POL YNEUROPATHIES ASSOCIATED WITH PLASMA CELL DYSCRASIAS

TOPICS IN THE NEUROSCIENCES

Other books in the series:

Rami Rahamimoff and Sir Bernard Katz, eds.: Calcium, Neuronal Function and Transmitter Release. ISBN 0-89838-791-4.

Robert C. A. Frederickson, ed.: Neuroregulation of Autonomic, Endocrine and Immune Systems. ISBN 0-89838-800-7.

Giuditta, et aI., eds.: Role of RNA and DNA in Brain Function. ISBN 0-89838-814-7.

Stober T., et al.,: Central Nervous System Controls of the Heart. ISBN 0-89838-820-1.

POL YNEUROP ATHIES ASSOCIATED WITH

PLASMA CELL DYSCRASIAS

JOHN]. KELLY,JR. ROBERT A. KYLE, AND NORMANLATOV

~.

" MARTINUS NijHOFF PUBLISHING

A MEMBER OF THE KLUWER ACADEMIC PUBLISHERS GROUP

BOSTON DORDRECHT LANCASTER

Distributors

for the United States and Canada: Kluwer Academic Publishers, 101 Philip Drive, Assinippi Park, Norwell, MA, 02061, USA

for the UK and Ireland: Kluwer Academic Publishers, MTP Press Limited, Falcon House, Queen Square, Lancaster LA 1 1 RN, UK

for all other countries: Kluwer Academic Publishers Group, Distribution Centre, P.O. Box 322, 3300 AH Dordrecht, The Netherlands

Library of Congress Cataloging in Publication Data

Kelly, John J. Oohn Joseph), 1943-Polyneuropathies associated with plasma cell dyscrasias.

(Topics in the neurosciences) Includes index. 1. Polyneuropathies-Etiology. 2. Plasma cell diseases-Complications and

sequelae. 3. Paraproteinemia-Complications and sequelae. I. Kyle, Robert A., 1928- II. Latov, Norman. III. Title. IV. Series. [DNLM: 1. Paraproteinemias-complications 2. Peripheral Nerve Diseases-etiology. WL 500 K29p] RC422.P64K45 1987 616.8'7 87-7793 ISBN-13: 978-1-4612-9226-5 e-ISBN-13: 978-1-4613-2065-4 DOl: 10.1007/978-1-4613-2065-4

© 1987 by Martinus NijhoffPublishing, Boston Softcover reprint of the hardcover 1st editon 1987 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, mechanical, photocopying, recording, or otherwise, without the prior written permission of the publishers, Martinus NijhoffPublishing, 101 Philip Drive, Assinippi Park, Norwell, MA, 02061, USA

CONTENTS

Foreword IX

P.]. DYCK

Preface Xl

KELLY

1. Plasma cell dyscrasias: Definition and diagnostic evaluation KYLE

2. Epidemiology of polyneuropathies associated with plasma cell dyscrasias 29 KELLY

3. Neurochemistry and neuroimmunology of peripheral nerve 39 LATOV

4. Waldenstrom's macroglobulinemia and nonmalignant IgM monoclonal gammopathies 51 LATOV

5. Nonmalignant IgG and IgA gammopathies 73 LATOV

6. Multiple myeloma 77 KELLY

7. Osteosclerotic myeloma 91 KYLE

8. Amyloidosis 105 KELLY

v

vi Contents

9. Diagnostic approach to patients with polyneuropathies associated with monoclonal proteins 129 KELLY

10. Future directions KELLY

Index

141

143

AUTHOR LISTING

John]. Kelly, Jr., M.D. Associate Professor of Neurology Director, Electromyography Laboratory Department of Neurology Tufts-New England Medical Center Boston, MA 02111

Robert A. Kyle, M.D. William H. Donner Professor of Medicine and Laboratory Medicine, Mayo Medical School Chairman, Division of Hematology and Internal Medicine, Mayo Clinic and Mayo Foundations, Rochester, MN. 55905

Norman Latov, M.D., Ph.D. Assistant Professor of Neurology Columbia College of Physicians and Surgeons New York, NY 10032

vii

FOREWORD

Plasma cell dyscrasias are common causes of peripheral neuropathy. Peri­pheral neuropathy may be the first manifestation of multiple myeloma, amyloidosis, or monoclonal gammopathy of undetermined significance (MGUS). Peripheral neuropathy occurs in more than one-half of patients with osteosclerotic myeloma. The hematologic disorders are such an important association with peripheral polyneuropathy that, for the last decade, we have obtained a metastatic bone survey and immunoelectrophoresis of serum and a 24-hour urine specimen on all patients older than 40 years with undiagnosed peripheral neuropathy.

This textbook on polyneuropathies and plasma cell dyscrasia is welcome, because the subject is of considerable medical importance and because the authors are expert in these disorders. Kelly's studies have shown that a systematic search for monoclonal proteins in plasma and urine among patients with neuropathy of unknown cause increases diagnostic yield. Latov's studies have focused on the role of myelin associated glycoproteins (MAG) in the induction of neuropathy. Kyle, director of the Special Protein Laboratory at Mayo Clinic, brings a broad clinical and laboratory perspective and experi­ence. The timing of the textbook is just right, because there is much new information which needs to be summarized.

Although one anticipates that this book will be a great help in drawing together known information about these disorders, more than is known remains unknown. Pathologic reactions of peripheral nerves have not been

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x Foreword

adequately studied. We know too little about the three-dimensional pathologic alteration, the cellular vulnerability (Schwann cell, myelin, or axon), or the role of nerve microvessels or microenvironment in development of neuro­pathy. Information on treatment is largely anecdotal. Prospective double­blind trials of the effectiveness of plasma exchange and of chemotherapy, quantitating plasma and urine proteins and endpoints of nerve function, are now needed. Possibly in the later editions of this book, we will begin to see these questions addressed and answered.

Peter James Dyck

PREFACE

To neurologists, internists, and family physicians, polyneuropathies have long been diagnostic and therapeutic challenges. Not long ