neuropathological investigation is to analyse the pathological lesions in such a way that the patient material to be studied and can be subclassified into homogeneous clinicopathological subgroups. In a biological research setting the goal is often to analyse one variable at a time. This can be achieved by selecting as many homogenous patient cases as possible from the histopathological point of view. This can only be done if a detailed histopathological analysis under standardized conditions has been performed and the results of this analysis are subsequently reported.

Pathogenesis Despite enormous research efforts into the pathophysiology of AD, the ethiopathogenesis of this disorder still remains elusive. Analytic epidemiological studies have provided us with some clues concerning risk factors for this disease and, more recently, molecular genetic studies have contributed to our understanding of the pathogenesis of AD. It has become increasingly evident that AD is a

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heterogeneous disorder influenced by various genetic and/or environmental factors. Several different mechanisms have been suggested to play an important role in the pathogenesis of AD. These include: overproduction and accumulation of amyloid (Checler 1995); hyperphophorylation of microtubule-associated protein tau (Goedert et al. 1992; Khatoon et al. 1992); events related to apoptosis (Smale et al. 1995); oxidative stress (Raina et al. 1999); inflammation (Breitner 1996); calcium homeostasis (Holscher 1998; Sulger et al. 1999); toxic (McKee et al. 1998), and vascular factors (Pasquier et al. 1998). Several research groups strongly advocate each of these specific mechanisms and, as a result, any proposed general mechanisms of pathogenesis are hotly debated.

Current concepts Considerable research on the pathogenesis of AD during the last 20 years has been focused on either beta-amyloid (Aβ) protein or on microtubuleassociated protein tau. The amyloid cascade hypothesis suggests that Aβ accumulation in the brain plays an essential pathogenetic role in the disease process (Hardy & Higgins 1992). The Aβ production/accumulation would be the primary event leading to the formation of PHF and SF and, consequently, to the formation of NFT (Giaccone et al. 1996; Hardy et al. 1998). The Aβ would also cause loss of synapses and neurones and finally lead to the clinical appearance of dementia symptoms (Yanker 1996). The role of Aβ has been supported by molecular genetic studies in particular. Studies in cell lines which express βAPP-complementary DNA-bearing mutations associated with familial AD (FAD) have shown a 6–8-fold increase in production of Aβ (Swedish mutation) (Citron et al. 1992) or predominant secretion of the longer Aβ42 peptide (APP717, PS1) known to aggregate more easily (Tamaoka et al. 1994; Mann et al. 1996). The tauopathy hypothesis suggests that the essential event in pathogenesis of AD would be the hyperphosporylation of microtubule-associated protein tau, formation of PHF and consequently NFTs (Goedert & Hasegawa 1999). Neuropathological studies have suggested that one of the first proofs of

degeneration are the NFTs found in the transentorhinal area (Braak & Braak 1991). With time, these lesions are seen in other limbic areas as well and finally in the neocortex. Recent molecular genetic studies have shown that mutations in the tau gene located on chromosome 17 cause dementia, supporting the essential role of tau protein, i.e. the tauopathy hypothesis (Lynch et al. 1994; Goedert et al. 1998). However, to date, known mutations on the tau gene have been associated only with non-AD types of dementia, namely frontotemporal dementia with or without parkinsonism (Lowe & Spillantini 1998).

Molecular genetics Molecular genetic studies of AD have disclosed a wide genetic diversity of this disorder (LewyLahad & Bird 1996). Ten to fifteen percent of AD patients show autosomal dominant inheritance, but familial occurrence is far more common, particularly in late onset cases. Three loci have been found to cause dominant disease: mutations in the APP on chromosome 21 (St George-Hyslop et al. 1987; Goate et al. 1991); presenilin 1 gene (PS1) on chromosome 14 (Schellenberg et al. 1992; Sherrington et al. 1995); and presenilin 2 gene (PS2) on chromosome 1 (Levy-Lahad et al. 1995a,b; Rogaev et al. 1995). To date, tens of different mutations in over 100 pedigrees have been detected in the PS1 gene and two mutations have been found in eight PS2 pedigrees (Mattson & Guo 1999). Most of these mutations are missense mutations leading to single amino acid changes (Hutton & Hardy 1997). Some deletions have also been found (Crook et al. 1998). APP mutations cover less than 1%, PS1 mutations 5–10% and PS2 mutations < 1% of FADs (Cruts et al. 1998). The rarity of APP mutations was also suggested when no mutations were found, during screening for APP665,670/671,717 mutations carried out in Finnish FAD and AD patients from Eastern Finland (Helisalmi et al. 1996). The APP mutation has been shown to influence the accumulation of Aβ in the brain tissue (Citron et al. 1992). The mutant APP transgenic mouse line shows markedly elevated Aβ levels at an early age and develops consequently extracellular AD-type

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Aβ deposits (Holcomb et al. 1998). The APP717 mis-sense mutation has been shown to affect the ratio of Aβ protein species by promoting the accumulation of Aβ42/43 species in the brain (Tamaoka et al. 1994). The function of PS1 and PS2 proteins is not fully understood but studies on PS1 knockout mice suggest that presenilins may play an important role during development (Mattson & Guo 1999). Mutant PS1 transgenic mice do not show abnormal pathology but do display subtly elevated levels of the highly amyloidogenic βA42 or βA43 (Holcomb et al. 1998) and in FAD patients with PS1 mutation βA42 or βA43 have been shown to be the predominant βA4 species (Mann et al. 1996). PS1 and PS2 are integral membrane proteins that are expressed ubiquitously in various tissues including the brain (Hutton & Hardy 1997). Immunohistochemical studies have shown that presenilins are localized intracellularly within the endoplasmic reticulum (Kovacs et al. 1996). Presenilins interact with different proteins including APP (Weideman et al. 1997) and β-catenin (Zhou et al. 1997) and are involved in altered APP metabolism (Scheuner et al. 1996). One possible way for presenilin mutations to act may be by altering calcium homeostasis in the endoplasmic reticulum (Mattson & Guo 1999).

Genetic risk factors Numerous reports have established that apolipoprotein E (ApoE) ε4 allele is a risk factor for late onset familial and sporadic AD (Corder et al. 1993; Strittmatter et al. 1993; Kuusisto et al. 1994; Farrer et al. 1997). The frequency of the ε4 allele is increased among AD patients compared to controls. A metaanalysis has shown that the risk associated with ε4 is highest in the age range 60–70 years and stronger in female than in male subjects (Farrer et al. 1997). The age of onset is about 10 years lower in AD patients carrying ε4 than in those without ε4 (Farrer et al. 1997). Supporting the important role of ApoE are results that show that the ε4 allele is associated with a more severe cholinergic defect (Soininen et al. 1995) increased load of Aβ (Schmechel et al. 1993), and higher number of neurofibrillary tangles (Alafuzoff et al. 1999). Furthermore, the ApoE

genotype has been shown to influence both astrogliosis and microglial activation (Overmyer et al. 1999a; 1999b). Other genetic risk factors have been searched for (Sandbrink et al. 1996) but not confirmed. Recently, as a result of its ability to mediate the clearance and degradation of Aβ, α-2 macroglobulin, a serum pan-protease inhibitor, has been implicated to play a role in AD pathogenesis. Genetic analysis has revealed that a deletion in the α-2 macroglobulin gene is associated with increased risk of AD, suggesting that the function of this protein might participate in AD pathogenesis (Blacker et al. 1998). Other genes proposed to increase the risk of AD are: α-antichymotrypsin allele A (Kamboh et al. 1995): VLDL receptor 5-triplet repeat allele (Okuizumi et al. 1995): HLA-A2 gene (Payami et al. 1991); LRP (Wavrant-DeVrieze et al. 1999); butyrylcholinesterase K-variant (Lehman et al. 1997; Hiltunen et al. 1998; Grubber et al. 1999); and mutations in mitochondrial genes (Shoffner et al. 1993). Recent results, using random genome search in AD, have suggested potential new loci that need further investigation to identify new candidate genes (Pericak-Vance et al. 1997; Kehoe et al. 1999) involved in the pathogenesis of AD.

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III.3

Vascular Dementia

Didier Leys, Elisabet Englund and Timo Erkinjuntti

III.3.1

Introduction

In 1896, Emil Kraepelin, following Alzheimer’s and Binswanger’s recent ideas, separated ‘arteriosclerotic dementia’, referring to vascular dementia (VaD), from ‘senile dementia’, referring to Alzheimer’s disease (AD) (Berchtold & Cotman 1998). However, up to the 1970s, cerebral atherosclerosis leading to chronic cerebral hypoperfusion was thought to be the prominent cause of dementia, while AD was considered rare, affecting only young patients. In the 1970s Tomlinson (Tomlinson et al. 1970) reinvented AD as a more frequent cause of dementia than arteriosclerotic dementia and Hachinski introduced the term multi-infarct dementia to describe the mechanism by which dementia is produced (Hachinski et al. 1974). During the 1980s the pendulum swung in the direction of AD, and VaD was relegated to a position of relative obscurity (Brust 1988). Up to the 1990s VaD was considered to be caused by multiple brain infarcts (Erkinjuntti & Hachinski 1993). However, VaD has now come full circle with the resurgence of interest of the whole spectrum of vascular causes of dementia (Hachinski 1990). This is supported by new data

III.3.2

Diagnosis

Key point The clinical assessment of patients with memory impairment relies mainly on clinical and radiological evaluation.

260

highlighting the complex interactions between vascular causes, changes in the brain, degenerative disorders, host factors and cognition (Chui 1989; Tatemichi 1990; Desmond 1996; Pasquier & Leys 1997; Skoog 1998). VaD is the second most common cause of dementia, accounting for 10–50% of cases, depending on the geographical location, population and criteria used (Rocca et al. 1991; Hebert & Brayne 1995). The frequency of VaD is higher than reported previously (Skoog et al. 1993). Strokes lead to a high risk of cognitive impairment and dementia (Tatemichi et al. 1992; 1994). In addition, vascular factors such as coexisting stroke and white matter lesions are frequent in AD (Snowdon et al. 1997). Thus vascular causes may even be the leading basis of cognitive impairment worldwide (Hachinski 1992). As vascular causes of cognitive impairment are common, and perhaps preventable, patients may benefit from therapy, early detection and accurate diagnosis of vascular cognitive impairment and VaD is a challenge (Bowler & Hachinski 1995).

The clinical assessment of patients with memory impairment consists of (i) a symptomatic diagnosis, i.e. evaluation of the type and extent of cognitive impairment; and (ii) an etiological diagnosis, i.e. the search of vascular cause(s) and related factors (Table III.3.1).

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Table III.3.1 Clinical examinations of patients with

suspected VaD. Symptomatic diagnosis (type and extent of cognitive impairment) Interview of the patient and care giver Bedside mental status examination Neuropsychological examination Assessment of social functions and activities of daily life Assessment of psychiatric and behavioral symptoms Etiological diagnosis (vascular cause(s) and related factors) Clinical and neurological history and examination Ischemic scores Brain imaging: computed tomography (CT) or preferably magnetic resonance imaging (MRI) of the brain Routine laboratory investigations Chest X-ray Electrocardiography (ECG) Single photon emission computerized tomography (SPECT) Electroencepahlogram (EEG) Extended laboratory investigations including coagulation studies Doppler ultrasonography/ magnetic angiography of the carotid arteries Echocardiography 24-h ECG 24-h blood pressure monitoring

Clinical assessment Evaluation of a patient with suspected vascular dementia (VaD) demands traditional clinical skills for eliciting a detailed clinical and neurological history and examination, including the interview of an informant. Assessment of social functions, activities of daily living, as well as psychiatric and behavioral symptoms, are intrinsic parts of the basic evaluation.

Mental status examination The bedside mental status examination includes the Mini Mental Status Examination (MMSE) (Folstein et al. 1975), which has limitations as it emphasizes language, does not include timed elements and recognition portions in the memory tests, is insensitive to mild deficits, and is influenced by education and age. Other screening instruments for VaD include a 4–10 word memory test with delayed recall, a

cube drawing test for copy, a verbal fluency test (number of animals named in 1 min), Luria’s alternating hand sequence or finger rings, and a letter cancellation test (Roman et al. 1993). Usually, a more detailed neuropsychological assessment is necessary. It should cover the main cognitive domains including memory functions (short- and long-term memory), abstract thinking, judgement, aphasia, apraxia, agnosia, orientation, attention, executive functions, and speed of information processing (Erkinjuntti et al. 1997; Pohjasvaara et al. 1998).

Brain imaging Brain imaging should be performed at the initial diagnostic work-up. MRI is better than CT scan, because of its higher sensitivity and ability to distinguish medial temporal lobe and basal forebrain areas. Depending on the criteria of VaD used, focal brain infarcts are found in 70–100% and more extensive white matter lesions in 70–100% of cases (Erkinjuntti et al. 1987; Roman et al. 1993; Erkinjuntti 1996). SPECT and positron emission tomography might reveal patchy reduction of regional blood flow and metabolism, as well as decrease white matter flow and metabolism (Launes et al. 1991).

Other investigations There is no specific laboratory test related to VaD. Chest X-ray, ECG, and screening laboratory tests are part of the basic evaluation. In selected cases extended laboratory investigations, as well as examinations of the extra- and intracranial arteries and detailed cardiological investigations (Erkinjuntti & Sulkava 1991; Amar & Wilcock 1996; Orrell & Wade 1996), are appropriate. Frequently, findings related to risk factors and concomitant disorders such as hyperlipidemia, diabetes and cardiac abnormality are revealed (Erkinjuntti 1987). Apolipoprotein E ε4 (ApoE ε4) is an established risk factor for Alzheimer’s disease (AD), but its consistent relationship with VaD has not been established. Therefore, determination of ApoE status is not part of the clinical evaluation in VaD.

262 CHAPTER III.3

Proposals for future research Is it possible to have a battery of neuropsychological

III.3.3

tests more appropriate for patients who have stroke lesions? How can the clinical recognition of diffuse and mild ischemic disease be improved?

Diagnostic Criteria

Key points • The NINDS-AIREN criteria are currently most widely used in clinical drug trials on vascular dementia (VaD), despite their limitations. The concept of VaD refers only to the latest stage of the cognitive decline that occurs in patients with cerebrovascular disease. It also encompasses many mechanisms. • Comparisons between studies remain impeded by the lack of common diagnostic criteria, differences in case ascertainment techniques, differences in patient assessment, and true differences between populations. Pathological evidence of stroke does not necessarily mean that stroke is the cause of dementia, because of the frequent coexistence of degenerative changes in the elderly. Therefore, diagnostic criteria are necessary. The most widely used criteria for vascular dementia (VaD) are the Diagnostic and Statistical Manual (DSM) DSM-IV (American Psychiatric Association 1994), the International Classification of Diseases (ICD) ICD-10 (World Health Organization 1993), the Alzheimer’s Disease Diagnostic and Treatment Centers (ADDTC) (Chui et al. 1992), and the NINDS-AIREN criteria (Roman et al. 1993). The two key elements implemented in the clinical criteria for VaD are (i) the definition of dementia (Erkinjuntti et al. 1997); and (ii) the definition of the vascular disorder (Erkinjuntti 1994; Wetterling et al. 1994; Wetterling et al. 1996). All of the clinical criteria used are consensus criteria, which are neither derived from prospective community based studies on vascular factors affecting the cognition, nor based on detailed natural histories (Chui et al. 1992; Roman et al. 1993; Erkinjuntti 1994;

Rockwood et al. 1994; Erkinjuntti 1997). All the cited criteria are based on the ischemic infarct concept and designed to have high specificity, although they have been poorly implemented and validated (Rockwood et al. 1994; Erkinjuntti 1997). Variations in defining the dementia syndrome (Erkinjuntti et al. 1997; Pohjasvaara et al. 1997), and the vascular cause (Skoog et al. 1993; Wetterling et al. 1996), have led to a critical consequence: different definitions give different point prevalence estimates, identify different groups of subjects and, furthermore, identify different types and distributions of brain lesions. The DSM-IV definition (see Appendix I) requires focal neurological signs and symptoms or laboratory evidence of focal neurological damage judged clinically related to the disturbance (American Psychiatric Association 1994). The course is specified by sudden cognitive and functional losses. Brain imaging requirements are not detailed. The DSM-IV definition for VaD is reasonably broad and lacks detailed clinical and radiological guidelines. The ICD-10 criteria (see Appendix I) require unequal distribution of cognitive deficits, focal signs as evidence of focal brain damage, and significant cerebrovascular disease judged to be etiologically related to the dementia (World Health Organization 1993). The criteria do not detail brain-imaging requirements. The ICD-10 criteria specify six subtypes of VaD. The ICD-10 criteria for VaD have been shown to be highly selective and only a subset of those fulfilling the general criteria for ICD-10 VaD can be classified into defined subtypes (Wetterling et al. 1994; Wetterling et al. 1996). The shortcomings of these criteria include lack of detailed guidelines (e.g. unequal cognitive deficits and neuroimaging), lack of etiological cues, and heterogeneity (Wetterling et al. 1994; Wetterling et al. 1996).

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The ADDTC criteria are exclusively criteria for ischemic VaD (IVD) (Chui et al. 1992) (see Appendix I). They require (i) evidence of two or more ischemic strokes by history, neurological signs or neuroimaging studies (CT or T1-weighted MRI); or (ii) in case of a single stroke, a clearly documented temporal relationship (not specified in detail), and (always) neuroradiological evidence of at least one infarct outside the cerebellum. Ischemic white matter changes on CT or MRI do not qualify as brain imaging evidence of probable IVD, but may support a diagnosis of possible IVD. The criteria list features supporting the diagnosis, as well as a list of features casting doubt on a diagnosis of probable IVD. The NINDS-AIREN research criteria for VaD (Roman et al. 1993) include dementia syndrome, cerebrovascular disease and a relationship between dementia and cerebrovascular disorders (see Appendix I). Cerebrovascular disease is defined by the presence of focal neurological signs and detailed brain imaging evidence of ischemic changes in the brain. A relationship between dementia and cerebrovascular disorder is based on the onset of dementia within 3 months following a recognized stroke, or on abrupt deterioration in cognitive functions or fluctuating, stepwise progression of cognitive deficits. The criteria include a list of features consistent with the diagnosis, as well as a list of features that make the diagnosis uncertain or unlikely. Different levels of certainty of the clinical diagnosis (probable, possible, definite) are included also. The NINDS-AIREN criteria recognize heterogeneity (Erkinjuntti 1994) of the syndrome and variability of the clinical course in VaD, highlight detection of ischemic lesions and a relationship between lesion and cognition, as well as stroke and dementia onset. The interrater reliability of the NINDS-AIREN criteria has been shown to be moderate to substantial (kappa 0.46–0.72) (Lopez et al. 1994). Brain imaging requirements in clinical criteria for VaD The DSM-IV (American Psychiatric Association 1994) and the ICD-10 (World Health Organization

1993) criteria do not specify brain imaging requirements. The ADDTC criteria for IVD (Chui et al. 1992) require for a diagnosis of probable IVD ‘evidence of two or more ischemic strokes by history, neurological signs, and/or neuroimaging studies (CT or T1-weighted MRI), and evidence of at least one infarct outside the cerebellum by CT or T1weighted MRI’. The diagnosis is further supported by ‘evidence of multiple infarcts in brain regions known to affect cognition’, but the sites are not detailed. Furthermore, features that are thought to be associated with IVD, but await further research, include ‘periventricular and deep white matter changes on T2-weighted MRI that are excessive for age’. In the category of possible IVD the criteria include ‘Binswanger’s syndrome’, with ‘extensive white matter changes on neuroimaging’, which are not specified. The NINDS-AIREN criteria for probable VaD (Roman et al. 1993) require ‘evidence of relevant cerebrovascular disorder by brain imaging (CT or MRI) including multiple large-vessel stroke or a single strategically placed infarct (angular gyrus, thalamus, basal forebrain, PCA or ACA territories), as well as multiple basal ganglia and white matter lacunes or extensive periventricular white matter lesions, or combinations thereof’. The criteria state that: ‘White matter lesions on CT/MRI alone may be considered evidence for cerebrovascular disease; however, to be significant, these changes must be diffuse and extensive, and characterized by irregular periventricular hyperintensities on T1 and T2 MRI extending to the deep white matter but sparing the areas thought to be protected from perfusion insufficiency (e.g. subcortical U-fibers, external capsule–claustrum–external capsule). Changes observed only on T2 MRI may be insignificant’, and ‘it has been suggested that, in VaD, white matter changes involve at least one-fourth of the total white matter’. The criteria list features that make the diagnosis of VaD uncertain or unlikely including ‘absence of cerebrovascular lesions on brain CT/MRI rules out probable VaD’. However, the class of possible VaD may include patients who have ‘focal neurological signs but in the absence of brain imaging confirmation of definite

264 CHAPTER III.3

Ischemic stroke Hemorrhage Focal signs Focal symptoms Causal relationship List of supporting and non-supporting features Different levels of certainty Structural neuroimaging

DSM-IV

ICD-10

ADDTC

NINDS-AIREN

+ + + + + −

+ + + − + −

+ − NS NS + +

+ + + − + +

− −

− −

+ +*

+ +§

Table III.3.2 Comparison of clinical criteria for VaD.

*One infarct outside multiple large vessel or cerebellum. §Single strategically placed or multiple lacunes or extensive white matter lesions (WMLs). NS, not significant.

cerebrovascular disorder’. Patients with subcortical VaD (small-vessel dementia) often have multiple lacunae and extensive white matter lesions on neuroimaging, but give only a clinical history of ‘prolonged TIA’ or ‘multiple TIAs’ (which mostly are minor strokes) without residual symptoms and only mild focal findings (e.g. drif, reflex asymmetry, gait disturbance). This underlines the importance of neuroimaging criteria in the definitions of VaD. Comparison of clinical criteria for VaD The current criteria for VaD are not interchangeable (Table III.3.2); they identify different numbers and clusters of patients labelled as VaD. The DSMIV criteria are less restrictive than those of ICD-10, ADDTC and NINDS-AIREN (Verhey et al. 1996; Wetterling et al. 1996). The clinical criteria for VaD of older origin (DSM-IV and ICD-10) do not specify brain-imaging requirements for the diagnosis in detail. The ADDTC requires one CT or T1 MRI infarct outside the cerebellum, but white matter lesions do not qualify for support of probable IVD. The NINDS-AIREN criteria require multiple infarcts (more than one cortico-subcortical or lacunar) or extensive white matter lesions (CT or T1 MRI), but accept also a clinically ‘strategic’ single infarct as evidence of ‘relevant cerebrovascular disease’. As

evaluated neuropathologically, the ADDTC criteria seem to be more sensitive and the NINDS-AIREN criteria more specific, but neither are perfect (Gold et al. 1997). In a neuropathological series sensitivity of the NINDS-AIREN criteria was 58% and specificity 80% (Gold et al. 1997). The criteria successfully excluded AD in 91% of cases, and the proportion of combined cases misclassified, as probable VaD, was 29% (Gold et al. 1997). Compared to the ADDTC criteria, the NINDS-AIREN criteria were more specific and they excluded combined cases (54% vs. 29%) more effectively (Gold et al. 1997).

Proposals for future research Is the concept of VaD valid? Is it not more clinically relevant to identify global cognitive dysfunction of vascular origin, including purely behavioral features, with or without criteria for dementia? How can an allegedly associated AD be excluded without autopsy? How can a better delineation of all subtypes of VaD be reached? Is the concept of Binswanger’s disease of other than historical interest? If this entity is real, a strict definition, based on etiopathogenetic designation (for instance, smallvessel disease with insidious strokes) should be provided based on the consensus of experts.

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III.3.4

Epidemiology

Key point The mortality rate is higher in vascular dementia (VaD) than in Alzheimer’s disease (AD). The incidence of VaD remains unknown and prevalence is a poor marker of frequency because of the high mortality rate in VaD. A major reason to study the epidemiology of VaD is that many cases of VaD may be prevented (Hachinski 1992). However, a policy of effective prevention requires results of epidemiological surveys. Epidemiological studies are limited by diagnostic uncertainties. However, all studies suggest that stroke increases the risk of dementia (Desmond 1996).

Mortality The mortality rate is higher in patients with VaD than in those with AD (Tatemichi et al. 1994; Mölsä et al. 1995). Dementia diagnosed 3 months after stroke remains an independent predictor of mortality, with a 3.1 relative risk of death (Tatemichi et al. 1994), after adjustment on demographic factors, cardiac diseases, severity of stroke, stroke subtype and stroke recurrence.

Prevalence Most studies include prevalent cases of VaD (Meyer et al. 1986; Ueda et al. 1992) and may be biased by factors associated with survival (Hebert & Brayne 1995).

Community-based studies The European Community Concerted Action on Epidemiology and Prevention Dementia conducted a collaborative reanalysis of all information available on the prevalence of VaD in Europe (Rocca et al. 1991). Of the 23 surveys of dementia taken into account, only five fulfilled the inclusion criteria (Sulkava et al. 1985; Brayne & Calloway 1989;

O’Connor et al. 1989; Rocca et al. 1990): (i) dementia defined by the DSM-III criteria (American Psychiatric Association 1987) or equivalent; (ii) case finding through direct individual examination; (iii) appropriate sample size (at least 300 subjects over 65 years); and (iv) inclusion of institutionalized persons. Because AD with associated vascular disorders (ADv) was not differentiated from VaD in two studies, they were combined in all studies. The overall sex-specific prevalence rates of VaD plus ADv over age 60 years, combining suitable information from two studies (Sulkava et al. 1985; Rocca et al. 1990), is 2.6% for men and 2.1% for women. The prevalence of VaD increases with increasing age in all countries and is generally higher in men, ranging from 3.2% to 4.8% (2.2% to 2.9% in women) between 70 and 79 years and from 3.5% to 16.3% (2.8% to 9.2% for women) between 80 and 89 years. Age-specific prevalence varies more widely from one study to another for men than for women and sex differences increase with age. The prevalence in women in Cambridge was consistently lower than in other studies (O’Connor et al. 1989). In these European studies, the prevalence of VaD is approximately half that of AD. Non-European community-based studies of the prevalence of VaD are scarce. In the USA (Folstein et al. 1985), the prevalence of VaD in individuals aged 65 years and above was 2.8%. However, ADv was separated from VaD but combined with unspecified dementia making re-aggregation, and therefore comparison with European studies, impossible. In a Japanese study (Hasegawa et al. 1986), no clarification was provided concerning the aggregation of patients with ADv. However, VaD is the most frequent cause of dementia in Japan: in residents aged 65 years and above, more than 50% of dementia syndromes are the result of VaD (Ueda et al. 1992). Beyond methodological issues, there are several consistent findings provided by these studies: (i) an age-dependence with prevalence rates doubling every 5 years; (ii) a sex difference, VaD being more frequent in men; and (iii) a nation-to-nation difference, VaD being more frequent in Japan, China and Russia (Desmond 1996).

266 CHAPTER III.3

Hospital-based studies Most hospital-based studies have included consecutive series of patients referred for memory complaints or dementia, leading to selection bias towards the most severely affected patients (Desmond 1996). A meta-analysis of nine hospital-based clinical studies involving a total of 784 patients found 10.8% of VaD and 65.9% of AD (Katzman et al. 1988); however, most of these studies had been carried out before the generalized use of modern imaging techniques in the diagnostic work-up of dementia, leading to an underestimation of vascular factors in dementia (Chui 1989). A significant cognitive impairment, defined as a score lower than 24 at the MMSE (Folstein et al. 1975), was found in 30% of patients consecutively admitted to a neurological department, with 22.2% presumed vascular in origin (DePaulo & Folstein 1978). In the University Hospital of Helsinki, 12.1% of consecutive patients are demented, ranging from 5.7% in the 65–69 years category to 20.7% over 80 years, VaD accounting for 69.4% of dementias (Erkinjuntti et al. 1988). Patients with VaD account for approximately 15% of patients attending a memory clinic (Pasquier et al. 1997).

Studies conducted in stroke patients Few studies have evaluated the prevalence of dementia in patients admitted for an acute stroke. Discrepancies in the prevalence rates are probably a consequence of different methodologies [56.3% (Ladurner et al. 1982), 23.5% (Hershey et al. 1987), 30.4% (Babikian & Ropper 1987) and 15.9% (Tatemichi et al. 1990)]. However, in several studies patients were evaluated after stroke (Ladurner et al. 1982; Babikian & Ropper 1987; Hershey et al. 1987), leading to an overestimation of the cognitive deficits existing prior to the stroke: in other studies, the diagnosis of dementia was based on the clinical judgement of the clinician, without standardization (Tatemichi et al. 1990). In order to avoid such bias, the authors used a standardized questionnaire applied to a close relative, to evaluate the pre-existing cognitive state at admission (Hénon et al. 1996; Hénon et al. 1998): in stroke patients aged 40 years and over, the

prevalence of pre-existing dementia was 16% (Hénon et al. 1996; Hénon et al. 1997), wherein most cases were presumed to be associated with AD (Hénon et al. 1998). These results suggest that in stroke patients, dementia may be present prior to stroke and is not always a direct consequence of the stroke lesions (Pasquier & Leys 1997).

Studies conducted in stroke survivors A crucial question from a public health point of view, is to what extent cerebrovascular disease may increase the risk of dementia. The frequency of dementia in a Japanese community-based study was 27.2% in patients with history of stroke and 3.4% in controls (Suzuki et al. 1991). In the New York study, the prevalence of dementia, 3 months after an ischemic stroke, in patients aged 60 years or more, was 26.3%, i.e. 9.4-fold higher than that of a stroke-free control group, after adjusting for age, level of education and ethnic background (Tatemichi et al. 1992). The frequencies of dementia reported after stroke in these studies are higher than those associated with any other known exposure associated with dementia. In the New York study, stroke is the underlying cause of dementia in 56.1% of cases of dementia, while 36.4% are presumably a result of the cumulative effects of stroke and AD, as suggested by a prestroke history of functional impairment, and 7.5% of dementias have other causes (Tatemichi et al. 1992).

Autopsy studies Autopsy studies provide the best diagnostic specificity but their findings can hardly be generalized because of obvious referral bias. In a small population, AD was the presumed cause of dementia in 25% of patients and ‘arteriosclerosis’ accounted for 18% of dementia (Tomlinson et al. 1970). These figures were confirmed by other studies (Chui 1989), leading to the conclusion that in European and in North American populations, Alzheimer lesions are the most common finding in the brain of patients with dementia, followed by stroke lesions. Vascular dementia accounts for approximately 15% of dementia cases in autopsy series, while up to 15% of dementia cases are explained by a combination

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of vascular and Alzheimer lesions (Katzman 1983; O’Brien 1988). Therefore, there is an imprecision between pure VaD and association of ADv. Some authors pooled both types (Katzman 1983; O’Brien 1988), leading to an overrepresentation of VaD and an underestimation of AD, while others separated them (Mirsen & Hachinski 1988). However, there are many clinicopathological discrepancies: vascular lesions of the brain are present in one fifth of patients with Alzheimer pathology ( Jellinger et al. 1990; Ince et al. 1995; Victorof et al. 1995) and patients with definite pure VaD at autopsy represent around 25% of all demented patients according to some (Brun 1994), but are considered very uncommon by others (Hulette et al. 1997).

studies. Incidence rates (per 100 000) increase approximately from 20–40 in patients aged 60–69 years to 200–700 in patients aged over 80 years. Proportions of men and women in all age groups are similar.

Incidence of dementia after stroke

Because of the excess in mortality in patients with VaD, cross-sectional studies may underestimate the frequency of VaD. Although incidence studies may provide more accurate measures of risk, they remain scarce because of multiple practical difficulties. In the few available data, substantial variations in the incidence rates have been observed, possibly because of methodological discrepancies.

Stroke patients have an increased risk of dementia: 1 year after stroke, the probability of new-onset dementia is 5.4% in patients over 60 years and 10.4% in patients over 90 years (Tatemichi et al. 1990). Four years after a first lacunar infarct, 23.1% of patients develop dementia, i.e. 4–12 times more than controls (Loeb et al. 1992). Even after exclusion of patients who are demented 3 months after an ischemic stroke, the relative risk of dementia within 4 years remains 5.5 (Tatemichi et al. 1994). In the community-based Rochester study, the standardized morbidity ratio for new-onset dementia was 8.6% for patients in the first year after stroke, with the rate of new-onset dementia doubling during up to 24 years of follow-up (Kokmen et al. 1996); the incidence rate of AD was also doubled in stroke patients, suggesting that stroke may induce an earlier expression of AD (Kokmen et al. 1996).

Incidence of VaD in the community

Time trends in prevalence and incidence

Of 460 subjects followed from 70 to 79 years of age in Gothenburg, Sweden (Nilsson 1984), 19 developed severe AD and 17 developed VaD (DSM-III criteria). The annual incidence rates of severe VaD (per 100 000) were higher than 1000 in men, compared with 100 (in the 5-year interval between 70 and 75) and 630/100 000 (in the 4-year interval between 75 and 79) in women. In a volunteer cohort of 488 individuals over age 75 years in New York City (Aronson et al. 1990), 35 developed AD and 26 developed VaD or ADv (DSM-III criteria), with 2–7-year follow-up: the annual incidence rates of VaD were 900/100 000 in men and 1200/100 000 in women. Other studies (Akesson 1969; Chandra et al. 1987) have attempted to ascertain incidence rates of VaD. They probably underestimate the incidence of VaD because many demented patients probably never reach medical services. The definition of VaD varies between

Age- and sex-specific prevalence at two distinct points in time are available in one European study: the prevalence of VaD in Lund, Sweden, remained relatively stable between 1957 and 1972 in both sexes in the 60–69 and 70–79 year age-groups. In the 80–89 year age-group, however, an approximately two-fold decrease in VaD prevalence was found. This decline was greater for men. Decline in incidence rates over time was also observed (Rocca et al. 1991). In the Rochester study, the annual incidence rates declined from 11/100 000 in 1960–64 to 9.6/100 000 in 1965–69 and 5.7/100 000 in 1970–74 (Chandra et al. 1987). This decline might be the result of the decline of stroke incidence, described between 1945 and 1974, in the same area (Broderick et al. 1989). In a Japanese study the VaD:AD ratio shifted from 1.8 : 1 to 1.1 : 1 between 1985 and 1992 (Kiyohara et al. 1994); the prevalence of VaD decreased more in men

Incidence

268 CHAPTER III.3

than in women and matched an overall decline in stroke incidence among men as a result of targeted efforts toward stroke prevention (Kiyohara et al. 1994). These findings suggest that stroke prevention may have a significant impact on the risk of VaD. That the control of arterial hypertension contributes primarily to the decline in stroke incidence and, secondly, leads to the decline in the incidence

III.3.5

of VaD, is a plausible hypothesis (Forette et al. 1998).

Proposals for future research What is the incidence rate of VaD? Will stroke prevention decrease the incidence of VaD in the community?

Determinants of Vascular Dementia

Key point In patients followed up after a stroke, the term ‘poststroke dementia’ may be more appropriate because it includes all possible mechanisms of dementia. Recognition of a vascular component in a dementia syndrome, irrespective of its cause, may be useful in terms of prevention. Few epidemiological studies have tried to identify risk factors for vascular dementia (VaD), but it is generally assumed that they are also risk factors for cerebrovascular diseases (Skoog et al. 1993). The major problem in determining risk factors for VaD is that some are included in the definition (having a stroke) or in the operationalization of the diagnostic criteria (hypertension in the HIS) (Hébert & Brayne 1995).

Role of risk factors for stroke as risk factors for VaD Higher blood pressure in patients of age 70 years is associated with an increased risk of developing either VaD or Alzheimer’s disease (AD) 9–15 years later (Skoog et al. 1996). The reasons why higher blood pressure may contribute to an increased risk for AD is outside the scope of this review and has been discussed extensively elsewhere (Pasquier et al. 1998). The prevalence of arterial hypertension is higher in patients with VaD than in controls (Meyer et al. 1989). However, among stroke patients, arterial hypertension is not identified as a risk factor for VaD (Meyer et al. 1989; Tatemichi et al.

1993). The reasons why arterial hypertension is not more frequent in stroke patients who are demented than in stroke patients who are not, remain speculative. It is possible that this is an artefact of the high prevalence of arterial hypertension in stroke (Zuber 1994); the contribution of arterial hypertension to VaD may be masked by its high contribution to stroke. Alternatively, mild systolic blood pressure increase in patients with VaD could also have some beneficial effects at this stage (Meyer et al. 1986). The impact of clinical manifestations of atherosclerotic disease on cognitive functions in elderly subjects has been estimated in the population-based Rotterdam study (Breteler et al. 1994a,c). Previous vascular events and presence of atherosclerosis result in a considerable increase of dementia: VaD occurred in 25.6% of subjects with a history of stroke, vs. 13.5% in those without stroke history (P < 0.0001); these proportions are 19.0% vs. 12.5% (P < 0.0078) in case of electrocardiographic evidence of myocardial infarction, 17.1% vs. 11.1% (P < 0.0001) in case of peripheral arterial disease, and 14.6% vs. 10.4% (P < 0.001) in case of plaques of the internal carotid arteries. The Rotterdam study suggests that the impact of atherosclerosis on cognitive impairment should be considered as a major problem of public health pertaining to the diffusion of the disease in the general population. Whether or not intervention on risk factors for atherosclerosis in a population can prevent cognitive decline needs to be evaluated. The Canadian study of health and ageing (Linsay et al. 1997) found that, in the community, factors associated with an increased risk of VaD are:

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low education level, arterial hypertension, alcohol abuse, heart disease, and occupational exposure to pesticides, herbicides, liquid plastic or rubber. Use of aspirin was also associated with an increased risk for VaD: the explanation may be that patients under aspirin therapy may have a longer life expectancy and therefore have a higher risk of VaD (Linsay et al. 1997). Additional epidemiological studies are needed to identify risk factors for dementia associated with stroke. In summary, risk factors for VaD are high blood pressure (Meyer et al. 1986; Ueda et al. 1992), cardiac disorders (Meyer et al. 1986; Ueda et al. 1992), hematocrit over 45% (Ueda et al. 1992), carotid bruit (Meyer et al. 1986) and diabetes mellitus (Meyer et al. 1986). Hyperlipidaemia, cigarette smoking and alcohol consumption are not risk factors for VaD once confounding factors are controlled (Meyer et al. 1986; Ueda et al. 1992), but these variables are highly correlated variables and the disappearance of any association does not rule out a causative role (Hébert & Brayne 1995).

The multifactorial origin of VaD Based on these various mechanisms underlying VaD, a classification into six subtypes of VaD has been proposed (Roman et al. 1993): multiinfarct dementia, strategic single infarct dementia, small-vessel disease with dementia, hypoperfusion dementia, hemorrhagic dementia and other VaD. However, epidemiological data on each subtype remain scarce (Leys & Pasquier 1999).

Role of stroke characteristics Stroke characteristics are probably the major determinant of VaD (Desmond 1996). In the New York study (Tatemichi et al. 1993), stroke features associated with an increased risk of dementia included lacunar compared to non-lacunar infarction (odds ratio, OR: 2.7; 95% confidence interval, CI: 1.2–6.0) and left-sided hemispheric lesions (OR: 4.7; 95%CI: 1.7–12.9), an effect that could not be explained by aphasia. Dementia was especially common with infarctions in the left posterior and left anterior cerebral artery territories. A major dominant hemispherical syndrome, reflecting size

and laterality, was also independently associated with dementia (OR: 3.9, 95%CI: 1.3–11.3). In a smaller study, patients with VaD had more cerebral infarcts and more cortical and subcortical left hemispheric infarcts than non-demented patients with multiple infarcts (n = 74) (Gorelick et al. 1992). Although the total volume of cerebral infarction is probably important (Tomlinson et al. 1970), the volume of functional tissue loss may be more important because it also includes the effect of deafferented cortex (Mielke et al. 1992). A ‘pure’ VaD may therefore occur irrespective of the underlying cause of stroke (Parnetti & Leys 1998). The cerebrovascular lesions are likely to be the only cause of dementia in strategic infarcts occurring in the following groups: in patients with previous normal cognitive functioning (Benson et al. 1982; Wallesch et al. 1983; Graff-Radford et al. 1984; Mendez et al. 1990; Roman et al. 1993; Leys & Bogousslavsky 1994; Pasquier et al. 1994); in patients with lacunar state (Marie 1901); in hereditary cystatin C amyloid angiopathy, formerly called ‘hereditary cerebral hemorrhages with amyloidosis, Icelandic type’ (Jensson et al. 1987); and in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) (Tournier-Lasserve et al. 1993; Chabriat et al. 1995). In these four circumstances, dementia is likely to be the direct consequence of the vascular lesions of the brain, although the contribution of white matter changes, presumably vascular in origin, is probable in the last three.

Role of white matter changes White matter changes in demented patients are one of the imaging hallmarks of a cerebrovascular disease associated with dementia (Erkinjuntti et al. 1987; Kinkel et al. 1985; Liu et al. 1992; Schmidt 1992). They are more frequent in individuals with VaD than in those with non-vascular dementias and in normal elderly subjects (Erkinjuntti et al. 1987; Inzitari et al. 1987; Aharon-Peretz et al. 1988; Schmidt 1992). However, most studies (Erkinjuntti et al. 1987; Inzitari et al. 1987; Aharon-Peretz et al. 1988; Schmidt 1992) were conducted before the NINDS-AIREN criteria for ‘VaD’ (Roman et al. 1993) were established, and

270 CHAPTER III.3

therefore the causal relationship between stroke and dementia remained unsettled in most cases. White matter changes are independent predictors of poststroke dementia in most studies (Liu et al. 1992; Miyao et al. 1992; Tatemichi et al. 1994). White matter changes are also found in AD patients (Rezek et al. 1987; Leys et al. 1991; Erkinjuntti et al. 1994), especially in cases with late-onset (Brun & Englund 1986; Scheltens et al. 1992), even after exclusion of risk factors for stroke (Leys et al. 1991; Scheltens et al. 1992). White matter changes are often associated with stroke (Inzitari et al. 1987; Hijdra & Verbeeten 1991; Leys et al. 1992). They are more frequent in stroke patients who have lacunae (Hijdra et al. 1990; Cadelo et al. 1991; Leys et al. 1992) or deep hemorrhages (Hijdra et al. 1990; Cadelo et al. 1991; Leys et al. 1992). The relationship between leukoaraiosis and lacunae or deep cerebral hemorrhages is stronger than that with arterial hypertension (Hijdra et al. 1990; Cadelo et al. 1991; Leys et al. 1992) suggesting that arterial hypertension leads to leuko-araiosis only after having caused smallvessel disease to such a degree that lacunae or deep cerebral hemorrhages are almost always present (Hijdra & Verbeeten 1991; Leys et al. 1992). In patients with multiple infarcts, white matter changes are associated with a higher risk for dementia (Gorelick et al. 1992). In patients with first-ever lacunar infarction, mortality, stroke recurrence, risk of dementia and risk of dependence are significantly higher in patients with white matter changes (Miyao et al. 1992). The so-called Binswanger’s disease (Binswanger 1894), may be the end-stage pathology of a lacunar state (Roman 1987; Fredriksson et al. 1992; Leys et al. 1992). Among stroke patients, those with white matter changes have a higher risk of stroke recurrence after adjustment on age and other vascular risk factors (van Swieten et al. 1991; Miyao et al. 1992; Inzitari et al. 1995). In contrast with the stroke-associated white matter pathology referred to above, white matter changes alone, with no lacunae, were found in a small proportion of individuals with clinical VaD but without any documented acute stroke (Englund et al. 1989; Englund 2000). White matter changes are often associated with risk factors for stroke such as age (Inzitari et al.

1987), arterial hypertension (Schmidt et al. 1991; Breteler et al. 1994c), cardiac diseases (Hénon et al. 1996) and diabetes mellitus (Hijdra & Verbeeten 1991; Schmidt et al. 1992). The results of two population-based studies of the relationships between white matter lesions and vascular risk factors have been reported (Breteler et al. 1994c; Lindgren et al. 1994). In the Swedish study (Lindgren et al. 1994), arterial hypertension was independently associated with white matter changes, while smoking was not. In the Rotterdam study (Breteler et al. 1994b,c), there was only a slight and nonsignificant increase in the risk of white matter lesions in subjects with arterial hypertension, the association being found in subjects aged between 65 and 74 years, but not over 75 years. These relations were not modified by exclusion of subjects with antihypertensive medications or after adjustment for previous stroke or myocardial infarction. Factor VIIc activity and fibrinogen levels were associated with an increased risk of having white matter changes, but total cholesterol, high-density lipoprotein cholesterol levels and body mass index were not. In the same population, atherosclerotic plaques of the carotid bifurcation were significantly associated with the presence of white matter lesions (OR: 3.9; 95%CI: 1.0–14.5) (Bots et al. 1996). Moreover, the intima-media wall thickness of the common carotid artery, considered an early marker of atherosclerosis (Salonen & Salonen 1990), was also related to white matter lesions (OR: 1.5; 95%CI: 1.2–1.9). White matter changes may induce specific cognitive decline. Several studies suggest that white matter changes may be associated with subtle cognitive (Schmidt et al. 1991; Ellis et al. 1996) and behavioral (Salloway et al. 1996; TarvonenSchröder et al. 1996) changes. In studies performed in large groups of ‘healthy’ individuals, white matter changes are associated with subtle neuropsychological deficits (Breteler et al. 1994a,b,c), especially for memory (Schmidt et al. 1991; DeCarli et al. 1995), attention (van Swieten et al. 1991), and frontal lobe functions (DeCarli et al. 1995). A threshold of white matter hyperintensities is required before cognitive deficits can be detected (Boone et al. 1992). Mild disturbance in attention and increased perseveration may be the cognitive

VASCULAR DEMENTIA 271

functions that decline first as a result of white matter changes (van Swieten et al. 1991; Schmidt et al. 1993; Ylikoski et al. 1993; Bots et al. 1996). Normal subjects with white matter changes are probably at increased risk for cognitive decline, but many of them will probably remain free of any clinical abnormality during their life expectancy (Leys & Bogousslavsky 1994; Leys & Pasquier 1999). White matter changes may also contribute to the cognitive decline in VaD, but this effect is probably masked by that of the focal lesions (Hachinski et al. 1987). In demented patients, white matter changes are correlated with the severity of dementia (Hachinski et al. 1987; Steingart et al. 1987; Tanaka et al. 1989; Jellinger et al. 1990; Liu et al. 1992) but, as in normal subjects, brain atrophy may be a confounding factor (Tanaka et al. 1989; Hijdra & Verbeeten 1991; Breteler et al. 1994b; Leys & Bogousslavsky 1994; Kokmen et al. 1996). The location of white matter changes might also influence cognitive functions: patients with lacunae and dementia have more white matter lesions in the frontal lobes and their severity correlates with the cognitive decline (Ishii et al. 1986; Fukuda et al. 1990). Lower perfusion rates of frontal and temporal cortical regions have been seen in demented patients with multiple cerebral infarcts (Terayama et al. 1992): underlying white matter changes causing cortical disconnection were held responsible.

Role of associated Alzheimer pathology Some dementias occurring after stroke have a progressive onset and course suggesting a degenerative rather than a vascular process (Tatemichi et al. 1994; Pasquier et al. 1995). In addition, mild progressive dementia may be present before stroke: in community studies, the prevalence of all types of dementia is high in the age category of most strokes (Rocca et al. 1990; 1991). Similar figures are expected by chance in stroke patients. Actually, prestroke dementia is frequent (Hénon et al. 1996) and may contribute to the increase in the incidence rate of AD after a first ischemic stroke (Kokmen et al. 1996). The prevalence of prestroke dementia has been estimated at 16% in patients with a mean age of 73 years (Hénon et al. 1996). Genetic risk

factors are shared by AD and stroke patients. The ApoE e4 allele of the apolipoprotein E (ApoE) gene is associated with a higher risk of ischemic stroke or coronary heart diseases (Lenzen et al. 1986; Gerdes 1994; Wilson et al. 1994). The ApoE e4 allele has also been firmly established as a major risk factor for late-onset AD (Frisoni et al. 1994; Pedro-Botet et al. 1992; Saunders & Roses 1993). These findings suggest pathogenic relationships between cerebral ischemia and AD (Coria et al. 1995). A unifying explanation of the association of the e4 allele with both stroke and AD might involve the role of ApoE in the repair processes in the nervous system and in normal brain lipid metabolism (Pitas et al. 1987; Rubinsztein 1995). Moreover, several data suggest, or show, that AD patients have some degree of vascular changes, such as cerebral amyloid angiopathy (Vinters 1987; Yoshimura et al. 1992), non-specific fibrohyaline thickening of the wall of the small, perforating intracerebral arteries (Brun & Englund 1986; Rezek et al. 1987; Leys et al. 1991), and increased common intima-media thickness in the common carotid artery (Hofman et al. 1997). In a community-based study, Ferrucci et al. (1996) found a higher risk of stroke in stroke-free elderly subjects with dementia than in others. Alzheimer and vascular neuropathological lesions are frequently associated. In a study performed before the NINDS-AIREN criteria for VaD were established, approximately 20% of patients with clinically diagnosed VaD and of those classified as having ‘mixed dementia’ fulfilled histopathological criteria for AD (Jellinger et al. 1990). Ten to 18% of AD patients have associated cerebro-vascular lesions (Jellinger et al. 1990; Ince et al. 1995). Therefore, the link between stroke and AD seems to be higher than expected by chance (Pasquier & Leys 1997; Pasquier et al. 1998). Also, each of the two disease processes may enhance and clinically unmask the other at early stages (Englund 2000).

Role of the summation of various lesion types Many cases of dementia occurring in stroke patients are multifactorial. They may be the consequence

272 CHAPTER III.3

of the cumulative effect of the cerebrovascular lesions, Alzheimer pathology, white matter changes and ageing. Even when these changes do not lead to dementia on their own, their cumulative effect may reach the threshold of lesions required to induce dementia (Boone et al. 1992; Erkinjuntti & Hachinski 1993; Pasquier & Leys 1997). When stroke, white matter changes, or both, occur in a patient with asymptomatic Alzheimer pathology, the period of preclinical AD may be shortened (Pasquier & Leys 1997). In the study involving nuns, among 61 patients who met neuropathological criteria for AD, those with brain infarcts had poorer cognitive functions and a higher prevalence of dementia than those without infarcts, while among 41 patients who did not meet neuropathological criteria for AD, brain infarcts were associated only weakly with poor cognitive functions and dementia (Snowdon et al. 1997). This study suggests that stroke may play an important role in determining the presence and severity of the clinical symptoms of AD.

of the deep perforators predispose hypoperfusion of the white matter during the fall in blood pressure. Arguments for hypoperfusion of the white matter as a potential primary basis for VaD have also been found by Skoog et al. (1996) in 4.1% of demented elderly patients and by Brun (1994) in 21.7% of autopsied demented patients. The misuse of antihypertensive drugs could lead to hypotensive episodes and be a potential factor of VaD in elderly subjects with vascular changes in the deep perforators (Desmond 1996).

Role of demographic characteristics and co-morbid disorders

Role of genetic factors

Increasing age, previous myocardial infarction, lower education level, non-caucasian, diabetes mellitus and current cigarette smoking are associated with an increased risk of dementia in stroke patients (Tatemichi et al. 1990; Gorelick et al. 1993; Tatemichi et al. 1993). Cerebral hypoperfusion resulting from comorbid disorders leading to hypoxemia, such as seizures, cardiac dysrhythmia or pneumonia, is another potential mechanism of dementia occurring in stroke patients (Moroney et al. 1996). Consistent with this finding and the concept of ‘cardiogenic dementia’ (Editorial 1977), Sulkava and Erkinjuntti (1987) reported hypoperfusion resulting from cardiac dysrhythmia or systemic hypotension in six out of 133 patients with a clinical diagnosis of VaD. In five of the patients the most prominent morphological feature was white matter lesions; patients who were autopsied had atheromatosous changes in the circle of Willis and vascular changes in the deep white matter, leading the authors to the conclusion that vascular changes

Role of cerebral atrophy Cortical atrophy is associated with a higher risk of poststroke dementia (Tatemichi et al. 1990; Gorelick et al. 1992; Liu et al. 1992; Loeb et al. 1992). Medial temporal lobe atrophy is more frequent in stroke patients with pre-existing dementia (Hénon et al. 1998). The hypothesis that stroke patients with medial temporal lobe atrophy have preclinical AD is plausible (Hénon et al. 1998).

CADASIL is an autosomal dominant disease of the small perforating arteries of the brain leading to lacunar infarcts and dementia (Tournier-Lasserve et al. 1993; Bousser and Tournier-Lasserve 1994; Chabriat et al. 1995). Genetic analysis demonstrated linkage to chromosome 19q12 (TournierLasserve et al. 1993) and later identified as a mutation in the Notch-3 gene (Joutel et al. 1996). Dementia usually takes a stepwise course and may also develop progressively without clinical cerebrovascular episodes (Bousser & TournierLasserve 1994). Lacunar infarcts are associated with confluent and symmetrical areas of increased signal intensity in the subcortical white matter, sparing the U fibres (Chabriat et al. 1995; Ruchoux et al. 1995). The underlying lesion is a widespread vasculopathy affecting the penetrating arteries of less than 400 μm in diameter, which are thickened by a granular, eosinophilic, nonamyloid, electrondense material in the media different from arteriosclerotic and amyloidal deposits (Chabriat et al. 1995). Other rare arteriolopathies leading to multiple

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lacunar infarcts have been recognized as possible causes of VaD. The origin of most of those arteriolopathies remains unknown, but genetic studies might help to classify them in the future: nonCADASIL Binswanger-like syndromes without arterial hypertension (Loizou et al. 1982; Estes et al. 1991; Berthier et al. 1992); autosomal recessive leukoencephalopathy with alopecia and lumbago, reported in 17 Japanese patients (Fukutake & Hirayama 1995); and cerebroretinal vasculopathy (Grand et al. 1988). Other hereditary vascular conditions, unlinked to Notch-3 gene mutations and responsible for cerebral infarcts leading to VaD, have also been identified (Jen et al. 1997; Adair et al. 1998). The ApoE ε4 allele has been associated with a higher risk of VaD (Shimano et al. 1989; Frisoni et al. 1994), but this has not been reproduced in all studies (Wieringa et al. 1997), and requires further evaluation with longitudinal studies. However, such studies need to be stratified by VaD subtypes and demographic factors.

III.3.6

Proposals for future research The rather high frequency of pre-existing dementia in stroke patients, and its failure to be recognized when a systematic evaluation of pre-existing cognitive functions is absent, raises several questions. What is the contribution of unrecognized pre-existing dementia to poststroke dementia? What are the proportions of pre-existing dementia resulting from VaD and AD, respectively? Is there a causal connection between the occurrence of stroke and the induction of Alzheimer pathology? In the absence of a reliable marker for AD, a large multicenter cohort study, with neuropathological examination, will be required to answer these questions. To what extent does VaD occur in the absence of identified stroke? In other words, can cerebrovascular disease lead to dementia in the absence of stroke? Is the concept of incomplete white matter infarction valid? The natural history and the penetrance of CADASIL and other genetic cerebral arteriolopathies with lacunae and leukoencephalopathies or increased sensitivity to arterial hypertension, should be identified (Pasquier & Leys 1998).

Clinical Patterns

Cognitive syndrome The cognitive syndrome of VaD is characterized by (i) memory deficit, (ii) dysexecutive syndrome, (iii) slowed information processing, and (iv) mood and personality changes. These features are especially typical for cases with subcortical lesions. Patients with cortical lesions often have, in addition, a combination of different cortical neuropsychological syndromes (Mahler & Cummings 1991). The memory deficit in VaD is often less severe than in AD, and consists of impaired recall, relative intact recognition and better benefit from cues (Desmond et al. 1999). The dysexecutive syndrome in VaD includes impairment in goal formulation, initiation, planning, organizing, sequencing, executing, set-sifting and set-maintenance, as well as in abstracting (Mahler & Cummings 1991; Cummings 1994; Desmond et al. 1999). The dysexecutive

syndrome in VaD relates to lesions affecting the prefrontal subcortical circuit including prefrontal cortex, caudate, pallidum, thalamus, and the thalamo-cortical circuit (capsular genu, anterior capsule, anterior centrum semiovale, and anterior corona radiata) (Cummings 1993). Relatively preserved personality and insight in mild and moderate cases of VaD is typical. Features that make the diagnosis of VaD disease uncertain or unlikely include early onset and progressive worsening of memory deficit or some other cognitive cortical deficit in the absence of corresponding focal lesions on brain imaging (Roman et al. 1993).

Clinical neurological findings Frequent clinical neurological findings indicating focal brain lesion early in the course of VaD disease

274 CHAPTER III.3

include: mild motor or sensory deficits, decreased co-ordination, brisk tendon reflexes, Babinski’s sign, field cut, bulbar signs including dysarthria and dysphagia, extrapyramidal signs (mainly rigidity and akinesia), gait disorder (hemiplegic, apracticatactic or small-stepped), unsteadiness and unprovoked falls, as well as urinary frequency and urgency (Ishii et al. 1986; Babikian & Ropper 1987; Erkinjuntti 1987; Roman 1987; Roman et al. 1993). On the other hand, features that make the diagnosis of VaD uncertain or unlikely include absence of focal neurological signs, other than cognitive disturbance (Roman et al. 1993). In cortical VaD typical clinical features are sensorimotor changes and abrupt onset of cognitive impairment and aphasia, and in subcortical VaD disease pure motor hemiparesis, bulbar signs and dysarthria (Erkinjuntti 1987).

Table III.3.3 Hachinski ischemic score. Item

Score value

Abrupt onset Stepwise deterioration Fluctuating course Nocturnal confusion Relative preservation of personality Depression Somatic complaints Emotional incontinence History of hypertension History of strokes Evidence of associated atherosclerosis Focal neurological symptoms Focal neurological signs

2 1 2 1 1 1 1 1 1 2 1 2 2

Time-course Behavioral and psychological symptoms of dementia Depression, anxiety, emotional lability and incontinence, and other psychiatric symptoms are frequent in VaD (Roman 1987). Depression, abulia, emotional incontinence and psychomotor retardation are frequent in subcortical VaD (Mahler & Cummings 1991; Cummings 1994).

Ischemic scores Cardinal features of VaD disease are incorporated in the Hachinski Ischemic Score (Hachinski et al. 1975) (Table III.3.3). In a recent neuropathological series stepwise deterioration (OR 6.0), fluctuating course (OR 7.6), history of hypertension (OR 4.3), history of stroke (OR 4.3) and focal neurological symptoms (OR 4.4) differentiated patients with definite VaD from those with definite AD (Moroney et al. 1997). Nocturnal confusion and depression had no discriminating value. However, the ischemic score was unable to differentiate the ADv from VaD.

Traditionally, VaD has been characterized by a relative abrupt onset (days to weeks), a step-wise deterioration (some recovery after worsening), and fluctuating course (e.g. difference between days) of cognitive functions. This is seen in patients with repeated lesions affecting cortical and corticosubcortical brain structures, i.e. in those with large vessel multi-infarct VaD, and in those with watershed infarcts related to hemodynamic problems. However, in patients with small-vessel dementia, subcortical VaD, the onset is relatively insidious and the course more slowly progressive (Erkinjuntti 1987; Roman 1987; Chui et al. 1992; Roman et al. 1993). The mean duration of VaD is around 5 years (Hebert & Brayne 1995). In most studies survival is less than for the general population or AD (Skoog et al. 1993; Mölsä et al. 1995). Surprisingly, little is actually known or can be predicted about the rate and pattern of cognitive decline, either overall or among different subgroups of VaD (Chui et al. 1992). This underlines the lack of studies detailing the natural history of VaD.

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III.3.7

Heterogeneity of Vascular Dementia

Key point The heterogeneity in patient populations derived using current criteria has highlighted the need for an updated systematization. One suggestion has been that, by dividing vascular dementia (VaD) into subtypes, a more homogenous group of patients might be identified. Classification of VaD may be based on (i) the underlying vascular pathology, (ii) the type of brain lesions, (iii) the location of brain lesions and (iv) the clinical syndrome. The subtypes of VaD included in current classifications are the cortical VaD (or multi-infarct dementia), the subcortical VaD (or small-vessel dementia), and strategic infarct dementia (Table III.3.4) (Erkinjuntti 1987; Roman et al. 1993; Brun 1994; Cummings 1994; Wallin & Blennow 1994; Loeb & Meyer 1996; Konno et al. 1997). Many classifications also include hypoperfusion dementia (Sulkava & Erkinjuntti 1987; Roman et al. 1993; Brun 1994; Cummings 1994). Further classifications include hemorrhagic dementia, hereditary VaD, and Alzheimer’s disease (AD) combined with cerebrovascular disease.

The current clinical criteria for VaD differ in their classification of VaD into subtypes. None of them include detailed criteria for their subtypes. The Diagnostic and Statistical Manual, fourth edition (DSM-IV) (American Psychiatric Association 1994) do not specify subtypes. The International Classification of Diseases (ICD-10) (World Health Organization 1993) include six subtypes with rather superficial clinical descriptions (acute onset, multi-infarct, subcortical, mixed cortical and subcortical, other, and unspecified). The criteria are selective as only a subset of those fulfilling the general criteria for ICD-10 VaD can be classified into defined subtypes (Wetterling et al. 1994; Wetterling et al. 1996). The ADDTC (Chui et al. 1992) criteria do not specify detailed subtypes, but highlight that classification of ischemic VaD for research purposes should spe-cify features of the infarcts that may differentiate the disorder, such as location (cortical, white matter, periventricular, basal ganglia, thalamus), size (volume), distribution (large, small, or microvessel), severity (chronic ishemia vs. infarction), etiology (embolism, atherosclerosis, arteriosclerosis, cerebral amyloid angiopathy, hypoperfusion). The NINDS-AIREN criteria (Roman et al. 1993) include, without detailed description, cortical VaD, subcortical VaD, Binswanger’s disease, and thalamic dementia.

Table III.3.4 Vascular mechanisms

and changes in the brain in main subtypes of VaD.

Vascular mechanisms

Changes in the brain

Cortical-subcortical vascular dementia or multi-infarct dementia Large-vessel disease Large- and small-vessel disease Arterial territorial infarct Cardiac embolic events Perifocal incomplete devitalization Hypoperfusion Distal field (watershed) infarct Subcortical vascular dementia or small-vessel dementia Small-vessel disease Lacunar infarct Hypoperfusion Focal and diffuse white matter lesions Incomplete ischemic injury Strategic infarct dementia Large-vessel disease Cardiac embolic events Small-vessel disease

Arterial territorial infarct Distal field (watershed) infarct Lacunar infarct

276 CHAPTER III.3

Table III.3.5 Subtypes of VaD.

Cortical VaD Cortical VaD relates to large-vessel disease, cardiac embolic events and also hypoperfusion (see Table III.3.4). It shows predominantly cortical and cortico-subcortical arterial territorial and distal field (watershed) infarcts. Typical clinical features are lateralized sensorimotor changes and abrupt onset of cognitive impairment and aphasia (Erkinjuntti 1987). In addition, a combination of different cortical neuropsychological syndromes has been suggested to be present in cortical VaD (Mahler & Cummings 1991). This group shows heterogeneity in etiologies, vascular mechanisms, changes in the brain, as well as clinical manifestations.

Strategic infarct VaD Focal, often small, ischemic lesions involving specific sites critical for higher cortical functions have been classified separately (see Table III.3.4). This group shows the most heterogeneity. Isolated brain infarcts or hemorrhages may lead to dementia. In such cases, dementia is a result of the location of the lesion, rather than the volume of brain loss. Each of the following cortical locations has been associated with neuropsychological impairment leading to dementia: left angular gyrus infarcts (Benson et al. 1982); right hemisphere angular gyrus infarcts; inferomesial temporal infarcts (Caplan & Hedley-White 1974; Ott & Saver 1993); and mesial frontal infarcts (Alexander & Freeman 1984; Damasio et al. 1987; Sawada & Kazui 1995). Isolated subcortical vascular lesions consist of lacunar infarcts, deep territorial infarcts and deep hemorrhages, disrupting specific subcortical– cortical functional loops crucial for the maintenance of cognitive status (Baron et al. 1992). Dementia has been reported in thalamic (Graff-Radford et al. 1990; Barth et al. 1995), left-sided capsular genu (Tatemichi et al. 1992; Tatemichi 1995; Pullicino & Benedict 1996), and caudate nuclei infarcts (Caplan et al. 1990; Mendez et al. 1990; Bhatia & Marsden 1994; Wenchiang & Caplan 1995).

Subcortical VaD The

currently

proposed

subtypes

of

VaD

Cortical vascular dementia or multi-infarct dementia Subcortical vascular dementia or small-vessel dementia Strategic infarct dementia Hypoperfusion dementia Hemorrhagic dementia Hereditary vascular dementia Other vascular dementia Alzheimer’s disease with CVD (combined or mixed dementia)

(Table III.3.5) incorporate a variable combination of the given categories reflecting heterogeneity. Subcortical VaD incorporates small-vessel disease as primary vascular etiology, lacunar infarcts and white matter lesions as primary types of brain lesions, and subcortical location as the primary location of lesions (Table III.3.6). The ischemic lesions in VaD affect especially the prefrontal subcortical circuit including prefrontal cortex, caudate, pallidum, thalamus, and the thalamo-cortical circuit (genu or anterior limb of the internal capsule, anterior centrum semiovale, and anterior corona radiata) (Cummings 1993). Accordingly the subcortical syndrome is the primary clinical manifestation. Dementia is not always present in patients with a lacunar state. Lacunar infarcts appear as small miliary softenings, mostly located in the putamen, thalamus or pons (Marie 1901), or in the deep white matter (De Reuck et al. 1980). They are small (5–15 mm) cavities filled by a fine network of astrocytic processes, macrophages and siderophages, surrounded by fibrillary and protoplasmic astrocytes and sometimes also by hemosiderin pigments. They are the consequence of the occlusion of one single, deep, perforating artery (Fisher 1965). Multiple lacunae, in association with diffuse white matter changes, have been reported as the anatomical substrate of progressive cognitive decline in some patients who were clinically diagnosed as having AD, in the absence of a history of stroke and of a stepwise course of dementia (Pantoni et al. 1996). Diffuse white matter changes without lacunae have been described neuropathologically in demented patients with similarly progressive decline and absence of clinical strokes, (Englund et al. 1989). These cases were, however, clinically diagnosed as VaD. Such arteriopathies are usually

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Table III.3.6 Etiology and brain

changes of the subcortical VaD.

Etiology Primary vascular mechanisms Small-vessel disease: obliteration and occlusion, increased resistance, decreased autoregulation, cerebral blood flow fluctuation, endothelia changes, blood–brainbarrier and -carrier changes, perivascular changes Secondary vascular mechanisms Hemodynamic changes of systemic vascular, cardiac and carotid origin Primary risk factors Arterial hypertension Age Secondary risk factors Arterial hypotension Hypoxic-ischemic events Blood pressure fluctuations Diabetes Hyperlipidemia Low education Brain changes Primary type Ischemic white matter lesions (WMLs): araiosis, état crible, demyelination, axonal loss, changes in oligodendrocytes and astrocytosis, incomplete infarct Lacunar infarcts Incomplete ischemic injury: laminar necrosis, focal gliosis, granular atrophy, incomplete white matter infarcts Primary location WMLs: Extending periventricular and deep WMLs affecting especially the genu or anterior lim of the internal capsule, anterior corona radiata and anterior centrum semiovale Lacunae: lacunes in the caudate, globus pallidus, thalamus, internal capsule, corona radiata, frontal white matter

a result of chronic arterial hypertension (Fisher 1965; 1969). Small-vessel disease is the consequence of the occlusion of one single, deep, perforating artery, caused by segmental fibrinoid degeneration with lipohyalinosis (Fisher 1965; 1969; Olsson et al. 1996). Many perforating branches have multiple stenosis and poststenotic dilatations, suggesting that some hemodynamic events might also play a role, rather than local thrombosis (De Reuck & Van der Eecken 1976). Stroke patients with lacunae are more likely to have white matter changes (Hijdra et al. 1990; Leys et al. 1992) and to develop dementia (Tatemichi et al. 1993) than patients with other stroke subtypes. Traditionally, VaD has been characterized by a relative abrupt onset (days to weeks), a step-wise deterioration (some recovery after worsening), and fluctuating course (e.g. difference between days)

of cognitive functions. This is seen in patients with repeated lesions affecting cortical and corticosubcortical brain structures. In patients with subcortical VaD, however, the onset of cognitive symptoms is relatively insidious and the course more slowly progressive (Babikian & Ropper 1987; Erkinjuntti 1987; Roman 1987; Chui et al. 1992; Roman et al. 1993; Skoog 1997). The mean duration of any individuals with VaD is around 5 years (Hebert & Brayne 1995), and their survival is less than for the general population or those with AD (Skoog et al. 1993; Mölsä et al. 1995). Detailed studies on the natural history of subcortical VaD are lacking, and little is known or can be predicted about the rate and pattern of cognitive decline, and prognosis in subcortical VaD (Chui & Gonthier 1999). The cognitive syndrome of subcortical VaD is characterized by:

278 CHAPTER III.3

1 A dysexecutive syndrome including impairment in goal formulation, initiation, planning, organizing, sequencing, executing, set-sifting and setmaintenance, as well as in abstracting (Mahler & Cummings 1991; Cummings 1994; Desmond et al. 1999). 2 Mild memory deficits consisting of impaired recall, relative intact recognition, less severe forgetting, and better benefit from cues than in AD (Desmond et al. 1999). 3 Behavioral changes including depression, personality change, emotional lability and incontinence, as well as inertia, emotional bluntness and psychomotor retardation (Mahler & Cummings 1991; Roman et al. 1993; Cummings 1994). The clinical neurological findings especially early in the course of subcortical VaD include episodes of mild upper motor neurone signs (drift, reflex asymmetry, incoordination), gait disorder (apractic– atactic or small-stepped), imbalance and falls, urinary frequency and incontinence, dysarthria, dysphagia, extrapyramidal signs (hypokinesia, rigidity) (Ishii et al. 1986; Babikian & Ropper 1987; Erkinjuntti 1987; Roman 1987; Roman et al. 1993). However, often these focal neurological signs are subtle only (Skoog 1997).

Can VaD occur without detected infarcts? One-third to one-half of patients with pathological evidence of VaD lack a history of clinically recognized stroke (Yoshitake et al. 1995; Moroney et al. 1997). The question remains whether chronic ischemia plays an important role in VaD. Unilateral or bilateral occlusion of carotid arteries is the most common cause of hemodynamic VaD (Tatemichi et al. 1995). The role of hemodynamic factors and hypoxemia in the pathogenesis of poststroke dementia has already been mentioned (Moroney et al. 1996). Several authors have found no evidence of chronic ischemic states in VaD, studied by means of positron emission tomography (PET) (Frackowiak et al. 1981; Brown & Frackowiak 1991). However, presence of arterial border zones in the deep white matter and the high susceptibility of oligodendroglial cells to ischemia, along with the findings of widespread, histopathologically verified non-infarct damage in patients with VaD,

suggest that chronic ischemic leukoe cephalopathies leading to VaD exist (Englund et al. 1989). Chronic ischemia without infarction in the carotid territory might be an exceptional cause of dementia, attributed to a ‘misery perfusion’ with PET studies (Baron et al. 1981). This type of dementia might be reversible after correction of the hemodynamic deficit. In a documented case, extra-intracranial arterial bypass surgery apparently improved the patient’s cognitive status (Baron et al. 1981). Hemodynamic VaD is probably underrecognized, although a potential for surgical treatment in certain patients might exist (Tatemichi et al. 1995). Brun and Englund (1986) have suggested the term ‘incomplete white matter infarction’, including rarefaction of the deep white matter; diffuse partial loss of myelin sheets, axons and oligodendroglial cells and mild astrocytic and macrophagic reactions in association with a central stenosing small-vessel disorder. It correlates with the frequent finding of white matter changes on CT and MRI scans in elderly patients (Brun & Englund 1986; Englund et al. 1988; Janota et al. 1989). The brain damage may be more severe, and affect several of the most sensitive structures of the brain, leading to laminar necrosis of the neocortex, hippocampal degeneration, Purkinje cell loss of the cerebellar cortex, and deep cerebral white matter demyelination. It is difficult to detect such lesions on macroscopic examination, andhistological sections using specific staining techniques are usually necessary. Brun (1994) has also described a rare cortical–subcortical dementia syndrome caused by a hypertensive and atherosclerotic angiopathy of intracerebral and leptomeningeal vessels, leading to small infarcts located in the white matter, the basal ganglia and the brainstem, as well as in the cortex (Brun 1994). They may represent a mixture of large- and small-vessel diseases rather than an isolated entity (Erkinjuntti 1987; Mas et al. 1993).

Future research How can a better delineation of all subtypes of VaD be reached? Is the concept of Binswanger’s disease of other than historical interest?

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Two major problems arise when ‘strategic’ locations have been described in single cases or in small series (Benson et al. 1982; Alexander & Freeman 1984): (i) in case reports with firstgeneration CT scans, another vascular lesion of the brain cannot be excludedaisolated subcortical infarcts on CT scans may be associated with cortical infarcts on MRI scans that did not appear on CT scan (Godefroy et al. 1992; 1994), and these associated lesions significantly change the neuropsychological profile after a single cerebral infarct (Godefroy et al. 1992; 1994); (ii) in elderly patients without follow-up after stroke, the contribution of Alzheimer lesions to the neuropsychological profile cannot be excluded (Pasquier & Leys 1997; Snowdon et al. 1997; Pasquier et al. 1998). Several concepts introduced 15 years ago should

III.3.8

therefore be revisited with modern imaging techniques and a longer follow-up. New criteria should be based on homogeneity in: (i) etiologies (primary vascular mechanism/etiology); (ii) changes in the brain (type and location of brain lesions); and (iii) the clinical syndrome. They should show a predictable (a) phenomenology and clinical picture, (b) clinical course and natural history, as well as (c) outcome and treatment response. Furthermore, they should be reproducible (intra- and interrater reliability), and practical in a variety of clinical settings. In this way, they should be able to identify homogenous and representative patient samples. Another point of debate is whether or not these suggested subtypes are distinct disorders, having pathological and clinicssal features, as well as response to therapy of their own (Wallin & Blennow 1994).

Differential Diagnosis

Alzheimer’s disease Alzheimer’s disease (AD) is characterized by insidious onset and slowly progressive intellectual deterioration, absence of symptoms and signs indicating focal brain damage, and absence of any other specific disease affecting the brain (McKhann et al. 1984). AD is a stage-concurrent, degenerative disorder with typical clinical stages ranging from mild cognitive impairment, or early AD, to profound AD dementia (Braak & Braak 1991; Petersen 1995), and is thus not a diagnosis of exclusion. Patients with vascular dementia (VaD) show in their clinical history, neurological examination and brain imaging findings compatible with ischemic changes of the brain. Accordingly, in typical cases the differentiation between probable VaD and AD using common clinical tools is direct (Erkinjuntti et al. 1988). The problem cases are those patients with combined AD and cerebrovascular disease (CVD), who are difficult to diagnose during life. Difficult clinical settings include stroke unmasking AD in patients with poststroke dementia, insidious onset

and/or slow progressive course in VaD patients, and cases where difficulty exists in assessing the role of less extensive WMLs or of distinct infarcts in neuroimaging. This clinical challenge may be solved when a sensitive and specific ante-mortal marker for AD is available, and the distinction between AD and VaD could be supported by more detailed knowledge on which site, type and extent of ischemic brain changes are critical for VaD and which extent and type of medial temporal lobe atrophy specifies AD.

Normal pressure hydrocephalus Normal pressure hydrocephalus (NPH) is characterized by slowly progressive apracticaatactic gait disorder and urinary incontinence usually precedes cognitive impairment, psychomotor slowing and abnormal executive function. CT or MRI scans reveal large ventricles, periventricular halo and relatively narrow cortical sulci. Subcortical VaD and NPH may coexist. Spinal tap, monitoring of intraventricular pressure and even installation of an intraventricular shunt is often needed in differential diagnosis.

280 CHAPTER III.3

White matter lesions and dementia Diffuse or patchy white matter lesions may also have a non-ischemic cause and be related to cognitive decline. These etiologies include, e.g. multiple sclerosis, encephalitis, neurosarcoidosis, leucodystrophies, brain irradiation and non-ischemic cerebral edema. Diffuse white matter lesions are seen concomitant with gray matter changes in neurodegenerative disease of frontotemporal dementia (Englund 2000).

Frontal lobe tumors Frontal lobe tumors relate to disinhibition and behavioral changes, as in frontal lobe dementia, or slowing, indecision and abnormal executive function, as in subcortical dementias. Symptoms and signs of increased intracranial pressure may arise. There are occasional focal neurological symptoms and signs. Brain imaging reveals diagnosis.

Intracranial mass Cognitive decline may relate to intracranial mass lesions such as tumors, metastases and cysts, as well as subdural hematoma. In some cases focal neurological symptoms and signs may be absent, and the course may be slow progressive. Brain imaging reveals diagnosis.

Lewy body dementia Individuals with senile dementia of the Lewy body type (SDLT) show prominent attentional deficits, subcortico-frontal dysfunction and visuospatial impairment and relative preservation of memory early in the course. Fluctuating cognition with pronounced variations in attention and alertness is frequent, as well as recurrent visual hallucinations that are typically well formed and detailed. SDLT patients show spontaneous motor features of parkinsonism, repeated falls, syncope, transient losses of consciousness, and neuroleptic sensitivity.

Frontotemporal dementia Frontotemporal dementia includes progressive

deterioration of personality and behavior, affective symptoms, speech disorders (reduced and stereotype speech, echolalia, late mutism), but relatively well-preserved spatial orientation and praxis. They have early primitive reflexes and incontinence. Patients show frontal dysfunction in neuropsychological testing, frontal and anterior temporal atrophy in brain imaging, and despite evident dementia, often a normal EEG.

Parkinson’s disease and dementia Extrapyramidal syndrome (tremor, hypokinesia, rigidity) usually precede the cognitive impairment in Parkinson’s disease (PD) with dementia. Individuals with PD show subcortical dementia with apathy, poor concentration and indecision. Parkinsonian features usually respond to dopaminergic drugs.

Progressive supranuclear palsy Progressive supranuclear palsy is similar to PD and dementia, but parkinsonian features are nonresponsive to dopaminergic drugs. Typical features include paralysis of upward or/and downward gaze and truncal ataxia.

Multisystem atrophy Multisystem atrophy. Include slowly progressive dementia with any combination of pyramidal tract signs, extrapyramidal features, autonomic failure, and cerebellar ataxia.

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III.4

Lewy Body Dementia

Douglas Galasko

Key points • Dementia may be a prominent feature in certain patients with Lewy body (LB) disorders. • In autopsy series of patients with primary later-life dementia, 15% or more show cortical and subcortical LBs. • Clinical diagnostic criteria for dementia with Lewy bodies (DLB) have been proposed, incorporating cognitive, motor and behavioral symptoms. These include dementia, prominent fluctuation of attention or cognition, visual hallucinations and parkinsonism. • Each proposed cardinal clinical feature is not unique to DLB, therefore clinical judgement is needed in making a differential diagnosis.

Vignette A 71-year-old retired lawyer had a gradual onset of decline in cognitive abilities over 2 years. His wife reported that he would forget appointments, dates and details of conversation. Also, he had periods of

III.4.1

Introduction

Parkinson’s disease (PD) was initially described as a disorder of movement that spared cognition. This concept has been amended, because dementia eventually develops in about 30% of patients with PD, a syndrome now termed Parkinson’s disease with dementia, or PD-D. Similarly the finding that

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increasing confusion, lasting hours and sometimes for a day or two. For the past 3 months he reported that he saw a man and a dog in the house during daytime. They were in the living room, and stood near to him, but did not seem to be threatening. He could describe details of the man’s clothes. The patient had no history of depression or prior psychiatric illness. His wife reported that he had lost interest in a number of hobbies, including playing bridge and gardening. On mental state examination, he scored 22/30 on the Mini Mental Status Examination (MMSE), with errors on orientation, recall and drawing pentagons. On the clock drawing test, he made errors with number placement. Neurological examination was notable for slight facial masking. Muscle strength was normal. Tone was mildly increased in the arms and performance of rapid movements was slowed. There was no tremor. Coordination, sensory testing and reflexes were normal. His gait was nonspecifically slow. As part of a research study, a single photon emission computerized tomography (SPECT) scan was obtained. It showed hypometabolic regions in the parietal and occipital lobes.

the Lewy body (LB), the signature lesion of PD, is restricted to subcortical regions such as the substantia nigra and nucleus basalis, has been revised. In the late 1980s, Kosaka described LBs in widespread sites in limbic and cortical regions (Kosaka 1990). These included the hippocampus, amygdala,

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cingulate and temporal, frontal and parietal neocortex. Review of clinical case records revealed that many patients with diffusely distributed LB had dementia. There were two main categories: patients with diffuse LB alone and, more commonly, those with coexisting Alzheimer pathology. The syndrome was further described in many clinicopathological studies, and because of the accompanying AD pathology, many different terms were adopted. To bring consistency to studies in this area, a Consensus Workshop Conference proposed the term dementia with Lewy bodies (DLB) (McKeith et al. 1996). A distinct borderline between the pathology of DLB and PD does not exist, because almost all patients with PD have at least a few cortical LB (Hughes et al. 1993). More accurately, there is a spectrum of LB disorders, with relatively restricted LB and idiopathic PD at one end, and diffusely distributed LB and a dementia syndrome that includes behavioral symptoms at the other. Review of clinical features of DLB is hampered because criteria for diagnosis have been introduced

III.4.2

fairly recently. These criteria have rarely been applied prospectively to identify DLB. Many published clinicopathological series involve retrospective assessment of case records. Retrospective studies of clinical features are of high quality only if the initial clinical data collection was comprehensive and systematic, with sufficient detail to allow clinical features to be directly ascertained from rating scales, questionnaires, or data forms. There is greater variability when narrative case records are retrospectively reviewed to extract clinical features; therefore, the evidence from studies based on case record review has been regarded with caution, unless an explicit description of the review process was provided. The clinical picture of DLB has been only recently described and diagnostic accuracy is uncertain. For descriptions of the clinical features, frequency and course of DLB, this review will favor studies that comprise autopsy-confirmed cases because they provide more reliable data than those with clinical diagnoses alone.

Definition and Diagnostic Criteria

Dementia with Lewy bodies (DLB) is a primary degenerative syndrome of dementia, with onset in later adult life, with neurobehavioral features that typically include parkinsonism, visual hallucinations and fluctuation of cognitive abilities. Usually dementia precedes parkinsonism, or the two begin simultaneously (McKeith et al. 1996). It is possible, however, to expand the category of DLB to include Parkinson’s disease with dementia (PD-D), even in patients where many years of PD preceded the onset of dementia. In PD-D, however, there is no clinical difficulty in determining that LB are a likely etiological factor, because of pre-existing PD. On the contrary, DLB may be a difficult clinical diagnosis because of its clinical resemblance to Alzheimer’s disease (AD). Several sets of diagnostic criteria for DLB were proposed based on single center studies (Byrne et al. 1991; McKeith et al. 1992b; McKeith et al. 1994), and in 1996 a set of consortium criteria, developed at an international meeting, was developed. These are outlined in Table III.4.1. Probable

Table III.4.1 Consensus criteria for DLB (adapted from

McKeith et al. 1996). Mandatory feature

Dementia

Core features

Spontaneous parkinsonism Fluctuation Visual hallucinations (The DLB Consortium criteria proposes the categories ‘possible DLB’ when only 1 core feature is present, and ‘probable DLB’ when 2 or 3 core features are present) Supporting features

Transient loss of awareness Systematized delusions Frequent falls Syncope Neuroleptic sensitivity Non-visual hallucinations

Absence of

Other factors that can account for the clinical picture, such as strokes

DLB can be diagnosed when dementia is accompanied by two or more cardinal features (out of parkinsonism, fluctuation and visual hallucinations), and

290 CHAPTER III.4

possible DLB is diagnosed when only one cardinal feature is present. Supporting features were proposed also, but because these are not essential to making the diagnosis, they will be described in the next section. It is important to rule out other conditions that can lead to the clinical features of DLB. The DLB consortium also proposed an approach to DLB pathology. In the absence of definitive information about whether a threshold number of LB

III.4.3

is important or not, LB should be semiquantitatively assessed, with scores of 0, 1 (mild) or 2 (moderate) in every cortical area examined. The pattern of distribution of LB should be described as brainstem predominant, limbic or transitional, or diffuse (cortical). Coexisting AD pathology should be assessed using semiquantitative evaluation of the density of senile and neuritic plaques and neurofibrillary tangles in the cortex and hippocampal regions.

Clinical Picture

The age at onset of dementia with Lewy bodies (DLB) overlaps with that of Alzheimer’s disease (AD). Most cases therefore occur in later life, with a typical range of onset between the ages of 60 and 90 years (Kosaka 1990; McKeith et al. 1996). As is the case for AD, in DLB the onset is insidious. Progression is steady in most studies, although centers that have reported fluctuation as a common and prominent clinical feature have also noted that the clinical course may also fluctuate. DLB occurs more commonly in men than women. For example, series of autopsy-confirmed cases typically report a male : female ratio ranging from 1.5 : 1 to 3 : 1 (Ditter & Mirra 1987; Gibb et al. 1987; Byrne et al. 1989; Hansen et al. 1990). The major differential diagnostic problem is in discriminating DLB from AD. This is complex because many patients with DLB have a significant burden of AD pathology and can meet diagnostic criteria for AD. Dementia in DLB comprises of decline of cognitive function of sufficient severity to lead to compromised social function. Early in the course of DLB, the cognitive impairment often includes less prominent deficits in memory and language than those typical of AD, while impairment of visuospatial abilities, speed of cognitive processing, and problemsolving may be more prominent than in AD (Galasko et al. 1996; Salmon et al. 1996; Shimomura et al. 1998). This profile is consistent with ‘frontalsubcortical’ dysfunction. It may be difficult to detect on brief clinical testing of mental status, although disproportionately severe impairment on clock drawing may be a clinical pointer to DLB. Detailed

psychometric studies of autopsied DLB and AD cases, matched for overall level of dementia at the time of clinical assessment, have shown more severe deficits in DLB on constructional tasks such as clock drawing and block design, problemsolving tasks such as Trails B, and category fluency (Salmon et al. 1996; Shimomura et al. 1998). This profile is similar to that seen even in non-demented Parkinson’s disease (PD) patients, and has been confirmed in clinically diagnosed DLB patients. When dementia progresses into severe stages, this type of profile is much more difficult to detect. The diagnostic utility of a psychometric profile has not been prospectively validated against autopsy. The timing of the onset of dementia with respect to parkinsonism in DLB is under scrutiny. The consensus criteria required onset of dementia before or simultaneous with parkinsonism, but allowed an arbitrary 12 month interval between the two. This cut-off separates DLB from PD-D. Although the timing of dementia in relation to parkinsonism may be an artificial boundary, it does focus attention on attempting to diagnose DLB in the setting of dementia. In patients with PD-D, by contrast, the presence of pre-existing PD makes a connection to Lewy bodies obvious. Motor features of parkinsonism occur in 40– 90% of cases of DLB (McKeith et al. 1994; Galasko et al. 1996; Mega et al. 1996; Gnanalingham et al. 1997; Louis et al. 1997). The prevalence in published studies is influenced by the diligence with which parkinsonism is sought, whether parkinsonism that arises after neuroleptic exposure is included or not, and whether DLB includes patients with PD

LEWY BODY DEMENTIA 291

that preceded dementia or not. In series where dementia precedes or is coincident with parkinsonism, the parkinsonian features are similar to those of idiopathic PD but are generally milder. They are usually symmetrical, whereas idiopathic PD is often asymmetrical, and rest tremor is uncommon in DLB, noted in 10–25% of larger series (McKeith et al. 1994; Galasko et al. 1996). In series where the order of onset of symptoms is not restricted which therefore include patients with parkinsonism preceding dementia, severe parkinsonism is found (Gnanalingham et al. 1997; Louis et al. 1997). The combination of dementia and parkinsonism can occur in many conditions (Ellis et al. 1996). Specific features on the motor or neurological examination call attention to these diagnoses, for example, eye movement abnormalities in progressive supranuclear palsy or cerebellar ataxia in spinocerebellar atrophy syndromes. More problematic are patients with dementia who receive high-potency neuroleptics for behavioral symptoms. In such patients, failure of parkinsonism to improve after withdrawal of neuroleptics may be an indicator of DLB. Another diagnostic problem is that many patients with AD develop findings such as bradykinesia, increased tone and masked facies as the dementia progresses. Therefore, when parkinsonism first appears when dementia is severe, it is not a specific indicator of DLB. In patients with AD, the development of parkinsonian features is a marker of accelerated cognitive or functional decline. Fluctuation refers to marked variation in alertness, cognitive function or daily living performance. Conceptually it is the cognitive analogue of the motor ‘on–off’ states that characterize idiopathic PD. Patients with DLB may show marked daytime somnolence, and may show rapid transitions between impaired and less impaired cognition. These can be difficult to quantify when taking the history. Fluctuation has been noted in 80% or more of cases of DLB in series from the Newcastle group (McKeith et al. 1992a, 1994). Investigators at other centers have found this historical feature difficult to assess reliably (Mega et al. 1996), and report lower frequencies of fluctuation in DLB. Clinical rating scales for fluctuation are being developed and will allow this feature to be more systematically assessed.

Visual hallucinations have been noted in 30–60% of cases of DLB, compared to about 5–15% of patients with AD (McKeith et al. 1994; Mega et al. 1996; Weiner et al. 1996; Klatka et al. 1997). They are typically unprovoked, well formed and vivid, with imagery of animals or people. They usually recur, and hallucinations that persist over months or years have been described. Hallucinations may also occur in delirium, which may be precipitated by conditions such as infections, medical illness or medications in demented patients. The DLB consensus guidelines note that brief hallucinations in the setting of a defined cause of delirium do not indicate DLB, unless the hallucinations recur after the underlying cause is corrected or treated. The criteria include a list of supporting features for DLB. These are of lower diagnostic significance because they are less specific or low frequency in DLB. They include transient loss of awareness, systematized delusions, syncope, neuroleptic sensitivity, frequent falls and non-visual hallucinations. Neuroleptic sensitivity has been noted in several studies, in which clinical deterioration and sometimes death followed the use of neuroleptics in patients with DLB (McKeith et al. 1992a; McKeith et al. 1995). Because of the potentially dangerous side effects of neuroleptics in patients with dementia and parkinsonism, atypical psychotic agents with low or negligible dopamine (D2) receptor blocking activity are recommended if necessary for behavioral symptoms. Neuroleptic treatment should not be considered as a diagnostic test for DLB. Since the publication of the DLB Consortium criteria, REM sleep behavior disorder (RBD) has been identified in patients with PD and DLB. This disorder includes vivid dreams which patients seem to act out, for example by repetitive motor actions such as kicking, cycling, arm paddling, punching, or by repeated vocalizations. In one study RBD in middle-aged men preceded the onset of PD or DLB (Schenk et al. 1996). RBD has been documented in patients later shown to have autopsy-proven DLB (Boeve et al. 1998). The clinical features of patients with RBD may meet clinical criteria for DLB, while psychometric profiles in such patients include deficits typical of DLB as discussed above. Biological markers for DLB are under

292 CHAPTER III.4

investigation. Positron emission tomography (PET) studies suggest that occipital lobe hypometabolism may distinguish DLB from AD (Ishii et al. 1999). The extent of temporal lobe atrophy in DLB is less, on average, than that in AD (Hashimoto et al. 1998), but there is much overlap between AD

III.4.4

and DLB. As in PD, SPECT scanning using β-CIT as a radio-ligand has shown decreased dopamine uptake at striatal sites in patients with DLB (Donnemiller et al. 1997). The sensitivity and specificity of this technique for identifying DLB has not yet been established in large-scale studies.

Incidence and Prevalence

Accurate information on the incidence and prevalence of dementia with Lewy bodies (DLB) is not available. Because the clinical criteria were only recently developed, DLB has not been studied in population-based samples. The incidence and prevalence could change if Parkinson’s disease with dementia (PD-D) and DLB are considered in the same category. Estimates of the relative frequency of DLB pathology come from consecutive autopsy series from academic centers that study dementia (Table III.4.2). There are obvious drawbacks and biases to such series, including clinical referral bias, varying rates of autopsy among demented patients, and potential selection bias regarding which patients undergo autopsy. Another problem relates to the diligence with which LB are sought and the staining methods that were used. Immunostaining with antibodies against αsynuclein is the most sensitive and specific method

for identifying LB, especially in the cortex, but has only recently been applied to autopsy surveys. Despite these potential drawbacks, larger series have consistently shown DLB in 15–25% of demented elderly patients (Joachim et al. 1988; Bergeron & Pollanen 1989; Mirra et al. 1991; Galasko et al. 1994; Ince et al. 1995; Holmes et al. 1999; Lim et al. 1999), while only a few series report lower frequencies (Jellinger et al. 1990; Bowler et al. 1998). An assumption behind these studies is that LB are always indicators of a symptomatic disease state. A frequency of 15–20% for LB in autopsy series in dementia greatly exceeds the prevalence of PD in the elderly, estimated at about 2% in clinical surveys. It is of great interest to ascertain how commonly asymptomatic, or incidental LB may be found in autopsies of elderly individuals who lacked neurological diagnoses during life. Table III.4.3

Table III.4.2 Frequency of diffusely distributed LB in autopsy series of demented patients. Study

Number of patients

Source of patients

Autopsy rate

% with LB

Joachim et al. (1988) Bergeron & Pollanen (1989) Jellinger et al. (1990) Mirra et al. (1991) Galasko et al. (1994) Ince et al. (1995) Hulette et al. (1995)

131 AD 150 675 142 170 92 78

Ref Ref Ref Ref Ref Comm Ref

n/a n/a n/a n/a 85% 41% n/a

Bowler et al. (1998) Holmes et al. (1999) Lim et al. (1999)

122 80 134

Ref Comm Comm

64% 43% 32%

18 25 8.2 23 26 20 20.5 (nigra) 10 (cortex) 13 15 23

Ref, referral; comm, community based. Autopsy rate is the percentage of deaths where brain examination was carried out.

Comments

Mainly subcortical

Not all demented

LEWY BODY DEMENTIA 293

Table III.4.3 Frequency of incidental LB in autopsy series. Study

Number of patients Source of patients Autopsy rate % with LB

Comments

Forno (1969) Gibb and Lees (1988) Bergeron et al. (1989) Perry et al. (1990)

1090 207 75 131

Included psychiatric patients

Ince et al. (1995) Lindboe and Hansen (1998)

23 284

Hosp Hosp Hosp Hosp

n/a n/a n/a n/a

Comm Ref

41% n/a

4.5 6.8 5 2.3 17 7.7 (nigra) 3.2 (cortex)

Subcortical LB Patients with neuropsychiatric symptoms excluded Mean age > 80 years

Comm, community based; hosp, hospital; ref, referral.

summarizes the available studies. Most of these studies can be criticized because of lack of detailed clinical assessment of the patients during life. Also, there are questions about whether general hospital autopsies provide representative, unbiased samples. Incidental LB have been found in 3–17% of cases, with most series reporting a range of about 3–8% (Forno 1969; Gibb & Lees 1988; Bergeron & Pollanen 1989; Perry et al. 1990; Ince et al. 1995; Lindboe & Hansen 1998). These rates

III.4.5

exceed the prevalence of PD, which is estimated to occur in 1–2% of people over the age of 70. This suggests that LB may indeed be asymptomatic at times. In some series the frequency of incidental LB increases with age, but this has not been found consistently. Incidental LB are usually restricted to subcortical regions. Further studies of prospectively characterized elderly subjects will be important to provide more conclusive data on incidental LB.

Etiology

As is the case for Parkinson’s disease (PD), dementia with Lewy bodies (DLB) is an idiopathic, degenerative disorder. Genetic factors have been studied to a limited extent. The apolipoprotein E (ApoE) ε4 allele, a major genetic susceptibility factor for lateonset Alzheimer’s disease (AD), is over-represented in DLB, but chiefly in cases where an appreciable amount of AD pathology coexists (Lippa et al. 1995; St Clair 1997). α-synuclein mutations have been found in rare familial cases of early onset autosomal dominant PD. Autopsies in members of autosomal dominant PD in members of these families have shown DLB. However, mutations in α-synuclein are not found in sporadic PD. Even in sporadic cases of LB, cortical and nigral LB as well as Lewy neurites can be immunostained very well using antibodies against α-synuclein (Spillantini et al. 1997; Dickson et al. 1998), suggesting that regardless of the proximal causative factors, a disturbance of α-synuclein

handling by neurones is a common pathway in LB formation in general. Aggregation of α-synuclein to form fibrillar structures may be an important step in the formation of LB (Baba et al. 1998; Spillantini et al. 1998). Factors that promote such aggregation are beginning to be studied. The association of LB with AD pathology suggests that there may be overlapping etiological factors between AD and DLB. In about one-third of cases of DLB, there is enough AD pathology to fulfil diagnostic criteria for AD. In many other cases of DLB, widespread amyloid plaques are found, but neurofibrillary tangles are rare except in the entorhinal cortex and hippocampus. An asso-ciation with AD pathology is further suggested by the presence of DLB in the brains of about 20% of cases of early onset autosomal dominant familial AD (Lippa et al. 1998), and in about 15% of cases of Down’s syndrome. Mechanisms through which AD lesions may predispose to LB formation have not been established.

294 CHAPTER III.4

III.4.6

Prognosis

The average survival from onset of dementia until death overlaps markedly with that reported in AD, and ranges from 2 to 12 years. Several series have reported slightly shorter survival, by about 1–2

III.4.7

years, in DLB compared to AD (McKeith et al. 1994; Galasko et al. 1996; Mega et al. 1996; Olichney et al. 1998), whereas one study found no difference (Heyman et al. 1999).

Accuracy of Diagnostic Criteria

A number of studies have compared features in patients with clinically ascertained dementia with Lewy bodies (DLB) and Alzheimer’s disease (AD), in the absence of neuropathological data. There is a tautology in determining sensitivity and specificity from such studies, because the clinical features are used in making the diagnosis. Several studies have compared clinical criteria and pathological diagnoses of DLB in autopsy series of patients with dementia (Table III.4.4). The published studies to date vary in the quality and rigor of clinical data collection and represent the experience of tertiary referral centers. In most studies, medical records were examined retrospectively to extract clinical features. Clearly this approach is influenced by the quality and detail of the medical records and by the raters’ experience. The clinical data were not necessarily collected with the features of DLB in mind. Not surprisingly, the sensitivity

and specificity of the DLB criteria vary markedly. The Newcastle group (McKeith et al. 1994) reported very high sensitivity and specificity in distinguishing AD and DLB. A key reason for the high diagnostic accuracy was the presence of fluctuation in most cases of DLB. Other centers have reported high specificity of the DLB criteria, but lower sensitivity, and marked difficulty rating fluctuation (Mega et al. 1996; Luis et al. 1999). A recent community-based study (Holmes et al. 1999) found low sensitivity (30%) for the DLB consortium criteria, but the overall number of cases with LB at autopsy was small. Thus, one cannot yet conclude with certainty how well the criteria work in practice, and it is possible that they will be modified as further experience emerges, and as neuroimaging techniques are combined with clinical approaches.

Table III.4.4 Clinicopathological studies examining diagnostic features of DLB. In all studies, the subjects were diagnosed as

having dementia and had histopathological brain examination at autopsy. Study

Criteria tested

Setting

Number of subjects

Sensitivity/specificity

Reliability

Comments

McKeith et al. (1994)

SDLT (McKeith et al. 1992)

Tert ref

21 AD, 20 DLB, 9 VaD

74%/95%

78–94%

Retrospective record review

Mega et al. (1996)

CDLB

Tert ref

18 AD, 5 PD, 1 PSP

75%/79%

Good, except for fluctuation

Higher sensitivity if cases with high LB burden

Luis et al. (1999)

CDLB*

Tert ref

21 AD, 23 DLB, 12 DLB/AD

49–63%/ 90–100%

Good, except for fluctuation

Higher sensitivity for pure DLB than ‘mixed’ DLB/AD

AD, Alzheimer’s disease; CDLB, Consortium on Dementia with Lewy Bodies; DLB, dementia with Lewy bodies; PD, Parkinson’s disease; PSP, progressive supranuclear palsy; LB, Lewy body; tert ref, tertiary referral series; VaD, vascular dementia. *Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) criteria (requiring parkinsonism) performed slightly better than CDLB criteria in this series.

LEWY BODY DEMENTIA 295

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Frontotemporal Lobar Atrophies: The Pick Complex III.5

David G. Muñoz and Andrew Kertesz

III.5.1

Introduction

Key points The clinical presentations of frontotemporal dementia (FTD), primary progressive aphasia, and corticobasal degeneration syndrome are the manifestations of any of several substrates with distinct anatomical and biochemical pathologies. The term Pick complex encompasses the clinical and pathological spectrum. The clinical syndromes usually merge into each other as the disease progresses. Motor neurone disease may be associated in a minority of cases. The most common age of onset is the sixth decade. Pick complex is estimated to represent 25% of cases of presenile dementia. Clinical history and examination are the best diagnostic tools; the contributions of imaging and neuropsychology are confirmatory. Familial and sporadic forms occur. Diverse mutations in the tau gene on chromosome 17 are present in a number of families. In addition to the kindreds with tau mutations, alterations in tau are prominent in two of the substrates: dementia with Pick bodies (DPB) (three-repeat tau isoforms) and corticobasal degeneration (CBD) (four-repeat tau isoforms). Other substrates are characterized by ubiquitinated neuronal inclusions (dementia with inclusions tau and synuclein negative, ubiquitinated (ITSNU) or motor neurone disease-type dementia) or the absence of obvious inclusions (dementia lacking distinctive histology).

The conditions considered in this chapter share patterns of clinical presentations and overlapping pathological lesions, but no single feature is universally present. Even lobar atrophy (Plate III.2, facing p. 154), the feature for which the group is named, may be indistinct. Historical usage of the same termalike Pick’s diseaseawith different meanings has further muddied the field. The use of a single term to refer both to a clinical presentation and histopathological pattern, as in corticobasal degeneration or frontal lobe degeneration, is especially confusing, because there is no one-to-one correspondence between the clinical syndromes and the pathological substrates. The umbrella concept of Pick complex (Kertesz et al. 1994; 1998) attempts to incorporate biological and histopathological distinctions in a clinical framework using unequivocal terms while paying dues to historical context, particularly the seminal contribution of Arnold Pick. In this concept, several major clinical presentations, provisionally named FTD syndrome, primary progressive aphasia (including semantic dementia), and the corticobasal degeneration (CBD) syndrome can have any of the following pathological substrates: dementia with Pick bodies (DPB), CBD, dementia of the motor neurone disease-type (also known as dementia with ITSNU), the rare basophilic inclusion body disease, dementia lacking distinctive histology, and the diseases asso-ciated with mutations of the tau gene on chromosome 17 (Kertesz & Munoz 1998a) (Table III.5.1). This concept has received considerable support from the demonstra-

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Table III.5.1 Pick complex summary.

Clinical presentations Frontotemporal dementia (FTD) syndrome Primary progressive aphasia Corticobasal degeneration syndrome Pathological substrates Dementia with Pick bodies (DPB) Corticobasal degeneration (CBD) Dementia of the motor neurone disease-type Basophilic inclusion body disease Dementia lacking distinctive histology

Synonyms Pick’s disease Corticobasal ganglionic degeneration Dementia with ITSNU Frontotemporal degeneration Dementia of frontal type Frontal lobe degeneration

Progressive subcortical gliosis Tau mutation-associated diseases

tion that individuals in the same family (Bugiani et al. 1999; Nasreddine et al. 1999) or in families with the same point mutation (Bird et al. 1999; Bugiani et al. 1999) can exhibit considerable variation not only in terms of the clinical presentation, but also in histopathological classification. Recent

III.5.2

consensus conferences have accepted the lack of direct clinicopathological correlation, as reflected in the use of the terms FTD and frontotemporal lobar degeneration to refer to one of the clinical presentations and pathological substrates, respectively (Neary et al. 1998).

Clinical Features

The initial presentation usually falls into one of the prototypical syndromes described below. Progression commonly involves the addition of signs and symptoms from other syndromes; patients who survive to the final stages show a similar picture of dementia, mutism, and profound motor deficits, regardless of the initial presentation.

FTD syndrome The frontotemporal dementia (FTD) syndrome is characterized by alterations of behavior, personality, and affect, with at least relative sparing of memory and spatial orientation. Social and personal neglect, disinhibition, lack of judgement, and either euphoria or irritability dominate the clinical picture. The presentation may be dramatic, with extraordinary joviality, verbal output, restlessness, hypersexuality, and lack of respect for social constrains, but aspontaneity, apathy, social

withdrawal, and blunted emotional responses are more common. A diagnosis of depression is often rendered early in the disease. These manifestations represent a change from premorbid personality, which is usually reported as normal. Up to 50% of patients with FTD may manifest antisocial behavior (Miller et al. 1997a). The behavioral patterns associated with FTD can thus be construed as pseudodepressive or pseudopsychotic, a useful clinical concept (Blumer & Benson 1975). A change in ingestive behavior has been traditionally interpreted as the psychological phenomenon of hyperorality, but may have its basis on circuits related to vegetative activities. Excessive eating is manifested by weight gain, which exceeds 5 kg in 64% of the patients (Miller et al. 1995) and by change in food preference, sometimes with extraordinary partiality for a single food, to the point of exclusivity. Excessive drinking may lead to a wrong diagnosis of alcoholism. The hyperorality,

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hypersexuality, and compulsive touching (hypermetamorphosis) has been compared to the Klüver– Bucy syndrome seen in monkeys following bilateral resection of the amygdala and portions of temporal neocortex (Cummings & Duchen 1981). Auditory hallucinations and delusions are uncommon, in contrast to Alzheimer’s disease (AD). Preservation of orientation and visuospatial function are useful differentiating features (see neuropsychology). Obsessive interest in certain activities, such as word games, may be observed. An interesting phenomenon is the development of artistic talent in patients with no previous interest in art (Miller et al. 1998). The mean age of onset falls in the fifties in almost all published series, with equal numbers of affected men and women (Chow et al. 1999).

Primary progressive aphasia Although an aphasic presentation of Pick’s disease was recognized early (Pick 1892), the condition gained widespread attention after 1982 when Mesulam coined a descriptive name for the distinctive presentation of progressive language deficit in the absence of detectable abnormalities in other cognitive domains for at least 2 years from the onset (Mesulam 1982). The aphasia can be nonfluent or fluent; the latter is usually referred to as semantic dementia and it is construed as a separate syndrome by some authors (Snowden et al. 1996); it will be considered a variant here. Onset of either variant is usually before the age of 65 years.

Non-fluent aphasia The most common presentation is dominated by word-finding difficulty (anomia). At this stage, distinction from AD relies on the sparing of memory, orientation, and absence of constructional and visuospatial impairments (Snowden et al. 1992). Progression usually leads to a non-fluent type of aphasia characterized by short sentences with preserved syntax, decreased spontaneous speech output and relatively preserved repetition (Karbe et al. 1993). Comprehension appears intact. However, some patients demonstrate phonemic paraphasias and grammatical errors reminiscent of Broca’s

aphasia. Progressive articulatory difficulties, giving rise to stuttering or dysprosodic speech, is seen in other patients (Tyrrell et al. 1990). Some authors have emphasized the variability of the language disorder (Cappa et al. 1996). Most patients progress to mutism, often accompanied by impaired comprehension. The maintenance of activities of daily living (Weintraub et al. 1990), and even of professional performances (such as dentistry; Kertesz et al. 1994), demonstrates the preservation of other cognitive functions.

Semantic dementia Several authors have used this term to refer to patients with a fluent form of aphasia characterized by loss of meaning of words (Snowden 1989; Hodges et al. 1992). Face and object agnosia often accompany this peculiar aphasia, so that patients demonstrate loss of word and picture comprehension in the absent of deficits in episodic memory, or phonological and syntactic aspects of language. Meaning is preferentially loss for words not immediately relevant to the patient’s concerns (Snowden & Neary 1992). In some cases impairment is restricted to a category, such as living things or manufactured objects. Confrontation naming and comprehension are impaired for the same items (Kertesz et al. 1994); the errors are typically semantic, that is patients use a phonologically correct word related in meaning to the object presented (e.g. responding pear or fruit to the presentation of an apple) (Schwarz et al. 1998). Repetition of single words is preserved, whereas repetition of sentences is impaired. Loss of meaning has an interesting effect on reading in English and other orthographically irregular languages: patients can read phonologically regular words, but not irregular words, because the latter require recognition of meaning. Thus, patients tend to regularize when reading words that do not follow the common pattern. In spite of the preservation of episodic memory for recent events, patients may show loss of memory for early life events, in sharp contrast with the pattern observed in AD (Graham & Hodges 1997). Specific diagnostic criteria were proposed by Hodges et al. (1992).

300 CHAPTER III.5

Corticobasal degeneration syndrome This syndrome is characterized by asymmetric, often apparently unilateral, slowly progressive development of limb apraxia, bradykinesia, rigidity and dystonia, usually accompanied by tremor or myoclonus, and the alien limb phenomenon. First symptoms most commonly affect one hand, without simultaneous involvement of the leg. Contralateral extension or involvement of the ipsilateral unaffected limb occurs after three years on average. A rigid, dystonic posture of the hand is quite characteristic of advanced stages. Myoclonus can be induced by touch on the affected limb or on the face, or simply by carrying out voluntary motions (Brunt et al. 1995). Central sensory disturbances are manifested as dysesthesias and hemispatial neglect (Rebeiz et al. 1967; Rinne et al. 1994). Abnormal intonation and dysprosodia often accompanies involvement of the dominant hemisphere. Gait disturbance can be observed at presentation in up to one-third of the patients (Rinne et al. 1994).

III.5.3

Basic Biology of Tau

Tau, a microtubule-associated protein, plays a critical role in the organization of neuronal shape and function by modulating microtubule assembly, a process involved in axonal transport and neuronal plasticity. The tau gene, located in chromosome 17, gives rise to six different protein isoforms in the adult central nervous system, generated through alternative RNA splicing involving exons 2, 3, and 10. A sequence involved in microtubule binding is repeated three times in the isoforms lacking exon 10; the latter contributes a fourth repeat sequence. Pathological tau proteins extracted from brains suffering from a variety of neurodegenerative diseases

III.5.4

The alien limb phenomenon refers to the patient’s inability to perceive the limb as his own, especially if deprived of visual contact. The alien limb may engage in activities unrelated to tasks being carried out by the other hand, or to the situation in general. A slow, persistent levitation of the affected limb often brings the phenomenon to the attention of the examiner. The alien limb phenomenon is seen in almost half of patients within 2 years of onset (Rinne et al. 1994). Behavioral and cognitive symptoms in corticobasal degeneration are common and documented in about 30–50% of the pathologically examined material (Schneider et al. 1997). They tend to be underreported in series from movement disorder clinics where the parkinsonian-like syndrome dominates the presentation. However, behavioral and personality changes similar to the frontotemporal syndrome and even more frequently a speech problem, such as progressive aphasia appear at times early in the course of the illness (Kertesz & Martinez-Lage 1998). Onset is usually in the sixth or seventh decade. No risk factors have been identified.

differ from those extracted from normal brains by being phosphorylated at position serine422, and resistant to phosphatases at this and other sites. In contrast, tau proteins extracted from normal brain tissue are never phosphorylated at position serine422 and, in addition, those obtained at autopsy are dephosphorylated at other sites because they are susceptible to the action on phosphatases (Bussiere et al. 1999). Thus, pathological tau proteins can be recognized and quantified in a Western blot by using antibodies selective for phosphorylated tau.

Structural Substrates

The classification of the structural substrates presented below, based on both the presence of unique

cellular inclusions and isoforms of pathological tau proteins, is accepted by most neuropathologists

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working in this field (Cooper et al. 1995; Jackson & Lowe 1996; Dickson 1998; Munoz 1998). There is, however, an alternative classification based on the severity of gliosis, in which two histological types are recognized: frontal lobe degeneration type (slight gliosis, no ballooned cells or Pick bodies) and Pick type (severe gliosis with or without Pick bodies and ballooned neurones) (The Lund & Manchester Groups 1994; Neary et al. 1998). No criteria for the degree of severity are provided, and no biological justification has been offered for this classification; it will not be discussed further herein.

Common structural lesions All forms of Pick complex exhibit cortical neuronal loss and gliosis in the affected regions of the cortex, often accompanied by similar lesions in subcortical structures. Superficial linear spongiosis, a band of vacuolation of the neuropil of the upper layer II is present in all forms, but can also be seen in other neurodegenerative, metabolic and vascular conditions. Swollen neurones loaded with αB-crystallin and phosphorylated neurofilaments acalled Pick cells, or ballooned or achromatic neurones (Plate III.2, facing p. 154) can be seen in all forms of Pick complex, and have no value in differentiating among them, although significant quantitative differences exits between the diverse histopathological surtrates. Decreased synaptic density to levels comparable to those seen in Alzheimer’s disease (AD) is detected in the atrophic lobes (Liu et al. 1996).

inclusions stained by the Bielchowsky and related methods, and some modern authors continue to do so. Only in the latter usage can Pick bodies be said also to be present in corticobasal degeneration and other conditions. True Pick bodies are always present in the granular cell layer of the dentate gyrus, and are usually found in hippocampal, neocortical, and subcortical neurones. The laminar distribution of Pick bodies in the cortex is different from both that of ballooned neurones and neurofibrillary tangles in AD. Pick bodies are made up of straight, 15 nm-thick fibrils and long-period twisted fibrils (Munoz-Garcia & Ludwin 1984), rather than neurofilaments as stated in older literature. Tau, specifically the three-repeat isoforms, is the main component of these fibrils (Buee & Delacourte 1999). Delacoute et al. have proposed that Pick bodies develop in neuronal populations constitutionally expressing tau isoforms lacking the exon 10 sequence (Delacourte et al. 1998a). The synaptic protein chromogranin A prominently accumulates Pick bodies; its contribution to neuronal malfunction is conjectural. In addition to the cortical atrophy, subcortical structures often involved include the neostriatum, the hypothalamus, and the substantia nigra. The involvement of the lateral tuberal nucleus of the hypothalamus (Braak & Braak 1998) and altered serotonergic markers have been related to gluttony (Sparks & Markesbery 1991). The nucleus basalis of Maynert is usually spared, resulting in normal levels of cortical choline acetyltransferase (Hansen et al. 1988).

Corticobasal degeneration Dementia with Pick bodies The brain shows a distinct lobar atrophy with a sharp posterior limit; either the frontal or the temporal lobes may be predominantly affected, with a variable degree of asymmetry. The diagnostic histopathological criterion is the presence of Pick bodies, round argyrophilic inclusions in the neuronal cytoplasm (see Plate III.2). Braak and Braak (1989) first pointed out that Pick bodies, unlike other tauimmunoreactive inclusions, are not recognized by the Gallyas silver stain. However, the term Pick body has been traditionally applied to any round

The pathological entity of corticobasal degeneration (CBD) has only recently achieved consistent characterization, after several false starts. Cortical atrophy is usually markedly asymmetric, but not sharply circumscribed, and of variable distribution. The distinguishing histological features are not the abundant achromatic neurones emphasized in the early descriptions, but instead widespread argyrophilia secondary to the accumulation of pathological tau proteins in neurones, astrocytes, and oligodendroglia (Munoz 1998). The inclusions in neuronal perikarya show a round outline,

302 CHAPTER III.5

reminiscent of a Pick body, or else reniform or ring configuration (see Plate III.2, facing p. 154). Unlike Pick bodies, they are stained by the Gallyas method, and do not express ubiquitin or chromogranin A immunoreactivity (Cooper et al. 1995). Ultrastructurally the constituent twisted fibrils differ from those of AD by being wider, with longer periodicity, and less stable (Tracz et al. 1997). Cortical and subcortical neurones are affected; the hippocampus is typically spared. The astrocytic inclusions, called glial plaques, are pathognomonic: they consist of a crown-like cluster of short processes not associated with amyloid (see Plate III.2). The astrocytic perikaryon at the centre of the plaque is never visible on Gallyas stains, and only rarely on tau immunostains. Recent morphological evidence indicates that glial plaques can be distinguished from the tufted astrocytes of progressive supranuclear palsy (Komori et al. 1998). Oligodendroglial inclusions are numerous, giving rise to widespread, nonspecific, argyrophilia of the white matter, taking the form of ‘coiled bodies’ common to all forms of Pick complex and other conditions.

Dementia of the motor neurone disease-type (dementia with ITSNU) The hallmark of this entity is the presence of rounded nonargyrophilic inclusions in neuronal perikarya that express ubiquitin, but not tau, or α-synuclein (Okamoto et al. 1992) (see Plate III.2). The latter two features, and the lack of eosinophilia, distinguish these lesions from Lewy bodies. The staining characteristics are identical to the skeinlike inclusions seen in the motor neurones in motor neurone disease (Mather et al. 1993); similar inclusions are usually found in these patients, even in the absence of motor abnormalities. One of the terms by which this entity is known reflects this morphological relationship, as well as the fact that approximately one third of the patients demonstrate clinical signs of amyotrophic lateral sclerosis following or, more rarely, preceding the development of dementia (Morita et al. 1987). The other term (ITSNU) is an acronym for inclusions tau and synuclein negative, ubiquitinated, and replaces the former term UTNNE, ubiquitinated tau negative noneosinophilic inclusions (Munoz 1998). The

change is a result of the availability of synuclein antibodies, because absence of synuclein is more objective than lack of eosinophilia, and thus a better marker to distinguish these inclusions from cortical Lewy bodies. A favorite, but not universal, location of ITSNU is the granular cell layer of the hippocampal dentate gyrus. The hippocampus proper is spared, but the inclusions involve the superficial layers of the involved neocortex (Okamoto et al. 1992). Vertically orientated dystrophic neurites are also recognized by ubiquitin (but not tau) antibodies. Tau expression is generally restricted to glia, and quite variable in extent.

Basophilic inclusion body disease This rare condition can present as juvenile amyotrophic lateral sclerosis or as early onset dementia of the frontal type. The characteristic finding is the presence of neuronal inclusions, similar to ITSNU, but easily detectable on hematoxylin- and eosinestained sections by their intense basophilia (Munoz 1998). This variant has been reported previously as the generalized form of Pick’s disease (MunozGarcia & Ludwin 1984).

Dementia lacking distinctive histology Knopman et al.’s (1990) idea of stressing the common pattern of absence of specific lesions represents a major conceptual advance over the confusing use of the terms frontal lobe degeneration or frontotemporal degeneration, which have been applied to a clinical syndrome (with multiple structural substrates), the absence of Pick bodies in the face of lobar degeneration (with or without, including cases with severe gliosis), or lobar degenerations in general. The presence of balloned neurones (Pick cells) does not alter the classification. Dementia lacking distinctive histology is one of the common substrates of primary progressive aphasia, as well as dementia of the frontal type. Diffuse tau expression in the neuronal perikaryon without formation of inclusions has been reported in some cases, probably representing the structural correlate of the finding of pathological tau proteins at low concentration (Delacourte et al. 1998b).

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Progressive subcortical gliosis This entity should be considered a subvariety of dementia lacking distinctive histopathology in which gliosis and pallor of the hemispheric white matter predominate over the cortical and basal ganglionic atrophy (Verity & Wechsler 1987). Maintenance of a separate category is probably not justified. At least some familial forms are due to mutations in the tau gene (Goedert et al. 1999).

Alzheimer-type pathology A number of reports have described isolated cases presenting clinically with one of the prototypical

III.5.5

syndromes and demonstrating lobar atrophy, but in whom the brain showed senile plaques and neurofibrillary tangles on histological examination (Cooper et al. 1995). This Alzheimer-type pathology has not been reported restricted to the atrophic areas. It is thus possible that these patients suffer from a combination of two diseases: AD and some other process causing lobar atrophy, but not eloquent histologically. Dementia lacking distinctive histology and possibly dementia of motor neurone disease type (dementia with ITSNU) could fulfill that role. Dual pathology involving AD is well recognized, particularly in relation to dementia with Lewy bodies (Bergeron & Pollanen 1989).

Alterations in Tau Proteins and Gene

Isoforms of pathological tau proteins in sporadic forms Western blot studies have shown characteristic patterns of pathological tau proteins: a doublet at 55 and 64 kDa for dementia with Pick bodies, a different doublet at 64 and 69 kDa for corticobasal degeneration and progressive supranuclear palsy, and a triplet at 55, 64, and 69 for Alzheimer’s disease (AD) (Buee-Scherrer et al. 1996). Some cases of dementia lacking distinctive histology have shown a triplet typical of AD, but in much lower concentrations, and without the accompanying smears, always seen in AD. Other cases of dementia lacking distinctive histology and patients with dementia of the motor neurone disease type (dementia with ITSNU) lack detectable pathological tau proteins in their brains (Delacourte et al. 1998a). The use of antibodies selective for the different tau isoforms described above has provided further insights. Whereas all six isoforms are expressed in the brains of patients with AD, pathological proteins in dementia with Pick bodies (DPB) are comprised exclusively the three isoforms lacking exon 10, and in corticobasal degeneration and progressive supranuclear palsy of the three isoforms containing exon 10. Each of the 69 and 64 kDa

bands can be produced by two different isoforms; it is thus purely coincidental that a band at 64 kDa appears in both DPB and corticobasal degeneration (CBD) (Delacourte et al. 1998b; Sergeant et al. 1999). The levels of mRNA isoforms containing exon 10 are increased in the affected regions in progressive supranuclear palsy (Chambers et al. 1999); presumably a similar mechanism operates in corticobasal degeneration.

Tau mutation-associated diseases A number of families with different combinations of frontal dementia, psychosis, parkinsonism, and amyotrophy reported under a multitude of names, demonstrated linkage to a region of chromosome 17, where the tau gene is located (17q21–22); 13 kindreds were collected at the first consensus conference on frontotemporal dementia (FTD) and parkinsonism linked to chromosome 17 (FTDP-17) as the disorder became known (Foster et al. 1997). The location of the mutations in the tau gene first demonstrated in 1998 (Goedert et al. 1998) has been identified in 14 families at this point (September 1999) (Hulette et al. 1999). Mutations have not been reported in chromosome 17-linked families in any other gene in this region.

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The distribution of the atrophy varies between and within families; frontal and temporal cortices, basal ganglia, and substantia nigra bear the brunt of the pathology, which is always accompanied by tau deposits, even in families in which initial reports failed to show them (Spillantini et al. 1998b).

paired helical filaments identical to those of AD, with a diameter of 11–20 nm and 80-nm periodicity. All six isoforms participate in the formation of the pathological tau proteins. This family has a mis-sense mutation in exon 12 (V337M) of the tau gene.

Variants

Pathogenic mechanisms in tau mutationassociated diseases

Two major variants are recognized on the basis of the cellular distribution and isoforms of pathological tau proteins. The first group, which includes most of the other families with FTDP-17, shows tau deposits in both neurones and glia. The inclusions in neurones are usually globose and restricted to the soma. They are made up of twisted ribbons 6–22 nm in diameter, displaying variable periodicity at 140–300 nm (Spillantini et al. 1998a). These patients have mutations affecting exon 10, either mis-sense in the exon itself, or else intronic in the splice donor site. Pick bodies have been demonstrated in the P301L mutation (Nasreddine et al. 1999). Neuronal inclusions consisting of lattice-like aggregates of neurofilaments have been considered unique to chromosome 17linked dementia (Sima et al. 1996), but this finding has not been widely confirmed. The Seattle family A constitute the prototype of the second subtype, characterized by the restriction of tau deposits to neurones, where they take the form of neurofibrillary tangles extending into the apical dendrites. These tangles are made up of

III.5.6

Several mis-sense mutations (P301L, V337M and R406W) both in exon 10 and exon 12, result in tau proteins that aggregate into filaments more readily than the normal counterparts (Nacharaju et al. 1999). Moreover, the tau protein produced by these exonic mutations, as well as G272V, show reduced ability to promote microtubule assambly (Hong et al. 1998). On the other hand, intronic mutations result in an abnormally increased ratio of four-repeat to three-repeat isoforms of tau (Hasegawa et al. 1998), and pathological, insoluble tau proteins consisting mostly of four-repeat isoforms (Hulette et al. 1999), reminiscent of the conditions in corticobasal degeneration. Several molecular mechanisms altering the splicing of exon 10 have been identified and proposed to explain phenotypic variability (D’Souza et al. 1999). Although these mutations demonstrate that primary alterations in tau can lead to neurodegeneration with neurofibrillary tangles, patients with AD do not have mutations in the tau gene (Crawford et al. 1999).

Pathogenic Mechanisms in Pick Complex

Heredity is the only established etiology in this group of disorders. Besides the chromosome-17 linked families, one other family has been reported linked to chromosome 3 (Brown et al. 1995). A definite familial history was found in 40% of patients in a frontotemporal dementia (FTD) syndrome; this pattern was consistent with autosomal dominant transmission in 88% of these (Chow et al. 1999). Abnormalities in the metabolism of tau are likely to play a key role in the mechanism of neuronal

dysfunction and death, at least in dementia with Pick bodies (DPB), and corticobasal degeneration (CBD). However, discrepancies in the distribution of neuronal inclusions and neuronal death suggest that the former is not necessarily a precursor of the latter. The marked clinical and pathological variations between families with the same mutation (Bird et al. 1999) and even individuals within a family (Nasreddine et al. 1999) suggest the importance of modifying genes or environmental influences.

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Other mechanisms have been explored. The superficial laminar spongiosis does not resemble the transcortical spongiosis of prion diseases, and several studies have found no evidence of mutations in the prion protein gene or of deposition of prion protein in the brains of patients with dementia lacking distinctive histology or its variants (Pollanen et al. 1993). A report describing the presence of prion protein in the absence of mutations in the prion protein gene (Petersen et al. 1995) was in subsequent studies attributed to contamination (Gambetti 1997). A proposed role of inflammatory mechanisms is based on the presence of complement proteins in Pick bodies and ballooned neurones, with (Yasuhara et al. 1994) or without (Singhrao et al. 1996) development of the membrane

III.5.7

Incidence and Prevalence

There are no reliable figures for the incidence or prevalence of lobar atrophies. Patients are often misdiagnosed; as late as 1993 a diagnosis of Alzheimer’s disease (AD) had been applied to 18 out of 21 patients with the pathological diagnosis of Pick’s disease (Mendez et al. 1993). A variety of fanciful psychiatric diagnoses are at least as common, judging from published autopsy-confirmed series (Munoz-Garcia & Ludwin 1984). The proliferation

III.5.8

attack complex. There is no evidence of increased vulnerability to DNA fragmentation, or of expression of proteins involved in apoptosis (Ferrer 1999). Dementia with ITSNU and motor neurone disease could represent different manifestations of the same disease (Neary et al. 1990). Inclusions in motor neurones appear identical in both diseases, and many patients with classical amyotrophic lateral sclerosis show inclusions in the hippocampal dentate gyrus (Okamoto et al. 1991). Moreover, nondemented patients with motor neurone disease demonstrate subtle cognitive alterations similar in type, but far less pronounced than those seen in patients with dementia with ITSNU (Bak & Hodges 1999).

of terminology and the lack of recognition of relatedness probably hides a large number of cases (Kertesz & Munoz 1998). A common estimate among researcher clinicians and pathologists in this field is that one of the forms of the Pick complex represents the substrate in approximately 25% of cases with presenile dementia (Knopman et al. 1990; Snowden et al. 1996).

Diagnostic Tests

Imaging Computerized tomography (CT), magnetic resonance imaging (MRI) and single photon emission computerized tomography (SPECT) constitute the major diagnostic modalities. The frontal and temporal atrophy differs from the diffuse atrophy of Alzheimer’s disease (AD) on structural imaging (Plate III.3, facing p. 154). The anterior hypoperfusion demonstrated on SPECT contrasts with the temporal parietal hypoperfusion demonstrated in AD (see Read et al. 1995; Risberg & Gustafson 1997) (see Plate III.3). However, there has been no

evaluation of the sensitivity and specificity of SPECT in distinguishing patients with frontotemporal dementia from elderly patients with depression or psychosis, who often show frontotemporal hypoperfusion in SPECT. The MRI shows definite evidence of atrophy, often strikingly asymmetrical or even unilateral (see Plate III.3). Left frontotemporal atrophy is characteristic of primary progressive aphasia and right anterior hemisphere atrophy predominates in frontotemporal dementia (FTD), especially with disinhibition symptoms or antisocial behavior (Miller et al. 1993; Fukui & Kertesz 2000).

306 CHAPTER III.5

Systematic comparisons with SPECT have not been published (Miller & Gearhart 1999). The distribution of atrophy on MRI or of hypoperfusion on SPECT correlates to some extent with the clinical presentation. The usual correlate of FTD is bilateral frontal atrophy. Right frontal hypoperfusion is manifested by disinhibited, often offensive behavior, while left frontal hypoperfusion is associated with social withdrawal and depression, but retained social graces. Non-fluent aphasia may accompany these symptoms, or can be present in isolation when the atrophy is restricted to the left temporal lobe. Bilateral, predominantly left anterior temporal hypoperfusion is manifested as semantic dementia (Neary et al. 1998). A clear dissociation between atrophic areas on MRI and areas that fail to activate on positron emission tomography (PET) scans during specific tasks has been shown in semantic dementia. In this condition, the left posterior inferior temporal gyrus (Brodmann area 37/19) fails to activate on semantic tasks, but visible atrophy on MRI is limited to the anterolateral temporal region, predominantly on the left (Mummery et al. 1999).

Neuropsychology Psychometric testing has been found a useful diagnostic tool to separate patients with FTD from AD, but only to a certain degree. All studies show marked variability among patients, and although decreased average performance in tests related to frontal lobe function is observed, some patients demonstrate normal scores in the tests despite severe behavioral disturbances in the real world (Neary et al. 1988; Miller et al. 1991). In addition to perseveration in the Wisconsin Card Sorting test, deficits are usually found in word fluency, trail making, and picture arrangement. Memory is relatively preserved; the loss of recall memory is

III.5.9

proportionally greater than that of recognition, and possibly the psychometric substrate of the phenomenon of ‘forgetting to remember’ that relatives complain about. On the other hand, visuospatial task, such as block design and Raven’s Coloured Progressive Matrices, may show no abnormalities: deficits in trail-making tests can be attributed to impairment of the executive functions required by this test. The Mini Mental Status Examination may be normal in many initial examinations, except in primary progressive aphasia, when failure on the language items depresses the score, even without memory loss (Kertesz & Munoz 1997). The normal scores obtained in frontal tests measuring spatial working memory and planning tasks, in the early stages of the FTD syndrome with predominantly frontal manifestations, suggest the ventromedial frontal or orbitofrontal cortex as the initial site of pathology in these patients (Rahman et al. 1999). A different approach is to interview relatives to assess behavioral abnormalities in a semiquantitative manner, which several studies have found useful (Barber et al. 1995; Lebert et al. 1998; Mendez et al. 1998). The scores of FTD on the Frontal Behavioral Inventory showed no overlap with patients with AD or depression (Kertesz et al. 1997). A weakness in all these studies is the lack of pathological confir-mation in all but a few patients. Consequently, differences between the pathological substrates could not possibly be detected. Aphasia testing is useful to categorize and follow the deterioration in primary progressive aphasia (Kertesz & Munoz 1997). Semantic dementia often shows loss of naming and comprehension with preservation of syntax, digit span (short-term verbal memory), and Rey–Osterreich complex figure (visuospatial abilities) and non-verbal problemsolving Raven’s Progressive Matrices (Snowden et al. 1989; Hodges et al. 1992; Kertesz et al. 1998).

Diagnostic Criteria and Differential Diagnosis

The Lund and Manchester (1994) criteria (The Lund & Manchester Groups 1994) were the first proposed for the diagnosis of frontotemporal

dementia (FTD). These criteria were evaluated retrospectively by Miller et al. (1997b), using SPECT as the basis for patient classification. The criteria

FRONTOTEMPORAL LOBAR ATROPHIES 307

demonstrating discriminant power were lack of hygiene, hyperorality, stereotypic and perseverative behavior, progressive reduction of speech, and preserved spatial orientation. Other studies using a behavioral inventory used a cut-off score of 30 to separate FTD from Alzheimer’s disease (AD) and depressive dementia (Kertesz et al. 1997). Apathy, perseveration, disinhibition, and lack of insight were significant discriminators, but patients with vascular dementia often scored high on these items. A second consensus conference has elaborated broad inclusion and exclusion criteria for the generic entity of frontotemporal lobar degeneration, as well as specific criteria with core and supportive features for the prototypical clinical presentation FTD, progressive non-fluent aphasia, and semantic

III.5.10

dementia (corticobasal degeneration syndrome was not considered) (Neary et al. 1998). Cut-off points are not provided. From the other point of view, the capability of the National Institute of Neurological and Communicative Diseases-Alzheimer’s Disease and Related Disorders Association (NINCDS-ADRDA) criteria to separate AD from FTD in pathologically proven cases was evaluated by Varma et al. (1999). They found that their use for diagnosis of probable AD had high sensitivity (0.93), but low specificity (0.23) because many patients with FTD also fulfilled these criteria. Deficits in problem solving were much more common in patients with FTD, whereas deficits in orientation and praxis were significantly more common in patients with AD.

Clinical Vignette

History A store clerk showed a gradual onset of behavioral symptoms at the age of 61 years. She began obsessively closing windows and barring doors. At the same time she began to have some difficulty organizing her time, and with her regular household chores and shopping. She would call her husband frequently at work just to check that he was there. Initially she had difficulty concentrating. At times she would break into a conversation or say something that was inappropriate. She had difficulty counting change for store customers, remembering cards and knowing what to play in euchre or bridge. About a year and a half after onset she was noticed to have decreasing spontaneous speech; her responses became simpler and more slurred. She also showed decreased interest in her environment. Two years after her symptoms began she stopped speaking, began moaning, and was only able to perform simple commands. She was able to repeat simple statements but lost her speech initiation. At the end of the second year of her illness, she developed some stiffness on the right side, mostly in her right arm as well as her leg with mild tremor. Early in the third year of her illness she became

incontinent, was unable to feed herself and became less responsive to her husband. She needed help with dressing.

Examinations The patient had several admissions to hospital, the first a year after the onset of her illness after a fall and for her forgetfulness and personality change, and a clinical diagnosis of AD was given. Neuropsychological testing at this point showed a memory quotient of 103 (average). Oral fluency was very poor. She failed to sort cards by category. She had difficulty with common-sense judgements on the comprehension subtest of the Weschler Adult Intelligence Scale (WAIS) and sequencing a series of card from drawings (picture arrangement). She had trouble with frontal lobe functioning and visual scanning, and difficulty of upward and lateral gaze was noted. The neuropsychologist suggested progressive supranuclear palsy. The internist, who saw her shortly afterward, noticed she seemed to walk with a shuffle. Her writing became worse and very small. She was treated with antidepressants without improvement. When reassessed a year and a half after her

308 CHAPTER III.5

onset, she was noted to be echolalic and at times her speech was unintelligible. She also had receptive speech problems and a slight increase in tone. CT scans on both admissions showed frontal lobe atrophy. On neurological examination, 3 years after onset, she appeared to be in a fetal position, staring with repetitive moaning and no spontaneous speech. She followed some simple commands with her limbs and was able to repeat very short sentences with slurred and nasal speech. She answered a few questions with the occasional one word, such as her name. Upgaze impairment was noted again. She had a positive jaw jerk. She also had palmomental, labial and glabellar tap reflexes. EEG showed bitemporal dysrrhythmia that was prominent on the left side.

Pathology The patient died 6 years after onset. The brain weighed 965 g. The initial pathologist noted severe neuronal loss and gliosis in the globus pallidus and substantia nigra, and reached a tentative diagnosis of Parkinson’s disease with dementia. A recent review of the pathology identified typical corticobasal degeneration pathology.

Comment This case illustrates the FTD presentation of corticobasal degeneration, with subsequent addition of aphasic and motor syndromes. It also serves as a reminder of how easy it is to miss the pathological diagnosis, unless the pathologist is well aware of the condition and appropriate stains are used.

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III.6

Other Important Dementias

Juha O. Rinne

III.6.1

Introduction

In the diseases discussed below (Parkinson’s disease, Huntington’s disease, progressive supranuclear palsy, multiple system atrophy, corticobasal degeneration) extrapyramidal motor symptoms are common, often being the presenting features. Cognitive impairment and behavioral problems, however, occur in a considerable proportion of patients. Most common differential diagnostic problems arise with dementia with Lewy bodies, Alzheimer’s disease

III.6.2

Parkinson’s Disease

Key points • Motor symptoms (tremor, rigidity, hypokinesia) predominate. • Cognitive impairment associated with Parkinson’s disease (PD) includes executive, mnemonic and visuospatial functions. • The pathophysiological basis of this cognitive impairment is unclear, and is probably heterogenous. Parkinson’s disease (PD) is an adult onset, progressive disorder of the extrapyramidal motor system. The prevalence of PD is around 150–200/100 000 in the general population, but increases with age. Typical clinical features are rest tremor, bradykinesia and rigidity. Diagnosis is supported by a good response to levodopa treatment and asymmetrical

312

(AD), frontotemporal degeneration, and vascular cognitive impairment or dementia. Differential diagnostic problems may arise especially when the extrapyramidal signs and cognitive impairment have simultaneous onset, or when cognitive impairment precedes extrapyramidal signs. However, the focus of this review is to characterize the typical features of cognitive impairment of the various extrapyramidal syndromes.

onset. Clinical diagnostic guidelines have been published (Gibb & Lees 1988, Gelb et al. 1999). Pathologically, the hallmark of PD is progressive loss of pigmented dopaminergic neurones in the susbstantia nigra (and other brain stem nuclei). Neuronal loss in the substatnia nigra leads to deficiency of dopamine in the striatum, the posterior putamen being most severely affected. The severity of bradykinesia and rigidity in PD have been repeatedly shown to be related to both nigral neuronal loss and striatal dopamine deficiency. In addition to motor symptoms, cognitive impairment in PD is common. When discussing cognitive functions in PD, one must make a clear distinction between (subtle) cognitive impairment and dementia. Estimates of the prevalence of dementia in PD have varied considerably, ranging from 4% to 93%, overall frequency being 40% (for a review see Cummings 1988; Zhang

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& Roman 1993). Differences in patient populations, study designs, etc. contribute to this variation. Moreover, the definitions used for dementia have varied, a fact which affects the observed prevalence figures (Erkinjuntti et al. 1997). It is evident that cognitive impairment is far more common than dementia in PD. The cognitive changes most often associated with PD are executive, mnemonic and visuospatial impairments. Indeed, cognitive impairment in PD is said to be a progressive dysexecutive syndrome (Dubois & Pillon 1999). Executive functions consist in broad terms of the ability to plan, organize and regulate goal-directed behavior. These processes are typically impaired after frontal lobe damage. Deficits of executive functions have been repeatedly demonstrated in non-demented patients with PD. Impairments have been demonstrated in concept formation and rule finding (Pillon et al. 1986; Taylor et al. 1986), problem solving (Saint-Cyr et al. 1988), set shifting (Cools et al. 1984; Hietanen & Teräväinen 1986; Taylor et al. 1986; Owen et al. 1993) and set main-

tenance (Cools et al. 1984; Hietanen & Teräväinen 1986; Pillon et al. 1986; Taylor et al. 1986). Commonly used tests of executive functions include the Wisconsin Card Sorting Test, trail making task, Stroop test, Tower of London task, verbal fluency, etc. In general, PD patients have shown impaired generation, maintenance of set and slowness in set shifting. Patients benefit from external cues and difficulties are seen in shifting attention to novel stimuli, whereas perseverative errors are less common (Owen et al. 1992). More specifically, it has been suggested that in early PD there are extradimensional shifting problems (shifts to different perceptual dimensions), whereas intradimensional shifting (shifts between different exemplars of the same rule) is not impaired (Downes et al. 1989). Although the precise anatomical basis of these setshifting problems in PD is unclear, the deficits in extradimensional set-shifting have been linked with dysfunction of the dorsolateral fronto-striatal loop, whereas the oribtofrontal loop is considered more important for reversal shifting (Dias et al. 1996; Cools et al. 1999; Rogers et al. 2000). Figure III.6.1

Motor

Oculomotor

Dorsolateral

Orbitofrontal

Anterior cingulate

Supplementary motor area

Frontal eye fields

Dorsolateral PFC

Lateral orbitofrontal cortex

Anterior cingulate area

Putamen

Caudate body

Caudate dorsolateral head

Caudate ventromedial head

Ventral striatum

GPi / SNr

GPi / SNr

GPi / SNr

GPi / SNr

GPi / SNr

Thalamus ventrolateral

Thalamus ventroanterior mediodorsal

Thalamus ventroanterior mediodorsal

Thalamus ventroanterior mediodorsal

Thalamus mediodorsal

Fig. III.6.1 A schematic representation of the corticobasal ganglia-thalamo-cortical circuits and their parallel organization. These circuits are differently affected in various extrapyramidal syndromes and this contributes to the differences in the profile of cognitive impairment in these syndromes (see text for details).

314 CHAPTER III.6

shows a simplified scheme of the parallel organization of various corticobasal ganglia-thalamo-cortical loops. These circuits are differently affected in various extrapyrmidal syndromes which may contribute to the differences in the profile of cognitive impairment in these syndromes. Memory disturbances have been observed already in early PD. Both working and long-term memory, as well as procedural learning, have been reported to be impaired in PD. A characteristic feature of memory problems in PD is a severe deficit in free verbal and visual recall, whereas cued recall and recognition are normal (Taylor et al. 1990; Pillon et al. 1993). Using the Grober and Buschke procedure, it was found (Pillon et al. 1993) that PD patients had a severe deficit in free recall, but that their performance was considerably improved after semantic cueing. Under cued recall, patients’ recall scores were almost at the level of the values of healthy controls. This almost normal behavior in cued recall indicates that the ability to store and consolidate information is preserved, but that there is impaired ability to activate those neuronal processes that are involved in the functional use of memory stores (Dubois et al. 1994). Impaired executive functions may also contribute to the memory problems in PD, since it has been noted that patients have impaired learning strategies and temporal sequencing (Saint-Cyr et al. 1988). In addition, recall deficits are more severe in tasks that use material which is not semantically organized (Dubois et al. 1994), indicating that the patients’ ability to spontaneously generate encoding and retrieval strategies is impaired. Visuospatial impairment has been noted in PD, but no specific pattern of this impairment has emerged. Indeed, in a review (Cummings & Huber 1992), it was noted that visuospatial impairment in PD is seen in all subcategories of visuospatial functioning except in visual sensory abilities and visual recognition. Deficits in visuospatial functioning are especially seen in more complex tasks requiring planning and sequencing or self-generation of strategies. Risk factors for dementia in PD include older age at onset (Mayeux et al. 1988), severe motor deficit (Marder et al. 1990; Glatt & Koller 1994),

akinetic-rigid vs. tremor-dominant type (Mayeux & Stern 1983; Huber et al. 1988; Roos et al. 1996), although the latter is somewhat controversial (Paulus & Jellinger 1991). The risk of developing dementia in PD is about two to four times higher than in the general population (Rajput 1992; Marder et al. 1994). Mortality is also higher in demented PD patients than in non-demented ones (Marder et al. 1991), and this also affects the prevalence figures. Depression is one confounding factor when estimating cognitive impairment in PD. The frequency of depression in PD is high, and is more common in demented than in non-demented patients (Huber et al. 1988; Starkstein et al. 1989). Because of motor and cognitve disturbances, it may be difficult to detect depression. On the other hand, depression can cause cognitive symptoms, especially problems with attention and executive functions. Thus, depression, if present, should be adequately treated. Another confounding factor is anticholinergic treatment. Anticholinergic drugs have been reported to impair cognitive performance, especially frontal lobe functioning, in PD (Dubois et al. 1990). In addition, anticholinergics can provoke confusional states (De Smet et al. 1982). Magnetic resonance imaging (MRI) has revealed atrophy of the medial temporal lobe structures, especially the hippocampus, in AD. In one study, patients with AD, vascular dementia (VaD) and PD were studied and all groups of patients showed smaller volumes of hippocampus than normal controls (Laakso et al. 1996). Even in PD patients without dementia, significant hippocampal atrophy was present. Functional positron emission tomography (PET) imaging in early PD has revealed a decrease in frontal blood flow and oxygen metabolism contralateral to the affected limbs, but no change in glucose metabolism evaluated with fluorodeoxyglucose (FDG) (Perlmutter & Raichle 1985; Wolfson et al. 1985; Brooks 1998). Later, patients show more diffuse cortical hypometabolism, the degree of which correlates with cognitive performance (Kuhl et al. 1984; Peppard et al. 1988). In demented PD patients, an Alzheimertype pattern of hypometabolism (posterior parietal and temporal areas being most severely affected)

OTHER IMPORTANT DEMENTIAS 315

has been reported (Kuhl et al. 1984; Otsuka et al. 1991). This pattern is, however, not necessarily due to concomitant Alzheimer pathology. In one pathologically confirmed case a reduction in parietal and temporal metabolism was seen without any evidence of Alzheimer or cortical Lewy body pathology at autopsy (Schapiro et al. 1990). In PET studies with a dopaminergic ligand, fluorodopa, a correlation between reduction in fluorodopa uptake in the caudate nucleus and impaired performance in delayed recall of the selective reminding task (Holthoff et al. 1994; HolthoffDetto et al. 1997) or frontal cognitive function (Rinne et al. 2000) was seen. The uptake of fluorodopa mainly reflects its decarboxylation to fluorodopamine and the function of presynaptic dopaminergic terminals. Similar findings of reduced caudate uptake correlating with impaired frontal lobe functioning in PD were reported using a monoamine transporter ligand, nomifensine (Marie et al. 1999). The pathophysiological basis of cognitive impairment and dementia in PD is not clear. Deficits in executive functions and other frontal lobe tests suggest that disruption of the frontal-subcortical circuits may play an important role. In the case of frankly demented PD patients, suggested pathophysiological mechanisms include concomitant AD, cortical Lewy bodies, degeneration of subcortical projection nuclei (substantia nigra, locus coeruleus, nucleus basalis) or combinations of these processes. Alzheimer-type pathology (senile plaques, neurofibrillary tangles, or both) is common in PD, with estimates varying from 42% to 91% of cases showing these changes (Hakim & Mathieson 1979; Boller et al. 1980; Gaspar & Gray 1984, Jellinger 1999). In a pathological series of 200 cases with a clinical diagnosis of PD, 161 (80.5%) showed primary Lewy body disease. Fifty-seven patients were demented and of these, 16 (28%) had concomitant AD or Alzheimer-type pathology ( Jellinger 1999). In spite of the frequent occurrence of Alzheimertype changes in PD, their role in the development of cognitive impairment and dementia is not clear. The number of Alzheimer-type changes has been shown to be higher in demented PD patients (Jellinger 1999), although contradictory findings

have also been published showing no difference in the degree of Alzheimer-type pathology between PD patients with or without dementia (Ball 1984; Ince et al. 1991; Jendroska et al. 1996). There is a correlation between the severity of Alzheimer-type pathology and the degree of cognitive impairment of the patients in some studies (Jellinger et al. 1991), although dementia can be present without significant Alzheimer-type pathology. Moreover, increasing numbers of cortical Lewy bodies in patients with a clinical and pathological diagnosis of idiopathic PD have been shown to be associated with the degree of cognitive changes regardless of whether Alzheimer-type pathology was present or not (Mattila et al. 1998). Idiopathic PD must be distinguished from dementia with Lewy bodies (DLB), but the differential diagnosis may be problematic, especially in those PD cases showing cognitive impairment early in their disease. The relationship between idiopathic PD and DLB is discussed elsewhere (see Chapter III.4). The clinical picture of cognitive impairment is also different between AD and PD. Language, praxis and gnosis are more severely impaired in AD than in PD (Cummings 1986; Huber et al. 1989), memory impairment is also different, with Alzheimer patients showing severe recall deficits which are only slightly improved by cueing, whereas PD patients show impaired free recall but benefit from cueing (Pillon et al. 1993). Neurochemically the degree of cognitive impairment and dementia in PD has been found to correlate with the level of choline acetyltransferase in the frontal cortex (Ruberg et al. 1982; Perry et al. 1983). In another study all the PD patients considered clinically to be demented had Alzheimertype pathology at autopsy, but these changes did not, however, correlate with the degree of choline acetyltransferase activity (Dubois et al. 1983; Gaspar & Gray 1984). In PD, neuronal loss and shrinkage have been found in the nucleus basalis of Meynert where the cortical cholinergic projections originate. This neuronal loss is seen both in demented and non-demented PD patients, but the degree of cell loss is greater in the demented patients (Gaspar & Gray 1984; Jellinger 1989). In addition, a reduction in the number of nicotinic receptors in the frontal cortex in PD is associated with more severe

316 CHAPTER III.6

cognitive impairment (Rinne et al. 1991). Cortical somatostatin levels are reduced in PD and correlate with the degree of cognitive impairment (Epelbaum et al. 1986). There is also some pathological and clinical evidence linking cognitive impairment in PD with noradrenergic and dopaminergic hypofunction (Rinne et al. 1989; Paulus & Jellinger 1991; Jellinger et al. 1994; Yanagisawa 1996). Degeneration of the dopaminergic system is the basic pathophysiological mechanism in PD and clearly correlates with the severity of motor symptoms. However, there is also some evidence linking dopaminergic hypofunctiuon and cognitive impairment in PD. Cognitive symptoms, especially those thought to be related to frontal lobe functioning, are alleviated by levodopa in the early phase of the disease (Portin & Rinne 1980; Mohr et al. 1987; Gotham et al. 1988) Moreover, in patients already on levodopa therapy, temporary cessation of medication led to impairment on tests sensitive for frontal lobe functions (Lange et al. 1992). On the other hand, even negative effects of levodopa on cognitive function in PD have been reported (Gotham et al. 1988; Yanagisawa 1996; Cools et al. 1999). More specifically, impairment in reversal shifting in a study on shifting deficits in PD was noted (Cools et al. 1999). It is assumed that reversal

III.6.3

shifting is associated with the ‘oribofrontal loop’ and attentional set shifting with the ‘prefrontal loop’ (see Fig. III.6.1) (Dias et al. 1996; Rogers et al. 2000). On the basis of the uneven pattern of dopamine loss in the striatum in PD (Kish et al. 1988), it was hypothesized (Gotham et al. 1988; Cools et al. 1999) that the dopamine level is most severely depleted in that part of the striatum (putamen) that belongs to the ‘motor loop’, whereas the dopamine deficiency is less severe in the part of the striatum (dorsal caudate) belonging to the ‘dorsolateral loop’, and least severe in the ventral caudate which is a part of the ‘orbitofrontal loop’. Thus, levodopa treatment, while reversing the severe depletion of dopamine in the ‘motor loop’, at the same time produces too high dopamine levels in the less severely affected ‘orbitofrontal loop’. This is referred to as the ‘dopamine overdose hypothesis’ (Gotham et al. 1988; Cools et al. 1999). Taken together, in spite of the evidence suggesting involvement of dopamine in cognitive functions in PD, it is clear that dopamine is not a key player in the development of dementia in PD. It seems to contribute to certain (especially frontal) cognitive symptoms in PD, but the pathophysiology of the more generalized cognitive impairment and later dementia is also more generalized.

Huntington’s Disease

Key points • Autosomal dominant disease, the clinical picture of which includes motor, behavioral and cognitive impairment. • Motor features include chorea, dystonia and parkinsonism. • Executive dysfunction, memory deficits and impairment of visuospatial function are most often seen cognitive impairments. Huntington’s disease (HD) is an autosomal dominant disorder in which an excess of trinucleotide repeats (CAG repeats) is found in chromosome 4.

The prevalence of HD is approximately 5–10/ 100 000 in general population, less than one-tenth of the prevalence of Parkinson’s disease (PD). The clinical picture of HD includes motor, behavioral and cognitive symptoms. The motor features include chorea, dystonia and parkinsonism. In addition, eye movement abnormalities and dysarthria and dysphagia are present. Pathologically, the striatum is most severely affected and there is a considerable loss of medium-sized spiny projection neurones. Executive dysfunction is seen in the early phase of HD. The patients have difficulties in organizing their work and scheduling their daily activities (Caine et al. 1978; Shoulson 1990). In the Wisconsin Card Sorting Test, HD patients have

OTHER IMPORTANT DEMENTIAS 317

difficulties in changing set and they make perseverative errors (Saint-Cyr et al. 1988; Morris 1995). The deficits in executive functions in HD seem to be more severe than in PD. Memory deficits in HD resemble those seen in PD but are different from those of Alzheimer’s disease (AD). HD patients have problems with both declarative and procedural memory (Shoulson 1990; Morris 1995). HD patients perform poorly on tests of initiation (Paulsen et al. 1995), and retrieval of recent and remote memories is impaired (Aminoff et al. 1975; Caine et al. 1978; Brandt 1985). Immediate memory recall and recognition is relatively preserved in HD, and thus better than in AD. Visuospatial functions in HD have not been extensively studied. Visuoconstructive performance of HD patients was not significantly impaired, whereas salient deficits were seen when manuipulation of personal space was required (Brouwers et al. 1984). This pattern of visuospatial impairment was different from that seen in AD. Asymptomatic people at risk of HD have shown that gene carriers scored lower on all subtests of the Wechsler Adult Intelligence ScaleaRevised (WAIS-R) than non-carriers (Diamond et al. 1992; Foroud et al. 1995). An inverse correlation was noted between the trinucleotide repeat (CAG repeat) length and the performance on the WAIS-R (Foroud et al. 1995). The progression of cognitive impairment in HD is variable (MacMillan et al. 1993; Britton et al. 1995), with some individuals remaining cognitively preserved in spite of severe motor deficits. The estimates of the prevalence of dementia in HD have varied considerably, varying from 15% to 95%. Differences in patient populations, diagnostic criteria and definitions of dementia are obvious factors explaining at least part of the variation. Patients have executive dysfunction, memory retrieval difficulties and general slowing of cognition. Language problems may occur and consist of word finding difficulties, decreased production, increased pauses and occasional paraphasias (Gordon & Illes 1987). The degree of

cognitive impairment has been found to correlate with the duration of disease (Caine et al. 1978) and with the degree of atrophy (especially in the caudate nucleus) in computed tomography or magnetic resonance imaging (MRI) (Bamford et al. 1989; Starkstein et al. 1992). Functional imaging with positron emission tomography (PET) has shown reduced glucose metabolism in the striatum in HD, even when the computed tomography or MRI has been normal (Kuhl et al. 1982; Hayden et al. 1986; Leenders et al. 1986; Young et al. 1986). The decrease in striatal fluorodeoxyglucose (FDG) uptake is more severe with the increasing severity of cognitive changes, especially in the caudate nucleus, whereas the putaminal glucose metabolism correlates with motor symptoms (Young et al. 1986; Berent et al. 1988) Cortical impairment of glucose metabolism becomes evident later in the course of the disease, and is seen especially in the frontal areas (Kuhl et al. 1984; Kuwert et al. 1990). Since the mediumsized spiny neurones that degenerate in HD express dopamine receptors, reductions in both dopamine D1 and D2 receptor-ligand uptake have been noted (Wong et al. 1985; Turjanski et al. 1995) and can be seen even in at least some of the asymptomatic gene carriers (Weeks et al. 1996). Changes in opioid and bentsodiatsepine receptors are less clear (Holthoff et al. 1993; Weeks et al. 1995), however, the relationship between receptor changes and cognitive impairment of the patients in unclear. The pathophysiological basis of dementia in HD is suggested to be related to striatal pathology and disruption of the fronto-subcortical circuits. The cognitive changes seen in HD resemble those seen in focal caudate or frontal lobe lesions (Cummings & Benson 1984; Bhatia & Marsden 1994; Dubois et al. 1995). In addition to these ‘subcortical’ changes, patients with HD also have additional cortical pathology, which may contribute to the cognitive impairment. The frequent behavioral changes in HD which contribute to functional decline and certainly affect performance in cognitive tests are not discussed in this review.

318 CHAPTER III.6

III.6.4

Progressive Supranuclear Palsy

Key points • Typically a poorly levodopa-responsive akinetic–rigid syndrome with supranuclear gaze palsy and bulbar palsy. • Cognitive impairment is characterized by deficits in executive functions and in other tasks involving frontal lobes. • Cognitive impairment often progresses to dementia. Progresive supranuclear palsy (PSP, or Steele– Richardson–Olszewski syndrome) in its full blown form is a poorly levodopa responsive akinetic-rigid syndrome with supranuclear gaze palsy, bulbar palsy and cognitive impairment often reaching the severity of dementia. Pathologically, PSP is characterized by neurofibrillary tangles and neuronal loss in the basal ganglia, superior colliculi, brain stem nuclei and periaqueductal grey matter and cerebral cortex. Prevalence figures around 1.5 per 100 000 in general population have been reported making PSP approximately 1%, as common as Parkinson’s disease (PD). Slowing of information processing and deficits in executive functions are commonly seen in PSP (Kertzman et al. 1990; Johnson et al. 1991) but these changes are non-specific in nature. In spite of the lack of obvious qualitative differences, it has been shown that PSP patients are more impaired in frontal lobe testing than patients with Huntington’s disease (HD) or PD (Pillon et al. 1991). Executive dysfunctioning can be seen, e.g. difficulties in shifting between metal tasks and in verbal fluency tests (Dubois et al. 1988; Grafman et al. 1990). Memory is relatively preserved but deficits are seen in tasks demanding frontally mediated

memory search (Milberg & Albert 1989; Pillon et al. 1994). A recall deficit has also been reported in PSP (Litvan et al. 1989). In general, memory defects in PSP resemble those seen in PD and HD and differ from those seen in Alzheimer’s disease (AD). AD patients show more rapid forgetting than patients with PSP (Pillon et al. 1994). Computed tomography and magnetic ressonance imaging (MRI) changes (atrophy, signal changes in the striatum) which can be seen in most cases of PSP are non-specific, and have not shown clear correlations with the degree of cognitive impairment. Functional imaging with positron emission tomography (PET) has shown widespread cortical reduction in glucose metabolism, frontal areas being particularly affected. However, this pattern is not specific for PSP. The degree of glucose metabolism both in the frontal and non-frontal areas has been shown to correlate with the performance in cognitive tests and with disease duration (Foster et al. 1988; Blin et al. 1990). There is also a reduction in fluorodopa uptake (with equal affision of the caudate and putamen) (Leenders et al. 1988; Bhatt et al. 1991) and a reduction in the number of striatal dopamine D2 receptors (Baron et al. 1986; Brücke et al. 1991; Brooks et al. 1992). However, these changes in neurotransmitters have not been studied in relation to the degree of cognitive impairment of the patients. The pathology in PSP is widespread. There are changes in the cerebral cortex, the nigrostriatal pathway and other basal ganglia and the brainstem. The cortical (especially frontal) pathology and disruption of fronto-subcortical circuits are thought to be the pathophysiological basis of cognitive impairment in PSP. The cortical involvement is also supported by the occasional occurrence of aphasia in patients with PSP (Perkin et al. 1978).

OTHER IMPORTANT DEMENTIAS 319

III.6.5

Multiple System Atrophy

Key points • Clinically characterized by a combination of parkinsonian, autonomic, pyramidal or cerebellar symptoms or signs. • Cognitive impairment typically includes deficits on tests of frontal lobe functions. Multiple system atrophy (MSA) is sometimes difficult to distinguish from idiopathic Parkinson’s disease (PD). MSA is referred to as a disease characterized clinically by any combination of parkinsonian, autonomic, pyramidal or cerebellar symptoms or signs, and pathologically, by cell loss and gliosis in some or all of the following structures: putamen, caudate, globus pallidus, substantia nigra, locus coeruleus, inferior olives, pontine nuclei, cerebellar Purkinje cells, and the intermediolateral cell columns and Onuf’s nucleus of the spinal cord (Quinn 1994). The studies on the population prevalence of MSA are few. In a rural Bavarian population prevalence of MSA was 0.31% in persons older than 65 years (the corresponding figure for PD was 0.71%) (Trenkwalder et al. 1995). It has been estimated that MSA might account anything between 3.6 and 22% of cases of parkinsonism

III.6.6

(Quinn 1994). Clearly more epidemiological studies on MSA are needed. Cognitive impairment is seen in MSA and, in general the deficits are quite similar to those observed in patients with localized frontal lobe damage (Owen & Robbins 1994). MSA patients have shown significant deficits on tests of frontal lobe functions (Robbins et al. 1992). Especially attentional set shifting, speed of cognitive processing and spatial working memory were impaired. In a comparative study this pattern resembled more the performance of patients with frontal lobe damage than that of patients with PD (mild or severe) or progressive supranuclear palsy (PSP) (Owen & Robbins 1994). No evidence was found of impaired performance on tests of pattern and spatial recognition memory. The MSA patients showed minor impairments in tests of visuospatial memory and learning, although these deficits were said to be quite distinct qualitatively from those seen in patients with severe PD or in patients with Alzheimer’s disease (AD) (Shakian et al. 1988). In spite of these cognitive changes, MSA is not characterized by progressive dementia. Even in some proposed clinical criteria (Quinn 1994), both the striatonigral and olivopontocerebellar type of presentation of MSA is required to occur without dementia.

Corticobasal Degeneration

Key points • Classically an akinetic–rigid syndrome with cortical signs, dystonia, tremor and myoclonus. • Cognitive impairment often manifests as a dysexecutive syndrome. • Cognitive impairment and dementia may be the presenting feature. This rare syndrome has been called by various names, including corticobasal degeneration (CDB), corticobasal-ganglionic degeneration, and cortico-

detatonigral degeneration with neuronal achromasia. Major clinical features include asymmetrical akinetic–rigid parkinsonian syndrome, cortical signs (apraxia, cortical sensory disturbances, dysphasia, corticospinal tract signs), dystonia, tremor (action, postural or both), myoclonus, and alien hand/limb phenomenon (Watts et al. 1994). Cognitive impairment and dementia are often seen, and in some cases cognitive impairment may be the presenting feature (Lerner et al. 1994). Pathological features include frontoparietal cerebral cortical atrophy (often asymmetrical), neuronal loss, gliosis and swollen ballooned achromatic neurones in the cerebral cortex.

320 CHAPTER III.6

The cognitive impairment in CBD has received relatively little attention until recently. However, the reports on cognitive impairment as a presenting feature of CBD (Lerner et al. 1994; Bergeron et al. 1996) have aroused more interest in cognitive performance in CBD. Neuropsychologically, patients with CBD exhibit dysexecutive syndrome resembling that seen in progressive supranuclear palsy (PSP).

III.6.7

Conclusions

Cognitive impairment is common in many extrapyramidal diseases. This impairment is seen especially in cognitive tests sensitive to frontal lobe functioning contributing to problems with executive functions. Also, other cognitive functions are affected, but no pattern specific for only one given disease can be seen. There are some differences in the profile of cognitive deficits in various extrapyramidal disorders and also in whether the cognitive impairment progresses to fulfil the criteria for dementia. Patients with Parkinson’s disease (PD)

III.6.8

However, in CBD, problems with motor execution and praxis are prominent. In a study comparing CBD patients to patients with Alzheimer’s disease (AD), CBD patients performed better on tests of immediate recall and attention, but more poorly on tests for praxis and digit span (Massman et al. 1994; Pillon et al. 1995).

and multiple system atrophy (MSA) show especially frontal pattern of impairment, and more clear deficits in recall, planning and monitoring are seen in progressive supranuclear palsy and Huntington’s disease (HD). In addition, attentional and behavioral changes are more severe in HD. Patients with corticobasal degeneration (CBD) show signs of cortical involvement already early in disease. These differences may reflect differences in relative subcortical and cortical involvement in these disorders.

Infectious Dementias

Irina Elovaara and Irina Alafuzoff HIV-1-related dementia

Infection with the human immunodeficiency virus type 1 (HIV-1) frequently results in a dementing illness that is one of the most severe and common central nervous system (CNS) complications of untreated HIV-1 disease. This disease affects both adults and children and usually manifests late in the course of HIV-1 infection when patients have developed major opportunistic infections or neoplasms (Price et al. 1988; Price & Brew 1997). Occasionally dementia may develop when formal criteria of aquired immune deficiency syndrome (AIDS) are not fulfilled (Navia & Price 1987). Therefore, recognition of early presentation of dementia during systemic HIV-1 infection has resulted in the addition of dementia to the diagnostic criteria of AIDS (Centers for Disease Control 1987).

The annual incidence of HIV-1-related dementia is between 7% and 14% (Day et al. 1992; Bacellar et al. 1994; Dal Pan & McArthur 1996; Berger & Nath 1997). HIV-1-related dementia is associated with a worsened prognosis and a median survival time of 6 months after diagnosis (Melton et al. 1997; Price & Brew 1997). The risk factors for development of progressive dementia include decreased hemoglobin and body mass index before development of AIDS and older age at onset of AIDS (McArthur et al. 1993). The clinical syndrome was originally termed AIDS–dementia complex (Navia et al. 1986), but more recently the term HIV-1-associated cognitive-motor complex was introduced in order to include patients with mild symptoms and signs (World Health Organization 1990; American Academy of Neurology AIDS Task Force 1991).

OTHER IMPORTANT DEMENTIAS 321

The severity of dementia can be evaluated by a staging scheme based on functional severity in the cognitive and motor spheres (Price et al. 1988; Sidtis & Price 1990). Earliest symptoms consist of difficulties with concentration and attention, slight memory disturbance and emotional instability (Navia et al. 1986; Poutiainen et al. 1993). Later, progressive cognitive decline, behavioral dysfunction including organic psychosis and motor abnormalities follow. Vacuolar myelopathy is often present in the terminal phase of AIDS, reflecting the involvement of the spinal cord and results in progressive spastic paraparesis with sphincter disturbances and ataxia (Brew 1999). Computed tomography (CT) and magnetic resonance imaging (MRI) each reveal cerebral atrophy and/or abnormalities in the white matter (Post et al. 1988; 1991; Raininko et al. 1992; 1997). Cerebrospinal fluid (CSF) is used to exclude other diagnoses and reveals non-specific mononuclear pleocytosis, elevated protein level and intrathecal IgG synthesis (Elovaara et al. 1987; 1993; Resnick et al. 1995), presence of HIV-1 (Ho et al. 1995), HIV-1 p24 antigen and HIV-1 DNA (Price & Brew 1997). Formal neuropsychological tests may be used in monitoring cognitive performance (Poutiainen et al. 1996), but they do not substitute for the clinical neurological evaluation and should be interpreted in the clinical context. Electroencephalogram (EEG) may be diffusely or focally slow (Elovaara et al. 1991). Neuropathologically, HIV-1-induced CNS lesions are differentiated into three distinct syndromes (Budka & Gray 1993): 1 HIV-1 encephalitis is defined by the presence of foci composed of microglia, macrophages and multinucleated giant cells (MGCs) and affects mainly the white matter, the basal ganglia and the brainstem (Budka 1991). 2 HIV-1 leukoencephalopathy constitutes a diffuse damage of the white matter involving myelin loss, astrogliosis, microglial proliferation and MGCs (Lang et al. 1989). 3 Vacuolar leukoencephalopathy is another type of HIV-1-induced white matter damage. Gray matter damage, termed diffuse poliodystrophy, involves diffuse cortical astrogliosis, microglial activation and neuronal and synaptic changes (Budka 1991).

The diagnosis of HIV-1-related dementia is one primarily of exclusion. The criteria for diagnosis include HIV-1 seropositivity, history of progressive cognitive and behavioral decline, and exclusion of CNS opportunistic processes by CT, MRI, and CSF analyses (American Academy of Neurology AIDS Task Force 1991). The pathogenesis of HIV-1-related dementia remains poorly understood. The mechanisms suggested include toxicity by viral antigens, endogenous or cellular substances (Dewhurst et al. 1996; Nath & Geiger 1998; Chiodi et al. 1999; Elovaara et al. 1999). Antiretroviral therapy using zidovudine, a nucleoside reversetranscriptase inhibitor, improves neuropsychological function, prolongs survival and partially reverses cognitive abnormalities (Sidtis et al. 1993; Melton et al. 1997). The optimal dosage is not known. Improvement in cognitive performance is greatest with higher dosages (2000 mg/day) but is associated with neuropathic adverse effects, anemia, and leukopenia. The conventional dosage is 500–600 mg/day. The benefit of zidovudine therapy is transient; improvement in cognition is sustained for up to 4–6 months, but symptoms tend to relapse after 6–12 months of therapy. Higher rates of relapse are associated with lower dosages (Melton et al. 1997). Discontinuation of zidovudine may result in rapid progression in symptoms. Dideoxyinosine, another antiretroviral agent, may be used if the patient has progression of symptoms at the maximally tolerated dosage of zidovudine (Melton et al. 1997; Price & Brew 1997). The calcium channel blocker nimodipine that blocks the toxicity of HIV gp120 has been tested, but its efficacy is not known. A benefit of prophylactic use of zidovudine on the prevention of HIV-related dementia has been suggested.

Creutzfeldt–Jakob disease Creutzfeldt–Jakob disease (CJD), a fatal neurodegenerative disease, is the commonest form of the human prion diseases. Creutzfeldt and Jacob reported the first cases of CJD in 1920–21 (Creutzfeldt 1920; Jakob 1921). Although previously designated a slow viral disease, CJD is now classified as a transmissible spongiform encephalopathy, because the disease has been shown to be transmittable to

322 CHAPTER III.6

animals and humans, and because vacuolation of the brain tissue is seen by light microscopical examination (Gajdusek & Zigas 1957; Gajdusek et al. 1966; Gibbs et al. 1968). The worldwide incidence of CJD is about 1 per million per year and most of the CJD cases are sporadic (Masters et al. 1978; Alperovitch et al. 1994). Cases of iatrogenic CJD, acquired by accidental transmission, have been reported to occur with corneal transplantation, contaminated EEG electrodes and neurosurgical equipment (Brown et al. 1992; Alter 2000). In 1996, a new-variant CJD (nvCJD) was identified, associated with consuming products from animals affected with the bovine spongiform encephalopathy (Wilesmith et al. 1988; Collinge et al. 1996). Even though most of the CJD cases are sporadic, a dominantly inherited form of CJD is also known and is seen in 10% of cases. The first report of familial CJD is from 1924 (Kirschbaum 1924). Males and females are affected equally by CJD and the peak age at onset is around 60 years (Will 1991) with exception of nvCJD, which has an age at onset of around 26 years (Weber & Aguzzi 1997). Generally the disease has a rapid course leading to death within 4–12 months (Will & Matthews 1984). Familial CJD has a somewhat earlier age at onset compared to sporadic CJD with duration of the disease ranging from 8 months to 13 years (Weber & Aguzzi 1997). The characteristic clinical features of CJD are rapid progression of mental deterioration including dementia, myoclonus, motor disturbances and periodic short-wave activity on EEG registration. CT and CSF examinations are usually normal. When a patient presents with rapidly progressive dementia, myoclonus and EEG abnormality the clinical diagnosis is relatively certain. Variants of CJD with extensive cerebellar syndromes, visual disturbances and occipital pathology have also been described. Specific therapy for CJD has not yet been established. The brain tissue investigation, either as surgical brain biopsy or postmortem examination of the CNS is a necessity for a final diagnosis of CJD. The gross appearance of the brain is inconclusive whereas the histological examination of brain tissue reveals the hallmark lesions of CJD, i.e. the spongiform degeneration of neurones and their processes seen as vacuoles in the neuropil between the cell bodies (Lantos 1992;

Budka et al. 1995). Immunohistochemical methodologies used in diagnostics display deposition of a protease-resistant prion (PrP) protein in association with these vacuoles (Prusiner 1982; Lantos 1992; Weber & Aguzzi 1997). Furthermore, histological examination displays variable extent of neuronal loss, reactive astrocytosis and amyloid plaque formation (Lantos 1992; Bell & Ironside 1993). The hallmark lesions of CJD express a wide spectrum of intensity and distribution and the CJD may be divided into several clinicopathological subtypes. The etiology and/or the pathogenesis of CJD is related to the abnormality of the prion protein (Prusiner 1982; 1987; Prusiner & De Armond 1987; Prusiner et al. 1987). PrP is a physiological copper-binding cell surface sialoglycoprotein expressed at high levels in nerve cells (Kretzchmar et al. 1986). The infectious, ‘transmissible’ particle in CJD has been shown to be equal to an abnormal isoform of the PrP, designated in sporadic cases as PrPΔCJD and in familial cases as PrP. These normal and abnormal isoforms of PrP have identical molecular weight and the same amino acid sequence whereas they differ in the post-translational acquisition of β-sheet conformation and in their protease resistance (Pan et al. 1993). The conformational transition from physiological PrP to PrPCJD, the infectious isoform, is not clear. The gene for the physiological form of PrP, designated as PRNP, is encoded on the short arm of chromosome 20 (Sparkes et al. 1986). Several mutations on PRNP have been linked to the familial CJD disorders (Goldfarb et al. 1992; Weber & Aguzzi 1997). Whereas the mutations on PRNP gene have been shown to be associated with the familial CJD cases, it has been indicated that non-pathogenic genetic polymorphism is associated with susceptibility for the disease (Palmer et al. 1991). Recent reports have indicated a susceptibility to iatrogenic infection of CJD (nvCJD) by the genotype on codon 129 of PRNP (Collinge et al. 1991).

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Heterogeneity of cognitive impairment in progressive supranuclear palsy, Parkinson’s disease and Alzheimer’s disease. Neurology 36, 1179–1185. Pillon, B., Dubois, B., Ploska, A. & Agid, Y. (1991) Severity and specificity of cognitive impairment in Alzheimer’s, Huntington’s and Parkinson’s diseases and progressive supranuclear palsy. Neurology 41, 634–643. Pillon, B., Gouider Khouja, N., Dweer, B. et al. (1995) Neuropsychological pattern of striatonigral degeneration: comparison with Parkinson’s disease and progressive supranuclear palsy. Journal of Neurology, Neurosurgery and Psychiatry 58, 174–179. Portin, R. & Rinne, U.K. (1980) Neuropsychological responses of parkinsonian patients to long-term levodopa treatment. In: Parkinson’s Disease Current Progress, Problems and Management (eds U.K. Rinne, M. Klingler, G. Stamm), pp. 271–304. Elsevier, Amsterdam. Post, M.J., Tate, L.G., Quencer, R.M. et al. (1988) CT, MRI and pathology in HIV encephalitis and meningitis. American Journal of Neuroradiology 9, 469–476. Post, M.J.D., Berger, J.R. & Quencer, R.M. (1991) Asymptomatic and neurologically symptomatic HIVseropositive individuals: prospective evaluation with cranial MR imaging. Radiology 178, 131–139. Poutiainen, E., Elovaara, I., Raininko, R., Hokkanen, L., Valle, S.-L., Lähdevirta, J. & Iivanainen, M. (1993) Cognitive performance in HIV-1 infection: relationship to severity of disease and brain atrophy. Acta Neurologica Scandinavica 87, 88–94. Poutiainen, E., Elovaara, I., Raininko, R., Vilkki, J., Lähdevirta, J. & Iivanainen, M. (1996) Cognitive decline in patients with symptomatic HIV-1 infection. No decline in asymptomatic patients. Acta Neurologica Scandinavica 93, 421–427. Price, R. & Brew, B.J. (1997) Central and peripheral nervous system complications. In: AIDS Biology, Diagnosis, Treatment and Prevention (eds T. Vincent, DeVita Jr, S. Hellman, & S.A. Rosenberg), 4th edn, pp. 333–338. Lippincott-Raven. Price, R., Brew, B.J., Sidtis, J., Rosenblum, M., Scheck, A. & Cleary, P. (1988) The brain in AIDS. Central nervous system HIV-1 infection and AIDS dementia complex. Science 239, 586–592. Prusiner, S.B. (1982) Novel proteinaceous infectious particle cause scrapie. Science 216, 136–144. Prusiner, S.B. (1987) Prions and neurodegenerative diseases. New England Journal of Medicine 317, 1571–1581. Prusiner, S.B., Gabizon, R. & McKinley, M.P. (1987) On the biology of prions. Acta Neuropathologica (Berlin) 72, 299–314. Prusiner, S.B. & De Armond, S.J. (1987) Prions causing nervous system degeneration. Laboratory Investigations 56, 349–363. Quinn, N. (1994) Multiple system atrophy. In: Movement Disorders 3 (eds C.D. Marsden, S. Fahn), pp. 262–281. Butterworth–Heinemann, Oxford. Raininko, R., Elovaara, I., Poutiainen, E. et al. (1997) HIV1 affects the brain from the asymptomatic stage: a radiologic follow-up. European Journal of Neurology 4, 143–151.

328 CHAPTER III.6

Raininko, R., Elovaara, I., Virta, A., Valanne, L., Haltia, M. & Valle, S.-L. (1992) Radiological study of the brain at various stages of human immunodeficiency virus infection: early development of brain atrophy. Neuroradiology 34, 190–196. Rajput, A.H. (1992) Prevalence of dementia in Parkinson’s disease. In: Parkinson’s Disease: Behavioural and Neuropsychological Aspects (eds S.J. Huber, J. Cummings), pp. 119–131. Oxford University Press, New York. Resnick, L., di Marzo-Veronese, F., Shupbach, J. et al. (1995) Intra-blood–brain-barrier synthesis of HTLV-III specific IgG in patients with neurologic symptoms associated with AIDS or AIDS-related complex. New England Journal of Medicine 313, 1498–1504. Rinne, J.O., Myllykylä, T., Lönnberg, P. & Marjamäki, P. (1991) A post-mortem study on brain dopamine nicotinic receptors in Parkinson’s and Alzheimer’s disease. Brain Research 547, 167–170. Rinne, J.O., Portin, R., Ruottinen, H., Nurmi, E., Bergman, J., Haaparanta, M. & Solin, O. (2000) Cognitive impairment and the brain dopaminergic system in Parkinson’s disease: a [18F ]-fluorodopa PET study. Archives of Neurology 57, 470–475. Rinne, J.O., Rummukainen, J., Paljärvi, L. & Rinne, U.K. (1989) Dementia in Parkinson’s disease is related to neuronal loss in the medial substantia nigra. Annals of Neurology 26, 47–50. Robbins, T.W., James, M., Lange, K.W., Owen, A.M., Quinn, N.P. & Marsden, C.D. (1992) Cognitive performance in multiple system atrophy. Brain 115, 271–291. Robbins, T.W., James, M., Owen, A.M. et al. (1994) Cognitive deficits in progressive supranuclear palsy, Parkinson’s disease, and multiple system atrophy in tests sensitive to frontal lobe function. Journal of Neurology, Neurosurgery and Psychiatry 57, 79–88. Rogers, T.D., Andrews, T.C., Grasby, P.M., Brooks, D.J. & Robbins, T.W. (2000) Contrasting cortical and subcortical activations produced by attentional setshifting and reversal learning in humans. Journal of Cognitive Neuroscience 12, 142–162. Roos, R.A., Jongen, J.C. & van der Velda, E.A. (1996) Clinical course of patients with idiopathic Parkinson’s disease. Movement Disorders 11, 236–242. Ruberg, M., Ploska, A., Javoy-Agid, F. & Agid, Y. (1982) Muscarinic binding and choline acetyltransferase acitivity in parkinsonian subjects with reference to dementia. Brain Research 232, 129–139. Saint-Cyr, J.A., Taylor, A.E. & Lang, A.E. (1988) Procedural learning and neostriatal dysfunction in man. Brain 111, 941–959. Schapiro, M.B., Crady, C., Ball, M.J. et al. (1990) Reductions in parietal/temporal cerebral glucose metabolism are not specific for Alzheimer’s disease. Neurology 40 (Suppl. 1), 152. Shakian, B.J., Downes, J.J., Eagger, S. et al. (1988) Sparing of attentional relative to mnemonic function in a subgroup of patients with dementia of the Alzheimer type. Brain 111, 695–718.

Shoulson, I. (1990) Huntington’s disease: cognitive and psychiatric features. Neuropsychiatrics Neuropsychological Behavioral Neurology 3, 15–22. Sidtis, J.J. & Price, R.W. (1990) Early HIV-infection and the AIDS dementia complex. Neurology 40 (2), 323–326. Sidtis, J.J., Gatsonis, C., Price, R.W. et al. (1993) Zidovudine treatment of the AIDS dementia complex: results of a placebo-controlled trial. AIDS Clinical Trial Group. Annals of Neurology 33, 343. Sparkes, R.S., Simon, M., Cohn, V.H. et al. (1986) Assigment of the human and mouse prion protein genes to homologous chromosomes Proceedings of the National Academy of Sciences of the USA 83, 7358–7362. Starkstein, S.E., Brandt, J., Bylsma, F. et al. (1992) Neuropsychological corelates of brain atrophy in Huntington’s disease: a magnetic resonance imaging study. Neuroradiology 34, 487–489. Starkstein, S.E., Rabins, P.V., Berthier, M.I., Cohen, B.J., Folstein, M.F. & Robinson, R.G. (1989) Dementia of depression among patients with neurological disorders and functional depression. Journal of Neuropsychiatrics and Clinical Neuroscience 1, 263–268. Taylor, A.E., Saint-Cyr, J.A. & Lang, A.E. (1986) Frontal lobe dysfunction in Parkinson’s disease. Brain 109, 845–883. Taylor, A.E., Saint-Cyr, J.A. & Lang, A.E. (1990) Memory and learning in early Parkinson’s disease. Brain and Cognition 2, 211–232. Trenkwalder, C., Schwarz, J., Gebhard, J. et al. (1995) Starnberg trial on epidemiology of parkinsonism and hypertension in the elderly. Prevalence of Parkinson’s disease and related disorders assessed by a door-to-door survey of inhabitants older than 65 years. Archives of Neurology 52, 1017–1022. Turjanski, N., Weeks, R., Dolan, R. et al. (1995) Striatal D1 and D2 receptor binding in patients with Huntington’s disease and other choreas: a PET study. Brain 118, 689–696. Watts, R.L., Mirra, S.S. & Richardsson, E.P. (1994) Corticobasal ganglionic degeneration. In: Movement Disorders 3 (eds C.D. Marsden, S. Fahn), pp. 262–281. Butterworth-Heinemann, Oxford. Weber, T.H. & Aguzzi, A. (1997) The spectrum of transmissible spongiform encephalopathies. Intervirology 40, 198–212. Weeks, R.A., Cunningham, V., Waters, S. et al. (1995) A comparison of region of interest and statistical parametric mapping analysis in PET ligand work: 11C-diprenorphine in Huntington’s disease and Tourette’s syndrome. Journal of Cerebral Blood Flow and Metabolism 15 (Suppl. 1), S41. Weeks, R.A., Harding, A.E. & Brooks, D.J. (1996) PET demonstrates a parallel loss of D1 and D2 dopamine receptors in asymptomatic mutation carriers of Huntington’s disease. Annals of Neurology 40, 49–54. Wilesmith, J.W., Wells, G.A., Cranwell, M.P. & Ryan, J.B. (1988) Bovine spongiform encephalopathy: epidemiological studies. Veterinary Research 123, 638–644.

OTHER IMPORTANT DEMENTIAS 329

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III.7

Reversible or Arrestable Dementias

Lars-Olof Wahlund, Hans Basun and Gunhild Waldemar

Key points • Potentially reversible conditions may be identified in approximately 15% of patients referred for diagnostic evaluation of dementia. • The most frequently observed conditions are depression, drugs, metabolic disturbances,

III.7.1

space-occupying lesions, and normal pressure hydrocephalus. • Although treatment may not always result in full reversal of cognitive symptoms, identification of potentially reversible conditions should be included in the diagnostic evaluation of dementia.*

Introduction

Definition Reversible dementias may be defined as dementias that are partially or fully reversible. The reversibility may occur either spontaneously or following specific treatment. Likewise, arrestable dementias may be defined as progressive dementias, in which further progression may stop, either spontaneously or on specific treatment. Patients with symptoms sufficiently severe to fulfill international criteria for dementia only rarely have an underlying condition that is fully reversible. Reversible conditions are more often encountered in patients with mild cognitive disturbances referred for evaluation of a possible dementia disease. Moreover, the prevalence of conditions with full and actual reversibility is much lower than that of conditions with potential reversibility.

The identification of conditions with potential reversibility and conditions that may be arrestable, has important implications for the management of patients with mild cognitive disturbances as well as those with dementia. A treatment trial should be given, after which the patient may be reassessed. The identification of potentially reversible conditions also may prevent a misdiagnosis of a progressive brain disorder. It should also be noted that patients might present with potentially reversible concomitant conditions that have a possible influence on cognitive symptoms, even when the primary underlying cause is thought to be irreversible. Recognizing that the concept of reversible dementias is relevant for all conditions with cognitive impairment, and that ‘reversible’ may not always imply full and actual reversibility, this chapter

*The topics covered in this chapter are also discussed to some extent in other chapters (II.3, III.8 and V.5).

330

REVERSIBLE OR ARRESTABLE DEMENTIAS 331

comprises categories of conditions which may be associated with cognitive impairment, and in which the cognitive symptoms may be reversible or arrestable on treatment. The concept of ‘reversible dementias’ has not been described specifically in the international diagnostic classifications Diagnostic and Statistical Manual (DSM) DSM-IV (American Psychiatric Association 1993) and International Classification of Diseases (ICD) ICD-10 (World Health Organization 1993). However, the ICD-10 defines ‘dementia in other specified diseases’ and the DSM-IV defines ‘dementia due to other general medical conditions’. These categories will include potentially reversible dementias.

Evidence for reversible dementias For a condition to be classified as a ‘reversible dementia’, we require evidence that: • the condition may be associated with cognitive impairment; and • treatment of the condition may reverse/arrest cognitive symptoms. The evidence for treatment effects in a number of potentially reversible conditions is presented in Section V.

Prevalence of potentially reversible dementias in population studies Many studies have described the prevalence of potentially reversible dementia disorders in dementia populations (hospital based outpatients or inpatients) or in memory clinics (Table III.7.1). Most of these studies have been summarized in a meta-analysis of 32 studies by Clarfield (1988) and in a quantitative review of 16 studies by Weyting et al. (1995). The prevalence of potentially reversible dementias was 13.2% and 15.2%, respectively. However, the prevalence of potentially reversible conditions in the summarized studies varied from less than 1% to more than 30%. The variance may be explained by variances in the study population (memory clinic vs. geriatric psychiatry ward, population study), by different definitions of ‘dementia’ or ‘reversibility’, and by variations in the extent of ancillary investigations used to detect reversible conditions. The results of the two quantitative reviews and of similar studies published since 1995 are presented in Table III.7.1. In only a few studies did clinical follow-up after treatment allow for an evaluation of the prevalence of fully or partially reversible dementias, which ranged from 3% to

Table III.7.1 Prevalence of ‘reversible dementias’. Reversible (average) Study

Population type

N

Age (years) average

Clarfield (1988)

Meta-analysis of 32 studies, 1972–87

2889

Weyting et al. (1995)

Quantitative review of 16 studies, 1972–94

Nitrini et al. (1995)

Dementia

Potential

Actual

72.3

83–97% with dementia

13.2%

11% partial or full

1551

NR

Dementia

0–37% (15.2%)

0–23% partial (9.3%) 0–10% full (1.5%)

Out-patients, prospective

100

67.6

All DSM III-R dementia

9%

7% partial 2% full

Walstra et al. (1997)

Memory Clinic, prospective

170

79.2

DSM III-R dementia

18.2%

–

Hoegh et al. (1998)

Memory Clinic, neurology, prospective

400 184

63.6 NR

All referred Subgroup with dementia

26% 12%

– –

196

74.6

Definite or suspected

23%

3.6% partial or full

Freter and Clarfeld Memory Clinic, (1998) retrospective NR, not reported.

332 CHAPTER III.7

23%. The most frequent partially or fully reversible conditions in prospective studies were drugs, depression, metabolic disorders, space-occupying lesions and normal pressure hydrocephalus (NPH). Population studies with a limited number of demented patients are not likely to contain all potentially reversible disorders. Therefore, attention should also be paid to certain more rare reversible disorders (e.g. Wilson’s disease, cerebral vasculitis, infectious diseases) that may cause cognitive dysfunction.

Differential diagnosis Below, the occurrence and typical features will be considered for the following groups of potentially reversible conditions: • NPH and intracranial space-occupying lesions; • depression; • drugs; • metabolic conditions; and • other (rare) potentially reversible conditions. The association of alcohol abuse and infectious diseases of the central nervous system with cognitive symptoms will be discussed elsewhere. Although each of the specific potentially reversible conditions may present with characteristic features, which provide clues for the diagnosis, cognitive symptoms may be the initial or dominat-

ing clinical feature. Thus, all patients presenting with cognitive symptoms should be screened for the most common reversible conditions. Most clinical guidelines and practice parameters for dementia recommend the following investigations for the diagnostic evaluation of patients with possible dementia (Quality Standards Subcommittee of the AAN 1994; Small et al. 1997; Waldemar et al. 2000): • thorough interview of patient and care giver, with emphasis on general and organ-specific physical symptoms as well as mental status, and with collection of information on drugs and alcohol consumption, exposure to toxic compounds, and previous mental and somatic disorders; • clinical examination of the patient, including psychiatric evaluation and neurological examination; • laboratory screening (blood tests): blood sedimentation rate; complete blood cell count; electrolytes; glucose; renal and liver function tests; thyroid-stimulating hormone; • cranial computerized tomography (CT) or magnetic resonance imaging (MRI). With this program, the most frequent reversible conditions will be identified. More extensive tests may be required in individual cases, and care must be taken to consider also rarer potentially reversible conditions.

Normal Pressure Hydrocephalus and Intracranial Space-occupying Lesions

III.7.2

In the two quantitative reviews (Clarfield 1988; Weyting et al. 1995) and in four studies published since 1995 the prevalence of normal pressure hydrocephalus (NPH) ranged from 0% to 6% and the prevalence of space-occupying lesions (tumors, subdural haematoma) ranged from 0% to 1.4%.

Typical clinical features Cranial computerized tomography (CT) or magnetic resonance imaging (MRI) is performed in patients with cognitive symptoms to rule out (or identify) radiological signs of NPH, space-

occupying lesions, cerebrovascular lesions, and other focal lesions. In a study of the usefulness of practice parameters for diagnostic evaluation of dementia, 6% of patients had unexpected findings on neuroimaging (Chui & Zhang 1997). Potentially life-threatening conditions, such as a brain tumor or subdural hematoma, may be identified, as may ischemic lesions that are potentially amenable to treatment and may alter the course of dementia even in Alzheimer’s disease (AD) (Pasquier et al. 1998). Patients with intracranial tumors may present with focal neurological signs or signs of raised intracranial pressure

REVERSIBLE OR ARRESTABLE DEMENTIAS 333

Table III.7.2 Prevalence of potentially ‘reversible dementias’ visualized by structural neuroimaging (CT & MRI): NPH and

space-occupying lesions.

Study

Population type

N

Age (years) average

Dementia

NPH

Space-occupying lesions

Clarfield et al. (1998)

Meta-analysis of 32 studies 1972–87

2889

72.3

83–97% with dementia

0.4%

0.4%

Weyting et al. (1995)

Quantitative review of 16 studies, 1972–94

1551

NR

Dementia

1.0%

1.4%

Nitrini et al. (1995)

Out-patients, prospective

100

67.6

Dementia DSM III-R

6%

0%

Walstra et al. (1997)

Memory Clinic, prospective

170

79.2

Dementia DSM III-R

0%

0.6%

Hoegh et al. (1998)

Memory Clinic, neurology, prospective

400

63.6

Definite or suspected

4.8%

1.0%

Freter and Clarfeld (1998)

Memory Clinic, retrospective

196

74.6

Definite or suspected

2%

1.0%

NR, not reported.

(headache, nausea, blurred vision, reduced consciousness), which should prompt urgent CT or MRI to be performed. However, in patients with cognitive symptoms with slow onset, a tumor cannot be ruled out on clinical evaluation alone. Some tumors, particularly small, slow growing and frontal tumors, may not be associated with prominent focal neurological signs. In the original description of the disease (Adams et al. 1965; Hakim & Adams 1965), NPH was described as a disease with a characteristic clinical triad of gait ataxia, urinary incontinence and mental deterioration, enlargement of ventricles and normal intracranial pressure. Mild to marked

III.7.3

improvement may be seen on surgical intervention (shunting). The response rates vary considerably, the prediction of outcome is a difficult task, and the surgical complication rate considerable (Vanneste et al. 1992). Cerebral biopsy findings do not contribute to a better prediction of outcome, but hydrodynamic studies and cerebrospinal fluid (CSF) tap test may add to the diagnosis (Bech et al. 1999). The diagnosis of NPH is made clinically, but on CT or MRI the characteristic ventricular enlargement is visualized. Vanneste et al. (1997) formulated CT criteria for a positive response to shunting, of which the absence of white matter lesions and cortical atrophy are the most important (Table III.7.2).

Depression

The prevalence of depression was shown in five of the six key articles. The prevalence ranged from 2% to 12%. The diagnosis of depression differed between studies but DSM-II to DSM-IV as well as ICD-10 were used. Depression as a putative reversible dementia has been screened for in the literature using a search strategy shown below (Medline 1966–99). Seventyfive articles from 1966 to 1999 were found by this method. Eleven of these were more carefully scrutinized and two were found to deal explicitly

with treatment of depression and reversibility of cognitive impairment in a longitudinal follow-up setting. Rabins et al. (1984) examined three groups of subjects, one group consisting of 18 patients with depression and dementia, 18 patients with dementia only and 18 patients with depression only. After a treatment of either tricyclic antidepressants or electroconvulsive treatment 15 out of 18 in the depressive/demented group improved in their cognitive functioning (from 17 to 24 on the Mini

334 CHAPTER III.7

Mental Status Examination (MMSE) test). They were then followed up after 2 years. At this point two of the three who did not improve in the first treatment period were still cognitively impaired. The remaining subjects were cognitively normal as were the depressed patients. The authors conclude that coexistence of depression and dementia does not usually lead to a dementing illness. The other article, by Alexopoulos et al. (1993), studied rate of development of irreversible dementia in 57 elderly depressed patients with dementia symptoms that improved after treatment and compared this rate with depressed patients without dementia symptoms. They were followed approximately every year for 3 years. Irreversible dementia occurred more frequently in the group who had depression and reversible dementia symptoms (43%) at the treatment period compared to the group with depression alone (12%). The conclusions were that a group of depressed patients with

III.7.4

dementia symptoms includes subjects with early stage dementia disorders.

Typical clinical features Patients with depression might exhibit symptoms similar to those seen in dementia disorders. Psycho– motor retardation coupled with withdrawal of interest in the surrounding environment might mimic dementia. Memory impairment and slow thinking, as well as defective knowledge of recent events, are typically seen. Self neglect and weight loss are common features. The patients are usually visuospatially preserved and they seldom exhibit dyspraxia. When tested, ‘I don’t know’ answers are common (Lishman, 1998). These last features help to discriminate depression from Alzheimer’s disease (AD) and other similar dementias.

Drugs

The prevalence of drug-induced dementia was presented in three of the six key review articles (Table III.7.3). The prevalence ranged from 1.5% to 5%. In no case was the type of drug(s) that caused the cognitive symptoms presented.

Typical clinical features Nearly every drug may cause cognitive impairment in susceptible individuals. However, certain drug classes are more common, e.g. benzodiazepines,

Table III.7.3 Prevalence of potentially ‘reversible dementias’: depression and drugs.

Study

Population type

N

Age (years) average

Dementia

Depression

Drugs

Clarfield et al. (1988)

Meta-analysis of 32 studies 1972–87

2889

72.3

83–97% with dementia

4.5%

1.5%

Weyting et al. (1995)

Quantitative review of 16 studies, 1972–94

1551

NR

Dementia

3%

2%

Nitrini et al. (1995)

Out-patients, prospective

100

67.6

Dementia DSM III-R

–

–

Walstra et al. (1997)

Memory Clinic, prospective

170

79.2

Dementia DSM III-R

2%

–

Hoegh et al. (1998)

Memory Clinic, neurology, prospective

400

63.6

Definite or suspected

8.5%

–

Freter and Clarfeld (1998)

Memory Clinic, retrospective

196

74.6

Definite or suspected

12%

5%

NR, not reported.

REVERSIBLE OR ARRESTABLE DEMENTIAS 335

opioids, anticholinergic and tricycilic antidepresants. There are very few case reports or studies describing the typical clinical features in druginduced ‘dementia’. Delirium is usually reported as the typical effect of drug on cognitive functions (e.g. lithium, anticholinergic drugs). In a recent review by Gray et al. (1999) the authors state that drugs might affect all aspects of cognition.

III.7.5

Memory is often impaired by anticholinergic medication (Gray et al. 1999). Of the different drug classes, the effect of benzodiazepine is often reported to impair memory, slow down reaction times and decrease vigilance. The memory impairment is a consequence of deficient acquisition into long-term memory (Lishman 1998).

Thyroid

Psychiatric and neurological features have been observed together with thyroid diseases. In particular, hypothyroid dementia is considered to be a reversible condition. Following the suggested search strategy (Medline 1966–99), no more than six citations were found. Three categories of literature were found: (i) reviews of cases from studies in etiology of dementia, (ii) case histories of hypothyroidism and associated dementia, and (iii) neurocognitive symptoms in patients with hypothyroidism and the effect of replacement therapy. Only a few cases of hypothyroid dementia were found from studies of etiology in dementia (Clarnette & Patterson 1994). Hypothyroid patients show cognitive impairments (Osterweil et al. 1992) but these deficits are only partially reversible after thyroid hormone replacement (Osterweil et al. 1992; Dugbartey 1998). No epidemiological studies or studies with a randomized placebo-controlled replacement therapy design were found. There is little evidence in the available literature that hypothyroidism causes dementia, irreversibly or reversibly.

Typical clinical features Hypothyroidism The clinical picture of hypothyroidism is described in many medical textbooks. The onset is insidious and non-specific with a slowing of motor activity and intellectual functions. There is usually a small

weight gain despite the loss of appetite. Signs of dry hair, which tends to fall out, and dry skin, are common. Patients often complain of stiff and aching muscles. Their voice may become hoarse and deeper. Among the early presenting symptoms of hypothyroidism are sensory disturbances. In the florid myxedema, muscle cramps, limb pains, or paresthesiae occur. A carpal tunnel syndrome is often seen and tendon reflexes are slow to relax. The slowing of motor activity and the expressionless face seen at least in myxedema can mimic depression. A typical pattern of cognitive disturbances has not been associated with either hypothyroidism or hyperthyroidism. Hyperthyroidism There are varied symptoms of increased nervousness and emotional instability. Patients complain of weakness, excessive sweating, fine tremor, and heat intolerance. Loss of weight is often reported in spite of increased appetite. Disturbances of menstruation (amenorrhea or oligomenorrhea), nausea, vomiting and frequent stools are often seen. Goiters, warm and moist skin, fine and silky hair and a characteristic stare with widened palpebral fissures are commonly observed. Tachypnea, atrial dysrhythmias and cardiac failure may occur. Patients with hyperthyroidism are usually restless and overactive. In textbooks in psychiatry, hyperthyroidism has been associated with agitation, anxiety, psychosis, depression, mania, and delirium.

336 CHAPTER III.7

III.7.6

Vitamin B12

In order to identify treatable disorders, patients with dementia symptoms should undergo a thorough workup including physical examination, brain imaging, and a laboratory evaluation. Determination of serum vitamin B12 concentrations is usually recommended as part of this laboratory screening. Psychiatric symptoms attributable to pernicious anemia have been known since Addison’s description in 1855. Strachan and Henderson (1965) pointed out that vitamin B12 deficiency can exist without hematological abnormalities and that some dementias can be treatable. Several investigators have found low concentrations of vitamin B12 in selected groups of Alzheimer patients. Whether vitamin B12 levels are decreased or not in dementia disorders is still controversial (for a review, see Basun et al. 1994). Fifteen citations were found, when the suggested search strategy was applied (Medline 1966–99). When screening 110 unselected patients with dementia, 13 cases (12%) of vitamin B12 deficiency were found (Cunha 1990). No significant improvement of treatment was observed. In 170 consecutive dementia patients, subnormal serum vitamin B12 levels were found in 26 cases (15%). Vitamin B12 supplementation was given to all patients and the effect was evaluated after 6 months. When treated patients were compared with patients with Alzheimer’s disease (AD) (69 cases), vitamin B12 replacement did not result in slowing of the progression of dementia (Teunisse et al. 1996). In particular, no epidemiological studies or studies with a randomized placebo-controlled replacement therapy design were found. Contrary to widely accepted beliefs, there is little evidence that vitamin B12 is a common cause

III.7.7

of reversible dementia. There is also a skepticism that dementia with low B12 concentrations responds to treatment (Clarefield 1988; Cunha 1990; Crystal et al. 1994; Teunisse et al. 1996). However, other authors have suggested the existence of a timelimited window of effective treatment intervention (Martin et al. 1983).

Typical clinical features The clinical features of vitamin B12 deficiency are described in many medical textbooks. Hematological manifestations are mainly a result of anemia with typical symptoms of weakness, dizziness, and palpitations. There is a rapid turnover of gastrointestinal epithelium with gastrointestinal manifestations of diarrhea, anorexia and weight loss. Sometimes, neurological manifestations may occur in the absence of anemia. There is a gradual onset of symptoms resulting from a combination of peripheral nerve, posterior column, and/or cortico-spinal degeneration. The first neurological symptoms (paraesthesiae) occur in the peripheral extremities. There is no typical pattern of cognitive disturbances that can be associated with vitamin B12. Neuropathological features Focal demyelination is the typical pathological change. The lesions can be found throughout the white matter, from the cerebral white matter to the peripheral nerves, with pronounced demyelination changes in the posterior columns. Slight cerebral atrophy can be seen.

Folate

Evidence for a direct effect of folate on brain functioning is compelling, and folate deficiency has been associated with psychiatric illness, mainly depression (Hutto 1997). The relationship with dementia is weak, except for case reports. There is no pattern cognitive disturbances that can be attributed to folate deficiency.

Typical clinical features Symptoms resulting from anemia occur. Gastrointestinal manifestations with glossitis and diarrhea may be more prominent and widespread than in B12 deficiency. It has been suggested that myelopathy and neuropathy are associated with folate deficiency. (See Table III.7.4.)

REVERSIBLE OR ARRESTABLE DEMENTIAS 337

Table III.7.4 Prevalence of potentially ‘reversible dementias’: thyroid, vitamin B12 deficiency and folate deficiency are shown.

Study

Population type

N

Age (years) average

Dementia

Hypothyreosis

Vitamin B12

Folate

Clarfield et al. (1988)

Meta-analysis of 32 studies 1972–87

2889

72.3

83–97% with dementia

0.65%

–

–

Weyting et al. (1995)

Quantitative review of 16 studies, 1972–94

1551

NR

Dementia

0.7%

0.3%

0

Nitrini et al. (1995)

Out-patients, prospective

100

67.6

Dementia DSM III-R

0

0

0

Walstra et al. (1997)

Memory Clinic, prospective

170

79.2

Dementia DSM III-R

1.8%

15%

–

Hoegh et al. (1998)

Memory Clinic, neurology, prospective

400

63.6

Definite or suspected

–

–

–

196

74.6

Definite or suspected

1%

4%

0

Freter and Clarfeld Memory Clinic, (1998) retrospective NR, not reported.

III.7.8

Other Potentially Reversible Conditions

Reversion of symptoms, or prevention of further progression, may be possible in a range of other rarer conditions associated with cognitive symptoms (Hughes & Perkin 1999). Acute or chronic exposure to heavy metals (mercury, lead, manganese, aluminium, arsenic, cadmium) or carbon monoxide may lead to cognitive symptoms. When there is a history of chronic exposure the diagnosis may be established in some cases with laboratory tests. Cognitive symptoms may be the presenting feature of sleep apnea, a diagnosis that may be confirmed by sleep monitoring. The vasculitides are a group of diseases sharing the central feature of inflammation of the blood vessel wall with attendant tissue ischemia. Inflammation of the central nervous system (CNS) vessels is less common than inflammation of other vessel systems. The CNS may be involved in vasculitis in polyarteritis nodosa, systemic lupus erythematosus, Churg–Strauss angiitis, Wegener’s granulomatosis and temporal angiitis. Isolated vasculitis of the brain is recognized with increased frequency. Cerebral vasculitis is associated with recurrent multifocal or diffuse neurological

symptoms, which may be present for many years before a diagnosis is established. The diagnosis of cerebral vasculitis depends on a combination of clinical (cognitive deficits, seizures, focal neurological signs), radiological (focal or multifocal cerebral lesions), and angiographic findings. A brain biopsy may be needed to confirm the diagnosis. Systemic evidence for inflammatory connective tissue disease may or may not be present. Symptoms may reverse on immunosuppressive therapy. Wilson’s disease is a genetic disorder of copper metabolism The gene responsible is located on chromosome 13. Clinical symptoms are a result of excessive accumulation of copper in various organ systems, particularly the liver and brain. Neurological symptoms present in the second or third decade and may occur without overt signs of hepatic involvement. Initial symptoms may be abnormal behavior, cognitive dysfunction, in-coordination, slowness of movements, speech tremor, dysarthria, ataxia, mask-like faces. The diagnosis is confirmed by increased urinary copper excretion and liver biopsy. Chelation therapy reverses neurological sequelae, particularly if treatment is given early.

338 CHAPTER III.7

III.7.9

Summary

This review of treatable and arrestable dementias shows that the most common and clinically important disease statesadepression, space-occupying lesions, drugs and metabolic disturbancesa constitute up to 12% of all subjects referred for dementia investigation. The validity of these figures must be judged from the facts that no population-based study has been presented, that all studies referred present selected populations, and that the ‘selection criteria’ differ between studies. Depression and drug-induced cognitive decline are the most common causes and they show the highest probability of cure.

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REVERSIBLE OR ARRESTABLE DEMENTIAS 339

progressive intellectual deterioration. Archives of Neurology 333, 658–659. Freter, S. Bergman, H., Gold, S., Chertkow, H. & Clarfield, A.M. (1998) Prevalence of potentially reversible dementias and actual reversibility in a memory clinic cohort. Canadian Medical Association Journal 159, 657–662. Freter, S. & Clarfield, A.M. (1998) Prevalence of potentially reversible dementias and actual reversibility in a memory clinic cohort. Canadian Medical Association Journal 159, 657–662. Garcia, C.A., Reding, M.I. & Blass, J.P. (1981) Overdiagnosis of dementia. Journal of the American Geriatric Society 29, 407–410. Gilchrist, P.N., Rozenbilds, U.Y., Martin, E. & Connolly, H. (1985) A study of 100 consecutive admissions to a psychogeriatric unit. Medical Journal of Australia 143, 236–237. Gottfries, C.G. (1988) Dementia: classification and aspects of treatment (review, 23 refs). Psychopharmacology Series 5, 187–195. Gray, G.E. (1989) Nutrition and dementia. Journal of the American Dietetic Association 89(12), 1795–1802. Gray, L., Lai, K.V. & Larson, E.B. (1999) Drug-induced cognition disorders in the elderly. Drug Safety 21, 101–122. Hakim, S. & Adams, R.D. (1965) The special clinial problem of symptomatic hydrocephalus with normal cerebrospinal fluid pressure. Journal of the Neurological Sciences 2, 307–327. Hammerström, D.C. & Zimmer, B. (1985) The role of lumbar puncture in the evaluation of dementia: the University of Pittsburgh study. Journal of the American Geriatric Society 33, 397–400. Harrison, M.J. & Marsen, C.D. (1977) Progressive intellectual deterioration (letter). Archives of Neurology 34, 199. Hector, M. & Burton, J.R. (1988) What are the psychiatric manifestations of vitamin B12 deficiency? Journal of the American Geriatrics Society 36(12), 1105–1112. Hedner, K., Gustafson, L., Steen, G. & Steen, B. (1987) Screening of patients admitted to a geriatric hospital with supposed organic dementia. Comprehensive Gerontology A1, 55–60. Herzlich, B.C. & Schiano, T.D. (1993) Reversal of apparent AIDS dementia complex following treatment with vitamin B12. Journal of Internal Medicine 233(6), 495–497. Heuft, G. Nehen, H.G., Haseke, J. Gastpar, M., Paulus, H.J. & Senf, W. (1997) Early and differential diagnosis of 1000 patients examined in a memory clinic. Nervenarzt 68, 259–269. Hoegh, P., Waldemar, G., Knudsen, G.M. et al. (1998) A multidisciplinary memory clinic in a neurological setting: diagnostic evaluation of 400 consecutive patients. European Journal of Neurology 6, 279–288. Hughes, R.A.S. & Perkin, G.D. (eds) (1999) Neurology and Medicine. BMJ Books, London. Hutto, B.R. (1997) Folate and cobalamin in psychiatric illness. Comprehensive Psychiatry 38(6), 305–314.

Hutton, J.T. (1981) Results of clinical assessment for the dementia syndrome: implications for epidemiological studies. In: The epidemiology of dementia (eds) L.M. Schumann & J.A. Mortimer, pp. 62–69. New York Oxford University Press. Katzman, R. (1975) Personal communication. In: Dementia (ed. Wells, C.E., 2nd ed, pp. 250. Philadelphia. Katzman, R. (1978) Dementias. Postgraduate Medicine 64(2), 119–125. Kokmen, E., Okazaki, H. & Schoenberg, B.S. (1980) Epidemiologic patterns and clinical features of dementia in a defined U.S. population. Trans Am Neurol Assoc 105, 334–336. Kopelmann, M. & Crawford, S. Not all memory clinics are dementia clinics. Neuropsychological Rehabilitation 6, 1871. Larson, E.B., Reifler, B.V., Featherstone, H.J. & English, D.R. (1984) Dementia in elderly outpatients: a prospective study. Annals of Internal Medicine 100, 417–423. Larson, E.B., Reifler, B.V., Suni, S.M., Canfield, C.G. & Chinn, N.M. (1985) Diagnostic evaluation of 200 elderly outpatients with suspected dementia. Journal of Gerontology 40, 536–543. Lishman, W.A. (1998) Organic Psychiatry: The Psychological Consequence of Cerebral Disorder, 3rd edn. Blackwell Science, Oxford. Livingston, G., Sax, K., Willison, J., Blizard, B. & Mann, A. (1990) The Gospel Oak Study stage II: the diagnosis of dementia in the community. Psychological Medicine 20, 881–891. Maletta, G.J., Pirozzolo, F.J., Thompson, G. & Mortimer, J.A. (1982) Organic mental disorders in a geriatric outpatient population. American Journal of Psychiatry 139, 521–523. Marsden, C.D. & Harrison, R.T. (1972) Outcome of investigations of patients with presenile dementia. British Medical Journal 2, 249–252. Martin, B.A., Thompson, E.C. & Eastwood, M.R. (1983) The clinical intestigation of dementia. Canadian Journal of Psychiatry 28, 282–286. Nitrini, R., Mathias, S.C., Caramelli, P. et al. (1995) Evaluation of 100 patients with dementia in Sao Paulo, Brazil: correlation with socioeconomic status and education. Alzheimer’s Disease and Associated Disorders 9, 146–151. O’Neill, D. & Barber, R.D. (1993) Reversible dementia caused by vitamin B12 deficiency. Journal of the American Geriatrics Society 41(2), 192–193. Organizing Committee, Canadian Consensus Conference on the Assessment of Dementia. (1991) Assessment of dementia: the Canadian Consensus. Canadian Medical Association Journal 144, 851–853. Osterweil, D., Syndulko, K., Cohen, S.N. et al. (1992) Cognitive function in non-demented older adults with hypothyroidism. Journal of the American Geriatrics Society 40(4), 325–335. Pasquier, F., Leys, D. & Scheltens, P. (1998) The influence of coincidental vascular pathology on symptomatology

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and course of Alzheimer’s disease. Journal of Neural Transmission 54, 117–127. Pary, R., Tobias, C.R. & Lippmann, S. (1990) Dementia: what to do (review, 60 refs). Southern Medical Journal 83(10), 1182–1189. Pearce, J. & Miller, E. (1973) Clinical Aspects of Dementia, p. 81. Ballière Tindall, London. Pfeffer, R.I., Afifi, A.A. & Chance, J.M. (1987) Rates of senile dementia. Alzheimer’s type, in the Baltimore Longitudinal Study. Journal of Chronic Disease 39, 271–286. Quality Standards Subcommittee of the American Academy of Neurology (1994) Practice parameter for diagnosis and evaluation of dementia. Neurology 44, 2203–2206. Rabins, P.V. (1981) The prevalence of reversible dementia in a psychiatric hospital. Hospital and Community Psychiatry 32, 490–492. Rabins, P. (1998) Pernicious anemia and reversible dementia: Strachan and Henderson 30 years later. International Journal of Geriatric Psychiatry 13 (3), 139–140. Rabins, P.V., Merchant, A. & Nestadt, G. (1984) Criteria for diagnosing reversible dementia caused by depression: validation by 2-year follow-up. British Journal of Psychiatry 144, 488–492. Reifler, B.V. & Eisdorfer, C. (1980) A clinic for impaired elderly and their families. American Journal of Psychiatry 137, 1399–1403. Renvoize, E.B., Gaskell, R.K. & Klar, H.M. (1985) Results of investigations in 150 demented patients consecutively admitted to a psychiatric hospital. British Journal of Psyciatry 147, 204–205. Roca, R.P., Klein, L., McArthur, J.C. et al. (1984) Treatable conditions among demented medical inpatients (abstr). Clin Res 300A. Roder, E. (1970) Reversible psychosis and dementia in myxedema. Acta Psychiatrica Scandinavica 46 (1), 1–13. Rosenberg, I.H. & Miller, J.W. (1992) Nutritional factors in physical and cognitive functions of elderly people. American Journal of Clinical Nutrition 55 (6), S1237–S1243. Sabin, T.D., Vitug, A.J. & Mark, V.H. (1982) Are nursing home diagnosis and treatment adequate? Journal of the American Medical Association 248, 321–322. Sayetta, R.B. (1986) Rates of senile dementia. Alzheimer’s type, in the Baltimore Longitudinal study. Journal of Chronic Disease 39, 271–286. Schoenberg, B.S., Anderson, D.W. & Haerer, A.F. (1985) Severe dementia: prevalence and clinical features in a biracial US population. Archives of Neurology 42, 740–743. Small, G.W. Rabins, P.V., Barry, P.P. et al. (1997) Diagnosis and treatment of Alzheimer’s disease and related disorders. Consensus statement of the American Association of Geriatric Psychiatry, the Alzheimer’s

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III.8

Mild Cognitive Impairment

Alan Kluger, James Golomb and Steven H. Ferris

Key points Mild cognitive impairment (MCI) is an important clinical syndrome that lies on the cognitive continuum between normal ageing and dementia. Current evidence suggests the following conclusions: • Elderly individuals with MCI have mild but clinically significant memory impairment, often accompanied by mild impairment in other cognitive domains such as attention, language and psychomotor function. • Such cognitive decline may be noticed by family members and close friends and it may be

III.8.1

accompanied by subtle decline in very complex activities of daily living. However, these mild impairments are not sufficient to meet current criteria for dementia. • Cases with MCI are at substantially increased risk of progressing to a diagnosis of dementia. Recent research suggests that cognitive and neuroimaging markers may be useful in predicting future conversion to Alzheimer’s disease (AD). • Further research is needed to determine the prevalence and risk factors for MCI and its likely subtypes, as well as to determine the effectiveness of treatments for improving symptoms or delaying progression to dementia.

Introduction

Constructs such as Age-Associated Memory Impairment (AAMI) (Crook et al. 1986) and the broader Diagnostic and Statistical Manual (DSM) DSM-IV classification Age-Related Cognitive Decline (ARCD) (American Psychiatric Association 1994) describe the well-documented phenomenon of cognitive decline in normal ageing. These concepts represent an age-related syndrome in which there is an overall shift in the performance distributions between young and elderly populations in certain age-sensitive aspects of cognition such as memory function (see Fig. III.8.1). Because 5–10%

of the elderly population gradually progress to dementia (prevalence increases markedly with age), considerable work has been carried out in conceptualizing and studying mild cognitive impairment (MCI), the ‘at risk’ category that is intermediate in degree of impairment between ARCD/AAMI and mild dementia. Great emphasis has been placed on accurately detecting elderly patients with MCI that are at increased risk for future decline to dementia, because these individuals might benefit most from effective pharmacological treatments that delay or prevent dementia. Critical issues related to MCI

341

342 CHAPTER III.8

III.8.2

1 SD Frequency

include: (i) How can we determine whether or not an individual has really experienced significant cognitive decline when we are typically making the assessment cross-sectionally late in life? (ii) Are the cognitive deficits limited to problems in memory function or are other domains of cognitive function (or subtle decline in complex activities of daily living) also involved? (iii) What is the prevalence of MCI in the community, and to what extent does prevalence increase with age and other dementia risk factors? (iv) To what extent are subjects comprising this group heterogeneous with respect to underlying etiology, and especially in regard to future decline to dementia?

Elderly

Young

AD MCI AAMI Cognitive performance Fig. III.8.1 Ageing, AAMI (ACRD), MCI and AD.

Idealized standard unit normal distributions representing the cognitive performance of the young and elderly populations. The shift of the elderly population toward poorer performance [referred to as Age–Associated Memory Impairment (AAMI) or Age-Related Cognitive Decline (ARCD)] is small, and there is considerable overlap between the two distributions. The Alzheimer’s disease (AD; approximately 5%) and mild cognitive impairment (MCI; approximately 10%) cases represent extremes of the elderly population. The MCI group represents an intermediate stage of decline between AAMI/ARCD and AD. (Adapted from Ferris & Kluger 1996.)

Definition and Diagnostic Criteria

Investigators have proposed a variety of diagnostic labels for the elderly whose cognitive status lies between normal/AAMI/ARCD levels and mild stages of dementia. This terminology includes: (i) mild cognitive decline/mild neurocognitive disorder, equivalent to a global deterioration scale (GDS) score of 3 (Reisberg et al. 1982; Reisberg & Kluger 1998); (ii) questionable dementia, equivalent to a Clinical Dementia Rating (CDR) score of 0.5 (Hughes et al. 1982); (iii) mild cognitive impairment (MCI) (Reisberg et al. 1988; Flicker et al. 1991; Zaudig et al. 1991; Zaudig 1992; Petersen et al. 1999); (iv) cognitive impairment with no dementia, especially the subcategory of circumscribed memory loss (Ebly et al. 1995; Tierney et al. 1996a; Graham et al. 1997); and (v) isolated memory loss (Bowen et al. 1997). For a comprehensive discussion of alternative descriptors for MCI, see Ritchie et al. (2000). Diagnostic criteria for MCI vary somewhat from

investigator to investigator. For example, Flicker et al. (1991) based this diagnostic classification on ratings derived from a global clinical staging scale (GDS = 3), while Petersen et al. (1999) relied on the presence of memory complaints, abnormal memory for age, and normal general cognitive function and activities of daily living. Both classifications exclude cases manifesting cognitive impairments serious enough to meet standard criteria for dementia (DSM IV, American Psychiatric Association 1994; National Institute of Neurological and Communicative Diseases and Stroke (NINCDS)/Alzheimer’s Disease and Related Disorders Association (ADRDA), McKhann et al. 1984). Clinically, the MCI syndrome represents documented cognitive impairment (primarily in memory) that is worse than expected for age, but is not sufficient for a diagnosis of dementia. Clinicians are often unsure how to classify this condition, and there are no widely established, formal diagnostic criteria.

MILD COGNITIVE IMPAIRMENT 343

However, concrete operational criteria have been defined for selecting MCI cases for research protocols, especially clinical trials. Here the emphasis is on identifying mildly impaired elderly who are at increased risk for future decline to dementia using the following criteria: 1 There must be mild cognitive decline, as documented with global staging instruments such as the CDR (Hughes et al. 1982) or the GDS (Reisberg et al. 1982). Global ratings of 0.5 on the CDR or 3 on the GDS represent the MCI stage in the progression from normal ageing to dementia. 2 There must be objective confirmation of memory impairment, as demonstrated on a performancebased test such as the Rey Auditory Verbal Learning Test (Taylor 1959), Logical Memory II of the

III.8.3

Wechsler Memory Scale (WMS-R) (Wechsler 1987) or the NYU Paragraph Recall Test (Kluger et al. 1999). Cut-off scores on these tests used for selecting MCI cases are somewhat arbitrary, but typically represent performance at least 1.5 SDs below age norms, or scores indicative of increased risk for decline to dementia. 3 Exclusion criteria typically used in selecting MCI cases are those generally applied in diagnosing probable Alzheimer’s disease (AD): history of other neurological or major psychiatric disorders, brain injury, mental retardation, substance abuse, major systemic illness, and use of medications affecting the central nervous system (CNS). Applying these exclusions results in an MCI sample likely to progress to AD.

Clinical Picture

The primary clinical feature of mild cognitive impairment (MCI) is decline in memory (and often other cognitive functions) as reported by close friends or relatives and confirmed by psychometric testing. This presumably heterogeneous group includes individuals with greater than average forgetfulness related to ageing or other unknown causes, and those with subclinical or prodromal dementia (Ferris & Kluger 1996). Clinical rating scales such as the GDS (Reisberg et al. 1982) and the CDR (Hughes et al. 1982) have been used by a number of investigators to identify individuals with MCI. As previously noted, such cases have been described as being at stage 3 on the GDS and at stage 0.5 on the CDR. Normal elderly (including those with AAMI/ARCD) are typically at stages 1 or 2 on the GDS and at stage 0 on the CDR, while demented patients generally are rated with scores of 4–7 on the GDS and 1–3 on the CDR. As a group, MCI individuals are clearly at higher risk for developing dementia in the future than are cognitively normal elderly (Storandt et al. 1984; Rubin et al. 1989; Storandt & Hill 1989; Flicker et al. 1991; Kluger et al. 1999). Although some investigators (Minoshima et al. 1997; Petersen et al. 1999) have advocated that

patients with MCI manifest cognitive deficits relative to normal elderly that are limited to the memory domain, a number of reports have found that MCI also is related to measurable deficits in language (Flicker et al. 1991; Kluger et al. 1997; Petersen et al. 1999), orientation (Wolf et al. 1998), and psychomotor/motor function (Storandt et al. 1984; Reisberg et al. 1988; Storandt & Hill 1989; Flicker et al. 1991; Kluger et al. 1997). It can be argued that the poorer performance seen in nonmemory functions could be secondary to the deficits in memory. However, differences between normal and MCI individuals have been found in complex psychomotor performance, even after controlling for performance on motor-independent tests of memory, language and for measures of grosser motor function (Kluger et al. 1997). These findings indicate that the observed differences in psychomotor function cannot be accounted for adequately by differences in other domains of functioning, especially memory. Motor deficits detected on quantified neurological examination (Franssen et al. 1991; 1999), as well as mild changes in the activities of daily living (Reisberg et al. 1998; Albert et al. 1999) have also been observed in MCI. Results from a longitudinal

344 CHAPTER III.8

dementia. However, it seems reasonable to conclude that a deficit in recent memory function in MCI is the most prominent and the most troubling symptom for the patient, the most noticeable by the patient’s significant others, and the problem that most often compels the patient to seek medical evaluation. Nevertheless, this does not mean that impairments in additional domains of functioning are not detectable, especially when assessed by sensitive test instruments.

population study indicate that definitions of MCI based primarily on impairment in memory (i.e. excluding impairment in other areas of cognitive functioning), yield poor predictions of dementia within a 3-year follow-up period (Ritchie et al. 2001). Logically, if MCI frequently represents a prodromal stage of dementia, it is not surprising that MCI cases would manifest subtle impairments in the other cognitive domains that are impaired in

III.8.4

Diagnostic Tools

Global scales

Psychometric test performance in cross-sectional studies of MCI

The administration of global clinical scales has been particularly useful in identifying elderly with cognitive impairment consistent with current definitions of mild cognitive impairment (MCI). The GDS and the CDR have been widely used to select MCI cases for research studies (see Mohs & Ferris 1998 for a review of these instruments).

As summarized in Table III.8.1, studies examining differences in mean psychometric performance (Reisberg et al. 1988; Flicker et al. 1991; Morris et al. 1991; Kluger et al. 1997), differences in factor analytically derived cognitive functions (Mitrushina et al. 1989), and discriminant function analyses

Table III.8.1 Studies examining cross-sectional psychometric differences between normal and MCI elderly people. Subjects (N) Normal

MCI

Psychometric domains showing decline in elderly patients with MCI (cf. normal controls)

Study

Setting/MCI definition

Reisberg et al. (1988)

Clinical research center/mild cognitive impairment (GDS = 3)

60

44

Recent memory, language/semantic memory, attention, psychomotor function

Storandt and Hill (1989)

Clinical research center/questionably demented (CDR = 0.5)

83

41

Recent memory, language, speeded psychometric function

Mitrushima et al. (1989)

Clinical research center/outliers of well-functioning elderly

19

19

Recent memory and language

Morris et al. (1991)

Clinical research center/questionably demented (CDR = 0.5)

4

10

Recent memory, language, speeded psychometric function and comprehension

Flicker et al. (1991)

Clinical research center/mild cognitive impairment (GDS = 3)

32

32

Recent and remote memory, language, concept formation and psychomotor function

Kluger et al. (1997)

Clinical research center/mild cognitive impairment (GDS = 3)

41

25

Recent memory, language, and fine and complex motor/psychomotor function

Petersen et al. (1999)

Clinical research center/mild cognitive impairment (abnormal memory)

234

76

Recent memory and language/semantic memory

MILD COGNITIVE IMPAIRMENT 345

(Storandt & Hill 1989; Robinson-Whelen & Storandt 1992; Kluger et al. 1997) suggest that elderly with MCI perform more poorly than normal aged subjects on a number of tests that also separate mildly demented patients from normal individuals. However, there is also considerable overlap in cognitive-test scores between the MCI subjects and the scores of both normal elderly subjects and early demented cases (Storandt & Hill 1989; Kluger et al. 1997). These observations

III.8.5

reinforce the hypothesis that this borderline MCI group is composed of at least two subgroups, including subjects who perhaps have a benign form of age-related cognitive decline and individuals who are in a very early, subclinical stage of dementia. Longitudinal studies of MCI elderly (see Prognosis section below) are necessary to examine more directly possible psychometric predictors of future decline identified by cross-sectional approaches.

Incidence, Prevalence and Burden

Incidence The incidence of normal elderly individuals who convert to mild cognitive disorder (MCI) has been difficult to estimate, and there is a paucity of data available from community-based samples. A reexamination of recently published data from a research clinic sample (Kluger et al. 1999), indicates that of 126 normal elderly (GDS 1–2) followed over an average of 3.8 years, 19.0% (5% per year) converted to MCI (GDS 3) and 11.9% (3% per year) declined to dementia (GDS ≥ 4). More data are available concerning the proportion of MCI cases that subsequently decline to dementia. One recent investigation (Petersen et al. 1999) reported that MCI cases convert to Alzheimer’s disease (AD) at a rate of 12% per year, over 4 years of annual follow-up, as compared to a 1% to 2% per year conversion rate for healthy control subjects. Another recent study observed that 67.2% of individuals with MCI declined to dementia, compared to 11.9% of normal elderly, over an average follow-up period of 3.8 years (Kluger et al. 1999). Other studies found that MCI cases decline to dementia at a rates of 69% over 3–7 years (Rubin et al. 1989); 71.9% over 2 years (Flicker et al. 1991); 18.7% over 3.0 years (Daly et al. 2000); 47.6% over 4.0 years (Bowen et al. 1997); 19.5% over 2.7 years (Wolf et al. 1998); and 55% over 4.5 years (Petersen et al. 1995). (See also Chapter III.8.7). A review of studies examining decline to dementia in cognitively impaired elderly individuals reported rates of decline ranging from

1% to 25% per year (Dawe et al. 1992). Differences in rate of decline are a likely consequence of differences across studies in age, education levels and in definitions used to identify MCI elderly, resulting in variation in severity and extent of symptoms in the MCI samples. Relevant to this point, longitudinal studies of samples comprising various combinations of normal and MCI elderly have reported decline rates of 12.1% over 1 to 10 years (Grober et al. 2000); 18.0% over 3 years (Ritchie et al. 2000); 20.2% over approximately 4 years (Masur et al. 1994); 23.6% over 2 years (Tierney et al. 1996b); 34.7% over 3.8 years (Kluger et al. 1999); and 41.3% over 2.5 years (Devanand et al. 1997).

Prevalence Currently, the proportion of older individuals meeting criteria for MCI has not been clearly determined, in part resulting from the lack of consensus on diagnostic criteria for MCI that can be applied in epidemiologic studies. An estimate of the prevalence rate of MCI can be drawn from data reported on elderly from the Canadian Study of Health and Ageing (Graham et al. 1997). Based on combined samples of community and institutional Canadian elderly aged 65 years and older, the estimated prevalence of ‘cognitive impairment no dementia’ (CIND) was 16.8%, compared to a prevalence of 8.0% for all types of dementia combined. CIND is based on the exclusion of dementia and the presence of various categories of cognitive impairment,

346 CHAPTER III.8

including circumscribed memory impairment (the most common category), depression, other psychiatric illness, chronic alcohol and drug use, delirium, mental retardation, etc. Circumscribed memory impairment alone had a prevalence of 5.3% in this study. Because the current definitions of MCI are probably more inclusive than circumscribed memory impairment and less inclusive than CIND, the rate of MCI can be estimated to be between 5.3% and 16.8% of older persons. Yesavage et al. (2000) recently used mathematical modeling to derive prevalence by age of MCI. Normal to MCI conversion was estimated as a power function with an 8% increase in rate per year (age 60 = 0.5%; age 70 = 1.1%; age 80 = 2.3%).

III.8.6

There is a lack of direct evidence that MCI is associated with increased burden. However, reports of subtle decline in activities of daily living suggest that MCI could be linked to significant functional problems related to difficulty in complex activities. For example, elderly with CIND were three times more likely to be living in institutions than were cognitively unimpaired individuals (Graham et al. 1997). A report has linked mild levels of cognitive impairment in non-demented elderly with poor physical health (Frisoni et al. 2000), suggesting a possible relationship between MCI and increased burden.

Epidemiological Risk Factors

Although there apparently are no formal reports of epidemiological risk factors for mild cognitive impairment (MCI), it seems reasonable to speculate that demographic variables often identified as predictive of Alzheimer’s disease (AD), such as age and low education, may also increase the risk of future development of MCI. Relatedly, the

III.8.7

Burden

Canadian Study of Health and Ageing found that the prevalence of ‘cognitive impairment no dementia’ (CIND) increased with increased age. CIND was reported to affect 11.0% of participants aged 65–74 years; 24.0% of those aged 75–84; and 30.3% of those aged greater than 84 (Graham et al. 1997).

Prognosis

Longitudinal studies assessing psychometric prediction of cognitive decline and dementia Several studies have examined possible longitudinal decline among mild cognitive disorder (MCI) individuals. One investigation followed 16 cases with MCI (i.e. questionable dementia with a CDR of 0.5) over an 84-month period and reported that 69% had progressed to dementia by the end of the third year; there was no further conversion to dementia noted beyond that time (Rubin et al. 1989). Although no formal neuropsychological test data were reported, the memory subscale of the CDR correctly predicted all of the non-decliners and 64% of the decliners. Similarly, Daly et al.

(2000) followed 123 elderly people with MCI (CDR of 0.5) over a 3-year interval and found that 18.7% declined to AD. The sum of six subscales of the CDR at baseline (combined with questions from a clinical interview) correctly identified 83% of the decliners and 90% of the non-decliners. Another study followed 32 normal controls (GDS = 1–2) and 32 mildly impaired patients (GDS = 3) over a 2-year follow-up interval and found that 72% of the mildly impaired group progressed to a dementia diagnosis (Flicker et al. 1991). Classification analyses of the four cognitive tests that showed significantly poorer scores at baseline among the decliners revealed high levels of specificity and sensitivity. These tests assessed verbal recall, visuospatial recall and two aspects of language function.

MILD COGNITIVE IMPAIRMENT 347

Table III.8.2 Overview of relatively large sample studies (Ns > 70) examining accuracy of neuropsychological measures in

predicting decline to dementia. Predictive value (%) Study/(non-demented sample)

N

% Decline at follow-up

Samples containing normal elderly at baseline Fuld et al. (1990)/(community based) Dal Forno et al. (1995)/(community based)

474 196

11.8 12.2

Specificity (%)

Sensitivity (%)

Negative

Positive

84.0 –

57.0 –

89.0 91.0

39.0 62.0

50.0 76.0 81.0 72.9 87.5 85.0

88.1 – 83.3 86.6 94.4 –

68.1 – 73.9 84.4 89.1 –

91.5 95.7

81.5 90.9

90.0 91.8

Samples containing various combinations of normal and MCI elderly at baseline Masur et al. (1994)/(community based) 317 20.2 94.0 Tierney et al. (1996b)/(memory impaired) 123* 23.6 94.0 Devanand et al. (1997)/(memory clinic based) 75 41.3 76.9 Kluger et al. (1999)/(research clinic based) 213 34.7 92.8 179* 31.3 95.1 Grober et al. (2000)/(community based) 264 12.1 80.0 Samples containing MCI elderly at baseline Kluger et al. (1999)/(research clinic based)

87 71*

67.6 66.2

78.6 83.3

*Decline to AD.

The verbal recall test (learning a grocery shopping list) was the best single predictor; it correctly classified 90% of the decliners and 95% of the non-decliners. A more recent study followed 213 non-demented elderly (GDS 1–3), over an average follow-up interval of 3.8 years (Kluger et al. 1999). Of the 87 MCI (GDS 3) cases followed, 59 (68%) declined to dementia. Cut-scores from a paragraphdelayed-recall test assessing recent memory correctly identified 92% of the decliners and 79% of the non-decliners, yielding an overall predictive accuracy of 87%. A diagnostically more restrictive subset of this MCI sample (N = 71) was also examined, of whom 47 (66%) declined to diagnosis of probable AD. This same paragraph cut score correctly identified 96% of the decliners and 83% of the non-decliners, yielding an overall accuracy of 92%. Somewhat similar findings have been reported for a cognitively diverse sample of researchclinic-based, non-demented elderly individuals with scores on the GDS ranging from 2 to 3 (Tierney et al. 1996b) and individuals with scores of 0–0.5 on the CDR (Devanand et al. 1997), as well as for non-demented healthy community-residing elderly that are likely to be comprised of both normal and MCI individuals (Masur et al. 1994).

Table III.8.2 summarizes relatively large-sample longitudinal studies (N > 70) that have reported predictive accuracies of either individual or small sets of baseline neuropsychological test scores for predicting future decline to dementia. These studies are grouped according to the composition of the non-demented samples at baseline: (i) primarily normal/AAMI/ARCD elderly; (ii) various combinations of normal and MCI cases; or (iii) only MCI cases. The reported predictive accuracies include specificity vs. sensitivity and/or negative predictive value vs. positive predictive value. The specificity of a test indicates the percentage of all truly nondeclining cases accurately classified by the predictor variable while the sensitivity indicates the percent of all truly declining cases accurately classified by the predictor variable. The negative predictive value indicates the percent of all cases classified by the predictor variable as non-declining cases that actually do not decline, while the positive predictive value indicates the percent of all cases classified by the predictor variable as declining cases that actually do decline. The overall accuracy identifies the total percentage of subjects (true non-decliners plus true decliners) accurately classified by the predictor variable.

348 CHAPTER III.8

The results of these studies examining possible cognitive predictors of dementia indicate that a small set of psychometric measures can relatively accurately detect pathological decline in nondemented (especially MCI) elderly people. The best

III.8.8

single predictors were measures of recent verbal/ visuospatial learning and memory, especially tests of delayed recall. Other predictors, which have been frequently identified, include assessments of language function and psychomotor integration.

Pathology/Pathogenetic Etiology

Neuroimaging Both functional and structural brain-imaging techniques have revealed abnormalities in mild cognitive impairment (MCI) that are worse in Alzheimer’s disease (AD). Regional decreases in the metabolic rate of glucose utilization have been demonstrated in the temporal and parietal association cortices, as well as in the posterior cingulate gyrus in patients with MCI (Pietrini et al. 1993; Minoshima et al. 1997; Mielke et al. 1998; Berent et al. 1999). Cognitively normal subjects at risk for AD because of apolipoprotein E (ApoE) ε 4 homozygocity have been shown to exhibit glucose utilization reductions in regions similar to those that become involved in AD (Reiman et al. 1998). MRI studies in MCI and AD have focused on volume reductions affecting medial temporal lobe structures such as the hippocampus, entorhinal cortex and amygdala. Studies suggest that hippocampal atrophy is a frequent characteristic of MCI (Convit et al. 1993; Jack et al. 1997; Krasuski et al. 1998). Furthermore, hippocampal atrophy has been demonstrated to predict the occurrence of subsequent dementia in MCI subjects with varying degrees of overall accuracy (de Leon et al. 1993; Jack et al. 1999; Killiany et al. 2000). Hippocampal atrophy has also been demonstrated in cognitively normal subjects destined to develop AD as a result of amyloid precursor protein (APP) point mutations (Fox et al. 1996). Cross-sectional studies of cognitively normal older subjects demonstrate that hippocampal atrophy correlates with delayed verbal recall, even after adjusting for age and generalized brain atrophy (Golomb et al. 1993; 1994). In such individuals, hippocampal atrophy at baseline was shown to predict an accelerated trajectory of memory decline with a significantly greater proportion developing MCI within a 4-year period (Golomb et al. 1996).

While hippocampal volume loss may be one of the earliest indicators of AD pathology, this change appears not to be associated with a reduction in metabolism as indicated by preserved perfusion and glucose utilization rates for the hippocampus in mild AD (Ishii et al. 1998a; 1998b).

Neuropathology When MCI cases are identified at AD research centers, MCI appears associated with both the appearance of neuritic plaques and an increase in the density of neurofibrillary tangles (NFTs), the classically recognized histolopathological hallmarks of AD. Based on a large autopsy series of 2661 cases, Braak and Braak (1997) identified six age-related stages of neurofibrillary change where early NFT formation is restricted to the entorhinal and transentorhinal regions of the medial temporal lobe and tends to precede the development of amyloid plaques. A study correlating autopsy findings with antemortem psychometric performance suggests that memory decline occurs as neurofibrillary pathology spreads beyond the entorhinal cortex to involve the hippocampus (Braak stages II–III) while more global cognitive dysfunction becomes evident with the progressive involvement of temporal and frontal lobe neocortical regions (Braak stages IV–VI) (Grober et al. 1999). Price and Morris (1999) examined the brains of 39 non-demented subjects (CDR 0) and 15 mildly impaired subjects (CDR 0.5 and 0/0.5 [intermediary between 0 and 0.5]) who were clinically evaluated within 1 year of death. In the CDR 0 cases they found NFTs to be common and essentially confined to the limbic regions of the medial temporal lobe in densities that increased exponentially with advancing age. Only seven of these cases had neuritic plaques while 32 had either no amyloid deposition or only

MILD COGNITIVE IMPAIRMENT 349

diffuse amyloid plaques. On the other hand, virtually all of the subjects who were intermediary between CDR 0 and CDR 0.5 had some neuritic plaques, particularly in the entorhinal and perirhinal cortices as well as the hippocampus. These data suggest that at least some degree of neurofibrillary pathology may occur as an age-associated process without dementia and that the onset of cognitive impairment appears to coincide with the emergence of neuritic plaques and an accentuation of neurofibrillary change. In MCI, although the brunt of NFT and neuritic plaque formation occurs in the limbic structures of the medial temporal lobe, Price and Morris’s data (1999) indicate that the neocortex is also affected. These observations are consistent with the pattern of observed cognitive deficit in MCI where memory dysfunction may be most salient but other modalities of neuropsychological function are impaired as well. They are also consistent with neuroimaging data demonstrating the early appearance of medial temporal lobe atrophy. The accumulation of hippocampal and entorhinal NFTs in non-demented individuals may in part explain the relationship between delayed verbal recall impairment and MRI measured hippocampal volume loss observed in normal ageing.

Biological markers Over the past decade several groups have compared cerebral spinal fluid (CSF) from AD patients with fluid from cognitively normal controls in an effort to identify biological markers indicative of AD pathology. A large number of potentially useful biomarkers have emerged, including markers of inflammation (Alpha 1-antichymotrypsin, Matsubara et al. 1990; interleukin-6, Hampel et al. 1999), synaptic degeneration (chromogranin A, Blennow et al. 1995a; synaptotagmin, Davidsson et al. 1996), oxydative stress and lipid peroxidation (glutathione transferase, Lovell et al. 1998), lysosomal hydrolase activation (cathepsin D, Schwagerl et al. 1995), amyloid deposition (Aβ peptide, Galasko 1998) and neuritic degeneration (neural thread protein, de la Monte et al. 1992; tau protein, Blennow et al. 1995b). Although an absence of confirmatory data has diminished enthusiasm for many of these reports, interest has recently focused on observations that

CSF concentrations of the microtubule-associated protein tau is elevated in AD (Iqbal & GrundkeIqbal 1997) while levels of the 42 residue form of the Aβ peptide (Aβ1– 42) are decreased (Motter et al. 1995). Combining these measures may increase diagnostic sensitivities and specificities as high as 90% and 80%, respectively (Galasko et al. 1998). Further improvement in specificity might be achieved by detecting the abnormally phosphorylated form of the tau protein (PHF-tau) that occurs in neurones undergoing neurofibrillary degeneration in AD (Ishiguro et al. 1999). At present it is unclear how the diagnostic power of these assays will perform when applied to cases with very mild AD or MCI. In a recent large multicenter study, Kanai et al. (1998) demonstrated that a composite index comprising CSF tau concentrations multiplied by CSF Aβ1– 40 /Aβ1– 42 ratios increased only very slightly with advancing age in 54 normal control subjects (ages 16–86 years, r 2 = 0.10, P = 0.02). Using receiver-operating characteristic (ROC) analysis, to optimize diagnostic discrimination, a sensitivity of 71% and specificity of 83% for the diagnosis of AD was achieved. The sensitivity, however, was increased to 91% when CSF from a subsequent lumbar puncture (performed a mean of 18.6 months later) was used. These results suggest that many AD patients have CSF levels of tau and Aβ that are similar to cognitively normal controls at an early stage of their disease, casting some doubt on the diagnostic utility of these assays in MCI. On the other hand, one report (Kurz et al. 1998) found that CSF tau concentrations produced a diagnostic accuracy of 95% when discriminating 19 very mild AD patients with Mini Mental Status Examination (MMSE) scores above 25 from 36 comparably aged normal controls. Clearly, longitudinal studies are necessary to determine whether CSF concentrations of tau and Aβ are able to predict subsequent decline in MCI cases and ascertain how such measures compare with other predictive markers such as those based on neuroimaging or psychometric criteria.

Genetics In contrast to these CSF indicators of disease activity, the detection of genetic markers of AD has

350 CHAPTER III.8

recently become possible. While some mis-sense mutations in genes coding for the presenilin proteins (PS1 and PS2) as well as the APP are deterministic with respect to the AD phenotype, these abnormalities account for only a very small fraction of patients with AD (Blacker & Tanzi 1998). In elderly MCI patients without a family history of early onset AD, the presence of these mutations would not be expected. On the other hand, it is now well appreciated that persons carrying the ε 4 isoform of the ApoE protein are at increased risk for developing late-onset sporadic AD (Saunders et al. 1999). While it might be expected that the ApoE ε 4 would be over-represented in MCI cases as a group compared with normal controls, it would also be anticipated that the frequency of ε 4 representation would not reach the level seen in AD, given the assumption that MCI cases comprise not only preclinical AD, but also other more benign conditions predisposing to cognitive impairment. In one large study, the prevalence of nondemented persons with at least one copy of ApoE ε 4 was 22%, while in AD the frequency was 64% (Poirier et al. 1993). Values intermediary between these estimates were found in several studies of non-demented but memory-impaired individuals who would appear to satisfy criteria for the diagnosis of MCI (Petersen et al. 1995; Blesa et al. 1996; Tierney et al. 1996a). Some cross-sectional studies have shown ε 4-positive MCI subjects to have greater cognitive impairment than corresponding MCI persons without ε 4 (Blesa et al. 1996) and statistically significant differences in psychometric test performance have been demo-

III.8.9

strated in non-demented dizygotic twin pairs discordant for the presence of ε 4. Longitudinal studies have shown greater changes in MMSE performance over a 3-year period for a general population of older adults with ε 4 compared those without ε 4 (Feskens et al. 1994). Two studies have examined the extent to which ε 4 contributes to the risk of cognitive decline in patients with MCI. Petersen et al. (1995) followed 66 MCI cases longitudinally and found 25 who declined to a diagnosis of dementia (probable AD) at follow-up. Using a multivariate Cox regression models, ApoE ε 4 status was found to be a better predictor of subsequent dementia (risk ratio = 4.36) than cognitive test performance at baseline (risk ratio < 1.2). Tierney et al. (1996a) studied 107 MCI cases of whom 29 declined to AD when examined 2 years subsequently. Using logistic regression after adjusting for age and education, they found that ApoE ε 4 was a poor overall predictor of decline; although specificity was high (94.9%), sensitivity was only 17.2%. On the other hand, after adding psychometric test results to the model, overall predictive accuracy was increased to 92.5% with sensitivity increasing to 82.8%. Despite these discrepancies, the weight of the cross-sectional epidemiological data makes it reasonable to assume that ApoE ε 4positive patients carry at least some increased risk for developing dementia. However, because ApoE ε 4 is neither necessary nor sufficient for the development of AD, its clinical utility as a predictor of dementia could be questioned on a priori grounds alone.

Likely Subtypes of MCI

Research samples of mild cognitive impairment (MCI) cases, particularly when ascertained at dementia clinics, show a high rate of conversion to probable Alzheimer’s disease (AD) and tend to manifest the pathophysiological features of very early AD that are reviewed above. Nevertheless, MCI remains a heterogeneous entity, as not all cases show progressive decline and convert to AD (some actually show subsequent improvement). Furthermore, particularly in more representative,

community samples, other underlying dementia aetiologies are probably well represented. Table III.8.3 lists the likely subtypes of MCI. The occurrence of the first three categories, prodromal AD, prodromal vascular dementia (VaD), and prodromal mixed AD/VaD follows logically from the fact that these dementia categories are the most common dementia subtypes and that the transition from normal function to clinical dementia typically is a gradual process over a period of at least several years.

MILD COGNITIVE IMPAIRMENT 351

Similarly, the rarer dementias (e.g. Pick’s disease and other frontotemporal dementias) are also likely to include MCI stages as part of their clinical course. The final subcategory includes individuals who either remain mildly impaired for many years or improve and return to cognitively normal status. While longitudinal studies of MCI samples have consistently identified stable or backcrossing cases, the proportion of cases in this and in the other four subcategories remains to be determined.

III.8.10

Table III.8.3 Likely subtypes of MCI. Prodromal stage of AD Prodromal stage of VaD Prodromal stage of mixed VaD/AD Prodromal stage of other rare dementias Stable or reversible cognitive impairment (heterogeneous or unknown causes)

Treatment of MCI

Potential goals in the treatment of mild cognitive impairment (MCI) are either to improve symptoms or to slow progression. Producing an effect on progression might involve slowing or preventing the conversion from MCI to a diagnosis of dementia, as well as slowing or preventing the transition from normal cognitive status to MCI. Potential pharmacological approaches include the same treatment strategies that are under study for the treatment of dementia (e.g. cholinergic drugs, antioxidants, anti-inflammatory drugs, estrogens, neuroprotective agents, antiamyloid compounds and compounds that address cerebrovascular risk factors). Nonpharmacological cognitive enhancement methods are also worthy of study in this mildly impaired population.

A number of large, multi-site clinical drug trials in patients with MCI are currently underway, but no results are as yet available. Ongoing studies are designed to determine if cholinesterase inhibitors can produce short-term symptomatic improvement, and whether cholinesterase inhibitors, antioxidants and anti-inflammatory drugs can delay progression to a diagnosis of Alzheimer’s disease (AD) over a 2- or 3-year treatment period. One difficulty in designing these ‘delay to conversion’ trials is the need to determine with consistency and reliability the primary endpoint of conversion to AD. This problem is generally addressed by requiring that patients judged to convert meet accepted criteria for AD, and that they also demonstrate a worsening in symptoms since the baseline evaluation.

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SECT ION IV

Overview of Treatment and Management Edited by: Jeffrey Kaye, Lon Schneider and Nawab Qizilbash

IV.1

Aims of Treatment

Jeffrey Kaye

The patient with dementia comes to the clinician with a unique set of expectations. These expectations are dependent on a mixture of factors including the patient’s education, socio-economic status, cognitive and behavioral deficits and stage of dementia. Depending on the type or stage of disease, the dementia syndrome itself presents the special challenge of determining the degree to which a patient is capable of participating in their own decisionmaking about their treatment. Inevitably, as the dementia progresses, the treating clinician interacts increasingly with family members or surrogate decision-makers. In this process it is easy to lose sight of who is being treated: the patient or the care givers. However, the primary goal of treatment should be the same for all parties involved, maximizing patient function. By informing the patient and family with the evidence for efficacy of available treatments, both patients and care givers can be united in a management program that is geared to optimizing functional abilities and maintaining quality of life for the duration of the illness. Most of the studies of efficacy are performed in the context of a single focused treatment such as cholinesterase inhibition as a treatment for Alzheimer’s disease (AD). Strictly speaking, this approach does not address a large array of other available concomitant treatments ranging from additional medications used to manage common behavioral symptoms to educational programs for care givers. This is understandable under the constraints of how treatment trials are conducted, but for the clinician presents the formidable task of integrating a wide range of management options. Among these choices dementia treatments may be classified along a number of lines. The approach

that is common in conventional medicine is to describe single specific treatments by disease diagnosis (generally the approach used to evaluate efficacy for most of this book). When effective treatments targeted at a known pathophysiological mechanism unique to that disease exist, then this sort of classification works well. Another approach is to divide treatments more generally into those that are considered disease modifying and those that are symptomatic. This major division may be further subdivided into pharmacological and non-pharmacological treatments. This approach focuses more on types of treatments rather than on the process of providing treatment. Thus, as most of the dementias are chronic progressive conditions that affect multiple domains of function, their management is best addressed by a more integrated approach that recognizes both the available treatments as well as the strategies needed to effectively place them into practice. In this context there are several domains or areas of intervention that lend themselves to review in developing a general strategy of treatment or management (Fig. IV.1.1). It is important to emphasize that treatment in dementia is not limited, in the strict sense, to the patient. For example, management of excess morbidity among care givers is an important part of treating the patient. A fatigued and depressed family member is likely to be less effective in rising to the task of caring for a person with dementia. This chapter will present an integrated approach to the application of the available therapies for dementia. It is intended as a guide of principles to be applied to the sections on specific therapies and general management for identified dementia symptoms or syndromes.

357

358 CHAPTER IV.1

Dementia diagnosisaprognosis

Determine knowledge and expectations

Educate

Social–environmental interventions • • • •

Dementia prevention

Safety assurance Advance directives Legal–financial planning Care giver health

• Manage vascular risk factors (blood pressure control, aspirin) • ?Vitamin E

Health maintenance

Cognitive symptom management

• Manage chronic disease • Preventative medicine • Exercise and diet

• Cholinesterase inhibitors • Ginkgo biloba • Research trial participation

Behavioral management • Environmental modification • Behavioral modifications • Psychotropic medications Neurological management • Parkinsonism • Myoclonus • Seizures

Fig. IV.1.1 Treatment and management of dementia. This figure shows the major domains to be addressed by the clinician at initial as well as follow-up evaluations.

IV.2

Criteria for Clinical Decisions

Jeffrey Kaye

In developing a treatment plan there are several key questions to consider: 1 What is the diagnosis? 2 What are the patient’s principal problems?

IV.2.1

3 What is the prognosis? 4 What is the likelihood of treatment benefit? 5 What are the patient and family expectations?

What is the Diagnosis?

Key points • Emphasis is placed on precise diagnoses as the first step in treatment in that an accurate diagnosis dictates a more specific or targeted approach to dementia management. • Optimal dementia patient management requires a clear, focused description of signs and symptoms in order to follow outcomes in a consistent manner. In the previous section the approach to diagnosis was reviewed. Here we reiterate the importance of determining, to the best degree possible, the likely diagnosis while realizing that clinicopathological correlations indicate a degree of uncertainty to this process. The emphasis is placed on diagnosis as the first step in treatment, in that an accurate diagnosis dictates a more specific or targeted approach to management. There may be a general tendency to

assume that most late-life dementia is associated with the most common form of dementia, Alzheimer’s disease (AD). However, this assumption is not adequate for planning treatment or management. An obvious example of this principle is in the case of dementias secondary to medical illnesses, which are treated appropriately by instituting the specific therapy indicated for that medical condition. However, even in these specific cases it must be realized that many of the principles to be outlined for the chronic progressive dementias apply to those that may, unfortunately, only be arrested and not reversed by instituting a medical therapy. It is anticipated that as the number of more specific therapies grows and diagnostic capabilities improve it will be increasingly important to base treatment on more precise diagnoses. For the purposes of the following discussion, it will be assumed that the treating clinician has correctly identified the primary cause of the dementia.

359

360 CHAPTER IV.2

IV.2.2

What Are The Patient’s Principal Problems?

Dementia patients will present with a set of problems along two axes: a spectrum or cluster of symptoms and a degree of severity of those symptoms. The latter reflects a stage of disease. Thus, for example, a patient with early Alzheimer’s disease (AD) may only have relatively isolated memory impairment, minor functional disability and depression, while a patient with early frontotemporal dementia may present with modestly decreased language output, disinhibition and loss of social tact. An individual presenting with either of these disorders at a later stage of illness would present with a very different problem set such that the later stage AD patient might have severely impaired delayed recall, an inability to dress unassisted and night-time hallucinations. The frontotemporal dementia patient at a later stage may exhibit near mutism, except for echolalia, unusual food preferences and stereotyped repetitive behaviors. These symptoms form the anchor points or frame of reference for monitoring therapy in the individual patient. Thus it is important for the clinician to have as

IV.2.3

clear an account of the symptom cluster as possible, in the traditional sense: When is the symptom present? How often is it present? What if anything makes the symptom worse or better? How disturbing is it to the patient and family? The need to be specific about identified symptoms is particularly important for behavioral symptoms. For example, many behaviors are described as ‘agitation’. However, some behaviors that are reported as agitation, such as pacing or yelling, are not likely to be amenable to the same therapies. Furthermore, a disruptive behavior may be of the most concern to a family, especially if it is socially embarassing. Nevertheless, if it occurs infrequently it may, upon further discussion, be considered a minor problem relative to other ongoing issues such as sleeplessness or appetite loss. Clinicians may choose to describe these symptoms in a narrative or, if time and resources allow, use formal cognitive, behavioral and functional assessment scales. The most important principle here is to capture the key important symptoms and to follow them in a consistent manner.

What is the Prognosis?

Key point Optimal dementia patient management requires a clear, focused description of signs and symptoms in order to follow outcomes in a consistent manner. A troubling topic to consider for the patient and family is the idea of prognosis in dementia. Finnish (Molsa et al. 1986), Dutch (Van Dijk et al. 1991) and Canadian (Ostbye et al. 1999) surveys have all shown that for the dementias life expectancy is shortened, but this is highly variable and not easy to predict in an individual patient. A remarkable case report with autopsy confirmation is known of a patient whose entire dementia syndrome evolved

over the course of 1 year with the brain showing pathology typical of Alzheimer’s disease (AD) (Armstrong et al. 1991)! Obviously this is an unusual case. However, in a recent series of cases identified as having a high probability on clinical grounds of being Creutzfeldt–Jakob disease with durations of dementia less than 2 years, four of 95 cases coming to autopsy had AD as the pathological diagnosis (Poser et al. 1999). In general, because the onset of most dementias is insidious and there is no definitive biological marker of disease onset, the duration and thus long-term prognosis is dependent upon the methodology used to mark the time of onset of dementia. Thus most ‘duration of dementia’ estimates are basically drawing the time-line of dementia beginning at the time of diagnosis to the time of death or some other

CRITERIA FOR CLINICAL DECISIONS 361

clinical outcome. There is likely to be a delay of years between the onset of mild symptoms and clearly recognized or diagnosed dementia. Several prospective studies have shown, either with psychometric or neuroimaging methods, that there is dementia pathology present before what is commonly clinically recognized as dementia onset (Small et al. 1995; Kaye et al. 1997). This pushing of recognition of disease backward is important for future treatments targeted toward prevention and might be focused on those at highest risk for progression. Among very mildly impaired patients there is a subset that will present primarily with complaints of memory impairment. These patients have been described in a number of ways that likely overlap with one another (e.g. benign senescent forgetfulness, age-associated memory impairment, questionable dementia, incipient dementia) (Dawe et al. 1992). A recent popular description of these patients in the USA has been presented by Peterson and colleagues (Peterson et al. 1999) and designated as mild cognitive impairment (MCI). Over a mean of 48 months of follow-up of MCI patients of mean age 81 years, 48% (12% per year) progressed to dementia. As these patients are recognised only if they present with memory complaints, it is not known if others with similar degrees of memory impairment, but not coming to medical attention, have a similar prognosis. As there are currently no completed randomised controlled trials of therapies for the precursors of dementia such as MCI, it is not currently clear as to whether the treatments for dementia should be applied to these patients. The authors are aware of such studies currently being conducted and anticipate the results of these trials to be available in the next few years. Despite these uncertainties about the outcome of very early or mild dementia, broad statements can be made about patients with the clearly defined syndromes of dementia. These will frame the discussion of what to expect and how to manage symptoms proactively. For example, in the Canadian Study of Health and Ageing 5-year mortality rates were increased overall for those with a dementia diagnosis compared to the general population (Ostbye et al. 1999). However, these rates were

dependent on age, sex, and specific dementia diagnosis. Thus after 5 years, 57.9% of women with AD in the 65–74 year age group died while 68.4% of men with AD died among the same age group. However, the more telling figure is the mortality rate ratio (the number of deaths/person years relative to the general population) where for men in the same 65–74 year age group the ratio was 6.53 while for women it was 9.63. When one examines those with AD among the 85-year and older age group, there is not surprisingly a high overall mortality after 5 years (82% among women; 91.1% among men), but the mortality rate ratio is not as high as in younger elderly (1.85 for women; 1.69 for men). This points out the dramatic differences in mortality driven by age-associated diseases. The shortening of life associated with AD appearing in the seventh decade of life is about four- to five-fold greater than if AD develops in the ninth decade of life. Among the longest follow-up intervals to be completed in a population-based dementia cohort is 7 years. In this study (Aguero-Torres et al. 1998) of 233 initial prevalent dementia cases, lower survival rate was associated with older age, male gender, lower education, greater functional disability, and greater number of co-morbidities. In this study, the type of dementia (divided into AD, vascular or other dementias) did not influence survival, but did influence the rate of progression. The influence of other types of dementia (nonAD dementias) on survival is less consistently known. Other dementias are less consistently defined so that it is difficult, on a clinical basis, to know how many cases diagnosed with AD have concomitant cerebrovascular disease or other less common dementias such as Lewy body or frontotemporal dementia. In the Canadian Study of Health and Ageing 5-year mortality rates were greater for those with a vascular dementia (VaD) diagnosis compared to those with an AD diagnosis and the general population (Ostbye et al. 1999). Other studies have also reported that those classified with VaD have a worse prognosis than those with other types of dementia (Barclay et al. 1985; Molsa et al. 1986). However, this has not been observed universally (Aguero-Torres et al. 1998).

362 CHAPTER IV.2

A second major group of dementia patients that may have a worse prognosis relative to ‘pure’ AD patients are those presenting or developing extrapyramidal signs or psychotic symptoms. Some patients with these symptoms are often defined as, or at least suspected of, having a different neuropathological substrate (the Lewy body) to their dementia, and this clinicopathological complex, as noted in the section on diagnosis, is referred to as dementia with Lewy bodies (DLB). In most studies, patients with DLB (dementia with extrapyramidal signs and psychotic symptoms) appear to have faster rates of cognitive decline and shorter survival than those without (Chen et al. 1991; Ballard et al. 1996; Olichney et al. 1998; Heyman et al. 1999). This information is important to consider in the discussion of dementia treatments as most treatment decisions need to weigh the magnitude of benefit with the natural history of survival, anticipated quality of life and the likelihood of accrued risks. As will be apparent in the following sections on specific treatments, at this time there is little evidence for the long-term efficacy of many proposed or practised treatments for dementia. There are no blinded studies of treatment beyond 2 years. This reflects a stage of the field at large, not a lack of interest. Thus decision-making at this gross level of life expectancy is more of a qualitative process or projection of a family’s expectations. There is no strong evidence that any current treatments significantly prolong the life of a patient with dementia.

IV.2.4

Aside from considerations of shortening of life span, an additional important prognostic question often posed by families dealing with a dementing illness is: what is the likelihood of needing additional care such as going to a nursing home or longterm care facility? This question obviously assumes that such facilities are available and is likely to be dependent on alternative care models and payment schemes for care unique to the country in which a patient resides. In the USA about 75% of AD patients eventually reside in nursing homes (Welch 1992). Predictors of this change in living arrangement depend on measures of care giver burden (Colerick et al. 1986; Lieberman & Kramer 1991) as well as disease severity (Knopman et al. 1988; Cohen et al. 1993; Severson et al. 1994; Heyman et al. 1997; Scott et al. 1997; Stern et al. 1997). Unfortunately, there are no prospective studies of nursing home placement in which validated measures of disease progression have been used to determine outcomes. A study of a population enrolled for 2 years in a treatment trial showed that the rate of change on dementia severity scales such as activities of daily living predicted nursing home placement (Knopman 1999). This study was not designed to determine the predictive power of rate of change at earlier stages of dementia. However, it does suggest that, practically speaking, if the clinician observes a faster rate of decline than expected without remediable causes (e.g. worsening of a coexisting medical condition), the need to develop possible alternative care plans is more urgent.

What are the Patient and Family Expectations?

In considering treatment the clinician provides to the patient and family the best information with regard to the dementia diagnosis and likely outcomes if not treated. Ultimately it is the decision of the patient and carers to determine what is to be done. There is a wide possible range of responses. Thus one may encounter families where a seemingly mild degree of functional impairment results

in the patient entering institutional care, whereas another carer may choose to keep their affected family member at home to the very end. These decisions are likely to be influenced by social, cultural and economic considerations unique to each patient. The clinician should be especially sensitive to the needs of older minority populations (Espino & Lewis 1998).

CRITERIA FOR CLINICAL DECISIONS 363

IV.2.5

What is the Likelihood of Treatment Benefit?

Key point Quality of lifeathe sum of health and sense of well being of the patientais taken as the barometer of treatment benefit. This outcome may be influenced significantly by perceived benefits to all of the parties involved in care. In discussing treatment benefits with families, it is apparent that treatment benefit may be defined quite differently by each of the parties involved. The clinician may assume a benefit simply because a symptom is no longer complained about. The care giver may define a benefit in terms of their own functioning which may be only indirectly related to the patient’s symptoms. Thus, for example, the amount of sleep the care giver rather than the patient achieves at night may be perceived as an effect of a treatment. On the other hand, the patient may find a treatment benefit results in very minor degrees of improvement, such as increased alertness, that are not detected by routine psychometric tests or even noticed by the family. These sorts of benefits are rather subtle, depend on cultural and social milieu, and are not easily amenable to absolute measurement. Ultimately it is the quality of life, here taken to be the sum of health and sense of well-being of the patient, that is taken as the barometer of treatment benefit. This outcome may be influenced significantly by perceived benefits to all of the parties involved in the management plan, including the clinician. The greatest benefit detected by the clinician is seen for those treatments that have a large effect on target symptoms or problems: a depression that clears, a sleep disturbance that lifts or an activity program that keeps the patient engaged. In this sense the greatest benefits are likely to be seen in treatment of the non-cognitive symptoms of dementia and in terms of functional improvement. Of the medications for which there is some evidence of consistent cognitive symptom benefit (cholinesterase inhibitors, ginkgo biloba extract, others) the effect sizes are only on the order of 0.4–0.5. Thus, for example, among the cholinesterase inhibitors

there is only a 4–5% improvement (measured as a decrease in Alzheimer’s Disease Assessment Scale cognitive, ADAS-Cog, subtest score) seen among the various trials that have been conducted over approximately a 6-month period. In the next chapter a summary of evidence for dementia treatment benefit is presented from the perspective of differing classes of treatment, as well as the systems overseeing the approval and availability of these treatments.

References Aguero-Torres, H., Fratiglioni, L., Guo, Z., Viitanen, M. & Winblad, B. (1998) Prognostic factors in very old demented adults: a seven-year follow-up from a population-based survey in Stockholm. Journal of the American Geriatrics Society 46, 444–452. Armstrong, T., Hansen, L., Salmon, D. et al. (1991) Rapidly progressive dementia in a patient with the Lewy body variant of Alzheimer’s disease. Neurology 41, 1178–1180. Ballard, C., Patel, A., Oyebode, F. & Wilcock, G. (1996) Cognitive decline in patients with Alzheimer’s disease, vascular dementia and senile dementia of Lewy body type. Age and Ageing 25, 209–213. Barclay, L., Zemvoc, A., Blass, J.P. et al. (1985) Survival in Alzheimer’s disease and vascular dementias. Neurology 35, 834–840. Chen, J.Y., Stern, Y., Sano, M. & Mayeux, R. (1991) Cumulative risks of developing extrapyramidal signs, psychosis or myoclonus in the course of Alzheimer’s disease. Archives of Neurology 48, 1141–1143. Cohen, C.A., Gold, D.P., Shulman, K.I. et al. (1993) Factors determining the decision to institutionalize dementing individuals: a prospective study. Gerontologist 33, 714–720. Colerick, E.J. & George, L.K. (1986) Predictors of institutionalization among caregivers of patients with Alzheimer’s disease. Journal of the American Geriatrics Society 34, 493–498. Dawe, B., Procter, A. & Philpot, M. (1992) Concepts of mild memory impairment in the elderly and their relationship to dementia: a review. International Journal of Geriatric Psychiatry 7, 473–479. Espino, D.V. & Lewis, R. (1998) Dementia in older minority populations. Issues of prevalence, diagnosis and treatment. Journal of the American Geriatrics Society 6, S19–S25. Heyman, A., Peterson, B., Fillenbaum, G. & Pieper, C. (1997) Predictors of time to institutionalization of

364 CHAPTER IV.2

patients with Alzheimer’s disease. The CERAD experience, Part XVII. Neurology 48, 1304–1309. Heyman, A., Fillenbaum, G., Gearing, M. et al. (1999) Comparison of Lewy body variant of Alzheimer’s disease, part XIX. Neurology 52, 1839–1844. Kaye, J.A., Swihart, T., Howieson, D. et al. (1997) Volume loss of the hippocampus and temporal lobe in healthy elderly persons destined to develop dementia. Neurology 48, 1297–1304. Knopman, D.S., Berg, J.D., Thomas, R., Grundman, M., Thal, L.J. & Sano, M. (1999) Nursing home placement is related to dementia progression: experience from a clinical trial. Neurology 52, 714–718. Knopman, D.S., Kitto, J., Deinard, S. et al. (1988) Longitudinal study of death and institutionalization in patients with primary dementia. Journal of the American Geriatrics Society 36, 108–112. Lieberman, M.A. & Kramer, J.H. (1991) Factors affecting decisions to institutionalize demented elderly. Gerontologist 31, 371–374. Molsa, P.K., Marttila, R.J. & Rinne, U.K. (1986) Survival and cause of death in Alzheimer’s disease and multiinfarct dementia. Acta Neurologica Scandinavica 74, 103–107. Olichney, J.M., Galasko, D., Salmon, D.P. et al. (1998) Cognitive decline is faster in Lewy body variant than in Alzheimer’s disease. Neurology 51, 351–357. Ostbye, T., Hill, G. & Steenhuis, R. (1999) Mortality in elderly Canadians with and without dementia: a 5 year follow-up. Neurology 53, 521–526.

Peterson, R., Smith, G., Waring, S., Ivnik, R., Tangalos, E. & Kokemen, E. (1999) Mild cognitive impairment. Archives of Neurology 56, 303–308. Poser, S. Mollenhauer, B., Krauß, A., et al. (1999) How to improve the clinical diagnosis of Creutzfeldt–Jakob disease. Brain 122, 2345–2351. Scott, W.K., Edwards, K.B., Davis, D.R. et al. (1997) Risk of institutionalization among community long-term care clients with dementia. Gerontologist 37, 46–51. Severson, M.A., Smith, G.E., Tangalos, E.G. et al. (1994) Patterns and predictors of institutionalization in community-based dementia patients. Journal of the American Geriatrics Society 42, 181–185. Small, G.W., Mazziota, J.C., Collins, M.T. et al. (1995) Apoplipoprotein E type 4 allele and cerebral glucose metabolism in relatives at risk for familial Alzheimer’s disease. Journal of the American Medical Association 273, 942–947. Stern, Y., Tang, M.X., Albert, M.S. et al. (1997) Predicting time to nursing home care and death in individuals with Alzheimer disease. Journal of the American Medical Association 227, 806–812. Van Dijk, P.T., Dippel, D.W. & Habbema, J.D. (1991) Survival of patients with dementia. Journal of the American Geriatrics Society 39, 603–610. Welch, H.G., Walsh, J.S. and Larson, E.B. (1992). The cost of institutional care in Alzheimer’s disease: nursing home and hospital use in a prospective cohort. Journal of the American Geriatrics Society 40, 221–224.

IV.3

Clinical Decisions In Practice

Jeffrey Kaye

IV.3.1

Rationale For TreatmentcAssessing the Evidence

As is clear from the title of this book, and the preceding chapters, the rationale for treatment is derived from the evidence of valid clinical trials. The question faced by the clinician in practice, however, is more complex but distils down to: is the evidence applicable to my patient? The evidence for treatment efficacy as well as critical questions such as anticipated long-term response or side-effects are generally not fully known for many dementia treatments. Thus in reality, despite the clear emphasis of this book on the use of evidence to guide management, it is recognized that we are often in an early stage of knowledge in this field. In many cases we are presenting evidence that certain treatments don’t work, rather than certain others do. Even in these negative cases there may be subgroups of patients where a positive response is achieved, but the trial was not designed to detect these ‘responders’. This state of affairs is not unique to the field of dementia. In fact, even in other fields where there is a deeper trials database to draw upon, the clinician is still often faced with applying a treatment to a patient based on a randomized controlled trial that approximates, but doesn’t fully apply, to the patient in question. In practice the dementia patient may be older, less educated, and have more co-morbid medical conditions and take more concomitant medications than the typical patient evaluated in a clinical trial for dementia. Nevertheless, unless there are important biological reasons to suspect that the treatment effect observed in valid clinical

trials would not apply to your patient, it is a reasonable assumption that the direction of effect will be similar in most patients carrying the same specific dementia diagnosis. The clinical decision to apply a dementia treatment thus rests on answering the question: is my patient as significantly different from others participating in the clinical trials as an apple is from an orange? Related to this question of extrapolating the clinical trial cohort to the single case is whether a patient is part of a subtype or subgroup. There are perhaps only a few cases where this might be considered practically important in dementia treatment. Unfortunately such scenarios provide more questions to be definitively answered in the future as current dementia studies have not fully addressed these subgroups. One is the case of the very elderly (octogenarians or older) who will increasingly represent a larger proportion of those with dementia, and for whom we really don’t know if there are important age-related differences in either the biology of their dementias or their response to therapies. Although those who are older than age 80 years represent at least half of those with dementia in most populations, the average patient in clinical dementia trials is in their seventies with few nonagenarians exposed to treatments. A second group of patients that is likely to grow in the future as the human genome is fully sequenced and genes influencing the onset and progression of the dementias are uncovered, are subgroups of patients that differ according to genetic polymorphisms. At present

365

366 CHAPTER IV.3

there is only one common genetic polymorphism associated with Alzheimer’s disease (AD), the apolipoprotein E genotype (ApoE ε4), which at this time does not appear to confer a clinically relevant pharmacogenetic effect. However, as this polymorphism does affect the age at onset of dementia, it is possible that for disease-modifying therapies which might delay onset, this or related genes may become relevant in the future. Assuming that the patient about to be treated is reasonably similar to those in the relevant trials, one must then consider what the magnitude of benefit might be for this patient. Among the strategies for approaching this decision is to consider the number needed to treat (NNT) to reach the desired outcome. For many conditions this distils down to the NNT to prevent a poor outcome. Applied to data from many of the dementia trials this metric may not be as intuitively meaningful because, essentially one is asking the NNT to prevent a decline in a cognitive test score of a predefined magnitude, rather than a discrete clinical outcome. The more meaningful outcomes, such as functional ability or independence, are not always reported other than as secondary outcomes and the NNT cannot be calculated easily. In practice, if one has a measure of the prognosis or natural history outcome (either from the literature or by using the non-treated placebo group) one can estimate the NNT for a reported treatment by using the absolute risk ratio (ARR) derived from the data in the paper to determine the NNT. Thus, say that, in a dementia prevention trial conducted over 3 years, a placebo or control group had a 30% cumulative

IV.3.2

incidence of dementia but, on the other hand, the treated group has an incidence of 20%. The difference between these two measures is the absolute risk reduction or ARR (30% – 20% = 10%). The NNT is the reciprocal of the ARR or, in the hypothetical case cited, 10 (1/10%). Thus 10 patients would need to be treated to see this magnitude of reduction in dementia incidence in our hypothetical case. Another shorthand for determining the potential magnitude of benefit is to consider the effect size, which is essentially a measure of the magnitude of difference between the treatment and placebo groups relative to the combined variability or range of responses seen in both groups. This metric takes into account the ‘noise’ in the measurement. Thus, from our example above, say the placebo group had a dementia incidence of 30% with a standard deviation of 6% and the treatment group had a dementia incidence of 20% with a standard deviation of 5%. Then the effect size would be the mean difference between the groups divided by the mean variance (10/5.5 = 1.8). In general, effect sizes of > 0.20 are considered clinically meaningful but small, 0.5 as moderate and ≥ 0.8 as large (Cohen 1988). The magnitude of the effect size needs to be viewed in the context of the particular outcome assessed. One can see that the greater the variability in study groups overall, the smaller the effect size. Thus, if the mean variance in the groups was, for example, 20, then the effect size would be 0.5. This may have practical implications because in the ‘real world’ practice setting there is likely to be greater variance in the natural history of dementia outcomes in the treated population.

From Groups to Individuals

In the course of applying the evidence from trials to an individual patient there is often uncertainty as to whether the treatment is truly effective. This is especially important for dementia treatments where the therapies, if instituted, are often continued for long periods of time. Because we are often relying on a surrogate informant to provide feedback on efficacy the clinician may be highly

susceptible to placebo effects and exaggerated claims of family members. A method that has been proposed to address this uncertainty in individual patients is the n-of-1 trial. Essentially, this entails performing a mini-clinical trial with the individual patient. It requires the complete understanding and consent of the patient and care giver to be successfully carried out. The patient agrees that the

CLINICAL DECISIONS IN PRACTICE 367

treatment will be tried for an appropriate period of time, but that neither the clinician nor the patient will know whether a placebo or the active medication is being used. After an adequate trial period the placebo or drug is switched and again adequate follow-up is carried out to observe the anticipated response. In theory, this may be an attractive approach to assessing efficacy in an individual patient.

IV.3.3

Unfortunately, for many of the dementia symptoms to be treated the observational periods needed to see an effect (on the order of several months at a minimum) and the fact that the disease will have progressed further when the next cycle of treatment begins (meaning that the drug and placebo are not being compared to the same disease severity), renders this approach less feasible for most clinicians.

The Application of Specific Treatments for Dementia

Key point Initiating therapy for dementia requires a good baseline assessment of the identified target symptoms coupled with a thorough understanding of the knowledge base and expectations of the patient and family as they participate in therapy. As this section is meant as an overview, only general principles and pertinent examples are given with the details pertaining to specific treatments reserved for later sections. In general, one will be called upon to treat the various symptoms of dementia in those who present with a constellation of specific complaints, some of these treatments being unique to the underlying dementia and some of these applicable to symptoms present in many different dementias. These symptom targets may range from mild memory loss to extremely disruptive behaviors. The most important basic elements of successfully applying any therapy in dementia is a good baseline assessment of the identified target symptoms coupled with a thorough understanding of the knowledge base and expectations of the patient and family as they participate in therapy. Most dementia therapies have been developed with a particular underlying pathophysiology in mind. A classic example is the range of cholinergic therapies developed for Alzheimer’s disease (AD).

As the differential diagnosis of dementia is not a perfect science, there are many instances where therapies that are proposed and tested as specific to a particular dementing disease, end up being applied generically to other dementing illnesses. This may be most often the case for the common mixed dementias where patients have elements of AD and vascular dementia (VaD). As there is no a priori reason to expect that these specific therapies will not affect the dementia for which they were intended, even if there are additional causes present, these treatments should be considered for use in mixed dementias. In a similar sense, many of the behavioral changes observed in the dementias are seen across dementia types. As there is no overwhelming evidence that the underlying pathophysiology resulting in many of these behaviors is necessarily different, the general approach has been to treat these behaviors generically rather than specifically as a unique feature of a particular neuropathological type of dementia. Thus, for example, psychotic symptoms or depression emerging in AD are treated similarly to those presenting in VaD, dementia with Lewy bodies (DLB) or frontotemporal dementia (FTD). Of course, the clinician must be aware that these various dementias may differ with regard to potential side-effects that may emerge as a result of these generically applied treatments. Thus for example, patients with DLB may be more sensitive to the dopamine blockade of some of the neuroleptic drugs.

368 CHAPTER IV.3

IV.3.4

Care Givers in the Therapeutics of Dementia

Key point Educating the care giver is an important part of any treatment plan. Referral to available community resources is an important part of providing information and support to families. The success of dementia therapies will ultimately rely on the ability to involve care givers in the treatment plan. Although the person with dementia should never be marginalized unduly, there comes a time when she or he cannot truly participate effectively in decisions regarding treatment. It is for this reason that at least in the early phases or stages of dementia important decisions are made when the patient can fully participate. Not the least of these decisions involves advanced healthcare directives. Advanced directives allow the care giver sufficient authority and peace of mind to make future healthcare decisions without the uncertainty of second-guessing as to what the person with dementia would have wanted to happen to them. Along these lines, decisions with legal or financial implications should also be settled as early as possible so that the patient can participate fully in the decision-making process. In some settings advanced directives may also be applied to the patients wishes to participate in future treatment trials. In addition to ascertaining the patient’s treatment wishes, the clinician needs to also devote some time

IV.3.5

Table IV.3.1 Internet addresses of websites that may

provide useful dementia-specific information. Organization

URL

Alzheimer’s Disease Education and Referral Center (ADEAR) Alzheimer’s Association (USA) Alzheimer’s Research Forum Alzheimer’s Disease International

www.alzheimers.org www.alz.org www.alzforum.org www.alz.co.uk

Appendix III also lists contact details of dementia and Alzheimer’s disease societies and associations around the world.

specifically to the care giver. This part of a treatment plan includes educating the care giver and family as to what to expect, how to cope with common problems and scheduling regular follow-up. As the frequency of health problems among care givers related to that role is high, it is important that to the degree possible the care giver is offered counseling or referral for therapy when or if their burden becomes excessive. In many countries there are lay organizations often focused in name on Alzheimer’s disease (AD), but also quite willing to help people dealing with any number of diverse dementias. These AD associations or societies can be an important source of support or information to families. They often know the available community-specific resources that clinicians cannot track or keep up to date in their busy general practices. For those that are computer savvy, a number of websites may be of assistance (Table IV.3.1).

Treatment of Mood Changes and Depression

As any assessment of mental status will be coloured by the patient’s mood and attentional state, an important starting point for treatment is the management of behavioral change and, in particular, depressive symptoms. Thus any significant depressive illness present with a dementia should be treated prior to beginning cognitive treatments. The decision to treat depression in demented patients assumes that there has already been a thorough search for other causes of depression such as medications or

medical illness. There is no question that patients with dementia and symptoms of major depressive disorder should be treated when this syndrome is recognized. However, minor depressive symptoms are common in dementia and it is not as clear when or if these patients should be treated. As a degree of reflective capacity may be necessary to plan and initiate new activities, it may be difficult on clinical grounds to separate the cognitive changes of a gradual loss of recall and insight from an affective

CLINICAL DECISIONS IN PRACTICE 369

disorder that manifests itself as a loss of interest in life’s activities. Thus many dementia patients may appear apathetic and impassive, but report that they do not feel ‘depressed’. In practice, clinicians may choose to provide a trial of antidepressant therapy for these patients. This therapy should be preceded or accompanied to the degree possible by increased socialization and activity at a level appropriate for the severity of dementia. Choosing antidepressant medication for dementia patients who have Alzheimer’s disease (AD) should be guided by the pharmacological principle that these patients are theoretically more likely

IV.3.6

to be sensitive to anticholinergic effects. This is particularly a concern for antidepressants with prominent anticholinergic action such as the tricyclic antidepressants. In addition, antidepressant medications with significant sedating properties may impair cognition. On the other hand, antidepressants with greater sedating potential may be preferred for patients with depression-associated sleep disturbances. Once antidepressant therapy is instituted it must be continued for 2–3 months to ensure an adequate opportunity for effect. If effective the antidepressant should be continued with periodic re-evaluation.

Treatment of Behavioral Changes

Key point Beginning pharmacotherapy for behavioral symptoms requires a firm understanding of what the target behaviors are and the desired outcome. In most cases, a realistic goal is a reduction in the frequency or severity of these symptoms rather than a complete remission. The treatment of other behavioral changes is of equal importance to the treatment of mood disturbance as a principle for optimizing cognitive and functional abilities. These disturbances range from what are often termed psychotic symptoms, such as hallucinations and delusions, to disturbances of heightened anxiety, agitation or sleep. The first step toward treating these symptoms is to complete a careful search for precipitants or stimulants of disruptive behaviors. In addition to environmental triggers, common medical illnesses and concommitant medications should always be considered as potential culprits in causing or exacerbating these symptoms. As already emphasized, care giver expectations can play a major role in achieving a reasonable treatment outcome. Even minor adjustments in the care giver’s expectations may have significant impact on these behaviors. Thus, a patient who becomes agitated with bathing may simply not be required to bathe every day

despite a life-long pattern of this habit. Even with reasonable attempts at environmental or behavioral modifications, these may not always work. When non-pharmacological interventions are found to be ineffective, drug therapy is often tried. Despite this approach, there is only one study known by the authors (the results of which have not yet been published) comparing the efficacy of behavioral management, a neuroleptic (haloperidol), trazodone and community practice head-to-head (Teri et al. 1999). Whether any of these or related therapies have an advantage over the others for the treatment of agitated behaviors remains to be demonstrated. There is growing, but still surprisingly sparse, evidence for the efficacy of pharmacotherapy for specific behaviors. Part of this difficulty rests with older studies being targeted to ‘behavior’ in general as opposed to specific behaviors. For example, in treating agitation, it is a mistake to label all activities entailing increased activity as ‘agitation’. In so doing one might incorrectly lump pacing and wandering with increased anxiety. The latter may respond to antianxiety medications. Wandering and pacing may respond to medication only by severely sedating patients, an unacceptable approach. There is a wide range of classes of medications that have been used to treat these behaviors. These include the neuroleptics, antidepressants, general sedative-hypnotics and anticonvulsants. The degree

370 CHAPTER IV.3

of efficacy of psychotropic medications in dementia has not been evaluated thoroughly. There is evidence for the efficacy of neuroleptics for the treatment of delusions or hallucinations. Because there is often concern about the induction of parkinsonian side-effects with dopamine-blocking neuroleptics, there is now a preference for newer agents such as risperidone, olanzepine and quetiapine. Trials are currently being conducted to compare these newer agents for psychotic symptoms in dementia. When beginning pharmacotherapy for behavioral symptoms it is important to have a firm understanding of what the target behaviors are and the

IV.3.7

Cognitive Therapies

The typical adult-onset late-life dementia has a characteristic profile of gradual, progressive cognitive impairment. Acute changes in cognitive function warrant a search for medications or medical illnesses that impair mentation and, if present, require immediate diagnosis-specific therapy. At this time there are no therapies that are strikingly effective in improving chronic cognitive function for any dementia other than the rare case of a medically or surgically treated ‘reversible’ dementia.

IV.3.8

desired outcome. In most cases, a realistic goal is a reduction in the frequency or severity of these symptoms rather than a complete remission. Furthermore, the tendency to switch quickly to another agent without adequate increases in dose or time to observe an effect (usually on the order of weeks) must be avoided. Most behaviors are only present through a portion of the natural history of the dementia, and so it is important to reassess the need for these medications on a regular basis. Although formal studies have not been completed, combinations of environmental, behavioral and pharmacological therapies for behavioral disturbances would appear to have face validity at this time.

Nevertheless, current evidence supports provisional efficacy of a few therapies in specific instances. These include several cholinesterase inhibitors and possibly ginkgo biloba for Alzheimer’s disease (AD). There are several promising approaches to the treatment of vascular dementia (VaD), but unfortunately few confirmatory studies. These VaD agents include aspirin, pentoxyfylline, sulodexide and propentofylline.

Preventative Therapies

The ultimate goal of treatments for dementia would be primary prevention. There are currently no proven therapies for the prevention of dementia. There is one published trial for the secondary prevention of the progression of moderate Alzheimer’s disease (AD) to more severe stages or more severe functional impairment outcome. This randomized placebo-controlled trial of vitamin E or selegiline (see Chapter V.2.19) showed a significant difference in these functional outcomes for the treatment groups. There was no effect on secondary outcomes measuring cognitive decline. Although this single trial cannot be considered to be definitive evidence of efficacy, most clinicians will not hesitate to rec-

ommend vitamin E to patients with AD or mixed AD and vascular dementia (VaD) as this treatment is safe and relatively inexpensive. To the degree that it is related to stroke VaD should be prevented by therapies that have shown to prevent strokes such as aspirin or antihypertensive therapy. Unfortunately, there are few current studies that have been designed to prove this attractive hypothesis. One study that speaks to this issue of prevention of vascular dementia is the systolic hypertension in Europe (SYST-EUR) study (Fourette et al. 1998) which, in a subset of patients, showed that treatment of hypertension reduced the number of patients with dementia after a 5-year follow-up period.

CLINICAL DECISIONS IN PRACTICE 371

IV.3.9

Principles of Administration

For all therapies there are several principles of administration to be considered. For those of us with even excellent memory function it is difficult to adhere to a dosing regimen that requires a dose that is taken more than two times per day. Thus people with memory impairment should be taking medicines at the least frequent interval that is pharmacologically possible. This is also helpful to care givers who must remember to administer medications, in some cases not only for the dementia patient that they care for, but also for themselves as well. Thus, optimal dosing in general is ideally kept to one to two times a day.

IV.3.10

Patients with impaired brain function may be more sensitive to psychoactive medications. Thus, the old clinical adage to ‘start low and go slow’ is particularly appropriate for most dementia treatments. Finally, new medications are not always better. As the field of dementia treatment is burgeoning there will be an understandable tendency for patients to want to be on ‘the latest’ medication. In many instances such medications will either not have the weight of thousands of doses of experience or may be the common ‘me-too’ medications of a similar class to existing drugs, which differ only slightly in side-effect profile or pharmacokinetics.

Monitoring Treatment Effects

Key point A useful and meaningful way to monitor therapy in general is to assess at regular intervals functional status. This has the advantage of having immediate face validity to the clinician, patient and family, as well as being easily adjusted for the stage of dementia. An important principle to follow is the establishment of a clear baseline for comparison of treatment efficacy. This may be accomplished in a number of ways that are all complementary. It may be helpful especially for behavioral change to ask the care giver to keep a record of the frequency and severity of target behaviors. This might, for example, be the number of episodes of tearfulness or the frequency of expression of common delusions. There are many formal scales that can monitor such behaviors and provide a score to follow, but in common primary care practice these are not practical, requiring more time to administer than is often available. Similarly, when instituting therapy for cognitive deficit it is important to obtain some estimate of pre-treatment function to compare with at a later point while undergoing therapy. Many mental

status test scales, such as the widely used Mini Mental Status Examination (MMSE), exist that might help with this task. Unfortunately, however, because the natural history of cognitive decline is so slow, with a test–retest variability that approximates the yearly mean change, it is difficult to use these scales in routine clinical practice as a means of monitoring short-term efficacy. Thus, although it is useful over the term of the dementia to use these kinds of scales to track the trajectory of the illness and to communicate with other clinicians, they are not as useful for monitoring the effect of therapies during the first few months or year. Perhaps the most useful and meaningful way to monitor therapy in general is to assess functional status at regular intervals. This has the advantage of having immediate face validity to the clinician, patient and family, as well as being easily adjusted for the stage of dementia. The mild to moderately affected patient is likely to have disturbances of more complex and demanding activities of daily living (e.g. managing finances, tracking medications, driving) whereas the more severely impaired patient is more inclined to disturbances of basic activities (e.g. dressing, bathing, eating). Several brief scales exist to assess these domains. These scales comprise simple questions that should be asked at every follow-up visit for dementia patients

372 CHAPTER IV.3

and require no further effort than computing a score after recording the answers to questions about appropriate functional activity. Realistically, despite our best efforts to be ‘objective’ in cases where the magnitude of effects are currently small, clinicians find themselves falling back on patient or family self reports that ‘they are better since you began the medicine’. In such an instance, it is difficult to stop treatment in a dementia patient who has otherwise little hope for improvement. It is helpful if the clinician remains cautiously sceptical about any benefit that cannot be consistently documented by objective means, and to at least periodically consider a ‘drug holiday’ to determine if there is any difference off medication. Even in this instance it is currently difficult to assess benefit because in many cases one may be monitor-

ing not just an ‘improvement’, but a lack of the expected rate of deterioration.

References Cohen, J. (1988) Statistical Power Analysis for the Behavioural Sciences, 2nd edn. Lawrence Erlbaum Associates, Hillsdale, NJ. Fourette, F., Seux, M.L., Staesssen, J.A. et al. (1998) Prevention of dementia in randomized double-blind placebo-controlled Systolic Hypertension in Europe (Syst-Eur) trial. Lancet 352, 1347–1351. Teri, L., Raskind, M., Weiner, M. et al. (1999) Agitation Protocol Haloperidol, Trazodone, and Behavior Management Techniques in Alzheimer’s Disease Patients with Disruptive Agitated Behaviors: A Controlled Clinical Trial. Alzheimer’s Disease Cooperative Study Unit Website: http://www.alz.ucsd.edu/study/study-ag.vep.

Delivering an Integrated Treatment Plan

IV.4

Jeffrey Kaye

Consolidating the concepts presented above constitutes composing an integrated treatment plan. As the dementias are chronic illnesses, the treatment plan may be best conceived of as a cycle rather than a step-wise process (see Fig IV.1.1). The ultimate goal is to optimize and preserve function. For the purposes of this discussion we will review the composition of a treatment plan for a new early stage dementia patient. The approach presented for this instance is also applicable to patients being seen at later stages of dementia.

The cycle of treatment begins with the precise diagnosis of dementia and the recognition of its concomitant symptom complexes. It is further important at the outset to establish the care giver and family members who will support the patient. Once this is done the integrated treatment plan may be generically considered to cover seven domains of intervention or therapy: educational, socialenvironmental, general health, behavioral, neurological, cognitive, and preventative.

Establishing a Knowledge Base and Providing Education

IV.4.1

The first step is to educate patients and family members by providing them with the necessary background to make informed decisions and to track the responses to treatment. In addition to printed or electronic materials appropriate to the educational level of the patient and care givers, referral where available to the relevant Alzheimer’s

IV.4.2

disease society or association is also important. In educating the family it is important to tailor this information to the stage of dementia. Otherwise families may be easily overwhelmed by the volume of information potentially available, and the concern that everything they read and hear about will happen to them.

Addressing Social and Environmental Needs

Next, social and environmental needs should be addressed as these frame the context in which all other treatments operate. First among these are advanced directives, as one never knows what the immediate future may bring. This is an appropriate place to also bring up whether legal and financial

issues, such as asset management and wills, are in order. Issues of safety, such as driving, getting lost or operating machinery, also need to be reviewed and discussed frankly (or in more severely impaired patients issues such as wandering or using household appliances unsupervised). For those still working,

373

374 CHAPTER IV.4

a plan for retirement needs to be constructed. Finally, at this initial general discussion consideration may be given to the health status of the care giver as this will ultimately affect the efficacy of therapy over the long term. In practice, it may not

IV.4.3

Health Maintenance

Key point As the brain likes a healthy body, maintaining optimal general health is an important goal for dementia patients. There may be a tendency for families to assume that deterioration in cognitive or functional abilities is simply related to the underlying dementia when, in fact, such deterioration may be secondary to co-morbidities that are unrecognized or not well managed.

IV.4.4

Maintaining optimal general health is especially important for patients with vascular dementia (VaD) who will commonly have cardiovascular disease and hypertension. Adhering to a healthy diet, continuing to exercise and getting adequate sleep are points to be emphasized. Exercise, in particular, may be an exceptionally useful adjunctive therapy as it not only has general health benefits, but also, as a ‘non-cognitive’ activity, is failure-free for those with cognitive impairment and is an activity in which a dementia patient can achieve a sense of accomplishment.

Behavioral Management

Management of behavioral changes is the next domain to consider. This includes instituting, as needed, therapy for the commonly recognized depression associated with dementia, as well as other disturbing behaviors if present. In general,

IV.4.5

be feasible to accomplish all these goals at a single visit. The clinician may want to schedule other focused visits to cover specific areas or refer the patient to other specialists such as legal and financial planners, occupational therapists or counselors.

environmental, behavioral and medication therapies are applied either individually or in combination as appropriate. Referral to geriatric psychiatrists or behavioral specialists may be necessary for difficult cases.

Neurological Management

Key point An important part of integrated dementia management is attending not only to the behavioral and cognitive symptoms, but also to other signs and symptoms of neurological dysfunction such as parkinsonism, myoclonus or seizures. As the dementias are brain diseases usually affecting more than a single discrete area of the brain,

they are often associated with multiple neurological problems in addition to the defining cognitive and behavioral signs and symptoms. Some of these neurological signs are themselves signal symptoms, such as the parkinsonism associated with dementia with Lewy bodies (DLB) or the myoclonus seen with corticobasal degeneration (CBD). The focal signs of cerebral infarctions accompany the vascular dementias. Many of these dementias may be associated with seizures. Thus, an important part of integrated dementia management is attending

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not only to the behavioral and cognitive symptoms, but also to these other areas of neurological function. It is beyond the scope of this book to provide detailed treatment for each of these neurological disorders. Suffice to say here that optimal manage-

IV.4.6

Cognitive Function

Similar to behavioral therapies, cognitive deficits are treated as appropriate with environmental and medication interventions. In addition to the institution of anticholinesterase therapy, other simple but not always thought of suggestions can be made, such as keeping a pocket calendar, using a pill organizer and using a labeled ‘memory-dialing’

IV.4.7

ment of these symptoms may have dramatic impact on daily function of the dementia patient. Neurological consultation may be required for management of some of these problems.

telephone. In this context, a home visit by an occupational therapist knowledgeable about dementia can be instructive. For patients with very mild cognitive deficits evaluation by a neuropsychologist may be helpful in defining subtle deficits, pointing out remaining areas of strength and tracking decline in the earliest stages of dementia.

Prevention

Key point There is no major pharmacotherapy or lifestyle that has been proven to prevent progression of dementia. Current focus must be placed on the strategy of secondary prevention or preventative maintenance with careful regular attention to the patient’s general health, mental status and functional abilities that when maximized will reduce excess morbidity. Although there is no major pharmacotherapy or lifestyle that has been proven to prevent progression of dementia, vitamin E for Alzheimer’s disease (AD) and the therapies commonly applied

to prevent stroke for vascular dementia (VaD) (e.g. smoking cessation, antithrombic and antihypertensive treatment) are to be recommended. Another form of overall prevention is in the form of reducing excess morbidity. This returns us full circle to reconsider at the next visit what new information and education the patient or family needs, and what interventions among the multiple domains need to be modified or instituted to maximize the patients general health, mental status and functional ability. Although there is no formal outcome data to guide what the ideal follow-up interval should be, the typical pace of progression coupled with the therapies that are being monitored will primarily dictate the frequency of follow-up.

What is the Evidence that a Dementia Treatment Works?

IV.5

IV.5.1

Criteria Used by Drug Regulatory Authorities

Paul Leber

Introduction For nearly a decade, representatives of the Food and Drug Administration (FDA), the national drug regulatory authority of the USA, have advised the regulated industry that a ‘dual-outcome assessment strategy’ will ordinarily be used to evaluate the effectiveness of drug products that are advanced as ‘symptomatic’ treatments for dementia. This chapter not only explains the intent and operation of that approach, but also recounts the circumstances, events, and political considerations that influenced, if not ultimately controlled, the strategy’s development and subsequent implementation by the agency. It also evaluates to what extent, if at all, the strategy, as actually applied, has served its announced intent. It also makes a brief comparison of FDA’s approach with that currently being recommended by the European Medicines Evaluation Agency (EMEA). The chapter goes on to identify a number of issues not yet addressed by official agency policy that seem likely to confound efforts to develop regulatory assessment criteria for other types of antidementia drug product claims. Because some familiarity with the relevant aims and requirements of the Federal Food, Drug and Cosmetic Act (FD & C Act, the national drug regulatory law of the USA), is essential to an informed understanding of the agency’s assessment strategies, the chapter begins with a brief consideration of these subjects.

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The FD & C Act: its aims, provisions and enforcement by the FDA The provisions of the FD & C Act are intended to ensure that all drug products marketed within the USA will be ‘safe for use’, and ‘effective in use’, under the conditions of use described in their approved labeling.

Effectiveness determinations under the FD & C Act Under the requirements of the FD & C Act, the FDA may only conclude that a new drug works as claimed if the sponsor of the drug submits a new drug application (NDA) providing ‘substantial’ evidence of the product’s effectiveness in use. Substantial evidence is a term of legal ‘art’; that is, it has a unique and specific interpretation within the meaning of the Act. At the time that the agency’s antidementia assessment strategy was being developed, the agency’s official position was that the body of evidence submitted in an NDA could only be deemed substantial if it derived from more than one adequate and well-controlled clinical investigation. Support for that interpretation was based on the fact that the Act’s definition of substantial evidence uses the plural form of the word, ‘investigations’. (This interpretation is now arguable, however, under the Food & Drug Administration Modernization Act of 1997, wherein the FD & C Act’s definition of substantial evidence was

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revised, authorizing the agency to conclude, presumably with plausible scientific justification, that there is substantial evidence when there is but a single positive trial, provided that there is some other source of ‘confirmatory evidence’ available. Unfortunately, the revised definition fails to provide any hint as to what that confirmatory evidence might be.) The Act remains silent on what the evidence adduced in clinical trials must demonstrate in regard to the strength and qualities of the effects induced by a drug. The Act does not set a minimum size of effect below which an effect would be considered so trivial as to render a drug product ineffective in use. Neither does the Act require that a drug deemed to be effective in use should exert its effect in some minimum proportion of those to whom it is administered. The Act makes no demand as to how long the effect of a drug declared effective in use must last, nor does it speak to the importance of the effect. The Act is seemingly indifferent as to whether a drug declared effective in use provides a symptomatic or disease-modifying benefit. The Act does assert that for evidence to be deemed substantial it must be such that it would allow ‘… experts qualified by scientific training and experience to evaluate the effectiveness of the drug involved’, to conclude, ‘… fairly and responsibly that the drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the labeling or proposed labeling thereof.’ Importantly, the probative weight of evidence deemed to be ‘substantial’ need not be so great that it will persuade all, or even a majority of, experts of a drug’s effectiveness in use. On the contrary, the term ‘substantial’ identifies evidence that is only of sufficient weight to persuade a substantive proportion, but not necessarily a preponderance, of experts that a drug will be effective in use as claimed by its sponsor. Finally, the Act requires that the claims made on behalf of a drug in its approved product labeling not be false or misleading in any particular. This requirement must always be considered when extrapolating from experimental findings to effectiveness claims.

Regulations and guidelines The wording of the Act’s effectiveness standard allows the agency considerable flexibility in its interpretation. Although this is presumably the result that Congress intended, the flexibility is not entirely an unmixed blessing. In a pluralistic society comprising a diversity of groups and institutions with divergent, often conflicting, interests, what is deemed an act of enlightened regulatory discretion by one constituency can be viewed as an arbitrary and capricious enforcement action by another. Accordingly, like other federal regulatory agencies, the FDA is obliged to develop and promulgate regulations that explain in detail how it intends to interpret and enforce the Act’s provisions. These regulations are developed through a procedure known as ‘notice and comment rulemaking’; the procedure is intended to provide parties subject to the provisions of a federal law with an opportunity to influence the nature and content of an agency’s regulations before they are officially promulgated. Presumably, the availability of regulations produced in this manner reduces the risk that the courts will overturn an agency’s decisions on the grounds that they are inconsistent with the requirements of law, arbitrary, or capricious. The FDA, for example, promulgates regulations that explain how the agency interprets the Act’s provisions. Regulations that address the clinical testing of unapproved investigational new drugs appear in the Code of Federal Regulations at 21 CFR 312. Regulations appearing at 21 CFR 314 describe the nature and extent of evidential support required to gain approval of a NDA. These regulations, however, deal primarily with generic issues affecting all classes of drug products. Accordingly, since the middle of the 1970s, the agency has supplemented its IND and NDA regulations with a number of therapeutic area-specific product guidelines. These typically identify strategies and methods that have been used successfully by sponsors in a given therapeutic area to secure NDA approvals. Ordinarily, therefore, drug development guidelines are made available for therapeutic areas in which there is a de facto consensus among experts concerning what constitutes

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probative evidence of effectiveness for a member of the therapeutic class (e.g. guidance exists that speaks to the development of analgesics, anxiolytics, antidepressants, etc.).

The decision to develop antidementia guidelines Historical background During the middle to late 1970s, when the initial series of drug development guidelines were being issued by the agency, interest in the development of a rational pharmacological treatment of Alzheimer’s disease (AD) was confined largely to a few academic investigators. Although scientists working in the regulated industry were certainly aware that brain cholinergic activity was diminished in AD, commercial interest in cholinomimetic strategies for its treatment, if it existed at all, was limited, perhaps in part because AD was not yet widely perceived as a major public health burden. Moreover, even if there had been intense interest on the part of industry, in the absence of an already marketed antidementia treatment, there would have been little in the way of specific practical advice for the agency to offer. The question of what effects or actions would entitle a drug product to an antidementia claim had yet to be considered, let alone subjected to systematic public vetting. Among the many products that had once been marketed for uses and claims related to senility, only Hydergine had survived the Drug Efficacy Study Implementation review project and it had not been awarded a antidementia claim. (The Drug Efficacy Study Implementation review evaluated the effectiveness of products that had been approved between 1938 and 1962. During that period, the Act required only that marketed drugs be ‘safe for use’.) In the early 1980s, however, interest in finding effective means to care for the growing numbers of impaired and dependent elderly individuals began to expand. In 1981, anticipating an imminent need for regulatory standards for the assessment of products that would be advanced as treatments for the impaired elderly, the author organized, under the

auspices of the FDA’s Psychopharmacologic Drug Product’s Advisory Committee, a symposium to consider the matter (Leber 1981). Experts from the fields of clinical pharmacology, gerontology, psychology, psychiatry and neurology were asked to consider what might serve as appropriate outcome assessments for the evaluation of treatments intended for use in the management of the ‘cognitively and emotionally impaired elderly’. Although informative about efforts then ongoing in the field to develop appropriate measures, the symposium served primarily to confirm that a consensus on these matters lay beyond reach. Accordingly, a decision was taken to abandon efforts to develop formal guidance until the field had matured further. At the time (i.e. 1981), the decision to demur evoked neither substantive comment nor complaint.

A sea change occurs In October of 1986, an article appeared in the New England Journal of Medicine (Summers et al. 1986) that purported (Division of Neuropharmacological Drug Products 1991) to describe the results of a cross-over study of 17 demented patients in which nearly miraculous improvements in cognitive performance were brought about by tacrine, a cholinesterase inhibitor. Amidst the sanguine publicity that followed in the wake of the report, the facts that tacrine was a member of drug class (the acridines) long known to be toxic and that it had undergone no systematic assessment for toxicity went essentially ignored. Advocates and proponents of tacrine, and there were many, wanted the drug made available to all who desired it, immediately and without restrictions. Critics of drug regulation were quick to use the occasion for political advantage, arguing that the restrictions being imposed on access to tacrine were a quintessential example of how the FDA’s regulation of the drug supply did more harm than good. The adverse publicity was accompanied by demands for FDA to mend its ways and expedite, rather than thwart, as its critics contended it did, the development of antidementia treatments. Spokespersons for the pharmaceutical industry, ‘embarrassed’ perhaps by the ‘fact’ that the first effective treatment for dementia had been devel-

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oped by an academic team and not an ethical pharmaceutical house, implied that the lack of agency guidance on antidementia drug development had substantively contributed to industry’s previous lack of interest in antidementia treatments. The already inhospitable environment for new drug development created by the FD & C Act, they argued, was rendered even more unattractive and off-putting by the lack of official agency guidance. It was just too great a financial risk for a pharmaceutical firm to undertake the development of a treatment for AD, an uncertain venture under any circumstance, if a firm’s decision-makers could not know in advance just what the agency’s review staff would and would not accept as probative evidence of an antidementia effect. It was in the face of this tide of anti-regulatory, anti-FDA rhetoric that Frank Young, then Commissioner of Food and Drug, instructed the author, then the Director of the Division of Neuropharmacological Drug Products (DNDP), the agency review division responsible for the evaluation of central nervous system (CNS) drugs, to draft, with the advice and counsel of appropriately qualified non-agency experts, a guidance document that would provide the regulated industry with a clear understanding of the criteria the agency would use to assess the effectiveness of antidementia drug products.

The guidelines development effort First considerations When the intended effect of a new drug is the prevention, the delay of onset, or the cure of a condition, the comparative incidence of new cases or full recoveries obtained under treatment and non-treatment conditions can serve as an unchallengeable measure of the drug’s effectiveness. Admittedly, even in these seemingly unambiguous circumstances, disputes can arise if there are disagreements concerning the rules and means used to define and identify a new case or a recovered patient. In contrast, when a drug is expected to affect only some of the clinical manifestations of a disease, and then only irregularly and to a modest

degree, the question of what should serve as a measure of its efficacy turns almost entirely on personal sentiment and belief. That the effort to develop guidance for the assessment of antidementia drug assessment would prove to be a loadstone for criticism therefore should hardly have been unexpected.

Scope of the guidance In 1988, the expectation was that the drug products likely to enter commercial development would for the most part, like tacrine, be cholinomimetics. Even the most enthusiastic proponents of this pharmacological treatment strategy did not expect it to have a curative or preventative effect. On the contrary, it was generally believed that if cholinomimetic therapy worked in dementia, it would be analogous to the way in which L-dopa worked in Parkinson’s disease (PD), providing a symptomatic, rather than a disease-modifying benefit. Importantly, the extent of the benefit provided to a patient by cholinomimetic treatment was expected to diminish with the passage of time as the pathological process causing the loss of cholinergic neurones was expected to continue unabated. In light of these assumptions, the guideline effort was directed exclusively at strategies for the assessment of ‘symptomatic’ antidementia treatments. Basically, the task required the resolution of two major issues: (i) determining the nature and qualities of the symptomatic effects that experts would be likely to accept as bona fide ‘antidementia’ effects; (ii) identifying the nature of the specific findings of clinical experiments that would regularly persuade experts that a drug had such symptomatic effects.

The strategy proposed Experience gained in clinical work already completed and/or ongoing with tacrine and other cholinomimetics indicated that a sizeable proportion of experts would be likely to accept as a legitimate antidementia treatment a drug that substantively improved performance in those domains of cognitive functioning compromised in AD. This perception was confirmed by the experts who participated in a

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2-day agency-sponsored symposium on the topic held in 1989 (Ad Hoc FDA Dementia Assessment Task Force 1991). The symposium also considered the nature of the specific findings that would be likely to persuade experts that a drug did indeed have a symptomatic effect of the sort just described. To rely solely on a demonstration that a drug had the ability to improve performance on some sensitive laboratory test of cognitive function, seemed ill advised, however. There is, as experienced physicians regularly appreciate, a substantive distinction between a drug with an effect and an effective drug. An assessment approach proposed initially in a grant application submitted by Kenneth L. Davis (Mount Sinai Hospital, New York), for use in a multi-clinic study of tacrine, seemed tailor-made for the intended purpose. The fact that the approach had subsequently been adopted, without substantive modification, for use in the National Institutes of Ageing Warner–Lambert Consortium study (Davis et al. 1992) of tacrine, made it especially attractive, because it signaled the acceptability of the strategy not only to the academic investigators involved, and the FDA review staff who had ‘signed off’ on the protocol, but also to the industry. The consortium protocol identified the Clinician’s Global Impression (CGI) and the cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-Cog) (Rosen et al. 1984) as its two co-equal primary outcomes. Under the consortium protocol, a statistically significant difference favouring tacrine on both measures would be required for the study to be declared unambiguously positive. Although the experts attending the 1989 symposium readily endorsed the adoption of a dual-outcome assessment strategy, comprising of a clinician’s global and a multi-item test of cognitive performance, they demurred when asked to identify the specific test of cognitive performance to be employed. No objection was raised to the use of the ADAS-Cog, but, given the number and pace of ongoing developments in the field, the panel sought to avoid premature closure on the matter. It was not until November 1990, however, that clearance was given by agency officials for the circulation for comment of the guideline document that had been drafted by the author (Leber 1990).

The sections of that document explicating the dual assessment strategy are reproduced below: To gain an antidementia indication for a product, a sponsor must provide substantial evidence that the product (1) has a clinically meaningful effect and (2) exerts its effect on the ‘core’ manifestations of dementia. This compound requirement can be met by showing, in more than one adequate and well controlled clinical investigation, that the drug product is superior to an appropriate control treatment on both (1) a global assessment performed by a skilled clinician and (2) a performance based, objective test instrument providing a comprehensive assessment of cognitive functions. The global assessment ensures that the effects detected are clinically meaningful; the performance based assessment instrument ensures that the effect of the drug is upon the ‘core’ phenomena of dementia. Why a dual approach seemed especially important to adopt was explained as follows: A compound requirement for establishing an antidementia claim is considered necessary to (1) preclude the approval of drug products that produce no clinically meaningful effects on the overall status (e.g. health, function, etc.) of demented patients, but do, because of their pharmacologic activity, cause detectable changes in patient performance on objective tests that are of uncertain clinical relevance, and (2) preclude the award of ‘antidementia’ indications to drug products that exert a beneficial, but non-specific and/or pseudospecific effect on the overall clinical state of individuals who happen to be demented (e.g. effects on sleep, appetite, etc.).

Pseudospecific antidementia claims The immediately preceding quotation makes reference to the ‘pseudospecific’ effects of a drug. The word will not be found in standard English. ‘Pseudospecificity’ is a term that was coined by the author to identify a highly arguable inference often advanced by sponsors seeking to gain approval for labeling or identifying their product as a specific treatment of some disease or condition.

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In having successfully demonstrated that a drug has some therapeutic effect in a sample of patients suffering from a particular disease, the sponsor asserts (or implies) that the product is a specific treatment for that disease. Whether or not such an inference can be supported, however, is arguable. In instances where the signs and/or symptoms affected by a drug are unique to a disease, the claim seems reasonable enough. If a drug has an effect upon a sign or symptom that is not uniquely associated with the disease, however, the expression of the drug’s effect may have nothing whatsoever to do with the diagnosis given to the subjects who participated in that study. To give a hypothetical example, consider a sample of demented patients with pulmonary infections who are randomly assigned to treatment with penicillin or placebo. A finding that penicillin is more effective than placebo in this study in no way establishes that penicillin is a treatment for dementia, although it is evidence of penicillin’s effectiveness against pulmonary infections. Admittedly, the study is informative in that it documents that the presence of dementia does not interfere with an already established action of penicillin, but that is usually not the claim the sponsor is seeking to establish.

Vetting of the proposed approach Events confounding the guideline development effort The draft guidelines were circulated for comment at a politically trying time for the FDA. As noted earlier, the agency was under attack on a number of fronts by a host of anti-regulatory constituencies. A common theme of these canards was that not only was drug regulation a basically bad idea, but also that the FDA’s implementation of its regulatory mandate was incompetent and misguided. Critics offered the example of the National Institutes of Ageing/Warner–Lambert consortium investigation (Davis et al. 1992) that seemingly had been planned in full cooperation with the FDA. The study had been undertaken in the late summer of 1987 in the expectation that it would quickly adduce independent substantiation of the efficacy

of tacrine, while simultaneously providing information on the drug’s tolerability and common sideeffect profile. Unfortunately, shortly after the study’s initiation, a substantive proportion of patients who had been exposed to 120 mg and 160 mg daily doses of tacrine, developed clinically significant hepatic serum transaminase elevations. The finding was not only clinically disconcerting, but also unexpected, because the Summers et al. (1996) publication had not reported hepatoxicity developing among patients exposed to identical doses. In any event, because of the signal of hepatotoxicity, the trial was terminated. The delay necessitated by the steps that had to be taken before a revised trial could be responsibly initiated, evoked a further deluge of criticism. That the laboratory surveillance methods used in the trial, at FDA’s insistence, to detect just such an unexpected risk, had worked as intended was ignored. Presumably, in light of the great promise of tacrine, a non-risk-averse regulatory agency truly concerned with the suffering of patients and their families would have pressed ahead with clinical testing, the high incidence of clinically significant serum hepatic transaminase elevations notwithstanding. Because the incidence of clinically significant transaminase elevations was seemingly dose-related, the redesigned Consortium study only evaluated doses of tacrine that were approximately half (40 and 80 mg) those which Summers et al. (1996) had reported that patients could tolerate without risk. When the redesigned study was finally completed, it failed to document tacrine’s efficacy-by-test of its protocol-defined outcome criteria. Although the tacrine–placebo difference on the ADAS-Cog component was statistically significant, the tacrine– placebo difference on the CGI was not. In March 1991, the agency’s Peripheral and Central Nervous Systems Advisory Committee met to consider whether the evidence adduced was sufficient to allow the approval of tacrine. The Committee found that it was not. This recommendation only further intensified criticism of the agency. Given the numbers of patients suffering from AD and the great promise of tacrine, the agency’s critics could not fathom why the Committee was unwilling to set aside scientific principles and recommend

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approval of the drug. The Committee’s decision also created disquiet and discord within the agency.

Sources of dissatisfaction with the proposed guidelines Political and regulatory concerns The fractious political milieu heightened concerns among many of the agency’s politically appointed managers that the criteria that had been advanced in the draft guidelines presented an insurmountable hurdle for the generation of putative antidementia drugs then in development. Accordingly, these managers contended, the continuing endorsement of a dual-outcome assessment by the agency’s scientific and medical reviewers would serve only to court political disaster. The Commissioner’s instruction to produce guidelines had been intended to facilitate the development and marketing of antidementia drug products, not to create an insurmountable barrier to their approval. It was not as though tacrine was entirely devoid of a pharmacological effect, even when used at ‘subtherapeutic’ doses of 40 and 80 mg/day. Of even greater importance, a number of experts opined openly that the statistically significant findings on the ADAS-Cog alone were sufficient to convince them, the protocol-specified dualoutcome assessment criteria of Study 970-1 notwithstanding, that tacrine was effective in use as an antidementia drug product. A colorable argument could be made, therefore, that the evidence adduced in controlled trials of tacrine submitted to Warner– Lambert’s NDA, met the ‘substantial evidence’ standard. Those involved in the guideline development effort were therefore pressed vigorously to revise their proposal. If substantial numbers of experts were willing to conclude that a statistically significant difference on the ADAS-Cog alone was sufficient to support an ‘antidementia’ claim, why weren’t those responsible for drafting the guidelines on behalf of the agency willing to go along with it? Did not the advocates of the dual-outcome assessment strategy recognize the anguish and suffering of patients with AD and their families and their right to have access to a treatment that

not only they, but also experts considered effective? Why did the development team’s members not have more sympathy for the plight of physicians caring for these patients? To be fair, complaints about the dual assessment policy were not all politically motivated nor were they all advanced in an unctuous, self-serving or moralistic manner.

Concerns about the global component of the dual assessment strategy A substantial proportion of complaints from academic physicians and representatives of the regulated industry about the guideline proposal were not so much directed at the use of a dualoutcome strategy, but at the limitations of its global component. Is a ‘global’ assessment insensitive to small, but still clinically important, effects? It was widely anticipated on theoretical, but nevertheless reasonably sound, psychometric grounds that a clinician’s definition of ‘global’, and in particular one based on clinical observations made during an interview, would be less sensitive to the effects of a cognitive-enhancing drug than a multiitem performance test like the ADAS-Cog. Some critics, accordingly, could not reconcile the use of the global component with their perception that statisticians regularly endorse the use of the most efficient method available to test a null hypothesis. The rule applies, however, only if the methods under consideration are intended to measure the same attribute and are of equivalent validity for the proposed use. Given the divergent purposes that the ADAS-Cog and the global components were intended to serve in the dual assessment strategy, the author found criticisms directed at the relative inefficiency of the global component to be misplaced. Is a clinician’s global assessment intrinsically unreliable? Unstructured global assessments, even those offered by experienced clinicians, will tend to fare poorly

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when evaluated by criteria ordinarily used to measure the psychometric performance of multi-item rating scales. This ‘limitation’ led some scientists and clinical trialists to argue that the decision to use the global as one component of the dual assessment strategy was ill-advised. Once again, the author finds this objection misplaced. The global component of the dual-outcome assessment strategy was not employed to ensure that assessors would consistently and repeatedly evaluate the same facets of cognition in every subject on every occasion of use; that role was given to a multi-item performance test of cognition such as the ADAS-Cog. On the contrary, the global was intended to generate a holistic assessment of a patient’s overall state of well-being. The belief was that only such an assessment could determine, albeit in an unspecified way, whether the changes wrought by a treatment were of clinically substantive importance. Moreover, the relative psychometric unreliability of a global assessment operates in a conservative way. In general, ‘misclassifications tend towards the null’. Accordingly, the very fact that a drug’s effects were detected by a clinician’s global would speak, as it was intended to, the magnitude of the drug’s clinical effect. Are there unwanted, but controllable, sources of variability in the implementation of the global assessment? Notwithstanding the trouble Warner–Lambert was experiencing in securing an approval for its NDA for tacrine, by 1991 commercial interest in the development of antidementia treatments had grown to the point where perhaps a dozen or more candidate drugs were under active investigation for this indication. When sponsors of these products sought advice concerning their development efforts, they were regularly advised by DNDP staff to employ the assessment procedures outlined in the November 1990 draft guidelines. DNDP staff were therefore somewhat chagrined to discover that implementations of the global assessment varied considerably among sponsors. These differences did not necessarily threaten the internal validity of any between-treatment com-

parison made within a given clinical trial, but they did confound attempts to estimate the size of the clinical effect being produced. Of particular concern was the fact that some sponsors had instructed clinicians tasked to perform the global assessment, to carry out a structured Mini Mental Status Examination (MMSE) during the course of their interviews. While this maneuver had not been explicitly proscribed in the draft guidelines, the use of a structured MMSE, especially one expected to generate a score that correlated highly with a patient’s ADASCog score, undermined the validity of the clinician’s global assessment for the use intended by the guidelines. In response to this discovery, the DNDP advised sponsors, in a letter issued in November 1991, of its concern about the methods being used to collect information to inform global assessments. In its letter, the Division described how it expected a bona fide global assessment to be implemented. Toward this end, the Division defined the clinician’s interview based impression of change (CIBIC). The CIBIC was FDA’s variant of a clinician’s global assessment implementation (CIBI) that had received agency endorsement for use by Warner–Lambert in a placebo-controlled, 6-month long, parallel multi-arm design study of tacrine’s effects at doses as high as 160 mg/day (Knapp et al. 1994). The CIBIC was to be scored on the basis of information collected solely from the patient during a face-to-face interview; the only other information that could be made available to the assessor were the findings of tests performed prior to the baseline interview and information garnered during that interview. The letter also advised sponsors to keep records documenting how the data that served as the basis for their global assessments had actually been collected (e.g. holistic vs. structured). Sponsors were advised that a global score assigned on the basis of a structured MMSE would almost certainly be discounted and might even lead the Division to conclude that the entire assessment procedure was invalid. Sponsors were also cautioned that a global assessment developed on the basis of information obtained from family and care givers, as well as the patient, would not be given the same weight as a

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CIBIC. The Division identified such global assessments as comprehensive clinical methods of drawing attention to the multiple sources of information upon which they were based. The Division’s letter was not well received by industry and drew numerous complaints. A second formal vetting Those charged with developing the agency guidelines, notwithstanding the criticisms of the approach they advocated, remained persuaded that those within the community of experts who understood its intent, would continue to endorse the use of a dual-outcome assessment strategy. In the hope that some degree of closure could be reached in a public forum, a second special meeting of the agency’s Peripheral and Central Nervous Systems Advisory Committee was held in 1992. Once again, the dual assessment strategy was endorsed, but with two important revisions, both involving the global assessment. One change involved the implementation of the global, the second identified an alternative that could serve in its stead. Revised specifications for the implementation of the global assessment First, the conditions under which the data for a global clinical assessment were to be collected at interview were modified. Specifically, there was agreement that the interview upon which a clinician’s global assessment would be based could be conducted under less stringent conditions than those identified for the CIBIC. This alternative implementation became known as the CIBIC-PLUS. It was identical to the CIBIC in all respects except for the fact that it could be scored on information derived at interview not only from the patient, but also from relatives and care givers. Importantly, results obtained from formal psychometric tests were not to be made available to the clinician making either a CIBIC or a CIBICPLUS assessment.

A valid activities of daily living instrument to replace a global assessment The committee acknowledged that it was not the clinician’s global assessment, per se, but the use it served that was critical to the valid operation of the dual assessment strategy. As noted previously, the global assessment was intended to serve as an indicator, a surrogate so to speak, of the clinical impact of the changes in cognitive performance being detected by a multi-item test such as the ADAS-Cog. If an instrument other than the global assessment could serve that purpose as validly, it could be substituted for the CIBIC or CIBIC-PLUS. The Committee agreed, in particular, that a valid activities of daily living (ADL) instrument could serve as a tangible alternative to the CIBIC/CIBICPLUS, and therefore endorsed a dual assessment strategy employing a multi-item performance test and the ADL assessment as an acceptable variant of the dual assessment strategy. Official agency endorsement In 1993, the Peripheral and Central Nervous Systems Advisory Committee recommended that tacrine be approved for use for the management of patients with dementia. The basis for its recommendation was the finding that, in more than one adequate and well-controlled trial, patients randomized to tacrine were found by test of both a clinician’s global assessment (CIBI) and a multiitem test of cognitive performance (ADAS-Cog) to differ, at a statistically significant level, from those randomized to placebo. In light of the Committee’s action, there was no longer any urgency attached to the promulgation of guidelines. The agency’s approval of tacrine sufficed to make clear precisely what the agency would be willing to accept as ‘substantial’ evidence of a symptomatic antidementia product’s effectiveness in use.

Looking backwards At the writing of this chapter, some years after the report by Summers et al. (1986) appeared in the New England Journal of Medicine, the dual-

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outcome assessment strategy seems well established as the agency’s ordinary test of effectiveness for a symptomatic antidementia treatment. It is far from certain, however, that the strategy provides every protection that it was intended to offer, in part, because there has been no practical way to ensure that its global component has been implemented in the way those who drafted the policy intended. Contemporary (c. 1999) trials of symptomatic antidementia products tend to be considerably longer than those undertaken a decade ago. The active comparison phase of the original consortium study, for example, lasted but 6 weeks; today, a typical study lasts for a year or longer, notwithstanding the Peripheral and Central Nervous System Advisory Committee’s acknowledgement in 1992 that a study of but 3 months duration would suffice. Evolving views about the length of time that a patient may be reasonably assigned to a placebo control, however, may reverse the trend; evidently, it is becoming increasingly difficult to recruit patients willing to run the risk of being randomized to placebo for a full year or longer. Another impediment to conducting long trials is the risk that an excessive number of randomized patients will fail to complete the study as planned. The problem of censoring is not unique to studies of antidementia treatments, of course. The issue, nonetheless, is an important one because it can render the estimate of treatment effect adduced in a clinical trial unreliable.

Looking to the future New therapeutic goals In recent years, the scope of commercial interest in AD treatments has expanded. Interest in symptomatic cholinomimetic treatments for AD persists, but is much diminished. In addition to tacrine three other cholinesterase inhibitors, donepezil, rivastigmine and galantamine have been marketed in the USA as symptomatic treatments for dementia.

The control of untoward behaviors One area of interest involves symptomatic treatments for the non-cognitive aspects of dementia, in

particular, the management of disruptive behaviors that can make it difficult to care for and live with a patient with dementia. Products intended for such uses were not considered in the agency’s 1990 draft guidance document. As valuable as effective treatments for such untoward behaviors may be, their assessment is confounded by the fact that the goal of treatment is the suppression of behaviors that others, and critically, not necessarily the patient, find objectionable (e.g. purposeless activities, seemingly aimless wandering, particularly at night, screaming, etc). Moreover, if a treatment being evaluated for the control of a behavior is already marketed for some closely related use in another condition (e.g. an anti-psychotic), the problem of ‘pseudospecificity’, discussed earlier, adds yet another complication to the regulatory assessment of their claimed effect.

Disease-modifying treatments The other major area of emerging interest is in antidementia treatments that are disease-modifying. These would include treatments that can either delay the onset or slow the progression of dementia, be it AD or any other kind of progressive dementing disorder (e.g. Lewy body dementia, vascular dementia, Pick’s disease, etc.). The agency has yet to make an official pronouncement concerning how it will determine whether or not a treatment is entitled to a disease-modifying claim. During his tenure as Director of Division of Neuropharmacological Drug Products, this author (who resigned from the position in January 1999), regularly espoused the view that it would be impossible to determine in advance precisely what would or would not convince experts that a drug product had such an effect. This author has provided an extensive description of two experimental designs (randomized withdrawal and randomized start) that are capable of adducing what he believes would be compelling and persuasive evidence (Leber 1997) of a disease-modifying effect. Of the two strategies identified, this author believes the ‘randomized start’ to be superior. The use of biomarkers such as measurement of rates of cerebral atrophy or concentrations of amyloid protein species in body fluids as an outcome

386 CHAPTER IV.5

Table IV.5.1 Guidelines on approval of antidementia drugs by regulatory authorities. All regulatory authorities require

evidence of quality, safety and efficacy based on laboratory, animal and human toxicology, and phase I, II and III human studies. Quality of life or economic evaluations are not currently required by any regulatory authority. EMEA, Europe (1997, www.eudra.org) Based on the guidelines formulated by the FDA May be applicable to dementias other than AD Diagnosis, grading of severity and patient selection for trials discussed • Diagnosis of dementia based on DSM or ICD. NINCDS/ADRDA criteria of probable AD considered most appropriate for testing drugs Efficacy assessment • Concentrate on symptomatic improvement • Cognitive, functional and global endpoints are key • Statistically significant differences in two primary variables, one of which must be cognitive, followed by analysis of proportion who achieve a meaningful benefit • For a claim in behavioral symptoms, a specific trial required with this as the primary endpoint • In advanced disease, robust differences in functional and global endpoints (without cognition) may be sufficient Design issues • Six months duration for efficacy • One year for maintenance of efficacy • Twelve month open label for long-term safety, with at least 100 good-quality cases • Appropriate follow-up to detect withdrawal phenomena (at least 2 months, mentioned in previous draft) • Instruments not specified, though required to be valid and reliable FDA, USA (Leber 1990; www.fda.gov) Advice provided in planning, design, conduct and interpretation of antidementia trials with Investigational New Drug application Broadly similar to the EMEA guidelines Efficacy • Statistically significant differences in two primary variables, one of which must be cognitive, and the other a global assessment • Global measure chosen is a clinical interview-based impression of change • Cognitive instrument not specified, though the ADAS-Cog is most commonly used Design issues • Three months duration is sufficient • Minimum of 1000 patients exposed for several weeks to relevant dose range • Minimum of 300 patients exposed to doses above the median for 6 months to a year • Maintenance of efficacy in chronic use or withdrawal, encouraged but, not essential Japan (Sawada 1995; www.harmonization.org) (New guidelines in preparation [1999] ) Existing guidelines refer to ‘cerebral circulation’ and ‘metabolism improvers’ Approval of a new agent based on similar or better performance compared to the ‘standard’ drug in current use Efficacy assessments • Key outcomes are improvement rates, safety and ‘usefulness’ • Improvement rates measured on 5–7 point scale in terms of general physical findings, subjective symptoms, psychiatric signs (behavioral abnormalities, mood changes, cognition and memory), neurological signs and activities of daily life • Assessment instruments not specified Comment: These guidelines are not helpful for the assessment of antidementia drugs

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measure, is likely to be helpful in discerning an effect of a disease-modifying treatment.

Approaches taken by other drug regulatory authorities This author is aware of but one set of guidelines that have been officially promulgated by a regulatory authority that speak to the development of antidementia drug products. These may be found on the website of the European Agency for the Evaluation of Medicinal Products as ‘Note for Guidance on Medical Products in the Treatment of Alzheimer’s Disease’ (Committee for Proprietary Medicinal Products 1997). See Table IV.5.1 for a summary of the guidelines from the EMEA, FDA and the Japanese regulatory authorities. Although the advice offered is less detailed than that provided in the 1990 agency draft, it covers a wider number of topics. On the issues addressed by both guidances, the European recommendations do not appear to differ substantively from those advanced by the FDA.

Conclusions The strategies and standards used by a drug regulatory agency to determine whether or not a drug product works as it is claimed to work, are shaped not only by scientific principles and ethical medical concerns, but by the anxieties of the body politic,

IV.5.2

the media, private financial interests, pedestrian politics and personal sentiment. If there is a lesson to be learned from the FDA’s attempt to develop antidementia drug guidance, it is that there is no such thing as a truly objective and disinterested test of anything as inchoate as a symptomatic treatment for dementia, especially one that exerts neither dramatic nor enduring effects. On a more sanguine note, if a treatment eventually does become available that significantly delays the onset and/or slows the progression of dementia, there will little need to argue about the choice of outcome variable employed in its assessment. To be clear, the product’s efficacy will still have to be documented in appropriately blinded and controlled clinical trials, but the question as to whether or not the drug works as claimed can be decided, as noted earlier, from a comparison of the numbers saved under treatment and control conditions. Admittedly, gathering the evidence may prove difficult and quite costly. Indeed, the effect of a disease-modifying drug may not become obvious until large cohorts of individuals have been followed under treatment for several years, perhaps decades. The impact of censoring will have to be considered, but the fundamental question of whether or not the evidence shows that the drug is as effective as claimed will involve few, if any, of the value judgements that complicate the assessment of symptomatic antidementia treatments.

Criteria Used By Purchasers of Healthcare Services

David Millson, David Jolley and Harry Ward Introduction The decision to endorse the purchase of a new treatment for a chronic condition such as Alzheimer’s disease (AD) must be made within a complex framework. This framework takes into account societal views on ethical and healthcare policy, disease prevalence and diagnostic accuracy, robustness of the clinical evidence supporting efficacy, likely value for money offered by the treatment and

the ability of the health service to deliver treatment to those individuals most likely to benefit (Callahan 1991; Holmes et al. 1998; Melzer 1998, Walley 1998; Benbow et al. 1999; Kavanagh & Knapp 1999; Rawlins 1999). Whitehouse et al. (1998) describe a consensus reached at the first pharmaco-economic conference on AD summarized the issues facing purchasers of antidementia drugs as follows: 1 validity of the scales used for testing interventions;

388 CHAPTER IV.5

AD2000 trial schema 3000 patients 1

12 weeks placebo

2 12 weeks donepezil (5 mg) 1500

(a) 12 weeks donepezil (5 mg)

(b) 12 weeks placebo

750

1500 (c) 12 weeks placebo

750

36 weeks donepezil (5 mg/10 mg)

(d) 12 weeks donepezil (5 mg/10 mg)

750

36 weeks placebo

750

36 weeks donepezil (5 mg/10 mg)

2 definition of clinical outcome; 3 relationship between surrogate and clinical outcomes; 4 impact of treatment on patient and care giver; 5 accuracy of the estimate of clinical benefit; 6 system used to value the outcome; 7 purchasers’ willingness to pay; and 8 conflict between the regulatory approach and the purchasers’ need for information. This chapter will take this approach to examine the decision to purchase new symptomatic treatments for AD in the UK from societal, medical, and patient perspectives. Tensions will be highlighted between an evidence-based medicine (EBM) perspective of cost-effective and equitable treatment access at a population level (represented by the authors, Millson and Ward) vs. the desire to maximise and individualize patient care in a costconstrained healthcare system such as the National Health Service (NHS) (based on the experience of the author, Jolley). These different perspectives are not unique to the UK and will no doubt strike a chord with health care providers and clinicians across Europe, USA and the rest of the world. A number of models will be considered. 1 Restriction of use through further evaluation The first (AD2000) was a randomized placebo controlled trial in AD patients designed to offer equity of access to drug treatment with donepezil, across the West Midlands Region (and extended to centers across the UK). The trial was also designed ‘to

Fig. IV.5.1 Trial schema reproduced from the AD2000 investigators brochure.

produce reliable evidence on the value of donepezil in routine practice’ (Fig. IV.5.1). 2 Regional prescribing committees The second, MTRAC (Midlands Therapeutics Regional Advisory Committee), is a regional Primary Care Therapeutics Advisory Committee with a remit of advising general practitioners on the appropriateness of prescribing and encouraging evidencebased prescribing of drugs in primary care (MTRAC website 1999). 3 Individualized drug treatments for AD via a specialist memory clinic, with the psycho-geriatricians as the gatekeeper to new drugs therapies will be discussed.

Background: the UK societal framework for the purchasing and commissioning of drug treatments for AD In 1944 the government white paper that paved the way for the formation of the NHS (1944), stated The Government … want to ensure that in future every man, woman and child can rely on getting all the advice and treatment and care which they may need in matters of personal health; that what they get shall be the best medical and other facilities available; that their getting these shall not depend on whether they can pay for them, or any other factor irrelevant to the real need.

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At a recent conference the ability of the NHS to sustain this philosophy has been questioned by a consumer organization for the elderly (Age Concern: ‘Turning Your Backs on Us’ London Conference 1999). Two issues dominated: age discrimination and resources. By 2031 the proportion of elderly people in the UK over 60 years will have risen from the current 20% to almost a third. A transnational study funded by the European Commission, reporting in 1999, projected that the number of people with dementia is set to rise from the current 3.5 million to over 6 million by 2020. They concluded that institutional care for people with dementia ‘remains an underdeveloped area of policy’ even though the illness is now the fourth largest public health problem in Europe after stroke, heart disease, and cancer. (The Quality Challenge 1999). It is widely accepted that a health service which serves an ageing population will need substantially more money than is currently available. The UK Health Secretary (April 1999) stated ‘The Government is absolutely committed to the fundamental rule that the NHS is there to provide services for everybody on the basis of clinical need. However, based on a recent survey, Age Concern has expressed concern that “older patients are often refused treatment, forced to go private, have long waits or suffer rudeness and ageism from staff” ’. These findings have been corroborated by senior academics. Bowling (1999) reports that the usage rate for potentially life-threatening and lifeenhancing treatments decline as patients get older. She argues that clinical discrimination against older people is based on ageism within society. Melzer (1998), following the launch of the new drug treatments for AD, raised a number of issues for healthcare policy requiring resolution if access to information needed for clinical and other decision making was to be improved. • Licensing trials on highly selected patients may provide insufficient information on which to base clinical decisions, especially where effect sizes are small and co-morbidity is common. • All trial evidence should be published before new drugs are marketed, and medical journals should not carry advertisements referring to unpublished data.

• Communication of benefits and risks should emphasize clinical effect sizes rather than statistical significance. • Claims about effects on populations or services should be based on evidence. • Secrecy surrounding licensing should be ended and data from trials should be available for independent analysis. • Overvaluation of new technology could threaten funding for vital but more mundane care. This article highlights the difficulties faced by commissioners of healthcare. ‘The benefits of donepezil seem to be of a different order from those implied in the promotional literature’ (Melzer 1998). Indeed, the manufacturers of donepezil (Eisai & Pfizer 1998) were found to be in breach of the UK Prescription Medicines Code of Practice in relation to widely circulated launch advertising material, which provided: (i) ‘insufficient data to support the impression given by the advertisement that memory in particular improved following treatment with Aricept’ and (ii) a claim that ‘the carer would notice an improvement in her mother’s Alzheimer’s disease because of treatment’ was not supported (PMCPA report 1998). Unhelpful leaks about donepezil before its launch unfortunately raised the hopes of patients beyond the reality of the new treatments to deliver. It was largely left to the UK Alzheimer’s Disease Society to sound a note of caution by complaining, and being more realistic, about the modest health improvement to be expected. The arrival of new treatments for AD in the UK coincided with probably the most radical changes in the history of the NHS (Millson & Chapman 1998). The launch of the white paper A First Class Service announced for the first time the introduction of an explicit and systematic healthcare policy which set out to ‘prioritize’ treatments (some might say ‘ration’), based on their relative effectiveness and ability to deliver health gain to the NHS. The Special Health Authority created to democratically undertake this rational and objective review of both new and existing NHS treatments, and effectively creating a ‘Fourth Hurdle’ for the pharmaceutical industry, was launched in 1999 as the National Institute for Clinical Excellence (NICE).

390 CHAPTER IV.5

The UK Government position: command and control of prescribing via NICE Rawlins, Chairman of NICE (1999) described the tensions faced by health professionals in trying to practice their clinical disciplines: tensions between equity and choice; between efficiency and quality; and between demand and resource. Healthcare systems across the world have attempted various solutions. In some parts of North America Health Maintenance Organizations (HMOs) require health professionals to use mandatory care packages and even the smallest deviation has to be confirmed with the relevant HMO. There have been attempts, across the world, to develop external, or in the case of the UK, internal markets. The application of such market forces to the practice of medicine is not easy; and healthcare systems relying on external markets produce benefits to some, but major public health problems for others. Professor Rawlins (NICE 1999) also commented, that he believed it to be universally accepted that health professionals, including himself, are underachieving. He considered this to be a problem not confined to the UK but one that is a global manifestation of the difficulties all clinicians face. He concluded that the results of this underachievement led to unacceptable variations in clinical practice; poor uptake of effective treatments; too great a use of inappropriate treatments; and continued use of ineffective treatments. The role of NICE is to consider new treatments offered to the NHS, such as new treatments for dementia, in terms of cost-effectiveness. This will require looking at the direct and indirect costs and savings to the health service in comparison with other similar technologies, and in the wider interests of the NHS as a whole. Furthermore, where it is relevant and where there is adequate information, NICE will be looking at wider societal costs. NICE builds on the UK National Health Technology Assessment program, However, there have also been regional and district technology assessment programs which have resulted in disparate views about ‘evidence’, its nature, and its health significance. As a consequence the UK has witnessed

what has become known as ‘postcode prescribing’. Benbow et al. (1999) highlighted ‘rationing on a massive scale’ for donepezil, the first of a new generation of rational treatments for AD. A national survey of old-age psychiatrists showed patchy and generally low prescribing of donepezil, with the drug being freely available in some health authorities and totally unavailable in others. Such differentials in the provision of healthcare have appalled health professionals who are expected to apply them, and are bitterly resented by patients and their families. The authors called for an urgent ethical review of the current commissioning of treatments for AD. NICE is determined to completely rule out postcode prescribing for treatments that it has evaluated (Drug Utilization Conference London, Dec 1999). It is the job of NICE to contribute to the management of the NHS by providing a rationale for the use of its resources. In the areas that NICE will be called to evaluate products and therapies, its task will be to consider them against the background of providing the greatest good for the greatest number; and evaluating their worth in the whole context of health, health gain and a return to fitness. By making national recommendations about the use of products NICE expects to be able to play a part in getting patients their best value for money. NICE cannot make more money available, but can be expected to make the best use of money and resources available. If NICE does come across an innovation that has demonstrable benefits but will cost more money, then NICE will say so. NICE will look to the sponsors of the technology to demonstrate to NICE and the NHS how paying more results in a greater overall benefit. NICE hopes to be able to avoid the everyday dilemma facing NHS clinicians and managers ‘which of your 10 existing products shall I stop buying to make room for the 11th?’ The role that pharmaceutical companies and other healthcare industries have made to the health of the nation is immense. It is a challenge for the Institute to find ways for them to continue and extend their contribution for us all to benefit (www.nice.org.uk).

EVIDENCE THAT TREATMENT WORKS 391

What criteria will NICE use? Technologies will be selected for appraisal based on one or more of the following criteria: 1 Is the technology likely to result in a significant health benefit, taken across the NHS as a whole, if given to all patients for whom it is indicated? 2 Is the technology likely to result in a significant impact on other health-related government policies (e.g. reduction in health inequalities)? 3 Is the technology likely to have a significant impact on NHS resources (financial or other) if given to all patients for whom it is indicated? 4 Is NICE likely to be able to add value by issuing national guidance? For instance, in the absence of such guidance is there likely to be significant controversy over the interpretation or significance of the available evidence on clinical and costeffectiveness? How will NICE guidance be reported? NICE will produce guidance to local health commissioners and clinicians on the appropriate use of the intervention alongside current best practice. This guidance should, among other things, cover the following aspects: • an assessment of whether or not the intervention can be recommended as clinically effective and as a cost-effective use of NHS resources for NHS use, either in general or in particular circumstances (first or second line treatment, for particular subgroups, for routine use or only in the context of targeted research, etc.); • where appropriate, any priorities for treatment; • recommendations on any questions requiring further research to inform clinical practice; and • an assessment of any wider implications for the NHS. Will NICE in effect be a national rationing council, marking the end to clinical freedom? No. NICE will examine the evidence for the benefits and costs of new treatments and will give guidance to the NHS. But it will be for individual commissioners and clinicians to decide on treatment

in individual cases. In other words if NICE considers that the new treatments for AD are not cost-effective in NHS terms then ‘postcode prescribing’ is unlikely to occur, because very few individuals in the NHS will have access to such a therapy. Conversely, if NICE endorses a particular product then individual commissioners and clinicians will be able to treat patients according to clinical need. Will NICE prevent access to effective new treatments? NICE will promote access to the most effective new treatments. NICE may, on occasion, advise that certain new treatments, although offering limited clinical benefits, would not be cost-effective: that is, that the NHS could achieve much greater health benefits by using its resources in other ways. NICE considers a major part of its role to ensure that the NHS should seek to use its resources to achieve the greatest possible health gain for patients. It is very clear that the UK Department of Health will not tolerate any dissent in the new command and central control of prescribing with the ‘Action’: the following accompanies NICE’s guidance: We expect the guidance produced by NICE to be implemented consistently across the NHS and the uptake of this guidance will be monitored locally, and by the Commission. If guidelines are not being implemented locally, the Commission will want to satisfy itself about the reasons. The recommendations of the Commission will be implemented by NHS organizations, and followed up through existing NHS performance management. The Commission for Health Improvement (CHI) is an independent body, formally established in 1999 to provide external scrutiny of the quality of clinical care provided to NHS patients. This commission will have the power to investigate and agree actions to be taken where the guidance of NICE has not been implemented. In due course ‘postcode prescribing’ might be expected to become a thing of the past in the UK. However, the number of patients seeking private treatment for conditions such as AD might be

392 CHAPTER IV.5

expected to increase if the new treatments become unavailable on the NHS: introducing a new concept ‘costcode prescribing’. There is already some evidence in those health authorities where donepezil is currently rationed, of a burgeoning increase in private prescriptions, with up to 28% of the faculty of old-age psychiatrists being aware of this practice in their area (Benbow et al. 1999). How might prescribing under conditions of limited resource be applied within an ethical framework? Tunna (1998) proposes an ethical framework to aid prescribing decisions within the context of the new Primary Care Groups (PCGs) being set up in the UK. Whilst the NHS is effectively free at the point of delivery, recently cash-limited budgets have been introduced for all primary care groups, which prescribe for between 80 000 and 120 000 patients. This places an ethical responsibility on prescribing physicians. According to Tunna (1998) ‘In exercising their autonomy, doctors are not at liberty to prescribe in ways that necessitate excessive expenditures that are expected to result in no added therapeutic benefit over and above cheaper alternatives, provided those alternatives still satisfy the criteria of clinical effectiveness and safety’. How can justice be applied to the purchasing of healthcare for patients with AD? Tunna (1998) describes patients as contributors to the healthcare budget, as taxpayers, who are entitled to expect that those responsible for the distribution of healthcare funds will do so in as fair and just a manner as possible. Distributive justice is the mechanism through which benefits (healthcare) and burdens (taxes) are distributed fairly in society. But how is the decision to be made as to who gets what when clearly not everyone’s needs, let alone wants, can be met? The ethical imperative for clinicians remains, however, in that no matter how limited the benefits or resources are, they must act in such a way as to minimize harm and maximize benefit. As Goodwin (1995) argues, equity in health care is centered upon need.

Equity is about service being needs-based. People in equal need should have equal access to services and those whose needs are greater should be targeted to receive proportionately more of whatever resources are available. So while it may seem fair and just to use need as the material principle underpinning resource distribution, the problem is only too apparent: namely, that of defining need and, further, distinguishing between needs and wants. Even when need is clearly defined and easily recognized; it still may go unmet simply because resources are insufficient to answer all needs. According to Tunna (1998), how medical practitioners should adjudicate between competing needs will depend, to a large extent, upon individual practice and patient population variables. Considerations such as urgency, severity, age, potential to benefit, and responsibility for health may have proportionate relevance in any given situation. In the rest of this chapter, David Jolley combines his perspective as a psycho-geriatrician with those of the patient and carer, to consider how individualized treatments might be achieved for patients with AD.

Access to treatments for AD from a patient’s, carer’s and clinician’s perspective in the UK For the first time, from the perspective of a clinician (after conducting controlled clinical trials to evaluate a number of ineffective treatments for AD), the new generation of acetylcholinesterase inhibitors offer some prospect of helping, with acceptable side effects, a proportion of patients with AD. The benefits are not available to all patients; some will be intolerant, others will not respond, but some will find improvements in cognition and others will not deteriorate as quickly as expected. Careful discussion and debate resulted in advice from the clinical professions that treatment with these new drugs should be initiated only after assessment by a specialist team, which should remain available to the patient and family to monitor progress, provide support and advise on continued therapy (Arie & Jolley 1999). Within this framework (Royal College of Physicians &

EVIDENCE THAT TREATMENT WORKS 393

Wide variations: HAs use of donepezil 40

35

Number of HAs

30

25

20

15

10

5

0 Fig. IV.5.2 Wide variations and ‘postcode’ prescribing of donepezil from a survey of 74% of all health authorities in the UK. Reproduced from Benbow et al. 1999 with permission. HAs, health authorities.

0

1−10

11−20 21−30 31−40 41−50 51−60 61−70 71−80 Number of patients

Key points • National ‘postcode’ prescribing of the Alzheimer’s drug donepezil • Most health authorities had 10 patients or fewer on the drug last year • The ethics of the present position should be examined by a third party

Royal College of Psychiatrists report 1998) it was expected that the clinical significance of the new drugs and their place within the spectrum of help available through services, would be evaluated. Progress in this natural sequence has been arrested. Local Health Commissioners have found themselves receiving advice from Public Health Physicians and other experts, who declare themselves unimpressed by the evidence that these new medicines are able to affect the natural history of AD in any way or the degree to which they are deemed ‘clinically significant’. In so doing, they apply different standards to those used by the regulators (FDA, MCA and EMEA). Yet their influence has been immense. Most Health Commissioners are not personally, nor corporately, equipped to evaluate research evidence. They depend upon advice: when faced with con-

flicting interpretations, they have to weigh which to value. In many instances their daily work brings them into closest contact with Directors of Public Health, whose political and clinical voice will thus prevail. Thus, the modest and responsible national protocol (agreed by experts in the mental health of the elderly) for prescribing has been followed in some, but not all localities. A patchwork or ‘postcode lottery’ pattern has emerged which reflects constraints placed upon clinicians rather than lack of enthusiasm by people at the coalface (Fig. IV.5.2). The advent of NICE should at least replace this patchwork of local assessment and recommendations, which currently occur as a result of different interpretation of ‘evidence’ and the historical variation in demands and priorities for services.

394 CHAPTER IV.5

Items/million population

Donepezil prescibing in the West Midlands and the rest of England 120 100 80 60 40 20 0 Jun 97

Sep 97

Dec 97 Mar 98 Jun 98 Sep 98 Quarters ending West Midlands

Dec 98

Rest of England

Within the West Midlands region of the UK, two inter-related initiatives have combined to restrict prescribing within the NHS even more dramatically (Fig. IV.5.3): 1 National guidance on prescribing has been refined further by MTRAC, which requires that these drugs be prescribed by a specialist only. This requirement has been clarified to mean ‘not only initial prescribing, but continuing prescriptions where the treatment is deemed to be helpful to the patient’. This currently effectively restricts the budget available for the treatment to the limited prescribing budget of the local Mental Health Trust. The imminent launch of Primary Care Trusts will assume responsibility for unified cash-limited budgets, which will include prescribing and provision of mental healthcare services. This will abolish the current distinction between primary and secondary care budgets, but will not necessarily making further funding available. 2 All health authorities within the Midlands Region were persuaded to sponsor an independent double-blind trial (AD2000) to determine the clinical efficacy of the new treatments. NHS patients whose consultant felt they might benefit from treatment would be offered the opportunity to enter this trial. The design of this trial (AD2000; Fig. IV.5.1), the manner in which it has been conceived and progressed, and the ethical considerations behind it have caused much concern (see Table IV.5.2; summarizing the perceived pros and cons of AD2000 trial). From the perspective of a clinician with respons-

Mar 99

Fig. IV.5.3 PACT data showing the impact of the AD2000 trial and MTRAC on primary care prescribing of donepezil in the West Midlands compared with the rest of the UK.

ibility for the care of the elderly with mental illness both these devices seem designed to deny patients, families and clinicians access to treatment within the NHS. A clinician carries responsibility to prescribe treatment, which she/he believes will be to the benefit of that patient as an individual (SMAC guidelines 1998). Health authorities should not prevent the clinician from honoring that responsibility. But the present scenario suggests that NHS mandarins deem senior clinicians unfit to make prudent decisions on treatments for their patients and have contrived a framework, which controls their prescribing hand. The decision by some health authorities to restrict access to expensive new treatments on financial grounds (e.g. interferons for the treatment of Multiple Sclerosis [MS]) has been the subject of a legal challenge and a judicial review in the North of the UK (North Derbyshire Health Authority 1997), which ruled in favor of providing treatment based on clinical and not financial grounds. However, the health authority concerned has mounted an appeal to a higher court, the results of which are still awaited. Individual supply is also currently the subject of debate in the House of Commons in the UK Parliament (Hansard 1999), and the subject of NICE guidance (www.nice.org.uk). NICE does provide hope for the future. However, if NICE recommends use of an intervention it will be the newly formed Primary Care Trusts who will have to manage the new unified (healthcare and prescribing) and cash budgets. The requirement

EVIDENCE THAT TREATMENT WORKS 395

Table IV.5.2 Summarizing the perceived pros and cons of the AD2000 trial. Pros of the AD2000 trial

Cons of the AD2000 trial

Large (n = 3000), pragmatic reflecting clinical practice. This study was powered on two primary endpoints: (1) of stabilization or reduction in disability as measured by the Bristol Activities of Daily Living (BADL) Scale (Bucks et al. 1996); and (2) the requirement for formal domiciliary or residential care

Perceived coercion amongst clinicians to take part leads them to question the ‘ethics’ and setting of the trial. Critics have suggested that a negative trial will result because of initial under-powering (based on dependency and results from vitamin E trial; Sano et al. 1997): 4000 patients would be needed to be treated for 2 years to observe similar benefits (Bullock, pers. comm.); poor recruitment with only a few hundred patients randomized by end of 1999; with no characterization of probable AD from cerebrovascular disease (no CT scan necessary)

Independence from commercial interests

Lack of cooperation and ‘buy in’ from the drug industry anxious to avoid ‘double jeopardy’ neutral or negative studies following successful regulatory approval

Randomized, controlled data addressing the worthwhile clinical and social benefits for typical AD patients

Perceived as a way of rationing therapy, controlling clinical freedom and deferring expenditure. Not supported widely by psycho-geriatricians. Many confounding factors not considered in the design (e.g. carer support, physical frailty)

Assesses how long the benefits persist

Will trial achieve the support required to reach numbers needed to reach adequate power?

The use of a new, more relevant (BADL scale) instrument to reflect ADL

Will the BADL be sensitive enough to drug induced changes for which it was not originally powered?

Central support for treatment costs

Will trial support make it effectively the only access to new treatments?

Uses present resources more fairly and informatively

Depriving patients an effective licensed treatment; and not offering patients with AD or carers an informed choice according to their needs

Inclusion of patients for whom there is both probable AD diagnosis or with mixed or concomitant disease

Trialing drugs outside the designated indication may show that donepezil is ineffective

Sets a precedent for informative introduction and evaluation of future drugs

Pharmaceutical investment in the UK may be affected by the introduction of an effective ‘Fourth Hurdle’

ADL, activities of daily living; CT, computerized tomography.

to resource new treatments and the opportunity costs without additional funding will lead to significant tension within the system, particularly if the NHS executive continues to expect new interventions to accrue from greater efficiency rather than additional resources. Table IV.5.3 illustrates reflects the matrix of stakeholder interests.

How can the scarce cash-limited resources of the NHS be distributed in an equitable and ethically justifiable manner? The primary objective of regulatory agencies is to safeguard public health by ensuring that all

medicines on the market meet appropriate standards of safety, quality and efficacy. However, there are some notable omissions in the US Food Drugs and Consumer Act pointed out by Leber (Chapter IV.5.1). It was acknowledged by the UK Government Standing Medical Advisory Committee (SMAC) of the Royal College of Psychiatrists that: • there is evidence that donepezil produces improvement in a minority of patients with mild to moderate AD. However, SMAC also suggested that: • there is no evidence to date that donepezil has any effect on the non-cognitive manifestations of AD;

396 CHAPTER IV.5

• available evidence is not sufficient to give a clear verdict on cost-effectiveness; • it is important for clinicians not only to assess the benefits to individual patients, but also to be sensitive to the needs of the population as a whole, and … that treatment with donepezil should be initiated and supervised only by a specialist experienced in the management of dementia. Benefit should be assessed at 12 weeks. Treatment should continue only for those patients with evidence of benefit. Why then are drugs such as donepezil not being used uniformly across the UK under these restrictive conditions? What is responsible for the ‘postcode prescribing’ across the UK? How have the individual approaches taken by local healthcare commissioners across the UK led to the inequities in access to these drugs? In the resource-constrained system in which we find ourselves the severity of needs can be calculated either by using some index of expected mortality if treatment is withheld (e.g. Cardiovascular Risk Tables as employed by the UK National Service Framework for Treatment intervention with Statins), or of potential health gain if treatment is applied. These approaches establish the quality-adjusted life year (QUALY) as the common currency for assessment (Fig. IV.5.4), where this is accompanied by peer-reviewed evidence of clinical efficacy (Burls et al. 1998). Treatments fall into the ‘strongly supported’ or ‘supported’ category for use by the NHS (e.g. atypical antipsychotics to treat schizophrenia; Cummins et al. 1998) vs. the ‘borderline’ or ‘not recommended’ category (e.g. reconstructive surgery to treat severe obstructive airways disease; Young et al. 1999). The main difficulties with more recent treatments for dementia and MS are modest clinical benefits and no robust evidence of improved quality of life, where predicted long-term treatment costs per QUALY (> £100 000) are hugely in excess of those normally considered (Millson 1999). The West Midlands regional policy in both these cases has been to make limited provision for treatment, and for treatment to be initiated by tertiary referral centers or as part of either a formal clinical trial

(AD2000) or a monitored continuing treatment against continuing clinical response (interferons for MS; Otten 1998). Thus, individual health commissioners have to prioritize spending on different aspects of healthcare guided by National Service Framework initiatives such as Cardiovascular Disease, Mental Health and Cancer, reflecting national priorities and laying down minimum levels of provision governed by targets. They must also be aware of local imperatives, e.g. Health Action Zone status for other diseases (e.g. respiratory illness) as encompassed in the local Health Improvement Plans. Whatever their motivation, however, the delivery of healthcare militates against ‘systematic’ policies. Given the highly heterogeneous and contingent nature of medical interventions, any policy which seeks to justify its actions based on effectiveness will founder on the fact that individuals can very often benefit from procedures, which on average, appear to deliver at best only a modest benefit. Thus, the population data from clinical trials with new anti-Alzheimer’s drugs may suggest to the public health doctor systematically evaluating the data a modest benefit in a small proportion of patients. However, the specialist clinician faced with a patient with AD and familiar with using this therapy, will also be aware of the occasional exceptional case that responds in a more exaggerated fashion as either a spectacular success or failure. The approach taken by the West Midlands in encouraging all patients to access treatment via the AD2000 trial has led to greater equity across the region, but has also restricted access to treatment. This problem has frustrated the ability of some countries to implement a national package of core services available to all or with others explicitly excluded (e.g. ‘Clinton Health Care reforms’ in the USA; Fuchs & Merlis 1993). Where the policy has succeeded (in Oregon), it was a result of special circumstances and has been very controversial. Inevitably, therefore, it will be the specialist clinicians who will be the final arbiters of individual rationing decisions. One could argue that need-related criteriaaextent of ill health and cost-effectivenessa are the most appropriate for rationing health care (New & Le Grand 1996). In his contribution to Distributive Justice in an Ageing Society, Callahan (1991) suggests that ‘As it confronts ageing, medicine should have as its specific goals the

EVIDENCE THAT TREATMENT WORKS 397

Table IV.5.3 Matrix of interests of stakeholders in AD. Adapted from Jolley (2000) with permission.

Patient Family Clinician Health commissioner Social care commissioner Pharmaceutical company

Symptoms

Survival

Personal cost

Public cost

Present (influence on treatment)

Profit

+++ +++ +++ + + +++

+++ +++ +++ + + ++

++ ++ ++ − − −

+ + + +++ +++ −

− − − ++++ − +++

++++

Table IV.5.4 Patient characteristics and treatment outcomes for patients prescribed donepezil, surveyed across health authorities in the UK.*

Number of patients considered Number of patients prescribed drug

Mean

Median

Range

Total

17.80 10.73

10 6

0–200 0–88

2800 1277

Age (years)

Under 65 65–74 75–84 Over 85

1.12 4.36 4.23 0.63

0 3 2 0

0–8 0–25 0–48 0–10

124 484 478 71

Gender

Male Female

3.90 6.74

2 4

0–30 0–58

444 761

Diagnosis

Probable AD Other dementia

9.63 0.47

6 0

0–66 0–9

1088 53

MMSE score

0–10 11–20 > 20

0.66 5.28 4.01

0 3 2

0–10 0–38 0–31

72 576 437

Living situation

Alone With carer In care

1.11 7.51 –

0 5 0

0–18 0–45 0–5

121 818 28

Outcome

Improved No change Deteriorated Died

4.32 2.72 0.80 –

2 2 0 –

0–51 0–17 0–9 –

475 294 86 6

*Some respondents did not answer all questions.

West Midlands development and evaluation service < £3000 per £3000– > £20 000 per QALY £20 000/QALY QALY

Evidence

Fig. IV.5.4 West Midlands DEC decision matrix for evaluation cost-effectiveness.

Negative QALYS

I

Strongly supported

Strongly supported

Borderline

Not recommended

II

Strongly supported

Supported

Borderline

Not recommended

III

Supported

Borderline

Borderline

Not recommended

IV

Not proven

Not proven

Not proven

Not proven

398 CHAPTER IV.5

averting of premature death …’ and that ‘It should pursue those goals so that the elderly can finish out their years … with as much vitality as can be generated…. Above all, the elderly need to have a sense of the meaning and significance of their stage in life, one that is not dependent on economic productivity or physical vigor’. The latter is particularly pertinent to those elderly patients with AD where a symptomatic treatment may not delay entry to institutionalized care but may partially restore cognitive function and vitality to their life.

Donepezil and rivastigmine: evidence for effectiveness and likely cost utility values Donepezil A UK regional evaluation committee (DEC; June 1997) concluded that donepezil: • shows clear evidence of efficacy in a highly selected population with mild to moderate AD as measured by changes in cognitive performance; • effects on severity of disease are less clear and no robust effects on quality of life or disability have been shown; • appears safe in the short–medium term; • effectiveness in routine clinical practice remains uncertain; and • benefits are so small that the risk of greater sideeffects in more typical people with AD, many of whom have co-morbidity and may be on other drugs already, makes it difficult to conclude overall effectiveness. Cognitive changes are probably equivalent to about a 3- to 6-month delay in progression of cognitive performance. This would equate to a gain of about 0.05–0.08 QALYS for a 6-month delay in progression. The range of cost utility estimates is broad, ranging from approximately £21 000 to £200 000 per QALY. This lack of precision in the cost benefits for donepezil highlights the need for a definitive trial to provide more accurate estimates of cost utility. Rivastigmine A UK regional evaluation committee (DEC; Decem ber 1998) concluded that rivastigmine:

• trials showed modest benefits, subject to considerable uncertainty, achieved at considerable costs to the NHS; • is comparatively poor value for money; and • likely offers a clinically significant benefit to a small proportion of people. The DEC matrix, which illustrates the use of QALYS as a utility instrument, is shown in Fig. IV.5.4. Utility changes based on cognitive effects were judged to be of the same order as donepezil, with a 3- to 6-month delay in symptoms of disease progression, corresponding to a gain of between 0.05 and 0.08 QALYS. This did not include the likely negative utility changes associated with adverse events. The most optimistic NNT (number needed to treat to demonstrate a benefit over placebo) was 9.0 (95%CI = 6–17) for a change in CIBIC-PLUS (a carer-rated global improvement scale). The cost per QALY ranged from £14 543 to £88 915. The Cochrane Review substantive amendment (1999) concluded for rivastigmine: • the available evidence shows a modest benefit for high dose rivastigmine on cognition and ADL, but not on clinical global impression for patients with mild to moderate AD; • withdrawal rate resulting from side effects is significant; and • low dose rivastigmine shows significant benefit for clinical global impression, but has only small benefits on cognition and activities of daily living. The systematic review of the available evidence (full data unavailable from about half patients) shows a small benefit for rivastigmine, tested on a patient group with mild to moderate Alzheimer’s who have not been highly selected with respect to their general health and include all but the most seriously ill. Until all evidence is available this may be a biased result.

Related economic evaluation studies of drug interventions Economic evaluations (Chapter VII.8.6) have been confined to sophisticated attempts at modeling the impact of the new drugs (Stewart et al. 1998), which may, by reducing the cognitive decline, lead to a delay

EVIDENCE THAT TREATMENT WORKS 399

in the institutionalization of patients with AD or reduction in dependency of patients on their carers. Examples include: 1 A longitudinal survey, comparing the costs over 6 months of matched samples of patients receiving or not receiving donepezil, calculated the average direct medical expenditure per patient over the 6 months to be US$3443 in the donepezil group and US$3476 in the comparison group. • The costs of donepezil in the former group was offset by a slower rate of institutionalization. (Small et al. 1998). • An estimation of the total treatment costs of patients on donepezil therapy, using a Markov model to simulate disease progression over 5 years, showed that use of donepezil was broadly cost-neutral. • Higher expenditure on drugs was largely offset by lower care costs as a consequence of slower disease progression and less time spent in the state of severe dementia. (Stewart et al. 1998) 2 Using donepezil 30-week trial data, combined with a Markov model, to estimate costs and times in different stages of AD over a 5-year period, donepezil was estimated to reduce healthcare costs over this period, but increase care giver time costs. • Patients on donepezil spent less time in a nonsevere stage of AD (2.21 years) compared with those in the non-donepezil group (2.41 years). • If donepezil treatment was continued after patients’ MMSE scores fell below 10, costs were significantly higher per patient over the 5 years than in the non-donepezil group. (O’Brien et al. 1999). 3 Further modeling of the costs of donepezil suggested reduced costs of care as a consequence of better cognitive functioning and delayed progression to more costly levels of care. • The size of this offsetting effect varied substantially depending on the modeling assumptions used. • Cost-effectiveness of donepezil therapy depends crucially on the duration of the therapeutic effect of the drug. If the effect lasts for 6 months, the cost-effectiveness is very poor in the initially mild and moderate groups, with cost per QUALY of US$160 000 and US$440 000, respectively.

• If the drug effect is sustained for 24 months, the cost-effectiveness increases and for patients with initially mild disease it is actually cost saving (Neumann et al. 1999). 4 Based on clinical trial data in two international studies of rivastigmine therapy (n = 1333) to model disease progression and associated costs, healthcare costs (excluding drug costs) were reduced by a small amount at the end of the 26-week trial period, but the saving increased to approximately £1100 per patient (UK 1997) when extrapolated over 3 years. (Fenn & Gray 1999). The studies undertaken to date, are potentially flawed because of the open nature of the evaluation and/or the lack of proper randomized controls. Such results are highly dependent on an assumed link between cognitive functioning and care utilization, and also on the relative costs of different levels of care. A recent retrospective study of noninstitutionalized patients carried out by the pharmaceutical company Glaxo–Wellcome showed that the cost for care is, perhaps not surprisingly, directly related to the severity of the patient’s illness (Souetre et al. 1999). Gray (Chapter VII.8.7) sounds a note of caution about the use of such studies in trying to quantify the societal impact of a disease. He concludes that: Although cost analyses are fairly consistent in finding a strong association between disease severityanormally measured by MMSE scorea and costs of care, the causative links between cognitive functioning, behavioral and social change and patterns of resource use remain unclear. Longer-term trials and more use of longterm observational studies may clarify this area, which is of fundamental importance in assessing the cost-effectiveness of drug interventions that primarily affect cognition. Qizilbash (Chapter IV.5.4), on the appraisal of economic evaluations, lists the numerous problems that bedevil these studies and concludes that the weight given to evidence should be in proportion to its validity and reliability. The validity and reliability of economic evaluations in dementia remain in much doubt, judging by the evidence (Gray, Chapter VII.8.6).

400 CHAPTER IV.5

AD2000: a reliable assessment of the efficacy and safety of donepezil and aspirin in AD? This trial was set up in the absence of a coherent national trial program to address the likely impact of donepezil on socially and economically important outcomes, such as institutionalization, dependency, care giver’s psychological well-being and care time input. In particular, the effect of donepezil in delaying disease progression (not claimed by the manufacturer) or the need for institutionalization were considered important objectives, which would inform future practice. As a result of these deliberations the NHS Executive commissioned the AD2000 trial. The concept of a large, simple trial with a primary randomization to donepezil vs. placebo with eligibility based on the ‘uncertainty’ of the clinical relevance of the effects of donepezil developed. Funding (£2 million) was top-sliced from participating health authorities (£50 000 each). The AD2000 trial has recently been subject to scrutiny by the tabloid press in the UK with headlines such as ‘Patients who take a risk on dummy pills…. The NHS postcode lottery’ (Daily Mail, 17 November 1999) and in the popular medical press ‘NICE trial is denounced as a money saving sham … The government is hoping that each year it doesn’t make a decision it can save money (General Practitioner, 26 November 1999)’. Even the Alzheimer’s Society Newsletter (1999) with its reputation for impartiality, took a stance on this occasion with a headline claiming that the ‘Aricept trial design was flawed’. In response, the clinical trial director Richard Gray said ‘Drug companies are pushing it very hard. If you pay £1000 per year for NHS drugs, that money has to come from somewhere. It could be better spent on respite care’. The main issues for the AD2000 trial was to ensure recruitment of at least 1000 patients (with a 12-month follow-up) in order to deliver on the primary health economic endpoint, namely: ‘The requirement for formal domiciliary or residential care’ (i.e. testing the hypothesis that donepezil treatment will be cost neutral if it delays institutionalization by 2 weeks). The study had adequate power, with 800 patients continuing for 48 weeks,

to detect a 2-week average delay in transition to residential care (i.e. 10 to 5% institutionalized at 48 weeks) with 80% power (Gray & Raftery; AD2000 Clinical Trial Steering Group, pers. comm.). Bayesian estimates suggest that sample sizes in the region of 1600 with a 4-year follow-up may be required to confirm the null hypothesis (Professor Karl Claxton, pers. comm. 1999). The second primary endpoint of the trial is ‘Increasing disability as defined by the loss by the patient of two of four basic ADLs (eating, drinking, washing and using the toilet) and/or loss of six of 11 instrumental ADLs’. This is expressed numerically as a 20% proportional reduction in the disability rates of mild AD, i.e. from 25 to 20%, which is considered to be medically worthwhile (based on the data from the USA trial of vitamin E and selegeline; Sano et al. 1997). The study was originally powered based on 3000 patients completing at P < 0.05 with 90% power. Revisiting this in the light of likely recruitment (> 1000 patients) suggests that 400 patients completing 12 weeks of therapy would provide 80% power at P < 0.05 to detect a ‘small’ (0.2 standard deviation) effect. A ‘small’ effect equates to about an average 2 point difference in total neuropsychiatry inventory (NPI), total Bristol Activities of Daily Living Scale (BADLS) score, or a 1% difference in GHQ-30 score between baseline and 12-week assessment. It is unfortunate that some physicians from participating health authorities feel they do not a have a real choice of alternative supplies for donepezil for those patients they consider outside the remit of the trial (i.e. those patients in whom donepezil is considered to be definitely indicated). This had led some of them to question the ethical setting of the trial with a licensed product, where they feel compelled to enter patients in order to access treatment to donepezil. The authors are divided in their interpretation of these matters: Millson and Ward consider the potential benefits of the trial to outweigh the criticisms providing NICE with important objective clinical data; whereas Jolley remains convinced that the trial is ethically unsound, poorly designed and inadequately resourced to deliver findings which are robust enough to provide a definitive answer for NICE or any other competent authority.

EVIDENCE THAT TREATMENT WORKS 401

What is the likely demand for the new treatments for AD? According to the Alzheimer’s Society only 7000 patient in the UK are currently receiving donepezil, with half of them meeting the costs out of their own savings. Of an estimated 650 000 people with dementia living in the UK, around 400 000 have AD. Demographic change will result in an increase in prevalence, with an increase in the existing £1.5 billion per year that it already imposes on the UK economy. Assuming that half of the patients with AD present for assessment (including computerized tomography [CT] scanning) and treatment (i.e. 200 000 patients), and that they went on to receive either donepezil or rivastigmine at about £800 per year for up to 5 years, then treatment costs would be around £3666 and additional NHS costs £780 (CT scans and clinical assessments) (Wessex DEC report; Wessex Institute for Health Research and Development 1997; 1998). Thus, the total direct cost to the NHS could be of the order of £889 200 000 over a 5-year period (i.e. £177 840 000 per year). This assumes that no savings in indirect costs result from the use of these new drugs and that market penetration does not exceed 50% of the patients with AD. So, in round figures, the new Alzheimer’s drugs could increase NHS costs by up to £200 million per year based on relatively modest projections. This would amount to 4% of the total £5 billion UK NHS drug bill.

How did the West Midlands manage the introduction of new Alzheimer’s drugs into primary care? MTRAC is a regional Primary Care Therapeutics Advisory Committee with a remit of advising general practitioners on the appropriateness of prescribing and encouraging evidence-based prescribing of drugs in primary care. MTRAC carried out its own evidence-based reviews of both donepezil and rivastigmine at the time of launch. Specialist psycho-geriatric input was sought and the committee of primary care doctors (guided by medical ethics, clinical pharmacology, pharmaceutical and public health advisers) provided guidance, which was distributed to all general practitioners in the West Midlands region.

MTRAC verdicts for both donepezil and rivastigmine are given below. (Full details of the verdicts and accompanying literature summaries are in Appendix I or via the Midlands Therapeutics Regional Advisory Committee website [www.keele.ac.uk/depts/mm/MTRAC].) Donepezil: for the symptomatic treatment of dementia in AD Committee’s verdict: not appropriate It is not appropriate for donepezil to be provided through general practice as either initiation or maintenance therapy. The results of more extensive studies are needed to determine the benefits and risks of treatment. Supports the structured evaluation proposed within specialist facilities. Rivastigmine: an acetylcholinesterase inhibitor for the treatment of AD Committee’s verdict: not appropriate It is not recommended that general practitioners prescribe rivastigmine. Insufficient evidence is currently available to allow evaluation of the benefits and risks of treatment. This recommendation applies to both initiation and maintenance therapy. The verdicts produced by MTRAC are advisory only and provide guidance for general practitioners in the prescribing of new drugs. However, the prescribing data for the West Midlands for drugs such as donepezil, where a ‘not appropriate’ verdict is indicated, have generally shown a much lower prescribing ratio compared to the rest of the UK (e.g. see Fig. IV.5.3 for donepezil prescribing). While it is not possible to definitively and causally link this apparent reduction in prescribing solely to the influence of MTRAC and the AD2000 trial, it is likely that they had some influence.

Provision of open access to drug treatments for AD via a specialist memory clinic using psycho-geriatricians as gatekeepers The expense of treating individual patients is multiplied by the fear, from a public health perspective,

402 CHAPTER IV.5

that every person with a dementia syndrome would receive such treatment and result in millions of pounds of expenditure. In practice, not everyone with a dementia syndrome is judged by clinicians to be in need of such treatment, and not everyone who has AD will be brought forward for treatment by themselves or their families. Experience in Wolverhampton, UK, in common with other parts of the country (Benbow et al. 1999), is that an open access service for a population of 40 000 older people will screen something like 400 people with dementia syndrome within a 12-month period, of whom less than 200 will be deemed as possible candidates for treatment by the clinical teams involved with them. Something of the order of 100 patients are actually started upon therapy within a 12-month period. This is supported by marketing information for the UK (Eisai pharmaceuticals, pers. comm.) where use of donepezil is $16 per 1000 patients per month compared to France and Germany where comparable figures are US$76 and US$188 per 1000 patients per month respectively. Clinicians who have had the privilege to be able to use these compounds for a period of time, have found that not everyone is helped by them, and that some people cannot tolerate them. But at least half of the patients who can tolerate them improve markedly and around a quarter of patients started upon them are spectacularly improved. Improvements in cognition and general well-being, loss of symptoms of anxiety, depression and paranoid ideation are recorded in systematic reviews of patients progress on treatment.

What are the issues for purchasing an Alzheimer’s drug in the USA? Pharmaceutical lobbying A Public Policy statement by William C. Steere Jr., the Chairman and CEO of Pfizer, laid down his ‘Thoughts Toward a Medicare Drug Plan’. Access to health care for America’s senior citizens is a vital issue. A number of proposals to enhance health care for the elderly have been introduced at the state and federal level, includ-

ing plans to provide prescription medicines. The issues that surround expanded access are sure to play a significant part in next year’s election, as voters seek effective and cost-effective solutions. There is one point on which consensus is emerging: the near-poor elderly in America need expanded coverage for prescription drugs. Steere writes ‘Under a proposal introduced by the Administration, the Governmentathrough pharmaceutical benefit managersawould purchase prescription medicines for all seniors’. In this scheme: • federal government would become a purchaser of immense power, demanding deeper and deeper discounts from pharmaceutical companies, introducing price controls; • revenues would decrease sharply; and, • research would decrease to a trickle (as has happened in Europe) the torrent of innovative medicines that the USA are now producing. In short, government-driven price controls would undermine pharmaceutical innovation. Steere raises the spectre of disinvestment in the pharmaceutical industry as a threat to government policy makers (a familiar ploy used by pharmaceutical lobbyists in the UK). In asking ‘How do we keep the short-term benefit of broader coverage and avoid the long-term catastrophe of diminished drug discovery?’, he makes three proposals: • Leave the choice of medication to the doctor and the patient. It is critical that elderly Americans have access to all medicines approved by the FDA. But the choice of drugs should be a medical decision, not a political one. ‘Who chooses my medicine?’ is a fundamental question we must put to every Medicare reform proposal. • Help those who need help. Instead of spending billions of extra dollars to provide a governmentfunded program for people who already have excellent drug coverage, we should concentrate our efforts on providing support to those who lack coverage and desperately need it. By focusing on people truly in need, we can dramatically scale back costs in any government-funded pharmaceuticals program.

EVIDENCE THAT TREATMENT WORKS 403

• Promote innovation and pharmaceutical research. Medicare drug coverage cannot come at the price of inhibiting research that creates life-prolonging medicine. Price controls, whether explicit, implicit, current, or future, invariably stifle the creative engine of the pharmaceutical research industry. In making his case, however, Steere (1999) is highly selective and dismissive in his criticism of European drug development. This dynamic of profit paying for research is the engine behind innovation. When that dynamic is interfered with through excessive government regulation, innovation falters, as it has in Europe. Europe was once the world’s greatest medical innovator. But today it lags behind the US. The cause is excessive government interference in the marketplace. In most European countries, the government is the largest purchaser of pharmaceuticals. Governments use their power to negotiate down the price of drugs. The end result is significantly less profit for manufacturers and, consequently, significantly less revenue available for research. The numbers tell the tale. Between 1975 and 1994, the US developed 45% of new major drugs. France produced only 3%; Germany, 7%; and the UK, 14%. By the year 2002, European pharmaceutical companies will supply only five of the world’s top-selling drugs. US dominance is not a function of better scientists, only better policies. The US encourages R & Daand the innovation it producesaby allowing the industry a fair return on its investment. The reality is that a vibrant pharmaceutical industry is essential for a healthy UK economy, contributing nearly £2.5 billion to the trade balance as a direct result of significant successful R & D occurring in the UK. (Halliday & Walker 1999) More than 70% of the 69 leading medicines of the 75 top products were discovered by companies based in the USA, UK and Japan. Between 1992 and 1996 the proportion of leading medicines discovered by USA and UK companies also increased by 25%, compared to a 20% fall in Japanese discovery over the same period. Excessive pharmaceutical profits are controlled in the UK by the inaccurately named Prescription Pricing Regulation Scheme

(PPRS), which sets a limit on individual company profitability at 21%. The PPRS does not ‘fix’ prices but has the power to control excessive profits and has recently ordered a reduction in profits, which translates to a 5% price reduction with £1 billion to be recouped by the Treasury (for details see www.abpi.org.uk). In terms of proportion of sales for the 63 leading medicines, the UK (21% of sales) is second only to the US (35%). Thus, prescribing of new innovative drugs discovered in the UK would appear not to be inhibited by the PPRS. Indeed, the UK ranks eighth in worldwide sales, with an average of $716 million dollars per medicine by national origin compared to $718 million for the USA (Halliday & Walker 1999). Steere’s viewpoint fails to take into account the relative market dominance of the US and, some might say, excessive spending on healthcare in relation to the national wealth compared with the more modest expenditure in Europe. His arguments seem to suggest a ‘not invented here’ approach which does not stand up to closer scrutiny. Indeed, a recent survey carried out by the American Academy of Neurology (AAN News 2000) reveals the patchwork of access to neurological services and drug formularies across USA (Fig. IV.5.5).

Conclusions The purchasing of healthcare for elderly patients with AD requires healthcare commissioners to make difficult choices. Licensed specific new therapies are available for symptomatic treatment, with little evidence of effect on disease progression. There can be no doubt that this class of new drugs meets the stringent requirements of proof of efficacy and safety prospectively laid down by regulatory agencies across the world (Drug & Therapeutics Bulletin 1997; 1998). The issue is one of clinical effectiveness in the wider population. Leber (Chapter IV.5.1) clearly states that regulatory approval does not necessarily equate to or demand: • a minimum size of effect below which an effect would be considered so trivial as to render a drug product ineffective in use; • that a drug deemed to be effective in use exert its effect in some minimum proportion of those to whom it is administered; and

404 CHAPTER IV.5

Patients’ rights in the USA Comprehensive legislation Drug formularies Access to specialist

• as to how long the effect of a drug declared effective in use must last, nor does it speak to the importance of the effect. Unfortunately for the drug developers, who started their quest some 10–15 years ago, whilst the regulatory hurdles are now well defined, the sophistication of the Health Technology Assessments which the new medicines are exposed to has also become more rigorous. It is rapidly becoming the norm (in Australia, Canada, Italy, France and now the UK) to expect a prospective robust health economic evaluation of the health impact of a new medicine conducted as part of a randomized controlled trial (Freemantle & Bloor 1996; Hill et al. 1997), despite the great uncertainties in the methodology. Many healthcare systems (e.g. Australia, Canada, Italy, France and USA HMOs) now demand proof of clinical cost-effectiveness, before allowing full reimbursement of a recently licensed product (Freemantle & Bloor 1996). A similar system has been suggested for the UK (Walley 1998). This would at least allow clinicians to evaluate a new product, providing that the patient has the means and desire to pay for the medication, if and until it

Fig. IV.5.5 AAN maps of restricted access to neurology services and medications across the USA (AAN news 2000).

receives NICE approval. Effectively, this is what appears to be happening in the UK at the moment, with almost half of donepezil treatment being funded privately by desperate patients (Benbow et al. 1999; Jolley 2000). ‘Postcode prescribing’ is being replaced by ‘costcode prescribing’. A further problem for clinicians faced with an individual patient is that they may be either a nonresponder or an exaggerated responder to any new treatment. Unless some funding is available to specialist referral centers to conduct ‘therapeutic observation’, and n-of-1 trials (see Chapter IV.5.4) with new medicines, then the current preoccupation with EBM may deprive these patients of clinical benefits. It is also important to encourage and develop practical therapeutic knowledge in using new drugs within the NHS. A major issue facing the introduction of new treatment for AD is the inherent ageism in our society. This is further confounded by the inherent bias in evidence-based medicine in using cost per QALY assessments to compare the value of healthcare interventions. QALY measures, which use unequal utility weights in the ‘cost utility’ analysis, will

EVIDENCE THAT TREATMENT WORKS 405

systematically prejudice against the elderly (New & Le Grand 1996). This may lead to a shifting of resources from the old to the young, unless ethical issues surrounding such policy are challenged. It is imperative that assumptions being made in pharmaco-economic models are made explicit and understandable to all. This will then facilitate a common understanding amongst clinicians, public health doctors, economists and commissioners surrounding ‘uncertainties’ or ‘adjustments’ included in the sensitivity analyses required to operate any pharmaco-economic model.

Ten questions to consider in presenting your case to a health authority or primary care group 1 Financial value: consider all costs (cost of drug, cost of administration, opportunity costs of not spending the funding elsewhere). 2 Effectiveness: grade the effectiveness in relation to the treatment population (how many residents will benefit).

3 Present a ‘business case’: determine the likely size of the benefit/health gain in terms of impact on health outcomes (e.g. improvements in independent daily living). 4 What other interventions (e.g. day or institutional respite care) are available for the same condition and how do they compare with the drug in question? 5 How does the drug in question compare with interventions in other areas (cost per QALY, NNT, etc.)? 6 Does the drug make a contribution to a priority area of health? (Be familiar with National Service Frameworks and the Health Authority’s Health Improvement Plan.) 7 Is the drug likely to be of value in groups with demonstrable inequality to healthcare access? 8 Does the drug improve the utilization of scarce manpower resources? 9 Highlight any ethical issues relating to drug availability or enrolment into clinical trials. 10 Consider publications in ‘secondary sources’ that are evidence-based, such as this book, Cochrane, ACP Journal Club, etc.

Dementia Trials for Cognitive Symptoms and Modification of Prognosis: Past, Present and Future

IV.5.3

Nawab Qizilbash and Lon S. Schneider Introduction

There is clearly a need for pharmacological therapies that can treat the cognitive symptoms or modify the course of major dementias or, more importantly, demonstrate a delay in dependency and institutionalization without prolonging the time people spend in a severely dependent state. Such a benefit would be important irrespective of whether it were to be brought about by disease modification or merely reduction of symptoms without an effect on the underlying disease process. We largely bypass the debate of what can or cannot be defined as disease modification. In contrast, we focus on the term ‘prognosis modification’, which refers to endpoints that are meaningful to patients and, hence, easy to describe and measure, have good inter-rater agreement and which are largely irreversible, such as

clear levels of dependency and nursing home placement. Any therapy that might improve the well being of people with Alzheimer’s disease (AD), or make only a small percentage difference to its overall cost, would produce major benefits in both human terms and to health and social services. Conversely, therapies that do not do this but are used by large numbers would impose unnecessary costs and could hinder the development of effective therapies in the future. After two decades of an increasing number of clinical trials in this field how much progress has been made in reliably testing the potential agents that may make a difference to the lives of sufferers and their families, and the costs and benefits of these agents? Several pharmacological therapies are used around the world for cognitive impairment and dementia. Only a few of these have been given regulatory

406 CHAPTER IV.5

approval for use in dementia or cognitive impairment by several western regulatory authorities: hydergine (ergoloid mesylates) and the cholinesterase inhibitors tacrine, donepezil, rivastigmine and galanthamine. High dose vitamin E and selegiline for delaying dependency, institutionalization and death in patients with AD have their advocates (American Psychiatric Association 1997; Sano et al. 1997) but also their critics (Drachmann & Leber 1997; see also Chapter V.2.21), and the evidence arises from only one clinical trial, at present. The number of agents being developed by the pharmaceutical industry is rapidly growing with the help of combinatorial chemistry and genomics (and new indications are being found for old drugs, e.g. aspirin, non-steroidal anti-inflammatories, Gingko biloba and folate), and these and many new agents with different modes of action will be progressing through clinical testing over the next decade (Chapter IV.7). These agents demand ‘good’ trials. ‘Good’ clinical trials are those which provide unequivocal answers to important clinical questions, and hence lead to wide-ranging changes in practice so that the benefits of the tested agents are passed on to many sufferers of the disease, such as aspirin in acute myocardial infarction and stroke, and streptokinase in acute myocardial infarction (Second International Study of Infarct Survival [ISIS-2] Collaborative Group 1988; International Stroke Trial Collaborative Group 1997). They also lead to the reliable estimation of hazards associated with an agent and its discontinuation, such as heparin in acute stroke (International Stroke Trial Collaborative Group 1997). Using this simple criterion as the gold standard of a good clinical trial, how well has the field of dementia been served by the trials of the past two decades? How well are we likely to be served by the trials currently being planned? And, what other complementary types of trials, if any, are needed to answer the clinically important questions? Trials in dementia may be conveniently divided into those designed before the surge of cholinesterase inhibitors in the late 1980s and those that were spurred by the testing of cholinesterase inhibitors, notably tacrine.

Methods 1984 saw the introduction of the first widely accepted and used criteria for the diagnosis of AD and vascular dementia (VaD) (McKhann et al. 1984). In 1986 the first oral cholinesterase inhibitor trial was published, which gave rise to the interest and increasing flow of trials in dementia, especially of cholinesterase inhibitors (Summers 1986). Therefore, 1989 was arbitrarily chosen as the year to separate the pre- and post-cholinesterase inhibitor era, and from which time specific diagnostic criteria should have been employed. Also, the NIH tacrine trial, designed in the late 1980s and reported in 1992 (Davis et al. 1992), laid the foundation for regulatory approval which has persisted.

Search strategy and study selection The Cochrane Library (2000, issue 4) was searched for trials of pharmacotherapy using the terms ‘dementia’, ‘Alzheimer’, and ‘vascular dementia’. From the list of 2674 references provided by this search, random number tables were used to generate the following studies for review: • Before 1989: 20 trials. • 1990 and after: 20 cholinesterase inhibitor trials. Citations where the full reference was not obtainable were replaced. Non-intervention studies and trials which were not related to the treatment of cognitive symptoms or which aimed at modifying disease progression or prevention, were excluded.

Data extraction Two people extracted the following information independently from the final list of studies, with any supplementary information contained in available meta-analyses: • Study design: randomization; blindness; crossover or parallel design; duration of treatment. • Types of patients enrolled: diagnostic criteria; diagnoses; severity of disease; setting. • Interventions studies: whether the comparisons were unconfounded; nature of the comparison; doses. • Outcome measures: specific measures; specified primary and secondary outcomes.

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• Analysis: size; loss to follow-up; unspecified subgroup analyses.

Results The website of this book contains tables with details of the studies, whose features are collectively described and summarized below.

Trials prior to cholinesterase inhibitors Trials in the 1960s, 1970s and 1980s had many problems that made drawing reliable conclusions difficult and reviewing them even more unsatisfactory. Study design Many of the trials were not properly randomized, in that there could have been prior knowledge of which patients were allocated to which treatment group. This would destroy the comparability of the treatment groups and allow sufficient bias to be introduced as to invalidate the results. Many trials did not use double blinded assessment for evaluating outcomes. This is crucial where outcomes are so susceptible to observer bias, as in many of the outcome measures used in dementia. A large number of cross-over trials were conducted in the hope of requiring fewer patients to demonstrate statistically significant benefits. Apart from the inadvisability of using cross-over designs in a disease that is progressive with a declining baseline, sufficient care was not taken to allow for carry-over effects of treatment in one period to the next in many such trials (Qizilbash et al. 1997). However, although the first treatment period is available from these trials for a valid comparison, they are based on small numbers of patients (the original reason for adopting the cross-over design) and usually of short treatment duration. The trials were also of short duration and any benefits that might have occurred in the mediumto long-term would not have been detected. Indeed, some trials were of 6 weeks or less, when the placebo effect is at its greatest, and thus would not be able to evaluate the drug effect with much reliability.

Types of patients enrolled Before 1984 there were no reliable and validated criteria to diagnose AD from other dementias (McKhann et al. 1984). Therefore, many trials were performed with a mixture of patients, most of whom would have had AD by the sheer prevalence of the disease. This is not necessarily a disadvantage, but there was no way of identifying them to evaluate whether those with AD responded differently, especially if the therapy might have had a differential effect on different types of dementia because of its mode of action. The kinds of patients entered in the studies were of a mixed variety in their sources, ranging from relatively well outpatients to severely disabled patients in nursing homes. This variety of patients in a study may actually be an advantage, providing they are well characterized at baseline and the study is sufficiently powered to detect differences in such different type of patients, who would be likely to respond differently. Such heterogeneity of patients also allows for greater generalization of the trial results. Interventions studied Trials were often confounded by the introduction of other agents or non-pharmacological measures in addition to the drug of interest such that a valid assessment of the agent in question could not be determined. Some trials compared one drug with that of another, before the effect of either had been established. Such trials are often designed to attempt to show that the drugs are similar, though non-inferiority trials are often underpowered. The dose at which the drug would be effective was often not well established and trials that tried to identify the best dose were often not large enough to provide sufficiently reliable data to make an assessment of the treatment response with dose. Outcome measures Numerous outcome measures were used and were often not validated or tested for reliability,

408 CHAPTER IV.5

especially longitudinally. This makes both interpretation and comparison difficult. Furthermore, the clinical meaningfulness of these scales were not examined and most had no data about their relevance to important markers of disease progression or impact on the patient or carers. Hence, the clinical usefulness of any benefits detected was uncertain. Analysis The trials were usually small (often with far fewer than 100 patients) and, therefore, prey to false negative results, even if the treatment had beneficial effects. This was reflected in the size of the confidence intervals and significance levels of the treatment effects. Many trials often did not specify which outcomes were primary and which were secondary. This often led to an undue emphasis on data dependent analyses, which gave rise to many positive findings within trials where the main primary endpoints, where specified, often were not positive. Several results were derived after examining the data (‘subgroup analysis’). One in every 20 such analyses will discover a statistically significant result and in many cases this can be striking and appear convincing (ISIS-2 1987). Trials had problems of loss to follow-up and presentation of only completer’s analysis (and not intention-to-treat analysis) which often biases results in favor of treatment and overestimates any treatment effect (Schulz et al. 1995).

Study design All the trials were randomized, although the quality of the randomization was rarely reported. Most trials used double blinded assessment for evaluating outcomes, although none tested the quality of the blindness. A large number of cross-over trials were conducted in the hope of requiring fewer patients to demonstrate statistically significant benefits (Qizilbash et al. 1997). Many trials were also of short duration and any benefits that might have occurred in the medium- to long-term could not be detected. Indeed, several trials were 6 weeks or less when the placebo effect is at its greatest and so they would not be able to evaluate the drug effect with much reliability. None of the trials were longer than approximately 6 months. Types of patients enrolled Almost all the trials used specific criteria to obtain homogenous groups of patients. All used the McKhan criteria to include only those patients who were diagnosed as having ‘probable’ AD. The patients were also excluded from having many common concomitant diseases such as heart disease, depression, etc. This culling may have led to greater ‘homogeneity’ of patients in the trials but also meant that no reliable information was available for the 90% of patients with AD who were excluded from these trials (Schneider et al. 1997b). Therefore, the possibility of generalizing the results was very limited.

Trials of cholinesterase inhibitors Tacrine began this era of clinical trials in dementia in the late 1980s. It has left an indelible mark on the way trials are conducted in dementia, by shaping the regulatory requirements for antidementia drugs. The trial with the most remarkable results, and which was responsible for initiating the programme of trials with cholinesterase inhibitors by several pharmaceutical companies, contained many of the most serious deficiencies in trial design (Summers 1985; Anonymous 1991). However, later trials were not without their own methodological problems (Qizilbash et al. 1997).

Interventions A few trials were confounded by the introduction other agents in addition to the drug of interest such that a valid assessment of the agent in question could not be determined. The dose at which the drug would be effective was often not established and several trials used dose escalation or determined the best doses for individual patients before randomization. These studies made generalization difficult and were often not large enough to provide sufficiently reliable data to make an assessment of dose response.

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Outcome measures Over 40 different outcome scales were used in the tacrine trials and many had not been validated or tested for reliability (Qizilbash et al. 1997). This made both interpretation and comparison difficult. Furthermore, the clinical meaningfulness of these scales was not examined and most had no data concerning their relevance to important markers of disease progression or impact on the patient or the family. Hence, the usefulness of any benefits detected was uncertain. The later cholinesterase inhibitors were more restricted in their range of outcome measures. Analysis The trials were usually small (often with far fewer than 100 patients) and, therefore, likely to be falsely negative, even if the treatment had beneficial effects. Even the later trials were insufficiently large to detect reliably the modest differences that were expected in outcomes other than cognition. Some trials did not pre-specify which outcomes were primary and which were secondary. This often led to an undue emphasis on data dependent analyses, which gave rise to many positive findings within trials where the main primary endpoints, where specified, often were not positive. This led to claims for tacrine being better in mild and moderate, and younger and older patients! None of these subgroup findings were corroborated in a metaanalysis of all the individual data from all relevant trials of tacrine (Qizilbash et al. 1998). Several trials had problems of loss to follow-up with presentation of completer’s analysis which often biases results in favour of treatment and overestimates any treatment effect. For example, although the Knapp trial (Knapp et al. 1994) is often selectively cited in most literature reviews because it was the largest and longest of the tacrine trials, it had a dropout rate approaching 75% in the highest dose group. Many presented analyses were not of the more robust intention-to-treat type, but based only on those who had completed the protocol. This often biases results in favor of treatment. By comparison, in the published clinical trials of other

cholinesterase inhibitors, the effect size is usually smaller when the trial is evaluated by an intent-totreat analysis (see Chapter V.2.21; Qizilbash et al. 1998). Several results were derived after examining the data. One in every 20 such analyses will discover a statistically significant result and in many cases this can be striking and appear convincing (ISIS-2 1987).

Discussion Trials for new therapies The current crop of cholinesterase inhibitors (licensed and those in the pipeline) have overcome many of the deficiencies of the last two decades, i.e. they are properly randomized, unconfounded, parallel-group, double-blind, placebo-controlled studies of usually 6 months, and occasionally 12 months duration. They have used a common core set of outcome measures (with some variation in the behavioral and functional domains) to characterize cognition, clinical global impression of change, behavior, functional autonomy as assessed by activities of daily living, quality of life in the carer (and patient), and resource utilization measures, including carer time and burden. However, fundamental questions still remain about the clinical meaningfulness of a few points change over a period of 6–12 months on these complex scales, and changes in clinical global impression scales. What happens in the longer term to the benefit/ harm ratio as these drugs are used for a year or more in patients? What types of patients benefit, given that the number needed to treat for cognitive efficacy over 6 months is highly variable (from 40 to 6), even among similarly designed trials of one drug class? Is dependency and institutionalization delayed? Is time in a dependent state prolonged? How should therapy be monitored in clinical practice? Are the treatments cost-effective? Furthermore, the newly licensed agents, donepezil, rivastigmine and galanthamine are already being administered in patients in whom there is no or few controlled data, e.g. ‘possible’ AD, patients with co-morbid conditions and taking several other therapies, which were exclusion criteria in the

410 CHAPTER IV.5

trials. The results and conclusions of the systematic narrative reviews of therapies in subsequent sections of this book are sobering (Chapter V.2.21). Therefore, after two decades of testing agents in AD and other dementias, we are unable to state with any confidence what the meaningful benefits are of the drugs used in these conditions. The essential paradox is that we can see a consistent cognitive effect for cholinesterase inhibitors as a class, but we cannot clearly appreciate overall clinically meaningful improvements. Other randomized trial designs have been proposed to test the issue of symptomatic effects vs. disease-modifying effects of drugs (Leber 1996; 1997). Continued vs. discontinued therapycrandomized withdrawal design (Fig. IV.5.6) This design has a conventional first period in which patients are allocated to treatment or placebo. The second phase involves randomizing (either after each patient has been on therapy for a determinate period of time or at a single point in time to assess the effects of duration of treatment on benefit) those originally allocated to the treatment group to either placebo or further active treatment. The design is based on the premise that if a therapy acts only in a symptomatic manner, the gains achieved in the period on treatment should not be maintained on its withdrawal. Conversely, if benefits are produced by effects on progression of the underlying disease, the benefits acquired during treatment will not be completely eroded on withdrawal. However, there are several problems associated with this design. First, it is not clear what time period is required before any disease modifying benefits of therapy would be measurably sustained nor what time interval of follow-up after withdrawal is needed. Second, if this period of followup is prolonged, then loss to follow-up may become a problem in terms of bias and statistical power. Third, it requires a difference to have emerged at the time of withdrawal between the groups on treatment and placebo, and given that patients are not enrolled concurrently, it is not possible to guarantee this before the withdrawal phase has begun. Fourth, the willingness of

patients, carers and clinicians to a withdrawal of therapy may be difficult. Finally, the size of such studies is likely to be large and the statistical techniques to predict study size from change in slopes are not yet well established. It is not clear what would be a clinically meaningful change in slope that should not be missed. At any rate, showing equivalency of slopes is likely to require larger numbers than enrolled in the cholinesterase inhibitor trials. Also, increased variability in cognitive scales such as ADAS-Cog with increasing time may require as much as 70% more patients over an extra 24-week period of a randomized withdrawal/start phase (Whitehouse et al. 1998a). The numbers suggested by the International Working Group on Harmonization of Dementia Drug Guidelines, of 200–300 patients per treatment arm would appear to be severely inadequate (Bodick et al. 1997). This approach has not yet had success in the few propentofylline trials that were designed in this way (Kittner 1998). As yet, propentofylline has been rejected for approval by the Canadian and European regulatory agencies, and its development was abandoned in March 2000 by the manufacturer. Immediate vs. delayed treatmentcrandomized start design There appear to be two variants. The first has a conventional initial period in which patients are allocated to treatment or placebo. The second phase involves randomizing those originally allocated to the placebo group to either placebo or further active treatment. A variation is for all patients to commence on placebo and at staggered intervals be randomized to active treatment or to continue placebo. By the end of the study all patients receive active treatment, although fewer patients remain on placebo for long periods of time. The design still harbors several of the problems of the randomized withdrawal design. Neither of these designs directly address the most important questions for patients and carers. Are clinically important outcomes influenced? Is function meaningfully affected, is dependency delayed? Is time in a dependent state prolonged? Are behavioral symptoms affected?

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TRADITIONAL RANDOMIZED PHASE

WITHDRAWAL (OF ACTIVE TREATMENT) PHASE

Performance on cognitive, functional or global scales

Active treatment

Disease modifying effect: benefit of treatment sustained relative to control group

Control

Symptomatic effect: benefit not sustained or lost relative to control group Time

(a) Randomized withdrawal design.

TRADITIONAL RANDOMIZED PHASE

Fig. IV.5.6 Subjects are conventionally

randomized to active drug or placebo in the first phase. During the second phase (to the right of the dotted line) subjects are placed on placebo in the randomized withdrawal design (a), or on active drug in the randomized start design (b). Benefits attributable to the active drug attributable to the first phase are maintained in the second phase (the lines remain apart) if the agent modifies the underlying disease but not if the effect is purely symptomatic. Adapted from Leber (1996).

Performance on cognitive, functional or global scales

Active treatment

ACTIVE TREATMENT PHASE

Symptomatic effect only: delayed treatment does not compromise benefits

Control

Disease modifying effect: benefits are compromized by the delayed start Time (b) Randomized delayed start design.

Biological markers such as hippocampal volume loss with MRI (Fox et al. 1996; Kaye et al. 1997) have been proposed as surrogate markers to make trials more efficient (Bodick et al. 1997). However, further work is needed to establish the closeness of

these markers to clinically important endpoints, before they can be used as primary endpoints in trials. Also, caution should be noted in the use of surrogate markers as primary outcomes to gain regulatory approval and approval by clinicians

412 CHAPTER IV.5

Table IV.5.5 Anticipated effects of trial size on trial results. Adapted from Yusuf et al. (1984). Total number of events (treated and control)

Approx. number of patients randomized if risk of event is 10%

Probability of failing to achieve convincing significance* (P < 0.01) if true risk reduction is 25%†

Comments

0–50 50–150 150–350 350–650 > 650

Under 500 1000 3000 6000 10 000

> 0.9 0.7–0.9 0.3–0.7 0.1–0.3 < 0.1

Clearly inadequate‡ Probably inadequate§ Maybe adequate Probably adequate Definitely adequate

*Assumes 1 : 1 randomization. †Non-compliance and other protocol deviations mean that a 25% risk reduction may be produced by a treatment that actually reduced risk by some 30%, depending on the level of non-compliance to the protocol. ‡The vitamin E and selegiline study (Sano et al. 1997) contained 0–50 events, had relative risk reductions of 30% for vitamin E and 28% for selegiline—based on analysis without adjustment for initial imbalance in the prognostic variable of MMSE. Therefore, the size of this trial can be viewed as inadequate, to reliably detect this magnitude of effect. §The estrogen prevention trial (Shumaker et al. 1998) is expected to contain 160 events and will probably be inadequate on the basis of a more realistic 25% reduction.

and purchasers. Several examples exist of well established surrogate markers of disease producing erroneous results when compared with clinically relevant outcomes in fields as diverse as AIDS, diabetes and cardiology (Fleming & DeMets 1996). Therefore, although they are essential to help develop promising drugs and as supportive evidence, as secondary outcomes, within trials, they are not likely to be accepted by purchasers and many clinicians as providing definitive evidence. Randomized trials to delay the progression of AD from mild cognitive impairment (MCI) with vitamin E and donepezil (and placebo) are in progress in the USA. One of these is designed to demonstrate a 33% reduction or more, over a period of 3 years, with 85% power and a false positive alpha value of 0.025 with under 1000 patients in total, in a three-arm parallel study. Given the strict eligibility criteria and the use of tertiary specialist centers, it will have limited generalizability and this may also result in lower rates of the outcome of interest than predicted. However, again it is the size of the expected reduction in risk that may be the major problem of this trial. The vitamin E trial of Sano et al. (1997) observed about a 30% reduction in risk in a dubious composite endpoint, in the unadjusted analysis that was not convention-

ally statistically significant (see Table IV.5.5). This suggests that the trial was severely underpowered, in the composite endpoint and the individual endpoints that comprized the composite endpoint, in patients with moderate probable AD. Notwithstanding, the MCI trial is powered to observe a 33% reduction or greater, much earlier in the course of the disease. Should either of these agents delay progression to AD from MCI, then reductions of only one-quarter or one-fifth would be medically worthwhile, but may be easily missed in this trial because of its size. It is arguable that the trial should be much larger and the use of a factorial design (instead of being a three-arm parallel group trial) would help in achieving this objective efficiently, without any loss of statistical power, and with the ability to assess interaction of effects from the two drugs. Factorial designs have been used extensively without any problems and have provided two and more answers for virtually the price of the one (Fourth International Study of Infarct Survival 1995; International Stroke Trial Collaborative Group 1997). The vast number of secondary outcomes adds complexity and immense cost and detracts from the primary objective of the trial. If the primary outcome is not reliably assessed, then these secondary outcomes may

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become of academic interest only. If the outcomes occur at the rate expected and the benefits are as big or bigger than expected, then a larger sample would allow the trial to be terminated sooner, which would be of greater benefits to the patients in the trial and those not in the trial who may then get the treatment because of the production of robust results.

Large, simple, pragmatic trial designs are needed to meet the challenge Notwithstanding the problems of the randomized start or withdrawal trial designs, they will not in themselves reliably answer the important clinical questions posed above (Qizilbash & Schneider 2000). This failing is likely to be even more pronounced for therapies that do not produce symptomatic improvements in the short term, yet may produce clinically important benefits in the long term, as may occur with vitamin E and selegiline (Sano et al. 1997). Indeed, vitamin E and selegiline did not have any observed effect on cognition. Drugs acting through other mechanisms that may improve prognosis, such as delaying the development of behavioral symptoms, or functional impairment without benefits on cognition, would not be amenable to the randomized start/withdrawal designs, as the complexities of modeling noncognitive outcome scales have not been developed. Even so called ‘symptomatic’ therapies do not produce immediate improvements in many, but, rather, a slowing of the progression or development of symptoms; whether this is a result of alteration of the underlying disease process or not is of secondary importance to the patient in the light of any short-, medium- and long-term meaningful effects. (The issue is, of course, important for developing drugs.) Many of the major problems, however, could be overcome by large (but low cost per patient), longterm trials of simple treatments given to a wide range of individuals with AD evaluating clinically meaningful outcomes, as pioneered in cardiovascular disease, cerebrovascular disease, cancer and infectious disease by Richard Peto in Oxford, nearly two decades ago (Yusuf et al. 1984). This seminal work has transformed trials in these fields

(Fourth International Study of Infarct Survival 1995; CAST 1997; International Stroke Trial Collaborative Group 1997). With co-workers, the Oxford group are soon to complete a 5-year, factorial, large, simple, randomized trial into preventing coronary heart disease with simvastatin and antioxidants in 20 000 people at high risk of vascular disease in the UK, that will have cost approximately US$20 million in total (US$1000 per patient) (Meade et al. 1999). In dementia too, large, simple pragmatic trials could generate reliable and useful information of direct relevance for patients, carers, clinicians and purchasers (and regulators). Indeed, without such trials it is difficult to see how the clinically important questions can be answered reliably. The vitamin E and selegiline trial is an example of a trial that was hampered by randomizing far too few patients, as evidenced by the need to develop a composite endpoint comprised of very differing outcomes, and problems with imbalance in baseline Mini Mental Status Examination (MMSE) scores. The substantial controversy over adjustments in the analysis (Drachman & Leber 1997), led to an adjusted analysis (for minor differences in MMSE) that produced almost a doubling of the effect size to that of the unadjusted analysis (Sano et al. 1997). It also contained too many baseline and secondary outcome measures, thereby complicating it unnecessarily and increasing its cost substantially. The types of trials largely conducted before and during the cholinesterase inhibitor era are contrasted with the large simple trial in Table IV.5.6. The rationale for large simple trials is surprisingly simple (Yusuf et al. 1984). First, the discovery of effective treatments is likely to be more ‘important’ if the dementia to be studied is common than if it is rare, and studies of AD can be large. Secondly, the identification of effective treatments for common dementias is likely to be more ‘important’ if the treatment is non-toxic, widely practicable and relatively cheap than if it is so complex and expensive that it can be performed only in specialist centers. Treatment protocols for widely practicable treatments can, therefore, be simple. Thirdly, effects of treatment on major endpoints (e.g. loss of dependence, institutionalization) are more important than effects on minor endpoints

414 CHAPTER IV.5

Entry criteria Eligibility Recruitment Data collection Ancillary therapy Multi-drugs System Data collection Follow-up Interference with clinical practice Flexibility Compliance Duration Sample size Reliability Generalisability Clinical relevance Cost/patient in trial Cost-effectiveness

Table IV.5.6 Characteristics of

Pre-cholinesterase inhibitor era

Cholinesterase inhibitor era

Large simple trial

Broad Tight Difficult Large Restricted Forbidden Complicated Large/complex Extra to routine Rigid High

Narrow Tight Difficult Voluminous Restricted Forbidden Cumbersome Large/complex Extra to routine Rigid High

Broad ‘Uncertainty’ Easy Scanty Unrestricted Allowed Simple Simple Part of routine Flexible Low

None Moderate Short Small Poor Moderate Uncertain High

None Moderate Intermediate Moderate Poor Poor Uncertain High Invalid (Modeling needed)

High Moderate Long Large Good Good Clear Low Valid (Direct assessment plus some modeling)

(e.g. radiological or neuropsychological evidence of disease progression of which the patient may not be directly aware). Follow-up protocols for the assessment of only important efficacy and safety endpoints can therefore often be simple. Fourthly, few prognostic features that are recorded at entry, apart from measures of disease severity or stage, age and co-morbidity, are helpful. Duration of survival, time to institutionalization, loss of independence, etc. among apparently similar patients is rather unpredictable, so there is usually no great increase in statistical sensitivity by stratification and/or adjustment for many features. Thus, the reliability of the primary outcome measure is improved surprisingly little by adjustment for initial imbalances in prognostic features, other than those related to disease stage or severity, age and comorbidity, which suggests that entry protocols can be kept simple. Fifthly, the direction (though not necessarily the size) of the net effects of treatment on particular outcomes is likely to be similar in

pre-cholinesterase inhibitor and cholinesterase inhibitor era trials, and large simple trials (comparison of trial designs in dementia).

many different subcategories of trial patients. Again, therefore, the protocols can be simple. These arguments suggest that many trials designed to test effectiveness can be large, and can have simple protocols. Finally, if a widely practicable treatment had a large effect on an important endpoint (e.g. institutionalization or loss of dependency) in a common dementia like AD, this would probably already be known, so the true effect is likely to be either absent or, at best, moderate. Assuming plausibly realistic effect sizes has profound implications for trial size (see Table IV.5.6). Although the currently prevailing trial sizes may suffice to detect moderate treatment effects of clinically unimportant outcomes (change on a cognitive scale or a complex functional scale), they may well fail to detect a moderate (yet worthwhile) effect in important outcomes. The peculiarities of dementia require adjustments to the large simple trial design customary in the fields of cardiovascular disease and cancer. For

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example, issues of outcome scales, disease staging, dependency, short-, medium- and long-term effects, symptomatic vs. disease-modifying effects, diagnosis, and monitoring therapy need particular attention. Trials that do not appreciate the peculiarities of studying dementia may run into problems (Bullock et al. 2000; Chapter IV.5.2). Notwithstanding, these issues are capable of resolution and such trial designs should be encouraged. Adaptations of the large simple trial design for dementia requires attention to the following considerations: 1 Given that AD is a heterogeneous disease, of multifactorial etiology with a common final pathway leading to classical neuropathological findings, it should be possible to identify subgroups of patients (either in the design or the analysis) before the trial commences to assess responders, if sufficiently large numbers are randomized. These subgroups could be based on prognostic factors, which are intrinsic to the individual (such as ApoE4 status, sex and age), or factors related to the disease (such as diagnosis, stage of disease, concomitant co-morbidity and co-therapy). Without large trials subgroup analysis for responders will be subject to the play of chance, giving rise to potentially spurious results (Qizilbash et al. 1998). 2 Factorial designs provide economy in testing more than one agent without, in most cases, loss of statistical power from the same number of patients (e.g. randomized study of 58 000 patients that tested three agents simultaneously; Fourth International Study of Infarct Survival 1995). These designs allow patients to be randomized to two or more treatments independently, so that all combinations of the treatments are produced. For example, in the trial of Sano et al. (1997), patients with AD were randomized to vitamin E, selegiline, both or neither, in equal proportions. Such designs may also appeal more to patients and families and increase compliance as patients have less than a 50 : 50 chance of being allocated placebo; with equal randomization, a 25% chance if two treatments are used and 12.5% chance if three treatments are used. It is curious that current trials in dementia have not adopted this design feature. 3 The trial design needs to cater for the prescribing of other approved treatments for dementia; thus,

the trial should reflect clinical reality and avoid ethical dilemmas. 4 Drugs in development can be put into large early phase III studies that have some of the characteristics of large simple trials, while meeting regulatory requirements for monitoring safety and obtaining a product license. Results may be produced more quickly and cheaply in this way. Once the short-term efficacy and safety data for regulatory approval are available, the trial can then be continued in the true spirit of a large simple trial to detect long-term effects and provide more controlled safety data. Such a ‘pragmatic bridging trial’ may help both regulatory approval and convince purchasers to allow prescription of the drug for those patients who will benefit. 5 It is often said that work is required to choose appropriate and clinically meaningful outcome measures. However, much of the information is already present to make sensible choices and simple, well-validated (both cross-sectionally and longitudinally) scales such as the Dependency scale, that have clinical meaning should be used (Stern et al. 1994). Time to a defined level of dependency could be used, as in the vitamin E and selegiline trial. However, where there are patients with differing stages of dementia severity, a drop in two levels of the Dependency scale would be better, as it is relatively objective, stable, has little error in its assessment and, hence, could be used to monitor patients simply using a variety of follow-up (routine where possible) procedures, resulting in few losses to follow-up at affordable prices. The advantage of this ‘global’ scale is that it incorporates the protean disabilities that affect people with dementia and puts them into a measurable and meaningful index, and that changes in the index can be readily appreciated by all. Nursing home placement incorporates these features, but is highly dependent on culture, availability and finances, which would introduce more random variation and fewer events than assessing dependency or function in a trial. 6 Resource utilization assessments can either be kept simple and collected on all patients or for from a subsample of the trial patients. Large numbers are often not needed to assess the effects of the drug for quality of life, although economic

416 CHAPTER IV.5

evaluations may require sample sizes even larger than those needed for the primary endpoints (Gold et al. 1996). 7 Surrogate outcome measures, using complex procedures, can be carried out in subsamples of patients, in those centers where appropriate facilities exist, and may be needed to convince people of the disease-modifying power of an agent, irrespective of its benefits on reducing clinically meaningful events. Other important core outcomes such as change in cognition can also be analyzed, as occurs with current trials in dementia. 8 Randomized start and withdrawal designs may be incorporated into the large simple trial design. These adaptations could be useful for assessing how long treatment should be continued. The failure to appreciate the need for large trials may lead to underpowering of trials designed to prevent AD or modify prognosis. Many of the trials currently planned or underway are likely to lead to false negative results by being too small, even if the drugs are truly effective. The basic reason for this underpowering lies in not appreciating the reality that treatments effects on major endpoints are likely to be modest or, at best, moderate (Yusuf et al. 1984). For example, discussion of trials to prevent AD might be planned on the assumption of 50% risk reduction in the incidence of AD from treatment, by the International Working Group on Harmonization of Dementia Drug Guidelines (Thal 1996; Thal et al. 1997). The trial of estrogen in the prevention of dementia assumes a 40% reduction, with 100 cases of dementia expected in the placebo group and 60 in the treated group, in an overall sample of 8000 women in this portion of the trial (Shumaker et al. 1998). Magnitudes of benefit of this order are exceedingly rare in the field of chronic disease, barring exceptions such as lipid lowering and blood pressure lowering on cardiovascular and cerebrovascular disease. Indeed, the epidemiology summarizes the benefit of prevention from estrogen for dementia as being about 30% (Chapter V.7). Therefore, it is difficult to see how the trial will beat this figure by a further 10%. It is interesting that larger numbers will be used to test the main hypotheses of effects on breast cancer and coronary heart disease in the Women’s Health initiative study. Epidemiology often sets the upper

limit of benefit that trials may or may not achieve (Collins et al. 1990). Yet smaller effects that may still be medically worthwhile can easily be missed (See Table IV.5.6). Some are trying to conduct larger trials but, unfortunately, they remain underpowered (Bullock et al. 2000 trial; see Chapter IV.5.2). The UK AD2000 trial requires 4000 patients to be treated with a cholinesterase inhibitor for 2 years to demonstrate an expected benefit of 20% reduction in dependency in patients with mild to moderate AD, assuming 20% dropout, with adequate (90%) power (Bullock et al. 2000). However, the target trial size was 3000 patients treated for 1 year, and that figure is likely to be greatly underachieved, thereby almost certainly producing a negative result. Also, entry to the trial has not been based on the principle of uncertainty, as have most mega-trials (Bullock et al. 2000). Trials for evaluating disease progression might be planned on total sample sizes of 600 patients (Berg et al. 1992; Bodick et al. 1997). Cost-effectiveness analyses will be invalid and unreliable without large simple trials assessing clinically meaningful endpoints. Modeling will be required to evaluate long-term costs but without clinically meaningful endpoints, the analyses cannot even begin to have credibility. A recent 2-day Drug Information Agency workshop (April 2001) on Large Simple Trials in Neuroscience, chaired by Robert Temple (FDA), Stuart Pocock (London School of Hygiene) and Nawab Qizilbash (Oxford) discussed this design for dementia, depression and schizophrenia. A summary of the proceedings of this workshop will be provided on the website of this book.

Conclusion The trials performed to date to test antidementia drugs have provided several relatively safe drugs that could be used in dementia. Unfortunately, the trials have been unsatisfactory in providing reliable answers of the effects on clinically meaningful outcomes. These answers are unlikely to come from trials other than through the adaptation of the large simple trial methodology, as a complementary design for use in phase III and IV trials. Without large simple trials, the limitations encountered over the last decade are likely to be seen again, resulting in

EVIDENCE THAT TREATMENT WORKS 417

uncertainty about the real benefits of treatment and, hence, patients being deprived of drugs that may importantly affect their well-being and prognosis. The conclusions of the chapters on virtually all the pharmacological treatments reviewed in this book make for sobering reflection. Alternatively, drugs may be used which have marginal and uncertain benefits and that may divert limited resources away from other services for patients with dementia. Of prime importance to patients, carers, clinicians and purchasers is demonstration of improved prognosis and meaningful benefits, and not demonstration of effects on biological disease activity or questionable endpoints. Cardiology in the early 1980s conducted trials mainly with several hun-

IV.5.4

dred (and a small number with a few thousand) patients, the majority of which produced unreliable results (Yusuf et al. 1984). Today, it is almost the norm for cardiovascular trials to contain several thousand patients and provide more reliable results that can be generalized. The challenge is for trials in dementia to make a similar transition, while reducing the cost per patient randomized and keeping total costs affordable, as has been successfully done in cardiology, stroke and cancer (Third International Study of Infarct Survival [ISIS 3] 1992; Heart Protection Study [Meade et al. 1999]; International Stroke Trial Collaborative Group 1997), at least for drugs with sufficient reassuring data confirming their short-term relative safety.

Individualizing Symptomatic Therapy: n-of-1 Trials*

Nawab Qizilbash Key points

• The n-of-1 trial represents a useful method of individualizing therapy and improving the risk–benefit equation. • Uncontrolled clinical observation may be untrustworthy for monitoring the use of cholinesterase inhibitors in dementia. • Dementia (with exceptions), mild cognitive impairment (MCI) and age-related cognitive decline represent conditions where n-of-1 trials can be feasible and should be more widely adopted. • Where central cost containment and prioritization are key elements of a health service, n-of-1 trials may be one way to introduce long-

Introduction Traditional trial designs are required to establish the efficacy, effectiveness and safety of symptomatic treatment. Traditional trials provide only average results, which may not apply to a particular * I thank Professor Stephen Senn for helpful comments on this chapter.

term therapies for dementia, where they might not otherwise be available. • The collaboration of many clinicians conducting similar n-of-1 trials will help everyone, especially individual patients. • At worst, even without further clarification of the statistical methods for analysis, the controlled aspects of carrying out the procedures represent an improvement on conventional clinical observation. As methods of analysis are developed, an assessment of their usefulness and practical application will be provided on the website. • These considerations also apply to n-of-1 trials in the evaluation of non-pharmacological interventions.

individual patient. Often, we are unable to predict who will and will not benefit. Subgroups are often not trustworthy, except when based on very large numbers and pre-specified. Although subgroups of patients who may benefit from therapy based on their genetic make-up may be identified in the future, at present there is little good evidence to support the presence of the ApoE ε4 allele as an aid to predicting who will respond to cholinesterase

418 CHAPTER IV.5

inhibitors (see Chapter V.2.21). Identification of individual patient response from traditional trials, therefore, is often very difficult. Differences in age, sex, size, absorption, metabolism, elimination of drugs, enzymes, target responsiveness and genetics means that one size is unlikely to fit all. Many patients do not benefit from a given proven treatment and many benefit to varying degrees. In dementia, a number of medications are available for the symptomatic treatment of cognitive and non-cognitive symptoms; this chapter concentrates on the treatment of cognitive symptoms. Treatments are also prescribed for cognitive decline without dementia in several European countries, such as nimodipine for age-associated cognitive impairment in Spain (Chapter V.2.4). As described in later chapters of this book, the number needed to treat (NNT) for varying therapies for cognitive symptoms is far from 1 : 1. For tacrine, the NNT is 1 : 40 for a non-minimal (marked or moderate) improvement in the clinical global change scales (Chapter V.2.21). For donepezil, the NNT for any improvement is 8–11 depending on dose, for rivastigmine it is 8–20 (see Chapter V.2.21). In assessing the value of a therapy, these NNTs need to be balanced by the number needed to ‘harm’. There are always disadvantages to any therapy, even if it is only inconvenience. For health authorities and doctors who decide upon the use of limited resources, the treatment of only patients who benefit has obvious advantages for benefit/risk ratios, cost-effectiveness and cost containment. For patients and care givers, therapy for only those who benefit means not being subjected to side effects, less inconvenience and, for those who pay for their own medicines, either in part or whole, the lost opportunity costs of other activities, such as extra home help or a good holiday. For example, in the USA there are approximately 2.4 million patients with Alzheimer’s disease (AD) (Brookmeyer et al. 1998), of whom up to half might be eligible for a cholinesterase inhibitor, based on Mini Mental Status Examination (MMSE) criteria. Even if only 10% of these patients were suitable according to the tight trial eligibility criteria (Schneider et al. 1997a), at approximately US$1600 per patient per year, this would some represent US$160 million in drug therapy alone, leaving out the

costs of monitoring and dealing with side effects. These amounts would represent a sizeable chunk for many psychogeriatric services, and for drug budgets in national health services. Also, it may be wasted money for the majority of patients who would not symptomatically benefit moderately or greatly. In practice, many patients who fall outside of strict trial entry criteria are being treated with cholinesterase inhibitors, thereby increasing the potential demand, and whose NNT may be very different. Therefore, the individualisation of therapy may play an increasing role in the treatment of dementia. It may be one way to convince health purchasers to buy or allow reimbursement of therapies for dementia and even age-related cognitive decline (see Chapter IV.5.2). Uncontrolled clinical observation has been suggested as a means of translating the results of conventional trials of cholinesterase inhibitors to individual patients (Kelly et al. 1997). This is also the approach in the guidelines for the prescription of cholinesterase inhibitors by the Italian Ministry of Health and the UK National Institute of Clinical Excellence. However, these ‘clinical experiments’ lack the controlled conditions required to reduce the sources of substantial variation, overcome placebo effects, regression to the mean, and do not take into account the natural history of the disease and the prejudices of patients, care givers and clinicians. Most important is the lack of placebo and double blindness in a condition where the measurable outcomes are easily influenced by subjective notions from the clinician and patient or care giver. Lack of randomization to treatment periods and lack of meaningful choice of outcome measures also hamper valid assessment. For example, a patient of the author was started on a cholinesterase inhibitor. According to her husband, the therapy began to work days after commencement, although the effect was difficult to define by care giver or patient and no effect was observed on the Cambridge Cognitive Examination (CAM-COG) or MMSE cognitive scales. On trying to withdraw treatment to test its effect, the husband claimed that his wife deteriorated (again in only a vague way) within days of ceasing therapy, and he therefore recommenced treatment, believing it to be worth the £1000 (US$1600) per year. The ‘experiment’ was

EVIDENCE THAT TREATMENT WORKS 419

therefore not completed; indeed, such clinical experiments are very difficult to conduct objectively because of the huge placebo effect seen in some patients. Of the patients with AD on the placebo group in the tacrine trial of Knapp et al. (1994), about 25% were better at 6–12 weeks, and about 20% scored better at 30 weeks on the Clinical Interview-based Impression scale, when compared to baseline (Knopman et al. 1994). One method to apply conventional trial evidence of beneficial effect to individual patients is the n-of-1 trial (Verhey et al 1998; Qizilbash & Lopez-Arrieta 2000). Instead of studying many patients with the same treatment (or placebo), as in conventional trials, in n-of-1 trials the same patient is tested with many episodes of the treatment (and placebo). This eliminates between-subject variation. The withinsubject variation now depends on the number of times that the therapy can be tested on an individual. Therefore, it is this source of variation that must be controlled in n-of-1 trials to derive valid results by replication of treatments. The statistical concepts underlying n-of-1 trials are clearly exposed and discussed in detail by Senn (1997) and can be read by non-statisticians. The practical aspects are discussed by Guyatt et al. (1998). In principle, the greater the number of episodes tested, the smaller the within-patient variation and, hence, the greater precision in the data. This principle should be appreciated so that failure to find an effect with a small number of treatment episodes may be a false negative and reflect low statistical low power. The result of such a trial from one patient should not be extended to another, although when many n-of-1 trials have been conducted with similar methodology, generalizations may be derived and these data may feed into calculations for future patients on whom n-of-1 trials are conducted. How many periods are needed depends on statistical considerations and practicalities. Withdrawal symptoms following discontinuation of cholinesterase inhibitors have been postulated as some patients in the traditional trials deteriorated following withdrawal, although they had not improved relative to baseline. Such subgroup analysis is untrustworthy and requires further traditional trials to confirm the hypothesis or, more likely, it can be better assessed in n-of-1 trials than in open clinical experiments.

Stopping therapy, when it may cease to offer any benefits, can also be assessed by modifications in the practical design of the n-of-1 trial. Prescribing cholinesterase inhibitors for types of patients who were not represented in the traditional trials also should be done within a n-of-1 design; this would apply to those with ‘possible AD’, mixed AD and vascular dementia (VaD), and other dementias such as dementia with Lewy bodies (DLB), etc.

Appropriate situations for n-of-1 trials 1 Where the treatment response is highly variable, as with cholinesterase inhibitors, the NNT is low and predictors of response are not identifiable (Qizilbash et al. 1998; Chapter V.2.21). 2 When therapy is symptomatic and the response can be measured. 3 When there is a fast-acting response to treatment, occurring within several weeks of initiation of therapy. 4 When the effect of therapy is rapidly reversible, occurring within several weeks of ceasing therapy. 5 When the disease is chronic. 6 When the disease is relatively stable over the periods of the experiment. If the disease is slowly progressive, as with dementia, then either the slope of the decline needs to be modeled on the treatment effect, or the effects need to be large relative to the decline over the period of therapy and assessment. The requirement is for the rate of decline not to vary too much from patient to patient, so a common trend can be fitted, based on patients in traditional trials and other n-of-1 trials. 7 When the target symptoms for therapy are not short-lived. 8 When the carry-over effect is absent or subsides relative to the timing of the assessments. These conditions apply to dementia (although there may be cases, such as those who are rapidly deteriorating, who serve as exceptions) MCI and to age-related cognitive decline over the short to medium term.

Inappropriate situations for n-of-1 trials 1 When measuring progression of disease in the medium to long term, such as in stabilization of

420 CHAPTER IV.5

disease or primary prevention of dementia, where the outcome is delayed. 2 In short-lived episodes of a condition that do not recur frequently, such as some behavioral problems, like aggression.

Practical aspects of conducting n-of-1 trials There are several ways of conducting n-of-1 trials which can be directed by addressing the following questions (Guyatt et al. 1998): Is an n-of-1 trial appropriate? • Is effective therapy to be continued over a long term, if demonstrated to be beneficial? • Will the patient and care giver co-operate? Is the design feasible? • What is the rapidity of onset? • Do effects cease soon after discontinuing therapy? • What is the optimal duration of treatment? • What are the clinically meaningful outcomes to be measured? • What are the stopping rules? • Is an open run-in on treatment desirable? Can I apply the n-of-1 trial in my practice? • Are placebos available? • How will tablets be administered? • How will randomization take place? • How will data be analyzed and interpreted? • How will the blind be broken? Is ethical approval needed?

Is an n-of-1 trial appropriate for dementia, MCI and age-related cognitive decline? There exists considerable uncertainty about the real value of licensed therapy with cholinesterase inhibitors. At best, the majority of patients will not derive clinically meaningful improvement or reduction in decline, but it will be difficult to know to whom this applies under routine clinical conditions. Similar considerations are likely to apply for therapy given for non-progressive cognitive decline in some countries (e.g. nimodipine in Spain). Treatment is long term (i.e. at least greater than 1 year), as a 1-year trial of donepezil has recently demonstrated similar benefits to the results from

the 6-month studies (Winblad et al. 1999). Therefore, once a patient is considered a ‘responder’, therapy is likely to be given for several years. Yet we know that cholinergic neurones decay and a point will be reached when therapy may not have any useful further symptomatic effect. An analogy is the use of levo-dopa in Parkinson’s disease, in which good symptomatic benefit may be produced early in the disease, but after a few years of therapy symptoms escape its control and side effects outweigh benefits. Both the patient and care giver need to agree to the extra visits and assessments involved in this experiment. A minimum of 3-monthly visits for at least 1 year is necessary. The decline in dementia occurring over this time can be modeled and incorporated into the evaluation. For age-related cognitive decline, there are no concerns about decline.

Is an n-of-1 trial feasible in dementia? Maximum improvement in cognition occurs at about 12 weeks, with greatest separation between placebo and cholinesterase inhibitor (Knapp et al. 1994; Corey-Bloom et al. 1998; Rogers et al. 1998; Winblad et al. 1999). After discontinuation of therapy the effect wears off within 6 weeks (Rogers et al. 1998). This means that the optimal duration of treatment is over several weeks and the timing of the treatment periods and assessments need to accommodate these durations. Practically, this amounts to 3 months per treatment period, with assessments by the care giver on a weekly basis, although only the last 4 weeks would be used in the formal evaluation to avoid any carry-over effects. Clinically relevant outcomes can be applied (see below). What will decide success and failure? Low power of the test means that a couple of treatment periods may be insufficient. A minimum of four treatment periods is needed. A run-in period may be particularly useful if only an improvement from baseline is considered to be meaningful. During this period the highest optimal dose that has been shown to be clearly more efficacious can be titrated, depending on tolerability. If there is no improvement or intolerable side effects occur, then the trial can terminate at this stage. An active

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run-in period will offer little help, however, if a lack of improvement is considered to be consistent with lack of decline. This issue can only be addressed by the n-of-1 trial after randomization to the active and placebo periods. However, a run-in on nothing may be useful to get baseline progression on cognitive function and confirm that the disease is not rapidly progressive and is relatively stable; an important condition for n-of-1 trials. The design can also monitor withdrawal effects of medication.

Can I conduct n-of-1 trials in my practice? • Placebo is the ideal non-intervention control and most easily obtained by requests to the manufacturer. If placebos are not available, other tablets or capsules, similar to the drug should be found, e.g. vitamin tablets. • Placebos and active tablets need to be provided to the patient and care giver, and exactly how this is done will vary. Distribution may be through the local pharmacist, the clinic nurse or supplies directly from the manufacturer. • Randomization can be made easy using computers. The treatment periods should be randomized, either completely or in pairs. With four or at most six treatment periods, there is not much difference, but the paired randomization may be more easily interpreted. The number of treatments (i.e. active or placebo) needs to be balanced overall within any particular n-of-1 trial. • The analysis and interpretation of the data need to be decided at the start and how and when the blind will be broken. • Even if ethical approval is not considered essential, it is prudent to obtain written consent to the procedure.

Choosing outcomes to assess effects This depends on the desired aims and effects. There are two broad sets of aims with symptomatic therapies in dementia: 1 Symptomatic improvement. This can be accommodated by measuring improvement from baseline for outcomes that are meaningful to the patient and include clinical global impressions of change,

goal attainment scales, behavior, function and effects on care giver. 2 Reduction in worsening of symptoms. The types of outcome measures used for evaluation of symptomatic improvement may also apply. The initial improvement in cognitive performance, followed by a decline that parallels the placebo group, may represent a delay in ‘symptomatic decline’ (Rogers et al. 1998). It may be argued that even if no improvement from baseline were observed, decline would have been greater without the drug. What is clinically meaningful and useful to the patient and care giver? This needs to be discussed with each patient and care giver based on these two broad aims. There is no consensus on this matter, as the area is poorly developed and an individual decision needs to be reached between each patient, care giver and clinician (Chapter V. 2.21).

Individual goal attainment scales The patient and care giver discuss the areas that cause most problems in the life of the patient, and in which of these areas would improvement be considered valuable. These then form an individualized scale with which to assess the effects of therapy (Rockwood et al. 1996).

Clinical global improvement Although elaborate clinical global impression of change scales have been developed for clinical trials (Schneider et al. 1997b), there is not a great deal of empirical evidence that they perform better than more simple care giver assessment of change. Therefore, as it is the importance of symptomatic change to the patient and care giver, rather than the clinician that is important, simple care giver clinical global impression of change (and from the patient in early dementia) is probably sufficient. In the tacrine trials, there was no good evidence that the more elaborate CIBIC scale was any more sensitive to the treatment effect than the clinical global impression of change assessed by the care giver (Qizilbash et al. 1998). The global measure of change by the care giver is the preferred outcome measure of the author in most circumstances.

422 CHAPTER IV.5

Cognition The MMSE and Alzheimer’s Disease Assessment Scale cognitive scales (ADAS-Cog) have been the most widely used in trials of cholinesterase inhibitors. For measuring changes in individuals, the MMSE scale has far too much variation; it has been suggested that a change of 4 or greater is needed before it can be really concluded that this represents more than just random results (see Appendix II). The ADAS-Cog scale is useful along a wide spectrum of severity of dementia (see Appendix II) and changes of greater than 4 and greater than 7 have been proposed to represent clinically significant changes, as the annual decline over 1 year in ADAS-Cog in those with mild to moderate AD is in the range of 8–12 (Ferris et al. 1997).

capsules/tablets) but with full discussion with the care giver before the n-of-1 trial is commenced. Some local ethics committees may require special protocol approval and consent when considering this type of experiment to be ‘research’, while others may consider this to be a variation of normal clinical practice and not require such stringent measures as are needed for conventional trials. In any case, it would seem prudent to have written consent by the care giver and the patient, where insight and mental competence are maintained, as required in performing an invasive diagnostic test or therapeutic maneuver. As with conventional trials, the use of placebos needs to be made clear: that the experiment can be terminated for whatever reason without any prejudice to patient care, and follow-up should be close enough to detect any side effects as would occur in normal practice.

Behavior It is unclear what would represent minimally useful clinical change and what scale or instrument should be employed.

Function It is unclear what would represent minimally useful clinical change and what scale or instrument should be employed. This author would suggest that a change of one level on the Dependency scale would represent clinically useful change.

Care giver burden It is unclear what would represent minimally useful clinical change and what scale or instrument should be employed.

Ethics If benefits obtained on placebo occur on an active run-in period and are subsequently considered to be a result of the placebo effect, this placebo effect should, if possible, be kept. One option would be to continue the patient on placebo alone (either the original placebo or, more likely, on alternative placebos such as vitamin C or other similar looking

Evaluation of response and stopping rules Ideally, somebody who is not associated with the evaluation and has no contact with the patient/ care giver should carry out evaluation under blind conditions. As the n-of-1 trial is based on trying to identify the patients that may benefit from a therapy that has been demonstrated to work overall, the information from the conventional trials should be incorporated into the evaluation of the individual patient. Clearly, the contribution of this prior information will depend on the amount of information available from the particular n-of-1 trial. Where there are an infinite number of periods, the contribution of this prior trial information will be minimal. Also, information derived from other previous similar n-of-1 trials should also contribute to the evaluation of the particular n-of-1 trial. Practically, the number of treatment periods will be four or, at a stretch, six. This means that in practice prior information available will need to be used in the evaluation of a particular patient, to provide the most sensitive analysis. A random effect model is required, and possibly a Bayesian approach too (Senn 1997). There are several possible ways to analyse the data. 1 Simple plotting of the data with time and treat-

EVIDENCE THAT TREATMENT WORKS 423

Response

Change

Fig. IV.5.7 Ideal response in an n-of-1 trial with a symptomatic intervention in dementia.

3 months 6 months 9 months 12 months Drug Placebo Drug Placebo

ment plotted on the horizontal axis and the relevant outcome scale on the vertical axis. Unfortunately, this is easily open to false positives and false negatives with just four or even six treatment periods. However, if only large effects are important (i.e. marked or moderate improvement in a Clinical Global scale), then this type of evaluation may be adequate. This is the preferred method of the author, at the present time. Figure IV.5.7 shows an ideal response profile. 2 The sign test. This requires the scores in each pair to be assessed in terms of which treatment has the more favorable outcome. Unfortunately, with just four treatment periods, this is completely unsatisfactory. The probability that a treatment was favored in each pair could have occurred by the play of chance alone would be 1/2 × 1/2 = 1/4 or P = 0.25, which is completely statistically nonsignificant. 3 A matched t-test. This analysis takes into account not just the direction of the treatment effect, but also the magnitude and the consistency of the treatment effects. Unfortunately, this is too conservative and takes no account of the existing information from conventional trials and previous similar n-of-1 trials.

4 Random effect model using repeated measures and prior information (Senn 1997; Brown & Prescott 1999). Exactly how this would be done is yet to be established. Thus, at the present time, the methodology of the n-of-1 trial needs to be further validated, to enable it to be analysed in the best way.

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IV.6

Non-pharmacological Techniques

Robert T. Woods

IV.6.1

Introduction

The subject matter of this chapter is potentially extremely broad, given that in practice the bulk of the day-to-day management of dementia is nonpharmacological. However, most interventions in dementia care are not based on any structured or systematic approach; indeed, many dementia care workers would not recognize that the care environment they provide and their interactions do in fact constitute an intervention. Where specific approaches and techniques can be identified, the evidence base is generally rather limited, with methodologies not approaching the rigor of pharmacological trials (Orrell & Woods 1996). Extensive summaries of the evidence on each approach, including recommendations for practice, can be found on the website. Before beginning to consider the nature and extent of the available evidence, it is important to recognise the prominence that authorities in the field have for many years given to staff attitudes (e.g. Woods & Britton 1977; Kitwood 1997). The suggestion is that inappropriate staff attitudesa which dehumanize, diminish and devalue the person with dementiaawill reduce the impact of any intervention, to the extent perhaps of it leading to harm. As we shall see, this is a field where ensuring compliance with a planned intervention is especially challenging; the approach needs to be applied with attention to both the details of the technical procedure and the appropriate attitude to the person. It is not simply that there are non-specific aspects which must be controlled for; the intervention, it is suggested, potentially interacts with these non-specific features so that it may only appear to be effective

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where, say, attitudes are positive and respectful. Conversely, and of some significance, an approach may appear to have negative effects, if used in the context of inappropriate attitudes. The implicit model underlying many of the psycho-social approaches is based on the notion of excess disability. The person is thought to show a greater degree of disability than that which is necessitated by the neuropathological changes to the brain. The person’s interaction with their environment (physical and social) and their reaction to their situation are seen as major factors in leading to this additional disability. For example, depression, anxiety and agitation might be seen as reactions to the person’s situation, each clearly having the potential to lead to reduced function. Similarly, Kitwood’s theory of dementia care suggests that an invalidating, dehumanizing social environment interacts with the brain pathology to produce the behavior and function observed in the person with dementia. Kitwood also argues that such an environment can increase the rate of development of the neuropathological change, forming a spiral of decline and degeneration (Kitwood 1997). The important implication of this model for outcome studies is that the effect of an intervention may vary, depending on the baseline level of excess disability. Thus, in a residential home where there is a rich, individualized environment and where person-centered care is provided, the same intervention may have less effect than in a home where there is no activity, where care is delivered by routine rather than need, and where there is little

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positive staff–resident interaction. A possible example of this effect in relation to reminiscence ‘therapy’ is provided by Head et al. (1990). The immediate impact of some behavioral management programs, without time for any learning to have taken place, has also been attributed to the quality of the care environment, where independent behavior had not previously been encouraged or prompted (Burgio et al. 1986). As mentioned previously, in terms of evidencebased practice, this is a relatively under-developed field. However, two helpful reviews of psychological therapies with older adults are available. The first was commissioned by the Department of Health in the UK, as part of a strategic review of psychological therapies for all age groups (Woods & Roth 1996). This was subject to a process of international expert review. The second (Gatz et al. 1998), applies evidence-based criteria to studies involving older adults. The criteria adopted were developed by the Division of Clinical Psychology of the American Psychological Association for evaluating the effectiveness of psychosocial interventions. In addition, specifically relating to dementia, the American Psychiatric Association’s 1997 Practice Guideline includes a specific section on psycho-therapies and psycho-social interventions (American Psychiatric Association 1997). These overviews provide a check on the breadth of the current discussion, as well as making useful comments on the various types of therapy to be reviewed. There are now several Cochrane systematic reviews of specific psycho-social approaches to dementia, which will form the basis of the relevant sections of this discussion. The endeavor to apply the methodology of the drug trial to psycho-social approaches has led to a focus on ‘therapies’, which can be delivered in prescribed doses, according to a set protocol or treatment manual. In the dementia field, these have often been applied in a group context (e.g. reality orientation, reminiscence). Patients may be randomly allocated to such group therapies, and evaluations made by assessors who are blind to group membership. The nature of the intervention is, of course, transparent to the therapists and participants. Selecting appropriate control or comparison groups has proved difficult. A comparison with a

group receiving no intervention leaves doubt as to whether any effect of treatment arises from the specific approach rather than from the effects of additional (non-specific) attention and stimulation. Any comparison treatment needs to be delivered as expertly and enthusiastically as the target treatment. A few studies have been able to show changes with respect to convincing ‘placebo’ treatments, but these are the exception (e.g. Woods 1979; Baker et al. 1997). It is more difficult to evaluate changes to the overall care environment, but this is precisely what best practice in the field of dementia care would be seen to require. Randomizing some people to receive one type of intervention in a nursing home or day-center and others to receive another, outside a specific therapeutic context, is unlikely to be feasible. Thus, for example, a randomized controlled trial of physical activity and a night-time environmental intervention on sleep and agitation in a nursing home context was weakened by the control group receiving the environmental intervention also (Alessi et al. 1999). Where the therapeutic input cannot be delivered in a sessional package, the unit of intervention becomes the nursing home or day-center. This provides a strong case for comparison group studies, where, say, one or more experimental nursing homes or wards are compared with others where no intervention takes place. In such studies it is more difficult to control for the impact of influences other than the experimental intervention, and it is necessary to show clearly the comparability of the units on all relevant variables. The use of single-case designs is another approach that is worthy of consideration. O’Carroll (1999) points out that many of the group studies in this area in fact utilize small sample sizes, and that there is an argument for analysing results as a series of well-controlled single cases. This is well-accepted in fields such as applied behavior analysis and neuropsychological rehabilitation. Indeed, the American Psychological Association criteria (Gatz et al. 1998) simply require a series of 10 or more single cases, with good experimental designs, for a psychological treatment to be accepted as ‘well-established’, as long as certain other quality features are present. Given the wide range of severity of the dementias, the range of profiles of impairment and ability and

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the widely accepted need for a highly individualized, tailored approach (Woods & Bird 1999), there is a strong argument for this methodology not being seen as inherently weaker than the randomized controlled trial (RCT). While it is possible to have a protocol for tailored interventions within an RCT, the extent to which there is transparency regarding the nature of the intervention is inevitably reduced. If, on the other hand, the treatment is highly structured, with a well-defined treatment manual, while it will be easier for others to replicate the intervention, it will be likely to lack responsiveness to individual differences and have lower external validity. Finally, by way of introduction, the issue of identifying appropriate outcomes in this area needs to be considered, in the context of a disorder usually seen as having a natural history of decline. There are a number of possible relevant outcomes, reflecting, for example: cognitive function; mood and emotional state; quality of life; disturbed behavior and agitation; and aspects of independent function, such as continence, personal care and dressing. To some extent, the different types of interventions have been associated with the outcomes targeted by that approach. Thus, reality orientation (RO) has been assessed by its impact on cognition and verbal orientation; behavioral approaches by their effect on the particular target behaviors. Three key concerns have emerged that should be noted. 1 Outcomes studied in experimental interventions

IV.6.2

may not generalize to ‘real-life’ behavior and function, and apparent benefits which achieve statistical significance may not have any clinical significance. For example, RO might be reliably associated with improvements in verbal orientation, but the question is then posed as to whether knowing the day of the week or whatever makes any difference to the patient’s everyday life. 2 A focus on specific outcomes may obscure important aspects of the whole person; for example, RO may improve cognitive function, but if it also reduces life satisfaction (Baines et al. 1987), then is this worthwhile? This mirrors the concern in recent years regarding the broader effects of the antidementia drugs, with the realization that, in some cases at least, improved cognition and awareness of his/her condition may lead to a reduction in the person’s happiness and contentment. More generally, there is a clear need to monitor the occurrence of any negative effects of these approaches. 3 The impact on those providing care also needs to be considered. Psycho-social approaches often require the input and involvement of care givers, and their morale and strain may have a major influence on the well-being and quality of life of the person with dementia. The benefits to the person with dementia of any approach which adds to the care giver’s sense of strain would need to be considered carefully before it could be recommended. Conversely, an approach which reduced care giver strain might be recommended even if its impact on the person with dementia was negligible.

Reality Orientation

Key point Reality orientation (RO) has been proven to be an effective vehicle for cognitive and behavioral change; however, in view of concerns regarding the clinical significance of these changes and its insensitive use as a general approach, it is recommended that it is used where there are important orientation-related goals for the person, as part of a person-centered care plan.

RO was one of the earliest approaches to psychological intervention in dementia, and is certainly the most extensively evaluated. Developed in the USA in the late 1950s, two main components of the approach are usually described. 1 RO sessions. These involve small group work, typically for 30–60 minutes, up to five times per week, for 3–6 people with dementia. Sessions (or ‘classes’ in the original implementations) usually have a cognitive focus, typically beginning with rehearsal of orienting information and discussion

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of current events (in the immediate environment and more widely). Games and a variety of activities with a cognitive emphasis often feature. Sensory stimulation may be used in groups with more impaired members, aiming to increase awareness of the current situation through a variety of sensory modalities. Music is often used to encourage attention and engagement in the group. Refreshments are usually served to create a social atmosphere. There is typically a tangible focus to the group discussion: a whiteboard containing orienting information; objects and pictures reflecting the topic of discussion; notebooks and personal diaries extending the opportunities for repetition and rehearsal of information. 2 24 h RO. This involves an orienting approach throughout the day by all who come into contact with the person with dementia, reinforced by orienting information in the environment, such as RO boards, signposts and other memory aids. Originally, the emphasis was on a proactive approach by staff, feeding in current information at every opportunity; more recently, a more reactive approach has been developed, with staff responding to patients’ questions with accurate information, or by helping the person to discover the information for themself (Reeve & Ivison 1985; Williams et al. 1987). This approach probably has less risk of overwhelming the patient with information that cannot be readily digested or assimilated. A third component of RO, attitude therapy, was originally described, in which staff adopted ‘prescribed attitudes’ with particular patients (e.g. kind firmness or matter of fact or no demand) according to their assessed needs, in order to achieve greater consistency between staff in their approach to the specific patient. However, little systematic work has been carried out with this aspect of the original program (Holden & Woods 1995). Descriptions of the approach appeared in the mid-1960s, and a number of practical guides and manuals have subsequently been published (see Holden & Woods 1995). The first randomized controlled trial (RCT) was reported from the UK, appearing to give a positive evaluation of the effects of RO sessions on patients’ function in the

ward setting, rated by staff who were blind as to whether the patient was attending RO sessions or simply spending unstructured time in the specially equipped RO room, away from the ward (Brook et al. 1975). RO has also been applied with patient populations having diagnoses other than dementia, such as head injuries, learning disabilities and chronic psychiatric problems, and it is likely that some of the patients with whom it was developed in the US had chronic psychoses rather than a dementia. However, the almost universal occurrence of orientation problems in people with dementia has led to RO becoming particularly associated with the dementia care field. A systematic review of RO is available in the Cochrane Library (Spector et al. 1999a). The review focuses on RO sessions, including studies where patients attended groups for at least 3 weeks, the minimum number of sessions being 10. An extensive literature search was carried out, identifying 21 controlled studies of RO sessions. Two evaluated 24 h RO only, six were clearly not randomized and for five studies it remained unclear whether or not the trial was randomized despite efforts to contact the author. This left eight studies, of which only six could be included in the analysis, the others providing insufficient detail of their results (again unsuccessful efforts were made to contact the authors to rectify this). From the six that included RCTs there was a total of 125 patients, of whom 67 received RO and 58 were in control groups. All six studies utilized measures of cognitive function; the results overall were significantly in favor of an effect of RO on cognitive function (Standardized Mean Difference [SMD]: –0.586; 95% confidence intervals [CI] –0.952, –0.220). Measures of behavioral function could be analyzed from three studies, having a total of 48 patients (28 experimental, 20 control). In the individual studies the results on behavioral measures were insignificant, but the joint analysis indicated a significant effect of RO sessions in this domain also (SMD: –0.659; 95%CI –1.268, –0.050). Control groups used in the analyzed studies included some form of ‘social therapy’, to control for the effects of increased attention in half the

432 CHAPTER IV.6

studies and ‘no treatment’ in the other half. There was no obvious difference in the results obtained depending on the nature of the control group, and it would appear that the effects observed are not simply attributable to an increase in input from staff. The number and duration of RO sessions did not appear to influence the results, i.e. there was no evidence of a dose effect. However, the severity of dementia of the patients included in each study could not be compared directly, and the amount of RO required for a therapeutic effect could potentially co-vary with severity. More evidence is needed on these aspects. The effects reported are immediately following the intervention. Longer-term follow-up has been attempted in a few studies, with conflicting results. Maintenance of any benefits is generally regarded as an important issue in RO studies, with the expectation that further input, perhaps less intensively, or as ‘booster’ sessions, would almost certainly be required. Again this has yet to be thoroughly researched. 24 h RO may also have a part to play in the maintenance of improvements following RO sessions (Reeve & Ivison 1985). 24 h RO does not lend itself to evaluation through RCTs, in view of the change of environment and regime it requires. There have, however, been several comparison group studies (e.g. Zepelin et al. 1981; Williams et al. 1987). Early studies tended to be disappointing, at least in terms of behavioral change. Indeed, Zepelin’s study found a number of changes in behavioral function favoring an untreated control group over a 12-month period. However, this study also encountered a number of problems in relation to the reliability and comparability of the behavioral rating measures used. The modified 24 h RO approach adopted by Williams, Reeve and colleagues in Australia appears more successful, being associated with cognitive and behavioral change. Interestingly, in Williams et al.’s (1987) study, cognitive changes were achieved with 24 h RO alone, without RO sessions. Holden and Woods (1995) point out that behavioral changes appear to be more likely in studies where the implementation of the 24 h RO has been monitored to ensure that it has actually been carried out as planned. It cannot be assumed that training staff in

the approach ensures its implementation (Hanley 1984). Where the aim is for the patient to be better orientated around the ward or home, direct training for the patient, which can be simply monitored and evaluated, has much to commend it. Evidence of the effectiveness of simple training sessions in finding relevant locations on the ward or in the home is provided by a number of studies, including a small group study (five in each group), involving a comparison with no treatment (Hanley et al. 1981) and several single-case studies: Hanley (1981) reporting a series of eight single-case studies, Gilleard et al. (1981) a series of six, and Lam and Woods (1986) one case. All the single-case studies utilized experimental designs allowing the effect of intervention to be clearly demonstrated. There is some evidence that clear ‘sign posting’ may add to the effectiveness of the training. Gatz et al. (1998) conclude that ‘reality orientation is probably efficacious in slowing cognitive decline’. They point out, as do Holden and Woods (1995), a way in which RO can be implemented without sufficient sensitivity to the patient, leading to possible frustration and distress in the patient (Dietch et al. 1989). This consideration has led the American Psychiatric Association in their 1997 Practice Guideline (American Psychiatric Association 1997) to suggest that the small gains associated with approaches such as RO do not justify the risk of negative effects. Certainly RO, as a general therapeutic program, is now rarely encountered in practice, largely because of concerns that it was overly confrontational, tended to emphasize the patients’ deficits rather than strengths, and did not focus sufficiently on clinically relevant treatment goals. Holden and Woods (1995) argue that there is much to be learned from the research on RO that could be applied in the framework of person-centered care. There is a need to identify individual goals specific to each patient, to recognize the possibility of learning and change, and to work with the patient on the areas of concern in a collaborative and empathic, rather than a controlling or confrontational, manner. Further research needs to measure broader outcomes, including quality of life, to ensure that any changes are of real benefit to the patient.

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IV.6.3

Reminiscence Therapy

Key point Reminiscence therapy has not been adequately evaluated in dementia care; those using it should be careful to clarify the aims of their reminiscence work, as this will influence the selection of appropriate methods and measures. Reminiscence work has been a popular approach in dementia care since the early 1980s (Norris 1986). At its most basic, it involves the discussion of past activities, events and experiences, usually with the aid of tangible prompts such as photographs, household and other familiar items from the past, music and archive sound recordings. The approach has roots in psycho-therapeutic work in later life, which emphasizes the adaptive importance of life review in promoting a sense of integrity and adjustment. There is a fair degree of evidence that reminiscence work assists in the reduction of symptoms of depression in older people (Scogin & McElreath 1994). However, it is important to distinguish life review therapy, which involves evaluation of personal (sometimes painful) memories with a therapeutic listener, usually in a oneto-one setting, from a more general reminiscence discussion in a group context, which may have the aim of enhancing interaction in an enjoyable, engaging fashion (Haight & Burnside 1993). Reminiscence work also has a cognitive rationale. People with dementia often appear able to recall events from their childhood, but not from earlier the same day. Accordingly it may be sensible to tap into the apparently preserved store of remote memories. In fact, studies of remote memory suggest that recall for specific events is not relatively preservedaperformance across the lifespan is impaired, but people with dementia, like all older people, recall more memories from earlier life (Morris 1994). Some of the ‘memories’ represent well-rehearsed, much practised items or anecdotes. Morris points out there is an almost complete absence of autobiographical memories from the person’s middle years; conceivably the resulting

disconnection of past and present might contribute to the person’s difficulty in retaining a clear sense of personal identity. The Cochrane systematic review on reminiscence therapy for dementia (Spector et al. 1999b) identified only one randomized controlled trial (RCT), a comparison with reality orientation (RO) and no treatment reported by Baines et al. (1987). Groups met for 30 minutes a day, 5 days a week for 4 weeks, and a variety of reminiscence aids were used. A variety of measures were used; cognitive and behavioral changes were analyzed in the Cochrane review, both of which were not significant, although the behavioral scale slightly favored treatment. However, it should be noted that the sample size was very small, with just five residents in each of the conditions compared. At least one other RCT is available in the literature (Goldwasser et al. 1987). Twenty-seven nursing home residents with a diagnosis of dementia were randomly assigned to a reminiscence group, supportive group therapy or to a no treatment control. The groups met for 30 minutes, twice a week for 5 weeks. No changes were evident on a cognitive measure (the Mini Mental Status Examination [MMSE] ) or a measure of activities of daily living. There was a significant improvement on a depression scale for the reminiscence group compared with the other two conditions. However, Knight (1996) suggests this may be largely a result of their higher initial level of depression. The evaluative literature on reminiscence is then inconclusive, with regard to cognitive and behavioral change. However, it is not clear that what is required are more, larger RCTs of reminiscence groups, evaluated by means of cognitive and behavioral change. Two related areas need careful consideration. 1 The type of reminiscence work, and its aims needs to be clearly defined. There are a number of ways in which reminiscence may be used with people with dementia (Gibson 1994), on an individual or a group basis; as a basis for care-planning; for discussion of general memories or for more specific autobiographical memories as might be involved

434 CHAPTER IV.6

in creating a life-story book; involving family care givers or volunteers; with other people with dementia or with cognitively intact older people. Aims might be to enhance communication, to increase a sense of personal identity, to have an enjoyable activity in company with others, to improve mood and well-being, and/or to increase the individualization of care. 2 Different outcome measures may be appropriate according to the type of reminiscence work and its aims. The list given above suggests that cognitive and behavioral improvement might be the least of the changes expected, except as an indirect consequence of mood change perhaps. In both of the RCTs discussed above, affective change was monitored; in the Baines et al. (1997) study a life-satisfaction index was used, which favored (non-significantly) the reminiscence condition over RO groups. Baines et al. (1997) also examined staff knowledge of those attending group sessions; this increased in

IV.6.4

reminiscence groups compared with no treatment, but also increased with RO, and so may not be a specific effect. Knowledge regarding the person with dementia is of course a prerequisite for individualized care. Others have taken measures of engagement and interaction during the group session (in comparison with other activities) as an index of the impact of reminiscence (Head et al. 1990; Woods & McKiernan 1995), although this is perhaps more of a process than an outcome measure. As yet, there appears to have been no attempt to examine the effect of reminiscence on autobiographical memory, although this would appear to be the obvious cognitive focus of the approach. There is then a need for more evaluative research on reminiscence, matching the creativity of those who continue to develop the approach with designs and measures suited to the aims and structure of the specific form of reminiscence work being undertaken.

Validation Therapy

Key point The results of the one large, well-designed study of validation therapy (VT) were disappointing, but there is a need for further evaluative work, with carefully selected outcome measures. VT is an approach developed in the US by Feil, which began to receive attention in the 1980s (Feil 1993). In part, it is a response to the overconfrontational implementation of reality orientation (RO), which is seen as resulting in the person with dementia withdrawing or becoming aggressive. It involves communication at the level of the emotions underlying the person’s words, validating these feelings as true, irrespective of how the words relate to our conception of current reality. The aim is to restore the person’s dignity and prevent deterioration into vegetation, through listening empathically and non-judgementally, not challenging the person’s view of reality. The approach espouses a deep respect for the individual, valuing

him/her as a complete person. The person is seen as seeking to deal with unresolved issues from previous phases of life, and this process influences the person’s current state. As with RO, VT may be applied individually, as part of the overall practice of care, or in small group sessions. Music is used as a unifying activity in a VT group, and group members are encouraged to have a specific role, such as song-leader, welcomer, etc. Discussion of a topic chosen to draw on the wisdom and experience of the group members takes up the largest part of the group (Bleathman & Morton 1992). A Cochrane systematic review of VT (Neal & Briggs 1999) was able to identify only two published studies for inclusion in the meta-analysis; both studies focused on VT groups. Other studies were excluded, lacking adequate controls or randomization. One study (Toseland et al. 1997) ensured that VT group leaders received good initial training (from Feil) and regular supervision. In addition, tape recordings of group sessions were randomly sampled and monitored to ensure that

NON-PHARMACOLOGICAL TECHNIQUES 435

the VT approach was being followed appropriately. In total, the two studies included 87 participants, 32 receiving VT, 55 in control groups (social contact and usual care). A large number of measures was used in the two studies, covering cognitive performance, behavioral function and disturbance and affect. No significant differences (at the 0.01 level) were identified, although there were some trends in favor of VT, notably on a measure of depression. However, some trends (e.g. on verbal aggression) favored the social contact group in the Toseland et al. (1997) study; these were largely on

IV.6.5

ratings by external assessors, and were not consistent with those of staff working with the patients on a regular basis (both sets of raters were blind to group membership). Overall, the results of this review were inconclusive. Again, in future research attention needs to be given to the choice of appropriate outcome measures. Affect, agitation and engagement appear to be much more relevant than cognitive function, for example. The effects on staff and care givers and the impact of different types of VT (e.g. individual as well as group applications) requires further study.

Memory Training

Key point In the early stages of dementia, there may be a number of patients who wish to work on improving their memory function. A number of techniques, including spaced retrieval and errorless learning appear to be promising for this group. Memory-training approaches reflect the application of techniques that have been developed largely with those with static and specific memory difficulties (Wilson 1989). A number of strategies have been employed, largely on a single-case basis. These include the use of external memory aids, the teaching of mnemonics to assist memory, the enhancement of learning processes, and the use of relatively well preserved aspects of memory (such as procedural or motor memory). The major randomized controlled trial (RCT) to date in this area (Quayhagen et al. 1995) employed three types of cognitive stimulationamemory, problem solving and conversationain comparison with a placebo control (passive exposure to the activity) and a waiting-list control. There were several cognitive benefits in the experimental group, with less decline than the control groups in a follow-up period. External memory aids have been evaluated in a number of studies. For example, Hanley and Lusty (1984) in a single-case study, showed a positive

effect on personal orientation when the patient was trained to use a watch and diary as memory aids. Bourgeois (1990; 1992) has developed a memory book, with photographs and text; using this had a positive effect on conversational quality in three patients with dementia. Several techniques intended to enhance learning have been evaluated. Camp et al. (1996) have pioneered the use of the spaced retrieval technique, for instance, to teach a patient to use a memory aid. Spaced retrieval involves learning one item at a time, and gradually increasing the interval between retrieval trials. Sandman (1993) demonstrated that if the patient self-generated cues, then this facilitated later recall. Clare et al. (1999) have used errorless learning to assist in learning names and other information, in a series of single cases. Guessing is discouraged during learning, with prompts and cues being given, and gradually faded, to ensure that the person correctly retrieves the information, without errors interfering with the learning process. Arkin (1997) reports the use of memory quizzes to reinforce orientation. Capitalizing on implicit and procedural memory has been the focus of at least one study (Zanetti et al. 1997). Time taken to complete self-care tasks in 10 people with dementia was reduced using a procedural memory-training program, after 3 weeks of daily training sessions. Here the emphasis was on enacting and practising the tasks, with explicit memorising not required.

436 CHAPTER IV.6

This is a developing area, where more refined learning techniques are taking the place of more global approaches such as RO. As with RO, care will need to be taken to evaluate whether the negative

IV.6.6

effectsaon the person and care giversaenvisaged by the American Psychiatric Association (1997) are indeed prevalent.

Stimulation

Key point Multisensory stimulation, music and physical exercise appear to hold promise, with possible effects on agitation and disturbed behavior. Individuals may well have preferences for different forms of stimulation. Interest in providing more stimulation and activity for people with dementia dates back to the mid1950s, when studies on general activity and stimulation programs began to appear (Cosin et al. 1958). Such initiatives were an understandable reaction to the monotonous, unstimulating environments typically provided for people with dementia in care, fueled by awareness from experimental studies of young volunteers of the potential debilitating effects of severe sensory deprivation. Over the years, a background level of stimulation and activity has come to be accepted as good practice, and serves as a control condition for other approaches. The emphasis now is on the effects of more specific forms of sensory stimulation and physical exercise. There has been much interest in multisensory stimulation, often known as ‘Snoezelen’. This increases the amount of sensory stimulation, by using lava and fiber optic lamps to provide changing visual stimulation, pleasant aromas, gentle music, materials of interesting textures to touch and feel, and so on. Although described as stimulation, the emphasis is as much on calming as on activating, although engaging the person with the stimulation is seen as important. A randomized controlled trial (RCT) is available (Baker et al. 1997), where participants received either eight stimulation sessions or eight sessions of other activities. Both groups showed short-term improve-

ments in mood and behavior, immediately following the sessions, but the Snoezelen attenders showed longer-term reductions in disturbed behavior. Spaull et al. (1998) report a series of four singlecase studies, where patients received individual stimulation sessions. Ratings during sessions suggested that interaction and interest had increased; following the sessions, disturbed behavior was rated as having reduced. Brooker et al. (1997) report a series of four single-case studies of patients with severe dementia, showing a limited response to massage and aromatherapy. One patient did show significantly less agitation in the hour following the intervention; two others appeared more agitated, perhaps having felt constrained by the intensity of the intervention. Clearly, individual differences will be of particular importance with such approaches. Expressive and creative therapies, including art and drama have also been described. Music therapy is perhaps the best established in dementia care. Series of single-case studies indicate that music produces a reaction in the most severely impaired uncommunicative patients (Norberg et al. 1986; Gaebler & Hemsley 1991). A controlled trial is reported by Lord & Garner (1993). A group of 20 nursing home residents had sessions listening to ‘big band’ music for 30 minutes a day, over a 6-month period. Control groups took part either in puzzle exercises or other recreational activities. Mood, social interaction and recall of personal information improved in the music group, compared with the control groups. Studies looking at more active involvement in music would also be of interest; a protocol for a Cochrane systematic review has been prepared (Koger & Brotons 1999). The impact of physical exercise has been much discussed for many years. Morgan (1991) reviews earlier studies, pointing out their methodological

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weaknesses. An RCT of a ‘Psychomotor Activation Programme’ (Hopman-Rock et al. 1999) reports benefits for residents of homes for the elderly, diagnosed as having dementia, attending exercise sessions twice a week for 6 months. The effects were mainly on cognitive function, with suggestions of increased alertness, with little change on behavioral measures. Alessi et al. (1999) report an RCT of physical activity with incontinent nursing home

IV.6.7

residents (diagnosis not given), finding that residents taking part showed improved night-time sleep and less diurnal agitation. They also spent less time in bed during the day. There is then a growing body of evidence on the effects of various forms of stimulation and activity. Suggestions that reductions in agitation and disturbed behavior may be possible outcomes are particularly encouraging.

Cognitive–behavioral Therapy

Key point Progressive muscle relaxation merits wider use with tense and anxious patients with dementia. Depression in dementia may also be amenable to psychological therapy. Recent years have seen increasing attention being given to the non-cognitive features of dementia, recognising that these probably have as much impact on the quality of life of both the person with dementia and his/her family as the cognitive aspects (Donaldson et al. 1998). One focus has been on anxiety and depression, although measuring the presence and extent of mood disorders becomes more complex as cognitive impairment becomes more severe. For example, Ballard et al. (1996) identified anxiety symptoms in 30% of people with dementia evaluated in a Memory Clinic, and Reifler et al. (1990) report a similar prevalence of depression in their outpatient samples of people with dementia. A pioneering study on the effects of relaxation techniques with people with dementia (Welden & Yesavage 1982) has attracted little attention, despite reporting improved ratings of behavioral function and less use of sleeping medication in those attending relaxation groups three times a week for 3 months. Control patients attended a discussion group. A recent randomized control trial (RCT) (Suhr et al. 1999), involving 34 patients, has supported these findings, with reduced clinicianrated anxiety and behavioral problems, and improvements on some tests of cognitive function in the

group receiving training in progressive muscle relaxation (PMR). The control group in this study were trained in imaginal relaxation techniques. It is suggested that the PMR group responded better as learning this form of relaxation, with its successive tensing and relaxing of muscle groups, relies more on procedural memory, which is relatively spared in dementia. Imaginal relaxation, on the other hand, has a purely cognitive focus. Suggestions that cognitive–behavioral therapy for depression might be utilized for people with dementia with lowered mood (Thompson et al. 1990; Teri & Uomoto 1991) have now been the subject of a RCT (Teri et al. 1997). The interventions being evaluated involved working primarily with the family care giver, with the patient being included as far as possible. There were nine weekly 1-hour sessions in each condition. The first involved teaching the care giver to identify and develop pleasant events for the person with dementia, and later for themselves, as well as strategies for behavior management of difficult behavior. The second adopted a more flexible problem-solving approach, focusing on specific ‘depression behaviors’ of the person with dementia. A third condition offered a ‘typical care control’, with advice and support being offered, but no specific problem solving or behavioral strategies being adopted. In addition, there was a waiting list control group. Seventy-two patient–care giver dyads completed the study, having been randomly allocated to the four treatment conditions. Assessments were carried out blind to treatment allocation. Both the behavioral interventions were associated with reduced levels of

438 CHAPTER IV.6

depression, compared with the two control conditions. Care giver mood also improved. These gains were maintained at 6-month follow-up, with no differences between the two active treatments. It is noteworthy that in this trial the approach to treatment of the patient’s depression is predominantly behavioral, and does not appear to seek to engage directly with the patient’s thinking patterns. Also, the therapy actively involves a care giver, who is potentially able to ensure regular between-session practice and to enable generalization of skills and activities to the person’s everyday environment. There remains interest in a more cognitive approach, individually and in groups (Kipling et al. 1999), but an evaluation study would probably be premature until the techniques are more fully developed. There is also a growing interest in the application of a broad range of psycho-therapeutic techniques

IV.6.8

to dementia. Cheston (1998) provides a helpful review, illustrating the lack of outcome research in this area to date. Issues regarding the aims of such work need to be addressed. It may well be, for example, that psycho-dynamic listening is an effective way of communicating with a person where rational connections may be difficult to discern, and discourse becomes more symbolic and freeflowing. Mutual understanding rather than change may then be the aim. Indeed, Cheston suggests that the argument for formal psycho-therapeutic work is ‘essentially moralathat dementia must be understood as a personal tragedy, and that it is unacceptable that its most immediate victims should so often have to struggle unheard and unheeded against personal disintegration and social isolation’ (Cheston 1998).

Behavioral Approaches

Key point Evidence, largely from series of single-case studies, suggests that people with dementia can be encouraged to function with greater independence by using prompting, reinforcement and practice. Behavioral problems are often multifactorial in etiology, and careful individual assessment and analysis is needed to devise an intervention strategy. Some success with behavioral approaches is reported. The importance of the care environment, and of its influence on the person with dementia, is supported by the literature in this area.

Two major target areas for the application of behavioral approaches to dementia care may be identified. First, there are attempts to increase the patient’s level of independence (Woods 1999), re-learning skills apparently lost and maintaining existing skills. Secondly, there are efforts to reduce the levels of behavioral disturbance and difficulty (Allen-Burge et al. 1999).

Promoting independence Most of the studies aimed at promoting independence have utilized single-case designs; in some studies the diagnosis of dementia is not clearly specified, with participants being described, for example, simply as elderly nursing home residents. There are several examples of the areas where some such studies are available.

Self care McEvoy and Patterson (1986), using behavioral skill-training techniques, showed improvements in basic self-care skills, such as personal hygiene, dressing and bathing in patients with dementia. Josephsson et al. (1993) successfully used external memory aids to support a variety of everyday activities in three out of four patients with dementia. Beck et al. (1997), in a large study involving 90 nursing home residents with severe cognitive impairment, reduced the amount of help required in dressing. The intervention involved simple behavioral and problem-solving techniques for use by nursing assistants.

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Mobility Burgio et al. (1986) reported increased mobility in eight nursing home residents, four of whom had dementia, following the introduction of an approach involving prompting and praise for walking more independently. Distance walked increased and amount of assistance required decreased, with gains maintained at a 4-month follow-up. Improvements were so rapid that it is suggested they resulted from the environment having previously provided few opportunities for walking, rather than from re-learning lost skills.

Continence Here the main therapeutic success has been reported with the prompted voiding procedure, where the aim is not to reinstate independent toileting, but rather to help patients requiring assistance in getting to and using the toilet to remain dry (Burgio et al. 1988; Schnelle et al. 1989). The patient is asked on a regular basis if they wish to be taken to the toilet, and praised for using the toilet and remaining dry. Again, results have been so dramatic that it seems likely that an environmental contingency is being changed, rather than a learning procedure occurring as such. This notion is supported by the difficulty the research team have had in ensuring the program continues after the end of the project: staff appear to prefer to change patients when wet, rather than invest time and energy in reducing the frequency of incontinence (Schnelle et al. 1993). The Schnelle et al. (1989) study involved 126 nursing home residents randomly allocated to intervention or delayed-intervention conditions.

Activities Reinforcement and prompting were reported to be useful in increasing participation in purposeful activities in several early studies (Burton 1980; McCormack & Whitehead 1981), also reducing the amount of sleeping in activity sessions! In a controlled study involving 21 elderly patients, most having dementia, Melin and Gotestam (1981) report increased rates of use of activity

materials, following prompting and reinforcement for their use.

Environmental change It would be generally agreed that the pervasive nature of dementia and the severity of the related cognitive impairments require alterations to the environmental contingencies that are both extensive and intensive, if meaningful change is to be achieved. This has led internationally to the development of ‘special care units’ for people with dementia. However, as Sloane et al. (1995) indicate from experience in the USA of evaluating such units, the evaluation of attempts to change the overall pattern of care has proved to be difficult. Identifying appropriate control groups and comparable ratings of function leads to problems in an area where the unit of randomization would need to be the home or ward, but with most studies having, at best, a ‘special’, high profile, experimental unit and a ‘control’ unit where the usual pattern of care continues. Brane et al. (1989) report an evaluation of ‘integrity-promoting care’, from Sweden. This included a number of changes from the previous pattern of care, such as: individualized care; a more homely environment; more choice and participation for patients; more time allowed for patients to go at their own pace and participate more in self-care. The comparison group were in a second nursing home, with a 3-month intervention period, and a 6-month follow-up. Improvements favoring the intervention group were reported in confusion, anxiety, distractibility, mood and motor performance, with many of the benefits remaining at follow-up. Also in Sweden, there has been an evaluation of a group-living scheme, where a small number, around eight or so, of people with dementia are cared for in a small cluster of ordinary housing units, each person having his/her own room and possessions. A group of patients moving from institutional care were compared with a group who remained in care (Annerstedt et al. 1993). Six months after the move, the group-living patients showed benefits in mood and cognition. At 12 months, both groups showed decline, but this was reported to be of lesser extent in the group-living residents.

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In the UK, again reflecting an attempt to provide more homely, individualized care, there have been several evaluations of ‘domus’ units with a smaller group of patients, aiming to meet the patient’s psycho-social needs as well as the physical needs which have so often been the focus of institutional care. Dean et al. (1993), and Skea and Lindesay (1996) report prospective studies of such domus units, in comparison with traditional hospital wards. Improvements in communication, activity levels, quality of interactions, cognitive function and self-care were among those reported. A negative finding is reported from an evaluation of three experimental National Health Service (NHS) nursing homes for people with dementia (Sixsmith et al. 1993), where the comparison groups included other homes and a hospital ward. Specifically, it appeared that staff in the experimental homes spent no more time in ‘life-enhancing care’ (such as social interaction and group activities) than in the comparison units, devoting their additional resources to ‘routine care’.

Reducing problem behavior With the growing realization that challenging behavior is the greatest clinical problem in dementia, for families, staff and patients themselves, the evaluation of behavioral approaches has re-emerged as an active research area. Allen-Burge et al. (1999) provide an indication of some of the many projects currently underway in this area in the USA. There is also promising work from Australia, linking cognitive training and behavioral approaches through teaching the patient associations between specific cues and specific behaviors (Bird et al. 1995). Much of the work has been nursing-home based, despite some promising cases reported by Pinkston et al. (1988). Examples of studies targeting specific behavioral problems will be described here, but it should be emphasized at the outset that an individualized approach to problem definition and treatment planning is needed in view of the multiple, diverse factors which are known to underlie problem behavior (Woods & Bird 1999). Thus, two patients may both shout and scream frequently; for one it may be an expression of pain, but for the other a means of self-stimulation. Without careful

assessment and analysis interventions will be inappropriately targeted.

Noise-making ‘Disruptive vocalization’ includes a range of problemsashouting, screaming, repeatedly calling out for attention and so on. They are amongst the most distressing behaviors for all those who live with and/or care for the person with dementia. Burgio et al. (1994), working on the premise that either insufficient or excessive stimulation from the environment may be related to these problems, studied the effects of a variety of tactile and auditory stimuli, with a number of nursing home residents having high levels of such difficulties. None of the interventions were associated with a reduction in disruptive vocalizations at the group level of analysis, but for each of the interventions, some residents appeared to improve. In a subsequent study, involving nine residents (Burgio et al. 1996), the effects of ‘white noise’ audiotapes, played through headphones, were evaluated. There was a 23% reduction in disruptive vocalizations when these tapes were used.

Wandering ‘Wandering’ is also a term that incorporates a number of different and distinct patterns of behavior (Hope & Fairburn 1990). Attempts to assist with the type of ‘wandering’ which reflects the person’s spatial disorientation would include the ward orientation training programs discussed previously, as well as the use of cues in one of the single-cases reported by Bird et al. (1995); the aim here was to reduce the frequency at which the patient wandered into the rooms of other residents whilst looking for her own room. There have been reports of particular environmental features reducing the frequency of patients entering unsafe areas; these include a grid formed from masking tape lines on the floor (Hussian & Brown 1987) and a mirror in front of the exit door (Mayer & Darby 1991), although not all reports have been positive (Chafetz 1990). Enhanced environments have been evaluated (Cohen-Mansfield & Werner 1998). These simulate a home or an outdoor natural environment.

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Residents spent more time in these enhanced environments than in the usual nursing-home space, and exhibited more pleasure in the outdoor setting.

Aggression The single most likely setting for an episode of aggression in dementia is the provision of personal care (Ware et al. 1990). Hands-on training for nursing assistants by a specialist nurse, focusing on the communicationaverbal and non-verbala between the nursing assistant and the person with dementia during bathing, was related to a subsequent 24% decrease in physical aggression during baths (Hoeffer et al. 1997).

Agitation It has been suggested that increased agitation during the late afternoon and evening, sometimes described as the ‘sundowning’ phenomenon, may

IV.6.9

be related to disturbances in the patient’s circadian rhythm. Generally, exposure to bright light is an effective way of re-setting the circadian rhythm, and there have been several attempts to evaluate the impact of such exposure on agitation in dementia, including a small RCT (Lovell et al. 1995) that showed reductions in agitation in six patients on days when they were exposed to the lights. Lyketsos et al. (1999) report a randomized, controlled, crossover clinical trial. As in the previous study, light therapy was administered in the morning; the control condition involved a dull light, but was otherwise identical, controlling for the impact of increased attention. Sleep improved in the bright light condition, but there was no effect apparent on agitation or mood. However, the study was again small, with 15 commencing and eight completing the entire trial. Patients were selected who did not show a sleep–wake cycle disorder, although these would be the very patients who might be predicted to show the largest response to bright light therapy.

Conclusion and Integration

There is clearly a growing awareness of the need for a more secure evidence-base for non-pharmacological techniques in dementia care, as is evident from the extent of ongoing research across a broad range of areas. It has to be said that the current evidence-base is flawed in many respects, with problems regarding methodological adequacy and small sample size often apparent. Slavish adoption of the pharmacological evaluation model, of double blind randomized controlled trials, is neither generally feasible nor necessarily desirable. Great care is required in the choice of methodology, of target population and of outcome measures if justice is to be done to the many creative intervention models that are appearing in the field. Reliable measures consistent with the therapeutic aims; patients selected on clear criteria with regard to the aims and scope of the intervention; therapists trained fully in the intervention methods; checks on adherence to the intervention protocol; are among the features of trials which need to be developed further for real progress to be made.

The tension between the group-based randomized control trial (RCT) and the single-case methodology has been referred to previously. With the growing interest from specialists in neuropsychological rehabilitation in this field, there is no doubt that the use of single-case methods will continue to increase. One of the issues that wider adoption of single-case techniques might address is in applying the evidencebase to the individual case. Recognising that some techniques might work well with one patient but not another (e.g. aromatherapy or different types of stimulation), the single-case approach of a carefully measured baseline, with addition of therapeutic components sequentially, offers a method of assessing in the individual case the therapeutic impact of a specific intervention, rather than having to rely on a clinician’s global judgement of the relative impact of the intervention compared with other changes in the patient’s internal and external environments. Rather than being seen as a poor relation, such methodology might offer the possibility

442 CHAPTER IV.6

of evidence-based practice at the individual level. Ultimately, the tremendous variability and heterogeneity in dementia will always be a problem for group designs. Difficulties in implementation of the various approaches discussed have been a frequent theme. Approaches like reality orientation (RO) are misapplied; ‘prompted voiding’ is abandoned when the research team departs; and audiotapes of white noise are only used half the time, even when the research team are observing. At times it appears that it is staff who are the targets of the intervention rather than the patients, as would be predicted by Kitwood’s model of the influence of the social environment on function in dementia (Kitwood 1997). Should there not, then, be greater focus on the evidence-base for changing and maintaining staff behavior? This is the emphasis of much of the work of Burgio and colleagues (see Allen-Burge et al. 1999) and in the quality control methods adopted by Schnelle et al. (1993), as well as in the training in communication aimed at reducing aggression, described above (Hoeffer et al. 1997). Behavior problems are often not problems at all as far as the person with dementia is concerned, and in part they reflect the perceptions and attributions of those around them. Staff training may be effective if staff perceive particular behavior as less difficult, even if its frequency does not change (Moniz-Cook et al. 1998). As has been discussed previously, evaluating different care environments is a complex

IV.6.10

task, but given the impact of the overall culture of care and management practices on the individual staff responsible for day-to-day care, it is one that must be tackled. A shift is also required in interventions with family care givers. An emphasis on outcomes for care givers, in terms of strain and depression, for example, has been appropriate, but less attention has been given to their role in influencing outcomes for the person with dementia (Gilhooly 1999), with little follow-up to the pioneering work of Pinkston et al. (1988), until the Teri et al. (1997) study of working with care givers to reduce depression in the person with dementia. There is a need to identify the best ways of training and supporting care givers, friends and volunteers to assist therapeutically people with dementia not in institutions. Finally, it is important that non-pharmacological techniques are seen as part of the overall plan of care for the individual, complementing holistic assessment and management strategies. There is a growing reservoir of approaches and techniques that can be considered, and discussed with the patient, where possible, and with care givers and staff. There is some evidence on the effectiveness of multidisciplinary care-plans in reducing behavior problems in people with dementia at home (Hinchliffe et al. 1995), but far more work on how best to select and combine the key elements of a care-plan for a patient with dementia is required.

Summary of Key Points

1 The evidence-base regarding non-pharmacological approaches in dementia care is at an early stage of development. Conclusions regarding any of the approaches reviewed would be premature. 2 Evaluation in this area presents a number of methodological challenges, not least in evaluations of care environments. Series of single-case studies, using experimental designs, have an important place in the evidence-base in this field. 3 The approach for which ‘the evidence’ is strongest is reality orientation (RO), despite its current lack of popularity. This reflects the importance of assess-

ing negative effects; its insensitive, over-generalized use has led to it falling into disrepute. Its success augurs well for well designed, individualized, person-centered, sensitive interventions based on cognitive training. 4 Implementation of these approaches in the ‘real world’, outside the context of a research program, requires careful attention to issues of staff training, support and management, in the institutional context, and care giver training and support, where the person lives in the community. The effect of approaches on staff and families is

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an essential, but often neglected, aspect of a full evaluation. 5 The evidence tends to support the general model that non-pharmacological approaches have their primary impact on the ‘excess disability’ of the person with dementia, where the two major areas of the person’s reaction to their difficulties and the social environment are the major targets for intervention. This gives ground for cautious optimism, that potentially important changes may be possible, within the overall framework of the dementing process. Reducing depression, anxiety and agitation are likely to have important beneficial effects, whether or not the person continues to show increased cognitive impairment. However, the complexity of changing and maintaining change in the person’s social environment should not be underestimated. 6 Careful selection of outcome measures is required in evaluative studies, to reflect the realistic changes likely to be associated with the intervention, and to ensure that the overall impact on the person, in terms of quality of life, is not obscured by more specific, compartmentalized measures.

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Drugs in Development and Experimental Approaches

IV.7

Murat Emre

Key points • Treatment of dementia can be conceptualized as symptomatic treatment of cognitive or noncognitive symptoms and the treatment of underlying pathology. • The mainstay of symptomatic treatment of Alzheimer’s disease (AD) has been the cholinergic approach. Besides the acetylcholinesterase inhibitors (AChE-I) currently in use, cholinergic agonists and enhancers are in development. Other therapeutic approaches directed towards neurotransmitter substitution or modulation include serotoninergic, noradrenergic substances, neuropeptides and those acting via excitatory amino acid receptors such as ampakines or NMDA antagonists. • Introduction of atypical neuroleptics represent the most recent development in the treatment of behavioral symptoms. AChE-I also have some beneficial behavioral effects. • Efforts to treat the underlying pathology are based on modulation of amyloid precursor protein (APP) processing in order to decrease the accumulation of beta-amyloid, those to decrease tau hyperphosphorylation, use of nerve growth factors and those based on apolipoprotein E (Apo-E) modulation. Potential use of estrogens and non-steroidal anti-inflammatory drugs (NSAIDs) are also under investigation. Recently vaccination with amyloid beta peptide has been reported to be effective in an animal model of AD.

Following the introduction of the cholinergic hypothesis in Alzheimer’s disease (AD), there has been an explosion of clinical trials for treatment of dementia. In addition to drugs based on cholinergic replacement, a number of new approaches have been developed. In this chapter drugs in development or experimental approaches will be covered. Because a number of substances or approaches are included in other sections these will not be elaborated on in detail here, but will simply be mentioned. Given the nature of the studies and the limited information available for drugs that are not yet marketed, an evidence-based approach cannot be followed in this chapter. Treatment of dementia can be conceptualized as symptomatic treatment of cognitive or non-cognitive symptoms and the treatment of underlying pathology, including prophylaxis. It should be emphasized, however, that certain approaches have mixed effects; they may affect cognitive as well as non-cognitive symptoms and sometimes also the underlying disease process. Some of these approaches may be appropriate for more than one type of dementia.

Alzheimer’s disease Treatment of cognitive symptoms Treatments based on neurotransmitter replacement or modulation In addition to the dramatic decrease in the cholinergic innervation of cerebral cortex a number of other neurotransmitters and neuropeptides are also reduced in the brain of patients with AD. These

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include noradrenaline, serotonin, glutamate, somatostatin and corticotrophin releasing factor (CRF), among others. Drugs in this group are targeted at compensating for these deficits, either through substitution or modulation of neurotransmitter systems. Cholinergic treatment The mainstay of cholinergic treatment, acetycholinesterase-inhibitors (AChE-I) and cholinergic agonists are covered in detail in other sections. Other than these two classes of substances there are other compounds in development based on the cholinergic enhancement approach. These include ABT-418, a nicotinic receptor agonist which activates cholinergic channels (Arneric et al. 1995); alpha-7 nicotinic receptor partial agonist GTS-21 (Kem 1997; Kitagawa et al. 1998); acetylcholine (ACh) release stimulant XR-543, choline uptake stimulant MKC-231; and T-588 which stimulates acetycholine and noradrenaline release. These compounds are in Phase I or II of clinical development (Drug and Market Development 1998). Adrenergic compounds There is some evidence to suggest that noradrenaline may be permissive for the effects of ACh. Alpha-2adrenoceptor antagonists were found to potentiate AChE-I effects on passive avoidance learning in the rat, presumably by noradrenergic activation through presynaptic alpha 2-adrenoceptor blockade (Camacho et al. 1996). Guanfacine, but not clonidine, improved planning and working memory performance, and both compounds improved paired associates learning in healthy volunteers ( Jakala et al. 1999a; 1999b). Clonidine plus physostigmine resulted in improvement in cognitive scales in some patients with AD after short-term treatment, whereas physostigmine alone did not (Bierer et al. 1994). Besipirdine, a combined alpha-2-adrenergic and cholinergic agonist, demonstrated evidence of efficacy in a placebo controlled trial (Huff 1996). This compound is currently in Phase III of clinical development. Serotoninergic compounds The initial efforts of serotoninergic tretment in AD

with 5-HT3 agonist ondansetron yielded negative results (Dysken & Kuskowski 1998). The 5-HT1A antagonist, WAY 100635 was found to ameliorate cognitive impairment induced by fornix transsection in the marmoset, presumably by blocking the relatively increased inhibitory tone resulting from loss of cholinergic excitatory innervation (Harder et al. 1996). SL65.0102, a selective, partial 5-HT4 receptor agonist which is in clinical development, was shown to improve learning and memory in rodents (Moser et al. 1998). Another serotoninergic compound in clinical testing is FK 960. Excitatory amino acid agonists and antagonists Ampakines are substances that enhance glutamate activity by stimulating AMPA type of glutamete receptors. In animal experiments ampakines were found to improve the encoding of memory. Initial human studies in young and elderly healthy volunteers demonstrated favorable effects on memory functions (Lynch et al. 1997). The safety and efficacy of Ampalex, an ampakine, is currently being tested in a double-blind placebo-controlled study in patients with AD, sponsored by NINDS. Memantine, a glutamatergic-transmission modulator, is a noncompetitive NMDA-receptor antagonist. It exerts a rapid, voltage-dependent blockade of NMDA receptors and is suggested to allow glutamatergic transmission under physiological conditions and inhibit the excitotoxicity when there is excessive glutamate release (Wenk et al. 1994; Zajaczkowski et al. 1997). In a recent study memantine was found to protect from beta-amyloid induced neurotoxicity in hippocampus and improve learning in rats (Miguel-Hidalgo et al. 1998). Thus, the drug is expected to improve cognition and prevent the presumed excitotoxicity in AD. In a placebocontrolled, 3-month trial in patients with moderate to severe AD, vascular denentia (VaD) or mixed dementia, memantine was found to be significantly superior to placebo in overall and functional scales (Winblad & Poritis 1998). One large placebo controlled trial with memantine in patients with AD and two in patients with VaD have been recently completed, the drug was found to be effective both in cognitive and overall scales in mild to moderate VaD and in moderately severe to severe AD. Re-

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gistration files for memantine have been submitted in several countries. d-cycloserine, a partial agonist at the glycine site of NMDA receptor, was found to facilitate activation of NMDA receptor–ionophore complex in the AD brain (Chessell et al. 1991). The clinical trials, however, revealed mixed results: whereas earlier studies at lower doses revealed no beneficial effects (Fakouhi et al. 1995), more recent studies, one employing a higher dose, suggested that short-term treatment with d-cylcoserine may result in enhanced implicit memory (Schwartz et al. 1996) and improved cognition in patients with AD (Tsai et al. 1999). Benzodiazepine receptor modulation Because benzodiazepines impair memory and learning their antagonists or inverse agonists may have an opposite effect. Reactivation of cortical cholinergic input can be achieved by trans-synaptic disinhibition of basal forebrain cholinergic neurones. This can be accomplished by benzodiazepine inverse agonists which reduce the potency of GABA to block neuronal excitation (Sarter & Bruno 1997). The benzodiazepine partial inverse agonist S-8510 was found to improve spatial memory, increase ACh release and high-affinity choline uptake from the cortex in basal forebrain-lesioned rats (Abe et al. 1998). Nootropics Nootropics are a heterogenous group of compounds which effect brain metabolism at large and may exert complex metabolic, behavioral and protective effects in experimental studies. A separate section is dedicated to piracetam and its derivatives, as well as to gingko biloba. Several other nootropics are in clinical testing. Vincamine, an alkaloid isolated from Vinca rosea was tested in a mixed population of patients with AD or VaD in a placebo-controlled trial and found to have beneficial effects on cognitive tests and overall scales (Fischhof et al. 1996). Another nootropic in development, BMY 21 502, was demonstrated to improve cognition in patients with AD in a small placebo-controlled trial (Shrotriya et al. 1996). The use of the compound was, however, associated with increased liver enzyme levels and a relatively

poor tolerability. TA-0910 is another nootropic agent shown to improve cognitive performance in a small study of patients with AD (Nakata 1996). Others The potential role of neuropeptides in treatment of AD was also investigated. Thyrotropin releasing hormone (TRH) and montirelin (NS-3) a TRH analog, were demonstrated to improve behavioral abnormalities in senescence-accelerated mice and memory deficits in NBM-lesioned rats (Miyamoto et al. 1994; Ogasawara et al. 1996). In human studies TRH seemed to improve depression in patients with AD (Albert et al. 1993) and also to attenuate the memory impairment induced by anticholinergics (Bennett et al. 1997). Posatirelin, a tripeptide TRH analog with cholinergic, catecholaminergic and neurotrophic properties, was found to improve cognition and behavior in patients with AD (Parnetti et al. 1995). Several TRH analogs including taltireline, posatirelin, montirelin and protirelin (TRH itself), are currently in development. Another approach is to increase the level of brain, CRF thereby reversing learning and memory deficits. A CRF-binding protein antagonist, NBI-30775, is currently in Phase II (Aisen & Davies 1997). Treatment with testosterone had beneficial effects on visuospatial functions and spatial memory in patients with AD and healthy elderly men (Cherrier et al. 1998).

Treatment of non-cognitive symptoms Atypical neuroleptics Several atypical neuroleptics have been introduced in the past few years for the treatment of psychotic disorders. Among these olanzapine, quetiapine and risperidone were also tested in clinical trials for the treatment of non-cognitive symptoms associated with AD and were found to reduce hallucinations, delusions and anxiety. These drugs are covered in detail in another chapter. Others Although cholinergic drugs were initially expected to influence predominantly the cognitive symptoms

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of AD, it is now becoming apparent that they also improve the non-cognitive symptoms. The M1/M4 muscarinergic receptor agonist xanomeline was found to improve behavioral symptoms (including vocal outbursts, suspiciousness, delusions, agitation) in patients with mild to moderate AD (Bodick et al. 1997). Although this drug was associated with a number of adverse events which led to withdrawal in half of the high dose patients, the results suggest that muscarinergic agonists may be useful for the treatment of non-cognitive symptoms of AD. Favorable effects on behavioral symptoms of AD were also observed with AChE-Is such as rivastigmine, metrifonate and donepezil (Levy et al. 1999). As mentioned above, TRH was found to improve depression in patients with AD and beneficial effects on behavior were also observed with a TRH analog, posatirelin (Albert et al. 1993; Parnetti et al. 1995). Divalproex, a derivative of valproate was found to reduce aggressivity and promote socially appropriate behavior in patients with dementia (Haas et al. 1997); a placebo-controlled trial is under evaluation. Melatonin significantly improved sleep–wake cycle disorders in patients with AD in a small placebo-controlled trial (Tozawa et al. 1998). A multicenter placebo-controlled trial of melatonin for sleep disturbance in AD has been completed by the Alzheimer’s Disease Cooperative Study group; results have not yet been published.

Treatment of underlying pathology Beta-amyloid based approaches According to the amyloid cascade hypothesis of AD, pathologically increased breakdown of the transmembrane protein APP into the toxic betaamyloid peptide or its decreased clearance results in fibrillary aggregation of this peptide in the intercellular space and in consequent neuronal and synaptic loss. Although there is evidence both for and against this hypothesis, substances to avoid the assumed toxicity of beta-amyloid are currently popular targets. Several enzymes process APP. Whereas processing by beta-secretases results in the production of beta-amyloid peptide, processing by alpha-secretases results in the production of soluble fragments (sAPP) which do not form

amyloid fibrils and may even have neurotrophic effects. Gamma-secretase activity, on the other hand, modulates beta-secretase activity and determines the length of the beta-amyloid peptide, which is important for its toxicity. Strategies based on protection from putative beta-amyloid toxicity include secretion inhibitors, aggregation inhibitors and inhibiton of beta-amyloid induced toxicity. Protein kinases and phosphatases acting on APP or the secretases may be targets for therapeutic intervention (Checler 1995). It is assumed that increasing alpha-secretase activity or decreasing beta- and gamma-secretase activity can inhibit the production of toxic amyloid. In cell cultures bafilomycin, brefeldin and MDL 28 170 have been found to inhibit processing by beta- or gamma-secretases (Schenk et al. 1995). Serotonin 5-HT2 and 5-HT1c receptor agonists, vasopressin V1a and bradykinin B2 receptor agonists were found to stimulate alphasecretase pathway (Parnetti et al. 1997). AChE-I and M1 muscarinergic receptor agonists were shown to have similar effects (Racchi et al. 1999). Nicotinic receptor stimulation was found to protect neurones against glutamate and beta-amyloid induced cytotoxicity (Kihara et al. 1999). Protein kinase C activity may be essential for processing and regulation of expression of APP and substances that induce protein kinase C reduce the production of amyloidogenic fragments (Xu et al. 1995). The neurotoxicity of beta-amyloid seems to be dependent on an aggregated state that requires several steps to be achieved, each of which can be therapeutic targets. Some polysulphated or polysulphonated compounds including Congo Red, the antibiotic rifampicin and porphyrin compounds related to heme, were found to inhibit the aggregation of beta-amyloid and to protect cells from neurotoxic effects in cell cultures (Lorenzo & Yankner 1994; Tomiyamo et al. 1996; Howlet 1997). Aggregation of beta-amyloid was also prevented in vitro by monoclonal antibodies raised against the peptide (Solomon et al. 1996). A short, five-residue peptide partially homologous to the beta-amyloid that contains residues acting as beta-sheet blocker (betasheet breaker peptide), iAB5, was shown to prevent amyloid neurotoxicity in cell cultures, to reduce in vivo cerebral beta-amyloid deposition and formation of amyloid fibrils in the rat brain (Soto et al. 1999).

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Although the exact mechanism of beta-amyloid induced toxicity is not clear, calcium influx and oxidative stress are implicated and may represent potential targets. A number of compounds to reduce beta-amyloid secretion (Abetal-196) or to block beta-amyloid aggregation (NC-531, NE-503/NE531, 9-acridinone derivatives), and thus amyloid deposition, are currently in preclinical development (Drug and Market Development 1998). Melatonin, a hormone with a proposed role in the ageing process, was shown to inhibit spontaneous formation of beta-sheets and amyloid fibrils, and to prevent death and oxidative damage of neuronal cells exposed to beta-amyloid. With these dual anti-amyloidogenic and antioxidant properties, its natural occurrence, its ability to cross the blood–brain barrier, and its low toxicity, melatonin was suggested as a potential therapeutic agent for AD (Pappolla et al. 1999). Recently a putative beta-amyloid vaccine was developed, which was found to be effective in an animal model of AD. Transgenic animals overexpressing mutant human APP were immunized with amyloid-42 peptide either before the onset of AD-type neuropathological changes or at an older age when beta-amyloid deposition and several other neuropathological changes were established. Immunization prevented the development of amyloid plaque formation, neuritic dystrophy and astrogliosis in the young animals, and reduced the extent and progression of these AD-like pathologies in the older animals (Schenk et al. 1999). Single dose tolerability studies in humans have been reported to be completed, no undue adverse events were observed. Phase II studies with this vaccine called AN-1792 are currently ongoing. Tau phosphorylation Hyperphosphorylated tau protein is the major component of the neurofibrillary tangles. Hyperphosphorylation of the protein impairs its function resulting in impaired neurite outgrowth, disturbed synaptic function and reduced response to neurotrophic factors (Nuydens et al. 1995). Thus, aberrant tau may be a contributing factor to neuronal dysfunction (Lee 1996) and inhibition of the kinases responsible for tau hyperphosphorylation, or augmentation of phosphatases capable of depho-

sphorylating aberrant tau may have therapeutic potential. Whereas it is likely that a number of kinases are involved in hyperphosporylation, and disruption of their activity may impair other cellular functions (Iqbal 1996), dephosphorylation of tau by phosphatases 2A and 2B may represent a better therapeutic option, because these enzymes are present in higher levels than necessary in the tissue and their modulation is less likely to interrupt the normal cellular function. Both phosphatases 2A and 2B were demonstrated to dephosphorylate tau isolated from AD brain (Wang et al. 1996), and protein phosphatase 2B was also found to dephosphorylate tau in situ (Fleming & Johnson 1995). The activity of both phosphatase 2A and 2B is enhanced by activators such as Mn2+, which may be an option for treatment (Iqbal & Grundke-Iqbal 1996). Recently, muscarinergic M1 agonist AF150(S) was demonstrated to reverse the cognitive and cholinergic deficits and lead to a preferential dephosphorylation of the hyperphosphorylated tau in ApoE-deficient mice, suggesting that muscarinergic agonists may also offer some therapeutic potential in this regard (Genis et al. 1999). ApoE-based approaches ApoE ε4 genotype has been found to be associated with a higher risk of AD whereas ApoE ε2 allele may provide protection from AD or may delay the mean age of onset. It is not clear what roles, and by what mechanisms, the different ApoE alleles contribute toward accelerating or retarding the disease process. Recent findings suggest that ApoE ε2 and ε3 have greater avidity than ApoE ε4 for the tau protein. Thus the presence of ApoE ε2 and ε3 proteins may help prevent abnormal phosphorylation of tau (Huang et al. 1994). In addition, it was demonstrated that ApoE ε4 allele is more likely than ApoE ε2 and ε3 to bind beta-proteins of amyloid plaques; it is possible that the increased presence of the ApoE ε4 protein may accelerate the deposition of beta-amyloid (Strittmatter et al. 1993). In another in vitro experiment it was found that ApoE ε4 protein does not neutralise free radicals as well as ApoE ε2 and ε3 proteins (Miyata & Smith 1996). Taken together, these results imply that ApoE ε2 allele may be protective against AD

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by several different mechanisms and drugs that alter the production of ApoE ε4 or the clearance of ApoE/beta-amyloid complexes may be useful. Alternatively, therapeutic administration of ApoE ε2 or ε3 alleles through gene therapy or development of ApoE ε2 analogs can be pursued (Strittmatter et al. 1994; Kaplitt et al. 1996).

factor-I (IGF-I), among its other activities was also found to enhance cholinergic transmission, to protect hippocampal neurones from beta-amyloid toxicity and to reduce tau phosphorylation (Dore et al. 1997); intranasal administration was shown to provide sufficient concentrations of the substance in the rat brain (Thorne et al. 1998).

Nerve growth factors

Others

A number of neurotrophic factors have been identified of which nerve growth factor (NGF) seems to be the most promising for treatment of AD. In in vivo studies NGF was shown to enhance neuronal survival in axotomised cholinergic forebrain neurones (Hagg et al. 1989), to enhance the activity of cholineacetyltransferase and improve cognitive functions (Dore et al. 1997), including lesioned and aged rats (Fischer et al. 1987; Dekker et al. 1994; Markowska et al. 1994). Systemically administered NGF, however, does not cross the blood–brain barrier, intrathecal and nasal applications were associated with substantial adverse effects. One patient with AD was administered NGF via a cannula for 3 months with some improvement in tests of verbal episodic memory, but not in other cognitive measures (Olson et al. 1992). In addition to the direct administration of NGF, substances which increase the synthesis or release of NGF or enhance its effects are also being considered. One such compound, AIT-082, was shown to cross the blood–brain barrier, stimulate the production of NGF, augment the effects of NGF on cells in culture and enhance cognitive functions in aged animals (Glasky et al. 1994; Middlemiss et al. 1995; Parnetti et al. 1997a). Another small molecule NGF analog, SR 57746, is in clinical development. Lipophilic beta-adrenergic receptor agonists were also shown to stimulate the expression of NGF in vivo (Fabrazzo et al. 1991). Idebenone and propentofylline are other compounds which stimulate NGF synthesis; their repeated oral administration restored cholinergic activity and memory performance in lesioned rats (Nabeshima 1995; Yamada et al. 1997). Another approach is based on gene therapy to provide chronic secretion of NGF in the brain by genetically modified cells (Martinez-Serano et al. 1995). Insulin-like growth

Estrogen and its brain selective analogs, antiinflammatory agents including the new generation Cox-2 inhibitors, and antioxidants, are popular drug targets and a number of clinical trials with different compounds are currently ongoing. These therapeutic avenues are extensively covered in other chapters. One approach derived from estrogen’s effects are the ‘neurosteroids’. Nuclear estrogen receptors were demonstrated in the brain (Alves et al. 1998) and APBI-124, a neuroprotective oestrogen analog that does not act through the classical female estrogen receptors, and thus is assumed to be devoid of hormonal feminising side-effects, is currently in development. A link between neurosteroid receptors and beta-amyloid was suggested recently by Xu et al. (1998), who have demonstrated that physiological levels of 17-beta estradiol reduce the generation of beta-amyloid in primary cultures of human embryonic cerebro-cortical neurones. MAO-B inhibitor deprenyl as an antioxidant is discussed in a seperate chapter. Lazabemide, a selective and reversible MAO-B inhibitor was tested in two placebo-controlled trials over 1 year and was found to be significantly better than placebo with regard to cognitive and overall functions (Bowden et al. 1998; Kumar et al. 1998). Other, confirmatory clinical trials are underway. Several substances tested for therapeutic use in AD show multiple potentially beneficial effects in animal experiments. Some of these compounds including propentofylline, acetyl-l-carnitine, CDPcholine and nimodipine are covered elsewhere. Idebenone, which is a metabolite of coenzyme Q-10, is an antioxidant which inhibits lipid peroxidation, stimulates synthesis of NGF, protects against excitotoxic neuronal damage in vitro and improves behavior in aged and basal forebrain damaged rats (Nitta et al. 1994). In clinical trials

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idebenone was found to exert beneficial effects on cognitive, non-cognitive and overall measures in patients with AD (Weyer et al. 1997; Gutzmann & Hadler 1998). In addition to their substitutive, symptomatic effects cholinergic substances may also influence the underlying pathology. AChE-I have neuroprotective effects in vitro and they increase soluble APP. Both muscarinic and nicotinic agonists may modulate protein kinases and APP processing. Clinical trials with donepezil and rivastigmine are ongoing to assess the effects of AChE inhibitors on conversion of patients with mild cognitive impairment to AD. Excitotoxicity is thought to contribute to neurodegeneration in a number of degenerative diseases including AD, and NMDA antagonists may modify this process. Sabeluzole, a benzothiazole derivative, was suggested to have several effects in animal models including inhibition of lipid peroxidation, stabilization of neuronal cytoskeleton and inhibition of neurotoxin-induced tau expression and cell death (Domany et al. 1996; Geerts et al. 1996; Uberti et al. 1997). In a 1-year placebo-controlled study patients receiving sabeluzole were more stable in some cognitive measures than those on placebo, suggesting that sabeluzole may slow down the cognitive deterioration in AD (Mohr et al. 1997). Patients on an orally administered natural cytokine, PRP, seemed to do better than those on placebo in a pilot 1-year study (Leszek et al. 1998). Lypophilic vasoactive intestinal peptide (VIP) analogs may represent a potential treatment of AD because of their neuroprotective effects. St-Nle-VIP, a lypophilic analog of VIP with a potential for intranasal use was found to improve memory and learning capacity in animal experiments (Gozes et al. 1996).

Vascular dementia VaD differs from AD in that there is no specific neurotransmitter deficiency and thus no specific replacement therapy. Some of the treatment approaches developed for AD are potentially also valid for VaD including antioxidants, nootropics, neurotrophic and neuroprotective agents, compounds with multiple actions such as pentoxfylline and propentofylline. Many of these approaches are covered in another section. Several other com-

pounds have been recently tested in clinical studies. Posatirelin, a TRH analog with modulatory actions on the monoaminergic, cholinergic systems and neurotrophic effects was found to significantly improve cognitive functions including memory in a placebo-controlled study over 3 months. The difference was maintained after a 4-week withdrawal phase suggesting long-lasting effects (Parnetti et al. 1996). The nootropic agent nicergoline significantly improved cognitive and overall functions in patients with VaD in a 6-month placebo-controlled study (Herrmann et al. 1997). In a pilot study, calcium channel blocker nicardipine was compared to placebo over a 6-month period in patients who had a previous transient ischemic attack. Although no significant differences were found, patients on nicardipine tended to perform better in certain tests (Molto et al. 1995). The platelet anti-aggregant agent triflusal was tested in patients with vascular dementia over a 1-year period using no treatment as control. After 1 year a significantly smaller percentage of patients on triflusal showed a predefined amount of cognitive decline as compared to control group (Lopez Pousa et al. 1997). Suledoxide, a compound with antithrombotic-hemorheological properties, reduced plasma fibrinogen and factor VII-Ag levels, and seemed to improve cognitive performance in patients with VaD (Parnetti et al. 1997b). Recently, the non-competitive NMDA antagonist memantine was found to improve both cognitive and overall functions in patients with mild to moderate VaD in two large, prospective, placebo-controlled trials.

Other dementias The use of AChE-I and atypical neuroleptics in patients with dementia with Lewy bodies (DLB), and the use of SSRIs and atypical neuroleptics in patients with frontotemporal dementia are covered in the relevant sections.

Individual drugs The table available on the companion website to this book provides a list of many drugs in development, based on the approaches outlined above and other novel mechanisms.

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However, because of the commercial secrecy inevitably surrounding information on many of these pre-launched compounds, neither the precise phase of development (or whether it has been discontinued because of toxicity, lack of efficacy or other reasons) nor the accuracy of the information can be guaranteed. Nevertheless, it represents a useful and accessible source of information for people interested in attempting to track the development of drugs before approval. Regular updates will attempt to track any changes that appear in public domain sources and from the information which we hope many readers will supply by visiting the website.

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Jakala, P., Sirvio, J., Riekkinen, M. et al. (1999b) Guanfacine and clonidine, alpha 2-agonists, improve paired associates learning, but not delayed matching to sample, in humans. Neuropscyhopharmacology 20 (2), 119–130. Kaplitt, M., Fass-Holmes, B., Vahlsing, H.L., Manthrope, M., Conner, J.M. & Varon, S. (1996) Apolipoprotein E, beta-amyloid, and the molecular pathology of Alzheimer’s disease: therapeutic implications. Annals of the New York Academy of Science 802, 42–49. Kem, W.R. (1997) Alzheimer’s drug design based upon an invertebrate toxin (anabaseine) which is a potent nicotinic receptor agonist. Invert Neuroscience 3 (2–3), 251–259. Kihara, T., Shimohama, S. & Akaike, A. (1999) Nicotine receptor stimulation protects neurons against glutamateand amyloid-B-induced cytotoxicity. In: Alzheimer’s Disease and Related Disorders (eds Iqbal, K. et al.), pp. 715–722. John Wiley, Chichester. Kitagawa, H., Moriyama, A., Takenouchi, T., Wesnes, K., Kramer, W. & Clody, D.E. (1998) Phase I studies of GTS-21 to assess the safety, tolerability, PK and effects on measures of cognitive function in normal volunteers. Neurobiology of Aging 19 (4S), 182. Kumar, V., Cameron, A.M. & Amrein, R. (1998) Experience with the RIM-B Lazabemide in Alzheimer’s disease. Neurobiology of Aging 19 (4S), 328. Lee, V.M.Y. (1996) Regulation of tau phosphorylation in Alzheimer’s disease. Annals of the New York Academy of Sciences 777, 107–113. Leszek, J., Inglot, A.D., Janusz, M. & Lisowski, J. (1998) Oral cytokine administration-therapeutic approaches to Alzheimer’s disease. Neurobiology of Aging 19 (4S), 180. Levy, M.L., Cummings, J.L. & Kahn Rose, R. (1999) Neuropsychiatric symptoms and cholinergic therapy for Alzheimer’s disease. Gerontology 45 (Suppl. 1), 15–22. Lopez Pousa, S., Mercadal Dalmau, J., Marti Cuadros, A.M., Vilalta Franch, J. & Lozano Gallego, M. (1997) Trifusal in the prevention of vascular dementia. Revue Neurologique 25 (146), 1525–1528. Lorenzo, A. & Yankner, B.A. (1994) Beta-amyloid neurotoxicity requires fibril formation and is inhibited by Congo Red. Proceedings of the National Academy of Sciences of the USA 91, 12 243–12 247. Lynch, G., Granger, R., Ambros-Ingerson, J., Davis, C.M., Kessler, M. & Schehr, R. (1997) Evidence that a positive modulator of AMPA-type glutamate receptors improves delayed recall in aged humans. Experimental Neurology 145 (1), 89–92. Markowska, A.L., Koliatsos, V.E., Breckler, S.J., Price, D.L. & Otton, D.S. (1994) Human nerve growth factor improves spatial memory in aged but not young rats. Journal of Neuroscience 14, 4815–4824. Martinez-Serano, A., Fischer, W. & Bjorklund, A. (1995) Reversal of age dependant cognitive impairments and cholinergic neuron atrophy by NGF-secreting neuronal progenitors grafted to the basal forebrain. Neuron 15, 473–484.

456 CHAPTER IV.7

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SECT ION V

Therapies for Cognitive Symptoms, Disease Modification and Prevention Edited by: Jeffrey Kaye, Lon S. Schneider and Nawab Qizilbash

Introduction to Specific Therapies for Cognitive Symptoms or Modifying Disease Prognosis

V.1

Nawab Qizilbash

Current approaches to the treatment of dementia can be considered by the nature of the beneficial effect and the mechanism of action of drugs. Effects can be schematized as: 1 Symptomatic improvement from a baseline value (Fig. V.1.1). 2 Delay of symptomatic decline without any slowing (except briefly upon initiation of therapy, see Fig. V.1.1). 3 Slowing of symptomatic decline (Figs V.1.2 and V.1.3). 4 Improving prognosis and modifying the course of disease (Figs V.1.5–7). 5 Reversing the changes and curing the disease. Curing dementia is almost impossible to imagine, even with the supposedly neuroregenerative drugs in development such the nerve growth factor compounds like AIT-082 (Middlemiss et al. 1995), except for futuristic scenarios with transplantation, as being currently tried in Parkinson’s disease (PD). Reversing some changes may be possible with vaccines that mop up beta-amyloid and this could lead to arrest of further decline. Nevertheless, it is difficult to imagine that the damage caused to neurones could be reversed to ‘cure’ the disease. 6 Prevention of dementia. Strictly, secondary prevention is the term that applies when early signs of the disease are already manifest, as in mild cognitive impairment; primary prevention applies in cases with no evidence of early disease, such as blood pressure reduction in people without cognitive impairment. The shapes of Figs V.1.1–3 need to be put into the context of the stage of the disease, as cognitive

performance (as commonly measured) is curvilineara Fig. V.1.4. Mechanistic approaches can be conceptualized in several ways. 1 The augmentation of deficient neurotransmitters considered to be responsible for the symptoms and signs of the dementia; either by increasing the level of neurotransmitter within the synapse through increased release, decreased breakdown and supplying exogenous neurotransmitter, or modulating the end receptor. 2 Neuroprotection, whereby neurones are protected from further damage, as in established disease or secondary prevention (e.g. conversion of mild cognitive impairment to dementia), or from initial damage in primary prevention (e.g. blood pressure reduction to prevent vascular dementia). 3 Neuroregeneration, with the potential for regrowth of neurones and the theoretical possibility to reverse some of the changes in core symptoms, such as cognition. Unfortunately, compounds may not lend themselves to such clear cut classifications. Replacement of neurotransmitters, for example, with cholinesterase inhibitors may cause symptomatic improvement, slowing of symptomatic decline, delay of symptomatic decline (see Fig. V.1.3) and even improved prognosisadelay of nursing home placement (Knopman et al. 1996). Analogy with PD indicates that use of levodopa may improve shortterm prognosis from considerable improvement in symptoms but that long-term prognosis appears unaffected (Poewe & Wenning 1998; Hely et al. 1999). Protection of neurones from further damage

461

462 CHAPTER V.1

Performance of cognitive (or global) test

a b

Active drug

Placebo No intervention x

After time (x), active drug and placebo groups decline at the same rate. Other measures of effect could be the proportion improving by a certain level of performance on a cognitive or global test.

Time a Magnitude of maximum improvement from baseline and with respect to placebo b Delay of symptomatic decline

Performance on cognitive (or global) test

Fig. V.1.1 Pure symptomatic effects.

b

Active drug

Placebo No intervention Time b Delay of symptomatic decline

should improve prognosis and slow symptomatic decline of core symptoms. However, as the vitamin E and selegiline trial (Sano et al. 1997) suggests, it may be possible to observe an improved prognosis without slowing decline in a core symptom (cognition). The demonstration of symptomatic decline may depend crucially on the assessment tool used. A focus on surrogate outcomes such as cognitive scales in randomized start and withdrawal designs

Fig. V.1.2 Disease modification: pure

slowing of symptomatic decline. Slopes of placebo and drug are divergent.

employed in the vitamin E and selegiline trial would have led to a false negative conclusion about the effects of these two agents (see Chapters V.2.3 and V.2.19). The neuroregenerative approach was still at the experimental stage in 2001. The neurotransmitter approach was based on the observation that the cholinergic system is involved in memory and learning functions, and in Alzheimer’s disease (AD). The cholinergic system

Performance on cognitive (or global) test

THERAPIES FOR COGNITIVE SYMPTOMS 463

a b

Active drug

Placebo No intervention

x

Fig. V.1.3 Disease modification:

slowing of symptomatic decline and symptomatic effects. After time (x) the slopes of the active drug and placebo groups continue to diverge.

Time

a Magnitude of maximum improvement from baseline and with respect to placebo b Delay of symptomatic decline

Pre-symptomatic phase

MCI

Etiological factors (environmental and genetic)

Time Promotion of pathological processes

Dementia

30 25 MMSE

20 15 10 5 0

Fig. V.1.4 Lifetime course of cognitive decline in AD.

was shown to modulate memory and learning a long time ago (Deutsch 1971); centrally acting anticholinergic compounds produce attention and memory deficits (Dundee & Pandit 1972); enhancers of the cholinergic system relieve learning and memory impairments caused by lesions in the system (Collerton 1986); and cholinergic loss correlates with the degree of cognitive impairment in the brains of patients with AD (Perry et al. 1977). Results from the first of the cholinergic drugs to

receive regulatory approval (tacrine) led to variable results in trials with different designs and which were mostly underpowered. However, an individual patient data meta-analysis found the results to be homogeneous (Qizilbash et al. 1998) and three later-approved cholinesterase inhibitors (donepezil, rivastigmine and galanthamine) have found effects on cognition compatible with those of tacrine (see Chapters V.2.4, V.2.5, V.2.7 and V.2.21). The clinical usefulness of the benefits of

464 CHAPTER V.1

100

Proportion without event

No dementia (a)

Fig. V.1.5 Simple prognosis

Active drug

Placebo or no intervention

0

Time

100

modification. (a) The rate of decline in the general population without dementia, matched for age and sex, will be highly dependent on age. Examples of the type of event that could be used are: a given level of dependency; loss of levels of dependency; nursing home placement; or diagnosed dementia in patients with mild cognitive impairment.

Proportion without event

No dementia (a)

(b) Fig. V.1.6 Temporary prognosis

Active drug

Placebo or no intervention 0

modifications. (a) Rate of decline in the general population without dementia will be highly dependent on age. (b) Disease modification effect is lost and the rate of decline assumes that of the placebo group.

Time

100

Proportion without event (%)

No dementia (a)

Active drug (b) Fig. V.1.7 Curative prognosis

Placebo or no intervention

0

x Time

modification. (a) Rate of decline in the general population without dementia will be highly dependent on age. (b) When the rate of acquiring the event approaches the rate in an ageand sex-matched general population this represents a ‘cure’.

THERAPIES FOR COGNITIVE SYMPTOMS 465

100

Fig. V.1.8 Event-free survival of 341

patients with AD assigned to treatment with α-tocopherol or placebo. Reproduced from Sano et al. 1997 with permission.

Event-free survival (%)

90 80 70 60

α-tocopherol

50 40 30

Placebo

20 10 0 0

100

these drugs remains controversial (see Chapters V.2.4, V.2.5, V.2.7 and V.2.21). Improving prognosis and modification of the course of the dementia can be conceptualized with several scenarios (see Figs V.1.4 –7). 1 A lower proportion of individuals reaching the adverse outcome compared with controls, with the difference increasing with time and exposure to the drug (see Fig. V.1.5). Results from the trial of vitamin E and selegiline behaved in this manner (Sano et al. 1997; Fig. V.1.8). 2 A lower proportion of individuals reaching the adverse outcome compared with controls, until a point at which the rate of reaching the adverse outcome begins to parallel that in the control group (see Fig. V.1.6). 3 A lower proportion of individuals reaching the adverse outcome compared with controls, until a time at which the rate of reaching the adverse outcome parallels an age–sex matched population without dementia, but with the mix of diseases of old age reflected in the general underlying population (see Fig. V.1.7). This effectively represents ‘cure’ and would be analogous to surgery in certain stages of certain cancers, such as mastectomy for early breast cancer or chemotherapy for some childhood leukemias. Although many types of events could be used, it is important that they are relatively stable, have good reliability and, for practical reasons in trials, that they can be collected with little loss to followup over long periods of time (a few years). Useful events could be:

200

300

400

500

600

700

Days

a given level of dependency or function; loss of levels of dependency or function; nursing home replacement; or diagnosed dementia in people without dementia. Changes in cognition (reaching a given performance level or a given drop in performance) as an outcome event presents difficulties in interpretation due to variability in the assessment, requiring stability to be demonstrated on more than one occasion, as well as the challenge of assessing overall clinical significance. Use of behavior as an event also has the problems of variability and lack of stability, as behavioral symptoms come and go and can vary on at least the three dimensions of frequency, duration and severity. The results of approaches of neurotransmitter replacement and neuroprotection are described in the following chapters of this section; the approaches planned for drugs in development are described in Chapter IV.7. The drugs reviewed in the following chapters have been chosen becasue they are used at least in some countries around the world, or are in the preregistration phase with regulatory authorities. For example, the following types of drugs were used for patients with dementia (proportion of dementia patients treated in parentheses), in the health insurance system in Germany in 1994: peripheral vasodilators (45%)aGingko biloba, nimodipine, pentoxifylline, etc.; hypnotics and sedatives (40%)abarbiturates and benzodiazepines, etc.; nootropics (15%)apiracetam, meclofenoxate, vinpocetin, etc. (Schwarz et al. 1999). How much the situation has changed is 1 2 3 4

466 CHAPTER V.1

unknown, but it is likely that at least some patients will still be prescribed these drugs in Germany, other European countries, and elsewhere. Many of the contributors to this book have used meta-analyses from their Cochrane Reviews to provide graphs, with permission from Update Software. Cochrane Reviews are regularly updated as new information becomes available and in response to comments and criticisms. The reader should consult The Cochrane Library for the latest version of a Cochrane Review. Information on The Cochrane Library can be found at www.updatesoftware.com.

References Collerton, D. (1986) Cholinergic function and intellectual decline in Alzheimer’s disease. Neuroscience 19, 1. Deutsch, J.A. (1971) The cholinergic synapse and the site of memory. Science 174, 788. Dundee, J.W. & Pandit, S.K. (1972) Anterograde amnesic effects of pethidine, hyoscine and diazepam in adults. British Journal of Pharmacology 44, 140. Hely, M.A., Morris, J.G.L., Traficante, R., Reid, W.G.J., O’Sullivan, J. & Williamson, P.M. (1999) The Sydney multicentre study of Parkinson’s disease:

progression and mortality at 10 years. Journal of Neurology, Neurosurgery and Psychaitry 67, 300–307. Knopman, D., Schneider L., Davis, K., Talwalker, S., Smith, F., Hoover, T., Gracon, S. & the Tacrine Study Group. (1996) Long-term tacrine treatment: Effects of nursing home placement and mortality. Neurology 47, 166–177. Middlemiss, P.J., Glasky, A.J., Rathbone, M.P. et al. (1995) AIT-082, unique purine derivative enhances nerve growth factor mediated outgrowth from PC-12 cells. Neuroscience Letters 199, 1–4. Perry, E.K., Perry, R.H., Blessed, G. et al. (1977) Necropsy evidence of central cholinergic deficits in senile dementia. Lancet 1, 189. Poewe, W.H. & Wenning, G.K. (1998) The natural history of Parkinson’s disease. Annals of Neurology 44 (Suppl. 1), S1–S9. Qizilbash, N., Whitehead, A., Higgins, J., Wilcock, G., Schneider, L. & Farlow, M. (1998) On behalf of the Dementia Trialists’ Collaboration. Cholinesterase inhibition for Alzheimer’s disease: meta-analysis of 12 trials of tacrine with patients. Journal of the American Medical Association 1998 (280), 1777–1782. Sano, M., Ernesto, C., Thomas, R.G. et al. (1997) A controlled trial of selegiline, alpha tocopherol, or both as treatment for Alzheimer’s disease. New England Journal of Medicine 336, 1216–1222. Schwarz, U.I., Krappweis, J., Rebtsch, A., Pirk, O. & Kirch, W. (1999) Costs of dementia in Germanyaan analysis of 7490 health insurance files. International Society of Pharmacoeconomic and Outcomes Research Conference, Edinburgh, November, 1999. ISPOR, Princeton, USA.

Treatment of Alzheimer’s Disease (With or Without Cerebrovascular Disease)

V.2

Edited by: Lon S. Schneider

V.2.1

Introduction

Nawab Qizilbash

Chapter V.2 contains sections on individual cognitive- and prognosis-modifying therapies for Alzheimer’s disease (AD). Each is written in the form of a narrative systematic review of the therapy, and all valid trials relevant to the topic are evaluated and given due qualitative weight, irrespective of whether the data in the publications are amenable to pooling in a meta-analysis. In this regard these sections may differ from some metaanalyses and systematic reviews of dementia but we believe this to be a more appropriate approach to summarizing the evidence. Published metaanalyses and systematic reviews are discussed, as are new analyses carried out for the purpose of the chapters by various authors, where this aids assessment. Except for rare cases where individualpatient data meta-analysis is available (i.e. tacrine) and can be used to guide the assessment of benefits and harms, meta-analyses are given the influence they deserve after taking into consideration their methodological limitations (see Chapter I.8). Practical recommendations and prescribing guidance are provided within each narrative systematic review chapter to make them useful, as most are written by practicing clinicians. This feature also separates them from some meta-analyses and systematic reviews. Indeed, the narrative systematic reviews that comprise many of the chapters of this section were, prior to publication, requested by agencies such as the UK Health Technology

Assessment Group in its assessment of cholinsterase inhibitors for the UK National Institute of Clinical Excellence (A. Clegg, pers. comm.). Drugs used around the world or which are in late phases of development are given emphasis. Although some drugs have been discontinued since this book was commissioned, they have been retained as they may provide helpful evidence to assess class effects of drugs (e.g. metrifonate for cholinesterase inhibitors) and others as examples of approaches to test drugs (i.e. propentofylline for disease modification). Others will serve as a ready source of systematic evaluation of failed compounds, which may be helpful to researchers. In keeping with the style of this book, tables of the additional details of valid trials are provided on the website for the interested reader and researcher. Chapter V.2.21 gathers the information from all the other chapters together with information from evidence-based guidelines, to produce a practical summary and recommendations to guide the practicing clinician in the use of these agents. This systematic summary also involves further analyses of data not published elsewhere. Where expert opinion is divided, this uncertainty is discussed and the reader is provided with options that the authors might adopt. The skimming reader may wish to consult this chapter before deciding which of the other chapters in this section to read.

467

468 CHAPTER V.2

V.2.2

Acetyl-L-carnitine

Mary Sano and Fadi Massoud Key point

The preponderance of evidence suggests that there is minimal benefit to warrant treatment even with doses of 3 g.

Introduction Acetyl-l-carnitine is marketed in Italy, four South American countries, and South Korea for the treatment of Alzheimer’s disease (AD). The pharmaceutical product is sold under the names of Nicetile, Branigan, Branigen, Alcar and Neuroactil. In addition it is available in health food stores, however, the bioavailibility is variable across non-prescription preparations (Millington & Dubay 1993).

Rationale Acetyl-l-carnitine is the esterified form of l-carnitine. Three groups of mechanisms have been proposed as the basis for a benefit in aging and dementia. One set of mechanisms suggests support of cellular energy production via transport between cytoplasm and mitochondria to import long chain fatty acids and reduce toxic accumulation from mitochondria. Cholinergic agonist properties are proposed since acetyl-l-carnitine converts to acetyl coenzyme-α, which could stimulate cholinergic transmission. Finally, membrane stabilization properties have been proposed as mechanisms for therapeutic benefit in neurodegenerative diseases. From in vitro animal studies there is evidence that learning is improved in aged rodents with long-term treatment of acetyll-carnitine (Carta & Calvani 1991).

Evidence A systematic review of the literature (see search strategy on the website accompanying this book) identified 16 articles. The strategy yielded many theoretical papers which informally summarized clinical studies of elderly patients with non-specific

etiologies. Criteria for inclusion in this review were: (i) probable or possible AD; (ii) use of cognitive, functional or clinical global impression as an outcome measure; (iii) comparison to placebo; and (iv) reports of both central trend and variance of effect for treatment and placebo groups. These criteria lead to the exclusion of reports that used electrophysiological data alone, and compared acetyl-l-carnitine to another agent without providing a placebo control. Two randomized, placebo-controlled studies (Passeri et al. 1988; Carta & Calvani 1991) reported comparisons by alpha level, without providing effect-size and variance estimates. Both these studies showed significant slowing in deterioration on cognitive and functional measures in the acetyl-lcarnitine group compared with placebo. These two studies were also excluded from calculations of treatment effects. Five key studies were found which met these criteria (Rai et al. 1990; Livingston et al. 1991; Spagnoli et al. 1991; Sano et al. 1992; Thal et al. 1996). Three studies provided sufficient data on a global score or a mental status test that could be used to generate estimates of numbers needed to treat (NNT) and absolute benefit difference (ABD) (Table V.2.1). Data from three studies were used to estimate treatment effects on memory tests and mental status examinations (Table V.2.2). Data from two studies were available to assess the effects on verbal fluencyaa timed language test (see Table V.2.2). These results indicate a slight positive effect with greatest benefit in mental status and memory functions and no benefit in verbal fluency. However, there was significant variability in the effect size, suggesting that the effect may have little clinical utility. Several reports have suggested a benefit in a subset of patients with young-onset AD. However, this is based on a posthoc, non-randomized sample, and needs further research (Thal et al. 1996; Brooks et al. 1998). Also, one small study (N = 14/group) examined the effect of acetyl-l-carnitine on senile patients with depression and found significant

TREATMENT OF ALZHEIMER’S DISEASE 469

Table V.2.1 Numbers needed to treat for global cognitive measures.

Cognitive measure Sano et al. 1992 Livingston et al. 1991 Rai et al. 1990

MMMSE* Improvement on 5 neuropsychological tests Efficacy index†

% stable or improved in the placebo group

% stable or improved in treatment group

ABD

NNT

21.4 20

53.9 63

32.5 43

3 (NS) 2 (1.6–5)

6

17 (NS)

8

14

*Modified Mini Mental Status Examination. †From the Clinical Global Impression Scale. ABD, the absolute arithmetic difference in event rates between the treatment and control groups; NNT, calculated as 1/ABI, denotes the number of patients who must receive the experimental treatment to create one additional improved outcome in comparison with the control treatment (placebo); NS, not statistically significant.

Table V.2.2 Summary of effects of acetyl-l-carnitine on cognitive measures (reproduced with permission from Update

Software). Review: acetyl-L-carnitine in the treatment of AD Comparison: acetyl-L-carnitine vs. placebo Outcome: cognitive tests Experimental Experimental n mean (SD) Study Memory tests 206 Thal et al. 1996 13 Sano et al. 1992 48 Spagnoli et al. 1991 267 Subtotal (95%CI) Chi-square 3.27 (df = 2) Z = 3.64 Verbal fluency Sano et al. 1992 13 Spagnoli et al. 1991 46 Subtotal (95%CI) 59 Chi-square 0.23 (df = 1) Z = 0.89 Mental status examination 199 Thal et al. 1996 13 Sano et al. 1992 50 Spagnoli et al. 1991 262 Subtotal (95%CI) Chi-square 1.68 (df = 2) Z = 4.29 Total (95%CI) 588 Chi-square 16.97 (df = 7) Z = 4.54

WMD (95%CI fixed)

Control n

Control mean (SD)

7.40 (9.10) −0.40 (0.80) 0.20 (0.80)

211 14 56 281

7.00 (7.80) −0.40 (1.20) 0.80 (0.70)

1.5 7.0 48.4 57.0

0.400 [−1.228, 2.028] 0.000 [−0.764, 0.764] −0.600 [−0.891, −0.309] −0.499 [−0.767, −0.230]

0.90 (3.60) 2.50 (1.40)

14 55 69

0.20 (1.00) 2.31 (1.10)

1.0 16.5 17.5

0.700 [−1.326, 2.726] 0.190 [−0.308, 0.688] 0.219 [−0.265, 0.703]

3.40 (4.50) 1.30 (2.90) 1.60 (1.30)

204 14 56 274

3.80 (4.20) 2.80 (4.30) 2.60 (1.10)

5.7 0.5 19.3 25.5

−0.400 [−1.250, 0.450] −1.500 [−4.249, 1.249] −1.000 [−1.461, −0.539] −0.877 [−1.278, −0.476]

100.0

−0.469 [−0.627, −0.267]

624

−10

−5

Favors treatment

0

Weight (%)

5

WMD (95%CI fixed)

10

Favors control

Memory tests used: Thal et al. 1996, Alzheimer’s Disease Assessment Scale-cognitive portion (ADAS-Cog); Sano et al. (1992), Delayed recall on the Bushke Selective Reminding Test (SRT); Spagnoli et al. (1991), Prose memory test. Mental status examination tests: Thal et al. 1996 and Sano et al. 1992, Folstein’s Mini Mental Status Examination (MMSE); Spanoli et al. 1991, Blessed Information Memory Concentration Test (BIMC).

470 CHAPTER V.2

benefit on two measures of depression (Garzya et al. 1990).

Number needed to treat Few trials actually report the therapeutic response rate to acetyl-l-carnitine which makes calculation of absolute benefit difference (ABD) and NNT difficult. From the available information, NNTs were calculated for the global cognitive measure reported by each study (listed in Table V.2.1) and were two or three. For a global assessment the NNT was 17. The estimates were generally not statistically significant. However, when this was unavailable, a measure of mental status was used.

Who should be considered for treatment? Safety and efficacy studies have been conducted in demented geriatric patients and in patients with probable or possible AD.

studies reported rash (frequency not known) (Livingston et al. 1991; Thal et al. 1996), and one study reported that body odour and increased appetite were more common on drug than placebo (Thal et al. 1996). One study reported a single case of gastrointestinal bleeding while on active treatment which was thought to be unrelated to the drug (Livingston et al. 1991).

Drug interactions None reported.

Dose Most clinical trials use a dose of 1–3 g prepared as 500 mg capsules taken 2–3 times a day. One study used a 12-week escalation from 2500 mg/day to 3000 mg/day. There are no guidelines for medical monitoring or stopping treatment.

Future research Clinical pharmacology Pharmacokinetic studies indicate modest transient increases in acetyl-l-carnitine and carnitine levels with single oral doses of up to 5 g, with renal excretion maintaining normal acetyl-l-carnitine and carnitine stores. Peak serum levels are achieved 4 h after dosing. There is little increase with multiple days of dosing and no effect of food on bioavailibility (Parnetti et al. 1992).

Adverse effects Most trials report few adverse effects with no difference between drug and placebo groups in the number of serious adverse events. Two studies reported that abdominal pain, nausea or vomiting were more common in the treatment group than in the control group (acetyl-l-carnitine: 6/31 vs. placebo: 2/32; Rai et al. 1990; Sano et al. 1992). One study reported agitation was more common in the acetyl-l-carnitine group (acetyl-l-carnitine: 11% vs. placebo: 6%; Spagnoli et al. 1991). Two

Several studies have suggested that acetyl-lcarnitine may have a benefit in the subgroup of AD patients with an early age of onset, and this is a topic of ongoing research. Also, the possibility of enhancing the effect of cholinesterase inhibitors may also be worthy of further study.

Summary [Grade A-2]. While some studies demonstrate a trend of improvement on cognitive and clinical global measures, the largest study demonstrated a trend against active treatment. The preponderance of evidence suggests that there is minimal benefit to warrant treatment even with doses of 3 g. Safety is high and the inability to observe the effect at these doses is not due to limited tolerance. • Modest improvement on mental status examination. • Modest improvement in memory function. • No benefit in verbal fluency.

TREATMENT OF ALZHEIMER’S DISEASE 471

V.2.3

Antioxidant Vitamins

Jeffrey Kaye Key points

The cause of sporadically occurring Alzheimer’s disease (AD) is unknown. One prominent theory of the cause of AD is the free radical hypothesis. This theory proposes that the premature cell death or dysfunction associated with the disease is the result of oxidative stress and a failure of protective mechanisms that guard against the excessive or inappropriate generation of toxic free radicals (Volicer 1990; Jenner 1994). For this reason there is considerable interest in the possibility that antioxidants in general may have some therapeutic value in at least retarding the progression of AD. This chapter focuses on the antioxidant vitamins such as vitamin A (retinol), beta-carotene, vitamin C (ascorbic acid) and vitamin E (alpha-tocopherol). Other agents that may have antioxidant properties such as Gingko biloba are discussed in other chapters of this book (V.2.10 and V.7).

cognitive function and antioxidant vitamin status (Burns et al. 1989; Kalmijn et al. 1997).

Evidence There have been few randomized controlled trials (RCTs) of antioxidants for dementia of any type. A systematic search for those trials that included antioxidant vitamins A, C, E, retinol, or beta carotene, alone or in combination with other compounds, using the Medline, Embase, Psychlit and Cochrane Library databases yielded only one relevant report. In this search all studies of patients of any dementia severity with AD fulfilling or compatible with the NINCDS-ADRDA (McKahnn & Drachman 1984) or DSM (American Psychiatric Association 1987) or ICDanine or ten criteria were considered. Only one RCT with the antioxidant vitamin E and selegiline has been published (Sano et al. 1997).

Vitamin E and selegiline for AD Rationale Among strategies for the treatment of dementia, identification of those that may be relatively easily achieved especially through dietary changes or supplementation is particularly attractive. Antioxidant vitamins represent this kind of approach to treatment. Although not systematically reviewed here, some, but not all, epidemiological surveys have suggested that there is an association between cognitive performance and various indicators of antioxidant vitamin status. Several studies have shown associations between lower serum or dietary intakes of vitamin C (Goodwin et al. 1983; La Rue et al. 1997; Perrig et al. 1997) and beta-carotene (Jama et al. 1996; Perrig et al. 1997), and poor memory or cognitive function. Two studies have suggested an association of vitamin E and cognitive function (Jama et al. 1996; La Rue et al. 1997; Perkins et al. 1999). On the other hand, some studies have failed to observe an association between

This trial was a double-blind, placebo-controlled, randomized multicenter (23 sites) trial composed of four treatment arms: selegiline, vitamin E, both selegiline and vitamin E, or placebo. A total of 341 patients with probable AD of moderate severity were enrolled. Moderate severity was defined by a Clinical Dementia Rating (CDR) Scale (Morris 1993) score of 2.0. At entry, the mean age of the patients (all treatment groups) was 73.4 years; mean duration of illness 5.1 years; 64.8% were women; mean educational level, 12.5 years; and mean Mini Mental State Examination (MMSE) (Folstein et al. 1975) score, 12.6. The trial compared 10 mg a day (5 mg, twice a day) of selegiline (a monoamine oxidase B inhibitor), 2000 IU a day (1000 IU, twice a day of d-l-alpha-tocopherol racemic mixture) vitamin E, both agents or placebo for 2 years. The primary outcome measure was time to the occurrence of any of four milestones in the natural history of AD: institutionalization, loss of ability to perform at least two of three basic activities

472 CHAPTER V.2

of daily living (ADLs), severe dementia or death. Loss of ADL function was assessed by part 2 of the Blessed Dementia Scale (Blessed et al. 1968) which assesses functions such as eating, dressing and toileting. The transition to severe dementia was measured by achieving a CDR score of 3.0. Secondary-outcome measures were measures of cognitive function (Alzheimer’s Disease Assessment Scaleacognitive subsection or ADAS-Cog) (Rosen et al. 1984), ADL (total Blessed Dementia Scale score), behavior (Behavior Rating Scale for Dementia) (Tariot et al. 1995), and extrapyramidal signs (Unified Parkinson’s Disease Rating Scale) (Richards et al. 1991). Assessments were conducted one month after enrolment and at 3-month intervals for the remainder of the 2-year trial. Drug levels were monitored: serum vitamin E and the urinary metabolite of selegilineaamphetamine. Adverse events were monitored and recorded. The trial was of good quality, meeting category A criteria for RCTs. There was good follow-up especially considering the level of dementia severity at entry. Drug level monitoring resulted in a mean of 94% of treatment groups (those receiving selegiline, vitamin E or both) having levels suggesting compliance. Twelve percent of the placebo group had positive tests for vitamin E. For the primary outcome measure, i.e. whether there was a delay to reaching the combined endpoints, the analysis resulted in favor of the treatment groups (OR 0.51, 95%CI 0.28–0.95). Despite full randomization at entry, there was a difference in the severity of dementia as assessed by the MMSE score at baseline (mean placebo group MMSE score, 13.3 vs. 11.3–12.9 in the treatment groups). Secondary outcome measures could not be estimated for significant effects as only mean change scores of the patients with ratings were given. Based on the difference between the baseline and score at last visit, there was no significant difference between groups on the ADAS-Cog or MMSE. The results of this single randomized placebocontrolled trial for AD, cannot be stated at this time to provide unequivocal evidence for efficacy of antioxidant treatment in general, or that vitamin E specifically is a ‘proven’ treatment for this condition. No disease-modifying therapy for dementia is likely

to enjoy this status without confirmatory studies. Nevertheless, this trial stands among the first randomized controlled trials specifically designed to be able to detect the effect of an agent to slow the course of disease. Of particular note, the trial had a long (2 years) observation period necessary to detect a treatment effect on disease course. Further, the trial began with subjects already in a moderate stage of dementia severity and followed them to clinically relevant (functional) endpoints. The results as presented have remained controversial or at least open to interpretation at a practical level. By the strict interpretation of this review, there was a treatment effect in the expected direction, but unless the data were adjusted for differences among groups in baseline MMSE (not done in our review), there was no significant treatment effect. There is no a priori reason why data cannot be (and in everyday practice are) adjusted for unexpected variations. Nevertheless, there are several aspects to the study that skeptics might question with regard to this adjustment. First, other measures that correlate with MMSE scores in other studies did not differ at baseline in the trial under discussion. Second, the MMSE scores were very minimally different among groups (greatest mean difference, 2 points; P = 0.071). The practical significance of such a difference is difficult to appreciate in clinically relevant terms over the course of a 2-year trial. Finally, there was no observed significant difference among treatment groups in changes in cognitive test scores during the study. Thus a cognitive difference among groups was not detected as a treatment-related effect.

Who should be considered for treatment? Despite the fact that there is only one trial of vitamin E for the treatment of AD, it is likely that few clinicians will hesitate to recommend this vitamin to their mild to moderately impaired AD patients. The safety margin is wide, the drug is readily available and the cost is minimal relative to other drugs. The effective dose is not established but strict interpretation of the single published trial will generally see clinicians prescribing 2000 IU per day. Although relatively free of adverse effects, vitamin E supplementation can worsen the defici-

TREATMENT OF ALZHEIMER’S DISEASE 473

ency in vitamin K deficient states (such as patients receiving warfarin). Recommendations for other antioxidants do not have any evidence on which to base a decision. High doses of retinol may be associated with toxicity.

Clinical pharmacokinetics Vitamin E is a lipid-soluble vitamin most commonly found in dietary vegetable and seed oils. Vitamin E is absorbed from the intestine and secreted into the circulation in chylomicrons which in turn are transferred to circulating lipoproteins. The liver is the main regulator of the forms and amounts of vitamin E secreted into the plasma.

Adverse events Adverse events were reported as significantly greater for active treatment compared to placebo in three of 49 categories: dental events, falls, and syncope (OR 2.67, 95%CI 1.20–5.93, P < 0.05). The frequency of these events was not significantly different between any study group.

Future research Given the nature of the types of trials needed to show slowing of disease progression in AD, i.e. relatively

V.2.4

large, long in duration, and the widespread availability and use of vitamins, it is unlikely that a pure replication of the single existing vitamin E trial will be conducted. This state of the field is complicated by the worldwide introduction of acetylcholinesterase inhibitors for treatment of AD, which practically means that any attempt to demonstrate efficacy of vitamin E (or other common antioxidant vitamins) will end up in a more complex combination, multiarm study. At this time, studies are planned or underway to investigate vitamin E (or other anitoxidants) in preventing the progression from preclinical or mild cognitive impairment stages to frank AD. Generalization of results of these planned studies may be the closest we come to proving the efficacy of antioxidants in the treatment of AD.

Summary Despite the theoretical attractiveness of the concept that antioxidants may be of benefit in treating AD, there is almost no data to support the use of antioxidant vitamins for the treatment of AD (or other dementias). A single RCT of vitamin E has suggested some benefit of this vitamin. Future RCTs of antioxidant vitamins will be necessary to demonstrate their efficacy in prevention or delay of dementia.

Donepezil in the Treatment of Alzheimer’s Disease

Lon S. Schneider Key point

Donepezil is a long-acting cholinesterase inhibitor effective for improving cognitive and global symptoms in Alzheimer’s disease (AD). Side effects include the expected cholinergic and gastrointestinal effects, largely related to dosage titration.

Introduction Donepezil hydrochloride ((+/−)-2,3-dihydro-5,6dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-inden-1-one hydrochloride), Aricept™, is a long-acting piperidine-based relatively selective acetylcholinesterase inhibitor. It was specifically developed for the treatment of AD in the late 1980s and 1990s, based on the demonstration of cholinesterase inhibition in vitro and in ex vivo animal preparations, as well as evidence of efficacy in improving cognitive function and behavior in several animal models of cholinergic hypofunction and a

474 CHAPTER V.2

lack of unexpected adverse effects in the animal studies. Following an initial positive phase II study (Rogers 1996), two favorable phase III US clinical trials were conducted (Rogers et al. 1998a,b). Following the submission of a New Drug Application to the US Food and Drug Administration in 1996, which was approved, donepezil was marketed in the US in March 1997. Additional studies have subsequently been conducted, including an international study (Burns et al. 1999), a Scandinavian study (Winblad et al. 1999), and a study in institutionalized patients (Tariot et al. 1999).

Rationale The rationale for the use of donepezil in AD is its ability to boost acetylcholine (ACh) levels in synapses of central nervous system (CNS) neurones in tracts supporting cognitive function. Considerable evidence supports the concept of cholinergic insufficiency in AD (see Chapter III.2). When functioning normally, cholinergic neurones in the CNS release ACh into the synaptic cleft where it binds to postsynaptic receptors, either muscarinic or nicotinic, depending on the specific tract to which the cell belongs. ACh remains active until it is hydrolyzed to choline and acetate by acetylcholinesterase (AChE). By inhibiting the hydrolysis of ACh in the synaptic cleft, cholinesterase inhibitors (ChEIs) effectively increase the amount of ACh available for cholinergic receptors. This action, in theory, compensates at least partially for the effects of CNS cholinergic hypofunction in AD. While agents with various types of procholinergic action (e.g. precursor loading, ChEI, and muscarinic and nicotinic receptor agonism), have been evaluated for efficacy in AD, only the ChEIs have so far demonstrated clinically significant cognitive effects. AChE’s active site contains two subsites, an ionic subsite and an esteratic subsite. The ionic subsite normally binds the quaternary amine group of ACh. This brings the ester group of ACh in apposition to a catalytic esteratic site, which then cleaves ACh by acylation. Therefore, inhibition can occur as a result of interaction between the cholinesterase inhibitor and cholinesterase either at the catalytic esteratic subsite or at the ionic sub-

site, thus preventing the normal chemical interaction between ACh and the enzyme. Tacrine and donepezil act at the ionic subsite. Other drugs act at the catalytic esteratic subsite. Specific inhibition of AChE can occur with relatively little inhibition of butyryl-cholinesterase (BChE) when the side chains of the cholinesterase inhibitor interacts with the peripheral anionic site of AChE. Donepezil has this property and is therefore selective for AChE.

Evidence There have been at least eight published or presented randomized, double-blind placebo controlled trials including: one phase II trial (Rogers et al. 1996) and two phase III trials in outpatients (one lasting 12 weeks and the other 24 weeks) in the US (detailed in the prescribing information; the EMEA Summary of Product Characteristics; Rogers et al. 1998a,b), a 24-week international trial (Burns et al. 1999); a trial in nursing home patients (Tariot et al. 2001); a 1-year clinical trial in Scandinavia and the Netherlands (Winblad et al. 2001); a 1-year US trial in which loss of activities of daily living was the outcome; and a 24-week trial in more moderately to severely impaired outpatients (Feldman et al. 2001), all in patients with AD. Other clinical trials have been completed but not reported, including a 6-month trial in patients with mild cognitive impairment, and a trial in patients with vascular dementia. Key parameters of the published donepezil AD clinical trials are summarized in Table V.2.3. In these studies, donepezil was associated with significant cognitive improvement as compared to placebo. In addition, the Cochrane Library (2000, Issue 4) controlled trials register and Medline (1966– 2000) were searched with the term ‘donepezil and (Alzheimer or dementia)’. An additional source for identifying studies was contact with the manufacturer, which led to reports of trials published in conference proceedings. Irrelevant studies were discarded and only trials that were unconfounded, randomized, double-blind, placebo-controlled with greater than one day of treatment were selected for inclusion. See the website accompanying this book for details of the trials.

TREATMENT OF ALZHEIMER’S DISEASE 475

Table V.2.3 Description of donepezil placebo-controlled clinical trials. Author

Duration (weeks)

No. of patients

Age

% female

Phase

Dose (mg/day)

Rogers 1996 Rogers 1998a Rogers 1998b Burns 1998 Tariot 2001 Winblad 2001 Mohs 2001 Feldman 2001

12 12 24 24 24 52 52 26

161 468 473 818 208 286 431 207 (of 290)

71.8 73.7 73.4 72 85.6 72.5 75.4 74.3

60.2 63.5 61.9 57.6 82.5 64.3 62.8 63.0

II III III III IV IV IV

1, 3, 5 5, 10 5, 10 5, 10 5–10 5–r10 5–10 5–10

12-week clinical trials In a phase II trial to assess early evidence of efficacy, patients were randomized to receive single daily doses of placebo, 1 mg/day, 3 mg/day, or 5 mg/day of donepezil for 12 weeks. There was a statistically significant effect on the ADAS-Cog at the 5 mg/day dose. In the first phase III study (Rogers et al. 1998a), 468 patients were randomized to receive single daily doses of placebo or either 5 mg/day or 10 mg/day of donepezil for 12 weeks, followed by a 3-week placebo washout period. The 10 mg/day treatment followed an initial 7-day 5 mg/day treatment. After 12 weeks of treatment, the differences in mean ADAS-Cog subscale change scores for the donepezil-treated patients compared to the patients on placebo were 2.5 and 3.1 units, for the 5 and 10 mg/day donepezil-treatment groups, respectively. For Mini Mental State Examination (MMSE) the differences were 1.0 and 1.3 units, respectively. Although the effect size for the 10 mg/day group was slightly larger than that for the 5 mg/day treatment, the differences between active treatments were not statistically significant.

24-week clinical trials In a 24-week phase III clinical trial conducted in the US (Rogers 1998b), 473 patients were randomized to receive daily doses of either placebo, 5 mg/day or 10 mg/day of donepezil. To reduce the incidence of cholinergic adverse effects, the 10 mg/day treatment was started following an initial 7-day treatment with 5 mg/day doses. This trial was divided into a 24-week double-blind active

treatment phase followed by a 6-week single-blind placebo washout period. The percentages of randomized patients who completed the 24 weeks of double-blind treatment were: placebo 80%, 5 mg/day 85% and 10 mg/day 68%. The mean differences in the ADAS-Cog change scores for donepezil-treated patients compared to the patients on placebo were 2.8 and 3.1 units for the 5 mg/day and 10 mg/day treatments, respectively, and largely comprised of deterioration in the placebo group, as opposed to improvement in the medication groups. There was no statistically significant difference between the two active treatments. Significant drug–placebo differences were observed on MMSE scores at weeks 12, 18, and 24, with mean differences of 1.2 and 1.36 units for the 5 mg/day and 10 mg/day donepezil groups, respectively. The differences at week 24 were comprised largely of deterioration of the score in the placebo-treated patients of approximately 1.1 units without significant change from baseline in the donepezil-treated patients. Following 6 weeks of placebo washout, scores on the ADAS-Cog for both donepezil treatment groups were indistinguishable from those patients who had received only placebo for 30 weeks. This effect has been taken to suggest a symptomatic effect for the drug and not a change in the underlying disease. There was no evidence of a rebound effect 6 weeks after abrupt discontinuation of therapy. In a 24-week long clinical trial conducted in Europe, Australia, New Zealand, and South Africa (Burns et al. 1999), 818 patients were randomized to receive daily doses of either placebo, 5 mg or 10 mg of donepezil, in a design identical to a 24week long US trial (Rogers 1998b). Patients who

476 CHAPTER V.2

were randomized to medication were first started on 5 mg of donepezil for 1 week, and then either continued on that dose or were increased to 10 mg. The percentages of randomized patients who completed the study were placebo 20%, 5 mg per day 78%, and 10 mg per day 74%. After 24 weeks of treatment, mean differences in the ADAS-Cog change scores for donepezil-treated patients compared to patients on placebo were reported and 1.5 and 2.9 units for the 5 mg and 10 mg per day donepezil groups, respectively. As in the previous US trial, much of the effect was due to deterioration in the placebo group rather than to absolute improvement in groups treated with medication. Although not explicitly reported, there appears to be a difference of nearly 2.0 ADAS-Cog units between the 10 mg and the 5 mg dose, suggesting a significant difference in efficacy. Although MMSE scores were obtained, they were not reported. As in the previous trial, after 6 weeks of placebo washout, scores on the ADAS-Cog for both treatment groups were statistically significantly different from patients who received placebo for 30 weeks. A recent 24-week trial included 290 outpatients who were more severely impaired than the patients above with baseline MMSE scores between 5 and 17, inclusive (Feldman et al. 2000; 2001), and who were randomized to placebo or the 5 mg/day for 4 weeks, followed by 10 mg/day for 20 weeks based on physicians’ judgements. Statistically significant differences on the MMSE, the Severe Impairment Battery, a standardized cognitive battery, and a clinician’s global assessment were reported in the subset of 207 patients with MMSE greater than or equal to 10.

24-week nursing home trial Most AD patients entered into clinical trials of cognitive enhancers are outpatients. In this trial (Tariot et al. 1999), 208 nursing home patients with possible or probable AD or with AD and cerebral vascular disease were randomized to receive placebo or donepezil 5 mg per day for 4 weeks followed by 10 mg for 20 weeks. Unlike outpatient trials, patients could have MMSE scores between 5 and 26 inclusive, and had to have one behavioral

item on the neuropsychiatric inventory rated at a frequency of at least several times per week. These patients were about a decade older than typical Alzheimer’s outpatients, having a mean age of 85.6 and a range between 64 and 102. Also, unlike outpatient trials, 82% were female. A majority of patients were receiving both analgesics and antacids. 82% of donepezil-treated patients and 74% of placebo-treated patients completed the study. Although a significant difference on the MMSE in favor of donepezil had been observed at weeks 8, 12, 16 and 20, by week 24, the end of the trial, there was no significant difference. In effect, the cognitive effect as measured by the MMSE was lost.

52-week clinical trials A 1-year long, randomized, double-blind, placebocontrolled trial in outpatients, comparing an intention to treat with 10 mg of donepezil with placebo was carried out in several Nordic countries and the Netherlands (Winblad et al. 2001). In this trial, 286 patients were randomized to drug or placebo treatment. Approximately 67% of each group completed the trial, necessitating reliance on LOCF analyses. The mean daily dose of donepezil was 8.5 (1.9 SD) mg/day. There were statistically significant effects in favor of donepezil observed on the total score of the Gottfries, Brane and Steen scale (GBS) at weeks 24, 36, and 52, in observed cases, but not in the LOCF analysis, suggesting dropouts did not fare as well. Similar effects were observed on the intellectual impairment subscale of the GBS scale. Significant differences were observed on MMSE scores at weeks 24, 36, and 52, comprised largely of deterioration of the score in the placebo-treated patients of 2.2 units and no significant deterioration in the donepezil-treated patients, mean approximately 0.25 units. Another 1-year randomized, double-blind, placebo-controlled trial enrolled 431 outpatients with AD, MMSE scores of 12–20, and assessed the ability of subjects to perform at a certain minimum on an ADL scale (Mohs et al. 2001). Subjects were followed until they worsened to a certain ‘clinically evident decline’ as measured on one of three activities of daily living scales. At the end of 48 weeks 51% of donepezil treated patients, compared to

TREATMENT OF ALZHEIMER’S DISEASE 477

35% of placebo-treated patients, remained in the study.

Cognition The cognitive effects of donepezil as measured by the ADAS-Cog and MMSE, are described above. Generally, they are a 3-unit drug–placebo difference on the ADAS-Cog after 6 months, and a 1–2 point difference on the MMSE after 6 months to a year.

Mood and behavior Except for the nursing home trial (Tariot et al. 1999; 2001), the Nordic 1-year study (Winblad et al. 2001), and the more severely impaired outpatient trial (Feldman et al. 2000), these clinical trials did not assess changes in behavior. In the nursing home trial, there was no significant effect on total score on the NPI. Moreover, there was no significant effect in any subscale except for agitation/aggression. However, the multiple statistical comparisons and the small magnitude of the change leaves the clinical significance of this observation unclear. In the Nordic trial, there were no significant effects on the GBS emotional function scale. In a subset of the moderately to severely impaired outpatient trial there was a significant effect on total NPI score of about 4 points, with a nominally significant effect on the delusion, apathy, and aberrant motor behavior subscales.

Global ratings Global ratings were obtained in the 12-week and 24-week US, and 24-week international trials, and moderately severe trials; and a Global Deterioration Scale severity staging score was obtained in the Nordic trial. In the US 12-week trial (Rogers et al. 1998a), the mean drug–placebo differences on the global ratings were 0.3 and 0.4 units, for 5 mg/day and 10 mg/day, respectively. Eighteen percent, 32% and 38% of patients, treated with placebo, 5 mg/day and 10 mg/day of donepezil, respectively, were rated as showing clinical global improvement. In the US 24-week trial (Rogers et al. 1998b), the mean drug–placebo differences on the global ratings

were 0.36 units and 0.44 units for 5 mg/day and 10 mg/day, respectively. There was no statistically significant difference between the two active treatments. The percentage of patients rated as improved on global assessment were 11%, 26%, and 25% for the placebo, 5 and 10 mg per day donepeziltreated groups, respectively. Mean drug–placebo differences on global ratings were not explicitly reported in the international trial (Burns et al. 1999), but appear to be approximately 0.3 and 0.4, for the 5 mg and 10 mg doses, respectively. The percentage of patients rated as improved on global assessment were 14%, 21%, and 25% for the placebo, 5 and 10 mg per day donepezil-treated groups, respectively. In the subset of the moderately severe outpatient trial, the mean drug–placebo difference on the global rating was about 0.5 units, comprised entirely of worsening in the placebo group. In the 52-week Nordic trial (Winblad et al. 1999), there was significant difference in favor of donepezil on the Global Deterioration Scale at weeks 24, 36 and 52. There was no categorization of clinical global improvement in this trial.

Functional activity Activities of daily living were not formally assessed in the 12-week and 24-week US trials, except as included in the Clinical Dementia Rating severity scale. In the 24-week international study involving 818 subjects (Burns et al. 1999), functional activities were assessed with the Interview for Deterioration in Daily Living Activities in Dementia (Teunisse et al. 1991) and showed a significant difference in favor of donepezil for the 10 mg per day dose but not the 5 mg dose. In the Nordic 1-year trial, there was a significant effect on the care giver-rated Progressive Deterioration Scale in favor of donepezil, but no significant effect was observed on the motoric function or activities of daily living (ADLs) subscale of the clinician-rated GBS scale. In the 1-year trial to assess the maintenance of a given level of ability to perform ADLs, 51% of donepezil-treated patients, compared to 35% of placebo-treated patients, avoided a predetermined clinically evident decline on at least one of three

478 CHAPTER V.2

outcomes. However, there was no statistically significant difference between medication and placebo on the functional activities test scores among those subjects who completed them. (Note: overall 57% of the subjects were not followed over the 1-year duration because subjects who reached endpoint were terminated from the trial.)

Combined endpoints The EMEA has suggested the use of combined endpoints to better determine efficacy. In their Summary of Product Characteristics for AriceptTM (donepezil), EMEA applied a combination of three efficacy criteria that included ≥ 4 point improvement on the ADAS-Cog, no deterioration or improvement on the global rating, and no deterioration on an abstracted activities of daily living section of the Clinical Dementia Rating Scale. Applying this criterion to the 24-week trial (Rogers et al. 1998b) contained in the summary of product characteristics for Aricept™, the response rates (by intention to treat (ITT) analysis) were 10%, 18%, and 21% for the placebo, 5 mg/day, and 10 mg/day groups, respectively. This analysis, however, used only 365 patients of the 473 patients randomized to the trial. No comparable analyses have been published for the other trials.

Number needed to treat The number needed to treat (NNT) value (with 95%CIs) for overall changes in the patients’ condition measured by Clinical Global Impressions of Change were 8 (5–16). Based on global change scores the NNT for clinical global improvement over 6 months in outpatients is approximately 7–9 for 10 mg/day, and 7–15 for 5 mg/day when individual trials are examined. Using the combined endpoint criteria from EMEA, the NNTs were 9 and 13 for 10 mg/day and 5 mg/day respectively over 6 months, but based on data from only 365 subjects.

Who should be considered for treatment? The clinical inclusion criteria in the clinical trials included: a research diagnosis of probable Alzheimer’s disease, and outpatient status with

mild to moderate cognitive impairment severity (i.e. a MMSE between 10 and 26), except for patients in the nursing home trial. Patients were generally younger, medically less ill and more stable, and had fewer significant major behavioral problems than the typical population of elderly patients with dementia. Thus, the evidence for the safety and efficacy of donepezil is limited to this group and generally over a 6 month period. There is little information on patients with more severe or more mild cognitive impairment, or on those residing in nursing homes or other institutions. Therapy should only be started if a care giver is available who will regularly monitor drug intake by the patient.

Who should be excluded from treatment? The use of donepezil is contraindicated in patients with known hypersensitivity to it. Because it is metabolized by the liver it should be used cautiously in patients with hepatic impairment. (Such patients may have cognitive impairment due to their liver disease and probably should not be treated with a cholinesterase inhibitor until their liver disease is resolved.) Patients with pre-existing gastrointestinal disorders such as gastritis, ulcer disease, or problematic nausea and vomiting should be treated with particular caution, if at all, because of the potential for exacerbating these conditions. Gastrointestinal inflammation, ulcers or bleeding may be asymptomatic and not recognized early. Patients with pre-existing anorexia, cachexia, or recent weight loss should be treated with caution due to the effects of cholinesterase inhibitors on appetite and weight. A patient’s weight, appetite and food intake should be monitored during therapy. Cholinesterase inhibitors should be used with care in patients with sick sinus syndrome or conduction defects, in patients with syncope, in patients with a history of asthma or obstructive pulmonary disease, since the vagotonic effects may exacerbate these conditions. Also, cholinomimetics may induce or exacerbate urinary obstruction and seizures. Cholinesterase inhibitors may exaggerate the effects of succinylcholine-type muscle relaxants during anesthesia. The use of donepezil in patients with very mild or severe Alzheimer’s dementia, other types of

TREATMENT OF ALZHEIMER’S DISEASE 479

dementia or other types of memory impairment has not been investigated or fully reported. Therefore, specific guidance cannot be provided.

Clinical pharmacokinetics Absorption after an oral dose is nearly 100%. Food does not affect absorption. Maximum plasma concentration is reached in 3– 4 h and concentration and area under the curve increase proportionally with the dose. Elimination half-life is approximately 70 h; therefore, plasma steady state should be achieved approximately 16 days after starting therapy. Donepezil is 95% bound to plasma protein. It is both excreted in the urine unchanged (17%) and metabolized in the liver by CYP 450 isoenzymes 2D6 and 3A4 into multiple metabolites and glucuronidated. Its main active metabolite is 6-O-desmethyl donepezil. Pharmacokinetics are linear up to 10 mg. Approximately 28% of an oral dose remains unrecovered in the urine or feces, suggesting overall accumulation. The clearance of donepezil is reduced by 20% in patients with liver disease but does not seem to be affected by renal disease, age, gender, or race.

Pharmacodynamics Donepezil is an acetylcholinesterase inhibitor that does not significantly affect butyrylcholinesterase. On average, doses of 5 mg or 10 mg per day produce a steady state inhibition of red blood cell acetylcholinesterase activity of 64% and 77%, respectively.

Adverse effects In most reports common adverse events were reported as those occurring at a frequency of at least 5% in patients and at twice the placebo rate. Thus, little information is available on potentially serious adverse effects that occur at less than this rate but at potentially significant risk ratios. Most adverse effects are largely predicted by donepezil’s cholinomimetic effects. These include nausea, diarrhea, insomnia, vomiting, muscle cramps, fatigue and anorexia. These adverse events were generally of mild intensity and transient, resolving during continued donepezil treatment.

The frequency of the common adverse events related to cholinergic gastrointestinal effects may be affected by the rate of titration. For example, an open-label study was conducted with 269 patients who received placebo in the US 12- and 24-week studies. These patients were titrated to a dose of 10 mg/day over a 6-week period. The rates of common adverse events were lower than those seen in patients titrated to 10 mg/day over 1 week in the controlled clinical trials and were comparable to those seen in patients on 5 mg/day. However, in four of the latter trials medication was individually adjusted from 5 mg to 10 mg/day after 4 weeks and could be brought back to 5 mg/day if tolerability was a problem. Therefore these latter trials may provide more clinically relevant data. In the 24-week US trial involving 473 patients (Rogers et al. 1998b), fatigue (8 vs. 2%), diarrhea, nausea, vomiting, anorexia (7 vs. 2%), muscle cramps (8 vs. 1%), dizziness (8 vs. 4%), and rhinitis occurred from 2 to 8 times more often in the 10 mg/day donepezil group than in the placebo group. In the 24-week international trial involving 818 patients (Burns et al. 1999), there were nearly twice as many withdrawals due to adverse events in the 10 mg group compared to the placebo group (18% vs. 10%). Nausea, diarrhea, vomiting, and anorexia occurred from 3 to 8 times more frequently in the 10 mg/day donepezil group than in placebo group. Dizziness and insomnia occurred in 9% and 8% of the 5 mg/day and 10 mg/day groups, respectively, and approximately twice as frequently as in the placebo group. In the 24-week nursing home trial, including 208 patients with a mean age of 86 years, a decade older than those in the other trials (Tariot et al. 1999), gastrointestinal adverse events including diarrhea, nausea, and anorexia occurred more frequently in donepezil-treated patients than in placebotreated patients. The most common adverse events, occurring in greater than 5% of donepezil-treated patients and at more than twice the frequency of the placebo group, included weight loss, abdominal pain, nausea, tremor and myasthenia. Anorexia and weight loss occurred at nearly twice the frequency in donepezil-treated patients compared to placebo, with weight loss occurring in 19% of donepezil treated patients compared with 10% in

480 CHAPTER V.2

the placebo-treated group. Among patients with significant weight loss the mean loss of weight was 3 kg in each group. Changes in heart rate and instances of clinical bradycardia were not reported. In the Nordic trial involving 286 subjects (Winblad et al. 1999), although only 7% of donepezil-treated patients and 6.3% of placebotreated patients discontinued due to treatment emergent adverse events, the distribution of the adverse events indicated that among those events occurring in greater than or equal to 5% of patients, depression, anxiety, asthenia, vertigo, syncope, and accidental fractures, occurred nearly twice as often or more in the donepezil-treated patients than the placebo-treated patients. Number needed to harm (NNH) values for frequently observed cholinergic side effects were: 10 (8–15) for diarrhea, 17 (11–30) for anorexia, 7 (4 –16) for nausea, and 12 (9–19) for vomiting. NNH values for all withdrawals from clinical trials were 17 (9–194).

Starting/monitoring/stopping treatment The effective doses of donepezil in controlled clinical trials are 5 mg and 10 mg administered once per day, usually in the evening. 10 mg is clearly more effective than 5 mg when the trials as a group are evaluated. Indeed, recent clinical trials tend to aim the dose at 10 mg/day. Starting dosage should be 5 mg/day and then increased to 10 mg/day after at least 4 weeks. Earlier increase is likely to be associated with a higher incidence of cholinergic adverse events. Maintenance treatment can be continued for as long as a therapeutic benefit for the patient exists. Therefore, the potential clinical benefit of donepezil should be reassessed on a regular basis, especially for patients treated at the less effective 5 mg/day dosage. Discontinuation should be considered when evidence of a therapeutic effect is no longer present. As with other cholinesterase inhibitors, it is not possible to predict individual patient response to donepezil. Except for one trial (Winblad et al. 1999), treatment effect has not been studied in placebocontrolled trials beyond 6 months. Therefore, optimal duration of treatment with continuing

efficacy is unknown but overall efficacy extends at least 6–12 months based on the clinical trials and open-label extension phases. In the open-label discontinuation phases, in which patients discontinued from donepezil after 6 months, some patients worsen considerably with respect to cognitive function. With all cholinesterase inhibitors it is difficult to assess individual patient response because of the variability of the deteriorating course of Alzheimer’s disease, and because most of the effect of medication is due to a stabilization or lack of worsening of cognitive function while placebo-treated patients continue to decline. Therefore, the clinical observations of minimal or no clinical worsening may be sufficient reasons to continue medication treatment if patients are tolerating therapy.

Monitoring side effects Cholinergic side effects such as diarrhea, nausea, and vomiting tend to occur at higher doses and are often transient or self-limited and can often be managed with encouragement and maintenance of the present dose level, by omitting one or more doses, or by temporarily decreasing dosage. Most cholinergic side effects are related to the dose escalation/titration phase of treatment, just after starting 5 mg or increasing to 10 mg. Patients on maintenance doses should have few and very mild cholinergic side effects, if any. However, anorexia and weight loss may be clinically significant problems over the course of 6 months, especially in nursing home patients, so these parameters should be monitored and medication discontinued if anorexia or weight loss become clinically significant. Cholinesterase inhibitors such as donepezil may exaggerate the effect of succinylcholine-like muscle relaxants during anesthesia. The cholinergic and vagotonic effects may cause significant bradycardia, and this can be a particular concern to patients with supraventricular conduction impairments or sick sinus syndrome. Syncope observed occurring with donepezil may be related to this. Because gastric acid secretion may be increased with cholinesterase inhibitors, there may be an increased risk for developing ulcers or gastrointestinal

TREATMENT OF ALZHEIMER’S DISEASE 481

bleeding, although there was no increased incidence in the pivotal clinical trials (Rogers et al. 1998a,b). Patients receiving non-steroidal anti-inflammatory drugs may be at particular risk. It is possible that cholinesterase inhibitors such as donepezil may cause bladder outflow obstruction, seizures, and exacerbate asthma or obstructive pulmonary disease.

Future research Long-term safety and efficacy are essential research issues. The significance of weight loss, myasthenia, fatigue, anorexia, and possibly syncope or falling, although occurring infrequently, needs further investigation. The safety and efficacy of cholinesterase inhibitors in early Alzheimer’s disease or in mild cognitive impairment awaits definitive assessment. A trial sponsored by the National Institute on Ageing AD Cooperative Study, comparing donepezil to vitamin E and placebo in mild cognitive impairment (MCI), is ongoing. Potential neuroprotective or effects on beta-amyloid processing need further research.

Summary Donepezil is a reversible acetylcholinesterase inhibitor with a long half-life, allowing once per day dosing and rather constant plasma levels throughout the day. Several 6-month trials and a 12-month trial have shown cognitive or clinical efficacy, similar to other cholinesterase inhibitors. In these trials, both patients assigned to placebo and donepezil had a wide range of responses, but overall the active treatment groups were more likely to show greater improvements. Overall the medication appears adequately welltolerated over 6 months, especially with regard to cholinergic effects. However, both efficacy and safety results have not been fully reported so that magnitudes of effect or response rates cannot be clearly determined. Of concern, the publications do not adequately report less common adverse events, occurring less than 5% of the time, such as potential muscle weakness, bradycardia, syncope, weight loss, and anorexia: each of which may be, although infrequent, serious problems. Such

infrequent effects can be identified by pooling individual patient data from the clinical trials. Donepezil’s effect can be summarized as follows: [Grade A-2] 1 Modest improvement in cognitive performance compared to placebo. 2 Modest improvement in clinical global ratings. 3 Unclear effects on behavioral measures (based on subscores of a clinical global rating) in patients without particular or significant behavioral disorder. 4 Unclear improvements in activities of daily living. Donepezil is one of several cholinesterase inhibitor treatment options, along with tacrine, rivastigmine, and galantamine for patients with mild to moderately severe Alzheimer’s disease, and may be considered as either a first or second cholinesterase inhibitor for use in these patients, see Tables V.2.4–6. Results of several trials show consistently that, compared with placebo recipients, significantly more donepezil-treated patients respond to therapy. Indeed, after 24 weeks of therapy in one pivotal trial, significantly more donepezil than placebo recipients achieved clinically meaningful improvements as defined by three separate response criteria. Both the 5 mg/day and the 10 mg/day doses are efficacious. Individualized dosage titration from 5 mg/day to 10 mg/day is important to minimize cholinergic side effects and to maximize the potential for efficacy. Weight loss and anorexia may be significant problems in AD patients in this age group treated with cholinesterase inhibitors in general. The high potency and selective acetylcholinesterase inhibition differentiate donepezil from other cholinesterase inhibitors with respect to mechanisms of actions. However, thus far there are no apparent clinical differences in efficacy among the cholinesterase inhibitors.

Benefits The benefits of donepezil treatment, over 6 months, are as follows. • Modest improvement in cognitive performance similar to other cholinesterase inhibitors (and in one trial over 12 months).

482 CHAPTER V.2

Table V.2.4 Pooled results for ADAS-Cog for donepezil vs. placebo in mild and moderate AD (reproduced with permission from Update Software). Outcome: ADAS-Cog (change from baseline) ITT-LOCF Experimental Experimental Control mean (SD) Study n n Donepezil (10 mg/d) vs. placebo 150 Rogers 1998a 155 Rogers 1998b 305 Subtotal (95%CI) Chi-square 0.05 (df = 1) Z = 6.42 Donepezil (5 mg/d) vs. placebo 39 Rogers 1996 152 Rogers 1998a 156 Rogers 1998b 347 Subtotal (95%CI) Chi-square 0.39 (df = 2) Z = 6.15

Control mean (SD)

WMD (95%CI fixed)

Weight (%)

WMD (95%CI fixed)

−1.06 (6.20) −2.70 (5.40)

153 150 303

1.82 (6.30) 0.40 (5.40)

42.6 57.4 100.0

−2.880 [−4.287, −1.473] −3.100 [−4.312, −1.888] −3.006 [−3.925, −2.088]

−2.50 (4.60) −0.67 (6.30) −2.10 (5.40)

40 153 150 343

0.70 (4.60) 1.82 (6.10) 0.40 (5.40)

16.8 35.8 47.3 100.0

−3.200 [−5.229, −1.171] −2.490 [−3.882, −1.098] −2.500 [−3.710, −1.290] −2.614 [−3.447, −1.782]

−10

−5

Favors donepezil

0

5

10

Favors placebo

Table V.2.5 Pooled results for global ratings for donepezil vs. placebo in mild and moderate AD (reproduced with permission from Update Software). Outcome: CIBIC plus (unchanged or worse) ITT-LOCF Experimental Control Study n/N n/N

Peto OR (95%CI fixed)

Weight (%)

Peto OR (95%CI fixed)

Donepezil (10 mg/d) vs. placebo 188/157 Rogers 1998a 96/155 Rogers 1998b 214/312 Subtotal (95%CI) Chi-square 0.02 (df = 1) Z = 5.03

144/162 123/150 267/312

43.1 56.9 100.0

0.39 [0.22, 0.70] 0.37 [0.23, 0.61] 0.38 [0.26, 0.56]

Donepezil (5 mg/d) vs. placebo 114/154 Rogers 1998a 106/156 Rogers 1998b 220/310 Subtotal (95%CI) Chi-square 0.39 (df = 2) Z = 4.38

144/162 123/156 267/312

45.1 54.9 100.0

0.37 [0.21, 0.66] 0.48 [0.28, 0.80] 0.43 [0.29, 0.62]

0.1 0.2 Favors donepezil

1

5

10

Favors placebo

• Modest improvement in clinical global impression. • Minimal reduction in the rate of functional decline.

Number needed to treat

No benefits

• • • •

• No benefits in improving aspects of behavior have been established as of yet.

Cognitive improvement: 8–14. Clinical global impression: 7–15. Behavior: no reliable data. Functional activity: no reliable data.

Table V.2.6 Details of donepezil trials. Participants

Interventions

Outcomes

Notes

Rogers & Friedhoff 1996a. 12-week double-blind, placebo controlled, randomized

Multicenter, 161 outpatients with mild to moderate AD, MMSE between 10 and 26, mean age 72

Patients were randomized to placebo, 1 mg/day, 3 mg/day, or 5 mg/day donepezil

ADAS-Cog, CIBIC+, ADL, MMSE

Plasma levels were correlated with outcome ratings

Rogers et al. 1998a. 12-week double-blind, placebo controlled, randomized

Multicenter, 23 sites, 468 outpatients with mild to moderate AD, MMSE between 10 and 26, mean age 74

Patients were randomized to placebo, 5 mg/day, or 10 mg/day donepezil

ADAS-Cog, CIBIC+, MMSE, QoL, CDR-SBs

Rogers et al. 1998b. 24-week double-blind, placebo controlled, randomized

Multicenter, 20 sites, 473 outpatients with mild to moderate AD, MMSE between 10 and 26, mean age 73

Patients were randomized to placebo, 5 mg/day, or 10 mg/day donepezil

ADAS-Cog, CIBIC+, MMSE, QoL, CDR-SBs

Burns et al. 1998. 24-week double-blind, placebo controlled randomized

Multicenter, 818 outpatients with mild to moderate AD, MMSE between 10 and 26, mean age 72

Patients were randomized to placebo, 5 mg/day, or 10 mg/day donepezil

ADAS-Cog, CIBIC+, MMSE, CDR-SB, IDDL

Anorexia was 4 –8 times more likely, depending on dose, in patients treated with donepezil than with placebo

Tariot et al. 2001. 24-week double-blind, placebo controlled, randomized

Multicenter, 23 nursing home sites, 208 patients with possible or probable AD, or AD with cerebrovascular disease, with an average age of 86 years

Randomized to 10 mg/day donepezil or placebo

MMSE, NPI

Asthenia, myasthenia, anorexia, and weight loss occurred just under twice as often as placebo. Weight loss was particularly marked in patients > 85 years

Feldman et al. 2001. 24-week, double-blind, placebo controlled, randomized

Multicenter, 290 subjects, with moderate to moderately severe AD, MMSE 5-17, mean age 74 years

Subjects were randomized to placebo, or to 5 mg/day donepezil for 4 weeks, then 10 mg/day as tolerated in this study

CIBIC, MMSE, SIB DAD, NPI

Winblad et al. 2001. 52-week double-blind, placebo controlled, randomized

286 outpatients with probable AD, only about two-thirds of patients were able to complete the 1 year long study, mean age 73

Randomized to 10 mg/day donepezil or placebo

GBS Scale, MMSE, PDS, GDS

Asthenia, vertigo, syncope and bone fractures were 2–3 times more common in the donepezil treated group than in the placebo, and between 5.6–7.7% of the donepezil treated

Mohs et al. 2001. 52-week double-blind, placebo controlled, randomized

Multicenter, 431 outpatients with mild to moderate AD, MMSE 12 and 20, CDR 1 or 2, mean age 75

Randomized to 5 mg/day for 4 weeks then 10 mg/day donepezil or placebo

ADFACs MMSE CDR-SB

Used a survival analysis to determine drug-placebo differences In time to loss of certain level of ADLs

TREATMENT OF ALZHEIMER’S DISEASE 483

Design

484 CHAPTER V.2

V.2.5

Galantamine

Lon S. Schneider and Jason T. Olin Key point

Introduction

Galantamine is a longer-acting cholinesterase inhibitor effective for improving cognitive and global symptoms in Alzheimer’s disease (AD). Side effects include the expected cholinergic and gastrointestinal effects, largely related to dosage titration.

Galantamine (or previously, galanthamine), an alkaloid extracted from Amaryllidaceae (Galanthus woronowi, the Caucasian snowdrop, and daffodil bulbs), but now synthesized, is a reversible, competitive inhibitor of acetylcholinesterase (AChE) with relatively little butyrylcholinesterase activity (Harvey 1995; Pacheco et al. 1995). It is 10–50-fold more selective for acetyl-compared to butyrylcholinesterase (Thomsen & Kewitz 1990). Competitive inhibitors compete with acetylcholine (ACh) at the

Table V.2.7 Pooled results for activities of daily living from the Cochrane Collaboration Review withdraws for galantamine vs. placebo (reproduced with permission from Update Software). Comparison: Withdrawals before end of treatment Outcome: Proportion of all cause discontinuations (6 months) Treatment Control n/N n/N Study Galantamine (8 mg/day bid) vs. placebo 32/140 GAL-USA-10 32/140 Subtotal (95%CI) Test for heterogeneity chi-square = 0.0 df = 0 Test for overall effect z = 1.70 p = 0.09 Galantamine (16 mg/day bid) vs. placebo 60/279 GAL-USA-10 60/279 Subtotal (95%CI) Test for heterogeneity chi-square = 0.0 df = 0 Test for overall effect z = 1.65 p = 0.10

Peto OR (95%CI fixed)

Weight (%)

Peto OR (95%CI fixed)

46/286 46/286

100.0 100.0

1.57 [0.93, 2.65] 1.57 [0.93, 2.65]

46/286 46/286

100.0 100.0

1.43 [0.94, 2.18] 1.43 [0.94, 2.18]

26.6 35.5 37.9 100.0

1.59 [0.96, 2.63] 1.96 [1.27, 3.02] 1.50 [0.98, 2.28] 1.67 [1.29, 2.17]

36.6 27.2 36.2 100.0

4.79 [3.18, 7.23] 2.12 [1.31, 3.40] 2.93 [1.94, 4.43] 3.21 [2.51, 4.12]

Galantamine (24 mg/day bid) vs. placebo 44/220 29/215 GAL-INT-1 68/212 41/213 GAL-USA-1 61/273 46/286 GAL-USA-10 173/705 116/714 Subtotal (95%CI) Test for heterogeneity chi-square = 0.80 df = 2 p = 0.67 Test for overall effect z = 3.89 p = 0.000 10 Galantamine (32 mg/day bid) vs. placebo GAL-95-05 89/186 44/279 GAL-INT-1 55/218 29/215 GAL-USA-1 89/211 41/213 Subtotal (95%CI) 233/615 114/707 Test for heterogeneity chi-square = 6.81 df = 2 p = 0.033 Test for overall effect z = 9.22 p = 0.000 01 0.1 0.2 Favors treatment

1

5

10

Favors control

TREATMENT OF ALZHEIMER’S DISEASE 485

AChE binding site, while non-competitive inhibitors bind to the site independent of acetylcholine. Because competitive AChE inhibitors are dependent on ACh concentration, they will be less likely to bind to the enzymatic site in brain areas that have high ACh levels; while in brain areas where ACh is low, there will be a high amount of the competitive cholinesterase inhibitor binding to AChE relative to acetylcholine. Theoretically, competitive inhibitors will have more effect in areas with low levels of ACh and less effect in areas with higher acetylcholine. This may provide a selective effect in the brain areas affected in AD that have lower ACh levels. Conceivably, in areas where ACh is high, a non-competitive agent binding to the AChE molecule may further increase ACh levels and contribute to central cholinergic side effects. Additionally, galantamine is an allosteric modulator at nicotinic cholinergic receptor sites and thus may enhance cholinergic transmission (Sweeney et al. 1988; Maelicke et al. 1997). Animal trials indicate that galantamine improves learning and memory performance (Vincent et al. 1988; Sweeney & Bachmann 1990; Dal-Bianco et al. 1991).

Rationale The rationale for cholinesterase inhibitors to treat AD has been described in Chapters III.2 and V.2.4.

Evidence The Cochrane Library (2000, issue 4) controlled trials register and Medline (1966–2000) were searched with the term ‘galantamine or galanthamine and (Alzheimer or dementia)’. An additional source for identifying studies was contact with the manufacturer, which led to reports of trials published in conference proceedings. Irrelevant studies were discarded and only trials that were unconfounded, randomized, double-blind, placebo-controlled with greater than 1 day of treatment were selected for inclusion. See website for details of the trials. Several early small sample size trials have been published reporting galantamine’s effects in approximately 220 subjects with Alzheimer’s disease (Rainer et al. 1989; Thomsen et al. 1990a,b;

Rainer et al. 1993; Wilcock et al. 1993; Kewitz et al. 1994).

10–12-week clinical trials The larger scale placebo-controlled, double-blind multicenter trials include a 3 month double-blind phase II dose-finding trial in Europe (GAL-93-01, Wikinson & Murray 2001), comparing approximately 18, 24 and 36 mg daily doses of galantamine with placebo, divided into three times per day dosing. Effects on cognitive performance and side effects appeared dose-related. Cognitive performance (as measured by the Alzheimer’s Disease Assessment Scale-cognitive test, ADAS-Cog) was statistically superior at all doses vs. the placebo group. At 36 mg (12 mg tid) galantamine there was both greater efficacy and a very high dropout rate (50%) due to cholinergic side effects, while both cognitive efficacy and side effects were less at 18 mg. One multicenter, placebo-controlled trial involved 167 Alzheimer’s patients first entered into a 3-week single-blind, dose-titration phase, with an upper limit of 50 mg/day galantamine. The 141 drug responders were then randomized either to continue galantamine therapy, or to receive placebo for the following 10-week double-blind phase. Those who had remained on galantamine had improved by 1.66 ADAS-Cog points, while those switched to placebo had deteriorated by 1.40 points (Rainer 1997). One phase III trial (GAL-INT-2, Rockwood et al. 2001) involved 386 AD outpatients randomized to placebo or a flexible dose titration of galantamine over 4 weeks to between 24 and 32 mg/day in divided doses and was 3 months duration. The results indicated that treatment at between 24– 32 mg/day improved cognition, global ratings, and activities of daily living. Most frequent side effects included nausea, dizziness, vomiting and anorexia.

5–6-month clinical trials One earlier trial (GAL 95-05) was of 29 weeks duration, enrolled 554 patients who were randomized to placebo or a fixed-dose regimen of galantamine titrated to 32 mg/day by 8 mg/day at 2-week intervals.

486 CHAPTER V.2

There are three Phase III trials (GAL-INT-1, Wilcock et al. 2000; GAL-US-1, Raskind et al. 2000; GAL-US-10, Tariot et al. 2000) that have been published. The first two used a fixed-dose treatment regimen (galantamine 24 or 32 mg/day); subjects were titrated to doses of placebo, 12, or 16 mg galantamine, bid and followed over 6 months. The third trial used three dosing regimens (8, 16, or 24 mg/day) and slowly escalated dosage every 4 weeks, and was 20 weeks long. (The fourth trial, GAL-INT-2, was 3 months in length and is described above.) The results of the first two trials indicated that treatment with either 24 or 32 mg/day galantamine improved cognition, global impression, and ADLs. There were no significant differences in efficacy between the two galantamine treatment groups. Gastrointestinal side effects were among the most frequent adverse events in both groups and more common at the higher 16 mg bid dose. Sleep disturbance and agitation were other common side effects in the high-dose treatment groups. In the 5-month trial there was clear evidence of efficacy at 16 and 24 mg/day, with adverse events similar to placebo at 16 mg/day and somewhat greater at 24 mg/day. 8 mg/day was demonstrated as clearly subtherapeutic.

Cognition In the four larger-scale trials, galantamine maintained or improved cognitive function in that mean ADAS-Cog scores of the galantamine treated groups were generally significantly better than at baseline levels and produced significantly better outcomes than placebo on the ADAS-Cog. The Cochrane systematic review (Olin & Schneider 2000) reported that, overall, galantamine showed significant treatment effects at daily doses of 16–32 mg/day for trials of 3- to 6-months duration. For cognitive function over 5–6 months duration: at 24 mg/day improvements measured −3.5 points (95%CI between −4.3 and –2.8) on weighted mean difference on the ADASCog scale, and −4.1 points at 32 mg/day (95%CI between −5.4 and −2.8). This effect was composed of improvement in the medication treated groups and deterioration in the placebo groups. Two 6month trials expressed ADAS-Cog results in terms

of the people who improved by four or more points compared with those who improved less or worsened. The analyses gave statistically significant results in favor of treatment for daily doses of 16 mg (OR 2.2; 95%CI 1.5–3.4), 24 mg (OR 2.4; 95%CI 1.8–3.2), and 32 mg (OR 2.9, 95%CI 1.9–4.0).

Global rating For global ratings, trials of 3 months duration odds ratios (OR) were statistically significant in favour of treatment with doses of 24 mg/day (OR 2.2; 95%CI 0.9–5.3); 24–32 mg/day (OR 2.2; 95%CI 1.4–3.9); and 36 mg/day (OR 3.3; 95%CI 1.2– 9.3). For trials of 5–6 months duration, only doses of 8 mg/day failed to be statistically significant (16 mg/day: OR 2.3, 95%CI 1.6–3.3; 24 mg/day: OR 2.0; 95%CI 1.5–2.5; 32 mg/day: OR 1.9; 95%CI 1.4–2.5) (Table V.2.8).

Mood and behavior There is information from two double-blind, randomized clinical trials (Tariot et al. 2000; Rockwood et al. 2001) on the effects of galantamine on several aspects of behavior, rated by an informant, using the Neuropsychiatric Inventory. There were no significant effects detected in the former 12-week trial, but significant effects were reported over the course of 5 months on some individual items of the NPI. The latter trial gave statistically significant results in favor of treatment for daily doses of 16 mg (WMD −2.4; 95%CI between −4.5 and −1.3) and 24 mg (WMD (weighted mean difference) −2.4; 95%CI between −4.6 and −0.1). The ITT results were lower, with statistically significant findings in favor of galantamine only for the daily dose of 16 mg.

Functional activity Galantamine improved scores on activities of daily living in clinical trials on two ADL instruments: the Disability Assessment of Dementia (DAD) and the ADCS-ADL scales. Both observed cases (WMD 3.8; 95%CI 0.3–7.3) and ITT analyses using the DAD gave statistically significant results in favor of treatment for daily doses of 32 mg for 6 months duration.

TREATMENT OF ALZHEIMER’S DISEASE 487

Table V.2.8 Pooled results of clinical global change for galantamine vs. placebo (reproduced with permission from Update

Software). Comparison: CIBIC-plus OC Outcome: CIBIC-plus (no change or improvement at 6 months) OC Treatment Control n/N n/N Study Galantamine (8 mg/day bid) vs. placebo 54/106 GAL-USA-10 54/106 Subtotal (95%CI) Test for heterogeneity chi-square = 0.0 df = 0 Test for overall effect z = 0.53 p = 0.6 Galantamine (16 mg/day bid) vs. placebo 143/211 GAL-USA-10 143/211 Subtotal (95%CI) Test for heterogeneity chi-square = 0.0 df = 0 Test for overall effect z = 4.23 p = 0.000 02

Peto OR (95%CI fixed)

Weight (%)

Peto OR (95%CI fixed)

112/234 112/234

100.0 100.0

1.13 [0.71, 1.79] 1.13 [0.71, 1.79]

112/234 112/234

100.0 100.0

2.25 [1.55, 3.28] 2.25 [1.55, 3.28]

31.4 26.4 42.2 100.0

2.06 [1.33, 3.18] 1.89 [1.18, 3.03] 1.93 [1.33, 2.81] 1.96 [1.54, 2.50]

31.7 37.7 30.6 100.0

1.76 [1.09, 2.83] 2.18 [1.40, 3.37] 1.68 [1.03, 2.74] 1.88 [1.44, 2.46]

Galantamine (24 mg/day bid) vs. placebo 108/161 86/174 GAL-INT-1 95/135 88/159 GAL-USA-1 136/212 112/234 GAL-USA-10 339/508 286/567 Subtotal (95%CI) Test for heterogeneity chi-square = 0.08 df = 2 p = 0.96 Test for overall effect z = 5.43 p < 0.000 01 Galantamine (32 mg/day bid) vs. placebo GAL-95-05 47/186 38/235 GAL-INT-1 106/155 86/174 GAL-USA-1 80/118 88/159 Subtotal (95%CI) 233/459 212/568 Test for heterogeneity chi-square = 0.71 df = 2 p = 0.7 Test for overall effect z = 4.59 p < 0.000 01 0.1 0.2 Favors control

One trial provided data using the ADCS-ADL scale (Tariot et al. 2000). The observed cases (OC) analyses gave statistically significant results in favor of treatment for daily doses of 16 mg (WMD −3.5; 95%CI between −5.2 and −1.8) and 24 mg (WMD −2.4; 95%CI between −4.1 and −0.7). The ITT results were slightly lower, but still statistically significant in favor of treatment. In both trials the effect was composed of deterioration in the placebo groups and no change in the medication groups.

Number needed to treat NNTs were calculated from the current Cochrane review (Olin & Schneider 2001) and from the individual trials. For cognition the NNT overall was 7

1

5

10

Favors treatment

(5–10). For global change NNTs were calculated on the basis of improvement or no change vs. worsening, a dichotomy somewhat different from that used in other trials. The NNT value (with 95%CIs) for overall changes measured by Clinical Global Impressions of Change was 7 (5–12).

Who should be considered for treatment? The inclusion criteria in the clinical trials generally included: outpatients with a research diagnosis of probable AD (NINCDS-ADRDA criteria and/or DSM-IV criteria) and with mild to moderate cognitive severity, albeit with a somewhat narrower range of acceptable Mini Mental Status Examination (MMSE) scores than in most other phase III AD trials (i.e. a MMSE between 10 and 22). In

488 CHAPTER V.2

three studies (GAL-INT-1, GAL-US-1, GAL-INT2) the MMSE at baseline was 11–24, inclusive, and the cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-Cog) was > 11. In one study (GAL-US-10) patients had to have an MMSE score of 10–22 and ADAS-Cog score of > 18, whereas in the remaining study (GAL-95-05) patients had to have an MMSE score of 12–24. Patients included in these trials generally were medically healthy and had no major behavioral problems. Although allowed, concomitant illnesses could include hypertension, mild heart failure, non-insulin dependent diabetes mellitus and hypothyroidism, provided these illnesses were well controlled. Thus the evidence for the safety and efficacy of galantamine is limited to this group. There is no information on patients with more severe or milder cognitive impairment, or on those residing in nursing homes or other institutions. There is also little information on the effect of galantamine on patients with comorbid medical illnesses.

obstruction and seizures. Cholinesterase inhibitors may exaggerate the effects of succinylcholine-type muscle relaxants during anesthesia. The use of galantamine in patients with very mild or severe Alzheimer’s dementia, other types of dementia or other types of memory impairment has not been investigated or fully reported. Therefore, specific guidance cannot be provided.

Who should be excluded from treatment?

Adverse effects

Galantamine is contraindicated in patients with known hypersensitivity to it. Because it is metabolized by the liver it should be used cautiously in patients with hepatic impairment. (Such patients may have cognitive impairment due to their liver disease and probably should not be treated with a cholinesterase inhibitor until their liver disease is resolved). Patients with pre-existing gastrointestinal disorders such as gastritis, ulcer disease or problematic nausea and vomiting should be treated with particular caution, if at all, because of the potential for exacerbating these conditions. Gastrointestinal inflammation, ulcers or bleeding may be asymptomatic and not recognized early. Patients with pre-existing anorexia, cachexia, or recent weight loss should be treated with caution due to the effects of cholinesterase inhibitors on appetite and weight. A patient’s weight, appetite and food intake should be monitored during therapy. Cholinesterase inhibitors should be used with care in patients with sick sinus syndrome or conduction defects, in patients with a history of asthma or obstructive pulmonary disease. Also, cholinomimetics may induce or exacerbate urinary

The common side effects are the expected cholinergically mediated ones; nausea, vomiting, and diarrhea are usually transient over several weeks. Adverse events occurred more often in the fixed dose trials and at higher doses, and less often in the dose-escalation trial, in which the dosage was increased by 4 mg bid every 4 weeks and dosages were 16 mg/day and 24 mg/day (Tariot et al. 2000). In the 5-month trial with the slower escalation, nausea occurred in 13–16% of patients titrated to 16 or 24 mg/day, respectively, and in 4% of placebo patients. By contrast, nausea occurred in approximately 32% of patients in the 12-week trial at 24– 32 mg/day (compared to 11% of placebo patients) and in 40% of patients in the two 6-month trials who were escalated more rapidly to 24 or 32 mg/day, and in 12–13% of placebo patients. Vomiting was more frequent in the latter trials, occurring about 15% of the time in the 12-week trial and 20% in the 6-month trials, compared to 10% in the slower escalation trial both at 24 mg/day. The rates of anorexia and weight loss were about the same among the trials at 10% and about twice that of placebo except for one trial with virtually no

Clinical pharmacokinetics The drug is rapidly and well absorbed, pharmacokinetics are linear, food delays the time to maximal concentration (Tmax, 0.5–2.5 h); bioavailability is 80–100%; protein binding is approximately 10–17%; half-life is from 5.7 to 9 h. Galantamine is metabolized through the P450 2D6 isoenzyme to metabolites with very little activity, and glucuronidated; metabolites and unchanged galantamine are excreted in urine (Mihailova & Yamboliev 1986; Bickel et al. 1991; Kewitz et al. 1995).

TREATMENT OF ALZHEIMER’S DISEASE 489

significant anorexia or weight loss on placebo (Wilcock et al. 2000). NNH values with galantamine for frequently observed cholinergic side effects were: 30 (17–137) for anorexia, 5 (4–9) for nausea, and 10 (8–14) for vomiting. NNH values for all withdrawals from clinical trials were 13 (9–25).

Starting/monitoring/stopping treatment The effective doses of galantamine in controlled clinical trials are 16, 24, and 32 mg/day administered bid, usually with meals. In view of the trend for the higher doses to be more effective but to have greater adverse events, 16 mg/day should be considered a target dose, with the option to increase to 24 mg/day to maximize efficacy in the presence of good tolerability. Starting dosage should be 4 mg bid, and then increased to 8 mg bid after 4 weeks. Earlier increase is more likely to be associated with a higher incidence of cholinergic adverse events. Maintenance treatment can be continued for as long as a therapeutic benefit for the patient exists. Therefore, the potential clinical benefit of galantamine should be reassessed on a regular basis, especially for patients treated at the lower effective dosage range. Discontinuation should be considered when evidence of a therapeutic effect is no longer present. As with other cholinesterase inhibitors, it is not possible to predict individual patient responses. Treatment effect has not been studied in placebocontrolled trials beyond 6 months. Therefore, optimal duration of treatment with continuing efficacy is unknown but overall efficacy is likely to extend at least 6–12 months based on the clinical trials and open-label extension phases.

With all cholinesterase inhibitors it is difficult to assess individual patient response because of the variability of the deteriorating course of Alzheimer’s disease, and because most of the effect of medication is due to a stabilization or lack of worsening of cognitive function while placebo-treated patients continue to decline. Therefore, the clinical observations of minimal or no clinical worsening may be sufficient reasons to continue medication treatment if patients are tolerating therapy.

Monitoring side effects Cholinergic side effects such as nausea and vomiting tend to occur at higher doses, are often transient or self-limited and can often be managed with encouragement and maintenance of the present dose level, by omitting one or more doses, or by temporarily decreasing dosage. Most cholinergic side effects are related to the dose escalation/titration phase of treatment, just after increasing to 16, 24, or 32 mg/ day. Patients on maintenance doses should have few and very mild cholinergic side effects, if any. However, anorexia and weight loss may be clinically significant problems over the course of 6 months and longer, so these parameters should be monitored and medication discontinued if anorexia or weight loss becomes clinically significant. Cholinesterase inhibitors as a class may exaggerate the effect of succinylcholine-like muscle relaxants during anaesthesia. The cholinergic and vagotonic effects may cause significant bradycardia, and this can be a particular concern to patients with supraventricular conduction impairments or sick sinus syndrome. Syncope observed occurring with galantamine may be related to this.

Table V.2.9 Description of galantamine placebo-controlled clinical trials. Author (mg/day)

Duration (weeks)

No. of patients

Age

% female

Phase

Dose

Kewitz 1994 Wilkinson & Murray 2001 Rockwood 2001 Gal-95-05 Wilcock 2000 Raskind 2000 Tariot 2000

13 12 12 29 26 26 20

95 285 386 554 653 636 978

60 –87 73.7 75.0 72.9 72.2 72.2 77.7

NS 57 58 ns 63 62 64

2 2 3 2 3 3 3

20–15 18, 24, 36 24–32 32 24, 32 24, 32 16, 24, 32

NS, not significant.

490 CHAPTER V.2

Table V.2.10 Galantamine clinical trials. Design

Participants

Interventions

Outcomes

GAL-93-01 Wilkinson & Murray (2001) 12-weeks double-blind, parallel group, placebo controlled, randomized

Multicenter, 285 outpatients with NINCDS-ADRDA probable AD Mean age 73.7 MMSE 13.245 8 sites

Patients were randomized to placebo 6 mg tid, 8 mg tid, 12 mg tid galantamine. Treatment started at 4 mg bid and was progressively increased every several days and then weekly to assigned maximum dose (5, 8, and 14 days, respectively)

ADAS-Cog, CIBIC-Plus, IADL, PDS

GAL-95-05 (Unpublished) 29-weeks double-blind, parallel group, placebo controlled, randomized

Multicenter, 554 outpatients with NINCDS-ADRDA probable AD, MMSE 12–24 Mean age 72.9 ± 8.5

Patients were randomized to placebo 40 mg/day (galantamine 32 mg base) Treatment began at 8 mg/day and was progressively increased weekly by 8 mg/day for 2 weeks (16 mg/day, 24 mg/day), then raised by 4 mg/day at week 4 (28 mg/day) then to assigned maximum dose at week 5

EURO-ADAS, GRECO-ADAS (French) CIBIC-Plus, NOSGER, DSST, NAB

GAL-INT-1 Wilcock et al. (2000) 26-weeks double-blind, parallel group, placebo controlled, with 4-week placebo run-in, randomized

Multicenter, 86 sites, 653 outpatients with NINCDS-ADRDA probable AD, MMSE 11–24, ADAS-Cog > 11 Mean age is 72.2

Patients were randomized to placebo, 12 mg bid, or 16 mg bid galantamine Treatment began at 4 mg bid and was progressively increased 8 mg/day to assigned maximum dose

ADAS-Cog, CIBIC-Plus, DAD

Notes

2.9 and 3.1 point difference on ADAS-Cog, significant deterioration on CIBIC-plus of 34–39% vs. 50% on placebo; effects on ADLs

Multicenter, 43 sites, 386 outpatients with NINCDS-ADRDA probable AD Mean age is 75.0 ± 0.37

Patients were randomized to placebo, 12 mg bid, or 16 mg bid galantamine. Treatment started at 4 mg bid and was progressively increased 8 mg/day to 12 mg/bid. Dose could be increased to 16 mg bid at end of week 3 or maintained at 12 mg bid. At week 4 dose could be kept at 16 mg bid or reduced to 12 mg bid

ADAS-Cog, CIBIC-Plus, NPI, DAD

GAL-US-1 Raskind et al. (2000) 26-weeks/6 months double-blind, parallel group, placebo controlled, with 4-week placebo run-in, randomized

Multicenter, 33 sites, 636, NINCDS-ADRDA probable AD outpatients, MMSE 11–24, ADAS-Cog > 11 Mean age 72.2

Randomized to placebo, 12 mg bid, or 16 mg bid galantamine. Treatment started at 4 mg bid and progressively increased 8 mg/d to assigned maximum

ADAS-Cog, CIBIC-Plus, DAD

GAL-US-10 Tariot et al. (2000) 5-months double-blind, parallel group, placebo controlled, with 4-week placebo run-in, randomized

Multicenter, sites unspecified, 978 ADAS-Cog, CIBIC-Plus, ADCS-ADL outpatients with NINCDS-ADRDA probable AD, MMSE 10–22, ADAS-Cog score > 17 Mean age 76.0 ± 0.6 to 77.7 ± 0.4

Randomized to placebo 12 mg bid and 16 mg bid galantamine. Treatment started at 4 mg bid and was increased every 4 weeks by 8 mg/day to assigned maximum dose

ADAS-Cog, CIBIC-Plus, ADCS-ADL, NPI

Kewitz (1994) Randomized to placebo 13-weeks double-blind, parallel group, placebo controlled, with initial single-blind galantamine treatment randomized

Multicenter, sites unspecified, 95 outpatients with mild to moderately severe primary degenerative dementia Mean age is 60–87

Patients were randomized to placebo 10 mg bid increased up to 50 mg/day during first 3 weeks

ADAS-Cog, CGIC

1.9 points on ADAS-Cog, (P = 0.002) CIBIC-plus (deterioration in 21% vs. 37% on placebo; P < 0.001). Significant effects on ADLs but not on behaviour

TREATMENT OF ALZHEIMER’S DISEASE 491

GAL-INT-2 Rockwood et al. (2001) 12-weeks parallel group, placebo controlled, with 4-week placebo run-in, randomized

492 CHAPTER V.2

Because gastric acid secretion may be increased with cholinesterase inhibitors, there may be an increased risk for developing ulcers or gastrointestinal bleeding, although there was no increased incidence in the clinical trials. Patients receiving non-steroidal anti-inflammatory drugs may be at particular risk. It is possible that cholinesterase inhibitors may cause bladder outflow obstruction, seizures, and exacerbate asthma or obstructive pulmonary airway disease.

Future research Future research is needed in more heterogeneous and typical clinical populations, involving people with more severely impaired cognitive functioning, and with more mildly impaired cognitive functioning than the people included in these trials, and over durations longer than 6 months. Trials that contrast galantamine with other cholinesterase inhibitors are desirable. Given that adverse events are dose-related, an optimal dose is needed that provides sufficient improvement while minimizing adverse events. This dose may be 16 mg/day but further research is needed. It will be important to assess more accurately the effects of galantamine on ADLs, aspects of problematic behaviors, care giver burden, and the implications for health economics. Effectiveness in other dementia such as vascular dementia, dementia with Lewy bodies, and frontotemporal dementia needs to be assessed, as well as in mild cognitive impairment. In addition the possible contributions of its effect on modulating nicotine receptors needs to be further researched.

Summary Galantamine is a competitive reversible predominantly acetylcholinesterase inhibitor with a duration of action that allows twice per day dosing. Four 5–6-month long placebo-controlled trials, and several of shorter duration have shown cognitive and global efficacy, similar to other cholinesterase inhibitors. In these trials, both patients assigned to placebo and galantamine had a wide range of responses, but overall the active treatment groups were more likely to show greater improvements.

With regard to efficacy and safety, however, results have not been fully reported so that magnitudes of effect or response rates cannot be clearly determined. Of concern, the publications do not adequately report less common adverse events, occurring less than 5% of the time, such as potential muscle weakness, bradycardia, syncope, weight loss, and anorexia: each of which may be, although infrequent, serious problems. Galantamine’s effect can be summarized as follows: [Grade A-2] 1 Modest improvement in cognitive performance compared to placebo. 2 Modest improvement in clinical global ratings. 3 Statisically significant but clinically unclear effects on behavioral measures. 4 Statistically significant but clinically unclear improvements in activities of daily living. Galantamine is one of several cholinesterase inhibitor treatment options, along with tacrine, donepezil, and rivastigmine for patients with mild to moderately severe Alzheimer’s disease, and may be considered as either a first or second cholinesterase inhibitor for use in these patients, see Tables V.2.9–10. Results of several trials show that, compared with placebo recipients, significantly more galantamine-treated patients respond to therapy. The lower dosage range of 16 mg/day is statistically as effective as the higher doses overall. Individualized dosage titration is necessary from 4 mg bid to 8 mg bid and possibly higher to minimize cholinergic side effects and to maximize the potential for efficacy. Weight loss and anorexia may be significant problems in AD patients in this age group treated with cholinesterase inhibitors in general. The competitive inhibition, relatively selective ACh inhibition, and effects at nicotinic receptors differentiates galantamine from other cholinesterase inhibitors with respect to mechanisms of actions. However, thus far there are no apparent clinical differences in efficacy.

Benefits The benefits of galantamine treatment, over 6 months, are as follows. • Modest improvement in cognitive performance similar to other cholinesterase inhibitors.

TREATMENT OF ALZHEIMER’S DISEASE 493

• Modest improvement in clinical global impression. • Modest improvement in some behavioral symptoms. • Modest reduction in the rate of functional decline.

No benefits • No benefits have yet been demonstrated in more severely impaired patients, or in more mildly impaired patients.

V.2.6

Number needed to treat • Cognitive improvement: 7 (5–10). • Clinical global impression: 7 (5–12). • Behavior: no data available with which to calculate. • Functional activity: no data available with which to calculate.

Metrifonate

Lon S. Schneider Key points

In light of the stage in development, lack of approval by regulatory authorities for the treatment of dementia, the potential for significant adverse events and the need for further research on safety, metrifonate cannot be recommended for use in clinical practice even though it appears to be relatively well tolerated and effective over the 6-month clinical trials. It might have a role for some patients based on individual circumstances; but such practice does not conform to its current regulatory status.

Introduction Metrifonate (O,O-dimethyl-(1-hydroxy-2,2,2trichloroethyl)-phosphonate), an organophosphate compound synthesized in the 1950s, is widely used as an insecticide for fruit and field crops (brand name Trichlorfon, Bayer Pharmaceuticals, Inc.), as an antiparasitic agent for domestic animals, and as a second-line antischistosomiasis agent in humans (Lorenz et al. 1955; Schneider & Giacobini 1999; Extoxnet Pesticide Information Project, http:// ace.ace.orst.edu/info/extoxnet/pips/trichlor.htm). It was introduced for the treatment of schistosomiasis under the trade name Bilarcil in the 1960s and has been used extensively in developing countries around the world by millions of people. Although it is no longer the first-line medication for that indication, it remains a WHO-approved drug.

Metrifonate was observed to possess a number of in vitro and in vivo cholinesterase inhibitor characteristics suggesting its suitability for the treatment of Alzheimer’s disease (AD) (Becker & Giacobini 1988). In 1990 the results of the first clinical trial demonstrated the potential for its clinical efficacy in the treatment of cognitive deficits (Becker et al. 1990). In 1998 and 1999, the results of four phase III clinical trials of metrifonate for AD were published and were generally supportive of its essential cognitive efficacy (Cummings et al. 1998; Morris et al. 1998; Dubois et al. 1999; Raskind et al. 1999). Metrifonate is unique among the cholinesterase inhibitor class of medications in that it is a nonactive, prodrug that is non-enzymatically transformed into an active metabolite 2,2-dimethyl dichlorovinyl phosphate (DDVP, dichlorvos) (Nordgren et al. 1978; Hinz et al. 1996a). Very low concentrations of DDVP, an irreversibly binding cholinesterase inhibitor, steadily converted from metrifonate, lead to levels that are sufficient to inhibit cholinesterases in vivo. Thus, metrifonate can be viewed as a drug delivery reservoir providing steady, titrated administration of DDVP. Phosphorylating agents such as DDVP, react covalently and irreversibly with the cholinesterase enzyme to form an inactive phosphoryl enzyme. The controlled release of DDVP in the brain and DDVP’s slow inhibition kinetics for cholinesterase may contribute to the relatively mild acute cholinergic toxicity (see below). Although metrifonate has completed phase III testing, a New Drug

494 CHAPTER V.2

Application to the US Food and Drug Administration was initially disapproved because of concerns about muscle weakness and respiratory depression.

Rationale The primary rationale for the use of metrifonate in AD is in the use of any cholinesterase inhibitor in AD: the diminished cholinergic function in AD manifested by the loss of cholinergic cortical neurones in the basal forebrain, decreased choline acetyltransferase (the enzyme necessary for synthesis of acetylcholine (ACh) from choline and acetyl CoA) and correlations between low post mortem measures of cholinergic function and clinical ratings of cognition provide the rationale for the use of agent that enhance cholinergic function (see Chapter III.2). Cholinesterase inhibitors block acetylcholinesterase (AChE) and increase the availability of ACh in the synaptic cleft.

Evidence The Cochrane Library (2000, issue 4) controlled trials register and Medline (1966–2000) were searched with the terms ‘metrifonate and (Alzheimer or dementia)’. An additional source for identifying studies was contact with the manufacturer, which led to studies published in conference proceedings. Irrelevant studies were discarded and only trials that were unconfounded, randomized, double-blind, placebo controlled with greater than 1 day of treatment were selected for inclusion. Early metrifonate trials in AD used weekly doses; later trials used once-daily doses in order to reduce fluctuations between peak and trough inhibition level and achieve a more stable level of AChE inhibition (Pettigrew et al. 1998). The Phase III trials generally used a loading-dose strategy for the first 1 to 3 weeks of treatment, followed by individualization of dosage based on body weight, with the exception of one trial that used a fixed dosage throughout. Metrifonate clinical trials are summarized on the website (Becker et al. 1996, 1998; Morris et al. 1998; Dubois et al. 1999; Raskind et al. 1999). Metrifonate at various doses was associated with

significant cognitive improvement compared to placebo. Higher doses were consistently more effective than lower doses. Doses below 40 mg/day tended not to be efficacious. There are no obvious clinical or biological predictors of response. Mean red blood cell AChE inhibition tends to be weakly related to mean changes in cognitive scores, but there are wide measurement variations that make this determination not clinically useful.

Cognition Review of the clinical trial results indicates that the magnitude of the mean cognitive effect on the ADAS-Cog is comparable to that observed with other cholinesterase inhibitors, about a 1.3–3.25 point difference between drug and placebo on the ADAS-Cog score as dosage ascends from approximately 40 mg to 80 mg/day. This effect, however, largely reflects the expected deterioration in the placebo group combined with no significant change in cognitive scores over the 6-month trial duration. In two of the 6-month trials, the measurement variances were not reported so true effect sizes cannot be estimated. Neither were a proportion of responders (e.g. based on an ADAS-Cog cutting score or = 4 point improvement).

Global rating Somewhat different clinical global ratings were used among the trials, but all utilized input from care givers. In most trials there were significant drug–placebo differences from 0.2–0.3 points between mean scores on the 7-point ordinal rating scale. The differences were due to greater meanworsening in the placebo group than in the medication group. The variances of the differences were generally not reported; neither were the proportion of responders. Nevertheless, the magnitude of mean difference is similar to that observed in other cholinesterase inhibitor studies.

Mood and behavior In the three 6-month trials (Morris et al. 1998; Dubois et al. 1999; Raskind et al. 1999), patients

TREATMENT OF ALZHEIMER’S DISEASE 495

who received metrifonate were rated as better than those receiving placebo based on a care giver interview on a behavioral rating instrument, the Neuropsychiatric Inventory (NPI), (see Appendix II). Mean difference scores between medication and placebo ranged from a non-significant 1.4 to statistically significant differences of 2.7 and 3.4 on a 120 point scale. The differences were due to greater worsening in the placebo-treated patients compared to drug-treated patients. Individual items that may have contributed to this difference included hallucinations and aberrant motor behavior in two of the trials. Any clinically meaningful effect of metrifonate on disruptive behaviors in patients with AD is hard to assess however, because the patients selected for these trials were selected to assess cognitive change, and were not selected because of disruptive behaviors. Baseline behavioral scores were very low, between 9 and 14, among the trials, indicating very little if any significant behavioral symptomatology. Moreover, the clinical significance of very small differences on the NPI is unclear, and the definition and proportion of the responders was not reported.

Functional activity The Disability Assessment for Dementia (DAD) scale was used to assess functional activity in the three published 6-month trials. There were statistically significant mean differences between drug and placebo in two of the trials. The differences ranged from 2.7 to 5.5 on the 100 point scale. One trial reported that measurably better instrumental activities of daily living (ADLs), including dressing, telephoning, and ability to perform at leisure and at housework, were associated with higher doses of metrifonate of 60 –80 mg/day, but the total score was not significant. Similarly with behavior, the clinical importance of this finding is unclear.

Number needed to treat Although the main phase III trials used similar methodology and outcomes, the reporting of results varied such that the number needed to treat (NNT) could not easily be calculated. For

example, the proportion of responders using any classification on any instrument was not reported in any of the four phase III trials.

Who should be considered for treatment? The clinical inclusion criteria in the trials included: a research diagnosis of probable AD (either NINCDS-ADRDA criteria or DSM-IV criteria); and outpatients with mild to moderate cognitive severity (i.e. a Mini Mental Status Examination (MMSE) between 10 and 26). Patients were generally medically healthy and had no major behavioral problems. Thus the evidence for the safety and efficacy of metrifonate is limited to this group. There is no information on patients with more severe or more mild cognitive impairment, or on those residing in nursing homes or other institutions. There is also little information on the effect of metrifonate on patients with comorbid medical illnesses.

Who should be excluded from treatment? Since metrifonate is not marketed for AD, contraindications have not been established. Patients with a hypersensitivity to metrifonate should not receive it. Cholinesterase inhibitors interfere with succinylcholine-type muscle relaxants and should be avoided when surgery is contemplated. The extent of clinically significant bradycardia associated with metrifonate has not been fully estimated. It is prudent, however, for patients at risk of bradycardia or syncope, or those with sick sinus syndrome or other supraventricular conduction disturbances, to avoid using metrifonate. It is possible that occult gastrointestinal bleeding may occur so patients with prior medical histories should be managed cautiously, as should patients taking adrenal steroids or nonsteroidal antiinflammatory drugs (NSAIDs). In view of the known direct bronchial effects of cholinergic medications on pulmonary conditions such as asthma or obstructive airway disease, and the suspension of metrifonate’s development because of muscle weakness and respiratory failure requiring mechanical ventilation, possibly due to direct neuromuscular effects, metrifonate might be

496 CHAPTER V.2

better avoided in these conditions in favor of a shorter acting cholinesterase inhibitor.

Clinical pharmacokinetics Pharmacokinetic data for both metrifonate and DDVP in AD patients reflect both single and multiple oral doses (Nordgren et al. 1981; Abdi & Villen 1991; Unni et al. 1994; Pettigrew et al. 1998). In general, in late middle-aged subjects (mean age 62–64 years), absorption or bioavailability is over 50 –80% with a Tmax of 0.50 –0.7 h for metrifonate and 0.7–1.2 h for DDVP. It is extensively distributed with higher concentrations in metabolically active tissues; less than 20% is protein bound. Metrifonate spontaneously undergoes non-enzymatic dehydrochlorination to DDVP. It can also be metabolized through phosphonate hydrolysis. DDVP undergoes O-demethylation, and its main (and inactive) metabolites include demethyl-metrifonate, demethyl-dichlorvos, dimethyland methyl-hydrogen-phosphate, and phosphoric acid. The DDVP/metrifonate ratio in plasma is 3% to 4% in the elderly. The percentage of metrifonate reaching the brain as DDVP following a single oral dose is 2%. Elimination half-life, T12 is less than 2 h. Excretion is primarily (80%) in urine. Apparent oral clearance is 29.6–31.3 L/h in AD patients. Concomitant administration with food is associated with a prolonged Tmax and a reduced Cmax, but with only modest reductions in availability and a similar degree of cholinesterase inhibition when compared to a fasting state.

Reversal of cholinesterase inhibition is slow and correlates with enzyme resynthesis. Enzyme recovery half-life was 9–11 days for butyrylcholinesterase (BuChE) and 47–55 days for red blood cell AChE. DDVP more potently inhibits AChE in erythrocytes than BuChE activity in human plasma (BuChE/AChE = 22.5), and inhibits both AChE and BuChE activity in human brain cortex as well (Hallak & Giacobini 1987; Pacheco et al. 1995). Notably, despite a high level of AChE and BChE inhibition (80–90%), cholinergic side effects are mild and no more frequent than with other reversible, selective and non-selective cholinesterase inhibitors. Evidence for central nervous system (CNS) penetration and effect of metrifonate in the CNS is the 40% AChE inhibition measured in patients’ cerebrospinal fluid (CSF) 24 h after a secondweekly dose of 5 mg/kg (Becker et al. 1990). DDVP slightly interacts with the nicotine receptor binding site (35%), and conceivably could have an efficacious effect through this mechanism as well (Hinz et al. 1996b).

Adverse effects In clinical trials, metrifonate is generally welltolerated over periods of 6 months or less; tolerability over longer periods is not known. It is similarly or better tolerated than other cholinesterase inhibitors, in that the vast majority of metrifonate-treated patients enrolled in phase III studies completed these clinical trials, and cholinergic adverse events were reported as frequently or less, compared to patients in other cholinesterase inhibitor trials.

Pharmacodynamics

Cholinergic adverse events

In the early studies of metrifonate for AD, weekly dosing regimens were used. These dosing regimens resulted in variable levels of AChE inhibition approximately ranging from 40% to 90% but with some degree of intraindividual variation throughout the 1-week dosing interval. A daily dosage regimen has been used to minimize the betweendose variability in cholinesterase inhibition, and to ensure more stable steady-state levels of cholinesterase inhibition.

Significant cholinergic side effects occur in about 15% or fewer of patients receiving higher doses. Most adverse events are cholinergically mediated, and are characteristically mild in severity and short-lived, lasting only a few days. Patients tend to rapidly become tolerant to the adverse events when they occur. The most commonly reported adverse events include diarrhea, nausea, abdominal pain, leg cramps, and rhinitis. Leg cramps occur in from 7%

TREATMENT OF ALZHEIMER’S DISEASE 497

to 10% of patients, and from 3 to 10 times more frequently than with placebo. The most obvious reason for this is tonic stimulation of myoneural nicotinic receptors. Increased incidence of leg or muscle cramping also has been reported with other cholinesterase inhibitors as well. The statistically significant decrease in heart rate of about 5–9 bpm at higher doses of medication is likely due to vagotonic effects observed with some cholinesterase inhibitors, and might be of clinical concern. The extent of clinically significant bradycardia (e.g. HR < 50 bpm) was reported in only one trial, and was 7 and 32 times more frequent that with placebo, depending on dose. Because of the actions of cholinesterase inhibitors, these drugs require caution when used in patients with significant asthma, significant chronic obstructive pulmonary disease, cardiac conduction defects, or clinically significant bradycardia. The long-acting cholinesterase inhibitor effects and its effects on other esterases suggest that if surgery is needed, then regional or local anaesthesia should be used, if possible. Considerations involved in general anaesthesia include that metrifonate might decrease the activity of the BChE, that shortacting muscle relaxants be used that are not metabolized via BChE, and that higher doses of muscle relaxants may be required because of the increased intrasynaptic ACh, in addition to other considerations.

Potential neurotoxicity An extensive review of metrifonate’s adverse effects during its use for schistosomiasis is reported by Holmstedt et al. (1978) in which the major side effects were the typical cholinergic effects, similar to those reported for other cholinesterase inhibitors, and there were no instances of neurotoxicity. A detailed study of delayed neurotoxicity in humans or test animals concluded that to obtain critical levels of inhibition of neurotoxic esterase and to cause neuropathy in humans by repeated doses, would require each dose to be severely toxic and perhaps lethal (Johnson 1981). These data suggest that metrifonate at clinical doses used for AD has low neurotoxicity, but cannot be generalized to patients with AD. Neurotoxicity from organophosphates may be

acute or delayed. The delayed syndrome is one of myasthenia caused by neurotoxic esterase inhibition at the neuromuscular junction. Neurotoxic esterase inhibition by DDVP could be responsible for the muscular weakness that occurred in the clinical trials (Karalliedde & Henry 1993). Of significant concern, however, is that approximately 20 patients out of 3000 in the metrifonate clinical studies developed asthenia, myasthenia, malaise, and four patients with muscular weakness received respiratory support (Letter from Bayer Pharmaceuticals, September 18, 1998). Currently the medication has been withdrawn from subjects and the development program has been halted by Bayer and the US Food and Drug Administration (FDA) in order to investigate this further.

Starting/monitoring/stopping treatment At the time of writing, metrifonate is not approved for use in AD. The drug is available for prescription as an antischistosomiasis treatment. When used as an antihelminthic, metrifonate is given as a threedose course of 7.5–15 mg/kg at 2- to 4-week intervals (although the daily dose is 8–15 times higher than that used for AD, it is usually given only three times over the course of 4–8 weeks). Most of the development studies in AD used loading doses of between 25–140 mg/day for 2 weeks, followed by a maintenance dose based on subjects’ body weight, ranging from 30 to 80 mg per day. One clinical trial used a fixed 50 mg per day dosage. If the medication is even marketed for AD, dosing is likely to reflect that used in the clinical trials; metrifonate is likely to be available in appropriately sized tablets to be taken once per day. Metrifonate was most effective at the 60–80 mg/day maintenance dose range, and less effective or ineffective at lower doses. It is possible that, in view of the toxicity at the higher, albeit more effective, doses that, if the drug is approved, it will be at lower doses of 50 mg or less. The therapeutic effect of metrifonate is not an actual improvement over 6 months but rather a relative lack of deterioration in cognitive function and global assessment. Therefore, a lack of clinical

498 CHAPTER V.2

decline or a very slow clinical decline may be evidence of its effects. As with all cholinesterase inhibitors it is often difficult to determine whether a particular patient is benefiting, since the course of dementia is highly variable. Clinical management involves managing adverse events, realizing that the cholinergic effects are usually mild and self limiting. The potential for bradycardia, syncope, gastrointestinal bleeding, and respiratory distress needs to be monitored. Duration of treatment is unknown at this point. There is limited experience over periods longer than 6 months. Medication should be discontinued if significant side effects occur or if cholinergic signs and symptoms do not resolve after several days.

cholinesterase inhibitors that should be considered first. Appropriate safety precautions need to be taken.

Number needed to treat Cognitive improvement No reliable data published. Clinical global impression No reliable data published. Behavior No reliable data published.

Future research Safety, dosing, and long-term efficacy are essential research issues. The significance of respiratory impairment, bradycardia, and low hemoglobin need further investigation and may be significant problems. In view of the long duration of action, once per week dosing may be an option. Potential therapeutic effects on nicotinic receptors and on amyloid precursor protein (APP) processing need further research. Most importantly, the drug needs to be demonstrated to be adequately safe for use in the elderly.

Summary Metrifonate’s effect can be summarized as follows: [Grade A-2] 1 Modest improvement in cognitive performance compared to placebo. 2 Modest improvement in clinical global ratings. 3 Minimal improvements in behavioral measures of unclear clinical significance in patients without particular behavioral disorder. 4 Minimal improvement in instrumental ADLs of unclear clinical significance. In light of its modest benefits on cognition, its lack of regulatory approval and the availability of alternative cholinesterase inhibitors, metrifonate cannot be recommended for routine use as first line therapy in clinical practice, there are other

Functional activity No reliable data published.

Appendix V.2.1 Isomeric forms of AChE Mammalian brain AChE can be separated into multiple molecular forms. The globular tetrameric G4 form and the monomeric G1 form are predominant in the human brain. G1 is almost exclusively intracellular, whereas G4 is extracellular and almost entirely membrane-bound. Both G1 and G4 forms are important for neuronal function and ACh regulation. The presynaptically located G4 form is directly involved in the regulation of ACh transmission. AChE and its membrane-associated G4 form are selectively decreased in AD, while BuChE and the G1 form are unchanged or only slightly decreased in the brain of AD patients (Ogane et al. 1992a). Metrifonate non-selectively inhibits both monomeric (G1) and tetrameric (G4) molecular forms of AChE (Ogane et al. 1992b). By contrast, rivastigmine selectively inhibits the G4 form. The non-selectivity of metrifonate for the AChE forms may represent a theoretical advantage (over other more selective compounds) because by inhibiting both enzymes forms the drug may act throughout the disease process. Considering the progressive decrease in AChE activity taking place in the brain of AD patients, and the unvaried level

TREATMENT OF ALZHEIMER’S DISEASE 499

of BuChE activity, a non-selective AChE inhibitor may offer the advantage of a more prolonged effect as compared to a more selective AChE inhibitor.

Appendix V.2.2 Potential for metrifonate to influence beta-amyloid processing Metrifonate also inhibits other serine enzymes (esterases and phosphatases), which makes it an attractive candidate for potentially regulating APP cleavage and APP release (Mori et al. 1995). These investigators demonstrated that metrifonate at low concentrations increases significantly the release of APPs (but not APPb) from the rat brain cortex. According to these data, inhibition of AChE by metrifonate, by increasing ACh levels, will stimulate muscarinic receptors (mainly M1) and thereby increase the activity of protein kinase C, an enzyme involved in the regulation of the release of non-

V.2.7

amyloidogenic APP fragments. This mechanism could explain a potential stabilizing effect of the drug on cognitive deterioration in long-term clinical studies (Giacobini & Becker et al. 1996). Metrifonate may increase the release of APP by inhibiting AChE, raising ACh levels and stimulating cholinergic M1 receptors, thereby increasing protein kinase C activity. The latter is involved in the cleavage of APP into the presumed nonamyloidogenic soluble fragment rather than the non-soluble amyloidogenic fragment. Stimulation of the M1 muscarinic receptor by increased ACh concentration (resulting from AChE inhibition by metrifonate) in the cholinergic synapse leads to activation of protein kinase C (PKC). Subsequent stimulation of alpha-secretase cleaving the APP molecule in the middle of the amyloidogenic fragment releases APPs non-amyloidogenic fragments (Schneider & Giacobini 1999).

Rivastigmine

Lon S. Schneider Key point

Rivastigmine is a longer-acting cholinesterase inhibitor effective for improving cognitive and global symptoms in Alzheimer’s disease (AD). Side effects include the expected cholinergic and gastrointestinal effects, largely related to dosage titration.

Introduction Rivastigmine (Exelon) is a pseudo-irreversible, selective acetylcholinesterase (AChE) subtype inhibitor. Although it inhibits both peripheral AChE and butrylcholinesterase, it is relatively selective to AChE in the central nervous system (CNS) and, within the CNS, to areas of the cortex and hippocampus, and to the G1 monomeric form of AChE. Moreover, rivastigmine is not metabolized by the hepatic microsome system. Rather, after binding to AChE, the carbamate portion of rivastigmine

is slowly hydrolysed, cleaved, conjugated to a sulphate and excreted. Thus, it is unlikely to pharmacokinetically interact significantly with other medications. These characteristics distinguish this drug from other cholinesterase inhibitors. Rivastigmine was approved by a centralized procedure in Europe, including all 15 member states of the EU. A prescribing information document incorporates the most recent labelling revisions (The Exelon Summary of Product Characteristics & of the EMEA for Europe, www.eudra.org/ humandocs/humans/EPAR/exelon/Exelon.htm). The drug was approved for marketing by the US Food and Drug Administration (FDA) in April 2000 (see January 2001 US prescribing information, www.pharma.US.novartis.com/product/pi/ pdf/exelon.pdf).

Rationale The primary rationale for the use of rivastigmine in AD is in the use of any cholinesterase inhibitor in ADaas discussed in Chapters III.2, V.2.4 and

500 CHAPTER V.2

V.2.8, the well established cholinergic defects in AD include: decline of cholinergic baso-cortical projections; reduced activity of cerebral cortical choline acetyltransferase (ChAT), the key acetylcholine (ACh) synthesis enzyme, and cholinergic cell body loss in the nucleus basalis. Additionally, there are correlations between cortical ChAT reduction or nucleus basalis cell reduction and cortical plaque density. Such cholinergic deficits correlate with cognitive decline as measured by the Blessed-Roth Dementia Rating Scale. The cholinergic hypothesis proposes that the cognitive deficits of AD are related to the observed decrease in central acetylcholinergic activity, and that increasing intrasynaptic ACh could enhance cognitive function and clinical well-being. AChE in human tissue is present in several molecular forms. G4, a tetramer, is the most abundant AChE inhibitor in normal human brain but its presence in the CNS decreases somewhat with aging and to an even greater extent in AD. Because it is located on the presynaptic membranes within the cholinergic synaptic cleft, when ACh binds to it both hydrolysis and feedback inhibition of further ACh release occur. G1, a monomer, is found on postsynaptic membranes in the brain and participates in ACh degradation independently of its presynaptic release. Post-synaptic cholinergic receptor neurones and G1 monomeric AChE do not decrease significantly with AD or aging (Enz & Floersheim 1997). Hence, the G1 monomer on postsynaptic cholinergic neurones may be a relatively selective site of action for rivastigmine.

Evidence The Cochrane Library (2000, issue 2) controlled trials register and Medline (1966–2001) were searched with the terms ‘(rivastigmine, ENA-713, or Exelon) and (Alzheimer or dementia)’. An additional source for identifying studies was contact with the manufacturer, which led to studies published in conference proceedings. Irrelevant studies were discarded and only trials that were unconfounded, randomized, double-blind, placebo controlled with greater than 1 day of treatment were selected for inclusion.

In early trials, rivastigmine significantly improved cognitive test scores in patients with dementia (Anand et al. 1996; Sramek et al. 1996; Forette 1999; see Table V.2.11). Four phase III clinical trials were completed in patients with AD of mild to moderate severity, and all of similar design with respect to included subjects, duration, and outcomes, differing mainly in dosing methods. The results of two have been published (Corey-Bloom et al. 1998; Rösler et al. 1999). Some results of the third have been included in secondary reports (Schneider et al. 1998; Spencer & Nobel 1998; Birks et al. 1999). A fourth trial allowing a fully adjustable dosage between 2 and 12 mg/day, remains unpublished. Regardless, the results of all trials were reviewed by the FDA, EMEA (The European Agency for the Evaluation of Medicinal Products) and other regulatory agencies prior to the marketing approval granted to rivastigmine in most countries. The four trials were of 26 weeks duration and used a prospective, randomized, double-blind, placebo-controlled, parallel-group design. Details of each with respect to sample-size, study centers, location, and dosage regimen are provided in Table V.2.11. In the trials patients were randomized in even allocation ratios to placebo or to different fixed doses of rivastigmine (B351), to a dosage range (B304), or to two dose ranges of rivastigmine, 1–4 mg/day or 6–12 mg/day (CoreyBloom et al. 1998; Rösler et al. 1999). In the two dosage range trials, doses were titrated weekly (two capsules twice daily with food) during the first 7 weeks up to one of two preassigned dosage ranges, 1–4 mg per day (low-dose group) or 6–12 mg per day (high-dose group). Dose decreases were not permitted during this upward titration, possibly contributing to lesser tolerability during these stages of treatment. By week 7 patients were to have reached the minimum dose within the assigned dose range. During the flexible-dose phase (weeks 8–26), doses could be further increased or decreased within the lowor high-dose range, with the aim of administering the highest well tolerated dose. The fixed dose trial used a forced titration protocol to 3 mg, 6 mg, or 9 mg per day in which no dose adjustments were permitted at any stage; patients experiencing tolerability problems on their

TREATMENT OF ALZHEIMER’S DISEASE 501

assigned dose had to withdraw from the study. The fourth trial, using a broad dose-ranging strategy from 2 mg to 12 mg per day, was performed but results have not yet been published.

groups showed significantly less worsening than the placebo group on the ADAS-Cog.

Patients included in clinical trials

The most systematic pooled evidence, the Cochrane systematic review (Birks et al. 1999), combined phase II trials with three of the four phase III trials and showed significantly better ADAS-Cog scores for higher doses of 6–12 mg/day and for lower doses of rivastigmine compared to placebo at 26 weeks. For the higher doses the differences were, for an intent to treat (ITT) analysis, –2.4, 95%CI –3.1–1.7; and for observed cases (OC) analyses –3.3, 95 %CI between –4.2 and –2.4. For the lower doses (ITT, –0.9, 95%CI between –1.6 and –0.2; and for OC, –1.0, 95%CI between –1.9 and –0.2). Thus mean differences between medication and placebo on ADAS-Cog scores range between –4.2 and –1.7. The Cochrane systematic review of ADAS-Cog performance dichotomized into those showing less than 4 points improvement, and those showing 4 or more points improvement at 26 weeks showed benefit for the higher dose range of rivastigmine compared to placebo (ITT, 14% showed improvement compared to 9%) but not for the lower dose (ITT, 11% vs. 9%). By contrast, analysis combining only two trials considered pivotal by EMEA (Corey-Bloom et al. 1998; Rösler et al. 1999) and printed in the European prescribing information shows a 4-point ADAS-Cog response rate of 21% vs. 12% using an ITT analysis, and 25% vs. 12% using a last observation carried forward (LOCF) analysis for the higher dosage range. A pooled analysis (Schneider et al. 1998) of individual patients who completed three of the phase III trials revealed that the improvements in the largest proportion of patients were: word recall (58% rivastigmine vs. 43% placebo); word recognition (37% vs. 27%); orientation (36% vs. 28%); and remembering test instructions (75% vs. 17%; all P < 0.05). In the same pooled analysis the MMSE showed a significant rivastigmine vs. placebo difference (0.85, LOCF analyses), and the Cochrane systematic review showed a 0.5 difference, 95% CI, 1.0, –0.1, both for the higher doses.

Patients included were at least 50 years of age, had probable AD, and had Mini Mental State Examination (MMSE) scores between 10 and 26, inclusively. Patients with concomitant diseases were included unless the medical condition was severe or unstable; and they were allowed to continue most medications for coexistent diseases, excepting anticholinergic drugs, ACh precursors, health food supplements, putative memory enhancers, insulin, and psychotropic drugs (although chloral hydrate, short-acting benzodiazepines and lowdose haloperidol were allowed in one trial). Among the three trials previously combined in an analysis (Schneider et al. 1998), medical conditions were reported by 77–96% of all patients entered in the trials, and the proportion of patients taking concomitant medications ranged from 77% to 98% across the treatment groups.

Efficacy measures Efficacy measures were: the Alzheimer’s Disease Assessment Scale-Cognitive subscale (ADAS-Cog), a clinician’s global impression of change, and the Progressive Deterioration Scale (PDS), used to assess activities of daily living. Disease severity was assessed using the MMSE and the Global Deterioration Scale.

Results Available results from the phase II and III clinical trials are summarized in Table V.2.11. Results from the two similarly designed trials that were published were essentially similar. Patients receiving rivastigmine experienced either improvement or relative preservation on the three main cognitive, global clinical and functional activities outcomes compared with those receiving placebo. Available results for the fixed-dose trial revealed that at 26 weeks the 9 mg/day and the 6 mg/day

Cognition

Design

Participants

Interventions

Outcomes

Notes

B103 (unpublished) 13 weeks

405 patients with probable AD

Randomized to 3 mg bid (n = 133), 2·mg bid (n = 136), or placebo (n = 133). Patients were titrated to dose over 3 weeks, then maintained

Only observed case analysis available, CGIC: 42% vs. 32% vs. 30% improvement, at high, low, and placebo doses, respectively

Incompletely reported, various additional measures including MMSE, ADLs, and neuropsychological tests

B104 (Forette et al. 1999) Placebo-controlled, double-blind, randomized, parallel-group, two doses and placebo for 18 weeks, including 10-week titration phase

114 patients with probable AD, MMSE 10 –26

There was a 10-week titration period to a maximum tolerated dose or to 12 mg/day. Patients randomized to bid dosing (n = 45), tid (n = 45), or placebo dosing schedule, both in 6 –12 mg/day range

ADAS-Cog 4.84 drug–placebo difference at bid dosing: global rating: 57% vs. 36% vs. 16% improvers; bid, tid, and placebo, respectively

Corey-Bloom et al. 1998 (Study B352) Placebo-controlled, double-blind, parallel-group, dose-ranging to two doses and placebo for 26 weeks

699 patients with probable AD (DSM-IV criteria); MMSE 10–26; 243 were randomized to lower dose (1– 4 mg/day), 243 to higher dose (6–12 mg/day), and 239 to placebo; 85%, 65% and 84% completed

There was an upward dose titration for the first 7 weeks, followed by a flexible-dose phase to week 26 Patients were maintained in two dosage ranges: 1–4 mg/day and 6–12 mg/day Mean doses at week 26 were 3.5 mg/day and 9.7 mg/day

ITT analyses, drug–placebo differences at higher dose range ADAS-Cog: 3.78 [2.69–4.87] 95%CI CIBIC+: 0.29 [0.07– 0.51] 95%CI ADL: 3.38 [1.51–5.25] on Progressive Deterioration Scale Severity scale: 0.19 [0.06–0.32] on GDS Note: No information provided on proportion of responders for the ITT analysis Limited information from the observed cases analysis: 21% of higher-dose patients vs. 44% of placebo patients declined by 4 points or more on the ADAS-Cog. 24% vs. 16% placebo patients were rated improved on CIBIC+

Adverse events: 29%, 8%, and 7%, high dose, low dose, placebo respectively, discontinued because of adverse events In titration phase, higher dose vs. placebo: nausea (48% vs. 11%), vomiting (27% vs. 3%), anorexia (20% vs. 3%), flatulence (5% vs. 1%), sweating (6% vs. 2%), asthenia (10% vs 2%), somnolence (9% vs. 2%), fatigue (10% vs. 4%), dizziness (24% vs. 13%) Maintenance phase: nausea (20% vs. 3%), vomiting (16% vs. 2%), dyspepsia (5% vs. 1%), dizziness (14% vs. 4%) Body weight decreased 1.78 kg vs. increase of 0.5 kg, higher dose vs. placebo. 21%, 6%, and 2% of higher dose, lower dose, and placebo patients decreased weight by ≥ 7% of baseline. 4% vs. 1% cited decreased weight as an adverse event

502 CHAPTER V.2

Table V.2.11 Rivastigmine and ADatable of clinical trials.

Rösler et al. 1999 (Study B303) Placebo-controlled, double-blind, parallel-group, dose ranging to two doses and placebo for 26 weeks

725 patients with probable AD (DSM-IV criteria); MMSE 10–26; 243 were randomized to lower dose (1– 4 mg/day), 243 to higher dose (6–12 mg/day), and 239 to placebo; 86%, 67% and 87% completed

Doses were increased within the dosage ranges over the first 12 weeks, and then maintained within two dosage ranges, 1–4 mg/day and 6–12 mg/day, for the next 14 weeks. Mean doses at week 26 were 3.7 mg/day and 10.4 mg/day

ITT analyses, drug–placebo differences at higher dose range, all significantly favoring medication (lower dose generally ineffective except on global ratings). ADAS-Cog: 2.28. CIBIC+: 0.44. ADL: 2.73 difference in favor of drug on Progressive Deterioration Scale. MMSE: 0.88. Severity scale: 0.21 on GDS. Responders, all significant: 27% vs. 18% improved by ≥ 4pts on ADAS-Cog, high dose vs. placebo; 40% vs. 32% vs. 22% improved on global ratings, high, low, and placebo respectively; 33% vs. 20% improved by ≥ 10% on PDS

Adverse events: 23%, 7%, and 7%, high, low dose, placebo respectively, discontinued because of adverse events. Except for nausea (17% vs. 10%) there were no significant differences between low dose and placebo. Higher dose vs. placebo: nausea (50% vs. 10%), vomiting (34% vs. 6%), anorexia (14% vs. 2%), abdominal pain (12% vs. 3%), diarrhea (17% vs. 9%), malaise (10% vs. 2%), fatigue (10% vs. 3%), dizziness (20% vs. 7%), headache (19% vs. 8%). Body weight decreased 1.39 kg vs. increase of 0.72 kg, higher dose vs. placebo; 24%, 9%, and 7% of higher dose, lower dose, and placebo patients lost ≥ 7% of body weight

B351 (not published) Placebo-controlled, double-blind, parallel-group, titration to one of three fixed doses over the first 12 weeks, then to 26 weeks

702 with probable AD, MMSE 10 –26, randomized to one of four treatment levels

Treatments to placebo, to 3 mg/day, to 6 mg/day, and to 9 mg/day

Only observed cases analyses and means available ADAS-Cog Global rating

Note: Results presented incompletely in summary publications (Birks et al. 1999; Schneider et al. 1998)

TREATMENT OF ALZHEIMER’S DISEASE 503

B304 (not published) Placebo-controlled, double-blind, parallel-group, adjustable dosing between 2 and 12 mg per day

504 CHAPTER V.2

Global rating The global rating used in the phase III trials was somewhat different from the ratings used with other cholinesterase inhibitors, in that it was structured to elicit specific information on cognition, behavior, and function, to rate change in these areas, and then to calculate a specific ‘global’ score based on the scores of the three areas. Comparisons of the clinical global ratings of completers at 26 weeks showed a higher percentage of patients were judged to have improved with both dose ranges of rivastigmine, compared with placebo (31% higher dose, 27% lower-dose vs. 20% for placebo). On clinical global ratings, the Cochrane systemic review at 26 weeks showed a significant 22% improvement for higher doses compared to 16% for placebo, and no significant improvement for the lower doses. The EMEA analysis showed an improvement rate of 29% vs. 18% for the ITT analysis and 32% vs. 19% for an LOCF.

2.4 points 95%CI 3.6–1.1), and a lesser and not significant improvement at the lower dosage range. Thus, the mean differences are likely to be small and range from 1.1 to 3.6 on the 100 point scale. The pooled analysis (Schneider et al. 1998) reported measurably and nominally statistically significantly better function on 21 of the 29 PDS items in the range of 21–34% of higher dose rivastigmine-treated patients, compared to 17–27% of placebo-treated patients: including improvements in dressing, forgetfulness, and in pursuing hobbies. Because of the measure and the small mean differences, the clinical importance of these results is unclear but a 10% improvement has been accepted by regulatory authorities to indicate a meaningful response. The EMEA analysis combining the two pivotal trials and printed in the European Summary of Product Characteristicsprescribing information shows a PDS response rate of 26% vs. 17% using an ITT analysis, and 30% vs. 18% using an LOCF analysis for the higher dosage range. The pooled analysis of three trials reported a similar response of 26% vs. 17%, LOCF analysis).

Mood and behavior Changes in behavior were not assessed in these clinical trials using a specific rating scale. Rather, a semistructured global rating scale was used (see below) that utilized specific questions regarding behavioral change. From the global scale behavioral changes were estimated. Any clinically meaningful effect on disruptive behaviors is hard to assess because the patients selected for these trials were selected on the basis of their ability to cooperate with testing to assess cognitive change, and were not selected because they manifested disruptive behaviors. Functional activity The care giver-rated Progressive Determination Scale (PDS) was used to assess functional activity in the four 6-month phase 3 trials. There were statistically significant mean differences between drug and placebo in the three trials for which this information was provided. In the Cochrane systematic review the PDS shows an improvement due to higher dose rivastigmine compared to placebo of

Number needed to treat Although the phase III trials used similar methodology and outcomes, the reporting of results varied such that the number needed to treat for either an improvement of 4 points on the ADAS-Cog or global improvement could not easily be calculated individually for the two published trials. They could be obtained from pooled data from the Cochrane systematic review, the pooled analysis of three trials (LOCF or OC only) and from the EMEA publication. Therefore the NNTs are likely to be broadly estimated. For an ADAS-Cog improvement of 4 points the NNT ranges from about 8–20. For the clinical global rating, the pooled analyses of the three individually reported trials, based on the completer population, and the EMEA ITT data, the NTT ranges from about 8–17. For the PDS and the functional activities scale, the pooled analyses of most of the individual items indicated NNTs from about 6–15, and the EMEA pooled data based on a 10% overall score improvement, NNTs of about 9–12 depending on the analysis.

TREATMENT OF ALZHEIMER’S DISEASE 505

Who should be considered for treatment? The clinical inclusion criteria in the clinical trials included: a research diagnosis of probable AD and outpatient status with mild to moderate cognitive severity (i.e. a MMSE between 10 and 26). Patients generally had some degree of medical comorbidity and were using other medications. But they were medically stable and had no major behavioral problems. Thus, the evidence for the safety and efficacy of rivastigmine is limited to this group and over a 6-month period. There is no controlled clinical trials information on patients with more severe or more mild cognitive impairment or on those residing in nursing homes or other institutions. Open-label case observations do exist, however. Therapy with rivastigmine should only be started if a care giver is available who will regularly monitor drug intake by the patient.

Who should be excluded from treatment? The use of rivastigmine would be contraindicated in patients with known hypersensitivity to it or other carbamate derivatives. Even though the drug is not significantly metabolized by the liver, it should be used cautiously in patients with severe hepatic impairment. (Although such patients probably should not be treated primarily for the cognitive impairment of AD.) The use of rivastigmine in patients with very mild or severe Alzheimer’s dementia, other types of dementia or other types of memory impairment has not been investigated or fully reported. Therefore, specific guidance cannot be provided. A small randomized placebo-controlled clinical trial in patients with Lewy body dementia (LBD) has been completed but not reported (McKieth et al. 2000). Patients with pre-existing gastrointestinal disorders such as gastritis, ulcer disease, or problematic nausea and vomiting should be treated with particular caution if at all because cholinesterase inhibitors may cause increased gastric acid secretions. Gastrointestinal effects may occur particularly when initiating treatment and/or increasing the dose, and occur more commonly in women. Gastrointestinal inflammation, ulcers, or bleeding may be asymptomatic, and not recognized early.

Since weight loss is associated with many conditions among the elderly, in patients with AD and with cholinesterase inhibitors, a patient’s weight, appetite, and food intake, should be monitored. All cholinesterase inhibitors should be used with care in patients with sick sinus syndrome or conduction defects, in patients with a history of asthma or obstructive pulmonary disease. Moreover, cholinomimetics may induce or exacerbate urinary obstruction and seizures. Cholinesterase inhibitors may exaggerate the effects of succinylcholine-type muscle relaxants during anesthesia. According to its metabolism, metabolic drug interactions appear unlikely, although rivastigmine may inhibit the butyrylcholinesterase mediated metabolism of other drugs.

Clinical pharmacokinetics Absorption of rivastigmine is rapid and almost complete, but extensive, first-pass metabolism leads to bioavailability of approximately 35% of the administered dose and non-linear pharmacokinetics. Rivastigmine is completely metabolized; the major route of elimination of the metabolites is renal. Although patients with AD demonstrate 30% to 50% higher plasma concentrations of rivastigmine and its principal metabolite than do healthy elderly patients, there is no evidence of drug accumulation, consistent with its short pharmacokinetic half-life. The principal metabolite of rivastigmine has at least 10-fold lower activity against AChE compared with the parent drug. It is well distributed to the CNS and CSF: AChE inhibition is detectable about 1.2 h after oral dosing. Peak plasma levels occur within 1 h. Peak AChE inhibition activity is reached about 6 h after dosing and duration is about 10–12 h in AD patients, and more rapid in younger, healthy subjects. Rivastigmine is largely metabolized or inactivated by hydrolysis during the process of interacting with and inhibiting AChE. Although the hepatic cytochrome system is not involved in its metabolism, reducing the likelihood of interaction with the many drugs metabolized by the liver, the Cmax of rivastigmine is approximately 60% higher and the area-under-the-curve (AUC)

506 CHAPTER V.2

of rivastigmine was more than twice as high in subjects with mild to moderate hepatic impairment compared to healthy subjects. The carbamate compounds, such as physostigmine and rivastigmine, produce ‘pseudo-irreversible’ inhibition by mimicking ACh at the esteratic subsite and forming carbamoylated complexes. These bonds are hydrolysed more slowly than the acylated complexes formed between AChE and ACh (Enz & Florsheim 1997). Since the duration of inhibition is not permanent, the action of rivastigmine is designated as pseudo-irreversible to indicate its effect as intermediate between the reversible and irreversible inhibitors.

Pharmacodynamics Both preclinical studies and studies in human volunteers show that rivastigmine induces substantially greater inhibition of AChE in the CNS compartment than in the periphery (40% inhibition of central AChE compared with 10% inhibition of plasma butylcholinesterase in healthy volunteers). An oral 3 mg dose decreases AChE activity in CSF by approximately 40% within the first 1.5 h, and enzyme activity returns to baseline about 9 h afterwards. In patients with AD, inhibition of AChE in CSF by rivastigmine was dose-dependent up to 6 mg given twice daily, the highest dose tested. It preferentially inhibits the G1 monomer of AChE and is 4–6 times more potent at inhibiting the G1 form than the G4 form in the cortex and the striatum. Studies in vitro and with human volunteers have shown relatively little inhibition of peripheral AChE. Not only is rivastigmine characterized by selective binding and inactivation of AChE, The duration of AChE inhibition by rivastigmine is approximately 10 h. Rivastigmine is not bound appreciably to plasma protein, and so is not expected to displace protein-bound drugs.

Adverse events Adverse events are those that are generally those expected from AChE inhibitor. They are usually mild to moderate, of short duration and responsive to dosage reduction.

Unpublished data from 3989 patients indicate that rivastigmine and placebo were associated with similar incidences of serious adverse events and changes in laboratory parameters, ECG and cardiorespiratory vital signs. The most common events were gastrointestinal, central and peripheral nervous system and whole body adverse events. In the clinical trials, adverse events leading to treatment withdrawal were most frequently gastrointestinal, associated with increasing the dosage, more common at higher doses and more common in women than men. Significant weight loss, greater than 7% of body weight occured several times more frequently in rivastigmine-treated patients than controls. When restarting rivastigmine, the lowest initial doses should be used and titrated upward to avoid severe cholinergic effects. The Cochrane systematic review of withdrawals before the end of treatment shows that there are no significant differences between withdrawals from the lower dose rivastigmine group compared to placebo during the course of 6 months, but there are significant differences for the higher dose group with an OR for withdrawal due to adverse effects of 3.3, 95%CI 2.5–4.3.

Starting/monitoring/stopping treatment The recommended starting dose is 1.5 mg twice a day, taken with meals. If this dose is well tolerated after a minimum of 2 weeks of treatment, the dose may be increased to 3 mg bid. Subsequent increases to 4.5 mg and then 6 mg bid should be based on good tolerability of the current dose and may be considered after a minimum of 2 weeks of treatment at that dose level (the drug may be better tolerated if titration is slower). Dosage may be increased based on the consideration that higher daily doses, averaging about 9–12 mg, were associated with better efficacy than lower doses in the clinical trials which were generally not efficacious compared to placebo. (Exelon is also approved as a clear and tasteless oral solution (2.0 mg/ml) with identical pharmacokinetics and use). The effective maintenance dose is 3–6 mg twice a day. Patients may benefit most by being main-

TREATMENT OF ALZHEIMER’S DISEASE 507

tained on their highest well-tolerated dose. The recommended maximum daily dose is 6 mg bid. Maintenance treatment can be continued for as long as a therapeutic benefit for the patient exists. Therefore, the clinical benefit of rivastigmine should be reassessed on a regular basis, especially for patients treated at doses less than 3 mg bid. Discontinuation should be considered when evidence of a therapeutic effect is no longer present. As with other cholinesterase inhibitors, it is not possible to predict individual-patient response to rivastigmine. Treatment effect has not been studied in placebo-controlled trials beyond 6 months. Cholinergic side effects are often transient or self-limited and can usually be managed with encouragement and maintenance of the present dose, omitting one or two doses or by temporarily decreasing dosage. If adverse effects persist the daily dose should be temporarily reduced to the previous well-tolerated dose. Most side effects are related to the dose escalation/titration phase of treatment. Patients on maintenance doses should have few and very mild side effects, if any. However, anorexia and weight loss may be clinically

significant problems over the course of 6 months, and may be more likely to occur in lighter weight patients, so these parameters should be monitored and medication discontinued if anorexia or weight loss become clinically significant. When rivastigmine is discontinued and then restarted it should be at the low initial dosages and titrated, to mitigate the possibility of severe cholinergic adverse events such as severe vomiting. The optimal duration of treatment with continuing efficacy is unknown but is likely to be at least 6–12 months based on the clinical trials and open-label extension phases, in which patients discontinued from rivastigmine after 6 months worsen considerably with respect to cognitive function and improve when medication is restarted. With all cholinesterase inhibitors, it is difficult to assess individual patient response because of the variability of the deteriorating course of AD, and because most of the effect of medication is due to a stabilization or lack of worsening of cognitive function while placebo patients continue to decline. Therefore, the clinical observations of minimal or no clinical worsening is a sufficient reason to continue medication treatment.

Table V.2.12 Pooled results for ADAS-Cog for rivastigmine vs. placebo in AD (reproduced with permission from Update

Software). Review: rivastigmine for AD Comparison: rivastigmine vs. placebo Outcome: ADAS-Cog (change from baseline at 26 weeks) ITT Experimental Experimental Control mean (SD) Study n n

Control mean (SD)

WMD (95%CI fixed)

Weight (%)

WMD (95%CI fixed)

Rivastigmine (1–4 mg/day) vs. placebo 1.37 (6.90) 242 B303 1.68 (7.00) 175 B351 2.36 (6.00) 233 B352 650 Subtotal (95%CI) Chi-square 4.43 (df = 2) Z = 2.50

238 173 235 646

1.34 (7.00) 2.42 (7.00) 4.09 (6.00)

33.1 23.6 43.3 100.0

0.030 [−1.214, 1.274] −0.740 [−2.211, 0.731] −1.730 [−2.817, −0.643] −0.914 [−1.629, −0.199]

Rivastigmine (6–12 mg/day) vs. placebo B303 242 −0.26 (6.80) B351 354 1.00 (7.00) B352 231 0.31 (6.00) Subtotal (95%CI) 827 Chi-square 10.05 (df = 2) Z = 6.89

238 173 235 646

1.34 (7.00) 2.42 (7.00) 4.09 (6.00)

31.0 29.2 39.8 100.0

−1.600 [−2.835, −0.365] −1.420 [−2.693, −0.147] −3.780 [−4.870, −2.690] −2.416 [−3.103, −1.728]

−10

−5

Favors treatment

0

5

10

Favors control

508 CHAPTER V.2

Table V.2.13 Pooled results for global ratings for rivastigmine vs. placebo in AD (reproduced with permission from Update Software). Outcome: CIBIC-plus (no change or worse at 26 weeks) ITT Experimental Control Study n/N n/N

Peto OR (95%CI fixed)

Weight (%)

Peto OR (95%CI fixed)

Rivastigmine (1–4 mg/day) vs. placebo 181/243 B303 145/175 B351 184/233 B352 510/651 Subtotal (95%CI) Chi-square 2.03 (df = 2) Z = 2.56

195/239 144/173 204/235 543/647

41.7 24.8 33.5 100.0

0.66 [0.43, 1.02] 0.97 [0.56, 1.70] 0.58 [0.36, 0.93] 0.69 [0.53, 0.92]

Rivastigmine (6–12 mg/day) vs. placebo B303 180/243 B351 296/354 B352 196/231 Subtotal (95%CI) 672/828 Chi-square 1.99 (df = 2) Z = 1.52

195/239 144/173 204/235 543/647

40.8 31.4 27.8 100.0

0.65 [0.42, 0.99] 1.03 [0.63, 1.68] 0.85 [0.51, 1.43] 0.81 [0.61, 1.06]

0.1 0.2

1

5

Favors treatment

10

Favors control

Table V.2.14 Pooled results for activities of daily living for rivastigmine vs. placebo in AD (reproduced with permission from Update Software). Outcome: PDS (change from baseline at 26 weeks) ITT Experimental Experimental Control mean (SD) Study n n

Control mean (SD)

WMD (95%CI fixed)

Weight (%)

WMD (95%CI fixed)

Rivastigmine (1–4 mg/day) vs. placebo 3.37 (13.40) 241 B303 2.93 (13.40) 175 B351 5.19 (10.40) 233 B352 649 Subtotal (95%CI) Chi-square 0.60 (df = 2) Z = 0.68

237 173 235 645

2.18 (13.40) 3.13 (13.40) 4.90 (10.30)

29.7 21.6 48.7 100.0

1.190 [−1.213, 3.593] −0.200 [−3.016, 2.616] 0.290 [−1.586, 2.166] 0.451 [−0.858, 1.760]

Rivastigmine (6–12 mg/day) vs. placebo B303 241 −0.05 (13.20) B351 354 2.34 (13.40) B352 231 1.52 (10.30) Subtotal (95%CI) 826 Chi-square 2.75 (df = 2) Z = 3.68

237 173 235 645

2.18 (13.40) 3.13 (13.40) 4.90 (10.30)

27.9 26.7 45.4 100.0

−2.230 [−4.615, 0.155] −0.790 [−3.226, 1.646] −3.380 [−5.250, −1.510] −2.367 [−3.626, −1.107]

−10

−5

Favors treatment

Future research Long-term safety and efficacy are essential research issues. That efficacy is greater in more mildly and severely impaired AD patients needs to be assessed, as well as in other dementias. The significance of weight loss needs further investiga-

0

5

10

Favors control

tion. Potential therapeutic effects on APP processing need further research.

Summary Rivastigmine’s effect can be summarized as follows:

TREATMENT OF ALZHEIMER’S DISEASE 509

[Grade A-2] 1 Modest improvement in cognitive performance compared to placebo. 2 Modest improvement in clinical global ratings. 3 Clinically unclear improvement in behavioral measures (based on subscoring a clinical global rating) in patients without particular or significant behavioral disorder. 4 Modest improvement in instrumental ADLs. Rivastigmine is one of several cholinesterase inhibitor treatment options, along with tacrine, donepezil, and galantamine for patients with mild to moderately severe AD. It may be considered as either a first or second cholinesterase inhibitor for use in patients with mild to moderate AD. Results of the two pivotal trials and pooled analyses also show that, compared with placebo recipients, significantly more rivastigmine 6–12 mg/day recipients respond to therapy, and achieved improvements as defined by three separate response criteria. The lower dosage range of 1–4 mg/day was not as effective. Individualized dosage titration to doses from about 6 mg to 12 mg per day is important to minimize cholinergic side effects and to maximize the potential for efficacy. Weight loss and anorexia may be significant problems in AD patients in this age-group treated with cholinesterase inhibitors. The lack of hepatic metabolism and selectivity for G4 subtype of AChE differentiate it from other cholinesterase inhibitors; butrylcholinesterase inhibition is also more prominent than with the others. The clinical significance of this is unclear. Not all clinical trials results have been reported and results

V.2.8

are reported in ways that make it difficult to assess true effect sizes and responses.

Benefits (over 6 months) • Modest improvement in cognitive performance similar to other cholinesterase inhibitors. • Modest improvement in clinical global impression. • Reduction in the rate of functional decline

Numbers needed to treat The NNTs were discussed above. Because overall pooled analyses were not available the range of NNTs are estimated as the means of the various trials and limited pooled data from which they could be calculated. Cognitive improvement • 8–20. Clinical global impression • 8–17. Behavior • No reliable data. Functional activity • Approximately 9–12.

Tacrine

Nawab Qizilbash Key point

Summary of number needed to treat

New patients with mild to moderate ‘probable’ Alzheimer’s disease (AD) should be considered for tacrine only when other cholinesterase inhibitors are not available. Patients happily established on tacrine are likely to be the only recipients of this drug.

Cognitive Cognitive improvement of 7 points or more at 6 months (ADAS-Cog) on 160 mg/day: 40. Cognitive improvement of 4 points or more at 6 months (ADAS-Cog) on 160 mg/day: 30.

510 CHAPTER V.2

Global

Evidence

Clinical global impression at 3 monthsaany improvement: 10. Clinical global impression at 3 monthsa‘moderate’ or ‘marked’ improvement: 40.

Despite being the first drug to be licensed for the specific treatment of AD in several countries, the efficacy of tacrine in treating the symptoms remains controversial and uptake has been low in those countries where it has been approved. The use of cross-over designs, different outcome measures in different studies, an enrichment phase in some trials, confounding by lecithin, high dropout rates, emphasis on completer’s analysis rather than on intention-to-treat analyses, negative results in some trials and the overall modest treatment effects observed in the positive studies have all contributed to the uncertainty and lack of consistency between trials (Qizilbash et al. 1997). By 1996, although more than 30 trials had tested tacrine, only 15 efficacy trials were deemed sufficiently reliable for review after an extensive literature search (see companion website for details of search strategy and study selection). They all fulfilled the following inclusion criteria: randomized, unconfounded, double-blind, placebo-controlled human efficacy trials, where treatment had been given for more than 1 day (Qizilbash et al. 1998). For 12 trials, appropriate individual patient data were available providing 1984 (98% of all eligible) patients for analysis. All patients in these trials were diagnosed as having ‘probable’ AD (McKhann et al. 1984). The trials involved doses varying from 20 mg/day to 160 mg/day, varying duration of treatment (3–36 weeks). Details of the individual trials are on the website.

Behavior No reliable/meaningful data available.

Functional activity No reliable/meaningful data available.

Dependency: nursing home placement No reliable/meaningful data available. Tacrine was approved for the symptomatic improvement of cognitive impairment in AD in 1993 in the US, and subsequently was given approval in several other countries. Its approval was based on: 1 Improvement in cognitive performance; 2 Reduction in the rate of decline of cognitive performance; and 3 Improvement in clinical global impression. Claims have also been made for its benefits on: 1 Functional autonomy, in activities of daily living; 2 Behavioral disturbances; 3 Quality of life; and 4 Delay in nursing home placement.

Rationale Tacrine (9-amino-1,2,3,4-tetrohydroacridine) is a non-competitive reversible inhibitor of cholinesterase and one of the aminocridine class of compounds. It binds near the catalytically active site of the acetylcholinesterase (AChE) molecule to inhibit enzyme activity and prolong acetylcholine (ACh) activity on its receptor. Although this is considered to be its principal mode of action, at high concentrations (above those used clinically) it also blocks sodium and potassium channels (Freeman & Dawson 1991), has direct activity at muscarinic receptors (Adem et al. 1990), and inhibits monoamine oxidase (Adem et al. 1989).

Cognition At 12 weeks, tacrine clearly improved cognitive performance by 0.62 points (95%CI 0.23–1.00, P = 0.002) on the Mini Mental State Examination scale (MMSE; range 0–30) (Fig. 1, Qizilbash et al. 1998). Cholinesterase inhibition with tacrine appears to reduce deterioration in cognitive performance over 3 months by 50%. How this effect should be interpreted for patients is debatable. One method is to relate the treatment effect to the natural history of untreated patients. Annual deterioration of 4.6 points on the MMSE has been reported for a population of untreated patients with AD,

TREATMENT OF ALZHEIMER’S DISEASE 511

Table V.2.15 Summary of trial characteristics (with permission from Qizilbash et al. 1998).

Trial

Design

Enriched population

Chatellier 1990 Gauthier 1990 Åhlin 1991 Molloy 1991 Davis 1992 Farlow 1992 Wilcock 1993 Knapp 1994 Maltby 1994 Wood 1994 Forette 1995 Foster 1996

CO CO CO CO PG PG CO PG PG PG PG CO

No Yes Yes Yes Yes No No No Yes No Yes Yes

Treatment comparisons

Total patients randomized

Duration of treatment (weeks)

Age (years) median (interquartile range)

Females (%)

Mean baseline MMSE

T+L vs. P+L T+L vs. P+L T vs. P T+L vs. P+L T vs. P T vs. P T vs. P T vs. P T+L vs. P+L T vs. P T vs. P T+L vs. P+L

67 46 15 27 215 468 85 663 41 154 122 81

4 8 4 3 6 12 12 30 36 12 6 4

66 (61–73) 67 (61–71) 62 (56–65) 69 (64–71) 71 (66–75) 72 (67–77) 69 (64–76) 74 (68–78) 69 (64–75) 77 (69–81) 67 (62–75) 69 (64–76)

64 50 53 45 53 52 53 52 49 60 61 54

13.4 17.2 19.1 16.1 16.3 18.5 15.7 18.4 16.8 17.0 19.9 17.7

CO, cross-over; L, lecithin; P, placebo, PG, parallel group; T, tacrine.

similar to those who entered some of the trials of tacrine with baseline MMSE scores of 10–21 (Mackel et al. 1997). The magnitude of a 4.6 point decline translates to a deterioration of 1.2 points over a 12-week period. The effect of tacrine over 12 weeks of 0.6 MMSE points would therefore reduce symptomatic deterioration by 50%. Trials often have patients that are not representative of the generality of patients with the disease in question, and if the rate of decline in a particular patient was less than this figure, the proportional improvement would be greater than 50%. Conversely, if a particular patient has a rate of decline greater than this, then the proportional benefit would be less. There is a placebo response for the first 6 weeks with improvement in cognitive performance. Thereafter, the rate of decline is more rapid in the patients taking placebo but with a paralleling of the decline after several more weeks, until the end of the trial at 6 months (Knapp et al. 1994). This represents a delay in average cognitive decline equivalent to about 4 months. Although at 6 months there was a high dropout rate related to dose (Knapp et al. 1994), a better response was associated with higher doses. Some have suggested that a rigorous criterion for defining clinically useful improvement may be a 7 point or more change from baseline in the Alzheimer’s Disease

Assessment Scale-cognitive subscale (ADAS-Cog) (range 0–70) (Davis & Powchik 1995). A less rigorous criterion used is a 4 points or more change in the ADAS-Cog subscale. In patients taking 160 mg/day of tacrine, 20% achieved an improvement of 7 points or more on the ADAS-Cog subscale, compared with 9% on placebo. However, this analysis was a completer’s analysis and may well be biased towards more favorable results.

Clinical global impression of change The odds ratio for improvement on tacrine relative to placebo on the clinical global impression of change scale was 1.58 (95%CI 1.18–2.11, P = 0.002) (Qizilbash et al. 1998). Therefore, cholinesterase inhibition with tacrine appears to increase the odds of global clinical improvement by 50%. The clear effect on clinical global impressions of change suggests that the effects of tacrine are translated into clinically observable differences in overall conduct, behavior and function. What this clinically observable effect means in practice and which components of the symptoms of AD are involved in producing this change is unclear. For those patients experiencing improvement most of the improvement is considered to be ‘mild’, with far fewer patients experiencing ‘moderate’ or ‘marked’ improvement.

512 CHAPTER V.2

Behavior The behavioral non-cognitive subscale of the ADAS (range 0–50), showed a difference in favor of tacrine of 0.58 points (95%CI 0.17–1.00, P = 0.006) (Qizilbash et al. 1998). Such small effects observed on measures of behavioral disturbance are of questionable clinical significance. It may be that tacrine has little effect on behavior. Alternatively it may be that there is too much variability with this outcome measure and that it is insensitive in assessing behavioral abnormalities. Another consideration is that since behavioral symptoms were exclusion criteria for entry into these studies, a longer time interval may be necessary for behavioral symptoms to become prominent and hence affected by tacrine.

Functional activity There was a statistically non-significant trend towards improvement on the functional Progressive Deterioration Scale (Qizilbash et al. 1998). However, this magnitude of effect on measures of functional activity is questionable. There is much variability with the use of this instrument (it is a visual analogue scale composed of 100 mm lines for each question completed by the care giver) and this may be why differences were not significant.

Dependency: institutionalization Uncontrolled long-term follow-up of the treatment group from one trial (Knopman et al. 1996) showed that tacrine therapy appears to delay nursing home placement.

Predicting response to treatment There is no way to predict which patients will benefit (Qizilbash et al. 1998). Dose is the only clear predictor of response for cognitive function and the clinical global impression of change.

Number needed to treat Cognitive improvement 1 Of 7 points or more at 6 months (ADAS-Cog). Twenty-five percent of patients taking 160 mg/ day were able to tolerate the dose and remained on treatment for 6 months (Knapp et al. 1994). This figure combined with an 11% difference between treatment and placebo for achieving the goal of a 7 point improvement provides a figure of approximately 2.5%. Therefore, more than 40 patients need to be treated at 160 mg/day for one patient to benefit by this amount. If doses lower than 160 mg/day are used (for those who cannot tolerate this dose), then the number needed to treat (NNT) is likely to be less favorable as the benefits are dose related but the dropout rate is not very much lower at 120 mg/day (two-thirds were withdrawn). On the other hand, if evidence from a recent trial suggests that higher rises in transaminases can be tolerated without serious consequences, at least over a period of several months, then the NNT may become more favorable. The latter scenario is attested to by many clinicians; the rise in liver enzymes is, in the majority of cases, a short-term phenomenon which resolves and patients can either be continued on treatment or rechallenged. 2 Of 4 points or more at 6 months (ADAS-Cog). Twenty-five percent of patients taking 160 mg/ day were able to tolerate the dose and remained on treatment for 6 months (Knapp et al. 1994). This figure, combined with an 14% difference between treatment and placebo for achieving the goal of a 4 point improvement, provides a figure of approximately 3.5%. Therefore, approximately 30 patients need to be treated at 160 mg/day for one patient to benefit by this amount. Similar caveats apply as in the preceding paragraph. Clinical global impression 1 Any improvement. Overall the NNT for improvement at 3 months was approximately 10 (Qizilbash et al. 1998). 2 ‘Moderate’ or ‘marked’ improvement. Overall the NNT for improvement at 3 months was approximately 40 (Qizilbash et al. 1998).

TREATMENT OF ALZHEIMER’S DISEASE 513

Table V.2.16 Pooled results for MMSE for tacrine vs. placebo (reproduced with permission from N. Qizilbash and JAMA.)

Study

Final dose (mg/day)

Farlow et al. 1992 Maltby et al. 1994 Davis et al. 1992 Molloy et al. 1991 Foster et al. 1996 Forette et al. 1995 Wood & Castleden 1994 Gauthier et al. 1990 Wilcock et al. 2000 Chatellier & Lacomblez 1990 Åhlin et al. 1991 Knapp et al. 1990

39 56 62 64 65 66 70 71 82 91 94 135

Pooled

No. patients Tacrine/placebo

Estimates with 95%CI

391/77 19/20 103/111 16/6 40/41 68/53 76/75 20/25 42/43 34/33 9/6 466/180 1284/670

0.62 SE 0.2 −4

−2

0 Tacrine—placebo

Treatment worse

Nursing home placement No reliable data. Number needed to be treated for one withdrawal Approximately four (Qizilbash et al. 1998). However, this figure from trial data does not reflect current clinical practice as recommendations on the seriousness and management of raised liver enzymes have changed much since the trials were performed. The concern about raised liver enzymes has been diluted by further clinical experience.

Who should be considered for treatment? The medical criteria for inclusion in the trials were very tight and the majority of people with AD were excluded. • McKhann criteria for ‘probable’ AD. • MMSE between 10 and 26. • Global Deterioration scale of 3–5. • Clinical Dementia Rating scale of 1–2.

2

4

6

Treatment better

Who should be excluded from treatment? Those in whom treatment is contraindicated or cautioned • Concomitant disease: history of gastric bleeding. Obstructive airways disease. Bradycardia (pulse less than 60). Hypotension. Sick sinus syndrome. Epilepsy. Intracranial disease. Metabolic disordersaliver and kidney diseases. • Concomitant therapy: anticholinergic drugs. Tricyclic antidepressants. • Hypersensitivity to tacrine or other acridines. • History of liver problems or abnormal liver function tests. Those in whom the value of treatment is unknown • ‘Possible’ AD. • Other dementias.

514 CHAPTER V.2

• Very early symptoms, e.g. MMSE greater than 26. • Severe stage of disease, e.g. MMSE less than 10.

Clinical pharmacokinetics Tacrine is rapidly absorbed with 10–30% bioavailabilty and food can reduce absorption by up to 40%. Dose and plasma levels are not linearly related. Tacrine is 55% bound to plasma proteins and is extensively metabolized by the liver to, mainly, 1-hydroxytacrine (velnacrine), which also has cholinesterase activity. The half-life is 3.5 h in elderly patients and steady state concentrations are achieved within 24 h with four-times daily dosing. Peak concentrations occur between 30 min and 3 h of oral administration.

Adverse effects Withdrawal from studies was much higher for patients on tacrine relative to placebo. Elevated transaminases were the main reason for this in the two largest studies (Farlow et al. 1992; Knapp et al. 1994). For patients without prior exposure to tacrine, the odds of withdrawal during the study on tacrine relative to placebo were 3.63 (95%CI 2.80, 4.71, P < 0.001) (Qizilbash et al. 1998). No death has been reported during the placebo-controlled phase in the trials. The number requiring treatment to be discontinued because of liver enzyme rises will in practice be much lower than observed in the trials, as 87% of those rechallenged were able to tolerate and continue tacrine (Watkins 1994). Common symptomatic adverse effects are dose related and include (Parke Davis 1993): • Nausea and/or vomitingaoccurred in 28% of patients (20% in excess of the rate in the placebo group). • Diarrheaa16% (11% in excess of placebo). • Anorexiaa9% (6% in excess of placebo). • Myalgiaa9% (4% in excess of placebo). Less than 10% of patients had symptoms sufficiently severe that led to withdrawal from the studies.

Drug interactions 1 The cholinergic effect of tacrine may be inhibited by anticholinergic agents, and vice versa.

2 Neuromuscular blocking drugs, such as succinylcholine used in anesthesia, may be prolonged or exaggerated by tacrine. 3 Tacrine stimulates gastric secretion and hence may enhance gastric ulceration and bleeding. 4 Blood levels of tacrine are increased by cimetidine. 5 Blood concentration of tacrine are reduced by cigarette smoking. 6 Theophylline levels are increased by tacrine and need to be monitored.

Starting/monitoring/stopping treatment Dose The appropriate final dose to aim for is 160 mg/day, if tolerated. Whether lower doses are worthwhile in the majority of patients unable to tolerate 160 mg/day is unknown. Dosing should begin at daily doses of 10 mg qid. At week 7, increase the dose to 20 mg qid. At week 13, a further increase to 30 mg qid. At week 19, the final increase to 40 mg qid.

Monitoring adverse effects Many patients taking tacrine may need dose adjustments or discontinuation because of liver toxicity. Although some will develop nausea, vomiting or malaise, most will remain asymptomatic and require monitoring of serum alanine transferase (ALT or SGOT). ALT levels should be measured before initiating treatment and every 2 weeks for at least 3 months after each dose increase. After the dose has been stable for 3 months, long-term testing every 3 months is advised. If the ALT rises to between three to five times the upper limit of normal, the dose should be reduced to the prior dose. A later trial of the higher dose is often successful without a significant increase in ALT. If the ALT rises to 5–10-times normal, treatment should be temporarily stopped, with a rechallenge after ALT returns to normal. If the ALT rises beyond 10times normal, treatment should be discontinued. These recommendations may change and will be incorporated in the up-dates of this book on the Website. There is no way to predict who will develop liver toxicity.

TREATMENT OF ALZHEIMER’S DISEASE 515

The gastrointestinal side effects usually resolve with 24 h of discontinuing treatment. Most patients may be rechallenged without subsequent problems.

Monitoring usefulness Given the issues of safety, monitoring, cost and the large number needed to treat, conducting ‘N-of-1 trials’ may be appropriate (see Chapter IV.5.4 for details) at initiation and at periodic intervals (e.g. yearly) during the course of treatment to ensure that it remains useful. Criteria for defining a useful response may be: 1 A ‘moderate’ or ‘marked’ improvement in global function or quality of life as perceived by the patient or carer. 2 An absolute improvement from baseline in cognitive performance (e.g. a 4 or 7 point improvement in ADAS-Cog). The reverse of these criteria can be used to decide when to withdraw therapy.

Stopping treatment • Poor tolerance: if jaundice occurs or if serum ALT levels rise beyond five-times normal, treatment should be stopped immediately. Patients with ALT rises of less than 10-times above normal, but without jaundice or signs suggestive of an allergic response (rash, fever, eosinophilia), may be rechallenged with tacrine when the ALT levels return to normal. Of course, more intensive monitoring of serum ALT levels are required in this situation. • Persistent and bothersome side effects. • Poor compliance, as the benefits are unlikely to be achieved. Lack of useful benefit: • Reaching a severe stage of disease. • Lack of perceived improvement to the quality of life of patients or carers (even despite improvements in ‘objective’ measures such as MMSE) may constitute a reason for stopping therapy. • Trial of withdrawal of therapy makes no perceived difference to the patient or carer. • Rapid deterioration.

Future research The high rate of adverse effects of tacrine coupled with newer cholinesterase inhibitors that are associated with a much lower incidence of adverse effects means that tacrine will become a drug of the past, with no further controlled trials.

Summary Tacrine has been an important but modest advance in the development of treatments for AD. Its effects can be summarized as follows: [Grade A-2] 1 Improvement in cognitive performance, which is modest. 2 Reduction in the rate of decline of cognitive performance, equivalent to approximately 4 months of deterioration, at least in the first 6 months. 3 Improvement in clinical global impression, although this improvement is modest in most patients who improve. 4 Higher doses producing better responses for cognition and clinical global scales. There is poor evidence for: [Grade A-4] 1 Improvement or reduction in decline in functional autonomy, as assessed by scales of activities of daily living. 2 Improvement in behavioral disturbance, as assessed by the ADAS-noncognitive scale. 3 Improvement in quality of life of patient or carer. [Grade B-5] 4 Evaluating whether nursing home placement is delayed. The clinical relevance of the benefits are uncertain, especially in those unable to tolerate the highest dose of 160 mg/day, and need to be balanced alongside the risks associated with the high rate of adverse events, intensive and complicated monitoring, inconvenience and costs. However, the clinical experience of this author backs the controlled data which indicate that, for a small minority of patients, moderate or marked improvement occurs. The only patients with ‘probable’ AD who should now be prescribed tacrine are those in

516 CHAPTER V.2

countries where the safer and more convenient newer cholinesterase inhibitors are not yet avail-

able, and those who are already on tacrine and considered to be deriving benefit.

V.2.9 D-Cycloserine

Knut Laake and Anne Rita Øksengaard Key point d-Cycloserine is a partial agonist of glutamate at the glycine-NMDA-receptor site in the brain. Studies on animals and on humans pretreated with scopolamine indicate that d-cycloserine may enhance memory. However, controlled clinical studies available provide no evidence that d-cycloserine is effective for memory disorder in patients with Alzheimer’s disease (AD).

Introduction d-Cycloserine is an old antituberculosis drug which in former days was used at high doses (0.5–1.0 g/day) and had few side effects. It has been shown to influence the NMDA-receptors of brain neurones. This site is believed to play a role in memory processes. We present the background for this and an overview of randomized clinical studies of d-cycloserine in memory disorders. To our knowledge, d-cycloserine is not being marketed as a treatment of dementia.

Animal studies of the role of glutamatergic neurotransmission in memory l-Glutamate and l-aspartate are found in high concentrations in the brain and have powerful excitatory effects on neurones in all parts of the brain. There is very good evidence that the amino acid l-glutamate is an excitatory transmitter substance acting on the NMDA-receptor, the AMPA-receptor, and the metabotropic receptor (Fig. V.2.1). Various types of evidence indicate that memory is influenced by the activity at the NMDA-receptor site. Mediated by the NMDA-receptor, l-glutamate

produces long-term potentiation (LTP); a longlasting increase in the postsynaptic response to a presynaptic stimulus of a given strength. LTP is believed to express a sort of synaptic plasticity and is thought of by many researchers as a cellular model of memory. Glycine-NMDA-receptor antagonists exert negative effects on memory in animal models (Matsuoka & Aigner 1996; Bannerman et al. 1997) whereas the partial glycine agonist dcycloserine has been reported to increase learning in rats (Monahan et al. 1989). However, Quartermain et al. (1994) found that desensitization seemed to occur with long-term exposure to the drug.

Pharmacological studies in man Procter et al. (1989) labelled the NMDA-receptor in postmortem brain of 16 controls and 17 Alzheimer patients and showed that the receptor tends to be lost in this disease. There is evidence of a glutamatergic neurone loss in the brain of patients with AD (Procter et al. 1988), among whom the glutamate concentration in the brain is also significantly lower (Ellison et al. 1986). By means of SPECT and a non-competitive NMDA receptor antagonist, Brown et al. (1997) tried to visualize the pattern and extent of the NMDA receptor activation in subjects with AD and controls. They observed a higher retention of the NMDA receptor antagonist in the brain of the Alzheimer patients. This possibly reflects an increased NMDA receptor activation and indicates that the NMDA-receptor is still functioning in this disease. Jones et al. (1991) tested d-cycloserine at doses 5, 15 and 50 mg p.o. in a scopolamine model of memory disorders in young (0.5 mg scopolamine s.c.) and older (0.2 mg scopolamine s.c.) subjects. In the young subjects, 15 mg d-cycloserine coun-

TREATMENT OF ALZHEIMER’S DISEASE 517

L-Glutamate synapse

Presynaptic structure

L-Glu L-Glu

L-Glu Enz yme

L-Glu

Metabotropic glutamate receptor

L-Glu

L-Glu

L-Glu

Post-synaptic structure

teracted significantly the scopolamine-induced decrement on three memory tasks from the Cognitive Drug Research computerized assessment system. Only insignificant trends were found for the 5 mg and 50 mg dose levels. In the older subjects, an effect of d-cycloserine was only found regarding one of the memory tests (word recognition sensitivity), and only at the 5 mg dose level.

Randomized clinical trials of D-cycloserine in AD Published studies of d-cycloserine were sought in the Cochrane Library of RCT, the Medline database for the period 1966–May 1999, and the EMBASE 1982–May 1999 using ‘cycloserine’ as

Na+, Ca2+ NMDA-receptor

G-protein

Mg 2+ inhibitor

PCP

e

Na+(Ca 2+) AMPA-receptor

zym

PCP Zn inhibitor

DCyclocerine

synaptic structures of glutamatergic synapses.

L-Glu En

Glycine

Fig. V.2.1 Model of the pre- and post-

G-protein

phencyclidine agonist antagonist

a keyword and d-cycloserine as a textword and dementia/th, cognition, Alzheimer disease, cognitive defect and amnesia as subject headings. Searle Pharmaceuticals, known to have performed a couple of trials on the effect of d-cycloserine in disorders of cognitive impairment, kindly provided unpublished technical reports from three studies. The papers were assessed independently by both authors of this chapter and classified regarding design and quality as described in the Cochrane Collaboration Handbook. Only studies rated as double blind were accepted. According to this, seven published trials of dcycloserine in subjects with AD were identified. These are described on the website. The inclusion criteria, length of study and dose levels of d-cycloserine, clearly indicated that some

518 CHAPTER V.2

studies included patient data which was also presented as subgroup studies. Based on this, three studies were excluded (Searle Report 1993; Mohr et al. 1995; Schwartz et al. 1996; see table on the website).

Overview Of the three studies available on AD, two were conducted with the less conclusive cross-over methodology and also had few patients. Of these, the 4-week study by Tsai et al. (1999) showed an improvement in the scoring on the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADASCog) at the 100 mg/day dose level of d-cycloserine. In the much larger, parallel group study by Fakouhi et al. (1995) much lower cycloserine doses were used, the study period was much longer, and the primary outcomes were different. This study was negative. One particular problem is that Fakouhi et al. (1995) did not state whether d- or dl-cycloserine

V.2.10

was used. There is, however, no indications that l-cycloserine acts as an antagonist at the glycineNMDA-receptor site and that racemic cycloserine, for that reason, would be less effective than expected from its content of d-cycloserine. One possible explanation for the different conclusions reached by Tsai et al. (1999) and Fakouhi et al. (1995) is the development of tachyphylaxis as indicated in experiments in rats (Quartermain et al. 1994). The single 12-week study of cycloserine in ageassociated memory impairment proved entirely negative. There is thus no evidence available that d-cycloserine can produce a sustained improvement of memory in AD.

Acknowledgement The authors want to thank Searle Pharmaceuticals for providing unpublished material from randomized controlled trials of cycloserine.

Ginkgo Biloba

Barry S. Oken Key points

• There appears to be a fairly modest effect of Ginkgo biloba extracts on cognitive performance. • More quality evidence is needed. • The purity and potency of the preparation are not well controlled. Extracts from Ginkgo biloba leaves have been used for various medicinal purposes for thousands of years. Currently Ginkgo biloba extract (GBE) is widely used around the world by conventional, alternative and complementary health care providers to improve cognitive function associated with aging, dementia, ‘cerebral insufficiency’ and Alzheimer’s disease (AD).

Rationale Currently, most standardized Ginkgo biloba

extracts used for medicinal purposes are made from dried leaves and contain 24% Ginkgo-flavone glycosides and 6% terpenoids. The terpenoids include bilobalide and the ginkgolides A, B, C, M and J (BN52020aBN52024) which are 20-carbon cage molecules with six 5-membered rings. The ginkgolides have some antioxidant properties and are antagonists of platelet activating factor (PAF), which has numerous biologic effects (Koltai et al. 1991). Besides causing platelet activation and aggregation, PAF produces proinflammatory effects (e.g. vascular permeability), is an extremely potent ulcerogen in the stomach, and contracts smooth muscle, including bronchial. PAF has a direct effect on neuronal function and long-term potentiation (del Cerro et al. 1990; Wieraszko et al. 1993). The other major components of GBE are the flavonoids which contribute to Ginkgo’s antioxidant and free radical scavenger effects (Oyama et al. 1994). GBE or ginkgolide has been found to: 1 reduce cell membrane lipid peroxidation in

TREATMENT OF ALZHEIMER’S DISEASE 519

experimental spinal cord injury similarly to methylprednisolone (Koc et al. 1995); 2 reduce bromethalin-induced cerebral lipid peroxidation and edema (Dorman et al. 1992); 3 protect brain neurones against oxidative stress induced by peroxidation (Maitra et al. 1995; Oyama et al. 1996); 4 decrease neuronal injury following ischemia or electroconvulsive shock (Birkle et al. 1988); 5 reduce subchronic cold stress effects on receptor desensitization (Bolanos-Jimenez et al. 1995); 6 inhibit oxidative stress-induced platelet aggregation (Akiba et al. 1998); 7 partially prevent age-related morphological changes and indices of oxidative damage in rat mitochondria (Sastre et al. 1998); and 8 reduce hydroxyl radical induced apoptosis in rat cerebellar neurones (Ni et al. 1996). Since oxidative damage may play an important role in AD pathogenesis or progression (Frolich & Riederer 1995; Markesbery 1997; Pitchumoni & Doraiswamy 1998) and inflammation may be a contributor to the pathophysiology of AD (McGeer & McGeer 1995; McGeer et al. 1996) GBE may be useful in treating AD. There are other effects of GBE on neurotransmitter function that have been less well studied than the antioxidant effects. These effects may also be of potential benefit in AD.

Evidence Cognition (Table V.2.17) There are dozens of studies, mostly in the French and German literature, suggesting the efficacy of GBE in mild to moderate memory impairment associated with aging, dementia or AD, but only a limited number are properly blinded and placebo-controlled with adequate numbers of well-characterized subjects. We recently reviewed this literature (Oken et al. 1998) and found five out of over 50 studies that were acceptable for analysis based on the following criteria: 1 sufficiently characterized patients such that it was clearly stated there was a diagnosis of AD by either Diagnostic and Statistical Manual of Mental Disorders (DSM) or National Institute of Neuro-

logical Disorders and Stroke-Alzheimer’s Disease and Related Disorders Association (NINCDSADRDA) criteria, or there was enough clinical detail to determine the diagnosis by review; 2 clearly stated exclusion criteria including those for depression and certain central nervous systemactive medications; 3 use of a standardized GBE in any stated dose for at least 1 month; 4 randomized, placebo-controlled and doubleblinded study design; and 5 at least one outcome measure was an objective assessment of cognitive function. Four of the five studies had sufficient statistical description of the data for meta-analysis (Rai et al. (1991) was the only paper excluded on this basis from the meta-analysis). In total there were 212 subjects randomized in these studies to placebo or GBE. A significant but modest effect was found with GBE treatment (effect size 0.40 standard deviation units; P < 0.001). This effect size is exemplified in the two largest studies by an Alzheimer disease assessment scale-cognitive (ADAS-Cog) subtest difference of 1.7 in Le Bars et al. (1997) and a Synrom-Kurztest difference of 1.5 in Kanowski et al. (1996). There is one additional paper published after the meta-analysis (Maurer et al. 1997) that would meet the inclusion criteria stated above. It had similar results to the other studies and would not have affected the overall meta-analysis especially given that there were only 20 subjects in total. There has been a recent GBE clinical trial that was negative (Dongen et al. 2000). However, that study had significant design problems. Variable subject diagnoses were grouped and it appeared that most of the subjects in the study would fit closer into the diagnostic category of mind cognitive impairment rather than dementia.

Clinical global impression of change There are insufficient data for formal meta-analysis. Le Bars et al. (1997) found no difference in their clinician global rating scale (mean Clinical Global Impression of Change was 4.2 in both groups). Kanowski et al. (1996) did find a difference in the percentage of subjects rated much improved or very much improved in the Clinical Global

520 CHAPTER V.2

Table V.2.17 Evidence: cognition (adapted from Oken et al. 1998).

Study

Diagnoses

No. subjects analyzed

Study duration

Drop-out rate (%)

Daily dose

Formulation

Cognitive outcome measures

Other outcome measures

Hofferberth 1994 Kanowski 1996 Le Bars 1997

AD AD (DSM-III-R) AD (DSM-III-R)

40 125 207

EGb 761 EGb 761 EGb 761

SKT, choice reaction time SKT ADAS-Cog

SCAGS, EEG CGI, NAB, EEG CGIC, GERRI

AD (DSM-III-R)

20

?5 30 21* 56 10

240 mg 240 mg 120 mg

Maurer 1997

3 months 24 weeks 26 weeks 52 weeks 3 months

240 mg

EGb 761

SKT, ADAS-Cog, ZVT

Rai 1991†

Dementia with appropriate medical and psychiatric exclusions (?AD)

27

6 months

9

120 mg

Tanakan

Wesnes 1987

Dementia with appropriate medical and psychiatric exclusions

58

12 weeks

7

120 mg

Tanakan

MMSE, Kendrick Digit Copying and Object Learning tasks, digit recall, classification task 10-item battery including Benton, Digit Symbol, word list recall, reaction time

CGI, EEG, ADAS-noncog EEG, P300

Behavioral Rating Scale

*Le Bars (1997) trial drop-out rate is for 26 week data. †Rai (1991) trial met criteria for inclusion other than lack of sufficient statistics for meta-analysis. CGI, Clinical Global Impressions; CGIC, Clinical Global Impression of Change; GERRI, Geriatric Evaluation by Relative’s Rating Instrument; NAB, Nurnberger AltersBeobachtungsskala; SCAGS, Sandoz Clinical Assessment Geriatric Scale; SKT, Synrom-Kurztest; ZVT, Zahlen-Verbindungs-Test (trailmaking).

TREATMENT OF ALZHEIMER’S DISEASE 521

Impressions (32% in the GBE group and 17% in the placebo group, P < 0.05). Maurer et al. (1997) with only nine subjects completing the trial per group, found a nearly significant difference in the Clinical Global Impressions favouring the GBE group (P = 0.069).

Behavior and functional activity There are insufficient data for formal meta-analysis for either functional activity or behavior by itself. Le Bars et al. (1997) reported improvement in the Geriatric Evaluation by Relative’s Rating Instrument, either as a mean treatment change (0.19 favouring GBE, P < 0.001) or as percent of subjects improved (0.2 point change found in 37% of GBE group and 23% of placebo group, P = 0.003). Kanowski et al. (1996) reported no change in the Nurnberger Alters-Beobachtungsskala in terms of percent of subjects who improved by at least 2 points (33% in the GBE and 23% in the placebo group, P < 0.095). Hofferberth (1994) reported statistically significant differences favouring GBE in all 5 subscales of the Sandoz Clinical Assessment Geriatric Scale (cognitive disturbance, emotional disturbance, lack of drive, social behavior and somatic disturbance). Wesnes et al. (1987) found no treatment difference in a visual analogue scale of mood and alertness or in the Behavioral Rating Scale. Maurer et al. (1997) found no difference among their 18 subjects in the Alzheimer Disease Assessment Scale–noncognitive (ADAS-noncog) subscale.

Predicting response to treatment There is no reported way to predict which patients will benefit from treatment.

Who should be considered for treatment? Inclusion criteria for studies have varied significantly. Ages have ranged as low as 45 years and up to 90. Most studies just included subjects with mild or moderate impairments as assessed by screening cognitive tests or overall severity scores. Most of the exclusion criteria have listed significant medical illnesses, significant neurological illness other

than dementia, depression, and use of various central nervous system (CNS)-active medications.

Who should be excluded from treatment? There are no definite contraindications to treatment. However, given the case reports of hemorrhage, the possible effect of GBE on PAF and the only modest effect of GBE on cognitive function in AD, caution should be used in patients with coagulopathies, taking warfarin, or with a history of significant hemorrhage. The risk of complications from GBE in people taking aspirin is also unknown. The value of treatment with GBE is unknown in patients with possible AD, very mild dementia or severe dementia, and other dementias (with the possible exception of vascular dementia).

Clinical pharmacokinetics The clinical pharmacokinetics of GBE are not welldefined, in part because of the presence of multiple biologically active components. Serum concentrations of Ginkgo flavonoids peak 2–3 h after ingestion and the half-life is between 2 and 4 h (Kleijnen & Knipschild 1992). The half-lives of the terpenoid components (ginkgolide A, ginkgolide B and bilobalide) range from 3 to over 10 h (Fourtillan et al. 1995).

Adverse effects In a previous review (Kleijnen & Knipschild 1992), no serious side effects were noted in any of the older studies and the incidence of significant sideeffects was similar in all the placebo-treated and GBE-treated groups. In the studies we reviewed and the studies in our meta-analysis there were also no significant side effects. In all these studies doses have ranged up to 240 mg per day. While GBE is a PAF antagonist and could prolong the bleeding time, at usual doses this is not necessarily the case (e.g. Braquet 1993). There are now several case reports of hemorrhage in subjects who were taking GBE and these will be summarized here. A 33-yearold woman had been taking 120 mg GBE for 2 years prior to developing bilateral subacute subdural hematomas without a known history of trauma

522 CHAPTER V.2

(Rowin & Lewis 1996). Two simultaneously drawn bleeding times were 15 and 9.5 min with the upper limit for the laboratory being 9 min. One month after stopping GBE, two simultaneously drawn bleeding times were both 6.5 min. A second case report concerned a 70-year-old man who was taking daily aspirin for 3 years following coronary artery bypass surgery (Rosenblatt & Mindel 1997). He developed spontaneous bleeding from the iris into the anterior chamber 1 week after beginning 80 mg daily of Ginkoba, a Ginkgo extract. Another case concerned a 78-year-old woman on warfarin because of atrial fibrillation (Matthews 1998). The subject also had a history of myocardial infarction, pacemaker insertion and progressive decline in gait and cognition. Two months after being seen for the cognitive decline, the patient developed a left parietal hemorrhage with a prothrombin of 16.9 and partial thromboplastin time of 35.5. The patient was taking GBE but the dose was not stated. A fourth patient developed a headache, backache and nausea for several days and was found to have xanthochromic cerebrospinal fluid with 5 red and 1 white cells and a protein of 240 (Vale 1998). Head CT without contrast and routine lab studies were normal but a bleeding time was elevated (at 6 min, normal 1– 3 min) and he was found to have been taking GBE 40 mg 3–4 times per day for 6 months. His bleeding time went to 3 min after being told to discontinue the GBE. The patient was considered to have a subarachnoid hemorrhage. These case reports are not completely straightforward but are clearly of concern. However, given the large but unknown number of people taking GBE and the lack of such serious side effects reported in any of the published papers to date (totalling several thousand subjects), the incidence of bleeding complications with Ginkgo is of unknown magnitude and significance.

Starting/monitoring/stopping treatment Most studies have not titrated the GBE dose and have started by using the desired final dose. There are no data on monitoring or stopping treatment. It is not known whether GBE produces its effect symptomatically or in a disease-modifying way.

Thus, the absence of any improvement may not necessarily mean there is no benefit since its mechanism of action may allow it to alter rate of progression (as opposed to the cholinesterase inhibitors whose effect is better understood and is primarily symptomatic).

Future research There are numerous unanswered questions about the utility of GBE in AD. That there are so many unanswered questions about GBE probably relates to the development of its use through non-standard channels. This has resulted in limited data from animal and human research even on such basic issues such as dosing and toxicity. It remains uncertain if there is an effect of GBE on noncognitive function in AD. This includes overall clinical global rating scale, functional status or behaviour. The definition of the types of subjects who may benefit from GBE is not clear. The studies suggest some improvement in subjects with probable AD of mild to moderate severity. The effect of GBE in possible AD, severe AD, and other dementias is not known. The best dosing of GBE is not known. The studies reviewed here used a daily dose of 120 or 240 mg mostly divided three times daily but also into twice daily doses. It is not known if the higher dose is better or if an even higher dose that has not been previously evaluated may be even better. Of note, some animal studies have used up to a 150 mg/kg daily dose. It is not known if twice daily dosing, which would improve compliance, is as good as the three times daily used in most studies. The active ingredient or ingredients in GBE are not known. Is it one of the ginkgolides or is it the flavonoid component? If this were known a more effective extract of synthetic drug could possibly be developed. There are no data comparing efficacy of the various GBE preparations to know whether there are differences related to the specific process of making the GBE from the raw leaf. It is not known if there is a low incidence of significant complications including bleeding. If this is an issue the relative contraindications, such as use of anticoagulation or history of gastrointestinal bleeding, could be defined.

TREATMENT OF ALZHEIMER’S DISEASE 523

Summary There is an effect of GBE on cognitive performance in AD (evidence Grade A-2), although the effect is fairly modest. There is limited or inconsistent evidence for the effect of GBE on daily function, beha-

V.2.11

vioral disturbance or clinical global rating scales (evidence Grade A-4). There is no evidence concerning quality of life or delay of nursing home placement. As with other herbals, the purity and potency of a given preparation is not as well controlled as conventional medicines.

Estrogen

Fadi Massoud, Kristine Yaffe and Mary Sano Key point There are insufficient data to support the use of estrogen as a treatment for Alzheimer’s disease (AD). Among patients with AD, use of the drug for other indications may require additional supervision to ensure that appropriate gynecological care is maintained and that side effects are addressed.

Introduction Results of epidemiologic studies, laboratory models and animal behavior suggest that estrogen may be effective in the treatment or prevention of AD. However, there is virtually no well-controlled clinical trial data to address this question. The availability of this agent, its clinical benefit in other areas, and the perceived benefit in prevention of AD, may inadvertently encourage its use in clinical practice despite the fact than there is little to no satisfactory evidence to recommend its use. The purpose of this chapter is to evaluate the existing evidence.

Rationale The scientific rationale for estrogen use in the treatment of AD comes primarily from epidemiological and basic science data. Epidemiological studies suggest that lifetime use of estrogen is associated with a delay in the onset of AD. The data from 10 studies was summarized in a meta-analysis which yielded a summary odds ratio (OR) of 0.71

(95%CI 0.52–0.98) (Yaffe et al. 1998). Two large studies meeting the same rigorous criteria used to select studies for the meta-analysis were reported since that time (Baldereschi et al. 1998; Waring et al. 1999) and a re-analysis yielded a summary OR of 0.69 (95%CI 0.52– 0.90) (Yaffe et al. unpublished analysis). Some, but not all, studies report a dose response effect, with greater benefit after longer exposure. While the meta-analysis reflects a conservative approach to evaluating observational studies, it provides no control for the non-random confounding variables which occur in both clinical and population based studies. Laboratory studies also provide a rationale for estrogen use in AD. Neurotransmission in cholinergic neurones is known to be impaired in AD and augmentation of this system has been associated with some benefit. Both reduced cell count (Gomez-Isla et al. 1996) and reduced synapses (Masliah et al. 1994) have been reported in the brains of patients with AD. Estrogen works as a neurotrophin in cholinergic neurones, particularly in the pyramidal cells of the CA1 region of the hippocampus. Estrogen receptors are colocalized with mRNA for the nerve growth factor family of neurotrophins and their receptors in developing neurones of the basal forebrain (Toran-Allerand et al. 1992). Estrogen deprivation is associated with cell loss in the basal forebrain, and treatment with estrogen is associated with preservation of neurones as well as a return of neurotrophin-mRNA levels to near normal (McEwan et al. 1997). This implies that estrogen may influence neurotrophin synthesis and release or, alternatively, promote cell growth.

524 CHAPTER V.2

Estrogen appears to have protective properties against amyloid, the protein associated with the neuropathologic hallmark of AD, the cellular plaques. Estrogen protects hippocampal neurones in culture exposed to excitotoxins, oxidative stress, or amyloid-β (Aβ) (Behl et al. 1995). Estrogen may also reduce neuronal Aβ generation (Xu et al. 1998) by regulating the metabolism of the amyloid precursor protein. Estradiol decreases Aβ generation and increases the soluble form of the precursor protein, possibly by stimulation of α-secretase activity, a supposition supported by evidence of increase in protein kinase C (Maizels et al. 1992). These mechanisms reflect a reasonable approach to identifying the etiology of AD, however, it remains to be determined if they provide a rationale for intervention.

Evidence The systematic review of the literature provides little evidence for the role of estrogen in the treatment of AD. To date, five double-blind, placebocontrolled trials of estrogen for the treatment of AD have been carried out, one of which appears only in citation form in English (Honjo et al. 1993). The first report is of 14 patients with AD who received conjugated equine estrogen or placebo for 3 weeks. Results indicate improvement with active treatment compared to placebo on a mental status examination but no benefit on two other measures (Honjo et al. 1993). The second report is of a pilot study of 12 patients with AD who received transdermal 17 β-estradiol or placebo for 8 weeks (Asthana et al. 1999). The treated patients showed an improvement on measures of attention (number of self-corrections in the Interference condition of the Stroop test) and verbal memory (as shown by a significant group by weak interaction on delayed cued recall of the Bushke Selective Reminding Test). The improvement in memory correlated significantly with plasma levels of estradiol. The third study (Henderson et al. 2000) included 42 women who were treated with estrogen or placebo for 16 weeks. There were no significant differences on primary and secondary outcome measures between the placebo and treatment groups. Performance on exploratory cognitive measures (Trail-making task,

digit span, and verbal memory) showed inconsistent results between the two groups. The fourth study (Wang et al. 2000) randomized 50 women to conjugated estrogen or placebo for 12 weeks. There were no significant differences between the two groups on measures of cognition, affect, and behavior. Regional cerebral blood flow measured by single photon emission computed tomography (SPECT), which was also included as an outcome measure in this study, showed no significant differences between the two groups. Finally, a multicenter study by the Alzheimer’s Disease Cooperative Study (ADCS) (Mulnard et al. 2000) randomized 120 hysterectomized women to two doses of estrogen (0.625 mg/day and 1.25 mg/day) or placebo for 12 months. This study represents the longest clinical trial of estrogen in women with AD. At completion of the study, there was no difference on the primary outcome measure, the Clinical Global Impression of Change (CGIC), between the placebo and active treatment groups. However, the secondary outcome measure (the Clinical Dementia Rating scale, or CDR) showed significant worsening among women in the estrogen group. A transient benefit in the low-dose estrogen group was shown on the Mini Mental Status Examination (MMSE) at 2 months. Three other unblinded trials have been reported, all with sample sizes of 15 or less each using exposures of 6 weeks (Fillit et al. 1986; Honjo et al. 1989; Ohkura et al. 1994). In two of these reports a benefit over the baseline condition was seen on less than half of the tests, with improvement most commonly reported on Mental Status testing and memory tests (Fillet et al. 1986; Honjo et al. 1989). One trial used an unblinded control group and found a significant benefit in mental status testing among the treated group compared to the control group (Ohkura et al. 1994).

Number needed to treat Not applicable.

Who should be considered for treatment? There is no current data to recommend estrogen use for the treatment of AD. However, there is no

TREATMENT OF ALZHEIMER’S DISEASE 525

data to suggest avoiding estrogen for its other indications in patients with AD.

Who should be excluded from treatment? Estrogen therapy is contraindicated in women with known or suspected breast cancer, endometrial cancer, undiagnosed abnormal vaginal bleeding, active thrombophlebitis or thromboembolic disorders. In women with a past history of venous thrombosis, a non-oral form of estrogen is preferable as no changes in coagulation factors are observed (Chetkowshi et al. 1986). While recurrences of breast cancer have been reported up to 15 years after initial remission, several studies have shown that estrogen replacement therapy does not further increase the risk of recurrence in survivors of breast cancer (Henrich 1992). Studies have also shown that endometrial cancer survivors do not have an increased risk of recurrence with later estrogen replacement therapy.

Clinical pharmacokinetics There are marked intra-individual and interindividual variability in the pharmacokinetics of estrogens. Some of this variability is also accounted for by the different preparations and modes of administration available (Kaufman 1997). Two estrogen preparations were used in AD treatment trials: conjugated equine estrogen and micronized estradiol. Unconjugated estrogens are poorly bioavailable when administered orally. After oral administration, both preparations are extensively metabolized by the liver through the ‘first pass effect’ to conjugated and unconjugated forms of estrone. Conjugated estrogens are rapidly absorbed from the gastrointestinal tract, can be secreted in the bile, and are excreted in the urine. Rehydrolyzation in the intestine after excretion in bile allows uptake of estrogens through the enterohepatic circulation. Estrogens are widely distributed in the body and moderately bound to plasma proteins (mostly estrogen-binding proteins synthesized by the liver). Estrogen preparations administered by non-oral routes (subdermal and vaginal) are not subject to first-pass metabolism, but undergo hepatic uptake and metabolism and enterohepatic recycling.

Adverse effects In AD treatment trials, most subjects taking conjugated equine estrogens experienced vaginal withdrawal bleeding (71–87% of women), and temporary breast tenderness with redness of papilla mammae (up to 86%) (Honjo et al. 1989; Ohkura et al. 1994). In one subject on 0.625 mg of conjugated equine estrogen, a transient change on the Papanicolaou smear was observed with no abnormal changes found on follow-up biopsy after termination of treatment. In the trial using micronized estradiol, withdrawal bleeding was observed in one out of seven women, and breast tenderness was reported by another subject (Fillit et al. 1986). An endometrial biopsy in the woman experiencing withdrawal bleeding revealed dysplastic changes prompting administration of a progestational agent. A follow-up biopsy disclosed normal characteristics of postmenopausal endometrium. An increased risk of thromboembolic events (Jick et al. 1996; Hulley et al. 1998) and gallbladder disease (Hulley et al. 1998) have been observed in women on estrogens with demographic characteristics comparable to those who might eventually be considered for AD treatment. Four women in the ADCS study (Mulnard et al. 2000) developed deep vein thromboses, two in the low-dose and two in the high-dose treatment groups. Use of estrogens has been reported to be associated with breast and endometrial cancer (Clinical synthesis Clinical Synthesis Panel on HRT, 1999). The risk seems to be related to the dose and duration of estrogen therapy with wearing off of the effect on breast cancer after 5 years of stopping use. Concomitant use of progestational agents substantially reduces the risk of endometrial cancer but does not affect the incidence of breast cancer associated with estrogen therapy.

Dosage/monitoring/stopping treatment In treatment trials of AD, conjugated equine estrogens were used in a doses of 0.625 mg/day and 1.25 mg/day without concomitant progestational agents. Micronized estradiol was used at a dose of 2 mg/day in divided doses. Women on estrogen therapy should get an annual general physical

526 CHAPTER V.2

examination including breast and gynecological examination (with Papanicolaou smear). Abnormal vaginal bleeding should be promptly reported by patients and addressed by physicians. Patients with AD may require supervision to ensure that those health maintenance routines are adequately reinforced. Physicians should also have a low suspicion threshold for symptoms and signs suggestive of gallbladder disease and thromobembolic diseases in women using estrogen. Treatment should be stopped if poorly tolerated or if any serious side effect develops.

ized clinical trials (Shumaker et al. 1998; Sano 1999). The contribution of progestin needs to be assessed.

Future research

Benefits

Some observational data suggest that estrogen may enhance the effect of cholinesterase inhibitors and this may be clarified by ongoing controlled prevention trials. Epidemiologic data suggests that estrogens may have a role in preventing AD and future research is planned to evaluate this with random-

• No benefits on mental status examination. • No benefits on memory tests.

V.2.12

Summary Estrogen’s effect in clinical trials with women with AD can be summarized as follows: [Grade A-3 and C-9] 1 No improvement on mental status examination; and 2 No improvement on memory tests.

Numbers needed to treat Not applicable.

Hydergine

Lon S. Schneider and Jason T. Olin Key point The effectiveness of Hydergine (ergoloid mesylates) has not been adequately assessed in Alzheimer’s disease (AD) and remains unknown. It appears to be very safe with very few adverse effects.

Introduction Hydergine (ergoloid mesylates) is the brand name for a specific combination of four dihydrogenated ergot peptide derivatives: dihydroergocornine, dihydroergocristine, dihydro-α-ergocryptine, and dihydro-β-cryptine; in a ratio of 3 : 3 : 2 : 1. It was introduced to clinical medicine in 1949. Although it has been used in the past as a treatment for peripheral vascular disease, hypertension, angina pectoris, and tinnitus, its main use has been for

treating patients with either dementia, or ‘agerelated’ cognitive symptoms. In the US, the Food and Drug Administration (FDA) approved it in 1978 for the treatment of ‘idiopathic decline in mental capacity.’ It is still marketed in numerous countries as a non-disease-specific cognitive enhancer. The drug has also been advocated as a so-called ‘smart drug’, for use by cognitively intact young and older adults to increase mental abilities, although probably not to any great extent. The use of the drug for dementia and its efficacy has been historically controversial. As long ago as 1981, significant limitations in the evidence base were noted, including the lack of diagnostic rigor and the use of crude outcome instruments in clinical trials, leaving a less than convincing impression of its efficacy at cognitive improvement (Jarvik 1981). Although there have been over a dozen clinical trials since then, its efficacy remains uncertain.

TREATMENT OF ALZHEIMER’S DISEASE 527

Rationale A rationale for the therapeutic use of Hydergine for patients with Alzheimer’s disease (AD) would consider its possible effects on cognitive and global function and, possibly, also a neuroprotective effect. A potential mechanism for symptomatic improvement could be through its enhancement of noradrenergic, dopaminergic and serotoninergic function (Weil 1988). In preclinical studies, dihydroergocryptine reduced free radical formation (Favit et al. 1995), increased catalase and superoxide dismutase (Sözmen et al. 1998), and inhibited monoamine oxidase (Büyüköztürk et al. 1995), actions similar to other drugs and vitamins with putative antioxidant effects, thus supporting a potential neuroprotective role. No clinical trials have been performed, however, assessing possible neuroprotection with ergoloid mesylates in AD.

Evidence The most complete summaries of the evidence of Hydergine’s effects in cognitively impaired patients include one meta-analysis and a Cochrane Collaboration systematic review (Schneider & Olin 1994; Olin et al. 1998). The meta-analysis included 47 trials, but these patients did not all have AD. Clinical effects in patients who would probably have fulfilled criteria for possible or probable AD were significant only for combined neuropsychological measures in the five trials identified with such patients. The more recent Cochrane systematic review (Olin et al. 1998) included only those 19 clinical trials with explicit statistical data required for Cochrane reviews and showed similar findings, Table V.2.18. The nine clinical trials that included subjects that likely had a diagnosis of AD are described in Table V.2.19.

Cognition The clinical trials of dementia patients were generally performed two to three decades ago, and unlike modern-day trials, did not use standard methodologies or cognitive assessments, and often did not

directly assess cognition. When they did, various measures were used making a systematic assessment of them difficult. In the meta-analysis, there were a total of 23 trials that included a total of 93 tests. When weighted and combined the overall effect size was modestly in favour of Hydergine compared to placebo (about 0.25 of a standard deviation unit), but of unclear validity, considering the heterogeneity of tests and patients with and without dementia. Among the nine trials that included Alzheimer patients, listed in Table V.2.19, there were 18 cognitive measures with only one common to 4 trials. Two relatively recently conducted trials, involving 190 and 53 patients each, with trial durations of 6 and 12 months, respectively, showed significant improvement in delayed recall; two trials involving 80 and 41 patients, with durations of 6 months and 13 weeks, respectively, did not. Thus there is little direct evidence for beneficial cognitive or memory effects from ergoloid mesylates, largely because they have not been adequately assessed.

Global rating Somewhat different global ratings were used across trials. In the meta-analysis, there were 20 trials that provided information on global rating scales, with a moderate effect size of about 1/2 standard deviation unit in favour of Hydergine. In the Cochrane review, 12 trials could be combined to provide a fairly large odds ratio of 3.78 [95%CI 2.52–5.27] in favour of treatment, although none of the trials listed in Table V.2.19 individually showed a significant effect.

Mood and behavior Mood and behavior were inadequately and nonsystematically assessed, occasionally only by individual item scores from clinical rating scales. In two trials involving patients who probably had AD, significant improvements in depression scores compared to placebo treated patients were reported.

Functional activity There is no evidence for changes of functional

528 CHAPTER V.2

Table V.2.18 Pooled results for global ratings for Hydergine vs. placebo according to dementia diagnosis (reproduced with permission from Update Software). Outcome: global rating (% improved) Experimental n/N Study

Control n/N

Peto OR (95%CI fixed)

Weight (%)

Peto OR (95%CI fixed)

Not estimable

Alzheimer’s disease 0/0 Subtotal (95%CI) Chi-square 0.00 (df = 0) Z = 0.00

0/0

0.0

Vascular dementia Wilder, 1973 11/16 Winslow, 1972 13/25 Subtotal (95%CI) 24/41 Chi-square 0.02 (df = 1) Z = 0.78

7/12 11/25 18/37

4.7 9.1 13.8

Primary dementia 11/14 Cox, 1978 16/23 Gaitz, 1977 4/15 Peltz, 1969 31/52 Subtotal (95%CI) Chi-square 3.80 (df = 2) Z = 4.91

0/14 6/24 2/18 8/56

5.0 8.5 3.6 17.1

23.96 [5.40, 106.27] 5.77 [1.86, 17.92] 2.76 [0.48, 15.85] 7.46 [3.35, 16.64]

Cerebral deterioration 4/13 Hollister, 1955 19/26 McConnachie, 1973 28/47 Rouy, 1989 51/86 Subtotal (95%CI) Chi-square 1.05 (df = 2) Z = 3.63

1/13 9/26 19/50 29/89

3.0 9.4 17.5 29.9

4.17 [0.62, 28.26] 4.56 [1.55, 13.43] 2.35 [1.06, 5.19] 3.07 [1.67, 5.63]

Cerebral insufficiency 9/10 Arrigo,1973 13/15 Giove, 1973 28/111 Lazzari, 1983 13/23 Short, 1972 63/159 Subtotal (95%CI) Chi-square 10.29 (df = 3) Z = 5.69

1/10 1/15 8/93 9/26 19/144

3.8 5.5 21.1 8.8 39.2

20.91 [3.79, 115.43] 22.36 [5.46, 91.62] 3.12 [1.52, 6.42] 2.38 [0.78, 7.27] 4.65 [2.74, 7.89]

74/326

100.0

Total (95%CI) 169/338 Chi-square 23.53 (df = 11) Z = 7.87

0.1 0.2

activity in Hydergine trials due to the lack of these measures in the clinical trials. At best, the ‘selfcare’ item on a clinician-rated scale showed a modest effect in favor of ergoloid mesylates in some trials.

Number needed to treat Insufficient information is provided in the clinical trials to determine numbers needed to treat (NNT).

1

5

1.55 [0.33, 7.18] 1.37 [0.46, 4.11] 1.43 [0.58, 3.49]

3.78 [2.72, 5.27]

10

Who should be considered for treatment? Hydergine’s efficacy was established most strongly when using an aggregate of clinical trials that included a wide range of clinical diagnoses, making it difficult to define the best subjects to provide treatment. In the original meta-analysis, in-patient status, males, and decreased age predicted higher treatment effects. Studies that included subjects who likely would receive a diagnosis of AD show

TREATMENT OF ALZHEIMER’S DISEASE 529

variable effects. It may be that clinicians will be more likely to see effects in subjects who are in the more moderately impaired range (Mini Mental State Examination (MMSE) between 10 and 20) given that two trials with higher functioning patients (McDonald 1985a,b) failed to demonstrate efficacy. But in sum, since efficacy has not been established there is no basis to consider any individual for treatment.

Who should be excluded from treatment? Aside from hypersensitivity, there are no known absolute contraindications.

Clinical pharmacokinetics After oral administration, about 25% is absorbed. Ergoloid mesylates are rapidly absorbed from the gastrointestinal tract, with mean peak levels of 0.05– 0.13 ng/ml achieved within 0.5–1.0 h There is a considerable first-pass liver metabolism, with less than 50% of the ergoloids reaching the systemic circulation. Elimination is biphasic with half-lives of 4 and 13 h. The mean half-life of unchanged ergoloids in plasma is about 3–5 h.

Adverse effects Ergoloid mesylates do not appear to produce serious or significant adverse events. Of 47 clinical trials, 11 reported one or more adverse effects for Hydergine, 15 stated there were no adverse effects observed, and 21 did not provide data. Transient nausea and gastric disturbances have been reported in the clinical trials at daily doses below 12 mg. It is uncertain if hypotension is a problem, but it was equally distributed between drug and placebo groups.

side effects are not likely. The extent of significant drug–drug interactions is not known. Effects have been best characterized on the basis of global clinical impressions, and in some studies on modest changes observed after 3 months on such scale items as alertness, confusion, recent memory, orientation, emotional liability, self-care, depression, anxiety/fears, co-operation, sociability, appetite, dizziness, fatigue and bothersomeness. Cognitive improvement was best documented in 6 and 12 month long trials. Interestingly, the US prescribing information also warns that results may not be observed for 3–4 weeks. Therefore, the best evidence suggests that if Hydergine is used that clinicians monitor outcomes on these items. Stopping treatment could be contemplated if no symptomatic effect is observed after 3 months, but it may be difficult to discern a cognitive effect. A discontinuation trial might be considered to assess the continuing benefit of treatment.

Future research The essential unresolved issues with ergoloid mesylates are clear demonstrations of cognitive or global efficacy in AD or other cognitive impairment syndromes, and the lack of an underlying preclinical or mechanistic rationale, beyond neurotransmitter and putative neuroprotective effects, why it may be effective. Since its adverse event profile is close to ideal, especially when compared to other available medications, further work in these areas is desirable. The essential efficacy of ergoloid mesylates for AD has not been adequately explored. There is suggestive evidence for modest efficacy over the short-term that could be of similar magnitude to the efficacy of cholinesterase inhibitors. But the essential clinical trials have not been performed, and probably never will.

Starting/monitoring/stopping treatment In the US, the approved dosing is 1 mg tid. Clinical trials that suggested cognitive and global efficacy, however, tended to use daily doses between 6 and 12 mg. There is probably no need for titration although it might be a conservative approach when contemplating higher dose therapy. Significant

Summary Ergoloid mesylates, despite their availability for over half a century, have not been convincingly demonstrated effective for improving symptoms in patients with AD. The medication has been associated with modest improvements in behavior,

530 CHAPTER V.2

mood, and cognition in heterogeneous groups of older clinical subjects. It appears to be very safe and well tolerated. Therefore, it cannot be recommended as a treatment based on the available evid-

V.2.13

ence. Nevertheless, some practitioners do prescribe it and consider it useful for managing some patients with dementia.

Idebenone

Kentaro Hashimoto Key point

There is inadequate evidence to recommend idebenone in the treatment of Alzheimer’s disease (AD). It needs more high quality evidence.

Summary Benefits: • Improvement in cognitive performance. • Reduction in the rate of decline of cognitive performance. • Improvement in clinical global impression. • Higher doses producing better responses for cognition and clinical global scales. The clinical relevance of these benefits is not certain. There is poor evidence for: • Improvement or reduction in decline in functional autonomy. • Improvement in behavioral disturbance. Idebenone had been widely used, especially in Japan, for the treatment of patients with cerebrovascular disease until 1998 when it was withdrawn due to unsuccessful reassessment of its efficacy in placebocontrolled clinical study. But, in several European countries, idebenone has been given approval for the symptomatic improvement of cognitive impairment in AD. In June 1999, idebenone was licensed in Italy, Portugal, Argentina and Ecuador.

Rationale Idebenone (cv-2619), 6-(10-hydroxydecyl)-2,3dimethoxy-5methyl-1,4-benzoquinone, is a benzoquinone derivative. It was patented by Takeda

Chemical Industries Ltd, and marketed in 1986. The neurochemical study of idebenone in vitro suggests that it normalizes reduced levels of 5-hydroxy indole acetic acid (5-HIAA) and acetylcholine (ACh) in various regions of the brain and inhibits the decrease of adenosine triphosphate (ATP) and the increase of lactate after cerebral ischemia. It is suggested that idebenone activates mitochondrial respiratory function and it has a protective effect on lipid perioxidation in brain tissue.

Evidence In 1986, idebenone was licensed in Japan for cerebrovascular disease, although the efficacy of idebenone for cerebrovascular disease had been controversial in Japan. In 1992, Senin et al. conducted the first randomized, double-blind study in 102 patients with probable AD. By 1998, many trials had tested idebenone for the specific treatment of AD. But, the efficacy of idebenone in treating the symptoms remains controversial. Only six efficacy trials were deemed sufficiently reliable for review after an extensive literature search (see website for search and selection strategy). But, the use of different outcome measures in studies, negative results, high drop-out rates, imbalance between baseline in the treatment groups of the positive study, and improvement of cognition in the placebo group of the positive study have all contributed to the uncertainty and lack of quality evidence among these six trials (Hashimoto et al. 1999). They all fulfilled the following inclusion criteria: randomized, unconfounded, double-blind, placebo-controlled human efficacy trials, where treatment had been given for more than 3 months. For three of the six trials, appropriate individual patient data were available

TREATMENT OF ALZHEIMER’S DISEASE 531

providing 900 patients for analysis. All patients in these trials were diagnosed as having ‘probable’ AD. The trials involved doses varying from 90 mg/day to 360 mg/day, and varying duration of treatment (6–12 months). Details of the individual trials are available on the website (Senin et al. 1992; Bergamasco et al. 1994; Weyer et al. 1996; Sabe et al. 1997; Gutzmann & Hadler 1998).

Cognition The cognitive improvement (‘–7 points or more score’, 6–12 months duration) of the Alzheimer’s Disease Assessment Scale-cognitive test (ADASCog) range (0 –70), showed a difference in favor of idebenone of 0.49 Peto Odds Ratio (95%CI 0.38– 0.62, z = 5.72) (Hashimoto et al. 1999). In patients taking 360 mg/day of idebenone, 57% achieved an improvement of 7 points or more on the ADAS-Cog subscale, compared with 33% taking placebo at 12 months. However, such a good improvement ratio was observed not only in the idebenone group but also in the placebo group. Improvement of –3 points or more (on the ADAS-Cog subscale) from baseline in placebo group at 6–12 months was observed. This is very different from unselected AD patients, because it was reported that these patients declined by between 7 and 11 points per year (ADAS-Cog).

Clinical global impression of change The odds ratio for any improvement (‘little to very much’), at 6–12 months on idebenone relative to placebo on the clinical global impression of change scale was 0.50 (95%CI 0.39– 0.63, z = 5.96) (see Fig. 10, Hashimoto et al. 1999). What this clinically observable effect means in practice, and which components of the symptoms of AD are involved in producing this change, is unclear.

Behavior The behavioral non-cognitive subscale (4 points score or more improvement), at 6 months of the ADAS (range 0 –50), showed a difference in favor of idebenone of 0.47 Peto Odds Ratio (95%CI

0.27–0.81, z = 2.71; see Fig. 12, Hashimoto et al. 1999).

Functional activity The functional activity improvement (2 points or more score) at 6–12 months on the instrumental activities of daily living (IADL) subscale of NOSGER (maximum score is 25) showed a difference in favor of idebenone of 0.67 Peto Odds Ratio (95%CI 0.52–0.86, z = 68, 3.15) (Hashimoto et al. 1999). It may be that idebenone has little effect on functional activity, but such small effects observed on measures of the functional instrument activity are of questionable clinical significance.

Dependency: institutionalization No reliable/meaningful data available.

Predicting response to treatment Dose is the only clear predictor of response for cognitive function and the clinical global impression of change.

Number needed to treat Cognitive improvement Cognitive improvement of 7 points or more at 6 months (ADAS-Cog). This figure combined with a 10% and 23% difference between treatment of 270 mg and 360 mg respectively, and placebo for achieving the goal of a 7-point improvement provides a figure of approximately 30%. Therefore, for more than 11, five patients need to be treated at 270 mg, 360 mg/day for one patient to benefit by this amount. (a) Cognitive improvement of 7 points or more at 6 months (ADAS-Cog). The NNT for improvement at 6 months was: 270 mga11. 360 mga5. (b) Cognitive improvement of 7 points or more at 12 months (ADAS-Cog). The NNT for improvement at 12 months was: 270 mga8. 360 mga5.

532 CHAPTER V.2

Table V.2.19 Pooled results of ADAS-Cog for idebenone vs. placebo in dementia (reproduced with permission from Update

Software). Outcome: ADAS-Cog Study

Idebenone n

Mean (SD)

Control n

Mean (SD)

WMD (95%CI fixed)

Weight (%)

WMD (95%CI fixed)

270 mg −5.06 (6.39) 125 Gutzmann (98-12M) −4.92 (5.56) 134 Gutzmann (98-6M) 259 Subtotal (95%CI) Chi-square 0.35 (df = 1) P: 0.56 Z = 3.15 P: 0.002

128 140 268

−3.06 (6.25) −3.54 (5.92)

21.1 27.7 48.8

−2.00 [−3.56, −0.44] −1.38 [−2.74, −0.02] −1.65 [−2.67, −0.62]

360 mg 126 −6.93 (6.02) Gutzmann (98-12M) 139 −5.95 (5.45) Gutzmann (98-6M) 265 Subtotal (95%CI) Chi-square 2.02 (df = 1) P: 0.16 Z = 5.98 P: < 0.0 0001

128 140 268

−3.06 (6.25) −3.54 (5.92)

22.5 28.7 51.2

−3.87 [−5.38, −2.36] −2.41 [−3.75, −1.07] −3.05 [−4.05, −2.05]

100.0

−1.65 [−3.08, −1.65]

Total (95%CI) 524 Chi-square 6.05 (df = 3) P: 0.11 Z = 6.48 P: < 0.0 0001

536

−10

−5

0

5

Clinical global impression

Nursing home placement

(a) ‘Little to very much’ improvement. The NNT for improvement at 6 months was: 90 mga22. 270 mga9. 360 mga4. (b) ‘Little to very much’ improvement. The NNT for improvement at 12 months was: 270 mga10. 360 mga5.

No reliable data.

Behavior ‘At least –4 points’ improvement (ADAS-noncog). The NNT for improvement at 6 months was: 90 mga9. 270 mga9.

10

NNT for one withdrawal Approximately 100.

Who should be considered for treatment? The medical criteria for inclusion in the trials were criteria for ‘probable’ AD: Mini Mental Status Examination (MMSE) between 10 and 24.

Who should be excluded from treatment?

Functional activity

Those in whom treatment is contraindicated or cautioned

‘At least –2 points’ improvement (NOSGER-IADL). The NNT for improvement at 6 months was: 270 mga13. 360 mga8.

• • • •

Renal failure. Hepatic failure. Cardiovascular disorder. Hypersensitivity to idebenone.

TREATMENT OF ALZHEIMER’S DISEASE 533

Those in whom the value of treatment is unknown • Other dementias. • Very early symptoms, e.g. MMSE greater than 25. • Severe stage of disease, e.g. MMSE less than 9.

Clinical pharmacokinetics Idebenone is rapidly absorbed from the gastrointestinal system. Peak concentrations occur between 1 and 3 h of oral administration after a meal, and it is dose dependent.

Adverse effects • Insomnia (intervention (I)-9/46 : 20%, placebo (P)-1/46 : 2%), gastralgia (I-7/46 : 15%, P-6/46 : 11%), anxiety (I-6/46 : 13%, P-1/46 : 2%), nausea (I-5/46 : 11%, P-1/46 : 2%) (Bergamasco et al. 1994). • Dizziness, influenza-like symptoms, bronchitis, lumbar pain (Gutzmann & Hadler 1998). • Bronchitis, increased hepatic enzyme, dizziness, nausea, head pressure, headache, heartburn, angina pectoris (Weyer et al. 1997). • Dizziness, sleep disorder, psychomotor restlessness (Weyer et al. 1996). • Gastrointestinal in nature, gastralgia, vomiting, abdominal colic and diarrhea occurred, overall, in 7% (n = 339) of patients receiving idebenone, 4% receiving placebo (n = 150) and 30% receiving oxiracetam (n = 40), anxiety/irritability, headache, polyuria, drowsiness/dizziness, confusion, tachycardia, confusion, mild anxiety, mild gastric pain, mild psychmotor agitation (Gills et al. 1994). • Namely confusional state, mild anxiety, polyuria, polakisuria (Senin et al. 1992). • Abnormal behavior, delirium, drug-induced systemic lupus erythematosus (SLE), drug-induced Parkinsonism.

Drug interactions No reliable/meaningful data available.

Starting/monitoring/stopping treatment Dose: 90 –360 mg.

Monitoring adverse effects • • • • • • • •

Renal failure. Hepatic failure. Cardiovascular disorder. Parkinsonism. Abnormal behavior delirium. Psychmotor agitation. Confusional state. Anxiety.

Monitoring usefulness Given the issues of safety, monitoring, cost and the large NNT, conducting ‘N-of-1 trials’ may be appropriate (see Section IV.5.4 for details) at initiation and at periodic intervals (e.g. 6 monthly or yearly) during the course of treatment to ensure that it remains useful. Criteria for defining a useful response may be: 1 A ‘moderate’ or ‘marked’ improvement in global function or quality of life as perceived by the patient or carer. 2 An absolute improvement from baseline in cognitive performance (e.g. a 4 or 7 point improvement in ADAS-Cog has been suggested). The reverse of these criteria can be used to decide when to withdraw therapy.

Stopping treatment 1 Poor tolerance: there are some case reports of serious adverse side effects, such as abnormal behavior, delirium, idebenone-induced SLE, idebenone-induced Parkinsonism and persistent and bothersome side effects. 2 Poor compliance, as the benefits are unlikely to be achieved. 3 Lack of useful benefit: reaching a severe stage of disease. 4 Lack of perceived improvement to the quality of life of patients or carers (even despite improvements in ‘objective’ measures such as MMSE) may constitute a reason for stopping therapy. 5 Trial of withdrawal of therapy makes no perceived difference to the patient or carer. 6 Rapid deterioration.

534 CHAPTER V.2

Future research Idebenone is currently under development in US phase III clinical trials on AD patients. This trial will be added to this review and be made available in an update on the companion website to this book.

Summary There is inadequate evidence to recommend idebenone in the treatment of AD. It needs more high quality evidence. Its effects can be summarized as follows: There is poor evidence for: [Grade A-3] 1 Improvement in cognitive performance. 2 Reduction in the rate of decline of cognitive performance. 3 Improvement in clinical global impression (although this improvement is modest in most patients who improve).

4 Higher doses producing better responses for cognition and clinical global scales. (a) Improvement or reduction in decline in functional autonomy, as assessed by NOSGER-IADL. (b) Improvement in behavioral disturbance, as assessed by the ADAS-noncog scale. The clinical relevance of the benefits are uncertain, the only patients with ‘probable’ AD who should now be prescribed idebenone are those in countries where the newer, safer and more convenient cholinesterase inhibitors are not yet available, and those who are already on idebenone and considered to be deriving benefit.

Dependency: nursing home placement No reliable/meaningful data available.

Number needed to treat Although there is inadequate evidence to recommend idebedone, the NNTs are comparable to those of the cholinesterase inhibitors.

Cognitive improvement of 7 points or more at 6 months (ADAS-Cog) on: Cognitive improvement of 7 points or more at 12 months (ADAS-Cog) on: Clinical global impression at 6 months little to very much:

Clinical global impression at 12 months little to very much: Behavior improvement of 4 points or more at 6 months (ADAS-noncog) on: Functional activity improvement of 2 points or more at 6 months (NOSGER-IADL) on:

270 mg/daya11 360 mg/daya5 270 mg/daya 8 360 mg/daya 5 90 mg/daya22 270 mg/daya 9 360 mg/daya4 270 mg/daya10 360 mg/daya5 90 mg/daya9 270 mg/daya9 270 mg/daya13 360 mg/daya8

TREATMENT OF ALZHEIMER’S DISEASE 535

Table V.2.20 Clinical global impression for idebenone (reproduced with permission from Update Software). Review: Idebenone in the treatment of dementia and related disorders associated with chronic cerebral disorders of the elderly Comparison: Idebenone vs. placebo Outcome: CGI (little to very much) Peto OR Control Weight Peto OR Idebenone Study (95%CI fixed) n/N (%) (95%CI fixed) n/N 90 mg 22/79 Weyer G (97-6M) 22/79 Subtotal (95%CI) Chi-square 0.00 (df = 0) P: 1.00 Z = −0.65 P: 0.5

27/83 27/83

11.8 11.8

0.80 [0.41, 1.57] 0.80 [0.41, 1.57]

270 mg Gutzmann (98-12M) Weyer G (97-6M) Weyer G (96-6M) Subtotal (95%CI) Chi-square 0.52 (df = 2) P: 0.91 Z =

33/125 16/87 40/135 89/347 −3.18 P: 0.001

47/128 27/83 56/141 130/352

18.9 11.1 21.6 51.6

0.62 [0.37, 1.06] 0.48 [0.24, 0.95] 0.64 [0.39, 1.05] 0.59 [0.43, 0.82]

360 mg Gutzmann (98-12M) Weyer G (96-6M) Subtotal (95%CI) Chi-square 2.71 (df = 1) P: 0.26 Z =

26/126 17/139 43/265 −5.71 P: < 0.0 0001

47/128 56/141 103/269

18.0 18.6 36.6

0.46 [0.27, 0.79] 0.24 [0.14, 0.41] 0.33 [0.23, 0.48]

260/704 154/691 Total (95%CI) Chi-square 10.85 (df = 5) P: 0.09 Z = −5.96 P: < 0.0 0001

100.0

0.50 [0.39, 0.63]

0.1

V.2.14

0.2

1

5

10

Nicotine

Jesus López-Arrieta Key point

There is no evidence to recommend the use of nicotine, in any form of administration, in Alzheimer’s disease (AD). Nicotine is not currently prescribed for cognitive impairment and dementia in any country. Encouraged by several case control studies of AD and smoking, it has been tested for efficacy by administration as nicotine patches or intravenously in AD. It has also been promoted as an additional property for galantamine as it is an allosteric modulator at nicotinic cholinergic receptor sites and thus may enhance cholinergic transmission (Sweeney et al. 1988; Maelicke et al. 1997).

Rationale There is a well-established deficit in brain acetylcholine (ACh) of AD patients that correlates with cognitive decline (Blessed et al. 1968; Whitehouse 1982): it has been the rationale for trials with acetylcholinesterase (AChE) inhibitors. ACh has two important receptorsamuscarinic and nicotinic. The prototypical agonist of the nicotinic ACh receptor is nicotine, an alkaloid derived from the leaves of the tobacco plant (nicotiana tabacum and nicotiana rustica). The anticholinesterase antidementia drugs are presumed to exert their effect essentially through the muscarinic cholinergic system, quite different in the brain to the nicotinic system. It has, however, been shown that there is a profound loss of nicotine receptors in AD brains

536 CHAPTER V.2

while the muscarinic receptor brain density remains basically unchanged (Aubert et al. 1992). Nicotine is a cholinergic agonist that acts not only postsynaptically, but also releases presynaptic ACh (Araujo et al. 1988), and in animal models has been shown: (i) to reverse spatial memory decline in rats with lesion in the medial septal nucleus (Decker et al. 1992); and (ii) to show recovery of memory in aged monkeys (Buccafusco & Jackson 1991). Nicotine also has effects on other transmitters like serotonin, dopamine, or gamma-amino-butyric-acid. Acute nicotinic blockade with single oral doses of macamylamine, a central and peripheral nicotinic antagonist produces cognitive impairment in healthy male non-smokers (Newhouse et al. 1992). Nicotinic cholinergic stimulation can activate pituitary hormonal secretion in the human and it suggests that nicotinic cholinergic stimulation may constitute an important part of cholinesterase inhibitor-induced endocrine stimulation and behavioral activation (Newhouse et al. 1990). Transdermal administration of nicotine increases both regional cerebral glucose metabolism and semantic memory in AD patients but not in the elderly (Parks et al. 1996). Published studies in humans have addressed the effects of intravenous or subcutaneous nicotine administration in people with AD. Significant improvements were reported in several cognitve deficits such as: free recall, visual attention and perception (Newhouse et al. 1988; Jones et al. 1992) but not on memory (Sahakian et al. 1989; Sahakian & Coull 1994). These results suggested that central nicotinic cholinergic stimulation deserves further investigation as a treatment for AD. Information from 19 case control studies of AD shows a highly significant negative association of this disease with previous tobacco habit (Lee 1994), providing support for the notion that smoking, more probably through the action of nicotine which crosses easily the blood–brain barrier, reduces the risk of AD. Some of the potential bias of case control studies (elderly smokers who have survived long enough to get dementia may be a genetically unusual group) was excluded after one study (vanDujin et al. 1995) providing evidence of the protective role of tobacco for early onset in high risk individuals with apo E allele and a positive familial history of AD. This supports the observation that

nicotine cholinergic receptors are increased in smokers, compensating the loss of these receptors in Alzheimer’s patients (Schwartz & Kellar 1983). The results of the 40-year prospective British doctors’ study of smoking which has much more reliable data about the association of smoking and future dementia and AD are eagerly awaited and will be reported in an update of this chapter.

Evidence There are two double-blind, placebo-controlled cross-over studies of nicotine in AD patients looking for efficacy in cognition; neither meets minimum validity criteria as random allocation was not mentioned. In one study (Wilson et al. 1995) daily sessions evaluating learning, memory and behavior during 1 week on nicotine showed improvement in learning during nicotine administration. It is not possible to draw firm conclusions from the studies considered in this review because of the absence of reported results from adequate randomized doubleblind controlled trials. If anything, the evidence, at least according to one study (Snaedal et al. 1996), shows patients on nicotine doing worse than those on placebo for cognitive measures. Although these negative results are based on poorly designed trials with relatively small samples and could represent false negative results, they are far from encouranging.

Who should be considered for treatment? Nobody.

Clinical pharmacokinetics Absorption of nicotine from the 22 mg patch varied with a range of peak blood levels from 3.9–11.7 ng/ml. 48 h after removal of nicotinic patches no measurable amount of nicotine or its metabolite, cotinine, was in the blood.

Adverse effects Nicotine has adverse effects, especially concerning cardiovascular risks in elderly people, and also on sleep and behavior. In one study (Snaedal et al.

TREATMENT OF ALZHEIMER’S DISEASE 537

1996) it was well tolerated overall in old nonsmoking patients, however, one patient out of 18 died during nicotine treatment; the cause of death was not investigated. According to Wilson et al. (1995) there is a decrease in sleep at night, mild increase in heart rate and in ventricular and supraventricular ectopics, and no significant signs of ischemia.

and safe treatment for AD emphasizes the need for good randomized, double-blind, controlled trials with parallel group design, over several months with relevant and valid outcome measures evaluating cognitive status, activity of daily living function, institutionalization and mortality, and looking for adverse effects including mortality.

Starting/monitoring/stopping treatment

Summary

Not relevant.

There are insufficient data from randomized controlled trials to provide evidence to support the use of nicotine, in any method of administration, as a treatment for AD.

Future research The absence of evidence for nicotine as an effective

V.2.15

Nimodipine

Jesus López-Arrieta Key point

There are not sufficient available data to recommend nimodipine as a treatment for the symptoms of dementia, either unclassified or according to the major subtypesaAlzheimer’s disease (AD), vascular, or mixed. Nimodipine is currently and frequently prescribed for cognitive impairment and dementia in several European countries, such as Spain and Germany, although its approval is limited to neurological impairment due to brain vasospasm secondary to subarachnoid hemorrage. For example, in Spain the datasheet states that controlled clinical trials have shown improvement in age-associated cognitive impairments, and AD must be excluded before starting nimodipine. Its prescription is based upon: • Improvement in clinical global improvementa affectivity, social and physical function. • Mental performance.

Rationale The deterioration of calcium homeostasis of

healthy neurones during aging and AD leads to severe damage of these cells (Landfield 1989). This is more obvious in the hippocampus, which is extremely vulnerable in AD, and in Purkinje cells, which most consistently decline with aging. Calcium channel blockers are drugs that inhibit the entrance of calcium ions into the neurone and immobilize it. According to their chemical structures and tissue selectivity, these drugs are classified depending on selectivity for peripheral, coronary or cerebral vessels (Vanhoutte & Paoletti 1987). Nimodipine forms part of the last group, so it binds reversibly to brain dihydropiridine receptors on neurones and cerebrovascular cells, regulating glucose metabolism, neurotransmitter synthesis and release axonal transport, influencing the activity of both neuronal conduction and cerebral blood flow. It binds reversibly with high selectivity to brain dihydropiridine receptors, reducing the number of open channels, thus limiting calcium ion channel into the cell, that seems to protect neurones and so suggests nimodipine’s neuroprotective potential. The high density of nimodipine binding sites in hippocampus, caudate nucleus and cerebral cortex may play an important role in learning/memory processes (Nyakas et al. 1989). Because the bind-

538 CHAPTER V.2

ing sites are found both on neurones and cerebrovascular cells, its action influences the activity of both neuronal conduction and cerebral blood flow. In cerebral perfusion nimodipine exerts its action specially in smaller arteriolae; this is more evident in damaged brain regions than in healthy ones (Kazda & Towart 1982). Nimodipine can also modulate other calciumdependant processes such as acetylcholine (ACh) release which has been implicated in the functions of memory in AD.

Evidence The usefulness of nimodipine in patients with AD is still controversial and has mixed results. It is noteworthy that almost all the trials reported that nimodipine had benefits in the patients studied. Several ‘overviews’ have also been published indicating a beneficial effect of nimodipine, but the methods used were open to bias and the details of the data presented in these reviews were not usable (Dycka et al. 1984; Dycka 1985; Dycka et al. 1986; Schmage et al. 1989; Grobe-Einsler 1992). A systematic review after an extensive literature search using a detailed strategy (see Website for search strategy), by 1998, yielded more than 30 trials that had tested nimodipine vs. placebo or other drug (Qizilbash et al. 1998). Ten trials were identified which met the criteria for inclusion in this review. Each trial was designed to compare nimodipine with placebo. Except for one trial that had a third arm of 180 mg/day, all other trials used 90 mg/day. The eligible studies contained a total of over 1000 patients, but only two (Fischhof et al. 1989; Ban et al. 1990) of the 10 trials provided quantitative results in sufficient detail to allow inclusion and pooling in this review (Qizilbash et al. 1998). All 10 trials fulfilled the inclusion criteria, which is based on that for the Cochrane Library, unconfounded, randomized, double-blind, placebocontrolled efficacy trials where nimodipine was given for more than a day. However, no trial only included AD patients, but rather individuals with a mixture of old age dementias of degenerative or vascular origin using DSM III criteria (American Psychiatric Association 1980). The diversity of the outcome measures, and the poor clarity and com-

pleteness of reported results greatly constrained the pooling of results. The data were compatible with nimodipine producing improvement, no change or even harm for those with AD, vascular dementia, or mixed Alzheimers and vascular dementia. A recent literature search done by the author found one more randomized parallel group placebocontrolled trial of nimodipine for multi-infarct dementia (Pantoni et al. 2000). A total of 259 patients were originally randomized (128 to nimodipine and 131 to placebo). Cognitive, global and functional measures were used. The study failed to show a significant effect on nimodipine in all the outcome measures. These data were added to the data from the systematic review conducted by Qizilbash et al. (1998), using the Revman 4.1 software and whose results are displayed below.

Cognition The treatment benefit was statistically significantly different from placebo for the Mini Mental State Examination (MMSE) score (0–30; high = good) (WMD 2.6; 95%CI 1.74, 3.46) and for the Wechsler Memory Scale (WMD 8.0; 95%CI 2.93, 13.07) for the Ban et al. (1990) study. However, these analyses were based only on those who completed the study and not intention-to-treat analyses (ITT). Based on the study by Pantoni et al. (2000) no effect in favor of nimodipine was shown on MMSE in VaD (WMD 8.0; 95%CI −0.86, 0.82). These data produce a statistically significant positive effect of intervention (WMD −0.02; 95%CI −0.86, 0.82), although the heterogeneity (p < 0.0001) makes the pooled estimate questionable (Table V.2.21).

Clinical global impression The intention-to-treat analyses (with one study that did not conduct intention-to-treat analysis (Fischhof et al. 1989) despite stating so), in which all drop-outs were assumed to have worsened. Statistically significant results were found in favor of nimodipine, for patients improving moderately or markedly vs. other changes on the Clinical Global Impression scale (OR 6.93; 95%CI 3.13–15.31). However, no statistically significant result materi-

TREATMENT OF ALZHEIMER’S DISEASE 539

Table V.2.21 Nimodipine for primary and degenerative VaD: cognitive performance (reproduced with permission from Update Software).

Study

Treatment n

Mean (SD)

Placebo n

MMSE (completer’s analysis) 88 3.40 (2.90) 88 Ban 1990 125 −0.68 (3.49) 126 Pantoni 2000 212 214 Subtotal (95%CI) Test for heterogeneity chi-square = 18.23 df = 1 p < 0.00001 Test for overall effect z = 4 p = 0.00004 Wechsler Memory Scale (completer’s analysis) 13.80 (17.10) Ban 1990 87 Subtotal (95%CI) 87 Test for heterogeneity chi-square = 0.0 df = 0 Test for overall effect z = 3.09 p = 0.002

WMD (95%CI fixed)

Mean (SD)

0.80 (2.90) −0.66 (3.31)

88 88

Weight (%)

WMD (95%CI fixed)

5.2 5.5 10.7

2.6 [1.741, 3.46] −0.02 [−0.86, 0.82] 1.26 [0.66, 1.86]

0.2 0.2

8.00 [2.93, 13.07] 8.00 [2.93, 13.07]

5.80 (17.10)

−10

−5

0

Favors placebo

5

10

Favors treatment

Table V.2.22 Nimodipine for primary and degenerative VaD: clinical global impression (reroduced with permission from Update Software).

Study

Treatment n/N

Peto OR (95%CI fixed)

Placebo n/N

Weight (%)

Moderate or marked improvement vs. other changes 4/ 73 27/ 70 Fischof 1989 4/ 73 27/ 70 Subtotal (95%CI) Test for heterogeneity chi-square = 0.0 df = 0 Test for overall effect z = 4.78 p < 0.00001 Improving or no change vs. worsening 58/70 Fischof 1989 58/70 Subtotal (95%CI) Test for heterogeneity chi-square = 0.0 df = 0 Test for overall effect z = 1.82 p = 0.07

51/73 51/73

85/140 55/146 Total (95%CI) Test for heterogeneity chi-square = 4.72 df = 1 p = 0.03 Test for overall effect z = 4.63 p = 0.00001 0.1

0.2

1

Placebo

alized with improvement or no change vs. worsening (OR 2.04; 95%CI 0.95– 4.39). Data from Pantoni on change from baseline of the Clinical Global Impression scale failed to show any efficacy of nimodipine (SMD 0.12; 95%CI –0.13, 0.36), Table V.2.22.

5

Peto OR (95%CI fixed)

48.4 48.4

6.93 [3.13, 15.31] 6.93 [3.13, 15.31]

51.6 51.6

2.04 [0.95, 4.39] 2.04 [0.95, 4.39]

100.0

3.68 [2.12, 6.39]

10

Treatment

Death No deaths were reported in the studies during the trial period, up to 1 year.

Number needed to treat Data from trials not of sufficient detail to allow meaningful calculation.

540 CHAPTER V.2

Non-poolable results There are some narrative reviews published in books sponsored by the manufacturers of nimodipine (Schmage 1989). The major one refers to an individual clinical data pool of 11 double-blind, placebo-controlled nimodipine studies, some of which were not referenced, that included 391 patients treated with nimodipine and 398 treated with placebo. Only two double-blind studies did not show a difference between the treatment groups. The Sandoz Clinical Assessment Geriatric (SCAG), Trail Making Test (TMT) and the Clinical Global Impression (CGI) were the endpoints most frequently applied in the individual studies. After combining the data, the authors concluded that there was a much larger proportion of patients that did not respond or who showed deterioration in the placebo group compared to the nimodipine group. Although the Cochrane review of nimodipine did not include all valid studies, these should be discussed. There were seven valid trials not included in the Cochrane review of nimodipine (see details of studies on the website).

Who should be considered for treatment? Nobody.

Clinical pharmacokinetics The gastrointestinal tract absorbs nimodipine almost completely and plasma level can be detected after 15 min of oral administration. The plasma concentration peaks at 40–100 min and the halftime of plasma elimination is from 1.1 to 1.7 h. There is a high first-pass effect in the liver so the bioavailability of the drug is 10–15%. Nimodipine is distributed in all tissues and organs. Approximately 97–99% of the drug is bound to plasma proteins and is mainly metabolized in the liver and

the metabolites eliminated through the kidney (Ramsch & Lucker 1987).

Adverse effects The incidence of side effects and withdrawal were generally low except for one trial which reported dizziness in 28% of those taking nimodipine compared to 8% of patients on placebo. Typically, rates of side effects and withdrawal were less than 10% and largely consisted of dizziness, hypotension, headache, muscle weakness, dyspepsia and constipation.

Starting/monitoring/stopping treatment Not relevant.

Future research The current data based on published evidence are insufficient to make any definite conclusions but represent a selected sample of the dataset that is potentially available for an individual-patient data meta-analysis. Given the high levels of prescription of nimodipine in many European countries, its apparently safe adverse effect-profile and its cost, further research is needed. This should, initially, attempt to pool all the individual-patient data from existing trials. Future trials should focus on ADathe data for VaD appear to offer little promise.

Summary From the data in this review, nimodipine cannot be recommended for the treatment of patients with symptoms of dementia, either unclassified or according to the major subtypes: AD, vascular, or mixed Alzheimer’s and vascular dementia. It appears to be well tolerated but does have some side effects.

TREATMENT OF ALZHEIMER’S DISEASE 541

V.2.16

Non-steroidal Anti-inflammatory Drugs

John C.S. Breitner Key point

Non-steroidal anti-inflammatory drugs (NSAIDs) are a group of pharmacologically related compounds that inhibit cyclo-oxygenase (COX) enzymes. Based primarily on observational (epidemiologic) findings, there is intense interest in their potential for the treatment or prevention of Alzheimer’s disease (AD).

Rationale In mammals, including man, there are two known forms of cyclo-oxygenase: COX-1, which is typically present constitutively, e.g. in gastric parietal cells; and COX-2, which is generally synthesized in response to a local metabolic signal, e.g. at sites of inflammation. The classical NSAIDs such as ibuprofen, naproxen, or diclofenac are dual inhibitors that block the activity of both COX species. Their principal side effects, notably gastric ulceration and bleeding, are attributed to their inhibition of COX-1. The recent introduction of the selective COX-2 inhibitors celecoxib (Celebrex™, Searle) and rofecoxib (Vioxx™, Merck) promise considerable improvements in safety with comparable efficacy, at least for the treatment of osteoarthritis. Other drugs with relative COX-2 specificity available in Europe include meloxicam and nimesulide. Because the two isoforms of COX have numerous biological activities, the rationale for any therapeutic benefit of NSAIDs in AD is uncertain. In low to moderate doses (e.g. 400–1200 mg of ibuprofen daily), NSAIDs act centrally to inhibit fever and pain. At higher doses the drugs inhibit local inflammation by blocking the induction of interleukin-1β (IL-1β) and possibly IL-6 via pathways that rely on prostaglandin synthesis (Vane & Botting 1987). There is evidence that local inflammation, including induction of the classical complement cascade, surrounds the site of Alzheimer amyloid plaques (Eikelenboom et al. 1998; McGeer & McGeer 1998). Levels of IL-

1β and another inflammatory cytokine S-100β are increased in the Alzheimer brain (Griffin et al. 1989). NSAIDs may suppress these neuroinflammatory pathways, presumably through inhibition of COX-2athe principal isoform involved in inflammatory processes outside the central nervous system (CNS). Cyclo-oxygenases also have other important activities in brain. In neurones with NMDA-type glutamate receptors, inducible COX-2 is needed for signal transduction via the oxidation of arachidonic acid that in turn is liberated in the presence of a calcium signal from the inner cell membrane by phospholipase A2 (Lerea & McNamara 1993). In the phenomenon known as long-term potentiation, these cells modify their signal sensitivity in response to the level of glutamatergic stimulation. Sustained strong stimulation may result in ‘dendritic pruning’ of these cells, and excessive stimulation causes them to undergo excitotoxic cell death (Mattson & Kater 1989; Mattson 1996). Especially vulnerable cells are the large pyramidal neurones that are abundant in hippocampus and cortex (predominantly layers III and V), regions that are prominently affected in AD (Mann 1996; Arendt et al. 1998). It is not known whether inhibition of COX-1 or COX-2 (or both) is important for the apparent neuroprotective effect of NSAIDs. Both species are present in brain. Histochemical studies reveal intense species-specific staining for COX-1 in region CA-1 of hippocampus, but little or no staining elsewhere in the brain (O’Banion & Olschowka 1999). There is no apparent change in COX-1 staining intensity in the Alzheimer brain. By contrast, COX-2 specific immunoabsorption techniques show increased levels of this isoform in many areas of brain (Pasinetti & Aisen 1998; Yasojima et al. 1999), and it appears that COX-2 is the isoform involved in triggering excitoxicity (Ho et al. 1998). The enzyme is localized principally in dendrites and in the perikaryon of pyramidal neurones (Yasojima et al. 1999) where it ‘should’ be if it plays an important role in postsynaptic signal transduction. Whether NSAIDs act

542 CHAPTER V.2

Table V.2.23 Summary of meta-analysis of observational studies.

Type of study

Exposure or risk factor

No. of studies

Overall OR

95%CI

p

Case control Population based Case control Case control

Arthritis Rheumatoid arthritis Steroids NSAIDs

7 2 4 3

0.556 0.194 0.656 0.496

0.442– 0.700 0.092– 0.410 0.431– 0.999 0.343– 0.716

< 0.0001 < 0.0001 0.049 < 0.0002

through suppression of inflammation or of gluatmate toxicity, it is therefore likely, but not certain, that COX-2 inhibition will be key to their therapeutic potential in AD.

Evidence Because AD appears to be a chronic disease with latent, prodromal and active symptomatic phases, there are three potential uses of NSAIDs in AD: • In the latent stage, to prevent progression to later phases in at-risk individuals (primary prevention); • In the prodromal stage, to prevent progression of age-related cognitive decline or its march to dementia (secondary prevention); and • In established dementia, to prevent progression of symptoms (tertiary prevention). In each instance, the aim is to prevent disease progression; there is little reason to look for symptomatic improvement with NSAIDs.

Search and selection strategy A search of Medline was conducted for metaanalyses of observational studies and for trials of NSAIDs and dementia or AD. Irrelevant citations were discarded and those trials that were randomized, unconfounded, double-blind and placebo controlled were chosen for inclusion. With one or two exceptions, good quality meta-analyses of observational studies were chosen in preference to individual studies. Primary prevention There are no controlled trials of NSAIDs for primary prevention of AD. The evidence for their benefit is instead a collection of over 20 epidemio-

logic studies that suggest the risk of AD onset is reduced by half or more among sustained NSAID users (Breitner 1996). Most of these studies have been cross-sectional or retrospective. They have faced substantial difficulties in the accurate classification of prior NSAID exposure status, especially among their AD cases. Several ingenious methods of circumventing this problem have yielded similar findings to those from direct interviewing techniques. A recent meta-analysis (McGeer et al. 1996) classified 17 studies according to their approach in exposure classification. Table V.2.23 shows meta-analytic results from the three groups of studies. Some considered only the indication of chronic rheumatoid or osteoarthritis, reasoning that most patients with these conditions take sustained doses of NSAIDs. Others established exposure to NSAIDs by direct interview or by obtaining medical records. Still others established exposure to corticosteroids using the same methods. In each of the three groups, the odds ratio (OR, an estimate of the relative risk) with the indicated exposure was near 0.5. However, the OR with corticosteroids was closest to the null value of 1.0. Corticosteroids are potent anti-inflammatory agents, but they do not inhibit cyclo-oxygenases. There are two studies that examined use of NSAIDs and corticosteroids concurrently (Canadian Study of Health & Aging 1994; Breitner et al. 1995). Both found a stronger inverse relation of AD with NSAID use than with corticosteroid use. Two of the observational studies used a prospective design. One, conducted among 1684 elderly volunteers, used drug exposure data that were gathered before the subjects had become demented (Stewart et al. 1997). Similar to the retrospective results, that study estimated a relative risk near 0.5. A second prospective study (in’t Veld et al. 1998)

TREATMENT OF ALZHEIMER’S DISEASE 543

Secondary prevention in patients with minimal cognitive impairment Several randomized trials are now underway to test whether administration of selective COX-2 inhibitors can prevent progression of severity in agerelated cognitive decline, or its eventual march to dementia. Data will probably be available in 2001. There are no known trials of this type using conventional NSAIDs. Tertiary preventioncattenuation of disease progression One observational study (Rich et al. 1995) and two small randomized trials (Rogers et al. 1993; Scharf et al. 1999) suggest that NSAIDs may slow the progression of symptomatic Alzheimer’s dementia. The observational study considered the 1-year decline in cognitive test scores among 202 patients enrolled at a university AD clinic. The patients were classified as NSAID users or non-users according to information obtained at admission to the clinic. The NSAID users had a significantly lower rate of decline on several cognitive tests. Both of the treatment trials (Table V.2.24) were of 6 months’ duration. Both showed suggestive, but not conclusive, evidence that cognitive test scores declined less in the NSAID-treated groups. Drop-out rates for both studies were high, especially for the groups treated with indomethacin

1.0 0.9 0.8 0.7 Proportion surviving

investigated 306 subjects and abstracted exposure information from general practitioners’ records (i.e. ignored OTC preparations). Results were mixed, but suggested an OR below 1 in subjects under age 85, and in long-term users (OR again near 0.5). One of the retrospective studies employed a carefully evaluated cohort of family groups that were at unusually high risk of AD (Breitner et al. 1995). Survival analyses with stratification by sibship showed that the reduction of risk among NSAID users was attributable specifically to a delayed onset of AD (Fig. V.2.2). A lengthy randomized controlled prevention trial using both the conventional NSAID naproxen and the selective COX-2 inhibitor celecoxib has begun, having randomized its first subjects in March, 2001.

0.6 0.5 0.4 0.3 0.2 0.1 0.0 30

40

50

60

70

80

90

100

Years to AD/censoring Fig. V.2.2 Disease-free survival in subjects categorized by

exposure to NSAIDs. Survival curves plot the estimated probability of remaining free of disease as a function of age. The squares and triangles at the bottom of each riser in the step-plot indicate appearance of one or more new cases among the unexposed and exposed groups, respectively. The method intrinsically adjusts for attrition in the numbers at risk as older ages are considered. The cumulative survival estimates are obtained by chain-multiplying the individual survival fractions (number surviving free of disease divided by number at risk) at the appearance of each new case through the age in question. The cumulative incidence before age 90 in the exposed group is one minus the survival fraction of 0.75 or 0.25. The comparable figure for unexposed subjects is 0.97. The difference in lifetime risk between the two groups is highly significant. (Triangles represent exposure to NSAIDs.)

(38%) or diclofenac (administered with misoprostol, 50%). One large placebo-controlled randomized AD treatment trial was recently completed using a selective COX-2 inhibitor. Results of this experiment are not yet published. It will be revealing to compare its results with those from a randomized trial of low-dose prednisone, recently completed using a similar design by the consortium of the (US) Alzheimer’s Disease Collaborative Studies Unit (Aisen et al. 2000). The latter study

544 CHAPTER V.2

Table V.2.24 Summary of clinical trials with NSAIDs for treatment of AD. Design, setting, population and subject selection Study: Rogers et al. 1993 6-month double-blind, placebo-controlled clinical trial. Metropolitan US. Mild to moderate AD patients (n = 44) were volunteers with MMSE ≥ 16. Treatment groups were well matched on age, sex, and baseline cognitive measures Study: Scharf et al. 1999 25-week randomized double-blind placebocontrolled trial. Australia. Mild to moderate community dwelling volunteer AD patients (n = 41), age = 50, MMSE 11–25). Treatment groups were well matched on age, baseline MMSE, but not on sex

Definition of comparison groups

Outcome/exposure variables

Response rate and follow-up

Treatment group: 100 –150 mg indomethacin tid Control group: placebo tid

Outcome: % change in cognitive scores (MMSE, ADAS-Cog, Boston Naming Test, Token Test; mean of all 4) from baseline to 6 months later

Treatment group: diclofenac 25 mg + misoprostol 100 μg bid Control group: placebo bid

Outcome: change over time in IADL, ADAS-Cog, GDS, CGIC, care giver GIC, MMSE, Physical SelfMaintenance Scale

Results

Comments

14 of 24 in treatment group completed protocol; cf. 14 of 20 controls Gastro-intestinal side effects most common reason for dropout

Treatment group improved 1.3% (mean of 4 tests) Placebo group declined 8.4% (p < 0.01)

Small n; 36% dropout rate (42% in indomethacin group; 30% in placebo group)

12 of 24 in treatment group completed; cf. 15 of 17 controls. Dropout in treatment group was largely drug related

No significant difference on any single measure in intent-to-treat analysis. For completers, non-significant trends showed greater deterioration in placebo group

Small n. High dropout in treatment group. Effects of diclofenac and misoprostol cannot be distinguished

ADAS-Cog, Alzheimer Disease Assessment ScaleaCognitive subtests; CGIC, Clinical Global Impression of Change; IADL, instrumental activities of daily living; GDS, Global Deterioration Scale; GIC, global impression of change; MMSE, Mini Mental State Examination.

TREATMENT OF ALZHEIMER’S DISEASE 545

showed no benefit with treatment, and trends suggesting that the prednisone treated group may have done worse on some outcome measures.

Who should be considered for treatment? Ideally, any ‘treatment’ at this point should occur in the context of well designed randomized trials. With the possible exception of secondary prevention trials, however, most patients will not have access to such a resource. Physicians may then choose to treat mild cases of AD experimentally using a selective COX-2 inhibitor. This is an ‘offlabel’ use, but the safety profile of the new selective agents in clinical trials (for osteoarthritis) has been excellent. If no trial is accessible, similar offlabel use of these same drugs may be considered for patients showing evidence of mild cognitive decline, especially if there is a family history of dementia. If the treatment is tolerated, and if the patient fares well, consider continuation of the treatment until definitive results of current clinical trials are available. Because of safety concerns, the long-term use of NSAIDs for the primary prevention of AD is not advisable until more data are available. Exceptions may be considered in individuals with a strong family history, especially if there is concern about failing cognition. The optimal dose for NSAID treatment of AD is unknown, but epidemiological evidence has failed to show any incremental benefit with use of high (antiarthritic) vs. lower (analgesic) doses.

Adverse effects The principal concern is gastrointestinal hemorrhage or perforation, which can be fatal. When gastrointestinal (GI) bleeding occurs, there are commonly no prior warning symptoms of dyspepsia or ulcer pain. The risk of GI hemorrhage increases with age. Patients must be warned strictly not to use other NSAIDs concurrently. If the patient is currently taking aspirin for cardiovascular prophylaxis, it is probably wise to reduce the daily dose to 81 mg. All NSAIDs, including the new selective agents, are contraindicated in patients with a prior history of hemorrhagic peptic ulceration. The case fatality rate with GI bleeding

may be increased in those with pre-existing anemia. Patients taking warfarin or other anticoagulants must not be given NSAIDs. Early intervention in GI hemorrhage or perforation can be lifesaving, and the patient and care giver should be advised thoroughly about the typical signs and symptoms. Some NSAIDs cause a slight dose-dependent increase in blood pressure; this should be monitored. Liver and kidney damage can occur, especially in high doses, when patients have pre-existing compromise of hepatic or renal function. This change is generally reversible. Some authorities advise liver and renal function tests prior to initiation of NSAID treatment; most do not. Periodic monitoring of hepatic and renal functions should be considered to monitor for treatment-emergent adverse events that mitigate against continuation of the drug. Inhibition of COX-mediated functions of the distal renal tubule has resulted in edema in some patients receiving rofecoxib and celecoxib. Reducing the dose may avoid this problem.

Starting/monitoring/stopping treatment See above. Because of their risks, treatments should be stopped (even in the instance of selective COX-2 inhibitors) if published results from the current clinical trials fail to support the benefit of NSAID treatments.

Future research Clinical trials will continue. Given the failure of the prednisone trial to show benefit (in contrast to early trial results with NSAIDs), further research is needed into the role of cyclo-oxygenases in neural function and in neurodegeneneration. Long-term follow-up studies with low dose NSAIDs in a forthcoming prevention trial will provide important information about both efficacy and safety.

Summary With the new availability of selective COX-2 inhibitors, the risk–benefit balance has shifted, so that off-label use of selective agents may be considered for treatment or prevention of AD in specific circumstances. Careful medical monitoring is imperative.

546 CHAPTER V.2

Table V.2.25 Reproduced with permission from Update Software. Comparison: Global scales piracetam vs. control Outcome: Global impression of change Experimental Study n/N Gallai et al. 1991 Hermann et al. 1987 Kretschmar 1976 Macchione et al. 1976 Sano et al. 1990 Trabant et al. 1977

9/17 54/65 27/39 81/112 2/6 10/20

Control n/N

OR (95%CI random)

Weight (%)

1/15 18/65 12/39 39/70 2/9 13/20

10.7 20.4 19.5 21.9 10.3 17.2

Total (95%CI) 85/218 183/259 Chi-square 22.69 (df = 5) P: 0.00 Z = 2.47 P < 0.0 0001

100.0

0.1 0.2

1

Favors controls

V.2.17

5

OR (95%CI random) 15.75 [1.67, 148.72] 12.82 [5.50, 29.87] 5.06 [1.94, 13.24] 2.08 [1.11, 3.89] 1.75 [0.17, 17.69] 0.54 [0.15, 1.92] 3.47 [1.29, 9.30]

10

Favors treatment

Piracetam

Leon Flicker Key point

Piracetam has been widely used over the last 25 years for the treatment of dementia but the available evidence is inadequate to support its routine clinical use. Piracetam (2-oxo-1-pyrrolidine acetamide) was the first of the ‘nootropic’ drugs to be so-called because of its putative effects on higher brain functions. It is still widely used throughout Europe.

Rationale Piracetam is a cyclic derivative of γ-aminobutyric acid (GABA) which can cross the blood–brain barrier and selectively concentrates in brain cortex (Vernon & Sorkin 1991). Even at relatively high doses it is devoid of any sedative/stimulant, locomotor or autonomic activity. It is thought that it may work through three potential mechanisms. It could potentially increase oxygen and glucose utilization via ATP pathways. It may have platelet anti-aggregation and rheological effects with antithrombotic properties (Moriau et al. 1993) or it may enhance central and peripheral microcirculation by the promotion of red blood cell deformab-

ility. In spite of the uncertainties about its efficacy in dementia, piracetam is a frequently prescribed drug for cognitive impairment and dementia in several continental European countries.

Evidence A meta-analysis examining the use of piracetam for cognitive impairment and dementia has been performed (Flicker & Grimley Evans 1999). In the process of that review 68 studies were comprehensively reviewed over a publication time span of 25 years, from 1972 until the present. Of these 68 studies, 26 were considered suitable for inclusion in the meta-analysis but unfortunately data could be extracted from only a small minority. The type and methods of the included trials reflected the period of time in which the trials were performed. Many of the studies performed were short-term cross-over studies which is an unsuitable study design for the chronic conditions of cognitive impairment and dementia. Also, few of the studies incorporated what would be currently acceptable diagnostic criteria. This meta-analysis included any randomized study of subjects who probably had either cognitive impairment or dementia, but many of the studies used definitions such as ‘cerebral insufficiency’. Only one of the included studies

TREATMENT OF ALZHEIMER’S DISEASE 547

defined the subjects by a combination of DSM and NINCDS-ADRDA criteria: 4 of the studies used DSM criteria: 3 used NINCDS-ADRDA criteria, and one used ICD criteria. Of course these studies used previous versions of DSM and ICD criteria rather than those currently available. This meta-analysis noted the difficulty in determining the diagnostic filter through which the patients had passed and therefore the generalizability of the included studies is uncertain. The range of cognitive impairments experienced by the subjects in these studies ranged from minimal subjective complaints to the last stages of severe dementia in institutionalized individuals. The reporting of the included studies often prevented the extraction of data. The large variation in diagnostic criteria of patients included in the meta-analysis and the paucity of data obtained, made it impossible to separately analyse the different etiological types of dementia. The wide range of instruments to measure various aspects of cognition used in these studies created problems with multiple comparisons within and between studies. This problem was compounded by the lack of specification of the primary outcome measure prior to analysis. Thus, this systematic review emphasized the need for any interpretation of the data to be extremely conservative, as no allowance had been made for these multiple comparisons statistically. The dose of piracetam varied from 2.4 g/day to 9 g/day in the included studies. Only three studies observed the effects of treatment for a period greater than 3 months, and only one of the studies (Croisile et al. 1993) treated patients for longer than 6 months. All the included studies except the study by Gallai et al. (1991) reported that the studies were performed under double-blind conditions. The study by Gallai et al. (1991) was single blind and this may have substantially influenced their results of global impression of change. For this reason the meta-analysis of global impression of change was performed with and without the inclusion of this study. Only three of the included studies, Lloyd Evans et al. (1979), Vencovsky et al. (1980) and Israel et al. (1994), reported a significant number of drop-outs and none of these studies contributed data to the meta-analysis. Of the 26 studies included in the meta-analysis

(Flicker & Grimley Evans 1999) only 10 were equivocal or found no benefits whilst the remaining studies found at least some benefits from the use of piracetam. From the data that were pooled there was only one outcome where significant amounts of evidence were available, and this was for the global impression of change. There was evidence of heterogeneity in the results from the individual studies, χ2 test = 20.8 (d.f. = 5). There were no associated factors found for this heterogeneity of results. Using a random effects model the odds ratio (OR) for improvement in the piracetam group compared to the placebo group was 3.47 [95%CI (Confidence Interval) ] [1.29, 9.30] (see Table V.2.25). When the study by Gallai et al. (1991) was excluded, the OR was 2.89 [1.01, 8.24]. This last estimate is the most conservative and suggests only marginal evidence of increased chance of observing improvement in those individuals treated with piracetam as opposed to placebo. These estimates were calculated on the basis of ‘completers’ data rather than ‘intention-to-treat’ which could not be extracted from the reports. The remaining evidence of effects on cognition and other measures was inconclusive. There was a small trend for benefit on cognitive measures and dependency but this was not statistically significant.

Who should be considered for treatment? At this stage, the evidence available from the published literature does not support the use of piracetam in the treatment of people with dementia or cognitive impairment.

Adverse effects The drug appeared to be well tolerated and there seems to be no major side effects with no evidence of differential drop-outs in any of the studies.

Future research Unfortunately, despite there having been a large number of small studies, it was not possible to extract data from many of these. A review incorporating individual patient data may yield valuable additional data concerning the size of any benefit

548 CHAPTER V.2

with this drug, particularly for an effect on cognition as well as within particular diagnostic groups. There is a need for a randomized trial of piracetam in patients with the diagnosis of dementia of Alzheimer’s type or vascular dementia made by currently accepted diagnostic criteria for a period of at least 6 months incorporating global cognitive instruments which are sensitive to change as well as the global impression of change. Effects of piracetam on levels of dependency and care giver quality of life should also be incorporated in such studies.

Summary

and quality of evidence are poor. Many of the studies have been performed on subjects who have not been classified with the use of currently acceptable standardized criteria and have only had treatment for short periods of time, i.e. 3 months or less. These studies, on the whole, have not used standardized global cognitive scales which are sensitive to change, and instead used multiple outcome measures without specifying a primary outcome measure. There was only one outcome where there were significant data available to be pooled in a metaanalysis, and this was for subjective impression of global change. There was only marginal evidence for benefit found on this measure.

Despite widespread use of piracetam, the amount

V.2.18

Propentofylline

Kenneth Rockwood Key points

Propentofylline is available only experimentally or on a compassionate use basis in a few countries. In consequence several conditions apply, including use by specialists. A phase III program is under way in several countries, with one more pivotal trial planned in the US for use in Alzheimer’s disease (AD). Both the initial application and an appeal for use in these indications has been turned down by the European Agency for the Evaluation of Medicinal Products, largely on the grounds that not all the studies have demonstrated efficacy. Claims for the drug in AD and vascular dementia (VaD) have been made based on: • Improvement in cognition function. • Improvement in clinical global impression. • Modification of disease progression.

Rationale Propentofylline is a glial cell modulator with a number of effects. Chiefly, it is felt to interrupt signalling which activates neurotoxic effects of glial cells. (Schubert et al. 1997). In this context propentofylline has been shown in animals to

inhibit microglia proliferation in culture and to decrease the release of reactive oxygen intermediates and tumour necrosis factor. Stimulation of nerve growth factor has also been demonstrated in animals models of both AD and VaD (Schubert et al. 1997).

Evidence General comments To date, the clinical evidence for propentofylline consists of four small European studies carried out in the late 1980s and early 1990s, and four more recent phase III trials, of which two were carried out in Europe and in Canada and two were carried out in the US. Currently only the first four studies have been published in peer-reviewed journals, and they are the only data considered here in detail. Summaries of the four later studies, filed with the European Agency for the Evaluation of Medicinal Products, are publicly available through its website but have not been peer-reviewed. Briefly, these show that, in each indication, the studies carried out in Europe and in Canada showed statistically significant positive effects in favour of propentofylline, whereas the studies from the US showed no statistically significant differences between propen-

TREATMENT OF ALZHEIMER’S DISEASE 549

tofylline and placebo. (See also Future research, p. 553). The data from the four European studies have not all been published separately, but rather appear in the form of two meta-analyses (Kittner et al. 1997; Rother et al. 1998). One of these studies has been published separately (Marcusson et al. 1997). The company’s claim, based on the published data, for efficacy in AD and VaD rests on the combined results of all studies, with the argument being that the individual studies are too small to be considered separately for each indication. Each study was a phase III randomized placebo-controlled trial, using the same dose of propentofylline (300 mg tid 1 h before meals). In each trial, patients were included if they had AD, VaD, or mixed dementia of mild to moderate severity, and a Mini Mental Status Examination (MMSE) (Folstein et al. 1975) score of 15–25. Diagnostic criteria were similar in all trials (see below). The outcome measures were identical in all trials, although the designation of which were primary differed in one trial. The duration was 12 months in three trials, and 6 months in the other. Given the comparability of the trials, the acknowledged sample size problems when considering each indication (AD and VaD) separately, and the basis that the claim rests on the published meta-analyses, this chapter analyses the data presented in the overview reports. The overview reports indicate that, in total, 1273 patients (625 propentofylline, 648 placebo) were enrolled. Their mean age was 71.5 years, the mean duration of dementia was 3.3 years, and the mean MMSE score was 20.5. The studies in the 1980s necessarily were carried out prior to the current criteria for VaD being available. As reviewed elsewhere (Rockwood et al. 1999) the current criteria appear to be no better than the old criteria. They are based on consensus, not evidence, and some recent evidence (Hulette et al. 1997; Nolan et al. 1998; Rockwood et al. 1999 but not Esiri et al. 1997) appears to have undermined the very basis of ‘pure’ VaD in favor of mixed AD/VaD (reviewed in Rockwood 1997; Rockwood et al. 1999). In consequence, the lack of ‘current’ (but perhaps only transiently fashionable) criteria may not be as critical a problem as otherwise would be expected. While the studies included in all cases a cognitive/

neuropsychological test battery, and a global clinical assessment, they were carried out before the Alzheimer Disease Assessment Scaleacognitive subscale (ADAS-Cog) (Rosen et al. 1989) and Clinicians Interview Based Impression of Change (reviewed in Schneider et al. 1997) had established their current hegemony.

Alzheimer’s disease The combined Alzheimer arms of the four studies include 901 patients. The diagnosis of dementia in each trial was made using DSM-III-R criteria. AD patients were separated from mixed AD/VaD and VaD (the only dementia conditions allowed in the trials) based on the Hachinski Ischemia Score (HIS) (Hachinski et al. 1975) being 4 or less in two trials. In the other two, AD was diagnosed using the NINCDS-ADRDA criteria (McKhann et al. 1984) for probable AD. Cognition The chief test of cognitive function in each trial was the SKT (in German the Syndrom Kurztest; in English, the Syndrome Short Test) (Erzigkeit 1989). The test was chosen for its use in multicenter studies with varying languages. It comprises nine subtests, and performance is timed. The scores range from 0 to 27; scoring adjusts for age and for estimated premorbid intelligence quotient (IQ). A higher score equals a worse performance. At baseline, the mean scores were the same in both propentofylline and placebo-treated groups. The mean difference in the SKT scores between propentofylline and placebo was –0.5 points at 6 months (P < 0.05), and –0.8 points at 12 months (P < 0.001). A small difference (− 0.2 points) in favor of propentofylline was also observed at 3 months, but was not statistically significant. The MMSE was a secondary outcome measure in each trial. The mean change in the MMSE score (recall that better cognition is reflected in a higher score, so that a positive value represents a positive treatment effect) between propentofylline and placebo-treated patients was 0.4 points at 6 months, and 0.6 points at 12 months. Both were statistically significant (P < 0.05). The clinical importance of these changes has

550 CHAPTER V.2

been variably interpreted. Given the global clinical scores (see below) some might hold that these changes are clinically detectable. Another consideration in testing clinical significance is the magnitude of the effect. This can be interpreted through the ‘effect size’ in the calculation of which the mean differences between the active and placebo-treated groups is divided by a variance term (e.g. Cohen 1988). Based on the published data, we can calculate an effect size by taking the mean difference between the treatment and control groups, and divide by the pooled baseline standard deviation. In the case of propentofylline for the treatment of AD, the effect size of the SKT at 6 months is –0.08 and at 12 months is –0.13. The comparable results for the MMSE at 6 months is 0.13 and 0.26. Of note, with both measures the cognitive effect is larger with time, enhancing the interpretation of clinical importance. Both tests show similar trends, which also favors a clinically robust effect. Only one of these measurements, however, is greater than 0.20, which Cohen has suggested is the minimum clinically detectable effect. The data from the early studies must therefore be considered as showing statistically significant differences in cognition, but uncertain clinical detectability in cognitive performance. An alternative method of calculating the effect size is by using the standard deviation of the pooled change score as the denominator, sometimes called the standardized response mean. (Laing et al. 1990). While it might be expected that this would be a more valid estimate of the magnitude of the treatment effect in a longer-term dementia trial, the published data do not allow for this to be calculated. Clinical global impression of change All tests used two global clinical measures: item II of the Clinical Global Impression (CGI) which was a question on the degree of change, and which like the CIBIC-Plus is a Likert scale in which 1 = very much improved, and 7 = very much worse, and; the Gottfries Brane Steen (GBS) scale (Gottfries et al. 1982). The latter is a semi-structured interview scale in which 26 domains, each scored 0–6, are assessed by a clinician. Input from a care giver is

required, as well as direct patient observation. As with the SKT and CGI, a higher score represents worse function. For the pooled studies, both the CGI and the GBS were statistically significantly different in favor of propentofylline at 12 months. The GBS, but not the CGI, was statistically significantly different in favor of drug treatment at 6 months. The clinical importance of these findings is again subject to interpretation. It can be held that any statistically significant difference on a clinician’s global impression of change measure is self-evidently clinically important. As with the cognitive tests, the measures grow larger over time, and at 12 months, but not at 6, are self-reinforcing. An effect size cannot be calculated from the published data using the CGI item II. For the GBS, the effect size is –0.09 at six months, and 0.13 at 12 months. Behavior No published data. Functional activity Activities of daily living in all studies was tested using an informant scale (the Nurnberger AltersbeobachtungsskalaaNAB) as a secondary outcome measure. The NAB assessed 15 domains of (I) ADL function. A higher score in AD, the combined results from the four studies, showed a difference of −0.3 (P < 0.05) at 6 months and a difference of −0.5 at 12 months (P < 0.01). The effect sizes were −0.07 and −0.11, respectively. Dependency: institutionalization No published data available. Predicting response to treatment The published data do not allow firm conclusions to be drawn. Number needed to treat The published data do not allow any number needed to treat (NNT) data to be calculated. The

TREATMENT OF ALZHEIMER’S DISEASE 551

reader is referred to the effect size calculations presented above for an alternate means of quantifying clinical significance. Effect on disease progression One of the four studies included an 8-week withdrawal phase for those who had completed the initial, 12-month, placebo-controlled phase. In this first phase of this study, the CGI, GBS, SKT and MMSE had all showed statistically significant differences in the combined dementias analysis. At week 56, 8 weeks after drug withdrawal, these differences were maintained for the CGI, MMSE and SKT, increased for the GBS, and remained near statistical significance (P = 0.059) for the NAB. All measures except the NAB had effect sizes of about 0.20 or greater. There are no exact guidelines for the interpretation of disease modification claims. While the design of this study conforms to the recommendation of an expert consensus group in this regard (Bodick et al. 1997) some consider 8 weeks to be too short a time to test disease modifying effects. On the other hand, for a drug with such a short half-life, the persistence of treatment-differences for several weeks cannot plausibly be related to concurrent drug therapy. Again, the questions therefore revolves around whether the 8-week difference is clinically important. It appears to be at least clinically detectable (given the effect sizes) and is in contrast to withdrawal studies with donepezil (Rogers et al. 1998a,b). As clinical practice would not be to withdraw drugs that appear to be working, these data seem of most use in testing the hypotheses that propentofylline’s effects outlive its half-life. As this was the case in the one study reported, its overall importance will need to be based on the reproducibility of the claim.

Vascular dementia (including mixed AD/VaD) The combined VaD arms of the four studies include 359 patients. The diagnosis of dementia in each trial was made using DSM-III-R criteria. AD patients were separated from mixed AD/VaD and

VaD (the only dementia conditions allowed in the trials) based on the Hachinski Ischemia Score (HIS, Hachinski et al. 1975) being 4 or less in two trials. In the other two, AD was diagnosed using the NINCDS-ADRDA criteria (McKhann et al. 1984) for probable AD, and were considered in the AD indication. VaD was diagnosed using the NINDS/ AIREN criteria. Patients with mixed AD/VaD included in the VaD cases; 13 patients who clearly fit none of these categories are included in the overall reports of propentofylline efficacy, but were not considered in this chapter. Cognition The chief test of cognitive function in each trial was the SKT (see above). As noted, SKT scores can range from 0 to 27; scoring adjusts for age and premorbid IQ, and a higher score represents a worse performance. At baseline, the mean scores were the same in both propentofylline- and placebo-treated groups. The mean difference in the SKT scores between propentofylline and placebo was −0.5 points at 6 months and −0.7 points at 12 months. Neither difference was statistically significant. The MMSE was a secondary outcome measure in each trial. The mean change in the MMSE score (recall that better cognition is reflected in a higher score, so that a positive value represents a positive treatment effect) between propentofylline and placebo treated patients was 0.6 points at 6 months, and 0.9 points at 12 months; only the latter was statistically significant (P < 0.05). The clinical importance of these changes is not clear. While the global clinical scales did detect improvement (see below), and while the effects are consistent between cognitive scales, and increase over time, only the MMSE score at 12 months demonstrated an effect size large enough (0.29) to pass the threshold of clinical detection (~0.20). Clinical global impression of change All studies used two global clinical measures: item II of the CGI which was a question on the degree of change, and which like the CIBIC-Plus is a Likert scale in which 1 = very much improved and 7 = very much worse; and the Gottfries Brane Steen (GBS)

552 CHAPTER V.2

scale (Gottfries et al. 1982). The latter is a semistructured global clinical interview (see above). As with the SKT and CGI, a higher score represents worse function. For the pooled studies, both the CGI and the GBS were statistically significantly different in favor of propentofylline at 3, 6, and 12 months. The clinical importance of these findings seems more assured than in the case of AD. If statistically significant differences in clinical global impressions of change are held to be self-evidently clinically important, this is the case for propentofylline in VaD and mixed AD/VaD in these studies. As with the cognitive tests, the measures grow larger over time and are consistent between measures. An effect size cannot be calculated from the published data using the CGI item II. For the GBS, the effect size is −0.18 at 6 months, and −0.23 at 12 months, again suggesting that the difference is clinically detectable.

size calculations presented above for an alternate means of quantifying clinical significance. Working from these data, the NNT to achieve one patient with improvement above baseline at 12 months, over what might be expected with placebo treatment, for either AD or VaD, is approximately 15 (range 12.6–32.5). (Furukawa 1999; cf. Scholten et al. 1999).

Who should be considered for treatment? The criteria for inclusion were: For AD: probable AD using DSM-III-R criteria and an HIS < 4 (two studies); probable AD using DSM-III-R and NINCDS-ADRDA criteria (two studies). For VaD: (specified to allow mixed AD/VaD); dementia using DSM-III-R and HIS > 3 (two studies); dementia using DSM-III-R and NINDSAIREN (two studies).

Behavior No published data.

Who should be excluded from treatment?

Activities of daily living in all studies were tested using an informant scale, NAB, (Erzigkeit 1989) as a secondary outcome measure. The NAB assessed 15 domains of (I)ADL function. In VaD, the combined results from the four studies showed a difference of −0.2 at 6 months and a difference of −0.1 at 12 months (P < 0.01). The effect sizes were −0.04 and −0.02, respectively.

1 There is no specific contraindication beyond hypersensitivity to xanthine derivatives. 2 Pending further studies, concomitant use with antiplatelet and anticoagulants must be individualized. 3 Patients unlikely to adhere to the dietary/dosing requirements (1 h before tid on an empty stomach) are unlikely to benefit. The value of the treatment is unknown in: • Other dementia • Very early symptoms • Severe stage of the disease.

Dependency: institutionalization

Clinical pharmacokinetics

No published data available.

Propentofylline is a xanthine derivative. Absorption is of particular importance in the pharmacokinetics of propentofylline. The drug is inactivated by food, and must be taken 1 h before meals on an empty stomach.

Functional activity

Predicting response to treatment The published data do not allow firm conclusions to be drawn.

Adverse effects Number needed to treat The published data do not allow direct calculation of the NNT. The reader is referred to the effect

The most commonly reported side effects by the investigator felt to be related to propentofylline were: nausea (7–10% vs. 2–4% placebo); dizzi-

TREATMENT OF ALZHEIMER’S DISEASE 553

ness (6–9% vs. 3– 4% placebo); gastrointestinal pain (5% vs. 1–2% placebo); headache (5–7% vs. 1–3% placebo) and vasodilatation (5% vs. 1% placebo). An unusual symptom of the subjective experience of discoloration (dyschromotopsia) was reported rarely. In general, withdrawal due to adverse effects was seen in 13% of patients on propentofylline vs. 9% of patients on placebo. The total number of serious adverse events felt by the investigators to be related to the drug was two (0.3%) in the propentofylline group and five (0.8%) in the placebo group. The total number of deaths was 15 (2.0%) in the propentofylline group and 8 (1.0%) in the placebo group.

Starting/monitoring/stopping treatment No precise guidelines exist. The protocols to date follow start-up and withdrawal fully at the prescribed dose (300 mg po tid). In the withdrawal study, blinded abrupt discontinuation was not associated with an increase in adverse events.

V.2.19

Future research Future research is planned to test the reproducibility of the efficacy findings in AD and VaD. A more readily absorbed, longer-lasting formulation would be of use.

Summary Propentofylline, on the published data, has shown modest treatment benefits in AD and VaD. Its effect can be summarized as follows [Grade A-2]. 1 A modest improvement in cognitive performance, more evident for VaD and of uncertain clinical importance in AD. 2 Reduction in the rate of decline in cognitive performance, most evident for VaD. 3 Improvement in global clinical performance in AD and VaD. 4 There are statistically significant differences in activities of daily living, which do not cross the threshold of clinical detection.

Selegiline in the Treatment of Alzheimer’s Disease*

Mary Sano and Fadi Massoud Key point

In light of its modest benefits on cognition, behavior and function, the potential for significant drug interaction with most antidepressants, and the availability of alternatives such as vitamin E, selegiline cannot be recommended for routine use as first-line therapy in clinical practice. Selegiline might play a role for some patients based on individual circumstances.

Introduction Neurotransmitter dysfunction is thought to play a major role in the pathophysiology of Alzheimer’s *Permission to reproduce the figures used in this Chapter was explicitly obtained from Dr Jacqueline Birks who co-wrote the Cochrane Collaboration Review on selegiline.

disease (AD). In that context, selegiline, a monoamine oxidase-B (MAO-B) inhibitor, has been hypothesized as a potential agent for the treatment of AD. At the present time, selegiline is not approved in North America for the treatment of AD.

Rationale MAO-B is an enzyme that induces monoamine oxidation in the human brain. It accounts for 80% of human brain MAO and uses dopamine and phenylethylamine as substrates. MAO-B activity is increased in AD and is thought to contribute to the neurotransmission defects associated with the disease. At low doses (up to 10 mg daily), selegiline (l-deprenyl) is a selective irreversible inhibitor of MAO-B. Several mechanisms have been presented to explain the therapeutic effect in AD (Prichep et al. 1994): enhancement of neurotransmission in the mesolimbic neuronal systems through inhibition

554 CHAPTER V.2

of MAO-B, a stimulant effect on mood and arousal, reduction of neuronal apoptosis at concentrations too small to inhibit MAO-B, and neuroprotection by decreased production of oxidative free radicals.

Evidence The efficacy of selegiline for the symptomatic treatment of AD remains controversial (Birks & Flicker et al. 1999) which accounts for its low rate of prescription and the lack of approval for this indication in North America. Marginal or no overall effects are observed in clinical trials. The use of cross-over design with its inherent methodological drawbacks, and the use of different measurement scales and outcome measures make interpretation of the results difficult. Single-blind and open-label studies suggested that selegiline improved cognition, behavior, and function. Selegiline has been reported to be superior to l-acetylcarnitine, oxiracetam, and phosphatidylserine, but these studies involved small numbers of patients and brief durations of therapy ranging from 4 to 26 weeks. One study recruited a heterogenous population including patients with multi-infarct dementia further complicating interpretation of the results. Using a detailed and refined search strategy (see companion website for search strategy), 15 trials were found evaluating the role of selegiline in the treatment of AD. Inclusion criteria for these trials were: randomized, double-blind, placebo-controlled human efficacy trials, where treatment was given for more than 1 day. Results of these trials were pooled (Birks & Flicker et al. 1999) using weighted or standardized mean differences and 95% confidence intervals. All patients participating in these trials met standardized criteria for AD (McKhann et al. 1984; American Psychiatric Association 1987). The severity of the disease, as measured by the MMSE (Mini Mental Status Examination) scale, varied from 0 to 25 and the dose used was 10 mg daily. Details of the individual trials are displayed on the companion website.

Cognition Using standardized mean differences for the metaanalysis, the combined memory (Agnoli et al. 1990;

Piccinin et al. 1990; Mangoni et al. 1991; Agnoli et al. 1992) and cognitive tests showed improvement when compared to placebo. However, these findings were not confirmed in all studies focusing on cognitive function as a primary outcome measure (Burke et al. 1993; Riekkinen et al. 1994), or in studies using the MMSE as a measure of cognition (Burke et al. 1993; Riekkinen et al. 1994; Freedman et al. 1998). The two studies which used the Alzheimer’s Disease Assessment Scale-cognitive portion (ADAS-Cog) showed benefit compared to placebo when selegiline was used alone (Lawlor et al. 1997), or when it was added to pre-existing cholinergic medication (Schneider et al. 1993).

Mood and behavior Patients on selegiline showed improvement on some but not all measures of mood and behavior (Burke et al. 1993; Lawlor et al. 1997; Freedman et al. 1998). Studies including patients with moderate to severe dementia and already exhibiting behavioral manifestations seemed to show the most benefit.

Global rating There was no improvement in patients treated with selegiline on several global rating scales (Agnoli et al. 1990; Agnoli et al. 1992; Burke et al. 1993; Freedman et al. 1998) when the data was analysed using standardized mean differences.

Functional activity Only one trial assessed function as a primary outcome measure for treatment with selegiline. Sano et al. evaluated the role of selegiline alone, selegiline and vitamin E, vitamin E alone, and placebo on the progression of AD (Sano et al. 1997). Despite random allocation, baseline MMSE score, which was highly predictive of the primary outcomes, was higher in the placebo group than in the other treatment groups. Unadjusted analyses showed longer time to reaching the primary outcomes (time to occurrence of death, institutionalization, loss of the ability to perform basic activities of daily living, or severe dementia) in the selegiline group, but this was not statistically significant. However,

TREATMENT OF ALZHEIMER’S DISEASE 555

after adjustment for baseline MMSE, there was a significant delay to reaching those primary outcomes. Mangoni et al. (1991) showed that fewer patients markedly deteriorated on the Blessed Dementia Scale in the selegiline than in the placebo group at the end of their trial.

cyclic antidepressants, selective serotonin reuptake inhibitors (especially fluoxetine), and meperidine is contraindicated because it can precipitate the development of the serotonin syndrome which presents with hyperthermia, diaphoresis, shivering, tremor, myoclonus, seizures and even death.

Number needed to treat

Clinical pharmacokinetics

Few trials report the therapeutic response rate to selegiline. Therefore, numbers needed to treat (NNTs) were only calculated for functional activity from two studies. Sano et al. (1997) showed that 54% of the selegiline group and 69% of the placebo group reached their primary outcome yielding an absolute risk reduction of 15% and an NNT of 7. Mangoni et al. (1991) reported that 12.9% of patients in the selegiline group and 50% of those in the placebo group markedly deteriorated on the Blessed Dementia Scale yielding an absolute risk reduction of 37.1% and an NNT of 3.

After oral administration, selegiline is readily absorbed from the gastrointestinal tract. It is rapidly and completely metabolized by the liver to its active metabolites N-desmethyldeprenyl ( t 1 = 2 h), 1-amphetamine ( t 1 = 17.7 h), and 12 2 methamphetamine ( t 1 = 20.5 h). It is eliminated 2 by the kidneys. No pharmacokinetic information is available on selegiline or its metabolites in renally impaired individuals. Peak serum concentrations occur between 0.5 and 2 h of oral administration and the mean elimination half-life following a single oral does is 2 h. Under steady state conditions the elimination half-life increases to 10 h suggesting that a twice-daily dosing may be more appropriate. Administration is often recommended in the daytime (morning and afternoon) to avoid interference with sleep.

Who should be considered for treatment? The clinical inclusion criteria in the reviewed trials included: (i) probable AD (NINCDS-ADRDA criteria; (ii) MMSE between 0 and 25; (iii) Global Deterioration Scale between 3 and 5; (iv) Clinical Dementia Rating Scale of 1. The main study showing the efficacy of selegiline in delaying functional deterioration in AD patients also suggested an equal efficacy of vitamin E (Sano et al. 1997). Since vitamin E is less expensive and presents less risks of adverse effects and drug interactions, it might be preferable as first-line therapy for delaying progression of the disease. However, selegiline might be considered as second-line therapy in cases of hypersensitivity or intolerance to the side effects of vitamin E. The American Psychiatric Association has given selegiline a grade III recommendation (‘may be recommended on the basis of individual circumstances’) ‘. . . as an alternative to cholinesteras inhibitors in patients who are ineligible for, intolerant, or unresponsive to these agents.’(American Psychiatric Association 1997).

Who should be excluded from treatment? Concomitant administration of selegiline with tri-

Adverse effects At low doses (of up to 10–20 mg daily), selegiline is a selective MAOI-B inhibitor and avoidance of tyramine-containing foods or sympatomimetic medications is not necessary. Selegiline was well tolerated at the dose used in clinical trials (10 mg daily) leading to few withdrawals from treatment groups. The most common side effects include orthostatic hypotension, gastrointestinal symptoms, and psychomotor agitation (Mangoni et al. 1991; Freedman et al. 1998). Three patients (out of 68) in the selegiline treatment group and one subject (out of 51) in the placebo group withdrew in the study by Mangoni et al. (1991). In the study by Freedman et al. (1998), seven patients in the selegiline group and one subject in the placebo group withdrew during the double-blind phase. These drop-outs were unrelated to adverse effects of the medication. Sano et al. (1997), Agnoli et al. (1992) and Agnoli et al. (1990) found no statistically significant differences in side effects among the

556 CHAPTER V.2

Table V.2.26 Reproduced with permission from Update Software. Review: Selegiline for AD Comparison: Selegiline vs. control (change from baseline) completers Outcome: cognitive tests Experimental Experimental Control Control mean (SD) mean (SD) Study n n Memory tests 9 Agnoli 1990 5 Agnoli 1992 65 Mangoni 1991 10 Piccinin 1990 89 Subtotal (95%CI) Chi-square 2.91 (df = 3) Z = 3.36

−11.66 (23.50) −11.88 (14.20) −3.34 (9.80) −7.50 (16.20)

WMD (95%CI fixed)

Weight (%)

WMD (95%CI fixed)

−18.300 [−40.245, 3.645] −19.880 [−40.461, 0.701] −5.670 [−10.013, −1.327] −8.200 [−21.884, 5.484] −6.837 [−10.827, −2.847]

9 5 47 10 71

6.64 (24.00) 8.00 (18.70) 2.33 (12.70) 0.70 (15.00)

0.8 0.9 19.2 1.9 22.8

Mini Mental Status Examination (MMSE) 16 3.30 (8.00) Burke 1993b 0.00 (6.30) Freedman 1998 21 3.70 (6.70) Riekkinen 1994 35 72 Subtotal (95%CI) Chi-square 0.88 (df = 2) Z = 0.62

16 24 32 72

6.50 (8.70) −0.10 (7.60) 4.20 (7.11)

10.8 22.0 33.0 65.8

AD Assessment Scale—Cognitive (ADAS-Cog) Lawlor 1997 5 −2.66 (3.80) Subtotal (95%CI) 5 Chi-square 0.00 (df = 0) Z = 4.12

6 6

9.20 (5.70)

11.4 11.4

−11.860 [−17.508, −6.212] −11.860 [−17.508, −6.212]

100.0

−3.398 [−5.303, −1.492]

Total (95%CI) 166 Chi-square 20.17 (df = 7) Z = 3.50

149

−10

−5

0

5

−3.200 [−8.991, 2.591] 0.100 [−3.963, 4.163] −0.500 [−3.816, 2.816] −0.743 [−3.092, 1.605]

10

treatment and placebo groups of their trials. Three studies showed that selegiline was associated with few side effects, none of which resulted in dropouts (Agnoli et al. 1990; Piccinin et al. 1990; Burke et al. 1993). Two studies reported no significant side effects (Filip & Klaschka et al. 1994; Lawlor et al. 1997).

selegiline in subjects with mild to moderately severe disease. In light of its effects as an antioxidant and enhancer of neurotransmission, selegiline may have a role in the secondary prevention of AD. In that context, future trials should include patients in the prodromal stages of the disease (Mild Cognitive Impairment (MCI)).

Starting/monitoring/stopping treatment

Summary

The appropriate therapeutic dose in AD is 10 mg daily (in one or two doses) which is also the starting dose. Patients should be monitored regularly for appearance of adverse effects. Monitoring of laboratory tests is not necessary. Discontinuing selegiline should be considered if poorly tolerated or if it does not result in useful benefit in terms of cognitive performance and functional capacity.

Selegiline’s effect can be summarized as follows: [Grade A-2] 1 Modest improvement in cognitive performance. 2 Modest improvement in behavior. 3 Reduction in the rate of functional decline and institutionalization. 4 No improvement in clinical global impression. In light of its modest benefits on cognition, behavior, and function, and the potential for significant drug interaction with most antidepressants, and the availability of alternatives such as vitamin E, selegiline cannot be recommended for

Future research Most of the studies have evaluated the role of

TREATMENT OF ALZHEIMER’S DISEASE 557

Table V.2.27 Pooled results for Global Rating Scales from the Cochrane Collaboration Review (reproduced with permission from Update Software). Review: Selegiline for AD Comparison: Selegiline vs. control (change from baseline) completers Outcome: Global rating scales Experimental Experimental Control Control mean (SD) n n mean (SD) Study Clinical Dementia Rating (CDR) 17 Burke 1993b Subtotal (95%CI) 17 Chi-square 0.00 (df = 0) Z = 0.84

WMD (95%CI fixed)

Weight (%)

WMD (95%CI fixed)

16 16

2.60 (3.40)

7.8 7.8

−1.000 [−3.321, 1.321] −1.000 [−3.321, 1.321]

Gottfries Rating Scale for Dementia 9 −2.74 (11.70) Agnoli 1990 5 −2.00 (13.10) Agnoli 1992 Subtotal (95%CI) 14 Chi-square 0.07 (df = 1) Z = 0.19

9 5 14

−2.56 (5.80) 0.80 (13.90)

0.6 0.1 0.7

−0.180 [−8.712, 8.352] −2.800 [−19.542, 13.942] −0.720 [−8.322, 6.881]

Global Deterioration Scale Freedman 1998 21 Subtotal (95%CI) 21 Chi-square 0.00 (df = 0) Z = 0.00

24 24

0.10 (1.10)

91.5 91.5

0.000 [−0.676, 0.676] 0.000 [−0.676, 0.676]

100.0

−0.083 [−0.730, 0.564]

1.60 (3.40)

0.10 (1.20)

52 Total (95%CI) Chi-square 0.76 (df = 3) Z = 0.25

54

−10

routine use as first-line therapy in clinical practice. However, selegiline might be considered as secondline therapy on the basis of individual needs such as cases of hypersensitivity or intolerance to the side effects of vitamin E.

−5

0

5

10

Behavior • No reliable data available. Clinical Global Impression

Number needed to treat

• No reliable data available.

Cognitive improvement

Functional activity (delay in deterioration rate)

• No reliable data available.

• 3–7.H.

V.2.20

Thiamine

José Luís Rodríquez-Martin Key point There is inadequate evidence to recommend thiamine in the treatment of Alzheimer’s disease (AD).

Thiamine (often with other vitamins), either prescribed or as self medication, is taken by a few people for dementia and cognitive impairment in several countries in the hope of either ameliorating symptoms or slowing progression.

558 CHAPTER V.2

Table V.2.28 Pooled results for cognitive tests from the Cochrane Collaboration Review (reproduced with permission from Update Software). Alzheimer’s disease Thiamine (3 g/day) vs. placebo Cognitive function (MMSE)—change from baseline/competers analysis Thiamine Placebo Mean (SD) Mean (SD) n n Study 3 months −2.00 (9.06) 5 Nolan 1991 5 Subtotal (95%CI) Test for heterogeneity chi-square = 0.0 df = 0 Test for overall effect z = 0.53 p = 0.6 6 months −3.20 (9.20) 5 Nolan 1991 5 Subtotal (95%CI) Test for heterogeneity chi-square = 0.0 df = 0 p = 1 Test for overall effect z = 0.61 p = 0.5 9 months Nolan 1991 5 −4.40 (9.89) Subtotal (95%CI) 5 Test for heterogeneity chi-square = 0.0 df = 0 Test for overall effect z = 0.31 p = 0.8 12 months Nolan 1991 −6.20 (10.77) 5 Subtotal (95%CI) 5 Test for heterogeneity chi-square = 0.0 df = 0 Test for overall effect z = 0.76 p = 0.4

WMD (95%CI fixed)

Weight (%)

WMD (95%CI fixed)

5 5

1.00 (8.69)

100.0 100.0

−3.00 [−14.00, 8.00] −3.00 [−14.00, 8.00]

5 5

0.40 (9.58)

100.0 100.0

−3.60 [−15.24, 8.04] −3.60 [−15.24, 8.04]

5 5

−2.60 (8.58)

100.0 100.0

−1.80 [−13.28, 9.68] −1.80 [−13.28, 9.68]

5 5

−1.40 (9.09)

100.0 100.0

−4.80 [−17.15, 7.55] −4.80 [−17.15, 7.55]

−10

−5

Favors placebo

Rationale Vitamin B1 (thiamine) plays an important role in Wernicke–Korsakoff syndrome (a form of amnesia caused by brain damage occurring in long-term alcoholics who rely mainly on alcohol for nutrition). The acute syndrome is normally reversible but may proceed to profound dementia, although its progress can be stopped by a timely injection of a large dose of thiamine (Kril 1996). There have been suggestions that thiamine may also have a beneficial effect in AD (Butterworth et al. 1993; Mastrogiacoma et al. 1996; Mimori et al. 1996). From in vitro animal studies, there is evidence of a link between thiamine and the presynaptic release of acetylcholine (ACh). Thiamine binds to nicotinic receptors and may exhibit ACh activity. Biochemical abnormalities in thiamine-dependent

0

5

10

Favors thiamine

enzymes have been found in the brains of patients with AD (Gibson et al. 1988).

Evidence To evaluate the usefulness of thiamine in dementia we conducted a review. There are several nonrandomized studies relating vitamins, particularly thiamine, with cognitive functioning. A study that compared the intake and functional levels of vitamins B6, C and B1, in 15 pairs of AD and normal subjects, found a tendency for the Alzheimer’s group to show more B1-deficiency than in controls, despite both groups having a normal intake (Oluwafemi Agbayeba et al. 1992). Another study found that taking longterm vitamin supplements may influence cognitive functioning (Benton et al. 1995). These observational studies are, however, prone to substantial bias. A systematic review using a detailed search strat-

TREATMENT OF ALZHEIMER’S DISEASE 559

Table V.2.29 Result for the ADAS-Cog (selegiline + tacrine or physostigmine) vs. (placebo + tacrine or physostigmine) from the Cochrane Collaboration Review (reproduced with permission from Update Software). Review: Thiamine for AD Comparison: Thiamine vs. control Outcome: Cognitive function (MMSE)—change from baseline Experimental Experimental Control mean (SD) n n Study At 3 months 5 Nolan 5 Subtotal (95%CI) Chi-square 0.00 (df = 0) Z = 1.66 At 6 months 5 Nolan 5 Subtotal (95%CI) Chi-square 0.00 (df = 0) Z = 6.32 At 9 months 5 Nolan 5 Subtotal (95%CI) Chi-square 0.00 (df = 0) Z = 3.00 At 12 months Nolan 5 Subtotal (95%CI) 5 Chi-square 0.00 (df = 0) Z = 7.99

Control mean (SD)

WMD (95%CI fixed)

WMD (95%CI fixed)

1.00 (0.95)

5 5

2.00 (0.95)

100.0 100.0

−1.000 [−2.178, 0.178] −1.000 [−2.178, 0.178]

−0.60 (0.95)

5 5

3.20 (0.95)

100.0 100.0

−3.800 [−4.978, −2.622] −3.800 [−4.978, −2.622]

2.60 (0.95)

5 5

4.40 (0.95)

100.0 100.0

−1.800 [−2.978, −0.622] −1.800 [−2.978, −0.622]

1.40 (0.95)

5 5

6.20 (0.95)

100.0 100.0

−4.800 [−5.978, −3.622] −4.800 [−5.978, −3.622]

−10

−5

0

Favors placebo

egy (see website for details) found only three randomized trials assessing the role of thiamine in patients with ‘possible’ or ‘probable’ AD of mild to moderate severity (Rodríguez et al. 1999). The inclusion criteria were randomized, unconfounded, double-blind, placebo-controlled efficacy trials in humans where treatment had been administered for more than 1 day. Of the trials that met these criteria, two were unreliable because of cross-over designs without washout periods and without data available from the first treatment period. The one parallel trial of 1 year’s duration contained only 15 patients, of whom 33% failed to complete the study, with a lack of intention-to-treat analyses and possible imbalance of important prognostic variables between the treatment and placebo groups (Nolan et al. 1991). Only cognitive performance measures were assessed and no side-effect data were presented. Results did not favour thiamine.

Who should be considered for treatment? Nobody at present.

Weight (%)

5

10

Favors thiamine

Adverse effects Controlled data from trials in dementia not available.

Starting/monitoring/stopping treatment Not relevant.

Future research There are so little data that the role of thiamine in AD remains essentially untested in good quality trials. Therefore, it would be reasonable to consider it as a second or third therapy in a factorial trial.

Summary There is insufficient evidence to recommend the use of thiamine in AD. The results are consistent with thiamine producing harm, no change or improvement in cognitive measures.

560 CHAPTER V.2

Summary, Practical Recommendations and Opinions on Therapies for Cognitive Symptoms and Prognosis Modification

V.2.21

Nawab Qizilbash and Lon S. Schneider Overall summary Beneficial therapies

Table V.2.30 Therapies beneficial for the treatment of cognitive symptoms and prognosis modification. Donepezil

NNT NNH

Rivastigmine

NNT NNH

Galantamine

NNT NNH

Tacrine

NNT

NNH

9 (8–14) for a 4-point or more improvement in ADAS-Cog at 6 months 8 (6–15) for any improvement on a clinical global scale at 6 months 11 (7–15) for one withdrawal at 10 mg/day over 6 months 12 (8–20) for a 4-point or more improvement in ADAS-Cog at 6 months 15 (8–17) for any improvement on a clinical global scale at 6 months 5 for one withdrawal at 6–12 mg/day 6 for a 4-point or more improvement in ADAS-Cog at 6 months on 32 mg/day 13–50 for any improvement on a clinical global scale on 32 mg/day at 6 months 4–8 for one drop-out at 32 mg/day 30 for a 4-point or more improvement in ADAS-Cog at 6 months 10 for any improvement on a clinical global scale at 3 months 40 for ‘moderate’ or ‘marked’ improvement on a clinical global scale at 3 months 4 (withdrawal over 3 months)

NNH, number needed to harm; NNT, number needed to treat.

Probably beneficial therapies Table V.2.31 Therapies that are probably beneficial for the treatment of cognitive symptoms or prognosis modification.

Vitamin E

NNT: 16 at 1 year; 8 at 18 months to delay clinical milestones Delay of 71 days in clinical milestones at 2 years NNH: 44 (for loss to follow-up) at 2 years.

Selegiline

NNT: 17 at 1 year; 9 at 18 months to delay clinical milestones Delay of 102 days in clinical milestones at 2 years NNH: Not appropriate as more drop-outs observed in the placebo group at 2 years

Gingko biloba

NNT: 6 for a 4 points or more improvement in ADAS-Cog at 6 months 6 for any improvement on a clinical global scale at 6 months NNH: Not appropriate as drop-outs on placebo were greater than in the Gingko group

NNH, number needed to harm; NNT, number needed to treat.

TREATMENT OF ALZHEIMER’S DISEASE 561

Therapies of uncertain efficacy Table V.2.32 Therapies where effectiveness is uncertain for treatment of cognitive symptoms and modification of prognosis. Aspirin Hormonal therapy Hydergine Nimodipine Non-steroidal anti-inflammatory drugs Piracetam

Therapies unlikely to be beneficial Table V.2.33 Therapies unlikely to be beneficial for treatment of cognitive symptoms and modification of prognosis. Acetyl-L-carnitine Nicotine Thiamine

Therapies with problems of toxicity or development Table V.2.34 Potential therapies for treatment of cognitive symptoms and prognosis modification where there are problems with toxicity or development. Therapy

Problem

Cycloserine Metrifonate Propentofylline

Ineffective Toxicity Small effect dosing 3 times per day on empty stomach, development stopped Development stopped Development stopped

Idebenone Epstagmine

Aims The aims of this chapter are to: 1 Summarize the clinical effects of therapies detailed as narrative systematic reviews in the preceding chapters of this section. 2 Review the recommendations of these therapies in recent guidelines. 3 Provide the clinical context for the prescription of therapies.

4 Provide personal practice recommendations in the face of inadequate evidence from an American and a European clinician, which differ in places in the face of inadequate good evidence. 5 Provide clinically useful treatment algorithms.

Methods of this review 1 Review of the systematic reviews contained in the preceding chapters, which have used evidencebased methods to search, identify, select, appraise and summarize the results of the benefits and harms from therapies for AD. 2 Review of individual trials from the preceding systematic reviews (plus other new trials) with data at 5–7 months or beyond, which meet the criteria of being unconfounded, randomized, double-blind and placebo-controlled, and which used standard or clinically meaningful outcome measures. 3 Review of recent guidelines (1997–2000) identified by search of Medline, the DARE database and website search engine (Lycos) using the words ‘dementia’ or ‘Alzheimer’ plus ‘guideline’, with selection of those that used explicit and evidencebased methods to reach their recommendations. Only two guidelines published during 1997–2000 fulfilled our criteria (APA 1997; Eccles et al. 1998). Some guidelines mentioned ‘review of the world literature’ but provided no explicit methods of how the data were sought, appraised and summarized (Small et al. 1997). Further indications of the lack of evidence-based methods employed were found in the guideline by Small et al. 1997. Statements such as ‘tacrine and donepezil, . . . may also enhance [clinical and family assessments and] activities of daily living’ and ‘prolonged cholinergic therapy may delay nursing home replacement’, without there being reference to the lack of good evidence to support either of these two statements. Guidelines published before 1997 were excluded, as tacrine was the only approved antiAlzheimer drug licensed by several Western regulatory agencies. Guidelines that did not discuss therapy were also excluded from further review. This paucity of evidence-based guidelines is consistent with the lack of an explicit evidence-base for most guidelines found in the UK (Harvey 1999).

562 CHAPTER V.2

Methods of analysis

Benefits

1 We carried out calculations from published data using standard techniques: effect sizes; number needed to treat (NNT); number needed to harm (NNH); and pooled estimates of continuous and binary data. 2 Continuous data were categorized by an improvement of 4 points or greater on the Alzheimer’s Disease Assessment Scale-cognitive subsection (ADAS-Cog), when these results were reported. 3 L’Abbe plots were drawn with standard regression techniques (weighted by the sample sizes of the trials) to calculate the slope of the association between the placebo and treatment response. 4 Standard tests of heterogeneity were used to detect significant differences between trial results.

NNT (a) Cognitive improvement, 4 points or more at 6 months on the ADAS-Cog scale: 9 (5–186, 95%CI). (b) Any improvement on the Clinical Global Impression Scale at 6 months. For 10 mg/day, 8 (6–15, 95%CI); for 5 mg/day, 11 (7–15, 95%CI). (c) Improvement in function: No meaningful data available. (d) Nursing home placement: No data available.

Practical summary of beneficial or probably beneficial drugs used in practice Donepezil Practice recommendations General. Given its mild safety profile, once-daily dosing, easy titration and data at 1 year, donepezil is often suggested as the cholinesterase inhibitor of first choice and is consistent with some earlier guidelines (APA 1997; Small et al. 1997). However, others give it equal place with other cholinesterase inhibitors, with the exception of tacrine. Personal practice. In the US it is currently the most commonly prescribed cholinesterase inhibitor. In Europe it is also the first-line agent. In some European countries such as the UK, it was not reimbursed by the state and needed to be purchased with a private prescription, though this situation has recently changed due to the UK NICE (National Institute for Clinical Excellence) guidelines (NICE, 2001) for donepezil (and rivastigmine and galantamine). It is commenced at 5 mg/day and increased to 10 mg/day after 1 month. Although it is recommended that it is administered in the evening to reduce side effects, it can be given in the morning, which can help those who develop insomnia with the drug.

Harm Common symptomatic adverse effects are dose related and include: gastrointestinal: nausea, vomiting, diarrhea, anorexia and weight loss. Weight loss may occur over longer periods of time (Rogers & Friedhoff, 1998). Drug interactions. Drugs that inhibit the isoenzyme CYP3A4 such as ketoconazole, itraconazole, and erythromycin may raise plasma concentrations of donepezil, and by those that inhibit the isoenzyme CYP2D6 such as fluoxetine and quinidine. Enzyme inducers such as rifampicin, phenytoin, carbamazepine and alcohol may reduce plasma concentrations. NNH. Number needed to be treated for one withdrawal: at the 10 mg per day dose, 11 (7–34, 95%CI) need to be treated for one withdrawal. Comments. All data relate to outpatients with mild to moderately severe symptoms of AD. No data are available in severe AD or inpatients.

Rivastigmine Practice recommendations General. Rivastigmine was the second or third cholinesterase inhibitor introduced in most countries. Because it is prescribed twice per day and requires at least a two step dosage titration, some consider this to be a second-line cholinesterase inhibitor after donepezil or galantamine. Others, however, consider it on a par with the other cholinesterase inhibitors and as having theoretical advantages due to its effects on subtypes of acetylcholinesterase and on butrylcholinesterase.

TREATMENT OF ALZHEIMER’S DISEASE 563

Personal practice. The drug is administered twice daily with food, starting at 1.5 mg bid and increasing at a minimum of 2-weekly intervals to a target dose of 4.5 mg bid within an effective dosage range of 3 mg bid to 6 mg bid, and may be adjusted up or down depending on tolerability.

Personal practice. The authors have limited personal experience with this compound. As they gain experience over time, and from discussion with other experts, the website will provide more clinical guidance. Benefits

Benefits NNT (a) 4 points or more at 6 months on the ADASCog scale: 12 (8–25, 95%CI). (b) Any improvement on the Clinical Global Impression (CGI) Scale: 15 (9–59, 95%CI). (c) Any improvement in function: No meaningful data available. (d) Nursing home placement: No data.

NNT (a) 4 points or more at 6 months on the ADASCog scale: 6. (b) Any improvement on the CGI scale at 6 months: 13–50. (c) Improvement in function: No meaningful data available. (d) Nursing home placement: No reliable data. Harm

Harm Common symptomatic adverse effects are dose related and include: gastrointestinal: nausea, vomiting, diarrhea, anorexia and weight loss. Monitoring of patients’ weight during treatment is recommended. Female patients have been found to be more susceptible to nausea, vomiting, anorexia and weight loss. Drug interactions. None listed in data sheet. NNH. Number needed to be treated for one withdrawal due to side effects: 4–8. Comments. All data relate to outpatients with mild to moderately severe symptoms of AD. No data available in severe AD or inpatients.

Galanthamine

Common symptomatic adverse effects are dose related and include: gastrointestinal: nausea, vomiting, diarrhea, anorexia and weight loss. Less than 10% of patients had symptoms sufficiently severe that led to withdrawal from the studies. Drug interactions. There is little information in the data sheet regarding drug–drug interactions. NNH. Number needed to be treated for one withdrawal: 4. Comments. All data relate to outpatients with mild to moderately severe symptoms of AD. No data available in severe AD or inpatients.

Tacrine Practice recommendations

Practice recommendations General. Galanthamine was first marketed in most countries in 2001. Therefore, practice recommendations are limited. The clinical data as summarized below show a drug of similar tolerability and efficacy to donepezil and the other cholinesterase inhibitors. Administration requires bid dosing and one dosage increase. Provisionally it can be considered on an equal level as a first-line medication. A theoretical consideration, that may or may not be demonstrated to have clinical importance, is its presynaptic nicotinic modulating effects.

General. In the face of other drugs with similar efficacy that are easier to use without the need for monitoring of liver enzymes, it is not recommended as a first-line drug. This is consistent with published guidelines (APA 1997). Personal practice. In the US it might be used as third-line treatment in those that cannot tolerate or do not show efficacy with other cholinesterase inhibitors, and where adequate monitoring can be assured. Where it has been well tolerated with apparent benefits, it is continued. It is not available in the UK and some other European countries.

564 CHAPTER V.2

Tacrine is used to a very slight extent in the US with only 5000 new prescriptions in 1998. Patients who continue to receive tacrine have received it for a long time. Benefits The most thorough meta-analysis, including 12 trials with central analysis of individual data on 1984 patients, found that cognition and clinical global change were clearly evident. Effects on behavior and function were doubtful. The highest dose (160 mg/day) provided greatest benefit. NNT (a) 4 points or more at 6 months on the ADASCog scale: approximately 30 patients need to be treated at 160 mg/day for one patient to benefit. (b) Any improvement on the CGI scale: approximately 10 at 3 months. (c) ‘Moderate’ or ‘marked’ improvement on the CGI scale: approximately 40 at 3 months. (d) Improvement in function: No meaningful data available. (e) Nursing home placement: No reliable data. Harm Common symptomatic adverse effects are doserelated and include: gastrointestinal: nausea, vomiting, diarrhea, anorexia and weight loss; myalgia. Less than 10% of patients had symptoms sufficiently severe that led to withdrawal from the studies. Liver enzyme elevations are mainly reversible. Drug interactions. Anticholinergic agents, cimetidine, cigarette smoking, theophylline, neuromuscular blocking anaesthetic drugs. NNH. Number needed to be treated for one withdrawal: approximately 4. However, this figure is likely to be much greater (which is better) as the trial data do not reflect current clinical practice as recommendations on the seriousness and management of raised liver enzymes have changed much since the trials were performed. The concern about raised liver enzymes has been diluted by further clinical experience, which is shared by the authors. Comments. All data relate to outpatients with mild to moderately severe symptoms of AD. No data available in severe AD or inpatients.

Gingko biloba Practice recommendations General. The most widely prescribed medication for dementia in Germany but not yet recommended in guidelines. Not indicated with antithrombotics and anticoagulants. Not received approval from regulatory authorities (FDA and EMEA) for this indication. Personal practice. We checked the particular preparation, as there are several and they differ from those used in the trials. We find use is limited by a relative contraindication with aspirin. We reserve this drug for patients who have failed with other therapies, as drop-out in the trials was very high although the benefits appear similar to cholinesterase inhibitors. Benefits NNT (a) 4 points or more at 6 months on the ADASCog scale: 6. (b) Any improvement on the CGI scale at 6 months: 6. (d) Improvement in function: No meaningful data available. (c) Nursing home placement: No reliable data. Harm Adverse effects are few and only hemorrhage has been reported. Drug interactions. Agents that have an effect of prolonged clotting: warfarin, aspirin, and vitamin E. NNH. Number needed to be treated for one withdrawal not appropriate as the placebo group fared worse than the Gingko groups in the trials. Comments. Data relate to outpatients with mild to moderately severe symptoms of AD. No data available in severe AD or inpatients.

Vitamin E Practice recommendations General. There has only been one trial assessing the clinical effects of vitamin E versus placebo in

TREATMENT OF ALZHEIMER’S DISEASE 565

moderate to mildly severe AD outpatients. This trial found that vitamin E had an effect on prolonging survival in the community by approximately 6 months, and an effect on activities of daily living. There was no effect on cognition. The trial was underpowered and significant results were dependent on the analysis used. Vitamin E in the 1000 IU bid dosage used over an average of nearly one and a half years appeared safe, with a slight excess of falls. Thus, although evidence for its efficacy is not reliable or yet confirmed by supporting trials, its safety profile is such that it can probably be recommended. Personal practice. We use vitamin E for most people with probable and possible AD, except among very severe or institutionalized patients where a delay of further disability would not be appropriate, or with patients reluctant to take medications. We use it at 1000 IU bid because that is the clinical trial evidence and the mechanism of therapeutic action in AD is not known in vascular patients. Benefits NNT (a) 4 points or more at 6 months on the ADASCog scale: ∞ (this measure was not statistically significant in the trial). (b) Improvement on the CGI scale. Not appropriate (the CGI was not used in this trial). (c) Nursing home placement (and dependency or death). Using approximate values for survival in the placebo group, the NNT at 12 months was 16, and 8 at 18 months, based on the unadjusted analysis. Delay of 71 days in clinical milestones at 2 years. Harm Symptomatic adverse effects were uncommon. Falls and syncope were more frequent in the placebo group. Large doses may cause diarrhea, abdominal pain, and other gastrointestinal disturbances, and have also been reported to cause fatigue and weakness. Less than 10% of patients had symptoms sufficiently severe that led to withdrawal from the studies. Drug interactions. Warfarin and Gingko biloba.

NNH. Number needed to be treated for one withdrawal: 44 (for loss to follow-up) at 2 years. Comments. All data relate to one clinical trial of outpatients with probable AD with moderate to severe disease. Only this agent and selegiline (same trial) have truly meaningful outcomes with likely modification of prognosis, and long-term data at 2 years.

Selegiline Practice recommendations General. There has only been one clinical trial that has assessed selegiline in moderately severe AD outpatients. This trial showed that selegiline had an effect on prolonging survival in the community by approximately 6 months, and an effect on activities of daily living. There was no effect on cognition. The trial was underpowered and significant results were dependent on the analysis used. Selegiline, in the 5 mg bid dosage used over an average of nearly 18 months, appeared safe. Other trials suggest equivocal results on cognition over the short-term with selegiline. Personal practice. We tend not to use selegiline, largely because the evidence for its efficacy alone or in combination with vitamin E is no stronger than for vitamin E alone. Whereas vitamin E may have other salutary effects on health, additional therapeutic effects of selegiline in low doses may be only relevant for Parkinson’s disease. Concomitant therapy with antidepressants complicates its use. Thus, at present, we regard selegiline as secondline therapy for prognosis modification. Benefits NNT (a) 4 points or more at 6 months on the ADASCog scale: ∞ (this measure was not statistically significant in the trial). (b) Any improvement on the CGI scale: Not appropriate (the CGI was not used in this trial). (c) Nursing home placement. Using approximate values for survival in the placebo group, the NNT is 17 at 1 year and 9 at 18 months, based on the unadjusted analysis. Delay of 102 days in clinical milestones at 2 years.

566 CHAPTER V.2

Harm

1-year trials

Common symptomatic adverse effects are dose related and include: orthostatic hypotension, gastrointestinal symptoms and psychomotor agitation. Falls and syncope were few, but more frequent than in the placebo group. Evening doses should be avoided to reduce insomnia and abnormal dreams. Less than 10% of patients had symptoms sufficiently severe that led to withdrawal from the studies. Drug interactions. Selegiline can usually only be used safely without dietary restrictions at doses of up to 10 mg daily. Two weeks should elapse between stopping selegiline and commencing tricyclic antidepressants or SSRIs. Conversely, patients who have recently received these antidepressants should not be administered selegiline and at least 5 weeks should elapse between discontinuing fluoxetine and starting treatment with selegiline iproniazid and moclobemide pethidine and ephedrine. NNH. Number needed to be treated for one withdrawal: Not appropriate as more drop-outs observed in the placebo group at 2 years. Comments. All data relate to probable AD with moderate to severe disease. Only this drug, selegiline, and vitamin E (same trial) have truly meaningful outcomes with likely modification of prognosis, and long-term data at 2 years.

Then results of these studies will be posted on the website of this book once they are published.

Comparison of benefits and harms of approved symptomatic therapies A summary comparison of the benefits and harms of approved symptomatic therapies at approximately 6 and 12 months. We have chosen ADAS-Cog and clinical global change scales to compare efficacy as most current and approved agents have these data available, being a requirement for regulatory authorities. We have also documented function, which is also now being considered by regulators though they have not been uniformly used and their interpretation and clinical significance is fraught with problems.

Treatment considerations It is important to re-emphasize that drug therapy comprises only part of a multifaceted management plan of a patient with AD or other dementia, that changes with time (see Chapters IV.1–4). Also, even though the focus of this chapter is symptomatic treatments for cognitive symptoms and prognosis modification, of equal or more importance is the treatment of or prevention of the emergence of behavioral conditions, and other medical problems (see Section VI). The therapies considered in this review are donepezil, rivastigmine, galanthamine, tacrine, Gingko biloba, vitamin E and selegiline, which are widely used in many countries. In considering therapy, it is clear from Figs V.2.3–4 that current therapies provide modest benefits in terms of symptom improvement over the short term and modulation of symptom worsening over a 6–12-month period. Therefore, a thorough discussion is required with the carer, family, and, where possible, the patient, of the alternative management options available including the option of not taking or delaying drug therapy. The modest benefits need to be balanced against the potential to do harm from side effects (and inconvenience and cost, where applicable), both in the short term and long term, with continued use of therapy beyond the period of the controlled trials. Hence, it is necessary to be both realistic and seek the values attached to the potential benefits and harms that may arise from therapy. An important element in communication with the care giver and patient is the description of the benefits that may arise, as these are likely to be the main drivers of the decision to treat or not. Clearly, drugs need to be available and they may not be available in (or parts of) even rich, developed countries. Cost-effectiveness and cost-utility analyses are being increasingly used to decide whether health services or insurers will pay for such therapies. We do not consider this as a valid

TREATMENT OF ALZHEIMER’S DISEASE 567

Dubois 99.5

Dubois 99.50 Rosler 99.4 Burns 99.5 Tariot 00.8

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95% Confidence interval for ADAS-Cog (Tx−placebo)

inhibitors (all doses) in the 5–7 month trials. Change in ADAS-Cog from baseline between treatment and placebo groups. Point estimates and 95%CIs. Results ranked by size of treatment effect. Pooled estimate marked as ‘meta’. Bars et al. 1997 data excluded from the pooled estimate. The average pooled effect on ADAS-Cog is 2.25 (95%CI: 3.36–1.29). Numbers before the decimal point on the graph refer to the year of publication, numbers after the decimal point refer to the maximum dose.

Fig. V.2.4 Effect on ADAS-Cog between cholinesterase

approach, at present, for the very simple reasons that these analyses are flawed and subject to such imprecision that they should be given the weight in decisions that they scientifically deserve. The basic reasons for the flaws and imprecision in these analyses, arise from two fundamental facts. 1 Cost-effectiveness analyses are hampered by the highly selected and non-representative outpatients included in the trials, and the use of primary outcomes that lack clinical meaningfulness. These analyses then must rely on extrapolation of effects and secondary economic modelling based on, for example Mini Mental State Examination (MMSE) scores, as a surrogate for functional impairment, disability and nursing home placement. A possible

exception is the vitamin E and selegiline randomized trial where such outcomes were measured directly. 2 Cost-utility analysis is flawed by the inability to reliably assign values on the types of benefits encountered by patients (or carers) with current symptomatic therapies for dementia through representative samples of the general population, let alone by the patients themselves. The cost-effectiveness of vitamin E and selegiline is self-evident, given that they are probably beneficial. (However, whether or not patients whose nursing home admissions were delayed as a result of treatment continued to benefit in the nursing home is not known.)

inhibitors (lower doses) in the 5–7 month trials. Change in ADAS-Cog from baseline between treatment and placebo groups. Point estimates and 95%CIs. Results ranked by size of treatment effect. Pooled estimate marked as ‘meta’. Bars et al. 1997 data excluded from the pooled estimate. The average pooled effect on ADAS-Cog is 1.43 ( 95%CI: 2.51–0.35). Numbers before the decimal point on the graph refer to the year of publication, numbers after the decimal point refer to the maximum dose.

568 CHAPTER V.2

Rosler 99.12 Dubois 99.80 Rogers 98.10 Wilcock 00.24 Burns 99.10 Tariot 00.24 Wilcock 00.32 Raskind 00.32 Corey 98.12 Raskind 00.24 Knapp 94.160 Meta −8

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Fig. V.2.5 Effect on ADAS-Cog between cholinesterase

inhibitors (higher doses) in the 5–7 month trials. Change in ADAS-Cog from baseline between treatment and placebo groups. Point estimates and 95%CIs. Results ranked by size of treatment effect. Pooled estimate marked as ‘meta’. Bars et al. 1997 data excluded from the pooled estimate. The average pooled effect on ADAS-Cog is 2.87 (95%CI: 4.0–1.73).

Symptomatic therapy The results of trials from Fig. V.2.3 suggest that there is little reliable evidence of important differences in effects on cognition, clinical global changes, function and side effects among the newer cholinesterase drugs. The results are only secure from 6 months to about 1 year with controlled data and the possibility of loss of effect, increase in significant side effects or tolerance appearing later cannot be discounted. From the trials of symptomatic treatments, it would seem that there are two major benefits. 1 A symptomatic global improvement in the patient over several months, as judged by the clinical global change scales (as compared with placebo)a irrespective of whether this arises from cognitive, functional, behavioral or social improvements, or

a combination of all these domains. This global assessment by an experienced clinician, while consistent across clinical trials of effective medications, is difficult to convey in specific or practical terms to physicians, patients, consumers or insurers. The only guide here is clinical experience and descriptions from the trials. 2 A delay in the decline of cognitive performance or activities of daily living compared to placebo over the course of several months. This is also difficult to convey since treated patients overall as a group are declining in these functions even while benefiting from medication. Thus it is difficult to assess whether a particular patient is benefiting. One simple but tangible method is to ask the carer (and patient when appropriate) to compare what the patient was like 6 months ago and now. The difference may represent the benefit that might be obtained with therapy. Other more complicated ways to relate these cognitive benefits is to consider the yearly decline that might have occurred in the average patient and by how much it would decline with therapy. However, this interpretation is problematic as the rate of decline is highly variable and is dependent on the severity of disease; it is difficult to predict in individual patients, previous decline is a poor guide of future decline and lacks practical meaning for patients and carers, except to suggest that prognosis might be altered. However, this benefit should not be represented as a change in the evolution of the disease or prognosis, for which no good evidence yet exists. Hence, the benefits may be purely short-term, in which case the symptomatic global benefits may be the overriding consideration in the decision to treat. Once the benefits have been discussed, the balance of good vs. harm needs to be assessed. One easily intelligible way to communicate the benefits and harms is by use of NNT and NNH. Unfortunately, with cholinesterase inhibitors different NNTs have been produced by different authors for the same trials (e.g. an NNT of 40 for a greater than 3.4-point improvement in ADAS-Cog (Eccles et al. 1998), while others suggest NNTs ranging from 4–10 for a 4-point improvements in ADASCog (Allen 1999) for donepezil, owing to different definitions of outcome and methods of analysis.

TREATMENT OF ALZHEIMER’S DISEASE 569

We have attempted to provide intention to treat (ITT) analyses where possible, and by only comparing trials with approximately 6 month data, have strived to compare like with like. Thus we feel that the values in our tables are generally comparable across the range of drugs. We also conclude that is difficult to make a case for differences in benefits in cognition between the cholinesterase drugs and any differences observed between the trials can easily be explained by the play of chance. The data from Gingko biloba indicate less benefit on cognition than that observed with the cholinesterase inhibitors. The pooled values for the ADAS-Cog changes between drug and placebo from baseline of 2.25 overall and 2.87 for higher doses from Fig. V.2.3 and Fig. V.2.5, and 1.43 for low doses from Fig. V.2.4 are probably the most reliable values for the effects at 5–7 months, if and until individual-patient data meta-analyses appear. These values are group averages and can be adjusted to the individual patient by considering the influence of patient characteristics. For example, the NNT may well be less favorable for the group of patients who are unable to achieve the maximum dose used in the trials. A less favorable result than found in the trials is likely where compliance is suboptimal and less than the figure achieved in the trials, and use in those with possible AD, or in patients who have more severe disease than included in the trials. Clearly, if benefits are related to severity of disease, then the NNT will change with disease stage over time in an individual patient. The NNH may be less favorable for those with co-medications that could give rise to interactions, drug–disease interactions for those with comorbid diseases, and those who are subject to less supervision. The value of the possible likely benefits can also be approximately valued, as can the possible harms. The final ratio of NNT : NNH can be used to decide the appropriate course of action for an individual patient. Details of how, in principle, this clinical adjustment can be performed from the average figures produced in trials is found in Chapter I.7. The values can also be recalculated with the extremes of the confidence intervals of the NNT and NNH to assess how robust the decision is with the degree of imprecision contained in the trials. However, where a drug is reasonably safe,

with tolerable or transient side effects which are wholly reversible on withdrawal, the overriding determinant of this equation is the value the care giver and patient attach to the benefits, and the inconvenience of administration and monitoring that will be tolerated. In situations where the care givers or patients are personally paying for the cost of the drugs, it may be worthwhile to discuss opportunity costs, e.g. how would the patient benefit if the (approximately) US$1600 (£1000) per year required to purchase the drug were spent on buying an equivalent amount of help in the home or by taking holidays? This could also be factored into the equation of NNT vs. NNH. For the currently available drugs with good tolerability, these refined calculations do not usually change the decisions that might have been taken, but make the nature of the benefits (and harms) explicit during the discussions, help the approach of patients and carers to the problems and reinforce realistic expectations.

Patient eligibility and suitability It is clearly wrong to restrict the benefits of therapy to only those individuals who are identical to those in the trials, as the mechanism of action of the drug is likely to be similar for patients who have similar deficits. Strict eligibility criteria are generally the following (from the trials): • McKhann criteria for ‘probable’ AD, or the substantially similar DSM-IV criteria for dementia of the Alzheimer’s type; • MMSE between 10 and 26 (or sometimes narrower); • Modified Hachinski ischemic score ≤ 4; • Care giver available to supervise compliance; • Patient able to cooperate with medication taking, testing, and to give assent or informed consent; and • Absence of medical contraindications to therapy; absence of disruptive behaviors. Less strict criteria for treatment might be (in addition to the above strict criteria): • McKhann criteria for ‘possible’ AD; • AD with degrees of cerebrovascular disease;

570 CHAPTER V.2

• Patients on other therapies; and • Patients with other co-morbid conditions. Specific guidance on exclusion criteria is provided in the datasheets for the drugs. If a patient has failed therapy with a cholinesterase inhibitor for reasons of side effects, then we would try a second one, unless the side effect was a serious and potential class effect such as asthma or bradycardia. Should similar side effects occur on the second cholinesterase inhibitor, then we would move to a different class of compound. If a patient has failed therapy with an agent for reasons of lack of efficacy, with good compliance, then it seems reasonable to try a second agent. Should lack of efficacy also occur with the second agent in the same class, we would either consider a third cholinesterase inhibitor or move to a different class of compound. By this time, however, patients would have received their first and second cholinesterase inhibitor over a period of more than 1 year. They probably will have suffered some degree of clinical deterioration. Many behavioral problems may have emerged and therefore the third intervention may need to be considered in a different context. Unfortunately there are no established predictors of response to therapy to any of the agents, except for dose. Changes in the placebo group do not explain the variation in the treatment group between the trials; the higher the rate of deterioration in ADAS-Cog in the placebo group is not associated with greater benefit in the treatment group. These data do not support the impression from trials of greater benefit in those with initial MMSE scores between 20 and 10. Likewise, it does not suggest that with severe or mild disease benefits are less. The individual patient meta-analysis of tacrine (see Chapter V.2.8) and the grouped data analysis for all the cholinesterase inhibitors in Fig. V.2.6 support this suggestion. Changes in the placebo group may explain some of the variation in the treatment group for selected side effects, such as nausea (Fig. V.2.8), though side effects taken in total are not influenced by the side effects rate in the placebo group (Fig. V.2.7).

Commencement of therapy with cholinesterase inhibitors The titration schedule of the manufacturer should generally be followed to minimize side effects. Side effects, usually gastrointestinal, often appear early in starting treatment or after increases in dose and are usually transient, so patients and care givers should be warned at the outset to expect them and try to tolerate early minor side effects. Side effects can also be dealt with by temporary dose reduction or temporary discontinuation. Unfortunately, except for some side effects such as nausea, most side effects are unpredictable (Figs V.2.7–9). Maximum doses of the drug should be aimed for, unless side effects make this difficult, in which case switching to another drug should be considered. For donepezil 10 mg od, for rivastigmine 4.5 mg bid, for galantamine 8 mg bid and for tacrine 40 mg qid are target doses.

Monitoring therapy Side-effects are fairly straightforward to monitor, though their attribution to the drug is more difficult as the placebo group in trials also suffer side effects that appear to be cholinergic in origin. Nevertheless, this may warrant a change to another agent in the same class or a different class. Details of side effects need prompting from patients who will often not remember to volunteer this information, and from the carer. Compliance can be evaluated with pill counts, especially when there is supervision from a care giver.

Assessing efficacy Judging efficacy is more difficult, as the trials provide little guidance on how to translate the benefits seen in controlled studies to individual patients (see Chapter I.7). Our clinical practices are to consider the following assessments: 1 Make an overall ‘global’ clinical assessment taking into account change in cognition, behavior, function and tolerance to medication, and soliciting a care giver’s input. We consider this to be the most important assessment for two reasons. The

TREATMENT OF ALZHEIMER’S DISEASE 571

Tx change

ADAS-Cog 4.91

Knapp 94 Rogers 98 Burns 99 Corey 98 Rosler 99 Tariot 00 Raskind 00 Wilcock 00 Morris 98 Dubois 99 Bars 97

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−2.09

in the treatment group related to changes in the placebo group. L’Abbe plot for ADAS-Cog in 5–7 month cholinesterase inhibitor trials plotted by change in placebo group and change in treatment group. The treatment effect is not related to the underlying placebo change between the trials.

−3.09 −4.09 −5.09 Placebo change Side effects

0.30

Fig. V.2.7 L’Abbe plot for all side

effects in 5–7 month cholinesterase inhibitor trials plotted by rate in placebo group and rate in treatment group. Points above the solid line of the graph indicate higher rates in the treatment group. No overall relationship between the rate in the placebo group and the rate in the treatment group.

Proportion with side effects on therapy

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572 CHAPTER V.2

51 50 49 48 47 46 45 44 43 42 41 40 39 38 37 36 35 34 33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 0 −1 −2

Rogers 98 Burns 99 Dubois 99 Corey 98 Rosler 99 Tariot 00 Raskind 00 Wilcock 00

Fig. V.2.8 L’Abbe plot for nausea in

Proportion in placebo group

5–7 month cholinesterase inhibitor trials plotted by rate in placebo group and rate in treatment group. Solid line is line of no difference. Dotted line is the regression line. The amount of the variation explained by the regression relationship is 58%; p = 0.001. For every 1% increase in the rate of nausea in the placebo group, the nausea rate in the treatment group is about 3.4 times higher.

care givers are the people best placed to evaluate the impact of the therapy on patients’ daily lives, and we wish to achieve important benefits for our patients. Use of overall clinical assessments will pick up important impacts, which we feel should be worth targeting. 2 A cognitive scale or brief mental status examination that is validated longitudinally, has acceptable intraindividual variability, is sensitive to the magnitude of change expected, and feasible to use in a clinic setting is needed. The ADAS-Cog or the cognitive portion of the Cambridge Mental Disorders of the Elderly Examination (CAMCOG) (see Appendix II), while fairly sensitive and reliable (though not without within-subject variation) are of limited clinical usefulness for primary care, where most of the prescribing (initiation and maintenance) in the US occurs. In Europe, by contrast, specialists are likely to be required to at least initiate therapy, with varying degrees of shared management with general practitioners (SMAC 1998), in an effort to reduce ineffective prescribing. In such a setting, the ADAS-Cog and CAMCOG are

practical and more useful to objectively monitor response to therapy than more simple scales such as the MMSE. In primary care, the MMSE and the ‘IntentionaMemory–Concentration’ test of the Blessed Scale may be more appropriate for clinical use even though short-term response to therapy is hard to measure. Nevertheless, it may allow clinicians to at least monitor dramatic cognitive changes to therapy and the course of the cognitive decline over a longer period to provide a background for the place of drug therapy for the patient. The sensitivity to change on the MMSE is usually only apparent after a year or more, as there is typically only a 2–4 point deterioration on the MMSE over one year (studies suggest that at least a 4 point change is needed to be fairly certain that you have avoided within patient variation with the MMSEasee Appendix II). With reliance on a brief insensitive test for short-term response, greater emphasis should be put on the global clinical response, which is the most important measure of success, if it can be assessed validly. 3 A functional activity scale or inventory allows

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TREATMENT OF ALZHEIMER’S DISEASE 573

the assessment of deterioration in specific daily functions and can help to decide whether therapy should continue or be given a trial of withdrawal. Considerations include the use of the simple dependence scale or the Alzheimer Disease Cooperative StudyaActivities of daily Living (ADCS–ADL) inventory, both of which can be completed either by interview or by a care giver. The benefits on the functional scales used in the trials have shown small though statistically significant group benefits, largely because scores of individual items are summed. Clinically, an ADL scale may help clinicians target individual activities in individual patients. 4 Other instruments are also advocated such as carers and patients setting realistic targets of what they would consider a success. Other more complex variations on this theme include a global attainment scale (Rockwood et al. 1996). We do not use the latter which is very labor intensive and not yet properly validated, but the concept of individualized goals, that is what is considered important for the patient and carer, is crucial in the clinical assessment of success or failure of therapy for individual patients. There are two basic approaches to evaluate clinical response in individual patients. One is controlled evaluation usually through blinded n-of-1 trials, and the other is expert clinical observation. Most guidelines suggest clinical observation, with or without validated instruments, to assess the response to therapy (APA 1997; Eccles et al. 1998). Unfortunately, the randomized double-blind trials show clearly that improvement also occurs in patients placed on placebo. For example, of the patients on placebo in one trial, about 25% were better at 6–12 weeks, and about 20% scored better at 30 weeks on the Clinical Interview-based Impression scale, when compared to baseline (Knopman et al. 1994). Efficacy may be seen after a few weeks, but should be carefully assessed at 3–6 months, with maximum dosage of the drug for 2 months before assessment. This timing is adopted in most of the guidelines, though a few UK local policy documents suggest 6 months (Harvey 1999). The possible scenarios and courses of action are given in Fig. V.2.9.

The combined requirement for an improvement in cognitive performance by 4 points on an ADASCog scale and an improvement in a global assessment will severely reduce the number who are deemed to benefit. Nevertheless, without a blinded n-of-1 trial, these more stringent criteria may be the best policy to guard against patients and carers becoming wedded to a drug that is not helpful to them. Another problem with monitoring is the difficulty of remembering the baseline global performance by a carer beyond about 1 year. A discontinuation trial on a yearly basis will obviate this problem, though a change in regular carer will not! Intervening behavioral problems complicate this assessment and repeat assessment may be required after the behavioral condition has resolved or has become established and stable.

Stopping therapy Poor tolerability, side effects, poor compliance, withdrawal of consent, inadequate supervision by care giver or when the benefits do not appear to be clinically significant in terms of the overall clinical disability of the disease are reasons to discontinue therapy. The latter is an individual decision between the carer, patient and physician; for some this might be entry into a nursing home, for others this would not be a deciding factor, as the time of entry to nursing homes is dependent on family, cultural, social and economic circumstances. Also, there is some evidence for improvement in ADLs but not cognition in nursing home patients given cholinesterase inhibitors. There is no good evidence that there is a withdrawal effect from therapy, over and above the approximation to the placebo group over a period of 6 weeks. There is little evidence of a rebound phenomenon except for individual anecdotal reports of marked deterioration on withdrawal. Nevertheless, it seems prudent to decrease cholinesterase inhibitor therapy in steps similar to those taken in titrating medication upward at the beginning of therapy. In view of the lack of evidence for long-term effects of cholinesterase inhibitors, discontinuation could be considered on a yearly basis or when it seems that patients are not continuing to benefit.

574 CHAPTER V.2

Confirm diagnosis

Treat behavioral conditions Treat co-existing medical conditions, especially vascular disease

Vitamin E 2000 IU bid or uid

Not toleratedawithdraw

Fig. V.2.9 Treatment algorithm for

Alzheimer’s disease.

Not toleratedawithdraw Selegiline 10 mg uid (Withdraw while on antidepressants) Donepezil 5 mg uid for 1 month (or other drug of class or different class) Donepezil 10 mg uid for 2 months (or other drug of class or different class) Improvement

Not toleratedatry rivastigmine or galanthamine or Gingko

Not toleratedatry rivastigmine or galanthamine or Gingko

Not sufficient improvementatry rivastigmine or galanthamine or Gingko

3–4 monthly follow-up for 1 year Therapy for cognitive symptoms still appropriate? Discontinuation trial Try Gingko Clearly worse off drug Resume maintenance dose Annual discontinuation trial

n-of-1 trials This approach is described in Chapter IV.5.4 for evaluating individual response to symptomatic therapies. In essence it is trying to assess the symptomatic effects of treatment divorced from the placebo effect by blinding the patient and carer (and physician, in double-blind studies). The statistical analysis still requires development and there is the problem of how to deal with benefits seen with placebo, when no benefits are observed on treatment over and above placebo. Nevertheless, it takes away the psychological dependence on the

drug, especially from the care giver. Even with its limitations, the method can only improve uncontrolled clinical observation, and has been suggested in a Dutch guideline (Verhey et al. 1998). Alternative views suggest that patients should be put on to these symptomatic drugs without regard to symptomatic response. Their reasoning is, first, they lessen the decline in cognitive performance, even in those individuals who show no absolute improvement from baseline. Second, the clinical global improvement from the trials indicating that at least four out of every five patients will not benefit is the price to be paid for the one patient that

TREATMENT OF ALZHEIMER’S DISEASE 575

does benefit. This view is similar to the approach taken with cardiovascular drugs intended to prevent sudden death or modulate progressive heart failure, or anticancer drugs to prolong survival, in which the average small magnitude of benefit makes it impossible to determine whether any single individual patient is benefiting from medication treatment. However, the value attached to the benefits in these areas is driven by clinically meaningful and important endpoints such as survival and disability, something that is sorely lacking in dementia trials so far. We believe that all the above approaches may be appropriate and rational, depending on circumstances. The particular approach should be explicitly considered by the clinician and discussed with the carer and patient (if appropriate) so that there is agreement and a co-operative effort in treatment. Therapeutic approaches will vary among practitioners based on philosophical, cultural, and economic views, or their local health service policies.

Prognosis-modifying therapycfor clinically important endpoints We prefer to use the term prognosis modification, rather than disease modification, which is in general currency, as it focuses on the results of what the therapy does, rather than on a hypothesized mechanism or structural effect on the pathology of the illness. Patients and carers are more interested in results than theories. From trials evaluating delay in clinical milestones, the description of the benefits can be easily conveyed to patients and carers and can be represented as a modification of prognosis, e.g. a delay of placement to a nursing home by a median number of months or a delay in reaching a given severe state of dependency, or the reduced chance of reaching such a state. The only therapies where this information is available is from the one trial of vitamin E and selegiline (Sano et al. 1997). We believe that the evidence of benefit for vitamin E and selegiline is probable rather than definite, as stated in the APA guideline (APA 1997) because: the endpoints were merged posthoc due to insufficient numbers, the validity of collapsing

such diverse outcomes into one composite endpoint is questionable, univariate analysis was (marginally) not-significant at the 5% significance level, and the analysis adjusting for a modest imbalance in the MMSE scores between the allocated groups at baseline caused an almost doubling in benefit compared with the univariate results. Nevertheless, the results are probably true but that the magnitude of the benefit is likely to be closer to the univariate results than the adjusted results. This indicates a delay of 71 days for vitamin E alone, 102 days for selegiline alone and 55 days for vitamin E combined with selegiline. This is in contrast to the adjusted figures of 230 days for vitamin E alone, 215 days for selegiline alone and 145 days for vitamin E combined with selegiline (Sano et al. 1997). The adjusted figures are used in guidelines (APA 1997). We believe that (unlike the guidelines, APA 1997) vitamin E and selegiline should be considered for administration together, as the trial was underpowered to detect the main treatment effects, let alone to assess the interaction of the two drugs together. Reliably testing for interaction requires a much larger trial (see Chapter IV.5.3). The combination led to no more withdrawals and side effects than the single treatments individually (Sano et al. 1997). Therefore, the safety of the combination is comparable. Moreover, the combination of vitamin E and a cholinesterase or Gingko biloba, which has been advocated by some guidelines (APA 1997), is untested for adverse effects on safety or benefits. The recommendation of combining vitamin E and selegiline is based on the view that potential benefits on prognosis of clinically important outcomes outweigh the short-to-medium term modest benefits on outcomes which are difficult to interpret for patients, seen with symptomatic drugs. We are unaware of good biological arguments for an adverse interaction. The fact that cognitive performance was unaffected by therapy with either vitamin E or selegiline, suggests that cognitive tests are not useful for monitoring. Although, short-term trials (see Chapter V.2.19) and meta-analyses of selegiline (Chapter I.8) suggest a beneficial effects on cognitive function, these sources are untrustworthy because of severe methodological problems.

576 CHAPTER V.2

Deciding eligibility

Stopping therapy

Strict criteria: Probable AD of moderate severity (CDR = 2). Less strict criteria: All patients with probable or possible AD and mixed AD and vascular disease. This extrapolation beyond the trial population to include early and mixed AD is, in view of the good tolerability, lack of (extra) monitoring and its low cost and potential for prevention of vascular disease (which is both a risk factor for AD and vascular dementia and a prognostic factor for deterioration in AD as well as in vascular disease, see Chapters III.3.4, III.3.5 & IV.2.3). These relaxed criteria need revision in the light of the results of the UK Heart Protection Study, which should report in 2001 on a 5-year randomized trial of vitamins A, C and E in a wide range of vascular disease patients (20 000) followed for cardiovascular and cerebrovascular events (Meade et al. 1999). Should this trial be positive, we believe that the dose of vitamin E could be reduced to that used in this mega-trial (600 IU/uid), and administered once a day for AD, mixed and vascular dementia.

• Intolerance. • Poor compliance. • When a stage of disease severity is reached where delay in further disability is not appropriate. For rivastigmine, the slow escalation of dose to the maximum requires the timing of the assessment of efficacy to be longer than 3 months. We believe that this algorithm (see Fig. V.2.9), together with the instruments required to monitor therapy reliably, call for the services of a specialist clinic as recommended by UK committees (SMAC 1998; NICE 2001) and the Italian Ministry of Health.

Exclusions Patients in whom delay in further disability would not be appropriate. Risk of interaction with essential drugsa warfarin and Gingko biloba for vitamin E (see drug datasheets). Antidepressants with selegiline (see datasheet).

Commencing therapy Start with the maximum recommended dose without any need for titration for either vitamin E (1000 IU/bid) or selegiline (5 mg bid).

Monitoring therapy Apart from observing for side effects soon after commencement, no monitoring of efficacy is needed for vitamin E. For selegiline, monitoring for side effects is required periodically.

Acknowledgement We thank Graeme Archer for statistical analysis of the data and drawing the graphs.

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V.3

V.3.1

Treatment of Vascular Dementia

Introduction

Jeffrey Kaye

A comprehensive overview of vascular dementia (VaD) is presented in Chapter III.3 (Leys et al.). In the following section the evidence supporting specific therapies for VaD is presented. It is immediately obvious that despite VaD being a common cause of dementia, there are relatively few randomized controlled treatment trials of VaD to guide the clinician. This likely reflects a number of historical factors that in large measure have resulted in vaguely proscribed diagnostic definitions and wide variability in outcome measures. Nevertheless, in the last decade there have been a number of proposed diagnostic schemes with greater attention to the specificity of the VaD diagnosis that may improve the development of new treatments for VaD. Not the least of these improvements is an emphasis on documenting vascular brain injury including neuroimaging evidence. This sharpening of definitions has also pointed out some of the limitations of the general moniker ‘VaD’ which is really a syndrome composed of many possible vascular system-mediated neuropathologic scenarios leading to cognitive impairment (Erkinjuntti & Hachinski 1993; Rockwood et al. 1999). Unlike the major neurodegenerative causes of dementia, significant potentially modifiable risk

V.3.2

factors for VaD are known (Skoog 1998). Although their relationship to VaD subtypes is not fully understood, they form the basis for therapeutic strategies. This is more of a practical approach based on the face validity of believing that if vascular disease in the brain is prevented, then VaD will be avoided as well. However, this approach still awaits confirmatory studies (Forette et al. 1998). In the interim, unlike, for example, Alzheimer’s disease where major modifiable risk factors are uncertain, the approach to VaDs, aside from symptom management, is likely to be secondary prevention of cerebrovascular disease. The clinician seeing a patient with significant vascular disease with cognitive impairment who has otherwise not been treated for stroke or cardiovascular disease thus has a dual role. The first order of business is to institute a management plan for the dementia itself, while at the same time considering the best way to integrate a secondary prevention plan for cerebrovascular disease. This is particularly important in that there is consistent evidence that patients with dementia after stroke are significantly less likely to be treated with aspirin or warfarin than non-demented patients (Rockwood et al. 1997; Moroney et al. 1999).

Antioxidants

Nawab Qizilbash

There are no randomized, placebo-controlled data of the use of antioxidants in vascular dementia

(VaD), and hence their use cannot be recomended for VaD at this time. See Chapter V.2.3 for a

589

590 CHAPTER V.3

narrative systematic review of the use of antioxidants in AD. Nevertheless, trials are ongoing in vascular disease which may help to provide evidence of the effects of antioxidants in preventing or delaying dementia due to vascular disease (and

V.3.3

Alzheimer’s disease, AD). The most notable is based in the UK, and is a 5-year trial of antioxidants (vitamins A, C, E) in a factorial design with simvastatin in 20 000 people at high risk of vascular death, and is due to complete in 2001.

Antithrombotics

Helmi L. Lutsep

Although not sufficient to explain all cases, single strokes which are large or strategically placed, or multiple strokes accumulating over a period of time, can result in vascular dementia (VaD). The atherothrombotic etiology of many strokes provides a natural target for therapies intended to limit VaD. Prospective, randomized, double-blind studies have demonstrated the efficacy of antithrombotic therapies in stroke prevention (Antiplatelet Trialists’ Collaboration 1994). Although many patients with VaD have had previous discrete cerebral ischemic events, like those qualifying patients for the stroke prevention trials, none of the stroke trials specifically assessed efficacy in patients with VaD. Trials of these agents in VaD itself have been scanty. Of the antiplatelet agents evaluated in stroke prevention, only aspirin has been assessed to any degree in VaD. Small studies lacking in rigor have taken an initial look at the use of aspirin in the prevention and treatment of VaD in the elderly population. In addition, a drug showing efficacy in studies of peripheral vascular disease and myocardial infarction in Europe, sulodexide, has been assessed in one small treatment trial of VaD.

Rationale Aspirin inhibits thromboxane formation in platelets through the acetylation of cyclooxygenase. The suppression of thromboxane prevents platelet aggregation and hinders thrombogenesis. Sulodexide contains a heparin fraction with high affinity for antithrombin III, and a dermatansulphate with affinity for heparin cofactor II. The drug displays antithrombotic and fibrinolytic properties, as well as a hypolipidemic effect linked to lipoproteinlipase release (Parnetti et al. 1997).

Evidence: aspirin use in prevention of cognitive decline In vascular dementia One small study in patients with VaD has used a prospective, randomized design to assess the effects of aspirin, 325 mg daily, on cognitive performance (Meyer et al. 1989). However, the study was not placebo controlled: the control group simply received no aspirin, and an attempt was made to evaluate both cohorts in a blinded manner. By the third and final year of the study, only 11 of 33 patients remained in the control group (33%), and 16 of 37 remained in the aspirin group (43%). The Cognitive Capacity Screening Examination (CCSE) briefly assessed cognitive function, and 133xenon inhalation evaluated cerebral perfusion. The CCSE scores improved by 19.8% in the aspirin-treated group, while the CCSE scores decreased by 3.8% from baseline scores in the control group by the third year (P < 0.04). Cerebral perfusion showed significant improvements in the aspirin-treated group compared to controls in the first two years, with a trend toward better perfusion in the third year.

In the elderly population with cardiovascular risks The potential effects of aspirin (75 mg daily), warfarin (INR 1.5), warfarin plus aspirin, and placebo on preventing cognitive decline were compared in a group of 405 men at risk for cardiovascular disease (Richards et al. 1997). Although treatment was allocated in a randomized, double blind fashion, the subjects studied represented a subgroup of a larger trial designed for a different

TREATMENT OF VASCULAR DEMENTIA 591

purpose, the assessment of coronary and cerebral thrombosis prevention. They represented those individuals aged 55 years or more who were in the top quintile of risk for myocardial infarction or coronary death. Of this high risk group, those patients who had been on treatment for five years or more received a detailed neuropsychometric battery, but cognitive function was not measured at baseline. Patients on active treatment showed significantly better cognitive scores compared to patients in the placebo group by multivariate analysis of variance (P = 0.02). Univariate, but not multivariate, analyses suggested better performance in patients taking aspirin containing regimes compared to those assigned to warfarin. The etiology of any cognitive dysfunction was not determined.

In the elderly population as a whole A prospective, non-randomized trial hypothesized that aspirin could reduce the decline in cognitive function in an elderly population by influencing the component due to multi-infarct dementia (Sturmer et al. 1996). In this study of 3809 subjects aged 65 years or more, living in the community, investigators obtained limited mental status testing using the Short Portable Mental Status Questionnaire at baseline, 3 years, and 6 years. Subjects with low levels of cognitive functioning at baseline were excluded, since they could not decline any further on the scales. Aspirin users were defined as those subjects who had taken aspirin-containing drugs in the 2 weeks prior to the assessment. By the 6 years follow-up, 79.1% of subjects were available for mental status testing. Multivariate models adjusted for confounders showed that aspirin users had an odds ratio (OR) for cognitive decline of 0.97 (95%CI 0.82–1.15). When those subjects were excluded who were also on non-steroidal antiinflammatory drugs, the OR was 0.94 (95%CI 0.79–1.12), with a statistically insignificant 6% decreased risk of decline in cognitive function. A low frequency of aspirin use, aspirin taken on an ‘as needed’ basis, was associated with a trend toward lower risk of decline than higher doses of aspirin. The cause of decline in cognitive functioning was not determined.

Evidence: sulodexide use in vascular dementia One randomized double-blind study has compared the biological efficacy of oral sulodexide, 50 mg twice a day, and pentoxifylline, 400 mg three times a day, in patients with probable VaD (Parnetti et al. 1997). Ninety-three patients aged 65–80 years who fulfilled the NINDS-AIREN diagnostic criteria for probable VaD and had a Mini Mental Status Examination score between 11 and 22 entered the study, and 86 patients completed the six month evaluation. Coagulation and fibrinolytic parameters were assessed at baseline and every two months. To assess clinical efficacy, patients received the Gottfries–Brane–Steen (GBS) Rating Scale for Dementia at baseline, the fourth and sixth months of therapy, and at the end of the sixth month of treatment. The GBS scores showed improvement from baseline only in the sulodexide group at both 4 and 6 months, demonstrating increased scores in all three subscales (P < 0.01). The sulodexide group also displayed a significant reduction in factor VII-Ag levels at 6 months compared to baseline levels, and reduced high fibrinogen levels earlier (2 months) than pentoxifylline (4 months). One earlier report had examined the effects of daily intramuscular doses of sulodexide, 300 ULS, in 12 patients who ‘in the course of conversation . . . showed symptoms of cerebral senile involution’ (Galeone et al. 1988). The investigators assessed their performance on the Wechsler–Bellevue efficiency test at baseline, one month, at the end of treatment (day 60), and after a 60-day pharmacological washout period. Patients performed progressively better over the course of the treatment phase, but dropped their scores after the washout period to an average that was again comparable to that in the beginning of treatment, and significantly different from the score at the end of treatment.

Who should be considered for treatment? Those patients with VaD who have suffered a TIA or stroke should be considered for treatment with aspirin for the prevention of another stroke or vascular event, if they do not have aspirin intolerance.

592 CHAPTER V.3

In those patients without a clear preceding history of TIA or stroke who have possible VaD, aspirin can be considered, although evidence for its use is weak. Although it is not available in North America, in certain parts of Europe sulodexide provides another treatment option in patients with VaD based on one small, non-placebo-controlled trial.

Clinical pharmacokinetics While aspirin doses of 325 mg can completely inhibit platelet function, doses of aspirin as low as 30 mg may take several days to achieve maximal platelet inhibition (The Dutch TIA Trial Study Group 1991). The effects of aspirin last for the normal life span of the platelet. The enteric-coated tablet of sulodexide shows two phases of increased plasma levels. In the first phase, plasma levels peak at 2 h and again between 4 and 6 h. A second phase occurs at 12 h, when there is release from tissue reservoirs (Mauro et al. 1993). Effects are potentiated by repeated administrations of the drug. After 7 days’ administration, more clear-cut lowering of plasminogen-activator inhibitor, as well as plasma viscosity, are observed than on the first day (Crepaldi et al. 1992).

Adverse effects In controlled stroke prevention trials, aspirin is associated with bleeding, even at doses as low as 50 mg daily (Diener et al. 1996). Patients taking aspirin may experience epistaxis, gastritis and ulcers, and may be at slightly increased risk of hemorrhagic stroke (Hass et al. 1989; Antiplatelet Trialists’ Collaboration 1994; Diener et al. 1996). Sulodexide has generally been well tolerated, although large studies of this agent have not been performed.

Starting/monitoring/stopping treatment An aspirin dose of 325 mg per day has been assessed in patients with a diagnosis of VaD. No recommendations for aspirin monitoring or cessation in VaD can be made. A dose of 50 mg twice a day, without monitoring, was used in the small sulodexide study.

Future research Trials of antithrombotics in the primary prevention of VaD, particularly in those with risk factors for its development, are needed. Since aspirin has known efficacy in the prevention of stroke in patients who have a history of TIA or stroke, patients with VaD and a known cerebral ischemic event will likely be ethically prevented from participating in future trials in which they could be randomized to a placebo arm. However, aspirin may be compared with, or used in combination with, other antithrombotic agents in the patient with VaD and previous TIA or stroke. Additional trials of sulodexide may be warranted. Three other antithrombotic agents, ticlopidine, clopidogrel, and an extended release combination of dipyridamole and aspirin, have shown efficacy in stroke prevention (Hass et al. 1989; Gent et al. 1989; CAPRIE Steering Committee 1996; Diener et al. 1996). However, no trial has directly investigated the efficacy of these agents in VaD. It is likely that demented patients have even been underrepresented in some of these stroke prevention trials, which excluded patients with severe comorbidity or deficits (Gent et al. 1989; CAPRIE Steering Committee 1996). For the prevention of stroke or vascular events, these agents offer a useful alternative to aspirin in patients who are intolerant of aspirin or who have had an ischemic event despite aspirin use.

Summary There is weak evidence to recommend the use of aspirin in VaD [Grade B-5]. The results of a single, flawed study in patients with VaD are consistent with improvement in cognitive measures with aspirin therapy. Small studies in which the cause of cognitive decline was not determined are consistent with either improvement or no change in cognitive function with aspirin use. In Europe, one small, non-placebo-controlled study supports the use of sulodexide in VaD [Grade B-5]. Although there is strong evidence to support the use of aspirin to prevent stroke in patients with previous TIA or stroke [Grade A-1], no stroke prevention trial has been confined to patients with VaD.

TREATMENT OF VASCULAR DEMENTIA 593

Table V.3.1 Reproduced with permission from Update Software. Review: Cytidinediphosphocholine for cognitive and behavioral comparison: CDP-choline vs. placebo Outcome: Clinical measures Experimental Control Study n/N n/N Positive Global Clinical Impression 40/53 Agnoli et al. 1985 19/20 Angeli 1985 12/17 Capurso et al. 1996 24/25 Motta et al. 95/115 Subtotal (95%CI) Chi-square 3.07 (df = 3) Z = 7.96 Total (95%CI) 95/115 Chi-square 3.07 (df = 3) Z = 7.96

Weight (%)

Peto OR (95%CI fixed)

11/43 6/20 5/14 8/25 30/102

45.0 18.1 14.8 22.1 100.0

7.26 [3.26, 16.19] 14.94 [4.22, 52.89] 3.91 [0.97, 15.82] 15.21 [4.85, 47.73] 8.89 [5.19, 15.22]

30/102

100.0

8.89 [5.19, 15.22]

0.1 0.2

V.3.4

Peto OR (95%CI fixed)

1

5

10

Blood Pressure Reduction

Nawab Qizilbash Summary

Introduction

No randomized studies were found of blood pressure lowering in patients with vascular dementia (VaD). Randomized data on prevention of VaD from blood pressure lowering is currently inconsistent, but suggests a moderate benefit in the prevention of dementia. Patients with VaD and Alzheimer’s disease (AD) whose systolic blood pressure is greater than 160 mmHg or whose diastolic blood pressure is greater than 90 mmHg should be treated with drugs, after non-pharmacological means have failed, and where treatment is indicated to prevent a future major stroke. Randomized data indicate that blood pressure lowering is not associated with adverse effects on cognitive performance. The choice of drug therapy is based on achieving a systolic blood pressure of less than 160 mmHg (target of 140 –145) and a diastolic blood pressure of less than 90 mmHg (target of 65– 70), avoidance of side-effects, and compliance. Current guidelines indicate a thiazide as first line therapy.

Blood pressure (systolic and diastolic) is a risk factor for VaD and AD (see Chapters III.3 and V.7 for systematic reviews of the valid observational studies), Forette and Boller (1991) and Hofman et al. (1997). Blood pressure (systolic and diastolic) is also a potent risk factor for ischemic and hemorrhagic stroke (Prospective Studies Collaboration 1995; Qizilbash & Evans 2000). Reduction of blood pressure has been consistently shown to substantially reduce the risk of major stroke (Collins et al. 1990). The randomized data on blood pressure reduction pertinent to VaD were reviewed, for both treatment and prevention.

Evidence No unconfounded, randomized, controlled trials of blood pressure reduction in established VaD were found with the following strategy: Medline (1966–January 2001) and Current Contents (1993–January 2001) using the words Alzheimer’s disease or dementia or vascular dementia AND trial AND blood pressure.

594 CHAPTER V.3

Table V.3.2 Characteristics of the randomized trials with dementia as outcomes. SHEP (1991)

SYST-EUR (Forette et al. 1998)

Drugs used

Chlorthalidone ± atenolol

Age at entry Entry diastolic blood pressure Follow-up Proportion of dementia at baseline Rate of dementia in placebo group Rate of dementia in treated group Dementia type

72 17 or CDR > 0.5 and driving skills reported unchanged

Too severe Driving-oriented assessment by OT and/ or neuropsychology

Pass

Fail

Can drive only if accompanied; 6 month review (sooner if deterioration), advise on insurance and DMV disclosure

Fail/uncertain Pass Fail

On-road test

Advise patient and carers against driving, explore alternative strategies

both maintaining activities and exploring transport needs. The on-road test may be helpful as it may demonstrate deficits to a patient or care giver who is ambiguous about the patient stopping driving. At a therapeutic level, members of the team may be able to help the patients come to terms with the losses associated with stopping driving. The OT may be able to maximize activities and function and help focus on preserved areas of achievement, while the social worker can advise on alternative methods of transport. This approach should save time and valuable resources for OT, neuropsychology and road driver assessors. In addition to the usual work-up, the medical assessment should include a driving history from patient and care giver. Although Hunt has shown a poor correlation between care giver assessment and on-road driving performance (two out of five cases!) (Hunt et al. 1993), this single small study is insufficient to discount the collateral history. The Folstein MMSE (Folstein & Folstein 1975) would be perhaps the most reasonable choice of simple

Fig. VII.2.1 Driver assessment.

screening measures of cognitive impairment: a (quasi-)consensus paper in 1994 suggested that those who score 17 or less on an MMSE require further assessment in a formal manner (Lundberg et al. 1997). This is a rather low level and is represented in the qualification of the term ‘consensus’ in the title. The next stage of testing has been evaluated with both OT and neuropsychology assessments. None of the studies have been sufficiently large to have a reasonable predictive value or to determine cut-off points on neuropsychological test batteries. This situation is paralleled in Memory Clinics where there is a wide variation in test batteries used: it is likely that the important elements of successful assessment are choice of key domains, familiarity with a test battery, and the development of an understanding and close liaison between the physician and the OT and/or neuropsychologist. A wide range of tests has been correlated with driving behavior but few have been sufficiently robust to calculate cut-off points for risky driving. All of these

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tests can be criticized for taking an over-cognitive view of the driving task. Specific tests which show correlation with driving ability in more than one study include the MMSE (Odenheimer et al. 1994; Fitten et al. 1995; Fox et al. 1997), the Trail Making Test (Janke & Eberhard 1996; Mazer et al. 1998; Stutts et al. 1998), and a range of tests of visual attention (Klavora et al. 1995; Duchek et al. 1998; Marottoli et al. 1998; Owsley et al. 1998; Trobe 1998), including the Useful Field of View, a composite measure of pre-attentive processing, incorporating speed of visual information processing, ability to ignore distractors (selective attention) and ability to divide attention (Owsley et al. 1991). A range of other tests has been assessed in single studies (an interesting one is traffic sign recognition; Carr et al. 1998) and a comprehensive review is available from the US National Highway Transportation Safety Administration (National Highway Traffic Safety Administration 1999). In conjunction with the clinical assessment and collateral history, these tests will help to decide which patients require on-road testing, as well as those who are likely to be dangerous to test! The other interesting aspect is that there may be a disparity between scores on a test battery and the clinical assessment of the neuropsychologist. In a small paper by Fox et al. the neuropsychology test scores and the neuropsychology prediction were not found to be significantly associated, suggesting that the clinicians made their decisions on items not formally measured in the neuropsychology test battery (Fox et al. 1997). At the moment simulators of sufficient sophistication are not widely available but this may change in the near future with the advent of very powerful laptop and desktop PCs. The main benefit of large sophisticated simulators such as the Iowa simulator has been to try to develop and understand neuropsychological and behavioral test batteries in a safe way and to correlate them with unsafe driving behavior and crashes. The classic paper by Rizzo in 1997, which showed that 29% of patients with AD experienced crashes in the simulator vs. zero of 18 control participants (Rizzo et al. 1997). The drivers with AD were also more than twice as likely to experience ‘close calls’. There was also evidence

that drivers with mild AD did not crash and showed fair control of their vehicles compatible with the idea that some patients with mild dementia should be allowed to continue to drive. On-road driver testing is the gold standard and should be offered to all patients who are not clearly dangerous when driving and who do not disqualify from driving for other reasons, such as homonymous hemianopia or convulsions. The assessor will require a full clinical report, and may choose to use one of the recently developed scoring systems for on-road testing of patients with dementia. At least three different road tests have been devised specifically for dementia although the numbers put through these are still relatively small with 27 patients in the Sepulveda Road Test (Fitten et al. 1995), 65 in the Washington University Road Test (Hunt et al. 1997) and 100 in the Alberta Road Test (Dobbs et al. 1998). The quantification, operation and validation of these road tests needs to be carried out repeatedly in environments other than those used by the originators of the test. An extra spin-off may well be that just as the simulators had provided information on which neuropsychological tests are helpful in deciding which drivers are safe to drive, neuropsychological tests may be based on road test schedules. Psychological batteries have been developed for both the Sepulveda and Alberta Road Tests.

Are there any interventions that can improve the safety and comfort of driving for drivers affected by dementia? The only study which shows some benefit from intervention is the study by Bèdard, which showed that patients who drove accompanied were less likely to have accidents than those who drove on their own (Bèdard et al. 1996). It is reasonable to consider making a recommendation that patients with dementia should not drive unaccompanied. It is also reasonable to ask to review the patient in six months, or sooner should there be any significant deterioration. Unknown interventions include removal of medications. This is a thorny methodological area, as it is not clear whether it is the underlying illness or the medication used to treat

760 CHAPTER VII.2

the illness (particularly benzodiazepines, tricyclic antidepressants and neuroleptics) that is responsible for reported increases in crash rates.

What should doctors advise for those patients they assess as fit to drive? If the assessment points to safe driving, the decision to continue driving entails several components.

Duration before review As dementia is a progressive illness, it is prudent to make any declaration of fitness to drive subject to regular review: my own practice is to review again after six months, or sooner if any deterioration is reported by the care giver.

Possible restriction There is also preliminary evidence from Utah, USA, that those drivers with restricted driving licences have lower crash rates (Vernon 1999): patients should be advised to avoid traffic congestion as well as driving at night and in bad weather. Sensible advice would be stick to local areas, familiar runs and to avoid driving at night or in bad weather.

Driving accompanied Following evidence that the crash rate is reduced if the driver is accompanied, it could be considered sensible to restrict driving exclusively to when there is someone else in the car, using the co-pilot model (Shua-Haim & Gross 1996).

Licensing authority reporting relationship The patient and care givers should be advised to acquaint themselves with local driver licencing authority requirements, especially with regard to disclosure.

Insurance reporting responsibility The patient and care givers should be advised to acquaint themselves with the policy of their motor

insurance company, especially with regard to disclosure. All of the above should be clearly recorded in the medical notes. Except for jurisdictions where there is mandatory reporting of drivers with dementia (e.g. California, some Canadian provinces), there is no obligation on the doctor to break medical confidentiality in these cases.

How do older drivers with dementia deal with driving cessation when driving is no longer possible? There is strong evidence that drivers with dementia not only limit their own driving and cease driving voluntarily, but also are amenable to pressure from family and physicians. In one of the largest studies 18% stopped driving of their own accord, 23% because of physicians, 42% because of family members and the rest by a combination of interventions (Trobe et al. 1996). There is no data on how patients with dementia compensate for the transport needed to fulfil their social, occupational and health needs. Psychological adaptation to driving cessation may be helped by diagnosis and psychotherapeutic input, but this has not been tried in a randomized controlled experiment. In a single case study, the patient’s feelings and fears about giving up driving were explored with him (Bahro et al. 1995). The intervention was designed with the patient as collaborator, i.e. by sharing the diagnosis and discussing its consequences and by dealing with the events at an emotional rather than at an intellectual level. The patient was able to grieve about the disease and in particular about the loss of his car. This, in turn, enabled him to redirect his attention to other meaningful activities that did not involve driving. Although this approach may be hampered by the deficits of dementia, it reflects a more widespread trend towards sharing the diagnosis of dementia with the patient.

What should doctors advise for those patients they assess as unfit to drive? If the assessment supports driving cessation, patients and care givers should be advised of this, and a social worker consulted to help maximize transportation options. Giving up driving can have a

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considerable effect on lifestyle. Normal elderly drivers accept that their physician’s advice would be very influential in deciding to give up driving AA Foundation for Road Safety Research (1988), and many patients with dementia will respond to advice from families or physicians. If the positive approach described above is not successful, confidentiality may have to be broken for a small minority of cases. Most professional associations for physicians accept that the principle of confidentiality is covered to a degree by a ‘common good’ principle of protecting third parties when direct advice to the patient is ignored (General Medical Council 1985; Retchin & Anapolle 1993). Removal of the driving licence is not likely to have much effect on these patients, and the vehicle may need to be disabled and all local repair services warned not to respond to calls from the patient! In the event of a decision to advise cessation of driving, advice from a medical social worker helpful in planning strategies for using alternative modes of travel. This may be difficult in a rural setting: one estimate of community transport exclusively for older people in the US was $5.14 for a one-way trip in 1983 (Rosenbloom 1993), and there is a lack of adequate paratransit, i.e. tailored, affordable and reliable assisted transport, which is acceptable to older adults with physical and/or mental disability (Freund 1991). Paratransit is expensive, but may have benefits in reducing institutionalization and in improving quality of life.

increase in the number of those dying as pedestrians and cyclists, possibly in part by unnecessarily removing drivers from their cars. A more minimalist and less medical approach using very simple measures, such as a vision test and a written skill examination, may be more helpful (Levy et al. 1995): however, this approach is also associated with a reduction in the number of older drivers, with a possible negative health impact (Levy 1995). Another approach is opportunistic health screening, perhaps of those older drivers with traffic violations (Johansson et al. 1996). It remains to be seen whether these and other screening policies reduce mobility among older people, a practical and civil rights issue of great importance.

Summary Safe mobility is important at all ages and can be compromised by dementia. Safe driving is possible in the early stages of dementia and clinicians need to develop protocols to support those for whom driving is safe and to help find pathways to alternative mobility for those for whom it is not. Decision-making should occur in the setting of an interdisciplinary assessment, including access to specialized on-road driving tests. As models of driving behavior are complex, physicians should be cautious about an over-cognitive approach to the assessment of driving ability.

References Screening for dementia among older drivers Despite the lack of convincing evidence for an older driver ‘problem’, ageist policies in many jurisdictions has lead to screening programs for older drivers. In the absence of reliable and sensitive assessment tools, this approach is flawed, as illustrated by data from Scandinavia (HakamiesBlomqvist et al. 1996). In Finland there is regular age-related medical certification of fitness to drive, whereas Sweden has no routine medical involvement in licence renewal. There is no reduction in the number of older people dying in car crashes in Finland in comparison with Sweden but there is an

AA Foundation for Road Safety Research (1988) Motoring and the Older Driver. AA Foundation for Road Safety Research, Basingstoke. Bahro, M., Silber, E., Box, P. et al. (1995) Giving up driving in Alzheimer’s diseaseaan integrative therapeutic approach. International Journal of Geriatric Psychiatry 10, 871–874. Bèdard, M., Molloy, M., Lever, J. (1996) Should demented patients drive alone? Journal of the American Geriatrics Society 44, S9. Carr, D.B., LaBarge, E., Dunnigan, K. et al. (1998) Differentiating drivers with dementia of the Alzheimer type from healthy older persons with a Traffic Sign Naming test. Journal of Gerontology 53(2), M135–M139. Carr, D.B., Duchek, J. & Morris, J.C. (2000)

762 CHAPTER VII.2

Characteristics of motor vehicle crashes of drivers with dementia of the Alzheimer type. Journal of the American Geriatrics Society 48, 18–22. Dobbs, A.R., Heller, R.B., Schopflocher, D. (1998) A comparative approach to identify unsafe older drivers. Accident Analysis and Prevention 30(3), 363–370. Drachman, D.A. & Swearer, J.M. (1993) Driving and Alzheimer’s disease: the risk of crashes. [Published erratum appears in Neurology January 1994; 44(1), 4.] Neurology 43(12), 2448–2456. Dubinsky, R.M., Williamson, A., Gray C.S. et al. (1992) Driving in Alzheimer’s disease. Journal of the American Geriatrics Society 40(11), 1112–1116. Duchek, J.M., Hunt, L., Ball, K. et al. (1998) Attention and driving performance in Alzheimer’s disease. Journal of Gerontology 53(2), 130–141. Eberhard, J. (1996) Safe mobility for senior citizens. International Association for Traffic and Safety Sciences Research 20(1), 29–37. Fitten, L.J., Perryman, K.M., Wilkinson, C.J. et al. (1995) Alzheimer and vascular dementias and driving. A prospective road and laboratory study. Journal of the American Medical Association 273(17), 1360–1365. Folstein, M.E. & Folstein, S.E. (1975) Mini-Mental State. A practical method for grading the cognitive state of patients for the clinician. Journal of Psychiatric Research 12, 189–195. Foley, D.J., Masaki, K.H., Ross, G.W. & White, L.R. (2000) Driving cessation in older men with incident dementia. Journal of the American Geriatrics Society 48, 928–930. Fox, G.K., Bowden, S.C., Bashford, G.M. et al. (1997) Alzheimer’s disease and driving: prediction and assessment of driving performance. Journal of the American Geriatrics Society 45(8), 949–953. Freund, K. (1991) The politics of older driver legislation. Gerontologist 31 (Special Issue II), 162. Friedland, R.P., Koss, E., Kumar, A. et al. (1988) Motor vehicle crashes in dementia of the Alzheimer type. Annals of Neurology 24(6), 782–786. Galski, T., Bruno, R.L., Ehle, H.T. (1993) Prediction of behind-the-wheel driving performance in patients with cerebral brain damage: a discriminant function analysis. American Journal of Occupational Therapy 47(5), 391–396. General Medical Council (1985) Professional Conduct and Discipline: fitness to practice. General Medical Council, London. Hakamies-Blomqvist, L., Johansson, K., Lundberg, C. et al. (1996) Medical screening of older drivers as a traffic safety measure – a comparative Finnish-Swedish Evaluation study. Journal of the American Geriatrics Society 44, 650–653. Hansotia, P. & Broste, S.K. (1991) The effect of epilepsy or diabetes mellitus on the risk of automobile accidents. New England Journal of Medicine 324(1), 22–26. Hunt, L., Morris, J.C., Edwards, D. et al. (1993) Driving performance in persons with mild senile dementia of the Alzheimer type. Journal of the American Geriatrics Society 41(7), 747–752.

Hunt, L.A., Murphy, C.F., Carr, D. et al. (1997) Reliability of the Washington University Road Test. A performance-based assessment for drivers with dementia of the Alzheimer type. Archives of Neurology 54(6), 707–712. Janke, M.K. & Eberhard, J.W. (1998) Assessing medically impaired older drivers in a licensing agency setting. Accident Analysis and Prevention 30(3), 347–361. Johansson, K., Bogdanovic, N., Kalimo, H. et al. (1994) Neuropathological alterations found at forensic autopsy of dead old drivers. In: Aging and Driving (eds K. Johansson & C. Lundberg). Karolinska Institutet, Stockholm. Johansson, K., Bronge, L., Lundberg, C. et al. (1996) Can a physician recognize an older driver with increased crash risk potential? Journal of the American Geriatrics Society 44(10), 1198–1204. Jones, J.G., McCann, J., Lassere, M.N. et al. (1991) Driving and arthritis. British Journal of Rheumatology 30, 361–364. Klavora, P., Gaskovski, P., Martin, K. et al. (1995) The effects of Dynavision rehabilitation on behind-the-wheel driving ability and selected psychomotor abilities of persons after stroke. American Journal of Occupational Therapy 49(6), 534–542. Levy, D.T. (1995) The relationship of age and state license renewal policies to driving licensure rates. Accident Analysis and Prevention 27(4), 461–467. Levy, D.T., Vernick, J.S. & Howard, K.A. (1995) Relationship between driver’s license renewal policies and fatal crashes involving drivers 70 years or older. Journal of the American Medical Association 274(13), 1026–1030. Lundberg, C., Johansson, K., Ball, K. et al. (1997) Dementia and driving – an attempt at consensus. Alzheimer’s Disease and Associated Disorders 11(1), 28–37. Lundberg, C., Johansson, K., Bogdanovic, N. et al. (1999) Follow-up of Alzheimer’s disease and apolipoprotein E E4 allele in older drivers who died in automobile accidents. In: Proceedings of International Conference on the Older Driver, Health and Mobility, ARHC Press, Dublin. MacMahon, M., O’Neill, D. & Kenny, R.A. (1996) Syncope: driving advice is frequently overlooked. Postgraduate Medicine Journal 72(851), 561–563. Marottoli, R.A., Richardson, E.D., Stowe, M.H. et al. (1998) Development of a test battery to identify older drivers at risk for self-reported adverse driving events. Journal of the American Geriatrics Society 46(5), 562–568. Mazer, B.L., Korner-Bitensky, N.A. & Sofer, S. (1998) Predicting ability to drive after stroke. Archives of Physical Medicine and Rehabilitation 79(7), 743–750. Michon, J.A. (1985) A critical review of driver behavior models: what do we know, what should we do? In: Human Behaviour and Traffic Safety (eds L. Evans & R.C. Schwing), pp. 487–525. Plenum, New York. National Highway Traffic Safety Administration. (1999) Licensing the Older Driver: a summary of state practices and procedures. DOT HS 807 443. US Department of Transportation, Washington, DC.

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O’Neill, D., Neubauer, K., Boyle, M. et al. (1992) Dementia and driving. Journal of the Royal Society of Medicine 85(4), 199–202. Odenheimer, G.L., Beaudet, M., Jette, A.M. et al. (1994) Performance-based driving evaluation of the elderly driver: safety, reliability, and validity. Journal of Gerontology 49(4), M153–M159. Owsley, C., Ball, K., Sloane, M.E. et al. (1991) Visual/ cognitive correlates of vehicle accidents in older drivers. Psychological Aging 6(3), 403–415. Owsley, C., Ball, K., McGwin, G., Jr. et al. (1998) Visual processing impairment and risk of motor vehicle crash among older adults. Journal of the American Medical Association 279(14), 1083–1088. Ranney, T.A. (1994) Models of driving behaviour: a review of their evolution. Accident Analysis and Prevention 26(6), 733–750. Retchin, S.M. & Anapolle, J. (1993) An overview of the older driver. Clinical Geriatric Medicine 9 (2), 279–296. Rizzo, M., Reinach, M., McGehee, D. et al. (1997) Simulated car crashes and crash predictors in drivers with alzheimer disease. Archives of Neurology 54, 545–551. Rosenbloom, S. (1993) Transportation needs of the elderly population. Clinical Geriatric Medicine 9(2), 297–310.

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VII.3

Care-giver Interventions

Alisa Green and Henry Brodaty

Over the past 20 years, there have been many studies looking at how best to help family care givers (also called ‘carers’ or ‘informal carers’). The methodological rigour applied to these studies has varied considerably, and while there are many anecdotal accounts of interventions, only a minority have empirical data to support their effectiveness. Interventions vary in style, and this will be discussed below. The interventions described here are aimed mainly at the care giver, or sometimes through the care giver at the person with dementia (whom we will in this chapter call the ‘patient’).

Rationale for care-giver interventions Care givers (CGs) are a legitimate target for intervention in their own right. There is considerable evidence that caring for a person with a chronic mental condition is very stressful (e.g. Lezak 1978; Gilleard 1984; Poulshock & Deimling 1984; Mohide et al. 1988). The burden of caring is experienced psychologically, physically, socially and financially. Psychological effects include distress in general, e.g. as measured by the General Health Questionnaire (Morris et al. 1988; Brodaty & Hadzi-Pavlovic 1990) and depression (Gallagher et al. 1989; Baumgarten et al. 1992; Mittelman et al. 1995). Care givers also have poorer physical health than non-care givers; they have higher rates of chronic conditions, prescription medication use, doctor visits and physical symptoms, as well as poorer self-rated health (Haley et al. 1987; Schulz et al. 1990; Baumgarten et al. 1992). Pre-existing conditions, such as hypertension, are more likely to be exacerbated by the care-giver role (Schulz &

764

Williamson 1997). Care givers are also likely to be socially isolated because of the care-giving role (Brodaty & Hadzi-Pavlovic 1990). Finally, there is considerable financial strain on families looking after persons with dementia through direct (such as paying for nursing care) and indirect (such as through loss of earnings by the patient or by family carers) costs. Most of the expenses of patients living at home are borne by their families (Gray & Fenn 1993; Rice et al. 1993; Stommel et al. 1994). One study reported that informal care provided to patients with Alzheimer’s disease (AD) living at home averaged 286 h per month (Max et al. 1995). Even after patients were placed in a nursing home, the number of monthly informal care giving hours was reported to be 36. Another reason that care givers are a legitimate target for intervention is that they may be able to benefit patients’ quality of life. For example, the reported link between psychological morbidity in care givers and depression in patients (Brodaty & Luscombe 1998) implies that relieving the care givers’ psychological well-being could improve patients’ depression. Teaching care givers better coping strategies or specific behavioral techniques could, respectively, delay nursing home admission (NHA) or relieve depression in their spouses with dementia (Brodaty et al. 1997; Teri et al. 1997). Care-giver interventions in Sydney and New York have been demonstrated to delay nursing home admission and reduce care-giver psychological morbidity (Brodaty & Gresham 1989; Mittelman et al. 1996; Brodaty et al. 1997). The former has added importance because one of the major costs in dementia

CARE-GIVER INTERVENTIONS 765

care is institutionalization. The latter is important as care givers may become less psychologically distressed after patients have been admitted to residential care (Brodaty & Hadzi-Pavlovic 1990). This could pose a dilemma for the therapist if a delay in institutionalization were to improve the quality of life for the patient, but prolong the agony of the care giver.

Measuring the effectiveness of care-giver interventions Considering that psychological morbidity is the most often reported adverse effect of care giving and the most robust finding, it is not surprising that most intervention studies directed at care givers have used psychological measures, such as ratings of morale or depression, as their primary outcomes. Other measures have included care givers’ social activity and mediating variables, such as care givers’ capacity to cope or their knowledge about dementia. An important patient outcome variable is time to NHA. More direct measures of patient outcome include rate of cognitive decline, functional day-to-day abilities, mood and ability to relate to others.

The interventions We describe (in detail below) the interventions, which are quite heterogeneous in nature, under five broad categories: education, training, support, counseling and combined interventions. Respite care is considered in Chapter VII.6.

Method Search strategy An extensive literature search was performedasee website for details. Criteria for inclusion As there are relatively fewer good-quality evidencebased studies in this area of research compared to others, the criteria used for inclusion were less

strict than in some other chapters. The essential criterion was that the study employed either a control group or a comparison group. Randomization was preferred but not essential. Finally, in order to ensure that evidence was both recent and as comprehensive as possible, the search was limited to articles from 1985 to mid-2000. Thirty-five articles, which met these criteria, were included in the review. Scoring method The obtained articles were then scored according to the following criteria:

Criteria Design Randomized controlled trial Non-randomized, but comparable groups Non-randomized, non-comparable groups Patients Use of standardized diagnostic criteria All patients accounted for/withdrawals noted Outcomes Well validated, reliable care-giver measures; or Well validated, reliable patient measures; or Other objective outcomes* Blind ratings† Results/conclusions Statistical significance considered or Adjustment for multiple comparisons or Evidence of sufficient power Follow-up assessment six months or beyond

Score

2 1 0 2 1 1 1 1 1 1 1 1 1

Good quality

>7

Poor quality

6 months) + 1 (statistical significance considered) = 7. Reliability of ratings The two reviewers rated the papers independently according to the above criteria. Inter-rater reliability was estimated, the intraclass correlation coefficient being 0.91. Where there was disagreement, consensus ratings were achieved and these are the figures given in the tables.

Recommendations Recommendations for the five different types of interventions were graded A, B, C, for which the quality of evidence was assessed as level 1–10 according to the following schema. A ‘High’ quality evidence with minimal potential for bias 1 Extremely reliable, often requiring large-scale randomized trial, evidence from a single trial or a systematic review. 2 Moderately reliable, from moderate scale randomized trial, evidence from a single trial or a systematic review. 3 Questionably reliable, often small-scale randomized trial, evidence from a single trial or a systematic review. 4 Evidence from a single unplanned analysis of the aforementioned types of studies. B ‘Moderate’ quality evidence with moderate potential for bias 5 Evidence that is from a quasi-randomized or randomized trial with important potential sources of bias, e.g. lack of double blinding when crucial, cross-over study with possibility of carryover effect, numerous dropouts. 6 High-quality non-randomized prospective or case-control study of groups with and without interventions. 7 High-quality series of ‘N-of-1 trials’ where evidence from levels 1–5 is absent. 8 High-quality case series. C ‘Poor’ quality evidence with substantial potential for bias

9 Evidence from poor quality non-randomized prospective, case control and case series studies. 10 Opinions not based on the above levels of evidence (hypotheses, laboratory data, animal data, ‘experts’).

Outcomes The studies reviewed utilized a wide range of both patient and care-giver outcomes. For the patient they included measures of cognition, function, problem behaviors (e.g. agitation, wandering), depression, institutionalization, death, and coping responses. Care-giver measures included ratings of wellbeing, depression, anxiety, physical health, hassles, knowledge of AD and dementia, objective and subjective burden, satisfaction with life, quality of life, happiness, coping styles, healthcare utilization and expenditure, morale, decision-making confidence and skill, isolation, social support, physical strain, emotional strain, relationship strain, activity restriction, positive features of care giving, sleep quality, mood, assertiveness, self-esteem, social skills, communication with patient, responsibility for case management tasks for patient, and perceptions of and satisfaction with intervention.

Interventions Given the complexity of studies and heterogeneity of interventions in this area, we did not attempt to pool the studies, as is usually the norm in evidence-based reviews. We arbitrarily divided the interventions into five categories for ease of conceptualization and description. In some cases the categories are overlapping, such that some of the interventions could have been included in an alternative category.

Education (see Table VII.3.1) The prime focus of these interventions was to provide education or information to care givers. Interventions focused upon the provision of information about AD and the disease process, the enhancement of communication with the patient, stress management, and the management of prob-

Table VII.3.1 Details of key trials: education. Design

Patients/carers

Study: Ripich et al. (1998); Quality score (design): 7 Country: US Non-randomized N = 37 (experimental = 19, control controlled study1 Duration: 4 weeks = 18) Carers: Mean age 60.86 years (experimental) and 62.49 years (control) 58% spouses (experimental), 61% spouses (control) Patients: Early to mid AD (NINCDS-ADRDA)2 Mean MMSE 16.63 (experimental) and 17.06 (control) No withdrawals1

Outcomes

Results/comments

FOCUSED communication training: 8 h over 4 weeks in groups 8–10 Info about AD and communication, techniques to enhance communication

Subjective well-being: PANAS1 CESaD Subjective overall physical health questionnaire Caregiver Hassles Scale Knowledge Assessment Measure Assessment at baseline, within 3 week post-training, 6 months, and 12 months1

Lower negative affect overall than control group (P < 0.05)1 Higher overall scores for knowledge of AD and communication than controls (P < 0.001), which increased significantly from entry to 6 months (P < 0.001) and maintained at 12 months Significant decrease in Communication Hassles at 6 months, maintained at 12 months (P < 0.05) for FOCUSED group

Six sessions of training: education, stress management and problem behavior management in a group setting Superimposed on Alzheimer’s Association support groups Waiting list control Knowledge about dementia Assessed at pre- and post(6.3 ± 1.6 months)1

Problem Behavior Checklist1 Family Burden Interview GHQ SWLS PANAS Happiness Scale Two measures assessing

No significant differences in outcomes between the groups Partial completers had significantly higher burden scores both before (P < 0.02)1 and after (P < 0.03) the training compared to the other two groups There was improvement in knowledge for the entire sample over time, no group differences Of the 25% who responded, 62% reported that the program had been valuable Assuming moderate effect size (0.8) and a = 0.05, power was 0.67

Continued on p. 768

CARE-GIVER INTERVENTIONS 767

Study: Brodaty et al. (1994); Quality score (design): 7 Country: Australia Non-randomized N = 81: n = 33 (training controlled trial1 Duration: 18 h completed), n = 22 (partial spread over completed),1 n = 26 controls Essential criteria: four months Primary care givers Living with patient Members of the Alzheimer’s Association Carers: 77% female, 75% spouses, mean age 64.3 years Patient: carer reporta74% AD, MID 12%; CDRS mean 11 at entry2

Interventions

Table VII.3.1 (cont’d) Patients/carers

Study: Chiverton & Caine (1989); Quality score (design): 5 Non-randomized, Country: US N = 40 (20 each group) controlled trial1 aexcluding 7 withdrawals1 Duration: three Carers: spouses, mean age sessions, 2 h 71 years each

Study: McCallion et al. (1999); Quality score (design): 11 Country: US Randomized, N = 66 (FVEP = 32, UC = 34) controlled trial2 Duration: 8 weeks Patient: nursing home residents, Diagnosis of moderate dementia: MDS+, MMSE, GDS2 Carer: 80% female, 11% spouse, 29% adult children, 35% power of attorney, mean age 62 years (FVEP), 56.55 years (UC) Withdrawals: 91

Interventions

Outcomes

Results/comments

Three × 2 h sessions over 3–4 weeks Didactic presentation and group discussion Disease process, communication skills and behavioral management techniques, strategies for ADLs

HSFCI1: physical independence, therapeutic competence, knowledge of condition, general hygiene, health attitudes, emotional competence, family living, physical environment, community resources Assessor blind to conditions1 Assessed pre- and post- (4 weeks)

Significant difference in coping ability from pre- to post-HSFCI between treatment and control (P < 0.004)1aincrease for treatment group Increase in therapeutic competence (P < 0.01), knowledge (P < 0.001) and emotional competence (P < 0.03) No effect for gender

FVEP: verbal and nonverbal communication, effective structuring of family visits 8 weeksa4 × A h group sessions; 3 × 1 h family conferences UC control: usual social and recreation at nursing home

Carer: DMSS1ause of criticism, use of encouragement, active management CHS-M VSQ Patient: MOSES CSDD CMAI GIPD MPB MDS+ Assessed at baseline, 3 months, 6 months Blind assessor1

Carer: Significant increase in use of encouragement by 3 months (P < 0.004)1 but was not sustained at 6 months Carer reported that FVEP had significant impact on residents (cognitive functioning) Patient: FVEP residents showed reduced irritability (P < 0.01) and depression (P < 0.001) (MOSES, CSDD) FVEP residents engaged in significantly less verbally agitated behavior (P < 0.005) and less physically nonaggressive behavior (P < 0.001) (CMAI) FVEP patients had a significantly longer average length of stay in nursing home (P < 0.01) 80% power to detect moderate effect size (0.40) for condition–time interactions for all outcomes1 Bonferroni correction for multiple comparisons (a = 0.01)1

Numbers in superscript refer to points allocated according to the rating system. CDRS, Clinical Dementia Rating Scale; CESaD, Center for Epidemiologic Studies Depression Scale; CHS-M, Caregiving Hassles Scale; CMAI, Cohen-Mansfield Agitation Inventory; CSDD, Cornell Scale for Depression in Dementia; DMSS, Dementia Management Strategies Scale; FVEP, Family Visit Education Program; GDS, Global Deterioration Scale; GHQ, General Health Questionnaire; GIPD, Geriatric Indices of Positive Behavior; HSFCI, Health Specific Family Coping1 Index for Non-Institutional Care; MDS+, Minimum Data Set; MOSES, Multidimensional Observation Scale for Elderly Subjects; MPB, Management of Problem Behaviors, NINCDS ADRDA, National Institute of Neurological and Communicative Diseases Alzheimer’s Disease and Related Disorders Association; PANAS, Positive and Negative Affect Scales; SWLS, Satisfaction with Life Scale; UC, Usual Care; VSQ, Visit Satisfaction Questionnaire.

768 CHAPTER VII.3

Design

CARE-GIVER INTERVENTIONS 769

lem behaviors of the patient (Chiverton & Caine 1989; Brodaty et al. 1994; Ripich et al. 1998; McCallion et al. 1999). Some of the benefits of educational programs for care givers included increased knowledge about the disease process (Chiverton & Caine 1989; Ripich et al. 1998), reduced care-giver negative affect and communication hassles (Ripich et al. 1998), increased feelings of competence and independence (Chiverton & Caine 1989), and improved communication with the patient (McCallion et al. 1999). Moreover, McCallion et al. (1999) reported a reduction in the patient’s problem behaviors and a decrease in their symptoms of depression and irritability. However, the program used by Brodaty et al. (1994) did not find improvements in caregiver knowledge, psychological stress, burden, life satisfaction or well-being, although care givers reported that they were very satisfied with the program.

Support groups/programs (Table VII.3.2) Typically, support groups are forums for group discussion and emotional support; however, many of the groups in the studies reviewed also provided information on dementia, relaxation training and stress management, and role-played problemsolving strategies. One support program was even conducted through a computer support network (Brennan et al. 1995; Bass et al. 1998). The findings were mixed, with many studies finding limited or no beneficial effects. Some of the positive findings for carers included increased knowledge about AD (Hébert et al. 1994; Kahan et al. 1985), improved confidence in decision-making (Brennan et al. 1995), decreased care-giver burden and reduced caregiver depression (Kahan et al. 1985). By comparison, several studies failed to find an association between support group attendance and improvement in care-giver burden or psychological distress (Hébert et al. 1994), social isolation, depression (Haley et al. 1987; Brennan et al. 1995), health status (Brennan et al. 1995), strain (Bass et al. 1998), life satisfaction or coping ability (Haley et al. 1987). Support groups neither impacted on the rate of institutionalization of the patient (Hébert et al. 1995), nor affected the utilization of health-

care or community resources (Weinberger et al. 1993). Despite this, carers tended to report that the groups were useful and indicated high levels of satisfaction with them (Haley et al. 1987; Hébert et al. 1994).

Carer training (Table VII.3.3) Carer training programs have been wide ranging, and have focused on both the care giver and the patient. One patient-focused program trained care givers in cognitive stimulation techniques, i.e. performing activities that aimed to stimulate the mind of the patient in terms of memory, problem-solving skills, and conversational fluency (Corbeil et al. 1999). An improvement in carers’ satisfaction with their interaction with the patients was reported, which was attributed to an increased use of more positive re-appraisal of the stressful situation that attenuated the behavioral stressor effects. A similar program of cognitive stimulation showed that patients in the experimental group maintained their levels of cognitive and behavioral functioning while improving emotionally, compared to patients in the control group who deteriorated. Furthermore, care givers maintained their level of well-being and improved their coping resources (Quayhagen & Quayhagen 1989). A multicenter study of the treatment of depression in patients with AD compared two care-giver administered behavioral interventions: planning pleasant events for the patient and developing problem-solving skills, with two control conditionsatypical care and waiting-list (Teri et al. 1997). They found that both behavioral strategies, but neither of the control conditions, resulted in improvements in patient and care-giver depression. These improvements in patient rates and levels of depression were maintained at six months’ follow-up and were independent of the severity of the dementia. Only a few of the interventions that targeted the various needs of the care giver demonstrated positive findings. Training in behavioral management techniques was found to improve care givers’ knowledge of dementia and reduce stress associated with behavioral disturbances (Zanetti et al. 1998). Training care givers to perform case management duties for the patient in partnership with a social

770 CHAPTER VII.3

Table VII.3.2 Details of key trials: support groups/programs. Design

Patients/carers

Study: Hébert et al. (1995); Quality score (design): 8 Country: Canada Randomized, N = 45 (experimental = 24, controlled trial2 Duration: 8 weeks control = 21) Inclusions: carers of community dwelling, demented patients (as diagnosed by DSM-IIIR criteria)2; weekly contact with the patient; French speaking Withdrawals: 41 Exclusions: carers who had attended > 2 meetings of the Alzheimer’s Society Carers: Mean age: 60.3 years, 66.7% female, 64.4% spouses, 82.2% resided with patient Study: Hébert et al. (1994); Quality score (design): 9 Randomized, Country: Canada controlled trial2 N = 45 (experimental = 24, Duration: 8 weeks control = 21) As in Hébert et al. (1995)

Interventions

Outcomes

Results/comments

Structured program of eight weekly sessions of 3 h each; including: information on dementia, role-playing, discussion of problems with the patient, relaxation training. Control: referred to informal monthly meetings of the Alzheimer’s Society Experimental group: 29% participated in ≤ 3 sessions; 71% attended ≥ 6 sessions Follow-up at 32–42 months1

Date of termination of care giving (through institutionalization, death of patient, or change of care giver) or continuation or care giving1

24 months survival analysis showed no significant difference in institutionalization1 Lack of power due to sample sizeawould have needed 180 per group to detect a significant effect (P < 0.05) with 90% power

As in Hébert et al. (1995)

BI1 RMBPC BSI ADKT Health care utilization questionnaire Assessor was blind to the assignment of subjects1 Evaluated at baseline (T1), after eight weeks (T2), and after eight months (T3)1

Compared with the control group, subjects of the experimental group yielded a significant increase in knowledge about AD (P < 0.0001)1 RMBPC scores were significantly lower in the experimental group when only subjects who participated in > 3 sessions were considered (P < 0.05) No significant differences on any of the other outcome variables. 95.5% were satisfied or very satisfied with the intervention and 95% found it useful or very useful in their daily living. Study had 60% power to detect effect size 0.8

Study: Brennan et al. (1995); Quality score (design): 6 Randomized, Country: US controlled trial2 102 primary informal care givers of Duration: 12 community-residing AD patients months (n = 51 each group) Inclusion criteria: telephones, fluency in written and spoken English Withdrawals: four in the experimental group and two from the control group1 Age: median 64 years, 67% female, 68% spouses

Study: Bass et al. (1998); Quality score (design): 5 Country: US Randomized, 102 primary informal care givers of controlled trial2 Duration: 12 community-residing AD patients months Withdrawals: four in the experimental group and two from the control group1 See Brennan et al. (1995) for details

Decision-making confidence: Modified decision confidence measure Decision-making skill measure Isolation: Instrumental and Expressive Social Support Scale1 Assessed at baseline (T1) and 12 months (T2)1

Greater improvement in decision-making confidence than controls (P < 0.01)1 No significant difference in decisionmaking skill or social isolation

As in Brennan et al. (1995)

Mix of standardized measures (not specified) and other items that assessed carer’s perceptions of: physical strain emotional strain relationship strain activity restriction Assessed at baseline (T1) and 1 year (T2)1

Participation in the intervention did not alter the relationship between T1 and T2 carer strain ComputerLink access led to significantly greater reduction in emotional strain and activity restriction for carers with more informal support (P < 0.05)1

Continued on p. 772

CARE-GIVER INTERVENTIONS 771

ComputerLink: computer support network (24 h access) Communication component (public bulletin board, private mail, Q & A segment facilitated by a nurse) Solitary component (electronic encyclopedia on AD and treatment) 90 minute training session on use Monthly phone call on service use Control: 90 minute placebo training session on identifying local services and resources

Design

Patients/carers

Study: Weinberger et al. (1993); Quality score (design): 5 Randomized, Country: US controlled trial2 N = 264 (experimental Duration: six group = 193; control = 71) months Inclusion criteria: patients judged by MDC to have dementia Carers with primary responsibility for patient 6-month questionnaires completed by 86% of experimental and 87% of control group. Diaries returned by 52.3% of experimental and 56.3% controls1

Study: Haley et al. (1987); Quality score (design): 6 Country: US Randomized, N = 40 (support = 14, support/ controlled trial2 Duration: skills = 17, control = 9) 10 weeks Carer: Primarily spouses and daughters, mean age 56 years Carerbinclusions: weekly care of community dwelling patient Carerbexclusions: ≥ 6 sessions of Alzheimer’s Association support group Patient: mean age 78.3 years, Patientbinclusions: ≥ 60 years, diagnosis of dementia ≥ 6 months Patientbexclusions: MMSE > 24 Withdrawals: 7 support, 5 support/skills, 2 control1

Interventions

Outcomes

Results/comments

MDC social worker made contact with local service agencies to assess services offered and eligibility Individualized service plan including a mean of 3.6 recommendations given at 4-week visit Follow-up within one week of the 4-week visit to reinforce and assess compliance Control: given general information packet with written information about AD (usual care)

Questionnaires and diaries completed at baseline and 6 months noted: health care utilization1 patient’s health care expenditures

No significant impact on health care utilization (by care giver/patient) or expenditure1 even when factors such as age, race, months as carer were controlled for Post hoc calculations showed that 600 patients per group were needed to detect a significant difference (P < 0.05) with power of 0.80

10 sessions of 11/2 h each (seven weekly, then two at 2-week intervals, and one after 1 month delay) Support: information about dementia, emotional support, problem-solving Support/skills: same as above plus progressive relaxation training and managing negative cognitions Waiting list control

Severity of depression: BDI1 Perceived life satisfaction: (LSIZ) Negative affect toward patient: Negative impact on ECR Social activity: HDLF Carer’s ratings of satisfaction with social networks Carer coping responses (logical analysis, information seeking, problem solving, affective resignation, emotional discharge)ascales from HDLF Impressions of the Caregiver Group Assessment pre- and postgroup, and follow-up (4 months) Blind assessors1

Group participants did not show significantly greater improvement over time compared to controls on any of the outcome measures. Control group used higher levels of the coping style of emotional discharge than either treatment group (P < 0.05)1 Support group had lower scores on affective regulation coping style than support/skills and controls (P < 0.05) No difference in treatment satisfaction, but 76% endorsed highest level of satisfaction Carers were quite heterogeneous in pretreatment measures of distress, with some showing minimal levels of depression and other measures of distress: difficult to show improvement

772 CHAPTER VII.3

Table VII.3.2 (cont’d)

Study: Kahan et al. (1985); Quality score (design): 3 Non-randomized, Country: US controlled trial1 N = 40 (22 treatment, 18 control) Duration: eight Carers of AD patients: weeks Ranged from 16–77 years 32.5% > 60 years, 35% daughters, 47.5% spouses

Eight weekly 2 h meetings: education, group discussion, role-playing, stress management Waiting list control

Family Burden Interview1 SDS Dementia Quiz Program Rating Sheet Assessment pre- and postintervention

Controls showed an increase in total family burden (P < 0.01) and the experimental group showed decrease (P < 0.02)1 More of the experimental group showed improved burden scores and fewer showed deterioration than controls (P < 0.001) Small but significant decrease in depression in experimental group but not controls (P < 0.02)amore of the experimental group showed improvement and fewer deteriorated (P < 0.05) Experimental group showed increase in knowledge of dementia, controls did not (P < 0.000) 90% of experimental believed program was very or extremely helpful overall

Numbers in superscript refer to points allocated according to the rating system. ADKT, Alzheimer’s Disease Knowledge Test; BDI, Beck Depression Inventory; BI, Burden Interview; BSI, Brief Symptoms Inventory; CESaD, Center for Epidemiological StudiesaDepression scale; ECR, elderly caregiver family relationship; HDLF, Health and Daily Living Form; LSIZaZ, Life Satisfaction Index; MDC, Memory Disorders Clinic; MMSE, Mini Mental Status Examination; RMBPC, Revised Memory and Behavior Problems Checklist; SDS, Self-Rating Depression Scale.

CARE-GIVER INTERVENTIONS 773

Design

Patients/carers

Study: Corbeil et al. (1999); Quality score (design): 7 Randomized Country: US controlled trial2 N = 87 dyads (carer– patient)a Repeated although 95 completed pretest measures Carer: Duration: 12 weeks Age: mean 67.1 years 77% female Dyad inclusion criteria: > 40 years age Coresident Carer has primary responsibility for patient Patient has diagnosis of probable or possible AD. Functional level of patient was mild to moderate Not participating in any other active medication study for dementia Withdrawals: 91 Study: Zanetti et al. (1998); Quality score (design): 4 Country: Italy Non-randomized, N = 23 (12 experimental, 11 controlled trial1 Duration: control) six weeks Carers: 90% carers BSI score > 95th percentile Mean age: 53.8 years (experimental), 56.7 (control) 92% female (experimental), 55% female (control) Carers inclusion criteria: Home care Primary carer Patients: 11 AD, 6 VaD, 4 other dementia Patient NPI > 14 Two carers in the control group withdrew before follow-up1

Interventions

Outcomes

Results/comments

1 h, six days per week over 12 weeks of: Active cognitive stimulation (experimental): Trained in activities to stimulate the mind of patient in areas of memory, problem solving and conversational fluency (n = 28) Passive cognitive stimulation (placebo program): Passive activities; same time-frame and same exposure to researchers as experimental (n = 28) Waiting list control (n = 31)

Dyadic interactionacarer satisfaction (Marital Needs Satisfaction Scale)1 Mediating variables: Memory and behavior problems of patient (Part A of Memory and Behavior Problems Checklist) Carer perception of stress (Part B of Memory and Behavior Problems Checklist) Coping method (Ways of Coping Scale-Revised) Emotional support (subscale of the Social Support Questionnaire) Assessment at baseline, posttreatment (3 months) and followup (9 months)1 Blind assessment1

At post (3 months): Patient deterioration paralleled increased stress in the carer for all treatment groups (P < 0.05)1 Effect of stress on the dyadic interaction was somewhat attenuated in the experimental group compared to the control group (P < 0.05) The coping strategy of positive reappraisal had a positive role on dyadic interaction in the experimental but not control or placebo groups (P < 0.05) At follow-up (9 months): The stress levels of the experimental group reverted to the level of the control and placebo group Carer satisfaction via reappraisal remained positive in the experimental group and became negative in the control group (P < 0.05)

Six weekly 1 h sessionsa didactic presentation and group discussion: behavioral management techniques Controlanot specified

Questionnaire including objective measures of knowledge and psychosocial factors Carer depression: BSI1 Perceived stress: memory and behavior checklist: Carer Quality of life: LEIPAD scale (subscales of physical functioning, self-care, depression and anxiety, cognitive functioning, social functioning, life satisfaction) Knowledge of the disease: ADTK Follow-up at end of program and 3 months post-

Carers in the experimental group showed an increase in disease knowledge from baseline to post- (P < 0.005)1, which lasted for the following three months (P < 0.01), while controls showed none At three months, experimental carers showed a significant decline in perceived stress relating to patient’s disturbances (P < 0.04), even though the behavioral disturbances of patients did not change significantly. Carers in the experimental group showed a significant improvement in cognitive functioning (P < 0.01) and life satisfaction (P < 0.04), whereas controls did not No reduction in emotional symptoms such as depression or anxiety (LEIPAD)

774 CHAPTER VII.3

Table VII.3.3 Details of key trials: carer training.

Study: Teri et al. (1997); Quality score (design): 8 Randomized, Country: US controlled trial2 N = 72 carer–patient pairs Duration: nine (excluding 16 withdrawals)1 Inclusion criteria (patients): weeks NINCDS-ADRDA criteria for probable AD2 ≥ 6 month history of cognitive problems Live with carers in community RDC and DSM-III-R for major/minor depression Hamilton Depression Rating Scale score ≥ 10

Carer depression: SADS1 RDC HDRS Burden: Burden Inventory Positive aspects of caring: questionnaire on benefits of caring Assessed at pre-test, post-test (9 weeks) and follow-up (6 months)1

Overall treatment effect for carer depression on the HDRS (P < 0.01)1 No significant outcome differences between BT-PE and BT-PS carers BT-PE and BT-PS carers depression (HDRS) improved significantly more than TCC and WLC carers This improvement (HDRS) was maintained at 6 months (P < 0.05) Effects were found even though the treatment was not targeted to the carer, but rather trained the carer to aid the patient Patients in BT-PE and BT-PS showed improved depression compared to TCC and WLC (P < 0.001), maintained at 6 months

Phase 1: Active treatment (n = 7): 6 weekly small group sessions: sleep hygiene, stimulus control, sleep compression, relaxation techniques, community resource information, and behavioral techniques to reduce patient problem behaviors Waiting list control (n = 5) Phase 2: Active treatment (n = 14): same as above but condensed into four weeks. Individual sessions Waiting list control (n = 10)

Carer sleep: PSQI1 Carer mood: CES-D Reactions to patient behaviors: SCB; RMBPC Sleep diary: information on bedtime, onset sleep latency, nocturnal awakenings, rising time, naps, sleep quality, restfulness, medications Assessor was blind to carer treatment condition1 Assessed post-treatment and at three months follow-up

Overall sleep quality (PSQI) was significantly better for carers in the active condition at post-treatment and follow-up (P < 0.05) than for control carers1 There were no significant differences in carer mood, burden, or patient behaviors at posttreatment or follow-up, but there was a tendency for depression scores to decline at post-treatment in both conditions Sleep diary data from carers in the active group showed a significant improvement 4 weeks from baseline in carer sleep efficiency (P < 0.007) 60% of care givers were judged to have demonstrated clinically significant improvements

Continued on p. 776

CARE-GIVER INTERVENTIONS 775

Study: McCurry et al. (1998); Quality score (design): 6 Randomized, Country: US controlled trial2 N = 36 Duration: six Carers: 78% female, 75% weeks (phase 1) spouses or four weeks Mean age: 68.7 (phase 2) Inclusion criteria (carer): Average of 3+ sleep problems per week ≥ 50-year-old Carer of family member with dementia, living with patient or have primary responsibility for them No medication for sleep or stabilized for ≥ 6 weeks Exclusion criteria: Prior diagnosis of sleep disorder or chronic illness causing sleep disorder Withdrawals: 2 (second phase)1

Weekly, 60 minute sessions over 9 weeks: BT-PE: Pleasant Events Schedule-AD used by carer to generate ideas and plan pleasant activities for the patient BT-PS: problem solving strategies for patient depression behaviors of specific concern to carers TCC: typical advice and support usually provided by community services WLC

Design

Patients/carers

Study: Robinson & Yates (1994); Quality score (design): 4 Randomized Country: US controlled trial2 N = 33; n = 11 (BMSDP), Duration: n = 10 (SSDP), n = 12 (control) 12 weeks Twice-trained group: n = 6 Inclusion criteria: significant time spent providing at-home care Carers: 76% spouses, 76% female, 76% > 60 years

Interventions

Outcomes

Results/comments

CTP. six 90 min sessions over 12 weeks of either: BMSDPaunderstanding and managing problem behaviours; or SSDPateaching skills to gain social support network After post-test, both groups were offered the alternate CTP (29% availed) Control groupano training

Objective burden: objective burden scale1 Subjective burden: subjective burden scale Attitudes toward using adult day care and asking for help Satisfaction with social support and amount of help Assessed at pre-test (T1), 1 month post-test (T2), at pre-test cross-over (T3) at completion of alternate CTP (T4)

Post-test minus pre-test difference scores at T2 yielded no significant differences between the three groups At T3 compared to controls, the twice-trained carers had significantly less objective (P < 0.001) and subjective burden (P < 0.01), an improved attitude toward asking for help (P < 0.05) and an improved attitude toward using adult day care (P < 0.001)1 At T4 compared to controls, the twice trained carers had significantly decreased objective burden (P < 0.01), an improved attitude toward asking for help (P < 0.001) and an improved attitude toward using adult day care (P < 0.001). No significant difference in subjective burdenaboth groups experienced a decline

Care giver: Well-being: Burden Inventory; Hopkins Symptom Checklist; Health Assessment Scale1 Patient: Functional status: Dementia Rating Scale, Logical Memory and Associated Learning (WMS II); arithmetic problems Coping responses: Geriatric Coping Schedule, Memory and Behavior Problems Checklist1 Assessment at pre- 4-, 8-months follow-up

Care giver: Treatment-group carers: maintained mental health status and burden over time (P < 0.05) Control carers increased affective symptoms and burden (P < 0.05)1 Control carers increased obsessive compulsive responses over time (P < 0.05) Patient: Main effect for time: treatment group maintained level of behavioral functioning, controls deteriorated (P < 0.05) Cognitive functioning (DRS) of treatment group maintained over time, control decreased (P < 0.001) 70% of carers felt there had been positive emotional outcomes in patient due to program Small sample size (low power)

Study: Quayhagen & Quayhagen (1989); Quality score (design): 7 Non-randomized Home-based program of Country: US controlled trial1 cognitive stimulation for N = 16 (treatment = 10) Duration: patient 1 h/day (6 h/week) Carer: mean age: 67 years, 60% four months conversation, memory male exercises and problem Patient: mean age 68.3 years, solving Diagnosis of probable mildControl: no training moderate dementia of AD 2 (GDS) Control: Carer mean age 64.8 years, patient mean age 66.5 years Withdrawals: 41

‘

776 CHAPTER VII.3

Table VII.3.3 (cont’d)

Study: Gendron et al. (1996); Quality score (design): 6 Country: Canada Randomized, N = 35 (C-B = 18, I-S = 17) comparison 2 Carers: spouses, 66% female, group mean age 66.2 years, Duration: eight coresident with patient, weeks primary responsibility for patient Withdrawals: 91

Hopkins Symptom Checklist1: depression, anxiety, somatization, interpersonal sensitivity, obsessivecompulsive symptomatology The Automatic Thoughts Questionnaire: negative self-concept, perception of maladjustment, low self-esteem, helplessness Jalowiec Coping Scale: confrontive, emotive and palliative coping styles Rathus Assertion Inventory: assertiveness Dyadic Adjustment Scale: global perception, consensus, affectional expression, satisfaction and cohesion Burden Interview Scale: perceived burden, formal and informal support Program Evaluation Questionnaire Assessed pre-, post-, 3 months, 6 months Rater blind to assignment1

C-B showed significant increase in assertiveness with extended family members, I-S showed significant decrease (P < 0.01)1 Decrease in Perceived Global Marital Adjustment scores and perceived Marital Satisfaction in C-B and increase in I-S (P < 0.05) No significant differences on other outcome measures

SET: eight weekly training sessions; meditative relaxation, assertiveness training, cognitive restructuring Attention placebo procedureaviewed human interest documentaries

Carer: GHQ1; Beck Depression Scale; Rotter Locus of Control Test; RAI; Spielberger State–Trait Anxiety Inventory; PTT; RPS; Hierarchy of Coping Patient: BDS; Plutchik Geriatric Scale Assessed at baseline, posttraining and 6 months follow-up1

Depression: Scores on Beck Depression Scale and GHQ indicated minimal levels of depression and somatic complaints in all subjects at all assessment times Assertion: four trained carers improved from baseline to post, three maintained at follow up. One control showed improvement, two controls deteriorated Anxiety: trend toward increase in controls. Not pathological PTT: three trained carers showed increased PTT by one year or more. Increase for 11 of 12 problem situations. Among controls, increase in PTT in six problem situations, decrease in three, no change in three RPS: three trained carers achieved a mean gain across 12 problem situations > 1 level on hierarchy of coping, one showed mean gain > 2 levels. No gain in controls Small sample size Wide disparity among subjects with regards to age, sex, social class, level of dementia of patient, relationship of carer to patient Statistical significance not reported Continued on p. 778

CARE-GIVER INTERVENTIONS 777

Study: Gendron et al. (1986); Quality score (design): 5 Non-randomized, Country: Canada controlled trial1 N = 12 (experimental = 8, control = 4) Duration: eight Inclusion criteria: carer of weeks demented relative at home Carer: eight women, four men; aged from 45 to 83 years; five spouses, two sisters, four mothers and one mother-in-law Patient: aged 61–81 years; Diagnosis of dementia (Blessed Dementia Scale, Information–Memory– Concentration Test)2

Weekly, 90 minute session over eight weeks C-B skills training: coping skills, assertion training, problem-solving, cognitive restructuring I-S group: comparison group Information (presentations, videos) on health and aging, dementia, community resources, social and leisure activities, nutrition, respite services, legal issues and nonstructured discussions

Design

Patients/carers

Study: Robinson (1988); Quality score (design): 4 Randomized, Country: US controlled trial2 N = 20 (11 = treatment, Duration: eight 9 = control) weeks Carers of AD (mainly community-residing) patients

Study: Seltzer et al. (1992); Quality score (design): 6 Randomized, Country: US controlled trial2 N = 69 Duration: six Patient inclusion criteria: ≥ 55 months years Required case management services Did not require emergency services within 24 h of referral Patients: outpatients from Behavioral Neurology unit; mean age 73.98 years Carer: mean age 56.86 years, 72.4% female, 39.7% spouses, 44.9% adult children Withdrawals: 111

Interventions

Outcomes

Results/comments

Social skills training; four 2 h sessions; didactic knowledge and discussion Waiting list control

Self-esteem: Self Esteem Scale (Rosenberg)1 Social Skills: Assertion Inventory (Gambrill & Richey) Objective and subjective burden scales (Montgomery) NSSQ Assessed pre- and post-treatment (8 weeks)

No significant difference in assertion, self-esteem, and social support between treatment and control1 Objective (P < 0.001)and subjective (P < 0.05) burden were significantly reduced at post- for the treatment group, but the mean burden scores were not significantly lower for the treatment compared to control group Control group became significantly less assertive at post (P < 0.05) Since post- measures were given on last day of treatment, maybe not enough time had elapsed for effect

Systematic training in performing case management duties for patient in partnership with social worker. Information about case management also presented in workshop setting Follow up: support group meeting two weeks post workshop Control: services ordinarily provided

CMT: Number performed Number successfully completed Types performed Objective burden: number of daily living tasks (out of 31) for which assistance was provided by family member Standardized subjective burden scale1 Frequency of contact both with patient and family Assessed by social worker at preand post- (6 months)1

Experimental-group carers performed greater number of CMTs than controls (P < 0. 05)1 No difference between experimental-group and control carers for success or type of CMTs No differences in number, type, or success of CMTs by social workers for experimental or controls No differences between experimental group and control in objective or subjective burden More contact between patient and family for experimental than control group (P < 0.001)

Numbers in superscript refer to points allocated according to the rating system. ADTK, Alzheimer’s Disease Knowledge Test; BDS, Blessed Dementia Scale; BMSDP, Behavior Management Skills Development Program; BSI, Brief Symptom Inventory; BT–PE Behavior Therapy–Pleasant Events; BT–PS, Behavior Therapy–Problem Solving; C–B, Cognitive–Behavioral; CES–D, Center for Epidemiological Studies–Depression Scale; CMT, Case management tasks; CTP, Caregiver Training Programs; GDS, Global Deterioration Scale; GHQ, General Health Questionnaire; HDRS, Hamilton Depression Rating Scale ; I-S, Information-Support; NSSQ, NINCDS ADRDA, Norbeck’s Social Support Questionnaire, National Institute of Neurological and Communicative Diseases Alzheimers Disease and Related Disorders Association; PSQI, Pittsburgh Sleep Quality Index; PTT, Projected Tolerance Time; RAI, Rathus Assertiveness Inventory; RDC, Research Diagnostic Criteria; RMBPC, Revised Memory and Behavior Problem Checklist; RPS, Reactions to Problem Situations; SADS, Schedule for Affective Disorders and Schizophrenia; SCB, Screen for Caregiver Burden; SET, Supporter Endurance Training; SSDP, Social Skills Development Program; TCC, Typical Care Control; WLC, Waiting List Control.

778 CHAPTER VII.3

Table VII.3.3 (cont’d)

CARE-GIVER INTERVENTIONS 779

worker resulted in care givers assuming greater responsibility for case management duties without influencing their objective or subjective burden (Seltzer et al. 1992). However, the majority of interventions aimed at training care givers have shown mixed results. A behavioral program that aimed to treat sleep problems in care givers was successful in its main objective of improving their sleep, but was not effective in improving associated problems of caregiver mood, care-giver burden or patient problem behaviors (McCurry et al. 1998). A cognitive– behavioral program that focused upon coping skills, assertion training, problem-solving and cognitive restructuring, with an information-based program, resulted in increased care-giver assertiveness and a decrease in marital satisfaction (Gendron et al. 1996). However, reductions in psychological distress, negative thoughts, perceived burden nor enhancement of coping styles were found. Finally, in a comparison of two training programs aone aimed at behavior management and the other at social skills developmentaneither had any significant impact on objective or subjective burden, attitudes toward using adult day care, or satisfaction with social support care (Robinson & Yates 1994). However, in the second phase of the study, care givers in either of the experimental groups could enter the alternative program (participation in this second phase was by self-selection and was therefore not truly comparable). Those who took advantage of both training programs experienced a decrease in objective burden and a more positive attitude toward asking for help and toward using adult day care (Robinson & Yates 1994). This is consistent with the finding that a social skills training program alone was not found to influence the care-giver’s assertiveness, self-esteem, level of social support, or burden (Robinson 1988). The lack of efficacy may reflect an inadequate ‘dose’ of intervention in the first instance.

Counseling (Table VII.3.4) To date, there have been relatively few controlled studies examining the effect of counseling, per se, for the care giver. Perkins and Poynton (1990) found that counseling of care givers of patients in

residential care resulted in an increase in care-giver morale and knowledge. Counseling increased the number of physical and social activities performed by the care giver with the (institutionalized) patient, but had no effect on communication with the patient, or in the duration or frequency of visits to the patient. Sutcliffe and Larner (1988) compared two methods of counseling that either emphasized emotional support or information provision. They found that carers who received emotional support were less stressed, whereas those receiving information showed an increase in knowledge but no reduction in stress. The positive outcome from the New York University program of counselling (Mittelman et al. 1993, 1995, 1996) is discussed as a combined intervention below.

Combination interventions (Table VII.3.5) Several studies examined the effectiveness of combinations of different types of interventions for care givers, as well as their comparative effectiveness. Support and education Eloniemi-Sulkava et al. (1999) examined institutionalization and mortality rates in two groups. The experimental group received a combination of support provided by a Dementia Family Care Coordinator (who provided counselling, follow-up calls, home-visits, and arranged social and healthcare services) and courses that provided knowledge, stimulation and rehabilitation for the patients and their carers. There was no significant difference in the number of patients having moved to institutional care and that of deaths between the groups over a 2-year period. However, there was an effect for time to institutionalization: the median time of home care in those who were institutionalized was significantly longer in the intervention group (473 days) than in the control group (240 days). Although there was such a large difference, after two years 32% of intervention patients and 30% of control patients had moved to institutional care and 17% of each group had died. No survival analysis was reported. Baldwin et al. (1989) compared an educational

Design

Patients/carers

Study: Perkins & Poynton (1990); Quality score (design): 5 Randomized, Country: UK controlled trial2 N = 12 (6 each) Duration: 10 weeks Patient: institutionalized, Diagnosis of dementia (mean Mental Status Questionnaire: 9.83) Carer: main family visitor to patient, low/medium score on Kutner Morale Scale

Study: Sutcliffe & Larner (1988); Quality score (design): 7 Randomized, Country: UK controlled trial2 N = 15 Duration: 18 weeks Carers: primary carer, cohabitating Patients: Diagnosis of dementia (GMS (A))2; those with shortterm function disorders excluded

Interventions

Outcomes

Results/comments

Weekly, 1D h sessions of counseling Waiting list control

Kutner Morale Scale1 Knowledge about presenile dementia (questionnaire developed for study) Relative/patient communication Activities performed with patient Pattern of visiting Assessed at pre-, post(10 weeks) and 3 months Blind assessment1

Compared to controls, counseling group showed increase in morale post- and at follow up (P < 0.001)1 Counseling group had increase in knowledge post- and at follow up (P < 0.001) Counseling did not affect communication with patient, duration or frequency of visits Counseling group had increased number of physical and social activities performed with patient at post- and follow up (P < 0.001) Small sample size

45 minute weekly session Emotional support (n = 6): Conversational Model of Psychotherapy; relaxation tape Information provision (n = 4)a papers supplied and discussed Control (n = 5)

BDI1 GHQ Burden Scale DKQ Assessments blind1 Assessed at baseline (T1), 1- (T2), 6- (T3) and 12-weeks (T4)

At 12 weeks, scores on BDI lower in emotional support group than information group or control (P < 0.05)1 No significant differences on Burden Scale and DKQ between groups Control increased on GHQ between T2–T4 (P < 0.02) Emotional support carers decreased on GHQ between T1–T2 (P < 0.05) and on BDI between T1–T4 (P < 0.01), increased DKQ T1–T2 (P < 0.04) Information group increased on DKQ between T1–T4. (P < 0.04) Small sample sizes

Numbers in superscript refer to points allocated according to the rating system. BDI, Beck Depression Inventory; DKQ, Dementia Knowledge Questionnaire; GMS (A), Geriatric Mental Status Examination ScheduleaCommunity Version; GHQ, General Health Questionnaire.

780 CHAPTER VII.3

Table VII.3.4 Details of key trials: counseling.

Table VII.3.5 Details of key trials: mixed interventions. Design

Patients/carers

Interventions

Study: Eloniemi-Sulkava et al. (1999); Quality score (design): 8 Randomized, Country: Finland Support from DFCC: counseling, controlled trial2 N = 100 (treatment = 53, follow-up calls, home-visits, Duration: two years control = 47) arranged social and health care Diagnosis: DSM-IIIR (54% AD, services 35% VaD, 11% other dementia)2 Annual courses for patient and Age: ≥ 65, mean 78.8 carer: at baseline (10 days), 1 (intervention group) and 80.1 year (5 days) and 2 years (5 (control group). days)amedical check-ups, Inclusion criteria: Living at home psychological assessments, Support of an informal carer lectures, group meetings, No other severe disease (e.g. service plan from rehab team. stroke, cancer) Control: standard services from Able to participate in yearly the municipal social and health courses with carer care system or private sector Carers: 56% spouses, 34% children, No withdrawals1

CSP: care giver-focused health care, education about dementia and care giving, assistance with problem solving, 4 h block of weekly and on-demand in-home respite, 2 h monthly support group Control: conventional community nursing care for the patient

Results/comments

Institutionalization of the patient1 Period in home care from enrolment to institutionalization Death of patient Follow up > 6 months1

No significant differences in the number of the patients having moved to long-term institutional care and that of deaths between the groups over the two years1 The median time of home care in those who were institutionalized was 233 days longer in the intervention group (473 days) than in the control group (240 days) (P = 0.02)

Depression: CES–D Scale1 Anxiety: STAI Quality of Life: CQLI Life satisfaction: Cantril SelfAnchoring Striving Scale Self-rated health of carer Scale developed to measure the impact of caring on day-to-day life (extent to which each problem bothered them) Assessed at baseline, 3 months, 6 months Follow up at 12–18 months to assess service needs1

No significant differences in CES–D, STAI or CQLI at 3 or 6 months between experimental and control groups1 Intervention group showed a clinically important improvement in quality of life (↑20%). Would have needed 178 subjects per group to show a significant improvement No difference in day-to-day impact from pre–post between treatment and control groups Mean CES–D at baseline showed minor level of clinically important depressive symptoms (55% of experimental group CES–D ≥ 16) Intention-to-treat analysis did not alter values to clinically or statistically significant extent

Continued on p. 782

CARE-GIVER INTERVENTIONS 781

Study: Mohide et al. (1990); Quality score (design): 8 Randomized Country: Canada controlled trial2 N = 60 (30 each group) Duration: six Eligibility criteria: months Carers: lived with relative, primary carer, spoke English, no life-threatening illnesses, agreed to nursing services Patients: medical diagnosis of primary degenerative, multiinfarct or mixed dementia: ≥ 8 on DRS2 Moderately to severely impaired: ≤ 19 on MMSE, ≥ Stage 5 on Reisberg Global Deterioration Scale No serious concomitant illnesses No plans for institutionalization Withdrawals: eight from the intervention group and ten from the control group1

Outcomes

782 CHAPTER VII.3

Table VII.3.5 (cont’d) Design

Patients/carers

Study: Mittelman et al. (1993); Quality score (design): 8 Randomized Country: US controlled trial2 N = 206 Duration: four Carers: 58.3% female months of Age: 86% ≥ 60 years individual and Inclusion criteria: Spousal carer family counseling, of patient with clinically support ongoing diagnosed AD (31.5% GDS = 4; 40.3% GDS = 5, 28.2% GDS = 6)2 Living with patient At least one close relative in NYC area Exclusion criteria: Carers who had received formal counseling, were participating in a support group, or had a serious medical condition Withdrawals: 3 (from treatment group)1

Interventions

Outcomes

Results/comments

Counselling: 1 individual session for the carer at baseline; and four family sessions and one individual session (for carer) within four months (ranging from 1 to 3 h, mean 11/2 h) After 4 months, required to join an AD carer support group that met weekly and continued indefinitely (72% compliance) Continuous ad hoc informal consultation with counselors Control: standard assistance: resource info on request, but no active intervention or counseling

Predictors of nursing home placement of the patient one year postMediating variables: Care giver questionnaire (frequency of help, utilization of services, frequency of behavioral problems, patients need for assistance with ADLs) Care giver mental health: SPES; GDS1 Care giver burden: Burden Interview Frequency of patient behavioral problems: Memory and Behavior Problems Checklist Care giver social network: Stokes Social Network Scale Care giver physical health: adapted OARS Family cohesiveness: FACES III Global severity of patient dementia: GDS Physical health of patient: OARS Follow-up up to 12 months1

Within one year of intake, the treatment group had less than half as many nursing home placements as the control group (P < 0.05)1 After patient age was taken into account, care giver age was a significant predictor of placement (P < 0.05) Lower income increased odds of placement (P < 0.05) The odds of nursing home placement for treatment group patients was significantly less than for the control group patients (P < 0.05), when carer sex and age and patient age, income and need for assistance with ADLs are taken into account

Study: Mittelman et al. (1995); Quality score (design): 8 Country: US Randomized, N = 206 controlled trial2 Duration: four GDS2: 41.7% ≥ 11; 28.2% ≥ 14 months of 58% female individual and Age: 86% ≥ 60 years family Inclusion and exclusion criteria counseling, (as in Mittelman et al. 1993) support ongoing Withdrawals 1 year: three refused follow up from treatment group, 3 died from control group1

Number of symptoms of depression (GDS)1 Mediating variables: Frequency of patient behavioral problems: Memory and Behavior Problems Checklist Care giver social network: Stokes Social Network Scale Care giver physical health: adapted OARS Family cohesiveness: FACES III Global severity of patient dementia: GDS Physical health of care giver: OARS Assessed at baseline, 4-, 8- and 12-month follow-up1

Care givers in the intervention group were significantly less depressed than controls by eight months (P < 0.05) and 12 month follow-ups (P < 0.001)1 Deterioration in physical health had significant effect on depression at 4 months (P < 0.001), 8 months (P < 0.01) and 12 months (P < 0.001) Increase in family cohesion was associated with decreased depression at 4 months (P < 0.001), 8 months (P < 0.05) and 12 months (P < 0.01) Increased care givers’ satisfaction with social network was associated with decreased depression at 4 months, 8 months (P < 0.05), and 12 months (P < 0.001) Increase in carers’ reaction to problem behaviors was significantly related to depression at 4 months (P < 0.001), 8 months (P < 0.05) and 12 months (P < 0.001)

See Mittelman et al. (1993)

Time until nursing home placement of the patient1 Mediating variables: Global severity of patient dementia: GDS Physical health of care giver and patient: OARS Social network support: average of three questions from Stokes Social Network Scale Assessed every 4 months during the first year, every 6 months thereafter, with up to 8 years of follow-up1

Patients in the treatment group remained at home significantly longer than those in the control group (P < 0.02)1 Median time from baseline to nursing home placement of AD patients was 329 days longer in the treatment group than in the control group (P < 0.02) The risk of nursing home placement by treatment group carers was 65% of that by control group carers (P < 0.02) 40.8% control carers ultimately joined support groups on their ownanot unique to intervention carers

Continued on p. 784

CARE-GIVER INTERVENTIONS 783

Study: Mittelman et al. (1996); Quality score (design): 8 Country: US Randomized, N = 206 controlled trial2 Duration: four Carers: 58.3% female months of Inclusion and exclusion criteria: individual and as in Mittelman et al. (1993)2 Withdrawals: 151 family counseling support ongoing

See Mittelman et al. (1993)

784 CHAPTER VII.3

Table VII.3.5 (cont’d) Design

Patients/carers

Study: Baldwin et al. (1989); Quality score (design): 5 Randomized, Country: US controlled trial2 N = 79 Duration: eight Carer: daughters (81%) and weeks daughters-in-law (19%), mean age 52 years Patient: attends day care centre and resides with carer Withdrawals: 31

Study: Burgener et al. (1998); Quality score (design): 6 Country: US Randomized, N = 54 carer/patient pairs controlled trial2 Duration: one Patient: home-dwelling, AD or session (90 min) MID, mean MMSE 8.9 Carer: 74% female Withdrawals: 71

Interventions

Outcomes

Results/comments

Eight weekly 2 h sessions Educative/didactic, or psychotherapeutic/support, or placebo-control, or non-intervention control

Caregiver Strain Index1 Subscales of SCL-90 Jalowiec Coping Scale: affective and problem-solving coping Blood pressure Heart rate Biweekly diary of psychosomatic and stress symptoms in previous 14 days (from 4th to 8th week) Assessed at post, 1-, 3-, 6-, 12-month intervals1

Didactic/educative and support/psychotherapeutic groups were effective in reducing carer strain Support/psycho-therapeutic was most effective at post-, and over time Neither intervention was more effective than control in reducing other types of stress (SCL-90) No significant impact of interventions on blood pressure, heart rate, or affective or problem-solving coping Note: statistical significance levels not reported

Education group: knowledge of AD (video of program also provided) Behavior intervention: instruction and role modelling of behavioral approaches to problem patient behaviors Group 1: education and behavior (n = 11) Group 2: education (n = 12) Group 3: behavior (n = 12) Group 4: control (n = 12)

DBD scale Alzheimer’s Disease Knowledge Test1 Relative Stress Scale Assessment at baseline and 6 months post-1

Significant increase in knowledge for Group 1 (P < 0.05)1 Non-significant findings: slight decrease (Groups 1 & 2) and increase (Groups 3 & 4) in difficult behaviors; Group 3 patients increased self-care ability Approx. 50% of approaches in interventions were rated as ‘frequently’ or ‘always’ effective by 75% of Group 1 & 3 carers

Study: Zarit et al. (1987); Quality score (design): 8 Country: US Randomized, N = 184 (SG n = 44; IFC controlled trial2 Duration: eight n = 36, WLC n = 39) weeks Carers: mean age 62 years; 52% spouses, 41% adult children Patient: dementiaaMMSE < 20; MSQ < 8; 6 month history of progressive impairment, prior evaluation of dementia; community dwelling2 Withdrawals: 651

Eight sessions Provide information about disease and effects on behavior, behavioral problem solving, identifying support and either: SG: emphasis on reaching therapeutic goals though group interaction or; IFC: focus on intervening in carers family system or; WLC

Significant effect for time of measurement (P < 0.001)1: BI and BSI lower at T2 in SG and IFC, largest drop for IFC and WLC No effect for treatment, or treatment × time on BSI and BI Distress on MBP was significantly related to time (P < 0.05), but not condition effects or interactions Significant effect for time for social support (P < 0.001) SG felt more supported than IFC (P < 0.01) At T3, significant effect for time (P < 0.01), placement × time interaction (P < 0.001) Similar number of carers from each group had placed patient at T3 The global measures of burden and stress: floor effect for some carers

Carer: GHQ1 Zung Depression Scale Hamilton Rating Scale for Depression Health diary: health care visits and medications Patient: Orientation information memory concentration scale Dementia scale MMSE Problem behavior checklist ADL IADL Hamilton Rating Scale for Depression GDS CDR Rate of institutionalization of patient Assessed at baseline, 3-, 6-, 12months (and 18 months for WLC)1

At 12 months follow-up the DCP resulted in significantly lower GHQ scores than MRP (P < 0.05)1 Patients deteriorated over 12 months regardless of group allocation At 30 months, 65% in DCP, and 26% in MRP were still at home Significantly higher rate of survival at home for patients in DCP compared to MRP (P < 0.01) No differences in depression in carers among groups over time. Low initial depression scores (mean Zung 34.8, Hamilton 6.7) Sample size of 30 for each group was estimated to detect moderate effect (0.67) with 0.6 power (a = 0.05)1 Clinical observation of improvement of morale in patients

Continued on p. 786

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Study: Brodaty & Gresham (1989); Quality score (design): 9 Country: Australia Randomized, Ten days of either: N = 100 patient/carer pairs controlled trial2 DCP: didactic education, group Duration: ten days (33 = DCP, 31 = MRG, 32 = WLC) therapy, management skills, Patient inclusion criteria: 80assertiveness training, behavior year-old, mild–moderate AD management techniques; (DSM III)2, community dwelling, patients received memory English-speaking, did not retraining wander, not aggressive, MRP: reminiscence therapy, ADL = 0 or 1 reality orientation, ward Carer: mean age 67.7 years, 55% activities for patients only; female, 93% spouses carers given respite Patient: mean age 70.2 years; WLC: received DCP 6 months 73% AD, 20% MID, four and then later (delayed training) 7% other dementias; CDR mean All groups received follow-up 1.1 phone calls fortnightly over Withdrawals: none, but four had 12 months to six weekly insufficient data and were excluded from analysis1

Stress: revised BI and BSI1 Management of problem behaviors: MBP Use of social support: interaction with informal support network; amount of assistance provided by others; adequacy of social support Perception of treatment benefits: global rating (improved/ declined); Caregiver Change Interview Institutionalization of patient (at 12-month follow up) Assessed at baseline (T1), post(8 weeks) (T2) and 1 years (T3)1

786 CHAPTER VII.3

Table VII.3.5 (cont’d) Design

Interventions

Outcomes

Results/comments

Study: Brodaty & Peters (1991); Quality score (design): 8 Randomized, See Brodaty & Gresham (1989) controlled trial2 for details2,1 Duration: ten days

See Brodaty & Gresham (1989) for details

Costs of institutional care1, medication and health care at 39 months follow-up1

At 39 months the cumulative proportions surviving were 79.7% for DCP, 58.7% MRP, 78% WLC. Significant difference between WLC and MRP (P < 0.05). DCP and MRP combined were significantly different from WLC (P < 0.05)1 Patients whose carers received training were more likely to remain at home (55% DCP, 13% MRP/WLC) Mean duration in months spent in institutions was much the same in each group Significant differences in the rates of placement in institutions Institutional costs were AUD$19 918 for DCP, AUD$36 753 for MRP, and AUD$27 375 for WLC Health costs, at least for first 12 months, were equivalent for the three groups

Study: Brodaty et al. (1997); Quality score (design): 8 Randomized, See Brodaty & Gresham (1989) controlled trial2 for details2,1 Duration: ten days

See Brodaty & Gresham (1989) for details

Nursing home admission1 Time until death of patient Followed up for between 6.5 and 8.5 years1

No difference between DCP and delayed training in time to nursing home admission or time until death Significant difference between combined DCP and delayed training group (WLC) and MRP (P < 0.05) in nursing home admission1

Patients/carers

Study: Hinchliffe et al. (1995); Quality score (design): 9 Randomized, Country: UK controlled trial2 N = 40 patient/carer pairs Duration: 16 weeks (experimental = 22, control = 18) Carer: 73% female, mean age 68 years, 70% spouses Inclusion criteria: GHQ cut-off 4/5 Patient: 60% male, mean age 81 years Inclusion criteria: DSM-III-R criteria for dementia, MMSE > 8, GMS2, 1–3 difficult behaviors reported by carer, resides with carer Withdrawals: 14 (experimental = 9, control = 5)1

Individualized plan generated by multidisciplinary team aimed to reduce most distressing problem behaviors in patient (medication, psychological techniques, and social measures). Mean of 12 visits (Group 1aimmediate intervention) Wait list control (Group 2adelayed intervention)

Carer: GHQ1 ICD 10 GMS Support from health and social services, contact with friends and family, social activities Patient: PBE Assessed at baseline, 16 ± 2 weeks (phase 1), 38 weeks (phase 2)1 Blind ratings1

Clinical and statistically significant reduction in carer GHQ for the immediate intervention group (P < 0.001)1 Behavior of patients in Group 1 significantly improved compared to group 2 at phase 1 (P < 0.001). This was maintained at phase 2 No change in patient behavior in group 2 following delayed intervention Significant association for Group 1 between mental health (GHQ) and improved patient behavior (P < 0.01) No significant association when mental health is measured in terms of ICD10/GMS caseness No association both with fall in carer GHQ and either time input of certain aspects of the intervention No association both with number of phone calls received from friends and fall in GHQ score Small sample sizes

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Numbers in superscript refer to points allocated according to the rating system. ADL, Activities of Daily Living; BI, Burden Interview; BSI, Brief Symptom Inventory; CES–D, Center for Epidemiologic Studies–Depression; CDR, Clinical Dementia Rating Scale for Dementia; CQLI, Caregiver Quality of Life Instrument; CSP, Caregiver Support Program; DBD, Dementia Behavior Disturbance; DCP, Dementia Carer’s Program; DFCC, Dementia Family Care Coordinator; DRS, Dementia Rating Scale; FACES III, Family Adaptability and Cohesion Evaluation Scales III; GDS, Geriatric Depression Scale; GHQ, General Health Questionnaire; GMS, Geriatric Mental State; IADL, Instrumental Activities of Daily Living; IFC, Individual and family counseling; MPB, Memory and Behavior Problems Checklist; MRP, Memory Retraining Program; PBE, Present Behavioral Examination; SG, Support group; SPES, Short Psychiatric Evaluation Scale; STAI, State–Anxiety portion of State–Trait Anxiety Inventory; WLC Waiting list control.

788 CHAPTER VII.3

group, a psychotherapeutic support group, a placebo-control group and non-intervention control groups. They found that at 1-, 3-, 6- and 12months post-intervention, both the educational and the psychotherapeutic support groups were effective in reducing care-giver strain, although the psychotherapeutic group was more effective initially (1 month post-intervention) and consistently effective over time (over 12 months). However, neither group was more effective than the control groups in terms of reducing other types of stress, such as anxiety, somatization or depression. Support, education and respite Mohide et al. (1990) examined the effects of a Care giver Support Program (CSP) that involved care-giver focused healthcare, education about dementia and care giving, assistance with problem solving, respite, and a support group. Although there were no significant effects on the care givers’ quality of life, level of depression, or anxiety, there was judged to be a clinically important improvement in the quality of life of the care giver. Counselling and support Mittelman et al. (1993, 1995, 1996) found that a program of individual and family counselling followed by support group attendance decreased the likelihood of nursing home placement of the patient, and decreased the level of depression experienced by the care giver. Education and training Burgener et al. (1998) compared the effects of an educational group, a behavioral intervention aimed at managing problem patient behaviors, the combination of both, and a control group. They found that although knowledge increased for the care givers in the educational group, there was no effect on care-giver stress or on difficult patient behaviors for any of the groups. However, care-giver satisfaction with the program was high, with approximately 50% of the suggested approaches to manage problem patient behaviors rated as ‘frequently’ or ‘always’ effective by 75% of the care givers.

Education, support and counselling Zarit et al. (1987) examined the effect of the provision of information about AD and its effects on behavior, in combination with either a support group, or individual and family counselling sessions. They found that over time, there was a reduction in care-giver stress for both groups, more so for those who received the counselling. Care givers’ use of social support and the perceived adequacy of it increased over time, more so for the care givers who participated in the support group. There was, however, no difference in the rate of institutionalization between the groups. Hinchliffe et al. (1995), using a cross-over design, compared a program of individualized care packages for distressed care givers of patients with dementia who were exhibiting problem behaviors, with a waiting-list condition. The package included an appraisal by a senior psychiatric registrar, training in behavioral techniques for the care giver, medication for the patient and for the care giver as indicated, day center attendance and support groups. They found that care givers’ rates and levels of psychological morbidity and patients’ frequency of behavioral disturbances fell significantly more in the experimental group than in the waiting-list condition. These results were not replicated after the cross-over, in part because of the difficulties with this type of experimental design in dementia research. A comprehensive and intensive intervention program conducted in Sydney, Australia, was unique in that it was residential, within the psychiatric unit of a major teaching hospital (Brodaty & Gresham 1989; Brodaty et al. 1997). Care giver–patient pairs were randomly allocated to one of three conditions: immediate carer training, delayed (or waiting list) carer training or memory training. Patients in all three conditions received identical input: 10 days hospitalization, a memory training course and the ward occupational program. Care givers in both training conditions received the same intervention save for a six-month delay for the waiting list group. The comprehensive care-giver intervention comprised group, individual and family counselling, education, skills training and use of activities. The study coordinator contacted all care givers by

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group telephone conference at increasing intervals over 12 months. Patients declined uniformly on all measures regardless of group allocation. Care givers in the immediate training program had a decrease in their psychological distress scores, those in the delayed training experienced no change, while those in the memory training condition had an increase in their psychological distress score. Importantly, patients in the training conditions were less likely to be institutionalized over an eight-year followup. The program was also demonstrated to be cost effective (Brodaty & Peters 1991).

Summary We rated the broad categories of interventions using the schema of quality of evidence presented earlier and the clinical significance of the intervention.

Intervention Education Helpful with care-giver knowledge, affect, coping but not with more direct indicators of patient or care-giver outcome Support Support alone does not produce meaningful effects Training Some positive effects but no consistent improvement Counselling Only two studies, both demonstrating improvement Mixed Less care-giver depression, delay in nursing home admission, strong recommendation

Level of evidence*

NHA also reported improvements in psychological health of care giver. Other findings which may be less meaningful clinically, but appear consistent, are care givers’ high ratings of satisfaction with the intervention, their greater knowledge about dementia and its complications, improvement in care giver–patient relationships, and a more positive appraisal by care givers of their own abilities and coping styles. We considered these findings to be less meaningful clinically, as depression or burden scores appeared to be unaffected despite the reported improvements in these latter constructs. Perhaps what stands out most is the heterogeneity of results. Of the control trials of care-giver interventions that we reviewed, many of the comparisons did not demonstrate statistically significant benefits. However, care givers continually report satisfaction with the interventions, and health professionals anecdotally note appreciable benefits attributable to interventions. The reasons for these discrepancies may in large part be methodological, some of which are outlined below.

5

Heterogeneity of patients 2

2

3

1

*Level of evidence on 1–10 scale, 1 is highest.

Discussion Care-giver interventions can produce significant benefits that are meaningful to care givers and patients: less care-giver depression, improved caregiver morale, improved quality of life and delay to NHA. Patients staying at home longer may not be desirable if it leads to increased care-giver burden. However, both the studies reporting lower rates of

Patients varied according to age, gender, diagnosis of dementia, duration of dementia, severity of dementia, and presence of problem behaviors. A minority of studies had documented evidence to confirm that patients had a diagnosis of dementia, and only a handful described the actual type of dementia. Therefore, we do not know whether patient or dementia variables influenced the outcome of care-giver interventions. Heterogeneity of care givers Dementia affects care givers who are spouses differently to how it affects care givers who are children or other relatives (Gilleard 1984). Female care givers tend to be more stressed than male care givers (Collins 1992). Care givers’ physical health, psychological health, age, gender, attitude to institutionalization and reason for care giving could all potentially influence the outcome of interventions. Secondary role strainsarunning a household, having dependent children at home, juggling work

790 CHAPTER VII.3

commitments and having or not having a supportive familyaare just a few of the other variables that could influence outcome. It is impossible to control for all these variables. The usual strategy is to compare treatment and control groups for differences in known key mediating variables. If there are none it is assumed that they are not exerting an important effect; if there are, statistical techniques are employed to correct for differences. Recruitment Subjects who volunteer for care-giver intervention trials may be the ones least likely to benefit because the ones who are most stressed are probably less likely to have the initiative to discover new programs or to have the energy/time to participate. For example, in one study care givers who were not willing to travel to a research clinic were more depressed and provided more hours of care giving than those who were willing to travel (Dura et al. 1990). Care givers recruited from clinic populations may not be representative of the wider community of care givers. Ceiling and floor effects Researchers studying the effects of an antidepressant would insist that trial subjects had a minimum depression score. Yet care-giver interventions studies rarely insist on threshold scores on key outcome variables as precondition of study entry. For example, if depression (or similar constructs) is the outcome variable, the study should only enrol care givers who have a minimum level of depression (such as was done by Hinchliffe et al. 1995). However, it is acknowledged that this may create difficulties with recruitment of sufficient numbers of subjects, which astonishingly is almost a universal problem in care-giver intervention studies. Numbers of subjectscpower and intentionto-treat analyses If care-giver intervention trials were to emulate drug studies for AD, 150 subjects would be required for each arm of a three-group comparison (e.g. Rogers

et al. 1998). Very few studies had more than 30 subjects, and no study, with the exception of two, reported a power analysis of the number of subjects chosen. Brodaty and Gresham (1989) reported that a sample size of over 30 was calculated as necessary for an intervention of moderate power (0.6) to produce a relevant effect size (0.67) for α at 0.05; and Mittelman et al. (1995), chose ‘certain statistical procedures . . . to maximize power’. A second point here concerns those subjects that are included in the final results. Analyses based only on subjects who complete intervention studies are likely to overestimate the intervention’s efficacy. Care-giver intervention studies should, as drug studies do, routinely report intention-to-treat as well as evaluable patient analyses. Blindness Double blind studies are, of course, impossible with this kind of research. Even maintaining single blindness is a challenge as care givers, unless strictly instructed otherwise, will often inadvertently reveal to assessors to which intervention group they have been assigned. Multiple comparisons The more analyses performed on a data set, the more results will meet ‘by chance’ the conventional significance level (P < 0.05). In other words, one in twenty statistical tests will be false positives. Several of the studies reviewed did not make statistical allowances for the multiple comparisons undertaken (e.g. Bonferonni correction; Dunn 1961) nor did they use the Scheffé test for multiple post hoc comparisons (Scheffé 1953; 1959). This would allow for the possibility of over-estimating the effectiveness of some interventions. Duration of follow-up Most studies followed up patients for over six months. Shorter follow-ups are unsatisfactory for two reasons. First, we need to know whether any benefits are long-lasting. Secondly, it may be that

CARE-GIVER INTERVENTIONS 791

beneficial effects do not become apparent for several months (see discussions by Brodaty & Gresham 1992; Robinson & Yates 1994). Latency until benefits are achieved is a recognized phenomenon in the use of antidepressants and in psychotherapy research, but is insufficiently appreciated in the use of care-giver interventions.

fer more psychological stress and are less likely to institutionalize patients than are the siblings or children of patients (Morycz 1985). Furthermore, female care givers have been found to suffer from higher rates of psychological morbidity than males (Fitting et al. 1986; Baumgarten et al. 1992; Collins 1992).

Timing of intervention

Elements of successful care-giver interventions

On the face of it, it seems more likely that a care giver will benefit from a knowledge-based program early in the course of the dementia rather than near the terminal stages. Dementia is not a static illness; different problems emerge at different stages and care givers require different strategies to deal with them. Timing of assistance is rarely considered. It may be that interventions delivered early in the course of dementia are more effective than those provided in the moderate to severe stages (Brodaty & Gresham 1989; Chiverton & Caine 1989). It may be that different interventions are required at different stages. Specificity We have argued previously that prescription of psychosocial interventions should be applied with the same rigor used by physicians prescribing medications (Brodaty & Gresham 1992). However, there is an assumption sometimes that ‘one size fits all’. Thus we prescribe support groups or training in behavioral techniques for care givers and become disappointed when the results of the intervention are no better than the control group. It is important to diagnose what the care giver’s needs are and fit the intervention accordingly. Specific issues Which interventions help which patients and which care givers at what time? Unfortunately, most of studies are unable to answer such detailed questions. Studies usually compare interventions A and B, or intervention vs. no intervention. There is rarely homogeneity in patient diagnosis or in care giver relationship. Yet it is known that spouses suf-

We can deduce several elements in common from successful care-giver interventions. First, there is a strong bond between the helper or therapist and the care giver. Knowledge-based education from the front of a lecture hall will not provide this. Secondly, the helper or therapist will establish a long-standing relationship with the care giver and be available to support as necessary. This was the process in both the Sydney (Brodaty et al. 1997) and New York studies (Mittelman et al. 1996). In both studies, the acute phase of the intervention was conducted over two to several weeks but the support phase persisted for 12 months or longer. Thirdly, the program should have flexibility to deal with the differing needs of care givers. There may be a core component, such as counselling and support in the New York program, but other needs were dealt with as required.

Lessons for future research The common elements of successful intervention trials should be included in future studies. There is a pressing need to agree on suitable care-giver outcome measures. The summary of the studies shown above demonstrates the diversity of measures. This is partly because of differing theoretical frameworks, but often also because there is lack of clear direction in the field. With the arrival of effective drug treatments for AD, combination therapies of drug treatment plus care-giver interventions should be investigated.

Conclusions Care-giver interventions have the capacity to

792 CHAPTER VII.3

improve care givers’ psychological well-being and delay NHA and improve co-morbid depression in patients with dementia. However, the evidence for the effectiveness of interventions is limited, mainly by methodological shortcomings. This is not through lack of effort or commitment by researchers; care-giver intervention studies are timeand labor-consuming and financial resources cannot match those allocated for drug studies. Best practice will surely be to target what is required for each care giver from an armamentarium of interventions and to combine the most effective elements of these with treatment strategies directed at patients. Inevitably, more research is required.

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Zanetti, O., Metitieri, T., Bianchetti, A. & Trabucchi, M. (1998) Effectiveness of an educational program for demented person’s relatives. Archives of Gerontology and Geriatrics 6 (Supplement), 531–538.

Zarit, S.H., Anthony, C.R. & Boutselis, M. (1987) Interventions with care givers of dementia patients: comparison of two approaches. Psychology and Aging 2(3), 225–232.

VII.4

Genetic Counseling

A. Dessa Sadovnick

For over 95% of families with dementia, there is no test or biomarker that can predict on a oneto-one basis which asymptomatic family member will develop dementia in the future: 1 physicians should explain to asymptomatic individuals that no reliable test, including ApoE genotyping, is available at present; 2 referral to a genetic counselor is usually not necessary; 3 as the individual ages, the physician should monitor the individual for any observed cognitive changes, as with any other person seen in the physician’s practice; and 4 no ‘preventive measures’ including hormone replacement therapy, ginko biloba and antiinflammatories are universally recommended at this time (Patterson et al. 1999). If an autosomal dominant mode of inheritance is suspected, all available information on each reportedly affected family member must be obtained (hereafter referred to as ‘documentation’) to allow assignment of ‘best estimate’ dementia diagnosis. Documentation: 1 can be done by the physician, genetic counselor or other qualified health care professional;

2 must be done with the informed consent of the appropriate family member (and/or next-ofkin/substitute decision-maker); 3 should be based on the most appropriate available information such as medical records, hospital records, autopsy reports, ‘dementia questionnaires’, family correspondence, etc.; and 4 should be reviewed by a physician/health care professional experienced in the differential diagnosis of dementia. Once all documentation has been reviewed, the ‘best estimate’ diagnosis should then be assigned. If an autosomal dominant mode of inheritance is supported after the ‘best estimate’ diagnosis for each affected family has been determined, referral to a genetic counselor is needed if this has not already occurred. The genetic counselor will: 1 provide counseling based on the autosomal dominant mode of inheritance; 2 arrange DNA banking for family members as appropriate; 3 offer and organize predictive genetic testing as appropriate; and 4 provide longitudinal follow-up for family members as appropriate with respect to genetic risks.

Both genetic and non-genetic factors have roles in the ‘causation of’ and ‘susceptibility to’ dementia. It is now well recognized that dementia is characterized by etiological heterogeneity (e.g. purely genetic, purely environmental, genetic/environmental

interactions) and genetic heterogeneity (Cruts & Van Broeckhoven 1998; Katzmann et al. 1998; Lendon et al. 1998). Genetic counseling for dementia is multifaceted and constantly evolving as more is understood about causes and risk factors for this

Key points

795

796 CHAPTER VII.4

complex group of disorders. The following, although published in 1974 (Fraser 1974) is still one of the best available descriptions of genetic counseling: . . . a communication process which deals with human problems associated with the occurrence, or risk of occurrence, of a genetic disorder in a family. This process involves an attempt by one or more appropriately trained persons to help the individual or the family to (1) comprehend the medical facts, including the diagnosis, the probable course of the disorder and the available management; (2) appreciate the way heredity contributes to the disorder and the risk of recurrence in specified relatives; (3) understand the options for dealing with the risk for recurrence; (4) choose the course of action which seems appropriate to them in view of their risks and their family goals and act in accordance with that decision; and (5) make the best possible adjustment to the disorder in an affected family member and/or to the risk of recurrence of that disorder. In North America, genetic counseling is generally approached as a ‘team’ effort, involving a counselor who most often has a masters degree in genetic counseling and, as appropriate, a clinical geneticist and other health professionals such as a medical ethicist, psychologist, etc. The incidence and prevalence of dementia are high (CSHA 1994, 2000; Rocca et al. 1998). It is therefore unrealistic to expect genetic counseling services to address all inquiries about familial risks for dementia or to expect all persons with questions about genetic risks and genetic testing options to be able to travel to genetic centers, which are usually located in urban settings. The purpose of this section is to propose guidelines to assist clinicians in (i) identifying individuals who require formal genetic counseling services at specialized centers and (ii) responding appropriately to questions about genetic risks and genetic testing for persons who do not necessarily need to be referred for this service. These suggestions are based on current information. They will change as advances occur in areas such as the identification of biological markers, genetic testing options and treatment/prevention.

Cases not requiring referral to a genetic counselor Formal counseling on genetic risk factors for asymptomatic individuals is not necessary for over 95% of individuals who ask the following: 1 My mother/father/sibling has/had dementiaa Will I get it? 2 My distant relative (e.g. aunt, grandmother) has/had dementiaaWill I get it? 3 No one in my family has/had dementia but I am worried that I will get it. 4 My spouse has/had dementiaaWill any of our children get it? Information about genetic risks and the possibility of ‘testing’ for dementia is usually requested by asymptomatic first-degree relatives (children, siblings) of patients who are concerned about their own risks or by the spouse of a patient who is concerned about the risk to their children. These requests are generally initially raised with family physicians and, in the vast majority of cases, the physician can answer the question without any need to refer the individual for formal genetic counseling.

Markers/predictive tests to predict whether or not an asymptomatic individual will develop dementia At present, it is impossible to determine on an individual basis whether or not a specific asymptomatic individual will develop dementia in the future. Molecular/biochemical markers for dementia No biological marker for dementia in general or Alzheimer’s disease (AD) in particular is currently accepted for widespread use (The Ronald and Nancy Reagan Research Institute of the Alzheimer’s Association & the National Institute on Ageing Working Group 1998; Black 1999). This means that, at present, there is no recommended biomarker appropriate for the vast majority of asymptomatic individuals which can reliably predict who will develop dementia in the future.

GENETIC COUNSELING 797

Risk (susceptibility)/protective factors The presence or absence of a postulated genetic or non-genetic risk factor does not identify, on an individual basis, which asymptomatic person will develop dementia in the future. Dementia can occur in the absence of any known risk factors. Dementia can never occur despite the presence of any known risk factor(s). To date, the best-documented and most widely publicized genetic risk factor for a dementia is the apolipoprotein E (ApoE) gene for AD. (For background information on ApoE, the reader is referred to Chapter II.4.5.) ApoE genotyping is relatively simple for a physician to arrange through general laboratories and is, in fact, often done with respect to lipid disease. ApoE genotyping is not recommended for the asymptomatic individual although, in some circumstances, it may be helpful in determining the differential diagnosis for an affected individual with dementia (Roses 1996; Blacker et al. 1997). The role of the e4 allele in autosomal dominant AD (in the presence or absence of a known family mutation on chromosome 21, 14 or 1) remains unclear.

Summary: genetic and non-genetic risk factors in the asymptomatic individual Risk factors in dementia need further exploration. While population studies may suggest that certain groups of affected individuals may have specific genetic or nongenetic risk factors when compared to matched groups of unaffected individuals (e.g. apoE4/apoE4 genotype among persons with AD), this information cannot be extrapolated for use as a predictive test in a specific asymptomatic individual.

Cases requiring referral to a genetic counselor Less than 5% of individuals appear to have dementia in at least 3 family members over at least 2 generations. If there is a family history of autosomal dominant inheritance, referral to a genetic counselor is appropriate. Information on genetic services for a particular

geographical region or country can be obtained from the American Society of Human Genetics (http://www.faseb.org/genetics/ashg/geneintr.htm), by contacting the nearest major teaching hospital or medical school or from the author.

Autosomal dominant inheritance Autosomal dominant inheritance is suggested in about 5% of all families with dementia where there are at least three affected individuals over two generationsasee sample pedigrees in Figs VII.4.1– VII.4.3. In such situations, it is critical to determine the ‘best estimate’ differential diagnosis for the dementia in reportedly affected family members. To do this, it is necessary to obtain as much appropriate available information as possible, including medical records, hospital records, autopsy reports, family correspondence, dementia questionnaires (Ellis et al. 1998), family correspondence, etc. on each reportedly affected family member. Hereafter, information collected to help determine the ‘best estimate’ dementia diagnosis will be referred to as ‘documentation’. The physician may try to differentiate between a progressive dementia in an otherwise healthy individual and dementia subsequent to stroke, head injury, etc. by asking a few simple questions. Obtaining more in-depth documentation, such as medical records, death certificates, autopsy reports, etc., may be too time-consuming for a physician and the genetic counselor can arrange this. At present, specific gene mutations have not been identified for late onset (age 65 years and over) autosomal dominant dementia including AD and for most families having early onset autosomal dominant dementia including AD. Genetic counseling for asymptomatic individuals from such families involves explanation of the mode of inheritance, the individual’s risk based on this model and DNA banking for affected living family members. Vignette An asymptomatic 55-year-old states that her mother, maternal aunt, maternal uncle and maternal grandfather all had ‘memory loss/dementia’ in their 70s.

798 CHAPTER VII.4

(d. 80s)

(79)

(78)

Fig. VII.4.1 An asymptomatic 55-year-

(76)

Memory loss/dementia

(55)

(79)

(78)

old woman states that several of her relatives (as shown) have/had memory loss or dementia in their 70s. What do you tell her?

(76)

(55) Multi-infarcts with subsequent dementia Parkinson’s disease with subsequent dementia Dementia of unknown etiology Major head injury with subsequent memory loss

(79)

(78)

Fig. VII.4.2

(76)

(55) Autopsy confirmed Alzheimer’s disease Progressive dementia of unknown etiology

Fig. VII.4.3

GENETIC COUNSELING 799

Scenario 1 Through obtaining medical records, autopsy reports, family correspondence, etc., the following appear to be the most likely diagnoses: 1 mother: multi-infarct dementia; 2 maternal aunt: Parkinson’s disease with subsequent dementia; 3 maternal uncle: progressive dementia of unknown etiology; 4 maternal grandfather: memory loss following severe head injury. In this scenario, autosomal dominant inheritance is unlikely. The asymptomatic individual should be reassured. Scenario 2 Through obtaining medical records, autopsy reports, family correspondence, etc., the following appear to be the most likely diagnoses: 1 mother: progressive dementia of unknown etiology; 2 maternal aunt: autopsy confirmed AD; 3 maternal uncle: progressive dementia of unknown etiology; and 4 maternal grandfather: progressive dementia of unknown etiology. In this scenario, autosomal dominant inheritance is likely. The implications of this for the asymptomatic individual should be clearly explained by a genetic counselor. As the search continues for specific genetic mutations in late-onset as well as early-onset dementia including AD, DNA banking should be arranged by the genetic counsellor for affected living family members.

Predictive genetic testing In very rare circumstances where autosomal dominant inheritance of early onset dementia has been recognized, a specific genetic change (mutation) can be identified which travels through the family with the disease (e.g. St. George-Hyslop et al. 1987, 1992; Goate et al. 1991; Levy-Lahad et al. 1995; Cruts & Van Broeckhoven 1998). A specific mutation can be shared by more than one family or can be specific to one family. Predictive genetic testing

is presently possible if a family-specific mutation is identified in at least one affected family member [e.g. mutations on chromosomes 21, 14 and 1 for AD (Cruts & Van Broeckhoven 1998) and on chromosome 17 for frontotemporal dementia (Froelich et al. 1997; Lendon et al. 1998) ]. An asymptomatic family member (usually a first-degree relative of the affected individual with the mutation) may then be offered predictive genetic testing for the presence or absence of the specific mutation. In this asymptomatic family member, the presence of the mutation increases the likelihood that he/she will develop the family-specific form of dementia from the a priori risk predicted by the autosomal dominant model to virtually 100%. Conversely, the absence of such a mutation in the family member would decrease the likelihood that he/she will develop the familyspecific form of dementia from the risk predicted by the autosomal dominant model to virtually 0%. The absence of a family-specific mutation does not alter the age-specific background rates to develop other forms of dementia. Predictive genetic testing has many implications (e.g. psychological, social, economic) in addition to forecasting inheritance. Individuals followed longitudinally after disclosure of genotype can react in various ways that cannot necessarily be predicted. As has been seen clearly from longitudinal studies in Huntington’s disease and familial breast cancer, giving the ‘good news’ that the tested individual does not have the disease gene can at times be more disruptive than the ‘bad news’, i.e. that the individual does have the disease gene (Wiggins et al. 1992; M. Burgess & S. Cox, pers. comm.). A multidisciplinary team usually performs predictive genetic testing. When this is appropriate, the genetic counselor will ensure that the proper protocol, including pre-testing and post-testing counselling, is followed.

References American College of Medical Genetics/American Society of Human Genetics Working Group on ApoE and Alzheimer Disease (1995) Statement on use of

800 CHAPTER VII.4

Apolipoprotein E testing for Alzheimer disease. Journal of the American Medical Association 274, 1627–1629. Black, S.E. (1999) The search for diagnostic and progressive markers for AD. Neurology 52, 1533–1534. Blacker, D., Haines, J.L., Rodes, L. et al. (1997) ApoE-4 and age at onset of Alzheimer’s disease. The NIMH Genetics Initiative. Neurology 48, 139–147. Cruts, M. & Van Broeckhoven, C. (1998) Molecular genetics of Alzheimer’s disease. Annals of Medicine 30, 560–565. CSHA (Canadian Study of Health and Aging) Working Group (1994) CSHA: Study methods and prevalence of dementia. Canadian Medical Association Journal 150, 899–913. CSHA (Canadian Study of Health and Aging Working Group. (2000) CSHA: The incidence of dementia in Canada. Neurology 55, 66–73. Ellis, R.J., January, K., Kawas, C. et al. (1998) Diagnostic validity of dementia questionnaire for Alzheimer disease. Archives of Neurology 55, 360–365. Fraser, F.C. (1974) Genetic counselling. American Journal of Human Genetics 25, 636–659. Froelich, S., Basun, H., Forsell, C. et al. (1997) Mapping of a disease locus for familial rapidly progressive frontotemporal dementia to chromosome 17q12–21. American Journal of Medical Genetics Neuropsychiatric Genetics 74, 380–385. Goate, A.M., Chartier-Harlin, M.C., Mullan, M. et al. (1991) Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease. Nature 349, 704–706. Katzmann, R., Kang, D. & Thomas, R. (1998) Interaction of apolipoprotein E4 with other genetic and non-genetic risk factors in late onset Alzheimer disease: Problems facing the investigator. Neurochemistry and Research 23, 369–376.

Lendon, C.L., Lynch, T., Norton, J. et al. (1998) Hereditary dysphasic disinhibition dementia. A fronto-temporal dementia linked to 17q21–22. Neurology 50, 1546–1555. Levy-Lahad, E., Wijsman, E.M., Nemens, E. et al. (1995) A familial Alzheimer’s disease locus on chromosome 1. Science 269, 970–973. Patterson, C.J.S., Gauthier, S., Bergman, H. et al. (1999) The recognition and management of dementing disorders. Conclusions from the Canadian Consensus Conference on Dementia. Canadian Medical Association Journal 160 (Supplement 12). Rocca, W.A., Cha, R.H., Waring, S.C. & Kokmen, E. (1998) Incidence of dementia and Alzheimer’s disease: a reanalysis of data from Rochester, Minnesota, 1975–84. The American Journal of Epidemiology 148, 51–62. Roses, A.D. (1996) Apolipoprotein E and Alzheimer’s Disease. A rapidly expanding field with medical and epidemiological consequences. Annals of the New York Academy of Science 802, 50–57; St. George-Hyslop, P., Haines, J., Rogaev. E.I. et al. (1992) Genetic evidence for a novel familial Alzheimer’s disease locus on chromosome 14. Nature Genetics 2, 330–334. St. George-Hyslop, P., Tanzi, R., Polinsky, P. et al. (1987) The genetic defect causing familial Alzheimer’s disease maps on chromosome 21. Science 235, 885–889. The Ronald and Nancy Reagan Research Institute of the Alzheimer’s Association and the National Institute on Aging Working Group (1998) Consensus report of the working group on: Molecular and biochemical markers of Alzheimer’s disease. Neurobiology of Aging 19, 109–116. Wiggins, S., Whyte, P., Huggins, M. et al. (1992) The psychological consequences of predictive testing for Huntington’s disease. New England Journal of Medicine 327, 1401–1405.

Nursing Home Care for Patients with Dementia

VII.5

Ira R. Katz, Catherine J. Datto and Melissa Katz-Snellgrove

Nursing homes are the most widely used institutional facilities for the long-term care of individuals with Alzheimer’s disease (AD) and other dementias. The most recent US government estimate of the prevalence of dementia in American nursing homes is 41.7% for 1997, up from 34.7% in 1991 (Harrington et al. 1999), but it is important to recognize that estimates based upon administrative data may not include those with mild or moderate levels of impairment. In fact, such estimates are consistently below those derived from clinical and research assessments that find that a majority of the long-stay residents in nursing homes have dementia (Maslow 1993; Rovner & Katz 1993). Although nursing homes care largely for patients with dementing disorders, the design of most facilities, their programs and staffing patterns, and the regulations under which they operate were based upon the assumption that they would serve individuals with chronic medical illnesses. One highly informative study (Stern et al. 1997) followed patients with AD in the community and found that the probability of nursing home placement or the need for an equivalent level of care was predicted by observations at the patients’ initial assessments of greater cognitive impairment, extrapyramidal symptoms, psychosis, and younger age of disease onset. An algorithm derived from this study can be used to estimate an individual’s risk of placement (Stern 1999). Most of those admitted to a nursing home as a direct result of their dementia are those with severe cognitive and functional impairment, often complicated by psychotic, affective, and behavioral symptoms. However, some patients with mild or moderate

cognitive impairment may require nursing home placement because family care givers are not available in the community. Still others may require admission as a result of co-morbidity from other disabling medical conditions, either when these conditions are severe or when their dementia has interfered with the patient’s and family’s ability to manage them. At a first approximation, it is reasonable to assume that evidence-based treatments established for community patients with dementia will remain effective for nursing home residents with comparable impairment, psychological and behavioral symptoms, medical co-morbidity, and age. In addition, other issues related to care emerge specifically in the long-term care setting. The possibility that nursing home environments can be either therapeutic or toxic, raise questions about what constitutes effective care for patients with dementia in the institutional environment. Moreover, the high costs of institutional care imply that the costeffectiveness of interventions may differ across settings. Intensive interventions for community patients whose costs may be offset by the prevention or delay of institutionalization may not be as applicable after long-term care placement. There is a growing literature on studies of the pharmacological treatment of nursing home residents with dementia that has included placebo-controlled randomized clinical trials of antipsychotic agents and mood stabilizing anticonvulsants for psychotic symptoms and/or aggression and agitation, antidepressants for dementia with depression, and acetylcholinesterase inhibitors for cognitive and functional deficits. Although the effects of pharmacotherapy

801

802 CHAPTER VII.5

may, in principle, be moderated by the nature of the patients’ care environment, this issue has not yet been addressed in the literature and there is no available evidence suggesting that the efficacy of pharmacological treatment differs as a function of treatment setting. Complementing the pharmacological literature, there is also a growing body of evidence on behavioral and psychosocial treatments. However, the most significant literature on the nursing home care of patients with dementia is not related to the effectiveness of either pharmacological or psychosocial treatments established in other settings, but to the impact of the care environment itself. Recognition that the majority of long-term care nursing home residents have a dementia and that these facilities are, in fact, neuropsychiatric institutions, has evolved over the past generation as a result of both scientific studies and administrative data. It has become recognized that nursing facilities designed primarily for the long-term care of patients with disability from medical and surgical conditions may not serve the needs of the majority of their residents who suffer from dementia. Additionally, it has become clear that there were major adverse consequences from the historic widespread use of physical and chemical restraints to manage cognitively impaired residents in environments designed for residents with other types of impairments. The past generation has witnessed what has been described as a paradigm shift in the longterm care of nursing home residents with dementia. Although there is a growing body of research in this area, most of it is observational, and there are few randomized trials of specific interventions. In fact, governmental regulations, market forces, and patient advocacy may have driven changes in the care environment more than findings from evidence-based medicine or behavioral science. Nevertheless, it is important to review the available literature on evidence-based treatments for nursing home residents with dementia.

Search and selection strategy Review of the medical literature was conducted to identify interventions that specifically targeted the care of nursing home residents with dementia.

Broadband searches of the Medline database were followed by a review of titles and abstracts to reveal papers likely to meet criteria for inclusion in a review of evidence-based interventions. Search strategies were (nursing homes and (explode) dementia) and (nursing homes and (explode) clinical trials). Articles identified from these searches were supplemented with those derived from citations included in these papers and from recent reviews. Other criteria for including studies required that: they evaluated interventions specifically relevant for patients with dementia; they involved randomization of patients, staff, or facilities to intervention and control groups; and they included sample sizes of at least 12. The literature identified can be divided into studies of interventions targeting deficits in care such as physical and chemical restraints, those evaluating integrated care programs, and those that evaluate discrete elements of care.

Evidence Interventions targeting deficits in care: reducing physical and chemical restraints Concerns about the widespread use of physical and chemical restraints for purposes of discipline or convenience were one of the major factors leading to nursing home reform legislation in the USA in the late 1980s (Institute of Medicine 1986). Use of these practices was appropriately viewed as dangerous and inhumane in and of themselves, and as indicators that nursing homes were not providing more appropriate care. Review of trends over the past decade suggests that these regulations have had positive effects (Hawes et al. 1997; Snowden & Roy-Byrne 1998). Concerns about the use of physical restraints in nursing homes have recently been reinforced by a review from the Council on Scientific Affairs of the American Medical Association, which demonstrates that restraint use increases the risk of falls and other undesirable outcomes significantly (Guttman et al. 1999). It notes that legislative initiatives, regulatory activities, and alternative approaches to care have decreased restraint use in the US by 20%, and that many facilities have established restraint-

NURSING HOME CARE 803

free environments. However, patients with more severe degrees of dementia are still at increased risk for being restrained in the US nursing homes, and there is significant variability in the use of physical restraints across countries (Schnelle et al. 1992; Phillips et al. 1996; Castle et al. 1997; Ljunggren et al. 1997; Castle & Mor 1998; Sullivan-Marx et al. 1999). Thus, findings on the outcomes of interventions designed to decrease the use of physical restraints remain clinically relevant. In the only available report of a randomized trial, Evans et al. (1997) demonstrated that education and on-site consultation on the problems associated with use of physical restraints, alternatives to their use, and positive approaches to the day-to-day care of nursing home residents, including those with dementia, led to decreases in the use of physical restraints without adverse consequences such as falls (Capezuti et al. 1998). The key to restraint reduction in this program and related initiatives was not just recognition of the limitations in the effectiveness of restraints and of the dangers associated with their use, but also the need for developing individualized care plans that recognize and address the residents’ needs (Werner et al. 1994). There have been parallel concerns about the overuse of psychotropic medications as chemical restraints, but there has also been recognition that efforts to decrease their use must be balanced by efforts to facilitate the medically appropriate use of psychotherapeutic medications for patients with diagnosed mental disorders (Anonymous 1992). Thus, in a report that led directly to nursing home reform legislation, the US Institute of Medicine (1986), noted that antipsychotic medications were overused in US nursing homes, but that antidepressants were underutilized. More recently, the differential liability to misuse across classes of psychotropic medication has been recognized in quality indicators that are being incorporated into mandated survey process for US nursing homes (Center for Health Systems Research and Analysis 1999). Relevant items considered to be possible indices of poor care include the prevalence of the use of antipsychotic agents in the absence of psychoses or related conditions and the prevalence of depression not treated with an antidepressant medication.

A recent report by the US Health Care Financing Administration (1999) summarized changes in the use of psychotropic medications in nursing homes since the passage of nursing home reform legislation and found improvement in prescribing practices, with use of antipsychotics declining by 52.3%, and antidepressants increasing by 97% (to 24.9% in 1997). Although this report attributed these changes directly to the impact of regulations, other factors, including advances in clinical science and ongoing efforts at provider education may have also contributed. Outcomes of provider education interventions have been evaluated in several reports. In one study with random assignment of providers to conditions, Avorn et al. (1992) evaluated a provider education intervention, designed to improve the specificity of the prescription of psychotropic medications, and found that it decreased the use of antipsychotic but not antidepressant medications. In another study with random assignment of nursing facilities, Meador et al. (1997) provided education in the use of structured guidelines for the management of behavioral symptoms that included medical evaluations, modifications of routine care, behavioral approaches to management, use of low-dose antipsychotics for behaviors that were dangerous, distressing, or interfered with care, and gradual medication withdrawal in the absence of psychosis or a history of violence. The intervention led to decreases in antipsychotic drug use without increases in behavioral symptoms; affective symptoms improved in those for whom antipsychotic drugs were discontinued. Two earlier controlled studies were not included in Table VII.5.1 because they do not involve randomization of subjects. In one, Ray et al. (1993) found that a program of education for physicians, nurses and other staff led to decreases in antipsychotic drug use. However, in an earlier study, Ray et al. (1987) found that a less intense program of educational visits from physicians did not have significant effects. The basic premise of these studies, that much of the prevalent use of antipsychotic medications in nursing homes can be eliminated without adverse effects, has been confirmed in randomized clinical trials of drug withdrawal (Bridges-Parlet et al. 1997; CohenMansfield et al. 1999).

Table VII.5.1 Interventions for nursing home residents with dementia. Author

Intervention

Interventions targeting deficits in care Evans et al. Education about individualized Physical (1997) treatment and alternatives to use restraints of restraints (RE) vs. education plus 12 h per week on-floor consultation (REC) vs. usual care (C) Interventions in place for 6 months

Sample

Design

Outcomes

643 residents in three nursing homes

Random assignment by nursing home Assessments at baseline, 6, 9, and 12 months

Restraint use decreased significantly over time in REC but not RE or C. Decrease was greater in REC than C (P = 0.02), or RE (P = 0.09) at 6 months; greater than C (P = 0.02) at 12 months No significant changes in psychotropic drug use Restraint reduction was associated with decreased rates of falls and injuries (secondary analyses, Capezuti et al. 1998)

Use of antipsychotics in nursing homes with high utilization post-OBRA

Meador et al. (1997)

Educational program with psychiatrist visits to physicians and in-service training for other staff Administrative consultation and family meetings were available

1311 residents in 12 nursing homes

Random assignment by nursing home Study was conducted over a 6-month period

23% reduction in antipsychotic use in intervention homes vs. < 1% in controls (P = 0.014) No increase in behavioral problems related to decreased antipsychotic drug use

Overuse of psychoactive drugs

Avorn et al. (1992)

Academic detailing (with education for physicians, nurses and aides with a focus on reducing the overall use of psychoactive drugs by improving the selectivity of their use) vs. usual care Intervention was for 5 months

823 residents in six matched pairs of nursing homes

Randomization by nursing home Assessment of patient drug use and patient status at baseline and after completion of the intervention, blinded to intervention assignment

Score of an index of prevalence and probable appropriateness of psychotropic drug use improved 27% in experimental homes vs. 8% in usual care (P = 0.02) Antipsychotic use decreased 32% vs. 14% (P < 0.05) No post-intervention differences in disruptive behavior, hospitalization, or mortality

97 residents with dementia on two physically similar units in a single facility

Random assignment by unit to SCU or usual care Assessments at baseline, 6, 12 months

Increased external engagement and lesser decreases on sociability on SCU (P < 0.01) Less decline in observed pleasure but more anger on SCU No effects on progression of dementia or on functional decline

Evaluations of integrated programes Lawton et al. SCU for dementia vs. usual care Positive and (1998) SCU included augmented staffing negative affects with changes in unit administration and behaviors and programming Goal of the SCU was to provide each resident with an individualized program of additional stimulation or relief from stimulation as needed

804 CHAPTER VII.5

Target

Behavior disorders complicating dementia

Rovneret al. (1996)

AGE program (increased activities, guidelines for use of psychotropic medication, and education for staff) vs. usual care

Evaulation of discrete interventions Tappen Skill training (2.5 h/day × 5 Excess self-care (1994) days/week for 20 weeks) vs. disability increased recreational activities (2.5 h/day × 5 days/week for 20 weeks) Intervention involved intensive training and practice of ADL tasks

89 residents with problem behaviors (e.g., disruptive, wandering, demanding, intolerably noisy, combative, refuses directions, verbally abusive, paces restlessly) from a single nursing home

Randomization by subject Assessments were at baseline and 6 months

AGE program led to decreased rate of behavior disorders (P < 0.05), decreased use of physical restraints during activity times (P < 0.05), and trends toward decreased use of antipsychotic drugs and physical restraints on the nursing home unit

63 demented residents

Randomization by subject Assessments at baseline and 20 weeks by raters blind to group assignment

Post-intervention observations of self-care were greater in the skills training group (P = 0.01) No changes in laboratory tests of performance activities of daily living

Friedman & Tappen (1991)

Conversations about topics relevent to residents during a planned walk with staff, 30 min × 3 days/week for 10 weeks vs. preplanned conversations without walks

30 demented residents

Randomization by subject Assessments at baseline, 10 weeks No indication of blinding of raters to group assignment

Greater improvement in communication in ‘walk’ group (P = 0.024)

Sleep

Alessi et al. (1995)

Two separate studies of exercise vs. usual care One was 4 times/day × 5 days per week for 9 weeks The other was up to 30 min/day × 3 days per week for 9 weeks

65 subjects from 7 nursing homes who completed one of two trials of exercise programs and had sleep studies pre- and postintervention One program was for patients with incontinence, the other for those with physical restraints Dementia was not an explicit inclusion criterion; severe dementia was an exclusion

Secondary analyses of data from subjects who completed sleep studies during previous randomized clinical trials

No effect of exercise on night-time or day-time sleep

Continued on p. 806

NURSING HOME CARE 805

Verbal communication skills

806 CHAPTER VII.5

Table VII.5.1 (cont’d) Target

Author

Intervention

Sample

Design

Outcomes

Residents’ interaction behaviors and functioning

Wells et al. (2000)

Education on delivering abilitiesafocused morning care in 5 × 20–30 min sessions with ‘boosters’ every other week

40 residents, half from an experimental unit and half from 3 control units

Randomization by nursing unit Assessments at baseline and at 3 and 6 months postintervention

Greater improvements in experimental group in residents’ interactions (P = 0.040), agitation (P = 0.021), and functioning (P = 0.030) during AM care Greater improvements in care givers’ interactions (P = 0.021) and relaxed behaviors (P = 0.026)

Functional mobility

Tappen et al. (2000)

65 residents with AD

Randomization by subject Assessments at baseline and after 4 months of intervention

Decline in 6-minute walk performance 20.7%, 18.8 %, and 2.5% in 3 groups (P < 0.01) Findings may reflect impact of conversation on adherence to walking intervention

Agitation or withdrawal

Camberg et al. (1999)

54 subjects with AD from 9 nursing homes All subjects had significant agitation or withdrawn behaviors

Latin squares crossover design evaluating effects of treatment, time and facility type Multiple repeated time sampled observations by trained nonparticipant observers Staff logs and weekly staff ratings of behavior

Intention to treat analyses of direct observations of behavior demonstrated no differences in agitated or withdrawn behaviors Weekly staff ratings showed no effect of simulated presence on agitation but increased expression of ‘interest’ vs. usual care (P = 0.001) and neutral tape (P = 0.008)

Assisted walking 30 min 3 × per week for 16 weeks vs. conversation vs. combined walking and conversation

Audiotaped presentation of ‘simulated presence’ through headphones 2 × per day for 17 days, vs. neutral text at least twice a day for 17 days, vs. usual care at times when subjects exhibited agitated or withdrawn behaviors ‘Simulated presence’ was a personalized audiotape loop prepared by family members to simulate a telephone conversation

ADL, activities of daily living; AGE, activities, guidelines, education; SCU, special care unit.

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The importance of the altered regulatory environment as a major factor responsible for improved prescribing in the US has been supported by recent findings on the use of neuroleptic medications in nursing homes in one region of the UK (McGrath & Jackson 1996). Several recent reviews have addressed these issues both from US and international perspectives and suggest that in spite of both increasing knowledge and applicable policy initiatives, misprescribing of psychoactive medications in nursing homes remains a significant problem (Shorr et al. 1994; Stoudemire & Smith 1996; Furniss et al. 1998). Care recommendations Consultation to nursing homes that provides individualized patient assessments and alternative management strategies together with staff education, can minimize the use of physical restraints [Grade A]. Education of the nursing facility’s physicians and staff about the principles of geriatric psychopharmacology and of behavioral management or patients with dementia can improve the specificity of the use of psychoactive medications [Grade B].

Evaluation of integrated programs Special Care Units (SCUs) for patients with AD have proliferated as families, facilities, advocates, and policy-makers have worked to improve the long-term care of those with dementia (Grant & Ory, in press). At present 8–13% of nursing homes report that they have SCUs. However, the growth of these units has occurred without any evidencebased or consensus definition of what constitutes an SCU, what types of patients are best served by them, what components of care lead to favorable outcomes, or what domains of outcomes should be considered in evaluations. In response to the clear need for further evaluations of the effectiveness of this type of care, the US National Institute of Aging established a multisite cooperative study of ‘special care’. Findings from this initiative as well as those from contemporaneous research have recently been reviewed (Grant & Ory, in press). One component of the findings has been a deline-

ation of the dimensions of care that can be used for characterizing SCUs. These include: separation of demented residents (with less commingling of residents in SCUs), stimulation (with less ambient, potentially noxious noise), complexity of activities (with less complex planned activities), behavioral tolerance (with more tolerance of problematic behaviors), structured group activities (with greater participation of residents with dementia in activities such as music therapy, art therapy, exercise, religious programs, and sensory stimulation groups), promotion of functioning (with involvement of demented residents in activities promoting eating, swallowing and meal training, training in dressing and grooming, continence training), and staff training (with more staff training about dementia). At present, there has only been a single report of randomized study of the impact of an SCU (Lawton et al. 1998). It showed modest, but statistically significant, effects on engagement, sociability, and positive affect. The wider array of studies on the effectiveness of SCUs recently reviewed by Grant & Ory (in press) do not find dramatic effects on patient outcomes. However, this may be a result of heterogeneity of design of units, lack of clarity about what constitutes appropriate outcomes, questions about how best to define control environments for research purposes, compensatory effects of different components of care, and difficulties in controlling for variability in the quality of care in both SCU and traditional units. Other approaches to ‘special care’ for patients with dementia have also been proposed. Rovner et al. (1996) conducted a randomized clinical trial demonstrating that enhancing care on traditional nursing home units with a package of augmented activities, increased staff training, and guidelines for use of psychoactive medications can improve behavioral outcomes for nursing home residents with dementia and behavioral symptoms. The promise and the difficulties of applying hospice models to the care of patients with severe, endstage dementia have also been discussed (Luchins et al. 1997; Volicer 1997). Finally, it is important to note that assisted living facilities are increasingly being developed as sites for the residential care of patients with dementia, and that cost saving may result from a shift in the locus of care (Leon &

808 CHAPTER VII.5

Moyer 1999). However, virtually nothing is known of the extent to which the processes or outcomes of care vary between types of facilities. Care recommendations Augmented activities together with staff education and guidelines for the use of psychoactive medications can decrease behavioral and psychological symptoms in nursing home residents with dementia [Grade A].

Discrete elements of care In addition to research on outcomes from SCUs and other integrated care programs, there has been a complementary body of research designed to develop and test the effects of specific interventions that target discrete problems or needs. The interventions summarized in Table VII.5.1 are those that met the criteria for randomization and sample size; they differ significantly in their potential for replication and practical application. Other studies may inform care even though they do not meet the criteria for inclusion in Table VII.5.1. For example, in one study that included cross-over between intervention and control conditions, Cohen-Mansfield & Werner (1998) tested the effects of an environmental intervention in decreasing pacing and wandering. They found that symptomatic nursing home residents spent more time in corridors modified by creating nature or home-like scenes, but that there was no significant effects on trespassing or exit-seeking behaviors. In another study (Cohen-Mansfield & Werner 1997b), they found that music, family-generated video tapes, and 1 : 1 social interactions all decreased disruptive vocalizations as measured by analysis of audiotapes, or direct observations of behavior, but not by nursing staff report. Still other studies have evaluated nursing interventions designed to improve day-to-day functioning (Beck et al. 1997; Rogers et al. 2000) and the use of behavioral strategies and environmental modifications for the control of behavioral symptoms (Namazi et al. 1989; Chafetz 1990; Burgio et al. 1996; Cohen-Mansfield & Werner 1997a; Cohen-Mansfield & Werner 1998; Allen-Burge et al. 1999; Cohen-Mansfield 1999; Gerdner 1999).

Care recommendations Individualized social, behavioral, and environmental interventions may be useful for decreasing psychological and behavioral symptoms and for minimizing excess disability in nursing home residents [Grade B].

Conclusions Review of the literature demonstrates that few randomized clinical trials have been conducted on the nursing home care of nursing home residents with AD and related disorders. Taken as a whole, findings from the available studies serve as a proof of the concept that nursing homes can address the care needs of their residents with dementia, and that use of physical and chemical restraints can be minimized. However, many questions remain. From a strategic perspective, the lack of robust differences in clinical outcomes between SCUs and traditional nursing home units in the current, largely observational literature suggests that it may be useful to conduct controlled studies that begin to unbundle these comprehensive programs to evaluate what discrete elements of care may be associated with positive outcomes. In considering the available literature, it is important to recognize that the standards that are commonly used for evaluating evidence-based treatments may have been derived primarily from reviews of biomedical research, and that they may not be as applicable for the evaluation of behavioral and environmental interventions. As the value of establishing an evidence-based approach to the care of patients with dementia becomes established, it will be increasingly important to establish a consensus on the criteria that should be used for evaluating such studies, and for translating research findings into care standards.

References Alessi, C.A., Schnelle, J.F., Macrae, P.G. et al. (1995) Does physical activity improve sleep in impaired nursing home residents? Journal of the American Geriatrics Society 43, 1098–1102.

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Allen-Burge, R., Stevens, A.B. & Burgio, L.D. (1999) Effective behavioral interventions for decreasing dementia-related challenging behavior in nursing homes. International Journal of Geriatric Psychiatry 14, 213–232. Anonymous (1992) Psychotherapeutic medications in the nursing home. Journal of the American Geriatrics Society 40, 946–499. Avorn, J., Soumerai, S.B., Everitt, D.E. et al. (1992) A randomized trial to reduce the use of psychoactive drugs in nursing homes. New England Journal of Medicine 327, 168–173. Beck, C., Heacock, P., Mercer, S.O., Walls, R.C., Rapp, C.G. & Vogelpohl, T.S. (1997) Improving dressing behavior in cognitively impaired nursing home residents. Nursing Research 46, 126–132. Bridges-Parlet, S., Knopman, D. & Steffes, S. (1997) Withdrawal of neuroleptic medications from institutionalized dementia patients: results of a double-blind, baseline-treatment-controlled pilot study. Journal of Geriatric Psychiatry and Neurology 10, 119–126. Burgio, L.D., Cotter, E.M. & Stevens, A.B. (1996) Treatment in residential settings. In: Psychological Treatment of Older Adults: An Introductory Textbook (eds Hersen, M. & Van Hasselt, V.), pp. 127–145. Plenum Press, New York. Camberg, L., Woods, P., Ooi, W.L. et al. (1999) Evaluation of simulated presence: a personalized approach to enhance well-being in persons with Alzheimer’s disease. Journal of the American Geriatrics Society 47, 446–452. Capezuti, E., Strumpf, N.E., Evans, L.K., Grisso, J.A. & Maislin, G. (1998) The relationship between physical restraint removal and falls and injuries among nursing home residents. Journal of Gerontology: Medical Sciences 53, M47–M52. Castle, N.G., Fogel, B. & Mor, V. (1997) Risk factors for physical restraint use in nursing homes: pre- and postimplementation of the nursing home reform act. The Gerontologist 37, 737–747. Castle, N.G. & Mor, V. (1998) Physical restraints in nursing homes: a review of the literature since the nursing home reform act of 1987. Medical Care Research and Review 55, 139–170. (See also Zinn, J.S. (1998) Commentary. Medical Care Research and Review 55, 171–176.) Center for Health Systems Research and Analysis (1999) Nursing Facility Quality Indicators [online]. http://www.chsra.wisc.edu/CHSRA/QIs/QIs.htm. Chafetz, P.K. (1990) Two dimensional grid is ineffective against demented patients’ exiting through glass doors. Psychology and Aging 5, 146–147. Cohen-Mansfield, J. (1999) Global Patient Care. The role of non-pharmacological treatment. International Psychogeriatrics 11 (Supplement 1), 62. Cohen-Mansfield, J., Lipson, S., Werner, P., Billig, N., Taylor, L. & Woosley, R. (1999) Withdrawal of haloperidol, thioridazine, and lorazepam in the nursing home: a controlled, double-blind study. Archives of Internal Medicine 159, 1733–1740.

Cohen-Mansfield, J. & Werner, P. (1997a) Visits to an outdoor garden: impact on behavior and mood of nursing home residents who pace. In: Research and Practice in Alzheimer’s Disease Intervention in Gerontology (eds Vellas, B.J. et al.). Serdi Publishing, Paris. Cohen-Mansfield, J. & Werner, P. (1997b) Management of verbally disruptive behaviors in nursing home residents. Journals of Gerontology Series A: Biological Sciences and Medical Sciences. 52(6), M369–M377. Cohen-Mansfield, J. & Werner, P. (1998) The effects of an enhanced environment on nursing home residents who pace. The Gerontologist 38, 199–208. Evans, L.K., Strumpf, N.E., Allen-Taylor, L., Capezuti, E., Maislin, G. & Jacobsen, B. (1997) A clinical trial to reduce restraints in nursing homes. Journal of the American Geriatrics Society 45, 675–681. Friedman, R. & Tappen, R.M. (1991) The effect of planned walking on communication in Alzheimer’s disease. Journal of the American Geriatrics Society 39, 650–654. Furniss, L., Craig, S.K.L. & Burns, A. (1998) Medication use in nursing homes for elderly people. International Journal of Geriatric Psychiatry 13, 443–449. Gerdner, L.A. (1999) The effects of individualized vs. classical relaxation music on the frequency of agitation in elderly persons with Alzheimer’s disease and related disorders. International Psychogeriatrics 11 (Supplement 1), 8–9. Grant, L.A. & Ory, M. Alzheimer Special Care Units in the United States. Research and Practice in Alzheimer’s Disease, in press. Guttman, R., Altman, R.D. & Karlan, M.S. (1999) for the Council on Scientific Affairs, American Medical Association. Report of the Council on Scientific Affairs: Use of restraints for patients in nursing homes. Archives of Family Medicine 8, 101–105. Harrington, C., Carrillo, H., Thollaug, S.C. & Summers, P.R. (1999) Nursing facilities, staffing, residents, and facility deficiencies 1993 through 1999. [online] http://www.hcfa.gov/medicaid/nursingfac/nursfac99.pdf. Hawes, C., Mor, V., Philips, C.D. et al. (1997) The OBRA87 nursing home regulations and implementation of the resident assessment instrument: effects on process quality. Journal of the American Geriatrics Society 45, 977–985. Institute of Medicine. Committee on Nursing Home Regulations (1986) Improving the Quality of Care in Nursing Homes. National Academy Press, Washington, DC. Lawton, M.P., Van Haitsma, K., Klapper, J., Kleban, M., Katz, I.R. & Corn, J. (1998) A stimulation-retreat special care unit for elders with dementing illness. International Psychogeriatrics 10, 379–395. Leon, J. & Moyer, D. (1999) Potential cost savings in residential care for Alzheimer’s disease patients. Gerontologist 39, 440–449. Ljunggren, G., Phillips, C.D. & Sgadari, A. (1997) Comparisons of restraint use in nursing homes in eight countries. Age and Ageing 26 (Supplement 2), 43–47. Luchins, D.J., Hanrahan, P. & Murphy, K. (1997) Criteria for enrolling dementia patients in hospice. Journal of the American Geriatrics Society 45, 1054–1059.

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McGrath, A.M. & Jackson, G.A. (1996) Survey of neuroleptic prescribing in nursing homes in Glasgow. British Medical Journal 312, 611–612. Maslow, K. (1993) Current knowledge about special care units: Findings of a study by the US Office of Technology Assessment. Alzheimer’s Disease and Related Disorders 8, S14–S40. Meador, K.G., Taylor, J.A., Thapa, P.B., Fought, R.L. & Ray, W.A. (1997) Predictors of antipsychotic withdrawal or dose reduction in a randomized controlled trial of provider education. Journal of the American Geriatrics Society 45, 207–210. Namazi, K.H., Rosner, T.T. & Calkins, M.P. (1989) Visual barriers prevent patients from exiting through an emergency door. The Gerontologist 29, 699–702. Phillips, C.D., Hawes, C., Mor, V., Fries, B.E., Morris, J.N. & Nennstiel, M.E. (1996) Facility and area variation affecting the use of physical restraints in nursing homes. Medical Care 34, 1149–1162. Ray, W.A., Blazer, D.G., Schaffner, W. & Federspiel, C.F. (1987) Reducing antipsychotic drug prescribing for nursing home patients: a controlled trial of an educational visit. American Journal of Public Health 77, 1448–1450. Ray, W.A., Taylor, J.A., Meador, K.G. et al. (1993) Reducing antipsychotic drug use in nursing homes. A controlled trial of provider education. Archives of International Medicine 153, 713–721. Rogers, J.C., Holm, M.B., Burgio, L.D., Hsu, C., Hardin, M. & McDowell, B.J. (2000) Excess disability during morning care in nursing home residents with dementia. International Psychogeriatrics 12, 267–282. Rovner, B.W. & Katz, I.R. (1993) Psychiatric disorders in the nursing home: a selective review of studies related to clinical care. International Journal of Geriatric Psychiatry 8, 75–87. Rovner, B.W., Steele, C.D., Shmuely, Y. & Folstein, M.F. (1996) A randomized trial of dementia care in nursing homes. Journal of the American Geriatrics Society 44 (7–13), 1996. Schnelle, J.F., Simmons, S.F. & Ory, M.G. (1992) Risk factors that predict staff failure to release nursing home residents from restraints. The Gerontologist 32, 767–770. Shorr, R.I., Fought, R.L. & Ray, W.A. (1994) Changes in antipsychotic drug use in nursing homes during implementation of the OBRA-87 regulations. Journal of the American Medical Association 271, 358–362.

Snowden, M. & Roy-Byrne, P. (1998) Mental illness and nursing home reform: OBRA-87 ten years later. Omnibus Budget Reconciliation Act. Psychiatric Services 49, 229–233. Stern, Y. (1999) Predicting time to nursing home care and death in individuals with Alzheimer’s disease [online]. http://cpmcnet.columbia.edu/dept/ sergievsky/predictor.html. Stern, Y., Tang, M.X., Albert, M. et al. (1997) Predicting time to nursing home admission and death in individuals with Alzheimer’s disease. Journal of the American Medical Association 277, 806–812. Stoudemire, A. & Smith, D.A. (1996) OBRA regulations and the use of psychotropic drugs in long-term care facilities: impact and implications for geropsychiatric care. General Hospital Psychiatry 18, 77–94. Sullivan-Marx, E.M., Strumpf, N.E., Evans, L.K., Baumgarten, M. & Maislin, G. (1999) Predictors of continued physical restraint use in nursing home residents following restraint reduction efforts. Journal of the American Geriatrics Society 47, 342–348. Tappen, R. (1994) The effect of skill training on functional abilities of nursing home residents with dementia. Research in Nursing and Health 17, 159–165. Tappen, R.M., Roach, K.E., Applegate, E.B. & Stowell, P. (2000) Effect of a Combined Walking and Conversation Intervention on Functional Mobility of Nursing Home Residents with Alzheimer Disease. Alzheimer Disease and Associated Disorders 14, 196–201. US Health Care Financing Administration (1999) Study of Private Accreditation (Deeming) of Nursing Homes, Regulatory Incentives and Non-Regulatory Initiatives, and Effectiveness of the Survey and Certification System [online]. http://www.hcfa.gov/medicaid/exectv2.htm. Volicer, L. (1997) Hospice care for dementia patients. Journal of the American Geriatric Society 45, 1147–1149. Wells, D.L., Dawson, P., Sidani, S., Craig, D. & Pringle, D. (2000) Effects of an abilities-focused program of morning care on residents who have dementia and on caregivers. Journal of the American Geriatrics Society 48, 442–449. Werner, P., Koroknay, V., Braum, J. & Cohen-Mansfield, J. (1994) Individualized care alternative used in the process of removing physical restraints in the nursing home. Journal of the American Geriatrics Society 42, 321–325.

VII.6

Organization of Care

Michael S. Dennis and James Lindesay

VII.6.1

Introduction

The last three decades have seen considerable developments in service provision for people suffering from dementia. In general, this involves old age psychiatry services, community health services, elements of social care provided by social services departments, and nursing home or residential care provided by the private sector, voluntary organizations or the state. Services have been particularly well developed in the UK, Australia, New Zealand, and parts of the US (Riefler & Cohen 1998). Since the pioneering work of Macmillan in the late 1950s (Macmillan 1960), emphasis has been put upon providing care in patients’ own homes, with a variety of resources to facilitate this objective (domiciliary assessments and visits, inpatient and outpatient services and day hospitals and day centers). Over recent years specific multidisciplinary teams have evolved to assess needs and to coordinate and monitor care [‘community mental health teams’ (CMHTs) or ‘community resource teams’ (CRTs)]. This chapter deals with a number of issues concerning services for people with dementia, in particular: • determining population needs, and service planning; • individual components of a dementia service; and • monitoring and evaluating services. The particular service elements that are considered in detail in this chapter are community services, day hospital/day care, and residential/hospital respite care. When reviewing the effectiveness of services,

certain activities such as assisting the disabled with basic personal care and activities of daily living, providing warmth, food and safety, and managing acute physical and mental health emergencies are self-evidently necessary and desirable, and do not require evaluation per se. For this reason we have not examined the efficacy of acute hospital units, although there are issues regarding the optimum size, siting, design, and management of such facilities that could and should be studied. The resources, procedures, and facilities involved in assessing and coordinating care, and reducing care giver burden and stress may be organized and delivered in a variety of different ways, and therefore require evaluation of effectiveness and benefit. Multidisciplinary community teams, day care, and respite care are all considered vital services, and therefore also require evaluation. Other chapters in this book examine long-term nursing home and residential care, care giver support and education, and clinical assessment, and these will not be considered here. Despite the considerable development of services for dementia, the comprehensive literature search revealed a paucity of high-quality research in this area; in particular, there were very few randomized controlled trials (RCTs). For this reason we have also relied on evidence from non-randomized controlled trials (providing groups had baseline comparability), and from well-designed cohort studies. The cohort study can be a useful approach to examine service delivery, organization of care and clinical outcome. This is the case particularly

811

812 CHAPTER VII.6

when there are ethical difficulties, reluctance of service mangers to allow an RCT, or low statistical power (Muir Gray 1997). The case–control study would be a less appropriate design for evaluating the effects of service interventions. Because of the general lack of quality literature, the criteria for

VII.6.2

study inclusion in this chapter need to be less stringent than in other areas, and a separate scoring system has been devised (see Appendix VII.6.1). As a result of the substantial differences in the design of studies in all areas covered by this chapter, the results are summarized as a narrative review.

Determining Population Needs, and Service Planning

The most robust recent data concerning the prevalence of dementia come from the European Commission Concerted Action on the Epidemiology and Prevention of Dementia (EURODEM: Hofman et al. 1991). Age- and sex-specific prevalence rates of dementia are estimated, based upon 12 large European studies that include community and institutional populations. These estimates include people suffering from mild and borderline dementia, many of whom would have only minimal disability. Knowing the local prevalence of dementia is important when planning services, but a significant amount of further information is required for a more accurate assessment of population need. In particular, information is required concerning the special needs and disabilities of persons with cognitive impairment. Ideally, a survey of need would be performed for each defined geographical area, with service planning taking account of local demography and geography, and resources and facilities that are already available. These factors would also need to be considered in the context of clearly stated service objectives, and effectiveness of service interventions. It is also important to plan ahead, and use current demography to anticipate likely future demands upon the service. For all service providers to do this would be a considerable and expensive undertaking. To assist health and social services departments in planning services, Ely et al. (1995) have developed a model for estimating the characteristics and continuing care needs of people with cognitive disability, including moderate and severe dementia, in local populations. Not only does the model identify the nature and size of cognitively impaired groups, but it also allows the user to compare the

effects of different local policies. This project was funded by the UK NHS Executive, and published as a report to the NHS Executive Mental Health Research and Development Programme. The UK Office of Population Census and Surveys (OPCS) Disability Surveys (1985/6) were chosen as the main source of epidemiological data for the model; these were nationally based and included institutions, but used their own specific measure of cognitive impairment (‘SEVINT’ scale). A score of 4 or below on the 11-item SEVINT scale indicates ‘cognitive disability’, which approximates to 17 or below on the Mini Mental State Examination (MMSE). Importantly, the OPCS surveys also included measures of physical and psychological health, dependency in activities of daily living, use of health and social services, and even some data on the involvement of informal care givers. The estimates of disability provided by the model are comparable with other population-based studies. Cooper and Fearn (1998) compared comprehensive dementia case register data to an expected estimate of the frequency of moderate and severe dementia calculated, using the Cognitive Disability Planning Model. The case register depended on referrals from a variety of multiple service sources, i.e. day centers, nursing homes, residential homes, hospitals, and community psychiatric nurses. Confirmation of cases required a specialist clinical diagnosis, or MMSE score ≤ 24 followed by the application of standardized criteria. Cases identified from the dementia case register accounted for only 20% of the expected total prevalence. Interestingly, cases known to specialist services were no more severely disabled than those who were unknown. This exercise illustrates the difficulty in using local case register data in service planning.

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Gordon et al. (1997a,b) described a low-cost method to assist in providing a minimum dataset for planning purposes. First, they conducted a census to identify dementia sufferers. They used information from a wide range of professional staff who would potentially have contact with elderly cognitively impaired people, i.e. staff from health services, social services, and private homes. Secondly, having identified the elderly cognitively impaired, the assessment instrument [The Tayside Profile for Dementia Planning (TPDP)] was completed by both professional staff and care givers. This included a profile of need, focusing on mobility, personal care, domestic tasks, and indicators of behavioral problems. These criteria were measured by the degree of commitment required by services or informal care givers to care for the person using categories of ‘time interval’. Validity (determined by dimensions formulated from qualitative research with professionals and care givers), and retest reliability were acceptable. Inter-informant reliability however, was unsatisfactory. To compensate for this deficiency the authors suggest that the consist-

VII.6.3

ency of aggregated results offsets the low kappa scores for individual items, and they also recommend using a mix of informants (Gordon et al. 1997b). One particular problem with the census was that it identified only 66% of sufferers when comparing with estimates of expected dementia prevalence based upon EURODEM figures. In a further study involving a different population, Gordon et al. (1997c) repeated the census, and then used a stratified random sample to assess needs with the TPDP. On this occasion they used pro-rating to allow for identifiable non-response, which then gave a figure of 78% against the EURODEM-based estimate. Service planning also involves decisions about the most cost-effective use of the available resources. In the UK, a ‘Ready Reckoner’ for staff costs in the UK NHS has been developed to enable modeling and evaluation of the cost consequences of innovative use of staff resources (Netten et al. 1998a,b). Free prototype software is also available which enables users to alter the default values to reflect different assumptions and local circumstances.

Individual Components of a Dementia Service

Community services This section principally refers to multidisciplinary community mental health teams (CMHTs), or community resource teams (CRTs). These teams usually consist of community psychiatric nurses, social workers and a psychiatrist with appropriate administrative and clerical support, and may also include a psychologist, occupational therapist, and physiotherapist. Their principal role in dementia care is to assess patients, determine needs, support care givers, and coordinate appropriate packages of care. There is surprisingly little research that has evaluated community mental health teams for the elderly population. One of the major difficulties in determining the efficacy of community teams is deciding upon appropriate outcome measures. Appropriate objectives might be ensuring adequate assessment, effective delivery of treatment where appropriate, a reduction in care giver stress and

psychological morbidity, a reduction in psychological distress in sufferers, and improvement of quality of life. The evaluation and monitoring of services is discussed in more detail later in the chapter. Evidence concerning the work of CMHT members in supporting and educating care givers is reviewed by Brodaty elsewhere in this book, and has also been reviewed by others (Draper 1990; Knight et al. 1993). Although further work is required in this area, support and education techniques appear to be effective in reducing care giver stress and burden. Seidel et al. (1992) conducted a cohort study examining the function of a community team in Adelaide, Australia. Patients in nursing or residential care (n = 66) were rated at the time of initial referral for level of behavioral disturbance, and again after 3 months by referring care staff. Patients with dementia (n = 30) showed significant improvement following the involvement of the team (P = 0.001). Unfortunately, the instrument used to

814 CHAPTER VII.6

Table VII.6.1 Community resource teams: outcomes. Design

Patients

O’Connor et al. (1991); Quality score = 7 Non-randomized Country, UK. Screening of patients aged 75+ on GP controlled trial registers. All MMSE ≤ 23, 1 in 3 scoring 24, 25 assessed by psychiatrist using CAMDEX DSM III-R mild, moderate, or severe dementia

Riordan & Bennett (1998); Quality score = 7 Non-randomized Country: UK 19 dementia matched pairs sufferers (no clear standardized diagnosis), with care givers (cohabitants, or engaged in regular personal care), and 19 matched client–care giver pairs. Controls matched for age, sex, cognitive function, and relationship to client

Interventions

Outcomes

Results/comments

All from one area (86) referred to Resource Team (social worker, CPN, OT, physiotherapist, volunteer co-ordinator, psychiatrist). Controls from another area (73), ‘usual medical and social services’

Admission to institutions at 1, and 2 years

Early intervention, and referral to resource team did not affect admission rates in subjects living with supporters. 9/14 (64%) from study group with mod./severe dementia living alone admitted in 2nd year, compared to 1/13 (8%) of controls (P = 0.004) but team inexperienced. Some ‘at risk’ patients identified early, and justifiably referred for institutional care

Dementia Support Service (DSS) Trained, well supervised care staff providing practical, emotional help, and education and advice to main care giver Controls receive ‘normal’ care

Care giver: GHQ, Care giver, problem checklist, Machin Strain Scale Patients: MMSE, CRBRS, admission to residential care. Both groups assessed at baseline, 6, 12, 18 months

Reduction in admission to residential care for DSS group at 6 (P < 0.01), and 12 (P < 0.05) months. No differences in functioning of clients, or psychological profile of care givers (6 months) Problems: No standardized diagnosis. Assessor not blind. Small sample size, with attrition, support received by controls

ORGANIZATION OF CARE 815

rate behavioral disturbance was a four-point scale whose use had not been validated. One other objective of the individual ‘carepackages’ and emotional support organized and provided by CMHTs might be to delay admissions to institutional care. O’Connor et al. (1991) conducted a controlled trial examining the effect of help from a multidisciplinary team on admission rates for people with dementia. Early intervention, and support from the team did not affect admission rates (Table VII.6.1). Riordan and Bennett (1998) evaluated an extended domiciliary service [Dementia Support Service (DSS)]. This service involved trained care workers who, in addition to providing practical care, also supported care givers emotionally and provided information and advice. The care workers were managed closely by a project manager who had comprehensively assessed patients’ needs, and liaised closely with the local CMHTs. Dementia sufferers receiving DSS care had lower rates of admission to residential care at 6 and 12 months compared to a matched comparison group. Unfortunately, the numbers were small, dementia patients were not diagnosed according to standardized criteria, and the assessor was not blind (see Table VII.6.1). Intensive case management strategies to enhance home support and ensure more flexible and personalized care plans have also been evaluated to some extent (Table VII.6.2). Askham and Thompson (1990) studied a scheme for people with dementia that provided additional home support to fill the gaps in statutory care packages. There was no significant reduction in admissions to residential care compared to a control group, but this study lacked statistical power. There was a suggestion that some clients may benefit more than others from this type of intervention; individuals without care givers appeared to be supported for longer in the community than might have been the case otherwise. Challis et al. (1996) examined an intensive case management scheme based in a CMHT, comparing it with a similar team without this additional support. The care managers were responsible for the assessment, coordination, planning and review of demented clients referred to the team, with the flexibility to purchase social care outside the standard range of services available. The case

management scheme was associated with lower rates of institutionalization, but this was only apparent after it had been operating for two years. The scheme also had positive effects on the needs and satisfaction of both clients and their care givers. The intervention appeared to be cost-effective, with overall costs being only slightly higher in the intervention group. Two issues concerning the operation of CMHTs have generated much debate. First, should referrals to the team be solely from other medical practitioners, or should there be an ‘open’ referral system? Secondly, who is best placed to perform the initial assessment of a patient; should it always be the doctor (psychiatrist), or are other professionals able to reliably perform this task? When considering the first question there is a lack of quality research. Macdonald et al. (1994) audited 1477 consecutive referrals to a community-based psychogeriatric service operating an open referral system. They concluded that there was no evidence of more inappropriate referrals from an ‘open access’ policy. However, this study lacked standardized diagnostic criteria, or any evaluation of need, problems, or disability. Florio et al. (1998) conducted a well-designed study examining the effects of using ‘community gatekeepers’ on referrals to mental health services for the elderly (Table VII.6.3). Gatekeepers are trained laypersons working in a role likely to bring them into contact with isolated and vulnerable elderly. Examples of gatekeepers include utility workers, police, postal workers, meter readers, etc. They already operated an open referral system, and compared persons referred to services by normal channels to those referred by gatekeepers. Individuals referred by gatekeepers were more likely to be socially isolated, be enrolled in case management at time of referral, and remain in case management. Importantly, they were less likely to be receiving services at the time of referral. Despite this higher need at time of referral, after one year their utilization of services was no different from referrals from other sources. It has been traditional practice for the initial assessment of patients referred to community teams to be carried out by a medical practitioner (usually a trained psychiatrist), usually in the patient’s home. Increasing rates of referrals have led some

816 CHAPTER VII.6

Table VII.6.2 Case management schemes for dementia. Design

Patients

Askham & Thompson (1990); Quality score = 7 Country, UK. Action sample: 95 Two-centre nonControl sample: 71 (referrals randomized to two old-age psychiatry controlled trial services with a clinical diagnosis of dementia)

Challis et al. (1996); Quality score = 8 Country, UK. Action sample: 45 Non-randomized Control sample: 50 controlled trial 43 matched pairs. (referrals to two CMHTs with a clinical diagnosis of dementia)

Interventions

Outcomes

Results/comments

Case management to develop flexible care packages, including additional paid support as needed. Direct support/monitoring/budget-holding by case managers

Delay of residential care placement, receipt of services, mood (CARE-D), ADL, care giver strain, costs

No overall delay in institutionalization, but those living alone may benefit. No effect on mood, ADL. No effect on care givers. No evidence of costeffectiveness. Findings limited by small sample size / low statistical power. No standardized diagnosis; assessors not blind

Case management to develop flexible care packages, including additional paid support as needed. Direct support/monitoring/budget-holding by case managers. Intervention based in CMHT

Delay of residential care placement, mood, ADL, client/care giver needs, care giver input, care giver strain, costs

Residential care placement delayed in second year. No effect on mood. ADL needs reduced. Overall risk reduced. Care giver input/strain/need reduced at 1 year. Overall cost: slightly more for intervention group, indicating costeffectiveness. No standardized diagnosis; assessors not blind

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Table VII.6.3 Community resource teams: referral policy. Design

Patients

Florio et al. (1998); Quality score = 5 Cohort study. Country, US. 192 1 year referrals to elderly follow-up mental health services over 4 month period

Groups

Measures

Results/comments

Depending upon source of referral • Gatekeepers* • Other (‘open referral’ system)

Sociodemographic enrollment into case management or brief intervention/crisis management. If enrolled into case management: ‘Isolating life conditions’, Service Utilization, DSM-IV diagnosis

53% demented. Gatekeeper referred clients were: • more likely to be enrolled in case management at time of referral (P < 0.01) • remain in case management (P = 0.05) • more socially isolated (P < 0.001) • less likely to be receiving services (P < 0.004)

*Gatekeepers are trained laypersons working in a role likely to bring them into contact with isolated and vulnerable elderly.

researchers to question this policy, and to ask if there is a role for other health professionals to carry out the initial domiciliary assessment, or at least to screen referrals. There are no random controlled trials (RCTs) of medical vs. non-medical assessment, but Collighan et al. (1993) found that non-medical team members could adequately differentiate dementia from other major mental disorders (Table VII.6.4). Similarly, Seymour et al. (1994) found that a supervised community psychiatric nurse, using CAMDEX, was able to detect mild dementia in patients referred with early memory problems. These findings were further supported by a study involving referrals to a memory clinic (Dennis et al. 1998). In this study patients were seen by a community psychiatric nurse (who used a semistructured interview incorporating a variety of well-validated instruments) prior to their memory clinic appointment. The nurse reported her findings to an experienced psychiatrist, and the consensus diagnosis was then compared to a standardized diagnosis derived from the comprehensive clinic assessment. The nurse was able to detect dementia accurately in this population, but concordance for specific dementia subtypes was less good (see Table VII.6.4). Domiciliary social services such as home helps, bathing services and meals-on-wheels, form an important part of the spectrum of care provided to elderly people with dementia, and may enable them to remain at home rather than going into

institutional care. However, despite the considerable investment in these services, they have been subjected to very little in the way of formal evaluation. Social services tend to be organized, managed and resourced separately from health services, and access to research funding is much more limited. Research on social care is dominated by crosssectional interview surveys and quasi-experimental comparisons; longitudinal studies and RCTs are rare. Few studies have focused specifically on people with dementia; the limited evidence suggests that care givers derive benefit from these services, and they are most useful with less impaired individuals who live alone (Levin et al. 1989).

Respite care The process of caring for an elderly dementia sufferer at home is a cause of considerable emotional stress, and can significantly restrict the social activity of the care giver. Care givers themselves see respite care as an important area of service provision, and an important unmet need. Respite care can be provided in a variety of settings: day hospitals and day centers; short admissions to hospital or residential care; and by formal care givers in the patient’s own home (a ‘sitting service’). The principal objectives of respite care can be viewed from different perspectives. Giving a care giver a ‘well-deserved rest’ could reduce care giver burden/stress, but there may also be effects on the

818 CHAPTER VII.6

Table VII.6.4 Community resource teams: who makes the initial assessment? Design Collighan et al. (1993) Comparison of ‘team’ diagnosis with independent formal diagnosis and consensus diagnosis by ‘blind’ research psychiatrists

Seymour et al. (1994) Comparison of ‘supervised’ nurse diagnosis (CAMDEX) and research psychiatrist (GMS/AGECAT) Dennis et al. (1998) Comparison of diagnosis by ‘supervised’ nurse using semistructured interview, Memory Clinic clinical diagnosis, and ICD 10 diagnosis derived from Memory Clinic assessment

Patients

Outcome Measures

Results/comments

Country, UK. 100 referrals to two community mental health teams for the elderly

Concordance between team and research diagnoses (based upon AGECAT)

Good level of agreement for main diagnositc groups Dementia (63), k = 0.79. Depression (31), k = 0.89 No significant difference between medical and non-medical team members (though most medical assessments performed by ‘junior’ psychiatrists)

Country, UK. 33 referrals from primary health care with ‘early’ memory impairment

Concordance between doctor’s clinical and nurse’s CAMDEX diagnosis, and GMS/AGECAT vs. nurse CAMDEX (severity of impairment)

k = 0.61 for dementia type. (VaD/mixed or AD). For severity of impairment k = 0.71

Country, UK. 64 consecutive referrals to a Memory Clinic

Concordance between ICD 10 diagnosis, Memory Clinic diagnosis and diagnosis derived from nurse assessment procedure

For dementia: k = 0.75 for ICD and nurse diagnosis, and 0.76 for Memory Clinic and nurse diagnosis, but k = 0.46 for ICD 10 and nurse, and 0.6 for Memory Clinic and nurse for AD

AD, Alzheimer’s disease; VaD, vascular dementia.

ORGANIZATION OF CARE 819

patient’s behavior, cognition, and general health and functioning, and finally the net result of these benefits may be to postpone entry to residential care. There has been more research activity relating to respite care than other areas of service provision, particularly in the US. In addition to controlled trials, there have been a number of well-conducted cohort studies. The major studies are summarized in Table VII.6.5 (controlled trials), and Table VII.6.6 (cohort studies). There are many difficulties encountered in interpreting the results of these studies. In particular, major differences in study design make it hard to reach valid conclusions. Another major problem is that different types of respite care are frequently included in the same study, and may be linked to other service innovations. In addition, respite care may be utilized only sporadically, and may also occur in control groups. The controlled studies generally found little evidence that respite care reduced care giver stress/ burden, patients’ well-being (physical, functional or cognitive), or rate of institutionalization. Burdz et al. (1988) found an improvement in patients’ behavior, but a worsening of the care giver–patient relationship. Conlin et al. (1992) showed a statistically significant reduction in care giver stress, but this was unlikely to be of clinical significance. There was a delay in institutionalization for patients receiving respite intervention in the study of Lawton et al. (1989), but this was again of doubtful clinical significance. The results of cohort studies for institutional respite add little to the findings of the controlled studies (see Table VII.6.6). There is some indication that care giver well-being may improve whilst the relative is in respite, but on discharge the degree of psychological distress returns to pre-respite levels (Adler et al. 1993; Larkin & Hopcroft 1993). Patient cognitive function, and behavior appear little changed; at least helping to dispel the fear that institutional respite may cause a deterioration in patients’ cognitive and functional performance. Earlier concerns that institutional respite may increase mortality (Rai et al. 1986), have also been contradicted by more carefully designed studies (Harper et al. 1988; Selley & Campbell 1989).

The methodological shortcomings of these studies may account for their failure to provide evidence of the efficacy of respite care, despite the clinical observation that care givers have high levels of satisfaction with these services. In future, study sample sizes should be sufficient to provide adequate power, recipients of respite should satisfy well-used diagnostic criteria for dementia, and the respite programme should be restricted to one specific care setting and be used regularly.

Day care Day care for sufferers of dementia can be provided in a wide range of settings. These include dementiafocused day centers run by local authorities, or other non-health state-funded organizations, and the voluntary sector. The objectives of such day care are usually to provide social care, stimulation and company for dementia sufferers. In addition, it is thought that by providing respite for care givers there may be an improvement in care giver wellbeing, and possible delay in institutionalization. Day hospitals (provided and staffed by health services) have similar objectives, but in addition they have other important roles. The day hospital offers an important facility for assessment, treatment, and the long-term maintenance and monitoring of patients. Use of day hospital resources may reduce admissions to acute in-patient beds, and facilitate early discharge from hospital. Some research relating to day care is embedded in the controlled studies of respite care (see previous section); both Lawton et al. (1989) and Conlin et al. (1992) included day care in their respite programmes. As day care was only one component of a wider evaluation of service provision, it is impossible to assess its individual influence in both these studies. There were only two studies identified in the literature search that were specific to day care in dementia, and satisfied the required quality criteria (Table VII.6.7). In the study of Wells et al. (1990) of attendees of specialist dementia day centers, care givers showed a small improvement in well-being (measured by the General Health Questionnaire) after 3 months. However, the most significant improvement occurred in care givers whose dependants had been admitted to residential care. The

Design

Patients

Burdz et al. (1988); Quality score = 6 Non-randomized Country : Canada. Respite group: controlled study 15 dementia patients with care givers (clinicians diagnosis), 20 non-dementia, with care givers. Control: waiting list (12 dementia, 8 non-dementia) Lawton et al. (1989); Quality score = 7 Randomized Country, US. Volunteer family controlled trial care givers of demented patients (physician’s diagnosis)

Conlin et al. (1992); Quality score = 6 Non-randomized Country, US. 15 care givers of trial (10 weeks) patients with AD: 7 respite group, 8 waiting list control group Mohide et al. (1990); Quality score = 10 Randomized trial Country: Canada. Pairs of resident informal care givers and demented patients (standardized diagnosis, moderate-severe dementia, AD, VaD or mixed)

AD, Alzheimer’s disease; VaD, vascular dementia.

Intervention

Outcomes

Results/comments

15 days institutional respite, assessed 1 week pre- and 2 week post-respite

Care giver: Zarit Burden Interview Patient: Memory and behavior problems checklist (Zarit)

Care giver burden no different following respite, but attitude to patient worse (P < 0.01), behavior improved in respite group (P < 0.001) Care givers subjectively report benefit from respite

Intervention group (317) received 1 year programme: case management, care giver education and counselling, opportunity for in-home, residential, or day care respite. Control group (315) could also enter respite if arranged by themselves

Use of respite. Days spent in community. Care giver wellbeing (composite of 5 scales of caregiver attitudes, physical health, and psychological well-being) Assessment at 0 and 12 months

No difference in care giver well-being. Intervention group spent longer in community before institutionalization (P = 0.01), but probably not clinically significant Experimental group actually made little use of respite services

10 week respite programme, including day care and in-home respite

Care givers: Relatives Stress Scale, Profile of Mood States (POMS) at 5, 10 weeks Patient: rates of institutionalization

No significant differences despite reduction in care giver stress in respite group. Very small sample size

Experimental group (30) received 6 month programme of weekly in-home respite, care giver support and education, and support group Controls (30) received routine nursing support

Care givers: CES-D for depression, STAI for anxiety, CQLI for quality of life. Ratings at 0, 3, 6 months Patient: rates of institutionalization

No statistically significant difference controlled between groups for all measures. Authors, however, judged care givers’ improved QOL in experimental group to be clinically significant

820 CHAPTER VII.6

Table VII.6.5 Controlled trials of respite care.

Table VII.6.6 Cohort studies of respite care. Design

Patients

Seltzer et al. (1988); Quality score = 7 Cohort study Country, US. 37 patients (36 men, 1 woman) with AD (DSM-IIIR, NINCDS)

Adler et al. (1993); Quality score = 8 Cohort study Country, US. 37 males with DSM-IIIR diagnosis of dementia (25 AD, 12 non-AD)

Larkin & Hopcroft (1993); Quality score = 7 Cohort study Country, US. 23 patients and family (clinical diagnosis of AD)

Outcomes

Results/comments

First in-patient respite admission (2 weeks duration)

Patients’ cognitive and functional status on admission, and at end of respite Measures: included MMSE, Blessed IMC & PEA, Language and Behavioral adjustment scales (MACC)

No significant differences overall. However, those more severely impaired showed improvement in some measures of behavior

2 week in-patient respite

Care givers: Burden Interview, GDS (14 days pre- and post-respite, day of discharge). Patients: ADL -Physical self-maintenance scale, Behavioral Assessment Instrument (14,7 pre-, day of admission, 14 days post discharge)

No difference on patient outcomes. For nonAD significant decline in care giver burden (P = 0.001) and depression (P = 0.02) during respite, but effect disappears after discharge

Temporary Institutional Respite

Care givers: scales anxiety, depression, hostility, obsessive-compulsiveness Patients: ADL. Administered 3 days pre-, 3 days before discharge, and 14 days post discharge

Significant reduction in care giver psychological distress during respite, but returning to normal post-discharge One third dementia patients show reduction in ADL

AD, Alzheimer’s disease; ADL, activities of daily living.

ORGANIZATION OF CARE 821

Intervention

822 CHAPTER VII.6

Table VII.6.7 Day care for dementia. Design

Patients

Wells et al. (1990); Quality score = 5 Country, Australia. 52 care Cohort study giver–patient pairs. Patients cognitively impaired (principally demented)

Wimo et al. (1994); Quality score = 6 Non-randomized Country, Sweden. 100 controlled study patients with clinical diagnosis of dementia (55 day care, 45 waiting list control group)

Intervention

Outcomes

Results/comments

Attendance at special dementia day centres

Patient: problem checklist. Care giver: GHQ, DSSI/SAD (anxiety and depression), QOL questionnaire, guilt and grief scales. 0, 3 months

Patients: no significant change in problems Care givers: Improvement in GHQ at 3 months, reduction in anxiety. Greatest improvement in care giver of those in residential care Problems: • probably not clinically significant • no standardized diagnosis

Day care

Patient: QOL (index of well-being, Rosser Index) 0, 12 months. Use of resources (0,3,6 months). Costeffectiveness analysis

Indices of QOL fell over 12 months for both groups, with no significant differences. On model presented, no cost benefit of day care evident. Difficulty in measuring QOL

ORGANIZATION OF CARE 823

cost-effectiveness analysis undertaken by Wimo et al. (1994) failed to support the benefits of day care. Although the cost per patient per day was less for the day care group than the waiting list controls, this was not significant and there was no difference in quality of life between the groups. There may be considerable problems with measurement of the quality of life in this study, an issue that is dealt with in more depth in the next section. Despite their widespread availability, and a strong consensus supporting their use, there is a considerable lack of quality research specific to day hospitals. Gilleard (1987) conducted a welldesigned prospective study of referrals for psychogeriatric day hospital care. Unfortunately, although the vast majority of referrals had a clinical diagnosis of dementia, it is unclear exactly how many of those included in the outcome analysis were dementia sufferers. This study did indicate that day hospital care was associated with a significant reduction in relatives’ stress (measured by the General Health Questionnaire), particularly during the first three months of attendance (P < 0.001). High levels of problems, combined with a failure to reduce care giver stress, were associated with subsequent institutionalization of the patient.

Memory clinics Memory clinics have developed separately from other services for people with dementia, and have until recently been oriented more towards research than mainstream service provision (Lindesay & Morris 1998). Their focus is upon younger and less severe cases of dementia, and their main function is to provide detailed multidisciplinary diagnostic assessment, although a range of other services, such as advice, counselling, follow-up, onward referral and treatment, are also offered. With the advent of specific antidementia drug therapies, memory clinics are becoming increasingly popular as a means of identifying, assessing and managing those who may benefit from them, and their functions are being integrated into the broader range of service provision for dementia. The literature on memory clinics is almost entirely descriptive (e.g. Wright & Lindesay 1995); there has to date been no formal evaluation of their cost-effectiveness.

Services for younger people with dementia Dementia before the age of 65 years is relatively rare, and services for this group are less developed than they are for the elderly population. However, the special needs of younger people with dementia are being increasingly recognized, and attempts are being made to provide services that can meet them effectively. As with the elderly population, service planning requires good epidemiological data. A number of surveys have been carried out, with broadly consistent findings (Harvey 1998). An important difference compared to the elderly population is that unusual causes of dementia are proportionally more frequent, so there is a need for an expert diagnostic service. Neurologists have traditionally provided this, but memory clinics are playing an increasingly important role in this respect. With the identification of inherited forms of dementia, there is also a role for departments of medical genetics in the assessment and counselling of individuals at risk. The provision of long-term care and support to patients and their families is more problematic. Neurologists are not equipped to do this, and mainstream health and social services for dementia are designed for the elderly population and are not appropriate for or acceptable to younger patients. The small number of individuals affected makes specialist provision at district level impractical in most areas, and services may need to be organized for larger populations. There is no universally agreed service model for younger people with dementia, but a number of documents have set out guiding principles and strategies (e.g. Alzheimer’s Disease Society (UK) 1996). One way forward that has been effective in some areas has been to set up a local steering group of interested individuals with the responsibility of ensuring that there is an appropriate pathway of care for these patients (Quinn 1996). In the UK, there is a telephone helpline, based at the National Hospital for Neurology and Neurosurgery, London, that provides a point of contact for patients and care givers, and a source of information and advice to general practitioners and other professionals (Harvey et al. 1998).

824 CHAPTER VII.6

VII.6.4

Monitoring and Evaluating Services

The evaluation of health services presents the researcher with a number of problems that are difficult, if not impossible, to overcome within the conventional paradigm of the randomized controlled trial (RCT). Service innovations are rarely single new elements with all else held constant, and it is therefore difficult for evaluations to separate effective components from those that are ineffective. To be meaningful, evaluations need to examine entire service systems, and not just individual elements. RCTs are concerned with the average effect of interventions, and tell us little about what determines outcome at the level of the individual patient. The results of RCTs are rarely representative of ‘real world’ clinical populations, either because of restrictive inclusion and exclusion criteria, or because the trial is being carried out in a teaching centre with skilled and enthusiastic practitioners. New evaluation strategies are required to address these problems. In evaluating the effectiveness of services for people with dementia, appropriate outcome measures are required. These outcomes should be determined by the overall service objectives, and be realistically achievable. Monitoring of services is also required to assess equity of provision, accessibility, responsiveness and user satisfaction. Melzer et al. (1994) describe achievable objectives for health services for dementia, and also discuss simple monitoring and quality improvement strategies. In addition to collecting routine activity data these could be: ‘one-off’ sample surveys; inspections of facilities; investigations of untoward events; enhanced complaints mechanisms; quality improvement mechanisms; clinical audit; discussions with ‘stakeholders’; and following individuals through the services (care pathway analysis). One approach to clinical audit might be to examine the quality of assessment and investigation of patients with dementia against standards and consensus statements described by professional bodies such as the Royal College of Psychiatrists (1992), the World Health Organisation (WHO) and the World Psychiatric Association (WPA) (WHO/WPA 1998). In the UK, National Service Frameworks for mental health and the elderly are currently being developed, which will also provide benchmarks against which to compare local practice.

The selection and development of outcome scales is a constantly changing field. Measures can be either specific or generic. Disease-specific measures are designed to detect minor but important changes for that specific illness. Generic measures are broadly applicable and involve global estimates of health and life quality. In considering the selection of outcome measures for dementia services, it is important to select domains that are relevant to the original service objectives, e.g. outcome measures involving assessment of cognition and activities of daily living are appropriate for pharmacological research, but not for service evaluation. Appropriate outcomes could be: • service utilization; • behavioral problems and psychological well-being of the person with dementia; • care giver measures; • quality of life for the dementia sufferer. In addition, measures need to be valid, reliable, responsive to change, and brief and easy to administer. If this information can be collected routinely as part of clinical assessment and follow-up, so much the better. Service utilization is a frequently used outcome measure. As we have seen, however, a reduction in admissions to continuing care facilities does not appear to be a realistic outcome of increased community provision. There are other more achievable and equally appropriate objectives resulting from supporting care givers and patients. The stress of caring and the high level of psychiatric morbidity experienced by informal care givers are well known. Instruments that focus on measuring the psychological impact of caring, i.e. scales of ‘stress’ or ‘burden’ and symptoms of anxiety and depression in care givers, could be appropriate outcome measures. Other areas of importance for care givers could be indices of physical health, satisfaction with services, and time for leisure and social contacts. Scales that concentrate on behavior, mood, anxiety, and other psychiatric symptoms in people with dementia could also be useful outcome measures for mental health services. A full evaluation of the wide range of instruments available in these particular domains is beyond the scope of this particular chapter. The reader should refer to Ramsay et al. (1995),

ORGANIZATION OF CARE 825

who has extensively reviewed measures to determine the outcome of community services for people with dementia. Defining and measuring outcomes in Alzheimer’s disease (AD) was the subject of a recent international conference in Washington (Whitehouse et al. 1997). A broad range of assessment scales used in old age psychiatry can be found in the compendium by Burns et al. (1999a). The ultimate objective of any service for people with dementia must be to improve the quality of life (QOL) for the sufferer and those who care for them. To find appropriate, valid, and reliable measures for QOL in dementia is a significant challenge and an area of increasing research (Lawton 1997). Albert et al. (1996) have recently described a QOL measure for patients with AD. QOL ratings were given by formal and informal care givers for two domains, namely affect and activity. The instrument had good test–retest reliability, and validity. Measures of QOL in dementia have recently been

VII.6.5

reviewed by Selai and Trimble (1999), who conclude that its measurement in this patient group, while difficult, is feasible. The UK Royal College of Psychiatrists has developed a generic instrument to measure outcome in elderly people with mental health problems: the Health of the Nation Outcome Scales for Elderly People (Burns et al. 1999b). The instrument was designed for use in both functional and organic disorders, but incorporates domains pertaining particularly to problems related to dementia. Extensive piloting of the scale has shown that it discriminates well between patients with functional psychiatric disorders and those with dementia. Validity compared with known rating scales was generally good with excellent interrater reliability in one study (Burns et al. 1999c), although others have had problems with this (Allen et al. 1999). More work needs to done, in particular to assess its sensitivity to change over time and its ability to predict outcome.

Conclusions and Future Research Priorities

It is evident from this brief review that there is a considerable shortage of quality research concerning services for people with dementia. Current practice and service organization varies considerably, and is frequently based upon consensus rather than proven effectiveness. This chapter includes evidence provided by nonrandomized controlled trials, and well designed cohort studies in addition to the few randomized studies that have been conducted. In order to provide a detailed objective assessment of these studies a more refined grading system (‘Quality Score’) has been devised for use in this chapter (Appendix VII.6.1, p. 827). This ‘Quality Score’ is different to the Quality of Evidence levels used in other chapters of the book. Most of the evidence presented in this chapter would fall either in Grade B (Quality of Evidence level 7/8) or Grade C (Quality of Evidence level 9/10). In future, studies should be randomized (wherever ethical considerations allow), and be of sufficient power. Dementia should be diagnosed according to standardized and commonly used criteria. Confounding influences should be assessed and matched

if of primary importance, and outcome measures should refer to both patients and care givers, and be of proven reliability and validity. Wherever possible, data on costs should be collected. Robust evaluation of dementia services will require multicentre studies and systematic replications. There is also a requirement to look beyond the RCT; evidence of service efficacy needs to be complemented by evidence of clinical effectiveness and efficiency.

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with Dementia: a Review and Strategy. Alzheimer’s Disease Society, London. Askham, J. & Thompson, C. (1990) Dementia and Home Care. Age Concern Institute of Gerontology: Research Paper 4. Age Concern England, Mitcham. Burdz, M., Eaton, W. & Bond, J. (1988) Effect of respite care on dementia and nondementia patients and their caregivers. Psychology and Aging 3(1), 38–42. Burns, A., Lawlor, B. & Craig, S. (1999a) Assessment Scales in Old Age Psychiatry. Martin Dunitz, London. Burns, A., Beevor, A., Lelliott, P. et al. (1999b) Health of the Nation Outcome Scales for Elderly People (HoNOS 65+). Glossary for HoNOS 65+ score sheet. British Journal of Psychiatry 174, 435–438. Burns, A., Beevor, A., Lelliott, P. et al. (1999c) Health of the Nation Outcome Scales for Elderly People (HoNOS 65+). British Journal of Psychiatry 174, 424–427. Challis, D., von Abendorff, R., Brown, P. & Chesterman, J. (1996) Care Management and Dementia: an evaluation of the Lewisham Case Management Scheme. PSSRU: Discussion paper 1242. University of Kent, Canterbury. Collighan, G., Macdonald, A., Herzberg, J., Philpot, M. & Lindesay, J. (1993) An evaluation of the multidisciplinary approach to psychiatric diagnosis in elderly people. British Medical Journal 306, 821–824. Conlin, M., Caranasos, G. & Davidson, R. (1992) Reduction of caregiver stress by respite care: a pilot study. Southern Medical Journal 85, 1096–1100. Cooper, B. & Fearn, R. (1998) Dementia care needs in an area population: case register data and morbidity survey estimates. International Journal of Geriatric Psychiatry 13, 550–555. Dennis, M., Furness, L., Lindesay, J. & Wright, N. (1998) Assessment of patients with memory problems using a nurse-administered instrument to detect early dementia and dementia types. International Journal of Geriatric Psychiatry 13, 405–409. Draper, B. (1990) The effectiveness of services and treatment in psychogeriatrics. Australian and New Zealand Journal of Psychiatry 24, 238–251. Ely, M., Melzer, D., Brayne, C. & Opit, L. (1995) The Cognitively Frail Elderly: Estimating population characteristics and needs of people with cognitive disability, including dementia. NHS Executive Mental Health Research and Development Programme. pp. 97. University of Cambridge, Cambridge. Florio, E., Jensen, J., Hendryx, M., Rashko, R. & Mathieson, K. (1998) One year outcomes of older adults referred for aging and mental health services by community gatekeepers. Journal of Case Management 7, 74–83. Gilleard, C.J. (1987) Influence of emotional distress among supporters on the outcome of psychogeriatric day care. British Journal of Psychiatry 150, 219–223. Gordon, S.D., Carter, H. & Scott, S. (1997c) Profiling the care needs of the population with dementia: a survey of central Scotland. International Journal of Geriatric Psychiatry 12, 753–759. Gordon, D., Spicker, P., Ballinger, B. et al. (1997a) A population needs assessment profile for dementia. International Journal of Geriatric Medicine 12, 642–647.

Gordon, D., Spicker, P., Ballinger, B. et al. (1997b) Identifying older people with dementia: the effectiveness of a multiservice census. International Journal of Geriatric Psychiatry 12, 636–641. Harper, N., McDowell, D., Turner, J. & Sharma, A. (1988) Planned short-stay admission to a geriatric unit: one aspect of respite care. Age and Ageing 17, 199–204. Harvey, I. (1998) Young onset dementia: epidemiology, clinical symptoms, family burden, support and outcome. NHS Executive, London. Harvey, I., Roques, P., Fox, N. & Rossor, M. (1998) CANDID–Counselling and diagnosis in dementia: a national telemedicine service supporting the care of younger patients with dementia. International Journal of Geriatric Psychiatry 13, 381–388. Hofman, A., Rocca, W., Brayne, C. et al. (1991) The prevalence of dementia in Europe: a collaborative study of 1980–90 findings. International Journal of Epidemiology 20(3), 736–748. Knight, B., Lutzky, S. & Macofsky-Urban, F. (1993) A meta-analytic review of interventions for caregiver distress: recommendations for future research. Gerontologist 33, 240–248. Larkin, J. & Hopcroft, B. (1993) In-hospital respite as a moderator of caregiver stress. Health and Social Work 18, 132–138. Lawton, M.P. (1997) Assessing quality of life in Alzheimer disease research. Alzheimer’s Disease and Associated Disorders 11, 91–99. Lawton, M.P., Brody, E.M. & Saperstein, A.R. (1989) A controlled study of respite service for caregivers of Alzheimer’s patients. Gerontologist 29(1), 8–16. Levin, E., Sinclair, I. & Gorbach, P. (1989) The effectiveness of Home Help Service for confused old people and their families. Research Policy and Planning 3, 1–7. Lindesay, J. & Morris, J. (1998) Introduction. In: Diagnosis and Management of Dementia: a Manual for Memory Disorders Teams (eds G. Wilcock, et al.). Oxford University Press, Oxford. Macdonald, A., Goddard, C. & Poynton, A. (1994) Impact of ‘open access’ to specialist servicesathe case of community psychogeriatrics. International Journal of Geriatric Psychiatry 9, 709–714. Macmillan, D. (1960) Preventative geriatrics. Opportunities of a community mental health service. Lancet 1439–1441. Melzer, D., Hopkins, S., Pencheon, D., Brayne, C. & Williams, R. (1994) Dementia. In: Health Care Needs Assessment (eds Stevens, A. & Raftery, J.), pp. 305–340. Radcliffe Medical Press, Oxford. Mohide, E., Pringle, D., Streiner, D., Gilbert, J., Muir, G. & Tew, M. (1990) A randomized trial of family caregiver support in the home management of dementia. Journal of the American Geriatrics Society 38, 446–454. Muir Gray, J. (1997) Appraising the quality of research. In: Evidence-based Health Care (ed. J. Muir Gray), pp. 69–102. Churchill Livingstone, Edinburgh. Netten, A., Knight, J., Dennett, J., Cooley, R. & Slight, A. (1998a) A ‘Ready Reckoner’ for staff costs in the NHS, 1: Estimated unit costs. PSSRU, Canterbury. Netten, A., Knight, J., Dennett, J., Cooley, R. & Slight, A. (1998b) A ‘Ready Reckoner’ for staff costs in the NHS, 2: Methodology. PSSRU, Canterbury.

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Selai, C. & Trimble, M. (1999) Assessing quality of life in dementia. Aging and Mental Health 3, 101–111. Selley, C. & Campbell, M. (1989) Relief care and risk of death in psychogeriatric patients. British Medical Journal 298, 1223. Seltzer, B., Rheaume, Y., Volicer, L. et al. (1988) The short-term effects of in-hospital respite on the patient with Alzheimer’s disease. Gerontologist 28, 121–124. Seymour, J., Saunders, P., Wattis, J. & Daly, L. (1994) Evaluation of early dementia by a trained nurse. International Journal of Geriatric Psychiatry 9, 37–42. Wells, Y., Jorm, A., Jordan, F. & Lefroy, R. (1990) Effects on care-givers of special day care programmes for dementia sufferers. Australia and New Zealand Journal of Psychiatry 24, 82–90. Whitehouse, P., Maslow, K. & Smyth, K. (1997) Defining and measuring outcomes in Alzheimer Disease Research. Alzheimer’s Disease and Associated Disorders 11 (Supplement 6), 1–198. Wimo, A., Mattsson, B., Krakau, I., Eriksson, T. & Nelvig, A. (1994) Cost-effectiveness analysis of day care for patients with dementia disorders. Health Economics 3, 395–404. WHO/ WPA (1998) Organization of care in psychiatry for the elderlyaa technical consensus statement. Ageing and Mental Health 2, 246–252. Wright, N. & Lindesay, J. (1995) A survey of memory clinics in the British Isles. International Journal of Geriatric Psychiatry 10, 379–385.

O’Connor, D., Pollitt, P., Brook, C., Reiss, B. & Roth, M. (1991) Does early intervention reduce the number of elderly people with dementia admitted to institutions for long term care? British Medical Journal 302, 871–875. Quinn, C. (1996). The Care Must Be There. Dementia Relief Trust, London. Rai, G., Bielawska, C., Murphy, P. & Wright, G. (1986) Hazards for elderly people admitted for respite (‘holiday admissions’) and social care (‘social admissions’). British Medical Journal 292, 240. Ramsay, M., Winget, C. & Higginson, I. (1995) Review: measures to determine the outcome of community services for people with dementia. Age and Ageing 24, 73–83. Riefler, B. & Cohen, W. (1998) Practice of geriatric psychiatry and mental health services for the elderly: results of an international survey. International Psychogeriatrics 10, 351–358. Riordan, J. & Bennett, A. (1998) An evaluation of an augmented domiciliary service to older people with dementia and their carers. Aging and Mental Health 2(2), 137–143. Royal College of Psychiatrists (1992). Mental Health of the Nation: the Contribution of Psychiatry. Council Report CR16. Royal College of Psychiatrists, London. Seidel, G., Smith, C., Hafner, R. & Holme, G. (1992) A psychogeriatric community outreach service: description and evaluation. International Journal of Geriatric Psychiatry 7, 347–350.

Appendix VII.6.1 Scoring system for quality of randomized controlled trials, controlled trials and cohort studies in service delivery related research for Alzheimer’s disease Criteria

Score

Study design Randomized controlled trial (RCT) Non-randomized, but comparable groups* Non-randomized, non-comparable groups Cohort study Retrospective/audit

2 1 0 1 0

Patients Use of standardized diagnostic criteria All patients accounted for

2 1

Outcomes Well validated, reliable care giver measures Well validated, reliable patient measures Service utilisation Cost–benefit analysis Blind assessors

1 1 1 1 1

Results/conclusions Statistical significance considered Clinical significance considered

1 1

For inclusion in chapter the following are required: a minimum score of 1 in all sections giving a total quality score of ≥ 4. *Minimum comparability for age, sex, degree of cognitive impairment. Comparability would also be required on other factors, if crucial to outcome.

Memory Clinicsca Guide to Implementation and Evaluation

VII.7

Roger Bullock and Nawab Qizilbash

This chapter examines why memory clinics exist, their make-up and functioning. Armed with this background and practical guidance, we hope that the reader is able to adapt or mount a service, adapted to local circumstances. The chapter covers three areas: • Background: history, development and rationale of memory clinics.

VII.7.1

Background

Memory clinics first appeared in America in the mid-1970s, primarily aimed at the clinical diagnosis of relatively early cases of dementia (Fraser 1992). They developed in various ways while sharing common principles. Often hospital based, they perform detailed multidisciplinary assessments, to arrive at a diagnosis and management plan. This has encouraged research and education, creating platforms for prescribing new antidementia therapies and monitoring outcomes. Some clinics are researchbased, either based within public institutions or as part of business units (especially in the US). We do not consider these as memory clinics, as they do not usually provide clinical care, outside of the terms of trial protocols. The place of memory clinics remains in debate. They are potentially an expensive resource, increasing demand and changing practice patterns. They have a strong focus on diagnostic procedures and pharmacological treatment. Earlier diagnosis increases the need for sensitive counselling, as imparting information to the dementia sufferer is

828

• Practical aspects of setting up a memory clinic: staffing, functioning and content (assessment procedures and tools). • Future developments: a common minimum dataset to advance research from routine data collection in clinics.

complex (Drickamer & Lachs 1992). In adopting a more holistic approach, clinics are furthering the introduction of measurement into the psychosocial model of dementia care and helping to reduce the stigma of dementia. Early diagnosis of dementia seems increasingly important, as pharmacological (and psychosocial) interventions increase demand for something to be done at earlier stages of the disease. Overemphasis on prescribing may ‘medicalize’ the multidisciplinary nature of the clinic at the expense of other facets of management (Bender 1996). Validated instruments have improved the assessment of dementia in a clinic setting; better diagnostic accuracy leads to identification of new conditions, including mild cognitive impairment (MCI), which may represent preclinical dementia (See Chapter III.8). The diagnosis of dementia should generally be revealed to the patient (Rice & Warner 1994; Gilllard & Gwilliam 1996). Reluctance by professionals to disclose the diagnosis to the patient can be compounded by the care giver’s worries about the

MEMORY CLINICS 829

effect on the patient. Research shows a disparity in what care givers wish to be told and what they want their relative to hear (Maguire et al. 1996). Care pathways and guidelines in dementia are appearing. Memory clinics attract a patient group that is generally motivated and willing to take part in research. Referral patterns to clinics may change

as primary care clinicians become confident in diagnosing and treating straightforward cases of dementia. Memory clinics may again become tertiary services for difficult diagnostic and management problems (O’Neill et al. 1992); focusing on multidisciplinary research and education (Emmerson & Frampton 1996; Moniz-Cook & Woods 1997).

Summary of Rationale for Establishing a Memory Clinic VII.7.2

1 2 3 4

Diagnosis. Treatment. Helping to determine prognosis. Management of therapy and other interventions.

VII.7.3

5 Planning for the future. 6 Participation in research. 7 Education for professionals and care givers.

Setting Up a Memory Clinic

Most research on memory clinics is descriptive. The first survey in the UK identified 20 clinics (Wright & Lindesay 1995). Many more now exist. Several papers have described the activity of dementia clinics over more than a decade (Reding et al. 1985; Hogan et al. 1994; Bayer et al. 1997), while Kopelman & Crawford 1996 described a memory clinic for non-demented patients. In spite of the descriptive literature there is little significant research on the effectiveness of memory clinics (Lindesay 1995). Therefore, this chapter is based on the experience of the authors, common sense and a caring approach.

Staffing a memory clinic Memory disorder work is multidisciplinary. Understanding the relevant contribution of each professional helps to inform the choice of staff. The doctor is essential. The speciality is unimportant, provided they are trained and aware of the medical, psychiatric and social issues in dementia assessment, treatment and care. The focus is not just diagnostic, but also involves assessment and management of co-morbid conditions, therapy

for dementia and research. In dementia clinics, up to 80% of the dementia diagnoses will comprise Alzheimer’s disease (AD), vascular dementia (VaD) or dementia with Lewy bodies (DLB). This leaves approximately 20% of other memory disorders to evaluate, some of which may have reversible elements that can be treated (See Chapter V.5; Walstra et al. 1997), or factors affecting prognosis, e.g. malignancy. Early surveys suggested that a large number of attendees at a memory clinic are not suffering with dementia. In the UK the mean is 25% (Wright & Lindesay 1995), while in the US 6% is reported (Weiner et al. 1991; Hogan et al. 1994). The most common non-dementia diagnoses are ‘worried well’ (most of whom may now be termed age-related cognitive decline), mild cognitive disorders and primary psychiatric disordersa the main one being depression, with prevalence rates of 5–10% (Ames et al. 1992; Skerrit et al. 1996). Knowledge of drugs and their side effects, especially those affecting cognition, is an important part of the assessment. The psychiatric interview includes looking for the depression, psychosis and the psychiatric and behavioral phenomena that

830 CHAPTER VII.7

commonly occur in dementia (Burns et al. 1990). Psychiatric symptoms are associated with behavioral problems (Rockwell et al. 1994) and predict institutionalization (Steele et al. 1990), so effective early intervention is required. Detailed physical examination is a component of eliciting co-morbid conditions and aiding in the differential diagnosis; and although treatable co-morbidity gets rarer as age increases (Smith & Kiloh 1981), it remains an important factor in the assessment. Developing a management plan and initiating and monitoring therapy are also central to the doctor’s role. A nurse is often a member of the team. Nurses are good at identifying dementia (O’Connor et al. 1988, Dennis et al. 1998) and many develop various specialized skills. They can offer home assessments if necessary, although longitudinal testing should preferably be in the same setting, as people do better on tests like the Mini-Mental Status Examination (MMSE) when at home (Ward et al. 1990). Neuropsychological examination requires access to psychology staff. The tests determine specific cognitive deficits, aiding diagnostic and management strategies. A trained neuropsychologist has the ability to interpret test results and invoke other tests for clarification. Clinics without this support tend to use common instruments like the MMSE or the CAMCOG (Roth et al. 1986). Many of these are not particularly sensitive to early dementia. Huff et al. (1987) found 19% of their patients with AD scored over 27 on the MMSE, usually considered above the threshold for diagnosing dementia. However, this may have been a highly selected population unlikely to represent the generalized situation. Nevertheless, it is desirable for all clinics to have neuropsychological input, even if only for referral of unclear cases. Psychologists also practice psychosocial interventions, most of which are aimed at reducing disability and distress (Fenn et al. 1993; Woods 1994; Zanetti et al. 1994), or at education and planning for the future (Aneshensel et al. 1995; Bourgeois et al. 1996; Buckwalter 1996; Brodaty et al. 1997). These hope to enhance quality of life, and may reduce rates of institutionalization (see Chapter VII.1.4; Mittelman et al. 1993; Mittelman et al. 1996). Some interventions are directed at the

patient; either helping them to understand their situation, manage life events and develop coping strategies (Keady 1996; Mullen et al. 1996; Kitwood 1997) or using psychological treatments for the depressive disorders that commonly coexist. Communication problems are early features in dementia. Poor naming and reduced fluency are early signs of cognitive loss (Stevens et al. 1992; Hart et al. 1998). Hence, language assessment may be a useful contribution, and referral to a speech and language therapist, although uncommon in a memory clinic setting, may add diagnostic information (Stevens et al. 1996) especially with some less common aphasias (Obler & Albert 1985; Ripich 1991). Failure of communication is a big factor in patient and care giver stress in dementia (Kinney & Stephens 1989). Speech and language therapists can assess deficits, and also offer therapeutic strategies to assist patients in practical ways. Comprehensive assessment of a person with dementia is incomplete without a functional assessment. Subtle changes in ability to perform activities of normal living occur in mild dementia (Carswell & Eastwood 1993; Hill et al. 1995), usually in the instrumental activities of daily living (ADL), the complex tasks we learn in order to be independent (Green et al. 1993). The occupational therapist is a specialist in functional assessment. While not usually a member of the team, information from their assessment, usually in the patient’s own environment, adds to the holistic picture. Scales exist for measuring function which can be clinic based and performed either by staff or care giver (e.g. the Bayer ADL scale; Hindmarch et al. 1998). The occupational therapist can advise on such scales, and implement strategies aimed at addressing any difficulties identified, especially in the home. Finally, a team member, qualified or not, offering support and practical advice is needed. This may be a social worker, trained assistant or other member. They can work to provide a secure base for the care giver, and patient when appropriate, to express fears and concerns. Well-informed patients may plan and cope with the situation better (Smith et al. 1988) so work done after the bad news is broken may affect long-term outcomes.

MEMORY CLINICS 831

Table VII.7.1 Staff required in a memory clinic. Essential

Desirable

Optional

Medical doctor, old-age psychiatrist, geriatrician or neurologist

Psychologist

Neuropsychologist

Psychometrician, doctor, nurse or psychologist

Specialist dementia nurse

Speech and language therapist

Neuropsychological advice (for referral)

Administrative support

Occupational therapist Social worker

Few clinics have all disciplines available and many roles are interchangeable. Table VII.7.1 gives a summary of staff working in a memory clinic. What is required is a team capable of delivering a high quality service to patients and care givers. Where gaps exist, advice should be sought, as an efficient process of assessment and management is the key to making the specialist service work.

Functioning of a memory clinic The memory clinic, while fundamentally a clinical service, also collects usable information. Because the memory clinic is a new resource, with cost and practice implications, data are needed to monitor what it does, the patients it sees and its costeffectiveness within the context of an overall service. Audit of proceduresareferrals, response times, numbers and types of patients seenacan set referral criteria and meet agreed quality standards concerning outpatient services. Patients can be followed in the clinic or discharged into shared protocols of management and follow-up with primary care/ family doctor services. Shared protocols allow the efficient collection of follow-up data, freeing the specialist service to concentrate on difficult cases, research and trials. Clinical audit where standards can be set against the known evidence, bring research into practice while evaluating what is achievable and practical within the clinic. Such results may suggest trial designs for more definitive research into the delivery of care. Shared and pooled audits will help clinics move towards homogeneity of minimum standards of the delivery of care, make comparisons easier and help to defend their utility. Such data may set new standards for future clinics and their activity. Table VII.7.2 provides

some areas that would respond well to such examination. The last part of this chapter deals with the outline of a possible minimum dataset and how it may be used for audit and other purposes. Now that therapeutic options for dementia exist, it makes sense to use the memory clinic as the initiating centre for treatment. In the UK, this is a requirement for reimbursement for cholinesterase inhibitors. This is important as the usefulness and hazards of many treatments have not been evaluated in routine practice, and current guidelines leave many questions unanswered. Careful evaluation in clinics may help management monitor the better use of therapies, identify responders and help conduct effectiveness trials. The memory clinic promotes clinical research, and provides well-characterized patients for research. Much of the work in a memory clinic involves measurement, including cognition, ADL, behavioral rating and global scales. Many scales have evolved over time, but good follow-up is lacking in many areas. Validation and longitudinal assessment of new instruments remains important as well as intervention trials of efficacy and effectiveness. There is still much to learn about risk factors and natural history of a great deal of the dementias and cognitive decline. Memory clinics can look prospectively at their clinic populations. They also offer access to postmortem material and DNA for future study. In the first UK survey of memory clinics (Wright & Lindesay 1995), recruitment for drug trials was an important function for many of the memory clinics surveyed. Since then, many more clinics have evolved, some particularly for that reason, recruiting large numbers of patients for trials. For neuroscience and the pharmacology of the dementias, the memory clinic is an important clinical bridge.

832 CHAPTER VII.7

Table VII.7.2 Audit in memory clinics. Function

Aspect of care/service

Outcome measure

Activity Referral type Tests performed Diagnoses

Referral numbers Early vs. advanced cases Completeness and cost Differential cases

Demand/uptake

Therapy Drug name Indicators of response Response rate Type of response Duration of therapy

Number of cases Differential usage Define useful tests Look at result Assess what typifies response Duration of clinical response/cost

Usage

Guidelines National guidelines

Local pathways Adherence to national models

Adherence to local systems

Care giver data

Stress/burden scales

Care giver burden

Long-term consequences Effect on care giver

Effect on patient Quality of life/reduced burden

Quality of life effect

Institutionalization

Natural history/costs

Not all memory clinics perform research, especially smaller practices. However, they all can collect data. Table VII.7.3 suggests research activities that clinics can potentially contribute to, or undertake themselves.

What is done in memory clinics? Assessment is a central aim, gleaned from the: • clinical history; • detailed mental state and symptom elucidation; • neuropsychological evaluation using validated instruments to allow comparability between clinics; • physical examination; and • laboratory and other tests (such as neuroimaging). This information is used to: • make a diagnosis; • formulate a management plan; • offer practical advice; • plan on or follow-up longitudinally. In establishing a clinical history we look at the patient’s symptoms in the context of what we know of the risk factors, reversible elements, family history, co-morbid conditions and concomitant medication.

Table VII.7.3 Research activities in memory clinics. Clinical

Basic science

Drug trials Drug responder characteristics Validation of scales Generation of scales Epidemiological studies Care giver burden

DNA sampling Pharmacogenetics Postmortem material acquisition

The mental state examination is to evaluate the psychiatric state of the patient and elicit phenomenology that may help with the differential diagnosis. Psychiatric symptoms can be evaluated using validated instruments. Depressive symptoms can be elicited using standard scales, e.g. the Geriatric Depression Scale (Yesavage et al. 1983) or the Montgomery–Asberg Depression Rating Scale (Montgomery & Asberg 1979), but the validated scale for dementia is the Cornell Depression Scale (Alexopoulos et al. 1998). Psychosis is evaluated in several scales, usually with other behavioral elements as well. The closest to a psychiatric interview is the Behave-AD (Reisberg et al. 1987), while

MEMORY CLINICS 833

other common scales are the Neuropsychiatric inventory (Cummings et al. 1994), available in long and short form, and the CUSPAD (Devenand et al. 1992). One specific scale exists for anxiety symptoms in dementiaathe Rating Anxiety in Dementia scale (RAID, Shankar et al. 1999). The scales above all include questions about anxiety, while the Hospital Anxiety and Depression Scale (Kenn et al. 1987) is frequently used. The neuropsychological evaluation is a key component and many tests exist, ranging from measurement of individual areas to combined batteries for more convenient use. A full evaluation involves assessment of the following domains: memory (including prospective) praxis visuospatial skills recognition attention orientation language (comprehension and reading) executive function problem solving learning premorbid functioning. One factor in putting a test battery together is time. Neuropsychological assessment in routine memory clinics can take from less than 30 minutes to more than two hours, depending on the choice of tests and the ability of the patient. Tests chosen require relevant normative data that is culturally appropriate, or misdiagnosis can occur (La Rue 1987; Loewenstein et al. 1994). They also need minimal ceiling and floor effects. A final consideration is education attainment as low scores may be a consequence of this alone (Loewenstein et al. 1992). Serial testing is then needed to show genuine progressive decline. Prediction of pre-morbid functioning is often attempted in the clinic. The commonest test used in the UK is the short National Adult Reading Test (Beardsall & Brayne 1990). This has certain limitations, so is best used only in mild to moderate cases of dementia (O’Carroll et al. 1995). Because of restrictions on time, screening is sometimes used to target patients for more detailed

assessment. The MMSE cut-off of 25–26 is often used, although high functioning individuals continue to perform well. This means some early patients may go undiagnosed, and miss potential treatment options. Longer tests to screen for neuropsychological testing can reduce this loss of sensitivity, but even the CAMCOG provides false reassurance to 2% of people with AD with its cut-off levels (Huppert et al. 1995). However, if serial monitoring is undertaken, these errors should be detected. Which test is chosen in a battery is less important than covering the appropriate domains. Table VII.7.4 shows some commonly used tests. What is important is that the overall assessments have flexibility, for further evaluation of unusual cases. The presence of good neuropsychological advice aids this process, in the absence of which, most clinics use simplified batteries. These include the MMSE, the CAMDEX (Roth et al. 1986) and the Alzheimer’s Disease Assessment Scale (ADAS) (Rosen et al. 1984). The MMSE is simple to use, but is not a full assessment. It is biased towards language and education, and fails to test executive function. It may be better used in conjunction with other simple tests, e.g. the clock drawing test. The CAMDEX is a better instrument, testing many domains. The ADAS is another multidomain battery, the cognitive part of which is now a standard for clinical trials in drugs for dementia. It does not test all domains, and is really for AD rather than the other dementias. However, it is simple to use, and can be used to compare local results with clinical trial data. The CAMCOG or ADAS-Cog are perfectly adequate for the diagnosis and follow-up of the vast majority of cases. Several automated tests are also available. Advocates argue the accuracy of a machine, the ability to perform simultaneous testing on a number of subjects and the security of the data collected. Three systems commonly used have emerged since the 1980s: the Memory Assessment Clinic (Crook et al. 1986); the Cambridge Neuropsychological Test Automated Battery (Morris et al. 1987) and the Cognitive Drug Research computerized assessment system (Wesnes et al. 1987). These are well validated and tested in many published studies that highlight their diagnostic accuracy (Simpson et al. 1991; Sahakian et al. 1998). The few comparative

834 CHAPTER VII.7

Table VII.7.4 Commonly used neuropsychological tests.

Tests

Author

General cognitive tests Mini Mental State Examination (MMSE)* Wechsler Adult Intelligence Scalearevised (WAIS-R) Alzheimer’s disease assessment scale (ADAS-Cog)* Cambridge Cognitive examination (CAMDEX)*

Folstein (1975) Wechsler & Stone (1945) Rosen et al. (1984) Roth et al. (1986)

More specific domains Memory Adult Memory and Information Processing Battery (AMIPB)

Coughlan & Hollows (1985)

Verbal learning Hopkins Verbal Learning Test (HVLT)

Brandt (1991)

Executive function Benton Verbal Fluency Weigl’s Colour Form Sorting Test Trail Making

Lezak (1995) Grewal & Harward (1984) Spreen & Strauss (1991)

Language and semantic function Boston naming test (BNT)

Kaplan et al. (1983)

Visuospatial Clock drawing test Rey Osterrieth Complex Figure Test

Wolf-Klein (1989) Osterrieth (1944)

Pre-morbid IQ

Beardsall & Brayne 1990

*See Appendix II for details of these tests.

studies that exist between non-automated and automated tests conclude in favour of automated tests (Mohr et al. 1996). In spite of this, automated tests are not commonly found in memory clinics. This may in part be because of doubts about their added practical benefits over traditional paper and pen tests. As modern technology improves, the tests improve in accuracy, costs diminish and they become easier to use, the situation may change. Several facets of dementia are amenable to measurement: cognition, functional activity, language deficits, behavioral disorders and global severity scales. The use of validated scales to measure these domains allows for comparable data to be collected between clinics, which may give more precise data of the natural history of the dementias. Table VII.7.5 shows some commonly used scales in each of the domains associated with dementia. Functional assessment scales can measure the ability within a range of activities or the process of performing these activities. The process scales give a more accurate picture, assessing the manner in

which activity is attempted. Dementia sufferers underestimate their disabilities and care giver reports are more valid (Carswell & Eastwood 1993; Rogers et al. 1994). Consequently, most commonly used tests are care giver ratings. Which scale is used is the choice of the center; none has a proven advantage. Behavioral disorders occur frequently in dementia although less so in the mild cases of dementia usually seen in the memory clinic. Abnormal behaviors are worth screening for as they cause great distress to the care givers (Donaldson et al. 1997), and may be amenable to treatment. Many scales exist to measure behavior, and data on behavioral symptoms are important, as their natural histories are not fully understood. The behaviors are intermittent, yet treatment is often prolonged. Good records may indicate better treatment regimens based on real life practice. Physical examination is an essential part of any assessment. The look of the patient gives important information, and neurological signs may aid dia-

MEMORY CLINICS 835

Table VII.7.5 Commonly used scales in measuring non-cognitive domains in dementia. Domain

Scale

Author

Function

Functional Performance Measure (FPR) Assessment of motor and process skills (AMPS) Disability Assessment for Dementia (DAD)* Functional Assessment Staging Tool (FAST) Bayer ADL Dependency*

Carswell et al. (1995) Fisher (1995) Gelinas (1999) Reisberg (1988) Hindmarch (1998) Stern (1994)

Behavior

Behave-AD* Neuropsychiatric inventory* Cohen Mansfield Agitation Inventory Geriatric Depression Scale*

Reisberg et al. (1987) Cummings et al. (1994)

Global

Clinician’s global impression of change (CGIC and CIBIC) GDS* CDR*

Guy (1976) Reisberg et al. (1982) Morris (1993); Reisberg (1988)

Care giver

Relatives stress scale

Greene (1982)

Cohen Mansfield (1986)

*See Appendix II for practical details of these scales.

gnosis, e.g. gait abnormalities, focal signs, primitive reflexes and cerebellar signs. Cardiovascular examination is important, e.g. carotid bruits and atrial fibrillation. Physical signs may point to co-morbid conditions or aggravating factors, especially in those patients with dramatic changes. Laboratory tests are required to look for reversible causes (see Chapter III.7) and check safety before administering therapy. It would be too expensive to routinely test for all conditions, so clinical judgement should be the main indicator of what to use (Terry et al. 1994). Larson et al. (1986) showed that good judgement can offset 25–34% of costs by reduction in laboratory tests. Commonly agreed tests are: a full blood count and ESR, to detect anemia, infection, inflammatory, autoimmune and myeloproliferative disorders. If positive, further tests are required as appropriate and re-evaluation of the history and examination may be needed. Vitamin B12 and folate deficiency are associated with dementia (Chapters III.7.6 & III.7.7; Riggs et al. 1996; Joosten et al. 1997). Urea and electrolytes, liver function tests and calcium assess renal and hepatic function and bone and cardiac systems. Abnormalities need consideration within the differential diagnosis, and possibly treatment in their own right. Diabetes may be elicited from the history (Croxson & Jagger 1995)

and blood sugar remains part of the routine screen. Thyroid disease has cognitive implications that are well documented (Shetty & Duthie 1995). The best indicator of hypothyroidism is the TSH level, which should be measured in diagnostic work-up, and also at any other time if clinically indicated. Syphilis serology has become less frequently ordered; screening may not be appropriate, but continuing vigilance for the condition is. Screening for HIV is not usually routine, but indicated in high-risk groups. Of other useful tests, the ECG is useful for picking up silent conditions, especially conduction disorders or conditions that potentially may reduce cerebral blood flow. It may also inform a risk assessment in using anticholinesterase inhibitors. The EEG has limited diagnostic validity. Quantitative EEG is a low-cost investigation that may be useful if it can be shown to have good diagnostic performance (Hegerl & Moller 1997). Lumbar punctures are not a routine in most memory clinics. Neuroimaging is an increasingly important part of assessment, and longitudinal follow-up. Computed tomography (CT) is simple to use and relatively inexpensive. Magnetic resonance imaging (MRI) provides better resolution but its practical advantage over CT, in all but exceptional cases, is debated. However, the enhanced resolution pro-

836 CHAPTER VII.7

Investigation

Purpose

Commonly performed tests

Hematology

Anemia Infection Inflammatory disease Myeloproliferative disorders Autoimmune disease B12 deficiency Folate deficiency

Full blood count ESR

Biochemical

Renal function Hepatic function Endocrine disease Cardiac function Bone disease

U+E LFT TSH, blood sugar Cardiac enzymes Calcium studies

Neuroimaging

Atrophy Vascular changes Space occupying lesion White matter changes

CT scan

Cardiac disease Brain disease (e.g. CJD) Cerebral arteritis

ECG EEG Angiography

Other

Table VII.7.6 Common investigations in the memory clinic.

B12 if indicated Folate if indicated

MRI

vided by MRI of abnormalties and zones, including the hippocampus, can be more easily measured qualitatively and quantitatively (Fox et al. 1996; DeLeon et al. 1997), and may be useful in the future to evaluate pharmacological treatments. SPECT can show altered function and has been found useful in defining frontotemporal dementia (Miller et al. 1997) and confirming AD (Waldemar 1995). Again, its practical advantages over CT or MRI are debatable. The PET scan provides better resolution than SPECT, but is expensive and still largely a research tool available in only a few centers. Investigations are summarized in Table VII.7.6. Having collated all this information, the clinic offers a diagnosis, and discusses management. Management includes providing a guarded prognosis, discussing support services/benefits, competence, driving and genetic counselling. Genetic testing is not a routine memory clinic function, and needs a well-developed support and counselling service in a specialist setting if it is to be done at all (see Chapter VII.4). Management plans are established, including the future involvement of the memory clinic. This

depends on its function and resources and those of the primary care services. It may follow up all, or selected patients. It may return patients to the primary care services with clear plans and goals. Tertiary services may hand back patients to primary or secondary services with a diagnosis and/or management plan. There is no right choice, nor is there evidence to inform. The frequency of reassessment will vary from case to case, but in those without pharamcological intervention, the frequency can be between 3 and 12 months depending on the progression of the dementia and social factors. The relationship with primary care is integral to the functioning of a memory clinic. Good referral and hand-over practices enable efficient and quality care to be provided by the memory clinic. Many support services in the community arise or are best co-ordinated from primary care, with knowledge of local circumstances. Patient support groups are very helpful for care givers and a source of digestable information and practical advice. National offices of AD organizations (they also support people with dementias) put people in touch with local offices in the vicinity, as can the memory clinic.

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VII.7.4

The Future Development of the Memory Clinic

Information is key to the good functioning of memory clinics: to monitor and inform clinical practice locally, monitor treatment interventions and/or contribute to research. Data collected in a non-systematic way is likely to have limited use. No minimum dataset yet exists for memory clinics. Such a template would be useful, and help create large prospective clinic-based samples from collaborative pooling of such data. Memory clinics have evolved individually, many with local guidelines and differing structures, usually based on available resources. Researchoriented memory clinics can help provide and coordinate new data for the development of local policies. They could become centers of excellence at a local level from which national guidelines can be disseminated. They can collect prospective data concerning the natural history of the dementias. In some countries, such as the UK, where concerns around prescription of antidementia drugs exist, they may act as prescribing centers: taking responsibility for the assessment of suitable patients and monitoring outcomes in an effective manner. This may not be just in the form of traditional randomized trials, but also observational designs and n-of-1 trials (see Chapter IV.5.4). These new data could help inform important future commissioning and provide educational material, as increasing understanding of these diseases and their treatments occurs. Larger clinics should align themselves to form collaborative consortia to maximize the use of the data collected, a situation that already occurs in the US and Canada. This would help research and new developments, a problem in Europe where services do not have such cohesion. Whatever the level of the clinic, a minimum dataset could be derived from routine practice

from virtually all clinics claiming to have expertise in the field (Table VII.7.7). The chosen assessment scales are commonly used, and have been selected because they are short and easy to use in the specialist setting. Most can be used as outcome measures longitudinally, minimizing loss of information during follow-up, even when clinic visits are missed or stop. This information could be collected by two people (comfortably by three), which is the smallest number needed for a clinic. Further testing is desirable to clarify and pinpoint diagnosis; but coding this information is not essential, and would typify the more research-orientated center. The optional information allows flexibility for each individual center not to lose their local assessments. By utilizing an agreed minimum core dataset, useful information could accumulate in large numbers. Central pooling of such data would allow more reliable evaluation of prognostic factors and natural history. The most effective way to achieve this would be through the use of central information management systems, and electronic data extraction from participating centers. The necessary technology is available and models exist which could be refined for such use. The evidence base is constantly shifting and, as this book shows, there remains much to learn. Practising in a memory clinic is not just about introducing evidence into practice, but also adding to the evidence through practice. Clinics are a key research and development vehicle, whose utility could be easily improved immeasurably. The companion website to this book allows people interested in setting up a memory clinic, or considering adopting a common core dataset for pooling data, to be put into contact with the authors for practical advice.

838 CHAPTER VII.7

Table VII.7.7 Proposed minimum dataset for memory clinics (2000). Data Chosen by each individual centre Demographic

History

Drug treatment Cognitive enhancers:

Cardiovascular drugs

Physical examination

Domains* Cognition Function Behavior Global

Quality of life

Essential

Optional

Age/Date of birth Sex Place of residence: nursing home/assisted/family/alone Type of care giver and degree of contact Contact phone number When memory problems began Sudden onset Y/N Family history: Sibs (and no.) with possible/probable dementia Parents (and no.) with possible/probable dementia History of MI/Angina Y/N History of Heart failure Y/N History of stroke/TIA Y/N Diabetes Mellitus Hypertension History of depression Y/N History of other major psychiatric disorder Y/N History of significant head injury Y/N History of fits Y/N History of falls Y/N Years of education Smoking history Alcohol history

Date Date Date Date Date Detail Detail

Anticholinesterase inhibitors Vitamin E Vitamin B complex Folate Gingko biloba Antihypertensives Aspirin HRT NSAIDs Other BP Weight Height Carotid bruit Atrial fibrillation

Neurological examination

MMSE Dependency scale Short NPI Clinical dementia rating scale (CDR) Global Deterioration Scale

CAMCOG/ADAS-Cog DAD/Bayer ADL NPI/Behave AD

E5Q (informal care giver) SF 36 (informal care giver) (Cont.)

MEMORY CLINICS 839

Table VII.7.7 (cont’d) Data

Essential

Optional

Care giver burden

Caregiver time spent on supervision and care

Screen for care giver burden

Intellect investigations

NART CAT/MRI scan: disproportion in temporal lobe atrophy Ischemic change: If yes, mild, moderate or severe Small vessel, lacunar or infarcts Site

Diagnosis

Outcomes Cognition Function Behavior Global Quality of life

Plasma cell storage. ApoE status

AD probable/possible VaD probable/possible Mixed Frontotemporal dementia (FTD) Dementia with Lewy bodies (DLB) Mild Cognitive impairment (MCI) (CDR 0.5 or FAST 3) AAMI/ARCD (Crook criteria) Complicating features: Alcohol Hypothyroidism B12 deficiency Head injury Downs Syphilis serology +

MMSE Dependency scale Short NPI GDS or CDR E5Q (informal care giver) SF 36 (informal care giver)

Care giver burden Time/stage entry into institution Cause of death Postmortem Date of death Place of death

CAMCOG/ADAScog DAD/Bayer ADL NPI/Behave AD

Zarit scale

If available result

*See Appendix II for details of these scales.

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VII.8

Health Economics

Alastair M. Gray

Key points • Economic evaluations related to dementia are increasing rapidly, but are of variable quality and must be critically appraised using accepted guidelines. • Cost of illness studies uniformly illustrate the importance of informal carers as a source of help for those with dementia, and the need to include their costs and health status in comprehensive economic evaluations.

VII.8.1

Introduction

The proportion of the population aged 65 years and over is projected to increase from around one in six in the developed countries in 1999 to almost one in four by 2025 (World Bank 1993). This process is being accompanied by a steady increase in the number of people affected by chronic and degenerative diseases, including senile dementia, of which Alzheimer’s disease (AD) is the most common form. Projections using US Census Bureau data suggest that approximately 10.3 million people in US may be affected by AD by the year 2050 (Evans 1990). Senile dementia has very significant medical, social and financial implications for patients, informal carers and the health and social services, and the increasing numbers affected by dementia has been

844

• Cost studies show that costs of care rise with disease progression and are particularly influenced by institutionalization; however, these results are mainly cross-sectional and are seldom based on cohort analyses. • Cost-effectiveness studies of pharmacological interventions are highly dependent on assumptions concerning medium- and longer-term benefits of therapy. Reliable long-term efficacy data are required before cost-effectiveness estimates can be made more precise.

accompanied by a rapidly expanding literature on the health economics of dementia. Much of the early work took the form of ‘cost of illness’ studies, which attempted to estimate the resource impact of dementia on healthcare systems or national economies. However, since the mid-1990s there has been increasing interest in the evaluation of different ways of managing or treating dementia, using the framework of cost-effectiveness analysis, in which the incremental costs of an intervention compared to the next best alternative are assessed in relation to the incremental benefits. This chapter provides a brief introduction to each of these methods and summarises the published literature on economic aspects of dementia.

HEALTH ECONOMICS 845

VII.8.2

Methods

It is increasingly recognized that reviews of methodologies or of fields should be methodical and explicit but cannot exactly replicate the systematic review procedures used to find and synthesize numerical evidence concerning a specific technology’s effectiveness (Edwards et al. 1998). To ensure that all relevant methodological articles, cost analyses, cost-effectiveness studies, modeling exercises and other studies relevant to the subject were identified, a broad semi-structured literature review was performed, involving an initial search of Medline, Embase and Econlit (using the search terms: #1 DEMENT*; #2 ALZHEIM*; #3 #1 or #2; #4 COST in TI; #5 COST in AB; #6 #4 or #5; #7 ECONOM* in TI; #8 #6 or #7; #9 #3 and #8). This search was supplemented by secondary searches of reference lists. These search strategies yielded a total of 147 references from the bibliographic databases plus 45 from secondary reference searches, giving a total of 192 references. These confirmed the rapid expansion in published studies over time, from nine in the period 1980–82 to 50 in the period 1997–99. These references were then reviewed to assess whether they were substantive pieces of applied research or methodology, or simply made passing reference to costs or the economic dimension of their subject. References which were identified as substantive pieces of applied research or methodology were then assessed to see whether they were

VII.8.3

fundamentally flawed in terms of the methodological guidelines used to perform the economic evaluations. These guidelines are now well developed both in general terms (Drummond et al. 1997; (Gold et al. 1996), and in the specific context of dementia (Busschbach 1998; Neumann et al. 1997; Whitehouse 1997; Winblad et al. 1997; Whitehouse et al. 1998). It should be noted that additional guidelines exist concerning full disclosure by authors of interest or sponsorship to reduce risks of bias (Hillman et al. 1991) and this should be borne in mind when appraising published studies. Papers which passed these stages of the review procedure were then grouped into the broad categories of cost analyses and cost-of-illness studies; diagnosis, evaluations of care and treatment; and evaluations of drug interventions. Further subgroupings are reported below. Economic evaluation is likely to play an increasingly influential role in clinical decision-making and resource allocation: in some countries such as Australia, pharmaco-economic data is required if a drug is to be subsidised, while elsewhere guidelineissuing agencies, such as the National Institute for Clinical Excellence in the UK, make explicit use of cost-effectiveness criteria in their deliberations. Physicians will therefore have to become familiar with these techniques to appraise critically the many studies now appearing.

Cost Analyses and Cost-of-Illness Studies

Descriptive studies of the costs of particular interventions, disease processes or patient groups can aid understanding and help to inform economic evaluations. A number of such studies have been performed in the area of dementia and Alzheimer’s disease (AD), and are divided here into cost studies, which aim to measure costs per patient, and cost-of illness studies, which endeavour to quantify the societal impact of a disease. Fox (1997) reviews methods of measuring costs for patients with AD, while Rice (1994) gives an overview of cost-ofillness studies.

Cost studies Ernst and colleagues used data relating to a relatively small sample of 64 AD patients to estimate the relationship between disease progressionameasured using the Mini-mental Status Examination (MMSE) scoreaand cost (Ernst et al. 1997). For mild and very severely demented patients they found that the relationship was weak. However, for moderately to severely demented patients, a two-point decline in MMSE score (from a baseline of 7) was associated with an annual increase of US$3700 in healthcare

846 CHAPTER VII.8

40 000 35 000

$ (Can$)

30 000 25 000

Nursing home Community services Medications and fees Informal care and supervision

20 000 15 000 10 000 5000 0

Fig. VII.8.1 Annual cost of AD

Mild

Mild to moderate

Moderate

costs, while a two-point increase in MMSE would yield a reduction of US$7100 in annual healthcare costs. Another study estimated the total formal and informal care costs of people with AD living in the community and in institutions in northern California (Rice et al. 1993). Using data collected for a sample of 93 non-institutionalized AD patients and 94 institutionalized AD patients, they estimated that the annual cost of formal care was $12 600 (1990 US$s) for patients in the community and US$42 000 for patients in institutions, while informal care costs amounted to US$34 500 annually in the community and US$5500 when patients were in institutions; consequently, total care costs for a patient with AD were approximately US$47 000 per year for both groups, although the cost breakdown was markedly different in the two care settings. They also found that patients and their families had to pay for more than half of all costs. A survey of other studies (Lieberman & Fisher 1995) also indicated that the family contribution is of similar magnitude. One study of 182 families caring for someone with dementia in Michigan estimated expenditure on equipment and services but also estimated the valueain terms of the market rate for home health aides and informal household helpersaof the unpaid assistance given by care givers (Stommel et al. 1994). Over a threemonth period the cost per family averaged US$4550 in 1989 US$s, almost three-quarters of which consisted of the unpaid labor costs of informal care. They also found that these costs rose with the level of dependency.

Severe

per patient, by disease severity (1996 CA$).

However, another American study which estimated the expenditures incurred by 141 primary care givers over a period of 6 months in caring for a group of dementia patients living at home, indicated that $6986 (1992 US$s) per patient was attributable to formal services and a much lower proportionaUS$786ato informal services (Weinberger et al. 1993). Overall, these expenditures rose with family income and also rose in line with the severity of dementia. Leon et al. (1998) conducted a cross-sectional study of 679 patients with AD in a range of different care settings and US states, finding that the annual costs per patient (in 1996 US$s) were $18 408 for patients with mild AD, $30 096 for patients with moderate AD and $36 132 for patients with severe AD. Hux and colleagues reported the results of an analysis of the relationship between severity of AD as measured by MMSE score and costs of care (Hux et al. 1998). The results, summarized in Fig. VII.8.1, indicated that in 1996 Canadian dollars the cost per patient was $9451 for mild disease, $16 054 for mild to moderate disease, $25 724 for moderate disease and $36 794 for severe disease, with institutionalization the largest single category of cost. Informal care costs were substantial but declined in the severe category as patient care became institutionalized. A UK study took 128 patients with AD and 56 matched controls, and estimated the total costs by severity of AD (Souetre et al. 1999). Over a three-month period, these costs rose from £6616 in the mild category, to £10 250 in the moderate

HEALTH ECONOMICS 847

Pounds sterling (£)

35 000

Fig. VII.8.2 Annual AD costs per

patient, by time from diagnosis (1996 UK£).

30 000 25 000 20 000 15 000 10 000 5 000 0

Direct 0–2

category and £13 593 in the severe category. By comparison, costs for the control group over the same period were £387. The imputed value of informal care giver time was the largest single category of cost, accounting for 69% of the total. Another UK study examined service utilization and cost of elderly people with cognitive impairment, and estimated the health and social care costs associated with different care settings, ranging from living alone in a private household (£212 per week in 1992 UK£s) to nursing home care £433 per week) and long-stay hospital care (£773 per week) (Kavanagh et al. 1995). Finally, Holmes and colleagues estimated the relationship between age, time from diagnosis, and direct and indirect costs by means of a crosssectional survey which yielded 655 completed questionnaires (Holmes et al. 1999). They found that across all age groups the average direct cost per patient rose from £12 638 in the first three years after diagnosis to £22 402 per annum nine years after diagnosis. The steady increase in direct and total costs with time from diagnosis is shown in Fig. VII.8.2. Institutionalization was associated with an increase in annual costs of £20 688.

Cost-of-illness studies Cost-of-illness studies attempt to estimate the total costs to a community of a particular disease. They may take the form of prevalence or incidence studies, and may incorporate a range of different costs, from direct medical and nursing home costs through to estimates of the indirect costs which

3–5

6–8 9–11 Years from diagnosis

Total 12+

may be incurred by families and friends of patients, as discussed above, or even of the loss to society in the form of lost earnings or productivity as a consequence of morbidity or premature mortality from a disease. The value of such studies has been debated, as they do not in themselves provide useful information on what an appropriate level of expenditure might be, or what priority should be given to different disease areas: such decisions require information on the relative effectiveness and costs of available treatments or preventive strategies (Rice 1994). Despite these limitations, cost-of-illness studies are a popular way of obtaining some initial impression of a disease’s impact and the way in which resources for dealing with it are deployed. At least five studies attempting to place some overall figure on the cost of AD to society have been published. In 1988, Huang et al. published a study of the estimated costs of all senile dementias in the US for 1985 (Huang et al. 1988). They estimated that direct medical care costs amounted to $6.4bn, nursing home care costs $2.6bn, and other formal care costs $4.3bn, giving a total of $13.3bn for direct care costs. However, they also estimated that informal care provided at home to dementia patients could be valued at $31.5bn per annum, and that the loss of productivity as a consequence of premature mortality from dementia came to a further $43.2bn. Combining these, they found a total annual cost of $87.9bn. These costs, averaged across their estimated population of 4.28 million people with dementia, suggested a cost per demented person of $20 537.

848 CHAPTER VII.8

Following this, a study focused on AD alone estimated that in 1983 net medical expenditure in the US was $13.4bn dollars higher as a result of the disease, 80% of which was attributable to longterm care (Hay & Ernst 1987). This study did not attempt to estimate the costs of informal care, but did suggest that the value of lost labour output resulting from premature mortality amounted to between $14.5bn and $17.8bn per annum, so that the total cost to society each year was between $27.9 billion and $31.2 billion. In a later publication, the same researchers used different prevalence and cost estimates pertaining to 1991 to significantly revise their study (Ernst & Hay 1994). These revisions yielded figures of $20.6bn for direct care costs, $33.3bn for unpaid care giver costs, and $13.4bn for the value of lost labour output resulting from disability and premature mortality, giving a total figure of $67.3bn. Similar cost-of-illness studies have been performed for different countries. For UK, Gray and Fenn estimated that the costs of formal health and social service care amounted to £1.04bn (in 1990/91 UK£s), of which 66% was incurred in residential and nursing home accommodation (Gray

VII.8.4

& Fenn 1993). For Canada, it has been estimated that dementia in 1991 had an annual net cost of $3.9 billion, with patients in institutions accounting for $2.18 billion of the total (Ostbye & Crosse 1994). Bearing in mind different years, currencies and countries, it is nevertheless clear that the total economic burden of dementia or AD estimated by these studies varies considerably, and undoubtedly one reason is the diversity of methodologies employed, in particular concerning whether informal care is included and, if so, how its value is imputed. As noted above, cost-of-illness studies are of very limited use in informing decisions about resource allocation, but in the area of dementia they have served a valuable role in underlining the crucial role played by informal carers. In general, guidelines for economic evaluation have stressed that a broad societal perspective rather than simply a health care system viewpoint should be adopted (Gold et al. 1996). This is the case particularly in dementia: if an intervention reduces formal care costs, for example in institutions, but increases the burden on informal carers, any measure other than the overall societal balance of costs will be seriously misleading.

Diagnosis

Testing

Screening

The difficulty of diagnosing specific types of dementia during the patient’s lifetime has resulted in wide variations between clinicians in the diagnostic procedures used, and the consequent cost. One study found substantial differences between psychiatrists, physicians and geriatricians in Scotland in the use of investigative procedures such as EEG and CT scanning, with investigation costs per patient averaging £132 amongst psychiatrists and £127 amongst physicians, but £86 amongst geriatricians (Ryan 1994). These variations in resources committed to diagnostic investigation were not accompanied by significant differences in case ascertainment rates. Similar variations in the type and cost of diagnostic procedures were found in a US study (Larson et al. 1986).

In the absence of a reliable diagnostic test, screening for dementia has attracted little attention. The future economic and ethical implications of genotyping for AD have begun to be considered (Fleck 1996), while Tabarrok has set out an argument for genetic insurance with reference to diseases including AD (Tabarrok 1994). One cost-effectiveness analysis has been reported, in which six different screening strategies for identifying motor vehicle drivers aged 65 years and over whose mental status significantly increases their likelihood of collision (Retchin & Hillner 1994). This analysis compared the costs of testing with the potential benefits of reduced motor vehicle collisions, including fewer injuries and fatalities, and reductions in lost wages and damage. In the

HEALTH ECONOMICS 849

main results, the cost for each year of life gained was about 2.8 million dollars, which compares very

VII.8.5

unfavourably with many other screening and prevention interventions.

Evaluations of Care and Treatment

The range of possible care settings for people with dementia ranges from various forms of community care to day hospitals, residential and nursing home care and finally intensive or long-stay inpatient hospital care.

Home-based care Drummond et al. used prospectively collected trialbased data to conduct an economic evaluation of a Caregiver Support Program (CSP) compared with standard community nursing for informal carers of elderly demented relatives at home (Drummond et al. 1991). The intervention included regular visits from a support nurse to provide in-home respite, and attendance at a self-support group. The main outcome of interest was the quality of life of the care giver, measured using the Caregiver Quality of Life Instrument (CQLI). Over a 6-month intervention period, total healthcare costs per care giver averaged $3562 (1988 CA$) in the trial group and $2897 in the control group, giving a 20% difference in the quality of the care giver’s lives in favour of the experimental group. These cost and effect differences were not statistically significant as a consequence of the small numbers used in the study, but would have given a cost per quality-adjusted life year (QALY) gained of approximately Canadian $20 000, which compares favourably with many other funded healthcare interventions. (QALYs are used by economists as a summary way of integrating survival and quality of life weights into a single number: thus two years of life expectancy with a quality of life equivalent to 80% of full health would give 1.6 QALYs.) Brodaty and Peters (Brodaty & Peters 1991) have also conducted a cost-effectiveness analysis of an intensive hospital-based 10-day residential training program for dementia carers. Patients whose carers had trained in the program had much higher adjusted rates of survival at home (53% vs.

13%) and, unexpectedly, fewer deaths (20% vs. 41%) than those whose carers did not have training at 39 months follow-up. Primarily because the intervention delayed time to institutionalization, the carer training program was associated with an average saving of Aus $7967 (US$5975) per patient over the study period despite the (unnecessarily) high cost to the residential program.

Group living A form of care arrangement in which a private living arrangement is combined with some form of continuous staffed supervision has been established in Sweden since the early 1980s and is known as group living. It falls between home care and day care, and one study has reported on the costs of care for 24 patients with dementia over the 6 months prior to admission and the 6 months after admission to the group living unit (Wimo et al. 1991). Institutional, day care and social service costs were substantially reduced following admission, but these reductions were offset by the supervision costs of group living, so that the average costs per patient per day were not significantly different at £49 (in 1985 UK£s) before admission and £42 after admission. However, a later study of a larger group of patients with dementia found that group living may be a less costly alternative than other forms of non-institutional or institutional care when viewed over all stages of dementia progression (Wimo et al. 1994a). In a cost-effectiveness study of group living vs. living at home or in institutions, Wimo et al. (1994b) concluded that the group living alternative was less costly and had a better outcome measured in terms of QALYs.

Day hospital care An important component of care for elderly people with dementia in the UK and elsewhere is the day

850 CHAPTER VII.8

hospital. One analysis of the costs of a range of day care settings including day hospitals, found that the latter cost more than out-patient, General Practitioner (GP) or day center attendance (Gerard 1988). However, the study concerned frail elderly patients in general and not specifically those with dementia. Finally, Wimo et al. (1994) conducted a costeffectiveness analysis of day care compared to remaining on a waiting list for institutional care, but small numbers in the study resulted in quality of life differences between the groups that were not statistically significant.

Nursing home care The predominant form of institutional care for people with dementia is some form of nursing home. In a prospective cohort study of 126 patients identified via an AD registry at an American hospital clinic between 1980 and 1982, it was found that only four patients were in nursing homes at enrolment, but three-quarters of the cohort (92) eventually resided in nursing homes (Welch et al. 1992). The median length of nursing home stay was 2.75 years, which was over 10 times the national median length of stay for all diagnoses. Very few studies have considered whether the costs of patients with dementia in nursing homes differ from the costs of patients without dementia in nursing homes. One study used diaries to record

VII.8.6

the time given to senile demented patients by caregivers in three nursing homes, and found that on average such patients received 36% more time than that received on average by non-demented patients (Hu et al. 1986). The total nursing home costs of senile demented patients would therefore be around 12% higher per day than for nondemented patients.

Hospital care The care provided in a Dementia Special Care Unit (DSCU) has been evaluated against traditional long-term care in a prospective study conducted in two hospitals in the US (Hurley et al. 1993; Volicer et al. 1994). The main difference between the two care settings concerned the primary objective: the DSCU was focused on patient comfort, whereas the traditional care setting was mainly interested in maximizing survival. The study found that mortality was higher amongst patients in the DSCU than in the traditional care setting but that quality of life was significantly higher also. Costs in the DSCU were significantly lower (by approximately $1500 over 3 months), as a result of fewer referrals to acute medical wards, lower use of radiology, less aggressive treatment of infection, and less frequent tube feeding. The authors concluded that this form of palliative care may result in poorer survival but more patient comfort and lower costs.

Economic Evaluation of Drug Interventions

The publication of trial results showing that tacrine produced significant improvements in patients with AD across a range of outcome measures (Davis et al. 1992; Knapp et al. 1994; Knopman et al. 1996), followed by more recent trial results for donepezil (Rogers & Friedhoff 1996; Rogers et al. 1998) and rivastigmine (Rosler et al. 1999), have provided the opportunity for economists to publish economic evaluations of these interventions. Henke and Burchmore (1997) used data from an open-label follow-up study of 663 patients with AD to estimate the effectiveness of tacrine, and constructed a decision-analytic model to estimate

survival, nursing home time and costs of community and nursing home care. They estimated that tacrine use was associated with a cost saving of US$9250 (7.5% of total costs) from diagnosis to death, mainly attributable to reduced time in nursing homes. Wimo et al. adopted a similar approach, in modeling the impact of tacrine use on the placement of patients in different levels of care (Wimo et al. 1997). The model predicted a cost saving equivalent to approximately 1.3% of total costs. Other models have taken a similar approach, which depends on making a link between cognitive functioning

Cost per quality adjusted life year ($)

HEALTH ECONOMICS 851

Fig. VII.8.3 Cost-effectiveness of

donepezil vs. no treatment, by likely duration of drug effects (1997 US$).

500 000 450 000 400 000 350 000 300 000 250 000 200 000 150 000 100 000 50 000 0

and the likelihood of advancing to more expensive forms of care such as nursing home placement. Lubeck et al. estimated a cost saving equivalent to 17% of the annual per patient expenditure for AD (Lubeck et al. 1994). However, as they acknowledged, such results are very dependent on an assumed link between cognitive functioning and care utilization, and also on the relative costs of different levels of care. One study has used data from a longitudinal survey to compare the costs over 6 months of matched samples of 376 patients receiving or not receiving donepezil (Small et al. 1998). They found that the average direct medical expenditure per patient over the six months was $3443 in the donepezil group and $3476 in the comparison group, the costs of donepezil in the former group being offset by slower rate of institutionalization. Stewart also estimated the total treatment costs of patients on donepezil therapy, using a Markov model to simulate disease progression over five years (Stewart et al. 1998). This analysis found that use of donepezil was broadly cost-neutral, with higher expenditure on drugs largely offset by lower care costs as a consequence of slower disease progression and less time spent in the state of severe dementia. Another study of donepezil used 30-week trial data plus a Markov model to estimate costs and times in different stages of AD over a five-year period (O’Brien et al. 1999). This study estimated that donepezil reduced healthcare costs over this period by CA$929 per patient, but increased caregiver time costs by CA$48 per patient, and that patients on donepezil spent 2.21 years in a non-severe stage

Mild

6 months

12 months

18 months

Moderate

24 months

Estimated duration of drug effect

of AD compared with 2.41 years in the nondonepezil group. However, if donepezil treatment continued after patients’ MMSE scores fell below 10, costs were CA$1554 higher per patient over the five years than in the non-donepezil group. Neumann et al. also found that the costs of donepezil were offset by reduced costs of care arising from better cognitive functioning and delayed progression to more costly levels of care (Neumann et al. 1999). However, they found that the size of this offsetting effect varied substantially depending on the modeling assumptions used. As Fig. VII.8.3 shows, their main results indicate that the costeffectiveness of donepezil therapy depends crucially on the duration of the therapeutic effect of the drug. If the effect lasts for six months, the costeffectiveness is very poor in the initially mild and moderate groups, with cost per QALY of $160 000 and $440 000, respectively. However, if the drug effect is sustained for 24 months, the cost-effectiveness becomes much better, and, in the case of patients with initially mild disease, is actually cost saving. This underlines the need for reliable longerterm evidence on outcomes. Finally, Fenn and Gray used clinical trial data on 1333 patients recruited internationally in two studies of rivastigmine therapy to model disease progression and associated costs (Fenn & Gray 1999). Their results indicated that healthcare costs (excluding drug costs) were reduced by a small amount at the end of the 26-week trial period, but that the saving increased to approximately £1100 per patient (UK£s 1997) when extrapolated over three years, thus partially offsetting therapy costs and improving potential cost-effectiveness.

852 CHAPTER VII.8

VII.8.7

Conclusions

Dementia has been of growing interest to economists for a number of years, partly because of high costs of care and increasing prevalence, and in recent years because of the advent of therapies whose cost-effectiveness needs to be assessed carefully. The wide range of results obtained from cost-of-illness studies has arisen mainly because of methodological differences in the inclusion and valuation of unpaid care by informal care givers. Some more general guidelines in this area are now available and should help to move analysts towards a more standardized approach (Gold et al. 1996; Posnett & Jan 1996). Wide differences can also be observed in the estimates reported above of the costs of diagnostic testing, home-based care, day hospitals, nursing homes, and hospital care. These reflect different methodologies but also differences in patient groups, healthcare systems, definitions of care and of costs, the year in which studies were performed, and other factors, and underline the need for careful appraisal of published studies using accepted methodological guidelines. Although cost analyses are fairly consistent in finding a strong association between disease severity anormally measured by MMSE scoreaand costs of care, the causative links between cognitive functioning, behavioral and social change and patterns of resource use remain unclear. Longer-term trials and more use of long-term observational studies may clarify this area, which is of fundamental importance in assessing the cost-effectiveness of drug interventions that primarily affect cognition. Some consensus has emerged on the future research agenda (Whitehouse et al. 1998), and this will entail closer working relationships between economists, epidemiologists and clinicians in the design and analysis of trials and other forms of health services research. It seems certain that increasing demands on the scarce resources available for patients with dementia will sustain and give relevance to health economics research in this area for the foreseeable future.

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moderate Alzheimer’s disease [see comments]. Neurology 52, 1138–1145. O’Brien, B.J., Goeree, R., Hux, M. et al. (1999) Economic evaluation of donepezil for the treatment of Alzheimer’s disease in Canada. Journal of the American Geriatrics Society 47, 570–578. Ostbye, T. & Crosse, E. (1994) Net economic costs of dementia in Canada [see comments]. Canadian Medical Association Journal 151, 1457–1464. [Published erratum appears in Canadian Medical Association Journal, January 1995, 152, 158.] Posnett, J. & January, S. (1996) Indirect cost in economic evaluation: the opportunity cost of unpaid inputs. Health Economics 5, 13–23. Retchin, S.M. & Hillner, B.E. (1994) The costs and benefits of a screening program to detect dementia in older drivers. Medical Decision-making 14, 315–324. Rice, D.P. (1994) Cost-of-illness studies: fact or fiction? Lancet 344, 1519–1520. Rice, D.P., Fox, P.J., Max, W. et al. (1993) The economic burden of Alzheimer’s disease care. Health Affairs Millwood 12, 164–176. Rogers, S.L., Farlow, M.R., Doody, R.S., Mohs, R. & Friedhoff, L.T. (1998) A 24-week, double-blind, placebo-controlled trial of donepezil in patients with Alzheimer’s disease. Donepezil Study Group. Neurology 50, 136–145. Rogers, S.L. & Friedhoff, L.T. (1996) The efficacy and safety of donepezil in patients with Alzheimer’s disease: results of a US Multicentre, Randomized, Double-Blind, Placebo-Controlled Trial. The Donepezil Study Group. Dementia 7, 293–303. Rosler, M., Anand, R., Cicin, S.A. et al. (1999) Efficacy and safety of rivastigmine in patients with Alzheimer’s disease: international randomised controlled trial [see comments]. British Medical Journal 318, 633–638. Ryan, D.H. (1994) Misdiagnosis in dementia comparisons of diagnostic error rate and range of hospital investigation according to medical speciality. International Journal of Geriatric Psychiatry 9, 141–147. Small, G.W., Donohue, J.A. & Brooks, R.L. (1998) An economic evaluation of donepezil in the treatment of Alzheimer’s disease. Clinical Therapy 20, 838–850. Souetre, E., Thwaites, R.M. & Yeardley, H.L. (1999) Economic impact of Alzheimer’s disease in the United Kingdom. Cost of care and disease severity for noninstitutionalised patients with Alzheimer’s disease. British Journal of Psychiatry 174, 51–55. Stewart, A., Phillips, R. & Dempsey, G. (1998) Pharmacotherapy for people with Alzheimer’s disease: a Markov-cycle evaluation of five years’ therapy using donepezil. International Journal of Geriatric Psychiatry 13, 445–453. Stommel, M., Collins, C.E. & Given, B.A. (1994) The costs of family contributions to the care of persons with dementia. Gerontologist 34, 199–205. Tabarrok, A. (1994) Genetic Testing: an Economic and Contractarian Analysis. Journal of Health Economics 13, 75–91.

854 CHAPTER VII.8

Volicer, L., Collard, A., Hurley, A., Bishop, C., Kern, D. & Karon, S. (1994) Impact of special care unit for patients with advanced Alzheimer’s disease on patients’ discomfort and costs [see comments]. Journal of the American Geriatrics Society 42, 597–603. Weinberger, M., Gold, D.T., Divine, G.W. et al. (1993) Expenditures in caring for patients with dementia who live at home. American Journal of Public Health 83, 338–341. Welch, H.G., Walsh, J.S. & Larson, E.B. (1992) The cost of institutional care in Alzheimer’s disease: nursing home and hospital use in a prospective cohort. Journal of the American Geriatrics Society 40, 221–224. Whitehouse, P.J. (1997) Pharmacoeconomics of dementia. Alzheimer’s Disease and Associated Disorders 11 (Supplement 5), S22–S32. Whitehouse, P.J., Winblad, B., Shostak, D. et al. (1998) First International Pharmacoeconomic Conference on Alzheimer’s Disease: report and summary. Alzheimer’s Disease and Associated Disorders 12, 266–280. Wimo, A., Karlsson, G., Nordberg, A. & Winblad, B. (1997) Treatment of Alzheimer disease with tacrine:

a cost-analysis model [see comments]. Alzheimer’s Disease and Associated Disorders 11, 191–200. Wimo, A., Krakau, I., Mattsson, B. & Nelvig, A. (1994a) The impact of cognitive decline and workload on the costs of dementia care. International Journal of Geriatric Psychiatry 9(6), 478–489. Wimo, A., Mattsson, B., Krakau, I., Eriksson, T. & Nelvig, A. (1994b) Cost-effectiveness analysis of day care for patients with dementia disorders. Health Economics 3, 395–404. Wimo, A., Wallin, J.O., Lundgren, K. et al. (1991) Group living, an alternative for dementia patients. A cost analysis. International Journal of Geriatric Psychiatry 6(1), 21–29. Winblad, B., Hill, S., Beermann, B., Post, S.G. & Wimo, A. (1997) Issues in the economic evaluation of treatment for dementia. Position paper from the International Working Group on Harmonization of Dementia Drug Guidelines. Alzheimer’s Disease and Associated Disorders 11 (Supplement 3), 39–45. World Bank (1993) World Development Report, 1993: Investing in Health. Oxford University Press/World Bank, New York.

Appendix I: Diagnostic Criteria for Common Dementias

NINCDS-ADRDA clinical diagnosis of probable Alzheimer’s disease (McKhann et al.

• evidence of cerebral atrophy on CT with progression documented by serial observation.

1984)

The criteria for the clinical diagnosis of probable Alzheimer’s disease (AD) includes all of the following. 1 Dementia, established clinically. 2 Deficits in two or more areas of cognition. 3 Progressive worsening of memory and other cognitive functions. 4 No disturbances of conciousness. 5 Onset between ages 40 and 90. 6 Absence of systemic disorders or brain diseases that in themselves could account for the progressive deficits in memory and cognition.

Additional notes

Features consistent with diagnosis Other clinical features consistent with the diagnosis of probable AD, after exclusion of causes of dementia other than AD, include the following. 1 Plateaus in the course of progression of the illness. 2 Associated symptoms of depression, insomnia, incontinence, delusions, illusions, hallucinations, catastrophic verbal, emotional, or physical outburst, sexual disorder and weight loss. 3 Other neurological abnormalities in some patients, especially with more advanced disease and including motor signs such as increased muscle tone, myoclonus, or gait disorder. 4 Seizures in advanced disease. 5 CT normal for age.

Features supporting diagnosis The diagnosis of probable AD is supported by the following. 1 Progressive deterioration of specific cognitive functions such as language (aphasia), motor skills (apraxia), and perception (agnosia). 2 Impaired activites of daily living and altered patterns of behaviour. 3 Family history of similar disorders, particularly if confirmed neuropathologically. 4 Laboratory results of: • normal lumbar puncture as evaluated by standard techniques; • normal pattern or non-specific changes in EEG such as increased slow-wave activity; and

Features making diagnosis uncertain Features that make the diagnosis of probable AD uncertain or unlikely include the following. 1 Sudden, apoplectic onset. 2 Focal neurologic findings such as hemiparesis, sensory loss, deficits in visual field and in coordination early in the course of the illness. 3 Seizures or gait disturbances at the onset or very early in the course of the illness.

Clinical diagnosis of possible AD 1 May be made on the basis of the dementia syndrome, in the absence of other neurological, psy-

855

856 APPENDIX I

chiatric, or systemic disorders sufficient to cause dementia, and in the presence of variations in the onset, in the presentation, or in the clinical course. 2 May be made in the presence of a second systemic or brain disorder sufficient to produce dementia, but which is not considered to be the cause of the dementia. 3 Should be used in research studies when a single, gradually progressive severe cognitive deficit is identified in the absence of other identifiable cause.

Clinical diagnosis of dementia of the Lewy body type (McKeith et al. 1996) 1 A progressive cognitive decline of sufficient magnitude to interfere with normal social or occupational function. 2 Two of the following features are essential for a diagnosis of probable dementia of the Lewy body type (DLB); and one is essential for possible DLB: • fluctuating cognition with pronounced variations in attention and alertness; • recurrent visual hallucinations that are typically well formed and detailed; and • spontaneous motor features of Parkinsonism.

Additional notes Prominent or persistent memory impairment may not necessarily occur in the early stages but is usually evident with progression. Deficits on tests of attention and of frontalsubcortical skills and visuospatial ability may be especially prominent. Features supporting diagnosis Features supportive of the diagnosis are as follows. 1 Repeated falls. 2 Syncope. 3 Transient loss of consciousness. 4 Neuroleptic sensitivity. 5 Systematized delusions. 6 Hallucinations in other modalities. Features making diagnosis less likely A diagnosis is less likely in the presence of:

1 Stroke disease, evident as focal neurological signs or on brain imaging. 2 Evidence on physical examination and investigation of any physical illness or other brain disorder sufficient to account for the clinical picture.

Clinical diagnosis of Pick’s disease 1 Progressive dementia. 2 A predominance of frontal lobe features with euphoria, emotional blunting and coarsening of social behaviour, disinhibition, and with apathy or restlessness. 3 Behavioural manifestations, which commonly precede frank memory impairment. 4 Frontal lobe features are more marked than temporal and parietal, unlike AD.

Clinical diagnosis of vascular dementia DSM-IV definition for vascular dementia 1 Focal neurological signs and symptoms (e.g., exaggeration of deep tendon reflexes, extensor plantar response, pseudobulbar palsy, gait abnormalities, weakness of an extremity, etc.) or laboratory evidence of focal neurological damage (e.g., multiple infarctions involving cortex and underlying white matter). 2 The cognitive deficits cause significant impairment in social or occupational functioning and represent a significant decline from a previously higher level of functioning. 3 The focal neurological signs, symptoms and laboratory evidence are judged to be etiologically related to the disturbance. 4 The deficits do not occur exclusively during the course of delirium. 5 Course characterized by sustained periods of clinical stability punctuated by sudden significant cognitive and functional losses.

ICD-10 criteria for vascular dementia 1 Unequal distribution of deficits in higher cognitive functions with some affected and others relatively spared. Thus memory may be quite markedly

APPENDIX I 857

affected while thinking, reasoning and information processing may show only mild decline. 2 There is evidence for focal brain damage, manifest as at least one of the following: unilateral spastic weakness of the limbs, unilaterally increased tendon reflexes, an extensor plantar response and pseudobulbar palsy. 3 From the history, examination or test, there is evidence of significant cerebrovascular disease which may reasonably be judged to be etiologically related to the dementia (history of stroke, evidence of cerebral infarction).

ADDCT criteria for probable ischemic vascular dementia The criteria for the clinical diagnosis of probable ischemic vascular dementia (IVD) include all of the following: 1 Dementia. 2 Evidence of two or more ischemic strokes by history, neurologic signs, and/or neuroimaging studies (CT or T1-weighted MRI), or occurrence of a single stroke with a clearly documented temporal relationship to the onset of dementia. 3 Evidence of at least one infarct outside the cerebellum by CT or T1-weighted MRI. The diagnosis of probable IVD is supported by the following. 1 Evidence of multiple infarcts in brain regions known to affect cognition. 2 A history of multiple transient ischemic attacks. 3 History of vascular risk factors (eg, hypertension, heart disease, diabetes mellitus). 4 Elevated Hachinski Ischemia Scale (original or modified version). Clinical features that are thought to be associated with IVD, but await further research, include: 1 Relatively early appearance of gait disturbance and urinary incontinence. 2 Periventricular and deep white matter changes on T2-weighted MRI that are excessive for age. 3 Focal changes in electrophysiologic studies (e.g., EEG, evoked potentials) or physiological neuroimaging studies (e.g., SPECT, PET, NMR spectroscopy). Other clinical features that do not constitute strong evidence either for or against a diagnosis of probable IVD include:

1 Periods of slowly progressive symptoms. 2 Illusions, psychosis, hallucinations, delusions. 3 Seizures. Clinical features that cast doubt on a diagnosis of probable IVD include: 1 Transcortical sensory aphasia in the absence of corresponding focal lesions on neuroimaging studies. 2 Absence of central neurological symptoms/ signs, other than cognitive disturbance.

NINDS-AIREN criteria for probable vascular dementia The criteria for the clinical diagnosis of probable vascular dementia include all of the following: 1 Dementia. 2 Cerebrovascular disease, defined by the presence of focal signs on neurological examination, such as hemiparesis, lower facial weakness, Babinski sign, sensory deficit, hemianopsia, dysarthria, etc. consistent with stroke (with or without history of stroke), and evidence of relevant CVD by brain imaging (CT or MRI) including multiple largevessel strokes or a single strategically placed infarct (angular gyrus, thalamus, basal forebrain, PCA or ACA territories), as well as multiple basal ganglia and white matter lacunes or extensive periventricular white matter lesions, or combinations thereof. 3 A relationship between the above two disorders, manifested or inferred by the presence of one or more of the following: • onset of dementia within 3 months following a recognized stroke; and • abrupt deterioration in cognitive functions; or fluctuating, stepwise progression of cognitive deficits. Clinical features consistent with the diagnosis of probable vascular dementia include the following. 1 Early presence of a gait disturbance (small-step gait or marche à petits-pas, magnetic, apraxicataxic or Parkinsonian gait). 2 History of unsteadiness and frequent, unprovoked falls. 3 Early urinary frequency, urgency, and other urinary symptoms not explained by urological disease.

858 APPENDIX I

4 Personality and mood changes, abulia, depression, emotional incontinence, other subcortical deficits including psychomotor retardation and abnormal executive function. Features that make the diagnosis of vascular dementia uncertain or unlikely include: 1 Early onset of memory deficit and progressive worsening of memory and other cognitive functions such as language (transcortical sensory aphasia), motor skills (apraxia), and perception (agnosia), in the absence of corresponding focal lesions on brain imaging. 2 Absence of focal neurological signs, other than cognitive disturbance. 3 Absence of cerebrovascular lesions on brain CT or MRI.

Further reading American Psychiatric Association (1994) Diagnostic and Statistical Manual of Mental Disorders

(Fourth edn). Washington DC, American Psychiatric Association. Chui, H.C., Victoroff, J.J., Margolin, D., Jagust, W., Shankle, R & Katzman R. (1992) Criteria for the diagnosis of ischemic vascular dementia proposed by the State of California Alzheimer’s Disease Diagnostic and Treatment Centers. Neurology 42, 473–480. McKeith, I.G., Galako, D., Kosaka, K. et al. (1996) Consensus guidelines for the clinical and pathological diagnosis of dementia with Lewy bodies. (DLB): report of the Consortium on DLB international workshop. Neurology 47, 1113–1124. McKhann, G., Drachman, D., Folstein, M., Katzman, R., Price, D. & Stadlan, E.M. (1984) Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 34, 939–944. Roman, G.C., Tatemichi, T.K., Erkijuntti, T. et al. (1993) Vascular dementia: diagnostic criteria for research studies. Report of the NINDS-AIREN International Work Group. Neurology 43, 250–260. World Health Organization. (1993) ICD-10 Classification of Mental and Behavioural Disorders: Diagnostic Criteria for research. Geneva: WHO.

Appendix II: Dementia Rating Scales

The Mini Mental State Examination (MMSE) Time

10 minutes

Administration

Clinical or lay personnel after brief training

Purpose

Designed to differentiate organic from functional illness and quantify the organic deficit. Never intended to be diagnostic, only a screening tool. Mini because it does not include mood or behavior. Covers orientation, recall, short-term memory and arithmetic ability. The most commonly used screening instrument used today in clinical settings and as a screen for clinical trials.

Description

11 items, divided into two sections. The first section involves verbal responses to questions on orientation, attention and memory. The second involves naming, following written and verbal commands, writing and copying. The second half requires educational attainment. The test gives a maximum score of 30.

Section one

Orientation in time and place Registration/recall Attention

Section two

Recognition Repetition Verbal and written commands Writing and praxis

Reliability/validity

Reliability has been widely studied, examples of interrater reliability being 0.69 and 0.78. Test/retest reliability is 0.89. Correlations: WAIS verbal 0.78, performance 0.66, GDS 0.92, BDRS 0.79. BIMC 0.88.

Commentary

It is brief and can be used in any setting, by anyone. It is not diagnostic and as a screen may miss mild impairments and right-sided lesions. Poor education gives low results, no reliable method has been found to adjust for this. The test does not discriminate moderate and severe cases and may miss early ones. Many attempts to change the scale show it has perceived weaknesses, but so far have traded sensitivity for specificity.

Typical scores used are

Routine cut off for further testing 23/24 Mild cases have more sensitive pick-up at 24/25 Mild cognitive impairment 26/27 Typical change over 3 years is 7 points at beginning and end of disease, 2 points per year in middle (Cont.)

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860 APPENDIX II

MMSE (cont.) Change with treatment after 6 months

Two point rise: marked improvement One point rise: moderate improvement No decline: stability One point drop: expected rate

Normal variation

Same rater more reliable than interrater; can be up to 2 points While population data correlates with other tests, reliability and validity as a measure of change are unknown for an individual

Key reference

Folstein, M.F., Folstein, S.E. & McHugh, P.R. (1975) Journal of Psychiatric Research 12, 189–98.

Additional references

Burns, A., Brayne, C. & Folstein, M. (1998) International Journal of Geriatric Psychiatry 134, 285–94. Galasko, D., Klauber, M.R., Hofstetter, C.R. et al. (1990) Archives of Neurology 47, 49–52. Teng, E.L., Chang Chui, H., Schneider, L.S. et al. (1987) Journal of Consulting and Clinical Psychology 55, 96–100. Tombaugh, T.N. & McIntyre, N.J. (1992) Journal of the American Geriatrics Society 40, 922–35.

Address for correspondence

Marshall Folstein Department of Psychiatry Tufts University School of Medicine NEMC#1007 70 Washington Street Boston MA 02111, USA

Cambridge Mental Disorders of the Elderly Examination (CAMDEX) Time

80 minutes (60 with patient, 20 with care giver)

Administration

Trained observer

Purpose

A standardized clinical interview designed to lead to a diagnosis even in mild cases, and address the weaknesses of the MMSE. Arranged to include three sets of tests: cognitive screening tests, dementia severity tests and behaviour rating scales that test problems in ADL. The cognitive test is known as the CAMCOG and is often used alone, especially in memory clinics (UK).

Description

The instrument has eight sections (a–h) arranged in three sections: Clinical interview: (a) past history/past psychiatric history; (c) mental state; (d) physical exam; (e) lab tests; (f) list current medication; (g) added information CAMCOG: (b) 57 items, an extended version of the MMSE. It has a maximum score of 106. Interview with relative to get independent information Other tests can be extracted from the information, MMSE, mental status questionnaire and a depression scale

Reliability/validity

Interrater 0.83–0.94 (over the 8 sections). CAMCOG 0.88. Test/retest not available

Correlations

CAMCOG/BDS 0.7, GMS 0.94

Commentary

The CAMDEX is a full clinical interview, and felt to be long for clinical use. The CAMCOG is superior to the MMSE and has diagnostic validity, hence its more common usage. The CAMDEX results offer a diagnosis in all major psychiatric categories.

APPENDIX II 861

Scoring

Maximum for CAMCOG is 106 Cut off at 79/80 gives 92% sensitivity and 96% specificity for AD

Change with time

Unknown

Clinically meaningful change with treatment

Unknown

Normal variation

Unknown

Key reference

Roth, M., Tym, E., Mountjoy, C.Q. et al. (1986) British Journal of Psychiatry 149, 698–709.

Additional reference

O’Connor, D., Pollitt, P., Hyde, J. et al. (1990) Acta Psychiatrica Scandinavica 81, 78–82.

Address for correspondence

Felicia A Huppert Department of Psychiatry Level E4 Box 19 Addenbrooke’s Hospital Cambridge CB2 2QQ, UK

The Alzheimer’s Disease Assessment Scale (ADAS) Time

45 minutes

Administration

Trained observer

Purpose

This was designed as a short instrument to measure commonly observed clinical manifestations of AD. It divides into 11 cognitive (memory, praxis, language) and ten non-cognitive (affective, behavioural) aspects of the disease. It has become the main outcome measure in AD clinical trials.

Description

21 items are administered by a trained professional. Each item scores 0 (no impairment) to 5 (severe impairment): except for the memory tests (0–22). This gives a score of 0–70 on the tests involving cognition, (higher scores meaning more advanced disease), and 0–50 on tester observed non-cognitive symptoms. The 21 items are: Cognitive Non-cognitive Spoken language Tearful Comprehension Appears/reports low mood Recall of instructions Concentration Word-finding difficulty Poor cooperation in tests Following commands Delusions Naming objects Hallucinations Copying forms Pacing Ideational praxis Increased motor activity Orientation Tremors Word recall memory test Change in appetite Word recognition memory test

Reliability/validity

Interrater reliability is 0.99 for cognitive and total score; but 0.95 for non-cognitive symptoms. One month test/retest reliability was 0.92 for cognitive, 0.84 total and 0.59 non-cognitive scoring.

Correlations

Blessed MIT 0.67, BCRS 0.77, MMSE 0.71, CSF Ach 0.63. (Often small samples).

Commentary

Broad test with longitudinal reliability. Naming and praxis may be less sensitive in mild cases, reducing its utility in measuring improvement. Total score rarely used because non-cognitive test is less reliable. Often the ADAS-Cog is used alone, and other non-cognitive tests are used. Good utility instrument for general use. (Cont.)

862 APPENDIX II

ADAS (cont.) Typical scores for the cognitive portion

Mild dementia: 15–30 points Moderate dementia: 31–45 points Severe dementia: +45 points Typical change over one year: 8 points increase

Clinically meaningful change with treatment after 6 months

0 points: Stability 4 points drop: Moderate improvement 7 points drop: Marked improvement Normal variation: Unknown

Key reference

Rosen, W., Mohs, R. & Davis, K. (1984) American Journal of Psychiatry 141, 1356–1364.

Additional references

Mohs, R., Knopman, D., Petersen, R. et al. (1997) Alzheimer’s Disease and Associated Disorders 11(supplement 2), S13–S21. Schwarb, S., Koberle, S., Spiegel, R. (1988) International Journal of Geriatric Psychiatry 3, 45–53. Zec, R., Landreth, E., Vicari, et al. (1992) Alzheimer’s Disease and Associated Disorders 6, 89–102. Zec, R., Landreth, E., Vicari, et al. (1992) Alzheimer’s Disease and Associated Disorders 6, 164–81.

Address for correspondence

K Davis Department of Psychiatry Bronx VA Medical Centre 130 West Kingsbridge Road Bronx NY 10468, USA

Syndrom Kurztest (SKT) Time

20 minutes

Administration

Trained observer

Purpose

Designed to be a brief measure of cognition and attention, in the routine clinical setting

Description

Composed of nine sections: Object naming Object recall Reading numbers from blocks Arranging blocks Replacing blocks in original position Learning Simple recognition Two memory performance tasks The test is available in five parallel forms (A–E) to prevent any learning effect. Each subtest is scored in a 60-second time frame

Reliability/validity

Interrater 0.86

Correlations

Not available

Commentary

This is a utilitarian test from Germany, which requires some educational attainment, and an ability to comprehend its instructions, but is not language dependent. It needs the full set of equipment that it uses which limits its spread around clinics. It has been used successfully in conjunction with EEG. It has been used in European clinical trials but not FDA regulated ones. Its use has been mainly confined to Europe.

APPENDIX II 863

Scoring

9–13 Mild organic brain disease (Stage 2/3 on the FAST) 13–24 Mild dementia (24 points or less on MMSE)

Change with time

Unknown

Change with treatment

Unknown

Normal variation

Unknown

Key references

Erzigkeit, H. (1989) Diagnosis and Treatment of Senile Dementia. Berlin; Springer-Verlag, 164–174. Lehfeld, H. & Erzigkeit, H. (1997) International Psychogeriatrics 9(Suppl 1), 115–121.

Additional references

Erzigkeit, H. (1991) Dementia: molecules, methods and measures Chichester: Wiley, 101–108. Overall, J. & Schaltenbrand, R. (1992) Journal of Geriatric Psychiatry and Neurology 5, 220–227.

Address for correspondence

H Lehfeld Psychiatrische Universitatsklinik Erlangen Schwabachanlage 6 91054 Erlangen Germany

Global Deterioration Scale (GDS) Time

Two minutes

Administration

By clinician taking information

Purpose

A seven-stage overall rating as dementia progresses, starting with no cognitive decline and ending with severe. Serves as a staging instrument to show deterioration.

Description

Consists of seven categories, each with a detailed clinical description No impairment Subjective complaints Early, subtle, clear cut deficits Clear cut deficits Needs assistance to survive Largely unaware of recent experiences Losing verbal abilities

Reliability/validity

Both interrater and test/retest reliability are 0.9

Correlations

Clock drawing 0.56 MMSE 0.92

Commentary

Easy staging tool, based on the clinical interview. Has stood test of time and easy instrument for the routine clinical setting

Change with time

Continuous through stages

Change with treatment

Unknown

Normal variation

None

Key reference

Reisberg, B., Ferris, S., de Leon, M.J. & Crook, T. (1982) American Journal of Psychiatry 139, 1136–1139.

Additional references

Reisberg, B. et al. (1993) Neuroscience Research Communication 13, 551–554. Reisberg, B. et al. (1996) International Psychogeriatrics 8, 159–193. (Cont.)

864 APPENDIX II

GDS (cont.) Address for correspondence

Barry Reisberg Department of Psychiatry Aging and Dementia Research Center NYU Medical Center 550 First Avenue NY 10016, USA

Clinical Dementia Rating (CDR) Time

End of a clinical interview or 40 minutes as a stand alone test

Administration

Trained clinician

Purpose

Designed originally as a clinical staging tool, it was updated in 1992 and has now become a central instrument in clinical trials. It consists of six domains.

Description

The six domains are: Memory Orientation Judgement and problem solving Community affairs Home and hobbies Personal care These are scored using a descriptive staging with each item ranging from 0 to 3. The score is the aggregate of the sum of boxes, representing an average staging of an individual’s abilities.

Reliability/validity

Interrater reliability is 0.89

Correlations

IMC 0.81 BLS-D 0.80

Commentary

This is a test commonly used in clinical trials, but less frequently used in clinical work. It has been used to define MCI in Europe (CDR 0.5) and would be a useful instrument to standardize memory clinics. It was further adapted in Canada (FRS) to be used as a multidisciplinary tool.

Scoring

0 Healthy 0.5 Questionable dementia 3 year period 1 Mild dementia 3 year period 2 Moderate dementia 4 year period 3 Severe dementia 5 year period Treatment may delay the transition between stages

Normal variation

None

Key references

Hughes, C.P., Berg, L., Danziger, W.L. (1982) et al. British Journal of Psychiatry 140, 556–572. Morris, J. (1993) Neurology 43, 2412–2413.

Additional references

Berg, L., Miller, J., Baty, A. et al. (1992) Annals of Neurology 31, 242–249. Burke, W., Miller, P., Rueben, E. et al. (1988) Archives of Neurology 45, 31–32. Morris, J., McKeel, D., Fulling, K. et al. (1988) Annals of Neurology 24, 17–22.

APPENDIX II 865

Address for correspondence:

John Morris Memory and Aging Project Washington University School of Medicine 660 South Euclid Avenue PO Box 8111 St Louis MO 63110, USA

The Dependence Scale Time

End of a clinical interview, a five minute test

Administration

Trained clinician

Purpose

Designed to assess the function of a patient in relation to the effect on the carer and predict the likelihood of institutionalization. It was developed to correlate with the progression of the dementia. Scoring is simple to allow a broad assessment with minimal training.

Description

13 items are arranged in increasing order of dependency (labelled A–M). They all deal with reported patient needs and are informant based. The first three can be qualified into no need, occasional or frequent. A Does the patient need reminders to manage IADLs? B Does the patient need help remembering? C Does the patient forget things? D Do household chores need doing? E Does the person need watching when awake? F Do they need escorting when out? G Do they need help bathing or eating? H Do they need help with self care? I Do they need help toileting? J Do they have to be fed? K Do they need turning and help transferring? L Do they need pads or a catheter? M Do they need tube feeding? The scores can be used to derive dependency levels and equivalent care needs

Reliability/validity

Interrater reliability is 0.9 and for rating institutional care 0.73

Correlations

Modified MMSE 0.83, CDR 0.66, BDRS 0.62

Commentary

This test is simple to use with good reliability and validity. It gives a good idea of the patients’ dependence and the level of service they need. Its results are independent of where and by whom care is delivered.

Scoring levels

0 A score of 0 on all items 1 Either A, B or C = 1 2 Two of A, B or C = 1; or A or B = 2; or D = 1 3 E, F or G = 1 4 H, I, or J = 1 5 K, L, or M = 1 Treatment may delay the transition between stages.

Normal variation

Unknown (Cont.)

866 APPENDIX II

The Dependence Scale (cont.) Key reference

Stern, Y., Albert, S., Sano, M. et al. (1994) Journal of Gerontology 49(5), M216–M222.

Address for correspondence

Yakov Stern Gertrude H. Sergievsky Center 630 West 168th Street New York NY 10032

The Disability Assessment for Dementia (DAD) Time

15 minutes

Administration

Trained observer

Purpose

Designed to measure activities of daily living, both instrumental and basic, in AD. Informant-based scale. Now become common as a secondary outcome measure in clinical trials, especially in Europe where these scales are a regulatory requirement

Description

Consists of three sections: Basic ADL, Instrumental ADL and leisure activities. Each one is measured according to one of three cognitive dimensions: the ability to initiate the action, the planning and organization of it and the effective performance of the desired function. There are 40 items scoring 1 point for yes, 2 for no or N/A.

Reliability/validity

Interrater reliability is 0.95. Test/retest is 0.96

Correlations

None

Commentary

This is a workable ADL scale for routine and research use. It is used multinationally and has minimal cultural and gender bias. The measurement of the stages of a function, rather than presence or absence of function, gives a better picture of the capabilities of the test subject.

Scoring conventions

Scored as a percentage of all questions answered, excluding the N/A’s. Eg: 33/40 = 83%, while 33/38 (two N/As) = 87% Change with time Unknown Change with treatment Unknown Normal variation Unknown

Key reference

Gelinas, I., Gauthier, L., McIntyre, M. & Gauthier, S. (1999) American Journal of Occupational Therapy 53(5), 471–481.

Additional reference

Gelinas, I. & Auer, S. (1996) Clinical Diagnosis and Management of Alzheimer’s Disease. London: Martin Dunitz. pp. 191–202.

Address for correspondence

Serge Gauthier The McGill Center for Studies in Aging Douglas Hospital 6825 LaSalle Boulevard Verdun Quebec H4H 1R3 Canada

APPENDIX II 867

Interview for Deterioration in Daily Living Activities in Dementia (IDDD) Time

15 minutes

Administration

Multidisciplinary, interview with caregiver

Purpose

Designed to evaluate 33 self-care activities, their initiation and performance. The activity is compared to the level of functioning before the dementia. The scale was positively rated in the original study with cognition, disturbed behaviour and care giver burden. It frequently appeared in clinical trials but less so now .

Description

33 questions are rated on a four-point scale. The questions cover both basic (washing, dressing and eating) and instrumental ADLs (shopping, writing and answering the phone). It attempts to have no gender bias.

Reliability/validity

Reliability 0.94

Correlations

None

Commentary

This is a mixed scale testing all ADLs. It is longer than some of the newer ADL scales; but has little bias. The questions are a mixture of ability to initiate and perform the activity. As such they attempt to measure cognitive segments of ADL. It is a useful scale, used more in mainland Europe than elsewhere. The scale was thought to be sensitive enough to measure change in early dementiaahence its use in clinical trials.

Scoring convention

1 2 3 9

Score increases with disability

Change with time Change with treatment Normal variation

Key reference

Tuenisse, S. & Derix, M.M.A. (1991) Tijdschrift voor Gerontologieen-Geriatrie 22, 53–59.

Additional reference

Tuenisse, S., Derix, M.M.A. & van Crevel, H. (1991) Archives of Neurology 48, 274–277.

Address for correspondence

S Tuenisse Psychology Department Community Mental Health Unit St Charles Hospital Exmoor Street London W10 6DZ, UK

no help (or change in help) needed sometimes help (or more often help) needed help always (much more often) needed N/A Unknown Unknown Unknown

The Neuropsychiatric Inventory (NPI) Time

15 minutes

Administration

Trained clinician during interview with the carer

Purpose

Designed to capture the frequency and severity of a wide range of psychopathology. More recently an extra arm has been added to capture the distress the behaviour causes the caregiver (NPI-D). Also has a nursing-home version. (Cont.)

868 APPENDIX II

NPI (cont.) Description

The scale consists of twelve behavioral areas. Delusions Apathy Hallucinations Agitation Irritability Anxiety Disinhibition Aberrant motor disorder Euphoria Appetite disorder Depression Night-time behaviour For each one there is a stem question and if the answer is positive a series of qualifying questions follows, which increases the time shown. The short NPI uses just the stem questions and is equally reliable. The frequency is assessed on a four-point scale and severity on a three-point scale. The two are multiplied together to give a maximum score of 144. The time assessed is usually the four weeks before interview.

Reliability/validity

Interrater reliability 0.95–1.0 on each sub-question. Test/retest 0.79 for frequency, 0.86 for severity.

Correlations

Behave-AD 0.60–0.77 (excluding affective symptoms 0.33). Affective subset and HDRS 0.61. Relative stress scale 0.62.

Commentary

This scale has become the gold standard in clinical trials and a regular in the memory clinics. It is easy to use in the clinic setting. It measures a wide variety of behaviors; some critics feel not in enough depth, though evidence does not support this. It is good longitudinally and may have enough clinical information to distinguish some dementias.

Score conventions

Frequency: 1 occasionally, 2 often, 3 frequently, 4 very frequently Severity: 1 mild, 2 moderate, 3 severe Distress: 0 none, 1 minimal, 2 mild, 3 moderate, 4 moderately severe, 5 very severe

Change over time

Unknown. Behavioral symptoms in dementia come and go naturally at different rates.

Change with treatment

Unknown. While total scores drop with treatment, the individual area scores give more information. Apathy, hallucinations and agitation seem to respond to anticholinesterase inhibitors more than other domains.

Normal variation

Unknown.

Key reference

Cummings, J.L., Mega, M., Rosenberg-Thompson. et al. (1994) Neurology 44, 2308–2314.

Additional reference

Cummings, J.L. (1997) Neurology 48(suppl 6), S10–S16.

Address for correspondence

Jeffrey Cummings Neurobehavior Unit Psychiatry Service (116F) West Los Angeles, VAMC 11301 Wilshire Boulevard Los Angeles CA 90073, USA

The Geriatric Depression Scale (GDS) Time

10 minutes

Administration

Self-administered or any staff, no training needed

APPENDIX II 869

Purpose

Designed as a screen for depression in th elderly, containing factors relevant to age, derived from over 100 original questions

Description

Three versions are used. The original 30-item scale, the 15-item (most commonly) and the 4-item scale for primary care. The questions are yes/no answers, which the subject fills in. Points are scored at 1 per item if the depressed answer is given.

Reliability/validity

Interrater reliability is 0.85. The four-item scale has 0.89 sensitivity, 1/2 cut off and 0.93 specificity at 0/1.

Correlations

N/A

Commentary

This is a very widely used screening test. It is not so reliable in AD. It is often used longitudinally, little published work supports this as yet.

Scoring

30-item: Score of 11 is representative of a case of depression (sensitivity 84%, specificity 95%) 15-item: Score of 5/6 is representative of a case of depression (no published s/s) 4-item: Score of 1/2 is representative of a case of depression (no published s/s)

Normal variation

Unknown

Key reference

Yesavage, J.A., Brink, T.L., Rose, T.L. et al. (1983) Journal of Psychiatric Research 17, 37–49.

Additional references

Brink, T.L., Yesavage, J.A., Lum, O. et al. (1982) Clinical Gerontologist 1, 37–41. Katona, C. (1994) Depression in Old Age. Chichester: John Wiley & Sons. Shah, A., Herbert, R., Lewis, S. et al. (1997) Age and Ageing 26, 217–221. Sheikh, J. & Yesavage, J.A. (1986) Clinical Gerontology; a guide to assessment and intervention. New York: Howarth Press.

Address for correspondence

J.A. Yesavage Department of Psychiatry and Behavioral Sciences Stanford University Medical Center Stanford CA 94395, USA

Appendix III: National Alzheimer’s Disease and Dementia Associations and Societies*

Argentina

Belgium

ALMA (Asociacion de Lucha contra el Mal de Alzheimer) Lacarre no. 78 1407 Capital Federal Buenos Aires Argentina Tel/Fax: + 54 11 46711187

Ligue Alzheimer Clinique le peri 4B Rue Montagne Sainte Walburge 4000 Liege Belgium Tel: + 32 4225 8793 Fax: + 32 4226 7231

Australia

Brazil

Alzheimer’s Association Australia PO Box 6042 North Ryde NSW 1670 Australia Tel: + 61 2980 50100 Fax: + 61 2980 51665

FEBRAZ Federacao Brasileira de Associacaoes de Alzheimer Av Paulista, 726-cj 501 Sao Paulo SP Brazil 01310–100 Tel/Fax: + 55 11 2887428

Austria Alzheimer Angehorige Austria Obere Augartenstrasse 26–28 1020 Vienna Austria Tel: + 43 1332 5166 Fax: + 43 1334 2141

Canada Alzheimer Society of Canada 20 Eglinton Ave. W. Suite 1200, Toronto Ontario M4R 1KB Canada Tel.: + 1416 4888772 Fax: + 1416 4883778

*Email and web addresses are available on the website accompanying this book.

870

APPENDIX III 871

Chile

Dominican Republic

Corporacion Chilena de la Enfermedad de Alzheimer y Alecciones Similares General Parra 674, Providencia Santiago, Chile Tel: + 56 2236 0846 Fax: + 56 2236 3278

Asociacion Dominicana de Alzheimer y Trastornos, Relacionados Apartado Postal # 3321 Santo Domingo Republica Dominicana Tel: + 1809 2216115 Fax: + 1809 5624690

Colombia Asociacion Colombiana de Alzheimer y Desordenes Relacionados Calle 69 A no. 10–16 Santa Fe de Bogota DC Colombia Tel: + 57 1248 1614 Fax: + 57 1321 7691

Cuba Centro Iberoamericano de la Tercera Edad Hospital Universitario ‘Calixto Garcia’ Calle G y 27 Vedado, Ciudad Habana, Cuba Tel: + 537 33 3864 Fax: + 537 33 3319

Czech Republic

Ecuador Alzheimer’s Disease, Ecuador Avenida de la Prensa # 5204 y Avenida del Maestro Quito Ecuador Tel/Fax: + 593 594997

Finland Alzheimer Society of Finland Luotsikatu 4E 00160 Helsinki Finland Tel: + 358 96226 200 Fax: + 358 96226 2020

France

Ceska Alzheimerovska Spolecnost Simunkova 1600, Prague 8 Czech Republic 18200 Tel: + 4202 88 36 76 Fax: + 4202 88 27 88

Association France Alzheimer 21 Boulevard Montmartre 75002 Paris France Tel: + 33 14297 5241 Fax: + 33 14296 0470

Denmark

Germany

Alzheimerforeningen Sankt Lukas vej 6, 1 2900 Hellerup Denmark Tel: + 45 39 40 04 88 Fax: + 45 39 61 66 69

Deutsche Alzheimer Gesellschaft Kanstrasse 152 10623 Berlin Germany Tel: + 49 30 315 57 33 Fax: + 49 30 315 57 35

872 APPENDIX III

Greece

Luxembourg

Greek Society of AD and Related Disorders 92 Egnatia, Str, 546 23 Thessaloniki Greece, 56225 Tel: + 30 31 264380 Fax: + 30 31 283973

Association Luxembourg Alzheimer 45, rue Nicolas Hein Luxembourg, B.P. 5021,L-1050 Luxembourg Tel: + 352 421676 Fax: + 352 42 1679

Guatemala Asociacion Grupo Ermita 10a Calle 11–63, Zona 1 Apto B, PO Box 2978 01901 Guatamala Tel/Fax: + 502 2381122

Italy Federazione Alzheimer Italia Via Marino 7 20121 Milano Italy Tel: + 39 02 80 9767 Fax: + 39 02 87 5781

Japan Association of Family Caring for Demented Elderly c/o Kyoto Social Welfare Hall Horikawa-Marutamachi Kamigyo-Ku, Kyoto Japan 602 Tel: + 81 75 8118195 Fax: + 81 75 8118188

Mexico AMAES Insurgentes Sur no. 594–402 Col. Del Valle Mexico 12, D.F. Tel/Fax: + 525 5231526

Netherlands Alzheimerstichting Post Bus 183 3980 CD Bunnik The Netherlands Tel: + 31 30 6596285 Fax: + 31 30 6596283

New Zealand Alzheimer’s Society NZ Box 2808 Christchurch New Zealand Tel: + 64 3365 1590 Fax: + 64 3379 8744

Korea

Poland

Association of Family Caring for Demented Elderly in Korea #52, Machon 2-Dong Songpa-Gu Seoul 138–122 Korea Tel: + 82 2431 9963 Fax: + 82 2431 9964

Polish Alzheimer’s Association ul.Hoza 54/100–682 Warzawa Poland Tel/Fax: + 48 22 622 11 22

APPENDIX III 873

Puerto Rico

Spain

Asociacion de Alzheimer de Puerto Rico Apartado 362026 San Juan Puerto Rico 00936–2026 Tel: + 1787 7274151 Fax: + 1787 7274890

Alzheimer Espana Calle 2800 Madrid Spain Tel: + 34 91 3440394

Romania Romanian Alzheimer Society Bd. Mihail Kogalniceanu 49 Sc. A, Et. 1, Ap. 8. Sector 5 Bucharest Romania 70603 Tel: + 40 1686 3470 Tel/Fax: + 40 1311 3471

Scotland Alzheimer Scotland—Action on Dementia 22 Drumsheugh Gardens Edinburgh EF3 7RN Scotland Tel: + 44 131243 1453 Fax: + 44 131243 1450

Singapore Alzheimer’s Disease Assocation Blk 151 Toa Payoh Lor 2 #01–468 Singapore 1231 Tel: + 65 3538734 Fax: + 65 3538518

South Africa Alzheimer’s & Related Disorders Association PO Box 81183, Parkhurst Johannesburg 2120 South Africa Tel: + 27 11 4782234/5/6 Fax: + 27 11 4782251

Federated Association of Family Alzheimer Associations Avda. Pio XIL, 37 Entreplanta Oficina 5 31008 Pamplona Spain Tel: + 34 948177 907 Fax: + 34 948265 739

Sweden Alzheimer’s Society of Sweden Sunnanvag 14S 222 26 Lund Sweden Tel: + 46 46 14 73 18 Fax: + 46 46 18 89 76

Switzerland Association Alzheimer’s Suisse 8 Rue des Pecheurs Ch-1400 Yverdon-les-Bains Switzerland Tel: + 41 24 4262000 12 20 Fax: + 41 24 4262167

Turkey Alzheimer Association Cakiraga Cami Sok Katkas is Hani 29/11 Aksara Istanbul Turkey Tel: + 90 212588 2108 Fax: + 90 212588 2254

874 APPENDIX III

United Kingdom

Uruguay

Alzheimer’s Disease Society Gordon House, 10 Greencoat Place London SW1P 1PH UK Tel: + 44 20 73060606 Fax: + 44 20 73060808

Asociacion Uruguaya de Alzheimer y Similares Casilla de Correo 18951 Montevideo Uruguay Tel/Fax: + 598 2400 87 97

United States

Venezuela

Alzheimer’s Association 919 N Mitchigan Avenue Suite 1000 Chicago Illinois 60611 USA Tel: + 1312 3358700 Fax: + 1312 3351110

Fundacion Alzheimer de Venezuela Av. El Limon Qta Mi Mune El Cafetal Caracas Venezuela Tel: + 582 9859546 Fax: + 582 6901123

Abbreviations

AACD

aging-associated cognitive decline AAMI age-associated memory impairment AAN American Academy of Neurology AARP American Association of Retired Persons Aβ amyloid β ABD absolute benefit difference ACh acetylcholine AChE acetylcholinesterase AD Alzheimer’s disease ADAS-Cog Alzheimer’s Disease Assessment Scaleacognitive ADAS-noncog Alzheimer’s Disease Assessment Scaleanoncognitive ADCS Alzheimer’s Disease Cooperative Study ADDTC Alzheimer’s disease diagnostic and treatment centers ADH antidiuretic hormone ADL activities of daily living ADRC Alzheimer’s disease research centre ADRDA Alzheimer’s Disease and Related Disorders Association AHCRP Agency for Health Care Research and Policy AMPA American Medical Publishers Association AMTS Abbreviated Mental Test Score ANH artificial nutrition and hydration ApoE apolipoprotien E APP amyloid precursor protein ARCD age-related cognitive decline

ATP BCRS BCRS BDZ BNT BPRS BPSSD

BuChE CADASIL

CAM-COG CAMDEX CBD CBF CDLB CDR CERAD

CG CGI CGIC ChAT ChEI CI CJD

andenosine triphosphate Blind Comparison Reference Standard Brief Cognitive Rating Scale benzodiazapine Boston Naming Test Brief Psychiatric Rating Scale behavioral and psychiatric symptoms and signs of the disorder butyryl cholinesterate cerebral autosomal arteriopathy with subcortical infarction and leukoencephalopathy Cambridge Cognitive Examination Cambridge Mental Disorders of the Elderly Examination corticobasal degeneration cerebral blood flow Consortium on Dementia with Lewy Bodies Clinical Dementia Rating (Scale) Consortium to Establish a Registry for Alzheimer’s Disease care giver Clinical Global Impression (Scale) Clinical Global Impression of Change (Scale) choline acetyl transferase cholinesterase inhibitor confidence interval CreutzfeldtaJakob disease

875

876 ABBREVIATIONS

CMRglc CNS COX CRF CSF CT CVD DAD DAT DDVP DHEA DLB DNA DNDP

DPB DRS DSM DWR EBD EBM EEG ELISA EMEA eMMSE ERC FAD FAQ FDA FDG FSH FTD GABA GBE GBS GDS GDS GFAP

tracer to measure cerebral glucose metabolism central nervous system cyclo-oxygenase corticotrophin releasing factor cerebrospinal fluid computerized tomography cerebrovascular disease Disability Assessment for Dementia (Scale) dementia of the Alzheimer type 2,2-dimethyl dichlorovinyl phosphate dihydroepiandrosterone dementia with Lewy bodies deoxyribonucleic acid Department of Neuropharmacological Drug Products dementia with Pick bodies Dementia Rating Scale Diagnostic and Statistical Manual delayed word recall evidence-based dementia evidence-based medicine electroencephalogram enzyme-linked immunoadsorbent assay European Medicine Evaluation Agency expanded Mini Mental Status Examination entorhinal cortex familial Alzheimer’s disease functional activities questionnaire Food and Drug Administration 18 F-fluorodeoxyglucose follicle-stimulating hormone frontotemporal dementia γ-aminobutyric acid Gingko biloba extract GottfriesaBraneaSteen (Scale) Geriatric Depression Scale Global Deterioration Scale glial fibrillary acidic protein

GnRH GVD HAM-D HAS HD 5-HIAA HIS HIV 5-HT IADL ICD IDDD IGF IQ ISIS-2 ITSNU ITT IVD LB LBD LH LOCF LPD LR LTP MAO-B MCI MID MIS MMD mMMSE MMSE MPA MRI MSA MTA NAB NC NFT

gonadotrophin-releasing hormone granulovascular degeneration Hamilton Rating Scale for Depression Hamilton Anxiety Scale Huntington’s disease hydroxyindole acetic acid Hachinski Ischemic Score human immunodeficiency virus hydroxytryptamine (serotonin) instrumental activities of daily living International Classification of Diseases interview for deterioration in daily living activities in dementia insulin-like growth factor intelligence quotient Second International Study of Infarct Survival inclusions tau and synuclein negative, ubiquitinated intention to treat ischemic vascular dementia Lewy bodies Lewy body dementia luteinizing hormone last observation carried forward London Psychogeriatric Scale likelihood ratio long-term potentiation monoamine oxidase-B mild cognitive impairment multi-infarct dementia Memory Impairment Screen miscellaneous memory disorders modified Mini Mental Status Examination Mini Mental Status Examination medroxyprogesterone acetate magnetic resonance imaging multiple system atrophy medial temporal lobe atrophy Nurnberger Altersbeobachtungsskala normal control neurofibrillary tangles

ABBREVIATIONS 877

NGF NHA NHS NICE NIH NINCDS

NMDA NNH NNS NNT NOSGER NOSIE NP NPH NPI NPI/NH NPV NS NSAID OBRA-97 OC OND OPTIMA OR OTC PAF PCG PD PDS PEG PET PHF PPV PS PSMS PSP QALYS

nerve growth factor nursing home admission National Health Service National Institute for Clinical Excellence National Institutes of Health National Institute of Neurological and Communicable Diseases N-methyl-D-aspartate number needed to harm number needed to screen number needed to treat Nurses’ Observation Scale for Geriatric Patients Nurses’ Observation Scale for Inpatient Evaluation neuritic plaques normal pressure hydrocephalus Neuropsychiatric Inventory Neuropsychiatric Inventory, Nursing Home version negative predictive value neuroleptic sensitivity non-steroidal anti-inflamatory drug Omnibus Budget Reconciliation Act of 1997 observed cases other neurological disorders Oxford Project to Investigate Memory and Ageing odds ratio over the counter platelet activating factor primary care group Parkinson’s disease Progressive Deterioration Scale percutaneous endoscopic gastrostomy positron emission tomography paired helical filaments positive predictive value presenilin Physical Self Maintenance Scale progressive supranuclear palsy quality-adjusted life years

QEEG RAVLT RBD rCBF RCT RDRS REM RNA RO ROC ROI s.d. SCAG SCU SDLT SF SKT SLE SMAC SP SP SPECT SS SSRI TMT TRH VaD vCJD VT WAIS WAIS-R WCST WHO WLL WMD WMLA WMS

quantitative electroencephalogram Rey Auditory Verbal Learning Test REM sleep behavior disorder regional cerebral blood flow randomized controlled trial rapid disability rating scale rapid eye movement ribonucleic acid reality orientation receiver-operating characteristics region of interest standard deviation Sandoz Clinical Assessment, Geriatric special care unit senile dementia of the Lewy body type straight filaments Syndrom Kurztest (or Syndrome Short Test) systemic lupus erythematosus Standing Medical Advisory Committee specific plaques specificity single photon emission computerized tomography sensitivity selective serotonin reuptake inhibitor Trail Making Test thyrotropin releasing hormone vascular dementia variant CreutzfeldtaJakob disease validation therapy Wechsler Adult Intelligence Scale Wechsler Adult Intelligence Scale, revised Wisconsin Card Sort Test World Health Organization Word List Learning (test) weighted mean difference white matter low attenuation Wechsler Memory Scale

Index

Page numbers in italics represent figures, those in bold represent tables l’Abbé plot 571, 572 absolute risk ratio 366 ABT-418 448 accuracy 20 acetyl-l-carnitine 452, 468–70 adverse effects 470 clinical pharmacology 470 clinical trials 468–70, 469 consideration for treatment 470 dose 470 efficacy 561 number needed to treat 469, 470 rationale for treatment 468 acetylcholine 474 acetylcholinesterase 474 inhibition see cholinesterase inhibitors isomeric forms of 498–9 activities of daily living 101, 102, 400 rivastigmine 508 activities, promotion of 439 actovegin 647 AD2000 trial 394, 395, 400 ADAS-Cog 567, 833, 834 donepezil 482 rivastigmine 507 tacrine 509 Addison’s disease 629–30 ADDTC criteria 113, 116 vascular dementia 263, 264, 857 adrenergic compounds 448 Adult Memory and Information Processing Battery 834 adverse effects antioxidant vitamins 473 spontaneous reporting 15 see also individual drugs age effects 16 pretest probability 83

see also age-associated memory impairment age of onset of Alzheimer’s disease 233 age-associated memory impairment 342, 639 –53 benign senescent forgetfulness 643 –5 clinical trials 647, 648–9 decline of cognitive function 640 –3, 641 diagnostic problems 645–6 study selection 646 treatment 646, 647, 648, 649 outcomes assessed 649 results 649–50 age-related cognitive decline 342 see also age-associated memory impairment; cognitive impairment agitation 360, 369, 672, 705–7 treatment algorithm 721 treatment flowchart 721 aims of treatment 357 AIT-082 452 alcohol-related dementia 620–1 all or nothing measures 35 allocation bias 33 alternating hand sequences 121 aluminum poisoning 623 Alzheimer, Alois 215–17, 218 Alzheimer Disease Diagnostic and Treatment Centers see ADDTC Alzheimer’s disease 6, 228–59 age of onset 233 behavioral characteristics 125–6 case history 229 classification 238–9, 239 clinical criteria 106–7 clinicopathological correlations 108, 110 –11, 231 cognitive symptoms 447–9, 462

computed tomography 139 CSF-Aβ42 in 178–9, 178 CSF-tau protein 177, 178 diagnosis 106–13, 229–34, 230, 231 accuracy of 112 diagnostic tools 237–8 differential diagnosis 279 and disability 244 EEG 171–2 epidemiology 238–40 etiology 238–9, 239 etiopathogenesis 244–9 event-free survival 464 evidence 109, 112, 125–6, 171–2 genetic markers 133–7, 348–9 apolipoprotein E 134–5, 136, 137 presenilin mutations 133–4, 135, 137 genetic risk factors 249 histopathological diagnosis 245–7 historical aspects 219–20 institutionalization rate 243 life expectancy 241, 243 magnetic resonance imaging 154–62 molecular genetics 248–9 mortality 234, 241 natural history 233–4, 239–40 neurofibrillary tangles 245–7 neuropathology 244–7 non-cognitive symptoms 449–50 pathogenesis 247–9 pathological criteria 107–9, 108 presentation 232–3 executive function 233 language 232 loss of function 233 memory 232 neuropsychiatric symptoms 233 non-anterograde amnesia 233

879

880 INDEX

Alzheimer’s disease (cont.) orientation 232 visuospatial processing 232–3 prevalence 241–2, 242 protective factors 240 –1 risk factors 123, 240 –1 search strategy and study validation 107, 108, 110–11, 171 stages of 234–7, 236 mild 235, 236, 237 moderate 236, 237 severe 236, 237 very mild 234–5, 235, 236 treatment 467, 566 –9, 567, 568 acetyl-l-carnitine 468 –70, 469 antioxidant vitamins 471–3 benefits and harms 562– 6 cessation of 573 d-cycloserine 516 –18 donepezil 473–83 efficacy of 560, 561, 570 –3, 572 estrogen 523–6 galantamine 484 –93 Gingko biloba 518–23 hydergine 526–30 idebenone 530–5 metrifonate 493 –9 monitoring of 570 n-of-1 trials 574 –5 nicotine 535–7 nimodipine 537– 40 NSAIDs 541–6 patient eligibility and suitability 569–70 piracetam 546–8, 546 prognosis-modifying 575– 6 propentofylline 548 –53 rivastigmine 499 –509 selegiline 553–7 symptomatic 568–9 tacrine 509–16 thiamine 557–9 treatment algorithm 574 see also individual drugs underlying pathology 450–3 versus normal aging 122 Alzheimer’s Disease Assessment Scale (ADAS) 66, 861–2 amentia senilis 203, 204, 209 American Academy of Neurology, Quality Standard Subcommittee 88 American Psychological Association 31 amitriptyline 715 see also antidepressants ampakines 448

Ampalex 448 amyloid precursor protein 176 amytriptyline 715 analysis 77 analysis bias 34 Animal Fluency Test 96 anomia 299 anti-thrombotics 590–3 adverse effects 592 aspirin see aspirin clinical pharmacokinetics 592 clinical trials 590–1 consideration for treatment 591–2 rationale for treatment 590 sulodexide 591 treatment course 592 anticonvulsants 682–6 adverse effects 685–6 carbamazepine 682–3 clinical trials 682–5 consideration for treatment 685 divalproex sodium 683–4 number needed to treat 686 antidepressants 368–9, 695–8 adverse effects 696–7 clinical trials 695–6 consideration for treatment 696 course of treatment 697 efficacy 697–8 hypersexuality 709 number needed to treat 697 rationale for treatment 695 sleep disturbance 715 treatment course 697 antioxidant vitamins adverse events 473 Alzheimer’s disease 471–3 clinical pharmacokinetics 473 clinical trials 471 consideration for treatment 472–3 prevention of dementia 657, 658 rationale for treatment 471 vascular dementia 589–90 vitamin E and selegiline 471–2 antiparkinsonian agents 611–12 antiplatelet therapy 660–1 Antiplatelet Trialist’s Collaboration 43, 45 antipsychotics atypical 677–8, 704–5 conventional 675–6, 675–7, 703–4 duration of treatment 676–7, 704 efficacy and safety 675–6, 703–4 individual efficacy 676, 704 lack of data 703 hypersexuality 709

anxiolytics 678–82 benzodiazepines 678–81, 679, 680 adverse effects 680 clinical trials 679, 680 consideration for treatment 680 hypersexuality 709 Lewy body dementia 612 rationale for treatment 678–9 sleep disturbance 712 treatment course 680 buspirone 680–1, 681–2 adverse effects 681 clinical trials 681 consideration for treatment 681 rationale for treatment 681 treatment course 681 aphasia Alzheimer’s disease 232 nonfluent 299 primary progressive 299 testing for 306 apolipoprotein E 451–2 Alzheimer’s disease 134–5, 136, 137 vascular dementia 273 apolipoprotein E4 26 applicability of guidelines 62 of results 16–17 diagnostic tests 23–4 economic evaluation 68 interventions 37–9 prognostic studies 29 apraxia 121 Aretaeus of Cappadocia 203 arginine vasopressin 648 arrestable dementias see reversible/arrestable dementias arsenic poisoning 624 arteriosclerotic insanity 217–19, 218 artificial nutrition 751–3 aspirin Alzheimer’s disease 52, 561 clinical trials 52 bias in 44 efficacy 561 vascular dementia 590 assessment 87 assessment bias 33 Assessment of Motor and Process Skills 835 attitude therapy 431 attrition bias 33, 34 audit evidence-based 74–8, 75 memory clinics 831, 832

INDEX 881

autosomal dominant inheritance 797–9, 798 Avicenna 204 baclofen 612 basophilic inclusion body disease 302 Bayer ADL 835 Bech–Rafaelson Mania Scale 684 Behave-AD 835 behavioral characteristics 124 –9, 673 Alzheimer’s disease 125– 6 dementia with Lewy bodies 127–8 frontotemporal dementia 126 –7 search strategy and study validation 125 vascular dementia 126 behavioral disturbance 672 aggression 441 agitation 360, 369, 441, 672, 705–7 treatment algorithm 721 treatment flowchart 721 noise-making 440 reduction of 440–1 treatment 369–70, 374 wandering 440–1, 706 see also psychosis behavioral therapies 438– 41 promoting independence 438– 40 activities 439 continence 439 environmental change 439 – 40 mobility 439 self care 438 reduction of problem behavior 440–1 aggression 441 agitation 441 noise-making 440 wandering 440–1 see also cognitive therapies benefits to patient diagnostic testing 24 treatment 363 Benton Tests 96 Temporal Orientation 98 Verbal Fluency 834 benzodiazepines 449, 678 – 81 adverse effects 680 clinical trials 679, 680 hypersexuality 709 Lewy body dementia 612 sleep disturbance 712 Berkley, Henry John 214 besipirdine 448

beta-amyloid 248, 450–1 metrifonate effects on 499 vaccine 451 bias 15 –16 Cochrane reviews 44 sources of 33 Binswanger, Otto 215–17, 216, 217 Binswanger’s syndrome 263, 270 biomarkers in mild cognitive impairment 349 see also cerebrospinal fluid biomarkers; genetic markers blinding 19, 82, 93, 790 double blind 34 single blind 34 blood pressure reduction 593–5 clinical trials 593–5, 594 prevention of dementia 661–2 BMY21 502 449 books 71 hybrid print/internet 73 Boston Naming Test 834 brain tumors 627–8 Burton, Robert 207–8 Bushke Selective Reminding Test 524 buspirone 680 –1, 681–2 adverse effects 681 clinical trials 681 consideration for treatment 681 rationale for treatment 681 treatment course 681 see also benzodiazepines Cajal, Ramon y 215 Cambridge Cognitive examination (CAMDEX) 418, 833, 834, 860 –1 captopril 647 carbamazepine 682–3 carbon monoxide poisoning 622 care options day care 819, 822, 823 cost of 849 group living 849 home-based care 849 hospital care 850 nursing home 801–10, 804–6 cost of 850 organization of care 811–27 community services 813–17, 814 –18 day care 819, 822, 823 memory clinics 823, 828–43 monitoring and evaluation 824 –5 population needs and service planning 812–13

respite care 817, 819, 820, 821 younger people with dementia 823 special care units 807–8, 850 care-giver interventions 764–94 carer training 769, 774–9, 774–8 combination interventions 779, 781–7, 788–9 counselling 779, 780, 788–9 double-blind studies 790 duration of follow-up 790–1 education 766–9, 767, 768, 779, 788–9 effectiveness of 765–6, 765 multiple comparisons 790 number of subjects 790 rationale 764–5 recruitment 790 specific issues 791 specificity 791 success of 791 support groups/programs 769, 770–3, 779, 788–9 timing of intervention 791 see also non-pharmacological interventions care-givers heterogeneity of 789–90 in treatment of dementia 368 Caregiver Quality of Life Instrument 849 case–control studies 14 choice of controls 15 cause and effect 16 CDP-choline 53–4, 596–9 adverse effects 598 age-associated memory impairment 648 clinical pharmacokinetics 598 clinical trials 596–8 attention 597 behavior 598 clinical global impression 598 memory 597 tolerability 598 consideration for treatment 598 rationale for treatment 596 treatment course 598 celecoxib 541 Celsus, Aulus Cornelius 203 central nervous system infections 616–20 herpes simplex encephalitis 616, 617 neurosyphilis 213–14, 214, 616, 618–20

882 INDEX

central nervous system infections (cont.) cognitive function in 619 and HIV 619–20 treatment 618–19 cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) 269, 272–3 cerebral hypoxia/anoxia 621–7 carbon monoxide poisoning 622 normal pressure hydrocephalus 624–7, 625, 626 sleep apnea 622 toxins heavy metals 622– 4 organophosphate compounds 624 solvents 624 cerebrospinal fluid biomarkers 175–9, 176 rationale for use 176 search strategy and study validation 177 see also genetic markers chemical restraints 802 Chiarugi, Vincenzo 210 chloral hydrate 712 chlormethiazole 612 cholinesterase inhibitors 448, 688–9, 688–90 ADAS-Cog 567 adverse effects 691 Alzheimer’s disease 570 clinical trials 408–9, 414, 688–9 analysis 409 inverventions 408 outcome measures 409 study design 408 types of patients enrolled 408 consideration for treatment 691 cost effectiveness 69 Lewy body dementia 608–10, 609, 610 clinical trials 608–10, 609, 610 rationale for treatment 608 number needed to treat 690 process of treatment 691 rationale for treatment 688 see also individual drugs chronic obstructive pulmonary disease 630 chronic renal failure 631 Cicero, Marcus Tullius 202 citalopram 695 citicoline see CDP-choline

class of evidence 82 classification of dementias 238–9, 239 classification of studies diagnostic tests 92–3 neuropsychological assessment 130 –2 clinical audit 74–85 cycle 75 definition 75 clinical decisions 365–72 administration 371 application of specific treatments 367 care givers’ role in treatment 368 cognitive therapies 370 criteria for 359–64 diagnosis 359 likelihood of treatment benefit 363 patient and family expectations 362 principal problems of patient 360 prognosis 360–2 groups versus individuals 366–7 monitoring of treatment effects 371–2 preventative therapies 370 rationale for treatment 365–6 treatment of behavioral changes 369–70 treatment of mood changes and depression 368–9 Clinical Dementia Rating 103, 864–5 clinical expertise 4 clinical global impression 36 CDP-choline 598 Gingko biloba 519, 521 idebenone 531, 535 nimodipine 538, 539 piracetam 546 propentofylline 550, 551–2 tacrine 511 clinical history 119–20 family history 119–20 nature of symptom onset and progression 119 risk factors 119 clinical significance 83–4 clinical trials age-associated memory impairment 647, 648–9 anti-thrombotics 590–1 anticonvulsants 682–5 antidepressants 695–6 antioxidant vitamins 471 anxiolytics 679, 680, 681 benzodiazepines 679, 680

blood pressure reduction 593–5, 594 cholinesterase inhibitors 688–9 cognitive symptoms and modification of prognosis 405–17 data extraction 406–7 search strategy and study selection 406 trials of cholinesterase inhibitors 408–9 trials for new therapies 409–13 trials prior to cholinesterase inhibitors 407–8 n-of-1 366, 417–27, 574–5 appropriate situations for 419, 420 choice of outcome 421–2 ethics 422 feasibility in dementia 420–1 inappropriate situations for 419–20 practical aspects of conducting 420 response and stopping rules 422–3 NSAIDs 542–5, 542, 543, 544 sources of bias 33 see also individual drugs Clinician’s Global Impression of Change 835 clock drawing test 834 clomipramine 709 hypersexuality 709 clonazepam 680 see also benzodiazepines clonidine 448 co-existing medical problems 725–43 assessment and management 726–7, 727 co-morbidity 728 delirium 728–9, 729 causes 729 management 147, 729 frequency of 728 frequent medical conditions 728 general health status 727 see also individual conditions Cochrane Collaboration 31 Cochrane Controlled Trials Register 72 Cochrane Dementia and Cognitive Impairment Group 5, 43, 44, 45–7 reviews 50–9, 72, 676 Cochrane Library 72 Code of Federal Regulations 377

INDEX 883

cognitive enhancement see cognitive therapies cognitive function 375, 422 and aging 640–3, 641 neurosyphilis 619 see also cognitive impairment cognitive impairment 673 age-related 342, 640 –3, 641 Alzheimer’s disease 447–9, 462, 463 Parkinson’s disease 315 vascular dementia 273, 277–8 see also mild cognitive impairment cognitive impairment no dementia (CIND) 345–6 cognitive therapies 370, 447–9, 461–6, 750–1 clinical trials 405–17 donepezil 477 galantamine 486 Gingko biloba 519, 520 hydergine 527 idebenone 531 metrifonate 494 nimodipine 538 propentofylline 549 –50, 551 rivastigmine 501 selegiline 554 tacrine 509, 510–11 thiamine 558, 559 cognitive–behavioral therapy 437– 8 Cohen–Mansfield Agitation Inventory 684, 835 cohort studies 15, 16, 26 community mental health teams 811 community resource teams 811 community services 813–17, 814 –18 comparison groups 82, 93 competence assessment 749 computed tomography 138 –54, 139–42, 143–4, 145–50, 153, 835–6 cost-effectiveness 153– 4 diagnostic value 143–4, 145–50 frontotemporal dementia 305 progressive supranuclear palsy 318 confidence 20 confounders 16 confusion see agitation consecutive recruitment 19 Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) 97, 109 continence 731–3 see also incontinence controls, choice of 15 Cooke, John 211

cortical atrophy 272 corticobasal degeneration syndrome 300, 301–2, 319–20 cost minimization analysis 65, 66 cost studies 845–7, 846, 847 cost-benefit analysis 65, 66 cost-effectiveness 4, 83–4 computed tomography 153–4 of interventions 64, 65, 66 see also health economics cost-effectiveness axis 65 cost-of-illness studies 847–8 cost-utility analysis 65, 66 counselling of caregivers 779, 780, 788–9 genetic 795– 800 COX see cyclo-oxygenase COX-2 inhibitors 452 see also non-steroidal antiinflammatory drugs cranial nerve examination 120 Creutzfeldt–Jakob disease 221, 321–2 EEG 173– 4, 173 critical appraisal 12–13, 45 CSF-Aβ42 178 –9, 178 CSF-tau protein 177, 178 Cullen, William 209 Current Contents 72 cyclo-oxygenase 541–2 d-cycloserine 516–18 age-associated memory impairment 647 animal studies 516, 517 clinical trials 517–18 glutamatergic transmission and memory 516, 517 human studies 516–17 lack of effect 561 cytidine-5′-diphosphocholine see CDP-choline da Vinci, Leonardo 205 data collection 77 day care 819, 822, 823 cost of 849 death 739 nutrition and hydration 751–3 definition of dementia 199 Dejerine, Joseph Jules 220 Delayed Word Recall Test 97 delirium 728–9, 729 causes 729 management 729 dementia with Lewy bodies see Lewy body dementia dementia of motor neurone type 302 dementia paralytica 199

dementia praecox 199 dementia pugilistica 620 Dementia Rating Scale 97 dementia subtype 106–96 clinical criteria 106–19 diagnosis 195 see also individual types of dementia dementia-free life expectancy 243 Dependence Scale 865–6 depression and dementia 333–4 EEG 174–5 treatment see antidepressants desglycinamide 647 diabetes mellitus 630 diagnosis 81–5, 194, 359 Alzheimer’s disease 106–13, 112, 229–34, 230, 231 dementia subtype 106–96, 195 behavioral characteristics 124–9 cerebrospinal fluid biomarkers 175–9 clinical criteria 106–19 clinical history and neurological signs 119–24 computed tomography 138–54, 139–42, 143–4, 145–50, 153 EEG 170–5 functional imaging 162–70 genetic markers 133–8 magnetic resonance imaging 154–62 neuropsychological assessment 129–33 economics of 848–9 screening 848–9 testing 848 evidence-based 18–25 features consistent with 855 guidelines 86–91 initial assessment 87 Lewy body dementia 289–90, 289, 856 neuropsychological assessment 92–101 NIH concensus recommendations 90 NINCDS-ADRDA 855 Pick’s disease 856 possible Alzheimer’s disease 855–6 recommendations 87–8 study validation 81–3, 82 triggering symptoms 87 vascular dementia 113–15, 114, 260–2, 261, 856–8 see also diagnostic tests diagnostic bias 15

884 INDEX

diagnostic criteria 855– 8 Diagnostic and Statistical Manual 18 diagnostic tests acceptability of 18 applicability of results 23 – 4 clinical significance 83– 4 dementia 84 dementia subtype 84 –5, 84 evaluation 88, 89 properties of 20 validity of 18 diagnostic truth-telling 748 diazepam 680 see also benzodiazepines diethylstilbestrol 709 dihydroepiandrosterone studies 51–2 bias in 44 Disability Assessment for Dementia (DAD) 486, 495, 835, 866 disease-modifying treatment 385, 387, 462 divalproex sodium 450, 683– 4 donepezil 453, 690 adverse effects 479 – 80, 562 monitoring of 480 –1 Alzheimer’s disease 473 – 83, 690 benefits 481–2, 482, 562 clinical pharmacokinetics 479 clinical trials 51, 474 – 8, 475, 483 bias in 44 cognitive enhancement 750 consideration for treatment 478 cost of treatment 851 economic evaluation 398–9 efficacy 398, 560, 562 exclusion from treatment 478–9 Lewy body dementia 609 –10, 610 MTRAC prescribing 394 number needed to treat 478, 482 patient characteristics and treatment outcomes 397 pharmacodynamics 479 postcode prescribing 393 rationale for treatment 474 treatment course 480 dose–response effects 16 dotage 200, 203, 208 driving 755–63 driver assessment 757–9 driving cessation 760 –1 impact of dementia on 756 –7 interventions 759– 60 physician’s advice 760 screening for dementia 761 transportation needs of patients 756 type of dementia 757

drug intervention studies 10 cost-effectiveness 64 evidence-based 31–41 grading recommendations 10, 32 see also clinical trials; and individual drugs drug-induced dementia 334–5, 334 DSM-III criteria 116 Alzheimer’s disease 230 DSM-IV criteria Alzheimer’s disease 230 vascular dementia 262, 264, 856 duty of care 747 echolalia 308 ecological studies 15 economic evaluation 64–70 drug interventions 398–9 results 67– 8 applicability of 68 validity of 66–7 types of analysis 65, 66 see also health economics education of caregivers 373, 766–9, 767, 768, 779, 788–9 EEG see electroencephalography effect modification 16 efficacy of treatment antipsychotics 675–6, 703–4 assessment 376–427 criteria used by purchasers of healthcare services 387–405 Food, Drug and Cosmetic Act 376 regulatory guidelines 376–87 see also individual drugs electrocardiogram 835 electroencephalography 170–5, 835 Alzheimer’s disease versus normal aging 171–2 Creutzfeldt–Jakob disease 173–4, 173 depression 174–5 frontal lobe dementia 172–3 frontotemporal dementia 172–3 Lewy body dementia 174 methods 171 vascular dementia 172 electronic search strategies 9 EMBASE 71, 615 empirically validated treatments 32 encephalitis lethargica 221 environmental change 439–40 environmental needs 373–4 epidemiology Alzheimer’s disease 238–40 psychosis 700 vascular dementia 265–8

epistagmine 561 Erasistratus of Chios 202 Esquirol, Jean Etienne Dominique 211–12, 212 estrogen 523–6, 709 adverse effects 525 clinical pharmacokinetics 525 clinical trials 524 consideration for treatment 524–5 exclusion from treatment 525 hypersexuality 709 prevention of dementia 656–7, 657 rationale for treatment 523–4 treatment course 525–6 ethics n-of-1 trials 422 research 748–9 see also social and ethical issues ethnicity effects 16 etiology 238–9, 239 Alzheimer’s disease 238–9, 239 evidence-based 14–17 Lewy body dementia 293 European Medicines Evaluation Agency 376 evaluation of dementia 673–4 NIH concensus recommendations 90 evidence 122–4 Alzheimer’s disease 109, 112, 125–6, 171–2 class of 82 frontotemporal dementia 118, 127, 172–3 functional impairment 103 Lewy body dementia 117, 127, 174 neuropsychological assessment 94–8 parkinsonian symptoms 128 sources of 71–3 bibliographical sources 71–2 books 71 Cochrane Library 72 dementia journals 72 evidence-based dementia practice 8, 9, 10, 11 hybrid print/internet books 73 Internet 72–3 vascular dementia 115–16, 126, 172 see also clinical trials; and individual drugs evidence-based audit 74–8, 75 evidence-based cardiology 4 evidence-based dementia practice 3–4 compliance with protocols 76–7 finding of evidence 6–11

INDEX 885

implementation of 76 parameters 87 evidence-based diagnosis 18–25 evidence-based etiology 14 –17 evidence-based interventions 31– 41 evidence-based medicine 3, 5 evidence-based nursing 4 evidence-based prognosis 26 –30 evidence-based public health 4 evidence-based surgery 4 executive function 233 expert opinion 86–7 external validity 12–13 extrapyramidal signs 120 falls 731–3 false negative rate 20 false positive rate 20 family expectations 362–3 family history 119–20 FD & C Act see Federal Food, Drug and Cosmetic Act feedback of findings 77 feeding problems 733– 4 finding of evidence 6–11 FK 960 448 flesinoxan 648 fluvoxamine 621 focal neurologic signs 120 folate deficiency dementia 336, 337, 628 follow-up 27–8 follow-up bias 16, 33 Food and Drug Administration 376 Food, Drug and Cosmetic Act 376 –7 fractures 731–3 frontal lobe dementia, EEG 172–3 frontal lobe tumors 280 frontotemporal dementia 118–19, 297–311 behavioral characteristics 126 –7 case history 307–8 clinical criteria 118 clinical features 298–300 corticobasal degeneration syndrome 300 frontotemporal dementia syndrome 298–9 primary progressive aphasia 299 diagnostic criteria 306 –7 diagnostic tests imaging 305–6 neuropsychology 306 differential diagnosis 280, 306 –7 EEG 172–3 evidence 118, 127, 172–3 familial 137

genetic markers 137 historical aspects 221 incidence and prevalence 305 pathogenic mechanisms 304–5 pathological criteria 118 search strategy and study validation 118 structural substrates 300–3 Alzheimer-type pathology 303 basophilic inclusion body disease 302 common structural lesions 301 corticobasal degeneration 301–2 dementia lacking distinctive histology 302 dementia of motor neurone disease type 302 dementia with Pick bodies 301 progressive subcortical gliosis 303 tau protein alterations in 303–4 basic biology 300 frontotemporal dementia syndrome 298– 9 functional activities questionnaire 87 Functional Assessment Staging Tool 835 functional imaging 162–70 clinical background 162–4, 163 evidence 165–9, 166, 168 research recommendations 169–70 search strategy and study validation 164 –5 see also computed tomography; magnetic resonance imaging functional impairment 101–4 evidence 103 recommendations for practice 103 search strategy 102 Functional Performance Measure 835 gabaminergic agents 612 gait disturbance 120 galantamine 484–93, 484, 690 adverse effects 488–9, 563 monitoring of 489, 492 benefits 492–3, 563 clinical pharmacokinetics 488 clinical trials 485–7, 489, 490–1 5– 6 month 485–6 10 –12 week 485 cognition 486 functional activity 486–7 global rating 486, 487 mood and behavior 486 consideration for treatment 487–8

efficacy 560, 563 exclusion from treatment 488 number needed to treat 487, 493 rationale for treatment 485 treatment course 489 Galen of Pergamum 203 gamma-secretase 450 gender effects 16 genetic counselling 795–800 autosomal dominant inheritance 797–9, 798 cases requiring referral 797–9, 798 markers for dementia 796 predictive genetic testing 799 risk/protective factors 797 genetic factors Alzheimer’s disease 249 mild cognitive impairment 349–50 vascular dementia 272–3 see also genetic markers genetic markers 133–8, 348–9 Alzheimer’s disease 133–7 apolipoprotein E 134–5, 136, 137 presenilin mutations 133–4, 135, 137 familial frontotemporal dementia 137 hereditary vascular dementia 127–8 genetic risk 749 genetic testing 655–6, 799 Geriatric Depression Scale 835, 868–9 Gingko biloba adverse effects 521–2, 564 age-associated memory impairment 647, 648, 649 Alzheimer’s disease 518–23 benefits 564 clinical pharmacokinetics 521 clinical trials 519–21, 520 consideration for treatment 521 efficacy 560, 564 exclusion from treatment 521 rationale for treatment 518–19 treatment course 522 vascular dementia 599 ginseng 647, 649 Global Deterioration Scale 863–4 global rating donepezil 477 galantamine 486, 487 hydergine 527, 528 metrifonate 494 rivastigmine 504, 508 selegiline 554, 557

886 INDEX

glycine 649 gold standard 18, 20, 31, 82 Golgi, Camillo 215 grading information 10, 11 interventions 32 group living, cost of 849 GTS-21 448 guanfacine 448, 647 guidelines 60–3, 84, 88, 376 – 87, 386 antidementia 378–9 applicability of 62 clinical 60 consensus 86–7 definition 60 development of 378– 80 events confounding 381–2 history 378 proposed strategy 379–80 scope of guidance 379 diagnostic 86–91 FD & C Act 376–7 pseudospecific antidementia claims 380–1 recommendations 62 scope of 379 sources of dissatisfaction 382– 4 global component of dual assessment strategy 382– 4 political and regulatory concerns 382 validity of 61 Hachinski Ischemia Score 115 vascular dementia 274 haloperidol 676, 677 Haly Abbas 204 Haly Regalis 204 Hammond, William Alexander 213 health economics 844 –54 cost studies 845–7, 846, 847 cost-of-illness studies 847– 8 day hospital care 849 –50 diagnosis screening 848–9 testing 848 drug interventions 850 –2, 851 group living 849 home-based care 849 hospital care 850 methods 845 nursing home care 850 health maintenance 374 heavy metal poisoning 622 – 4 Herophilus of Calcedonius 202 herpes simplex encephalitis 616, 617

heterogeneity of caregivers 789–90 of patients 789 hippocampal dementia 155 hippocampal volumetry 157, 159, 160 Hippocrates 201–2 Hirano bodies 244 histopathology 214–15 history of dementia 199–227, 200 ancient era 199 classic era 200–3 6th century BC 200–1 5th century BC 207–8 3rd century BC 202 2nd century BC 202 1st century BC 202 1st century AD 203 2nd century AD 203 middle ages 204–7, 205, 206 16th century 206–7 modern era 214–22, 215 arteriosclerotic insanity 217–19, 218 cellular neuroanatomy and histopathology 214–15 Creutzfeldt–Jakob disease 221 Huntington’s chorea 220–1 Lewy body dementia 221 Pick’s disease and frontotemporal dementias 221 senile dementia and Alzheimer’s disease 219–20 vascular dementia 215–17, 216, 217 scientific era 207–14, 207 17th century 207–9, 208 18th century 209–10 19th century 210–14, 212 neurosyphilis 213–14, 214 HIV, and neurosyphilis 619–20 HIV-1 encephalitis 321 HIV-1 leukoencephalopathy 321 HIV-1-related dementia 320–1 HOE 427 648 home-based care, cost of 849 Hopkins Verbal Learning Test 834 Houel, Charles 212–13 human immunodeficiency virus see HIV humours 201 Huntington’s chorea 128, 220–1, 316 –17 positron emission tomography 317 huperzine A 647 hybrid print/internet books 73

hydergine adverse effects 529 Alzheimer’s disease 526–30 clinical pharmacokinetics 529 clinical trials 54, 527–8, 528 consideration for treatment 528–9 efficacy 561 exclusion from treatment 529 number needed to treat 528 rationale for treatment 527 treatment course 529 vascular dementia 599 hydration 751–3 hydrocephalus 139 hyperparathyroidism 628–9 hypersexuality 707–11 case studies 710 management of 707–9, 709, 710 prevalence 707, 708 hypertension control see blood pressure reduction hyperthyroidism 335 hypocortisolism 629–30 hypoparathyroidism 628–9 hypopituitarism 629 hypothyroidism 335, 629 ICD-10 criteria Alzheimer’s disease 230 vascular dementia 262, 264, 856–7 idebenone 452, 530–5 adverse effects 533 monitoring of 533 clinical pharmacokinetics 533 clinical trials 530–1 behavior 531 clinical global impression 531 cognition 531 dependency 531 functional activity 531 response to treatment 531 consideration for treatment 532 development problems 561 exclusion from treatment 532–3 number needed to treat 531–2, 532, 534 rationale for treatment 530 treatment course 533 imaging studies 162–70 frontotemporal dementia 305–6 mild cognitive impairment 348 vascular dementia 261, 263–4 see also functional imaging implementation of changes 77 incident cases 15

INDEX 887

incontinence 734–8 assessment 735, 736 behavioral therapy 439 causes 735 incidence and prevalence 735 management and treatment 735, 735–8, 737 morbidity 738 pathology 735 prognosis 738 symptoms and signs 735, 736 incremental value 83 independent assessment 19 indicators 76 indomethacin 648 infectious dementias 320 –2 information bias 15–16 informed consent 748–9 insomnia see sleep disturbance institutionalization rate 243 insulin-like growth factor-I 452 intention to treat 34, 47 internal validity 12–13 internet sources 72–3 intervention studies see drug intervention studies Interview for Deterioration in Daily Living Activities in Dementia (IDDD) 867 intracranial space-occupying lesions 280, 332–3 intravascular lymphomatosis 628 Jackson, John Hughlings 213 journals 72 Kaplan–Meier survival curves 28 knowledge base 373 Korsakoff’s syndrome 620, 621 Kraepelin, Emil 217 Labyrinth Test 96 language disturbance see aphasia lazabemide 452 lead poisoning 623 lecithin studies 54–5 leuprolide acetate 708–9, 709 hypersexuality 709 levadopa 612 Lewy body dementia 116 –17, 221, 288–96 behavioral characteristics 127–8 case history 288 clinical criteria 116 –17, 290 –2 definition 289 diagnosis 289–90, 289, 856 diagnostic criteria 294

differential diagnosis 280 EEG 174 etiology 293 evidence 117, 127, 174 incidence and prevalence 292, 293 pathological criteria 117 prognosis 294, 362 search strategy and study validation 117 treatment 608–14 antiparkinsonian agents 611–12 cholinesterase inhibitors 608–10, 609, 610 gabaminergic agents 612 neuroleptics 610–11 versus Alzheimer’s disease and Pick’s disease 123–4 likelihood ratio 21, 82–3 neuropsychological assessment 93 nomogram 22 linopirine 648 lithium 709 hypersexuality 709 liver disease 630–1 lorazepam 680 see also benzodiazepines loss of function in Alzheimer’s disease 233 magnetic resonance imaging 154–62, 835– 6 frontotemporal dementia 305–6 Parkinson’s disease 314–15 progressive supranuclear palsy 318 search strategy and study validation 155– 6 vascular dementia 261 manganese poisoning 623 markers cerebrospinal fluid 175–9, 176 for dementia 796 genetic 133– 8 mild cognitive impairment 349 matched t-test 423 MCK-231 448 medial temporal lobe atrophy 155, 157 magnetic resonance imaging 154–62 medical problems see co-existing medical problems Medline 9, 61, 71, 615 medroxyprogesterone acetate 708, 709 mega-trials 31 melatonin 450, 451 memantine 448, 453

memory clinics 823, 828–43 activities of 832–6, 832, 834, 835, 836 audit 831, 832 background 828–9 functioning of 831–2, 832 future development 837–9, 838, 839 minimum dataset 838–9 setting up 829–36 staffing 820–31, 831 memory deficit 232 Parkinson’s disease 314 see also age-associated memory impairment Memory Impairment Screen 96 memory training 435–6 mental state examination 832–3 mental status test 87 mercury poisoning 623 meta-analyses 12, 42–59 dementia prevalence rates 242 metrifonate 493–9, 689–90 adverse effects 496 cholinergic 496–7 potential neurotoxicity 497 and beta-amyloid processing 499 clinical pharmacokinetics 496 clinical trials 494–5 cognition 494 functional activity 495 global rating 494 mood and behavior 494–5 consideration for treatment 495 exclusion from treatment 495–6 number needed to treat 495, 498 pharmacodynamics 496 rationale for treatment 494 toxicity 561 treatment course 497–8 milacemide 647, 648 mild cognitive impairment 84, 341–54, 342 biological markers 348–9 burden 346 clinical picture 343–4 definition and diagnostic criteria 342–3 diagnostic tools global scales 344 psychometric test performance 344–5, 344 genetics 349–50 incidence 345 neuroimaging 348 neuropathology 348–9 prevalence 345–6

888 INDEX

mild cognitive impairment (cont.) prognosis 346–8, 347, 361 risk factors 346 subtypes of 350–1, 351 treatment 351 Mini Mental Status Examination 6, 33–4, 66, 96, 683, 833, 834, 859–60 intervention studies 37 Lewy body dementia 289 vascular dementia 261 MMSE see Mini Mental Status Examination mobility 439, 731–3 moclobemide 648 montirelin 449 mood changes, treatment 368–9 morbidity, prolongation of 750 –1 Morel, Benoit Agustin 212 Morgagni, Giovanni Battista 210 morosis 203 mortality Alzheimer’s disease 234, 241 vascular dementia 265 Moses ben Maimonides 204 MTRAC 394, 401 multi-infarct dementia 113 versus Alzheimer’s disease 122 multiple system atrophy 319 multisystem atrophy 280 music therapy 59 Myerson’s sign 121 myoclonus 121 n-of-1 trials 366, 417–27, 574 –5 appropriate situations for 419, 420 choice of outcome 421–2 behavior 422 care giver burden 422 clinical global improvement 421 cognition 422 function 422 individual goal attainment skills 421 ethics 422 feasibility in dementia 420 –1 inappropriate situations for 419–20 practical aspects of conducting 420 response and stopping rules 422–3 National Adult Reading Test 833 National Institute for Clinical Excellence 43, 65, 390 –2 access to new treatments 391–2 criteria used by 391

guidance produced by 391 prescribing with limited resources 392 role of 390 NBI-30775 449 negative predictive value 82 nerve growth factors 452 neuroanatomy 214–15 neurofibrillary tangles 107, 176 Alzheimer’s disease 245–7 neuroleptic sensitivity syndrome 610 –11 neuroleptics atypical 449 Lewy body dementia 610–11 see also individual drugs neurological examination 120–1 alternating hand sequences 121 apraxia 121 cranial nerves 120 extrapyramidal signs 120 focal motor or sensory signs 120 gait disturbances 120 myoclonus 121 pathological reflexes 121 neurological management 374–5 neuropil threads 246 Neuropsychiatric Inventory (NPI) 835, 867–8 neuropsychiatric symptoms 233 neuropsychological assessment 87, 92–101, 129–33, 833–4, 833, 834, 835 classification of studies 93–4 clinical significance 98 diagnostic accuracy 95 evidence 94 –8 frontotemporal dementia 306 patient referral 99–100 recommendations 98–101, 99, 132 research issues 100–1, 132–3 search strategy 92, 129, 130 study validation 92–3, 129, 130 neuroregeneration 461, 462 neurosyphilis 213–14, 214, 616, 618 –20 cognitive function in 619 and HIV 619–20 treatment 618–19 nicardipine 453 NICE see National Institute for Clinical Excellence nicotine 535–7 adverse effects 536–7 clinical pharmacokinetics 536 clinical trials 55–6, 536 consideration for treatment 536

efficacy 561 rationale for treatment 535–6 NIH consensus recommendations 90 nimodipine adverse effects 540 Alzheimer’s disease 537–40 clinical global impression 538, 539 clinical trials 55, 538 consideration for treatment 540 efficacy 561 number needed to treat 539 rationale for treatment 537–8 vascular dementia 600 NINCDS-ADRDA criteria 230 NINDS-AIREN criteria 116 vascular dementia 262–3, 264, 857–8 noise-making 440 non-pharmacological interventions 57–9, 428–30 behavioral approaches 438–41 promoting independence 438–40 reducing problem behavior 440–1 cognitive–behavioral therapy 437–8 memory training 435–6 music therapy 59 reality orientation 58, 430–2 reminiscence therapy 58–9, 433–4 stimulation 436–7 subjective barriers to prevent wandering 59 support for carers 59 validation therapy 57–8, 434–5 non-randomized clinical trials, sources of bias 33 non-steroidal anti-inflammatory drugs 541–6 adverse effects 545 clinical trials 542–5, 542, 543, 544 consideration for treatment 545 efficacy 561 prevention of dementia 656 rationale for treatment 541–2 treatment course 545 nootropics 449 normal aging 122 EEG 171–2 normal pressure hydrocephalus 279–80, 332–3, 624–7, 625 outcome 625–6, 626 predictors of response 626–7 NSAIDs see non-steroidal antiinflammatory drugs null hypothesis 36

INDEX 889

number needed to treat 39, 40, 46, 366, 418 acetyl-l-carnitine 469, 470 anticonvulsants 686 antidepressants 697 cholinesterase inhibitors 690 donepezil 478, 482 galantamine 487, 493 hydergine 528 idebenone 531–2, 532, 534 metrifonate 495, 498 nimodipine 539 propentofylline 550 –1, 552 rivastigmine 504, 509 selegiline 555, 557, 688 tacrine 509–10, 512–13, 513 nursing home care 801–10 cost of 850 discrete elements of care 808 evaluation of integrated programs 807–8 evidence 802–8, 804–6 reductions of physical and chemical restraint 802–7, 804–6 search and selection strategy 802 occupational risk factors 657–9, 658 odds ratio 35, 121, 123 olanzapine 449, 677, 677–8, 705 Old Americans Resources and Services Procedures 103 ondansetron 647 options 88 organization of care 811–27 components of dementia service community services 813–17, 814–18 day care 819, 822, 823 memory clinics 823, 828– 43 respite care 817, 819, 820, 821 younger people with dementia 823 monitoring and evaluation of services 824–5 population needs and service planning 812–13 organophosphate poisoning 624 Oribasius of Pergamum 204 orientation disturbance 232 outcome clinical importance of 39 probability over time 28–9, 29 see also results outcome criteria 28 oxazepam 679 see also benzodiazepines

Oxford Project to Investigate Memory and Ageing (OPTIMA) 109, 165 Paracelsus 206 –7 paraneoplastic limbic encephalopathy 628 parkinsonian symptoms 128 Parkinson’s disease 280, 289, 312–16, 313 cognitive impairment in 315 magnetic resonance imaging 314 positron emission tomography 314 risk factors for dementia 314 see also Lewy body dementia paroxetine 709 hypersexuality 709 pathological reflexes 121 patient expectations 362 patient selection 27 appropriate spectrum of disease 19 random versus consecutive 19 patient selection bias 33 patient support groups 836 patients benefit to 24 representative sample 27 stage of dementia 27 willingness to participate 24 pentoxifylline 453 adverse effects 602 clinical trials 600–2, 602 consideration for treatment 602 rationale for treatment 600 vascular dementia 600–2 pharmaceutical lobbying 402–3 phosphatidylserine 647 phrenitis 208 physical restraints 802–3, 804 Physical Self Maintenance Scale 683 Pick bodies 301 Pick complex see frontotemporal dementia Pick’s disease 221, 238 diagnosis 856 pindolol 709 hypersexuality 709 Pinel, Philippe 210 piracetam adverse effects 547 age-associated memory impairment 647, 648 Alzheimer’s disease 546–8, 546 clinical global impression 546 clinical trials 52–3, 546–7 consideration for treatment 547 efficacy 561

rationale for treatment 546 vascular dementia 603 placebo effect 34 placebos 34 Plato 201 population needs and service planning 812–13 posatirelin 449, 453 positive predictive value 82 positron emission tomography 162–70 clinical background 162–4, 163 evidence 165–9, 166, 168 Huntington’s chorea 317 Parkinson’s disease 314 research recommendations 169–70 search strategy and study validation 164–5 post-test probability 21–3, 22, 83 postcode prescribing 393 precedent autonomy 748 precision 29 predictive genetic testing 799 presenilins 133 mutations 133–4, 135, 137 pretest probability 19, 20–1 age-based 83 estimation of 23 preventative treatment 370, 375, 654–66 approaches to 654 levels of evidence 654–5 medical history factors 659, 660 medications anti-inflammatory drugs 656 antioxidants 657, 658 estrogen replacement 656–7, 657 occupational risk factors 657–9, 658 predictive genetic testing 655–6 preventive strategies 655 vascular dementia 659–63, 661 antiplatelet treatment 660–1 control of hypertension 661–2 improvement in society 663 risk factors 662–3 Primary Care Groups 392 prions 239 problems of dementia patients 360 prognosis 360–2 evidence-based 26–30 incontinence 738 Lewy body dementia 294, 362 mild cognitive impairment 346–8, 347, 361 see also individual drugs prognosis modification 463, 464

890 INDEX

prognostic factors 26 applicability of results 29 prognostic models 29–30 prognostic variables 28 Progressive Determination Scale 504 progressive subcortical gliosis 303 progressive supranuclear palsy 239, 280, 318 propentofylline 452 adverse effects 552–3 Alzheimer’s disease 548–53 clinical global impression 550, 551–2 clinical pharmacokinetics 552 clinical trials 548–52 consideration for treatment 552 development problems 561 exclusion from treatment 552 number needed to treat 550 –1, 552 rationale for treatment 548 treatment course 553 vascular dementia 603 prospective studies 93 protein kinase C 450 protirelin 449 pseudospecific drug effects 380 –1 psychiatric diagnosis 673 Psychlit 72 psychosis 671–4, 671, 698–705, 699 complications of 701 and dementia progression 701, 702 demographic/clinical factors 700–1, 702 rate of cognitive decline 701 rate of functional decline 701 survival 701 epidemiology 700 etiology 701, 703 evaluation of 673– 4 frequency of 472 interpretation of published data 699–700 longitudinal course 699 management of 673– 4 phenomenology 698– 9 prevalence 700–1 treatment see antipsychotics psychosocial factors 673 psychotropic drugs 675–94 anticonvulsants 682– 6 adverse effects 685– 6 carbamazepine 682–3 clinical trials 682–5 divalproex sodium 683– 4 number needed to treat 686 anticonvulsants consideration for treatment 685

antipsychotics atypical 677–8, 704–5 conventional 675–6, 675–7, 703– 4 anxiolytics 678–82 benzodiazepine 678–81, 679, 680 buspirone 681–2 atypical antipsychotics 677–8 cholinesterase inhibitors see cholinesterase inhibitors conventional antipsychotics 675–7 efficacy and safety 675–6 duration of treatment 676–7 see also individual drugs purchasing of drug treatments 387– 405 AD2000 trial 394, 395 distributive justice 392, 395–8, 397 prescribing with limited resources 392 UK Government position 390–2 USA Government position 402–3 see also National Institute for Clinical Excellence pyroglutamic acid 648 Pythagoras 200 quality of life 363, 750–1 quality-adjusted life years 66, 153, 396, 849 questions, formulation of 6, 7, 8 quetiapine 449, 678 random effect models 45 random recruitment 19 randomized controlled trials 32 paucity of, grading information 11 sources of bias 33 rapid eye movement 127 rationale for treatment 365–6 see also individual drugs Raven’s Coloured Progressive Matrices 306 reality orientation 58, 430–2 receiver-operating characteristic (ROC) curves 22, 83, 96 regulatory guidelines see guidelines Relatives Stress Scale 835 reminiscence therapy 58–9, 433–4 research ethics 748–9 respect for patients 747 respite care 817, 819 clinical trials 820 cohort studies 821

results 16 applicability of 16–17 computed tomography 151–3 diagnostic tests 23–4 economic evaluation 68 intervention studies 37–9 prognostic tests 29 effect on clinical management 23–4 intervention studies 35–7, 36, 37 precision of 29 quality of 19–23, 20, 22 validity of, economic evaluation 66–7 see also outcome; and individual drugs retrospective studies 93 reversible/arrestable dementias 330–40 definition 330–1 depression 333–4 differential diagnosis 332 drug-related 334–5, 334 evidence for 331 folate 336, 337 normal pressure hydrocephalus 332–3 prevalence of 331–2, 331, 333 thyroid 335 treatment 615–38 sources of evidence 615 vitamin B12 336, 337 Rey Auditory Verbal Learning Test 94 Rey Osterrieth Complex Figure Test 834 risk assessment 16 risk factors 119, 122, 123 Alzheimer’s disease 123, 240–1 genetic 797 mild cognitive impairment 346 vascular dementia 123, 240–1, 268–9 risk ratio 35 risk–benefit analysis 38, 39– 40 risperidone 449, 677, 704–5 rivastigmine 450, 453, 499–509, 690 adverse effects 506, 563 benefits 509, 563 clinical pharmacokinetics 505–6 clinical trials 56, 500–4, 502–3 cognition 501 efficacy measures 501 functional activity 504 global rating 504, 508 mood and behavior 504 patients included in 501 consideration for treatment 505

INDEX 891

efficacy 398, 560, 562 –3 exclusion from treatment 505 number needed to treat 504, 509 pharmacodynamics 506 rationale for treatment 499 –500 treatment course 506 – 8, 507, 508 robustness of data 5 ROC curves see receiver-operating characteristic (ROC) curves rofecoxib 541 Rush, Benjamin 210 S-8510 449 S-12024 648 sabeluzole 453 Saint Isidore of Seville 204 sample selection 76–7 Scottish Intercollegiate Guidelines Network 68 screening tests 98–9 search engines 72–3 search strategies 8–11, 9, 121–2, 125 Alzheimer’s disease 107, 108, 110–11, 171 behavioral characteristics 125 cerebrospinal fluid biomarkers 177 cognitive symptoms 406 computed tomography 142, 144 diagnosis 92 electronic 9 frontotemporal dementia 118 functional imaging 164 –5 functional impairment 102 Lewy body dementia 117 magnetic resonance imaging 155– 6 neuropsychological assessment 92, 129, 130 vascular dementia 115 second childhood 200 seizures 730–1, 731 causes 731 selection bias 15, 33 traditional reviews 43 selegiline 471–2, 553–7, 686 – 8 adverse effects 555– 6, 566, 688 Alzheimer’s disease 553–7 benefits 565 clinical pharmacokinetics 555 clinical trials 37, 50 –1, 554 –5, 556 bias in 44 cognition 554 functional activity 554 –5 global rating 554, 557 mood and behavior 554 consideration for treatment 555, 687 efficacy 560, 565–6

exclusion from treatment 555 number needed to treat 555, 557, 688 process of treatment 688 rationale for treatment 553–4 treatment course 556 self-care 438 semantic dementia 299 senile dementia 219–20 senile plaques 176 senium 200 sensitivity 20, 22–3, 82 sequence of testing 24 serotoninergic compounds 448 alcohol-related dementia 621 sign test 423 single photon emission computed tomography 162–70 clinical background 162– 4, 163 evidence 165–9, 166, 168 research recommendations 169–70 search strategy and study validation 164 –5 SL65.0102 448 sleep apnea 622 sleep disturbance 711–15, 711–19 prevalence 711–12 treatment 712–14, 712–15, 712, 713, 713–14, 714 snoezelen 436 social and ethical issues 747–54 cognitive enhancing drugs 750–1 diagnostic truth-telling and precedent autonomy 748 dying well 751–3 morbidity protraction 750–1 quality of life 750–1 research ethics and informed consent 748–9 respect and care 747 social needs 373–4 solvent poisoning 624 Sophocles 201 sources of evidence 8, 9, 10, 11, 71–3 bibliographical sources 71–2 books 71 Cochrane Library 72 dementia journals 72 hybrid print/internet books 73 internet sources 72–3 special care units 807–8 cost of 850 specificity 20, 22–3, 82 standards 88 Steel–Richardson–Olszewski syndrome see progressive supranuclear palsy

stimulation 436–7 stroke risk factors 268–9 and vascular dementia 269 white matter changes 270 see also vascular dementia Stroop Test 313 study design 8 cholinesterase inhibitors 408 study selection bias 33 study validity 9, 10, 81–3, 82, 121–2, 125 Alzheimer’s disease 107, 108, 110–11 cerebrospinal fluid biomarkers 177 computed tomography 144, 151 diagnosis 18–19, 81–3, 82, 92–3 frontotemporal dementia 118 functional imaging 164–5 interventions 34–5 Lewy body dementia 117 magnetic resonance imaging 155–6 prognosis 27–8 vascular dementia 115 subgroup analyses 45 unreliability of 37–8 subjective barriers to prevent wandering 59 sulodexide 453, 591 support for carers 59, 779, 788–9 support groups 769, 770–3 surrogate gold standard 82 survival bias 15 Syndrom Kurztest 549, 862–3 Syndrome Short Test 549, 862–3 systematic reviews 42–59 definition 42 T-588 448 TA-0910 449 tacrine 689 adverse effects 514, 564 monitoring of 514–15 Alzheimer’s disease 509–16, 689 benefits 564 clinical pharmacokinetics 514 clinical trials 46, 50, 510–13, 511 consideration for treatment 513–14 dose 514 drug interactions 514 efficacy 560, 563–4 Lewy body dementia 609 number needed to treat 509–10, 512–13, 513 rationale for treatment 510 treatment course 514–15 taltireline 449

892 INDEX

tau gene 300 mutation-associated diseases 303–4 tau protein 245 Alzheimer’s disease 177 basic biology 300 cerebrospinal fluid 177–9, 178 frontotemporal dementia 300, 303–4 isoforms of 303 phosphorylation 451 variants of 304 Tayside Profile for Dementia Planning 813 testosterone 449 thiamine 557–9 adverse effects 559 clinical trials 56–7, 558–9 cognitive therapies 558, 559 efficacy 561 rationale for treatment 558 thioridazine 57, 676, 677, 680 see also benzodiazepines thyroid disease 335 thyrotropin releasing hormone 449 time of testing 24 Titus Lucretius 202 Tower of London task 313 traditional reviews 43 Trail Making Test 96, 834 training for care-givers 769, 774 –9, 774–8 traumatic brain injury 620 treatment access to 392–5, 393, 394, 395 age-associated memory impairment 639–53 aims of 357 Alzheimer’s disease 467, 566 –9, 567, 568 acetyl-l-carnitine 468–70, 469 antioxidant vitamins 471–3 benefits and harms 562– 6 cessation of 573 d-cycloserine 516 –18 donepezil 473–83 efficacy of 560, 561, 570 –3, 572 estrogen 523–6 galantamine 484 –93 Gingko biloba 518–23 hydergine 526–30 idebenone 530–5 metrifonate 493 –9 monitoring of 570 nicotine 535–7 nimodipine 537– 40 NSAIDs 541–6

patient eligibility and suitability 569–70 piracetam 546–8, 546 prognosis-modifying 575–6 propentofylline 548–53 rivastigmine 499–509 selegiline 553–7 tacrine 509–16 thiamine 557–9 treatment algorithm 574 see also individual drugs application of 367 behavioral changes 369–70 cerebral hypoxia/anoxia 621–7 cognitive impairment see cognitive therapies cost of 850 –2, 851 demand for 401 depression see antidepressants disease-modifying 385, 387, 462, 463 economic evaluation 398–9 efficacy see efficacy of treatment empirically validated 32 incontinence 735, 735–8, 737 integrated treatment plan 373–5 behavioral management 374 cognitive function 375 health maintenance 374 knowledge base and education 373 neurological management 374–5 prevention 375 social and environmental needs 373– 4 Lewy body dementia 608–14 antiparkinsonian agents 611–12 cholinesterase inhibitors 608–10, 609, 610 gabaminergic agents 612 neuroleptics 610–11 likelihood of benefit 363 mild cognitive impairment 351 monitoring of 371–2 mood changes 368–9 open access to 401–2 preventative see preventative treatment prognosis modification 463, 464 rationale for 365–6 reversible/arrestable dementias 615–38 sleep disturbance 712–15, 712, 713 –14 symptomatic effects 462 therapeutic goals 385 vascular dementia 453, 589–607

anti-oxidants 589–90 anti-thrombotics 590–3 blood pressure reduction 593–5 CDP-choline 596–9 Gingko biloba 599 hydergine 599 nimodipine 600 pentoxifylline 600–2 piracetam 603 propentofylline 603 treatment bias 33 trigger symptoms 87 uncertainty 62 US Agency for Health Care Policy and Research 31 vacuolar leukoencephalopathy 321 validation therapy 57–8, 434–5 validity of diagnostic tests 18 of guidelines 61 of results, economic evaluation 66–7 study see study validity study results 15–16 vascular dementia 113–16, 260–87 behavioral characteristics 126 behavioral and psychological symptoms 274 brain changes 275, 276 clinical assessment 261 brain imaging 261 mental status examination 261 clinical neurological findings 273–4 clinicopathological correlations 114 cognitive syndrome 273, 277–8 determinants of 268–73 diagnosis 113–15, 114, 260–2, 261, 856–8 diagnostic criteria 262–4 differential diagnosis 279–80 Alzheimer’s disease 279 frontal lobe tumors 280 frontotemporal dementia 280 intracranial mass 280 Lewy body dementia 280 multisystem atrophy 280 normal pressure hydrocephalus 279 Parkinson’s disease 280 progressive supranuclear palsy 280 white matter lesions and dementia 280

INDEX 893

EEG 172 epidemiology 265– 8 evidence 115–16, 126, 172 genetic markers 137– 8 hereditary 137–8 heterogeneity of 275–9, 275 history 215–17, 216, 217 incidence 267–8 in community 267 post-stroke 267 time trends 267– 8 ischemic scores 274 mortality 265 multifactorial origin 269–73 associated Alzheimer pathology 271 cerebral atrophy 272 demographic characteristics and co-morbid disorders 272 genetic factors 272–3 stroke 269 summation of lesion types 271–2 white matter changes 269 –71 pathological diagnosis 115 prevalence 265–7 autopsy studies 266 –7 community-based studies 265 hospital-based studies 266 stroke patients 266 stroke survivors 266 prevention of 659– 63, 661 antiplatelet treatment 660 –1 control of hypertension 661–2

improvement in society 663 risk factors 662–3 risk factors 123, 240–1, 268–9 search strategy and study validation 115 strategic infarct 275, 276 subcortical 276–8, 277 subtypes 276 time-course 274 treatment 453, 589–607 anti-oxidants 589–90 anti-thrombotics 590–3 blood pressure reduction 593–5 CDP-choline 596–9 Gingko biloba 599 hydergine 599 nimodipine 600 pentoxifylline 600–2 piracetam 603 propentofylline 603 vascular mechanisms 275 without detected infarcts 278 vasculitides 337 vasoactive intestinal peptide 453 verification bias 19, 151 vincamine 449 visuospatial impairment 232–3 Huntington’s chorea 317 Parkinson’s disease 314 vitamin B1 see thiamine vitamin B6 648 vitamin B12 deficiency dementia 336, 337, 628

vitamin E 471–2 adverse effects 565 benefits 565 clinical trials 35, 37, 52 efficacy 560, 564–5 von Gerlach, Joseph 215 wandering behavior 440–1, 706 see also agitation WAY 100635 448 Wechsler Adult Intelligence Scale 834 Wechsler Memory Scale 96 weight loss 733–4 Weigl’s Colour Form Sorting Test 834 Wernicke–Korsakoff syndrome 558, 654 white matter lesions of 280 stroke 270 vascular dementia 269–71 willingness to pay 66 Willis, Thomas 208–9 Wilson’s disease 337 Wisconsin Card Sorting Test 97, 306, 313 Word List Learning Test 96 work-up bias 93 xanomeline 450, 690 XR-543 448 zolpidem 715

Plate II.1 These images are PET scans taken with the glucose metabolic tracer 18F-fluorodeoxyglucose (FDG). The two upper

parts of the image show the normal distribution of glucose metabolism in a control subject at two different homographic levels. The lower parts of the image show hypometabolism in the parietal lobe (arrows) and temporoparietal cortex in a patient with Alzheimer’s disease. This is the metabolic lesion that has been suggested to be diagnostic of Alzheimer’s disease.

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Plate II.2 This is a PET FDG image from a patient with frontotemporal dementia. Glucose metabolism is reduced in the frontal and anterior temporal brain regions. See Plate II.1 for control images.

(a)

(b) Plate III.1 (a) Lewy bodies in pigmented neurones in the substantia nigra, immunostained with an antibody against

α-synuclein. (b) Lewy body and Lewy neurites, immunostained with the same antibody. (Courtesy of Eliezer Masliah, UCSD.)

Plate III.2 Pathology. (a) External view of the brain demonstrating frontal atrophy. The discolored defect corresponds to a

biopsy which showed non-specific findings. Dementia lacking distinctive histology. (b) Ballooned neurones (arrow) are highlighted by their perikaryal accumulation of phosphorylated neurofilaments. Parietal cortex, corticobasal degeneration patient (× 125). (c) Pick bodies (arrows) in three hippocampal neurones. Bielchoswky stain (× 240). (d) Rounded neuronal argyrophilic inclusion in the upper layers of the frontal cortex in corticobasal degeneration. Gallyas stain (× 600). (e) A ‘glial plaque’ (a crown-shaped cluster of argyrophilic astrocytic processes, arrows) in the frontal cortex of a patient with corticobasal degeneration. Gallyas stain (× 300). (f) Two ITSNU (arrow) in neurones of the hippocampal dentate gyrus of a patient with motor neurone disease-type dementia (× 800).

Plate III.3 Imaging. (a) Frontal atrophy on CT scan of a 65-year-old man presented in the clinical vignette. (b) Frontal

hypoperfusion on HMPAO-SPECT of the same case as in (a). Bright yellow, normal perfusion; darker brown, hypoperfusion; blue, no perfusion. (c) MRI: T2 weighted pulse sequence. Left central and perisylvian atrophy in a case of simultaneous onset of verbal difficulties and stiffness of right hand. Diagnosis: corticobasal degeneration syndrome with aphasia. (d) MRI: T2 weighted pulse sequence. Left temporal atrophy, same case as (c). This extent of asymmetry is not seen in AD and is characteristic of Pick complex.

Plate III.4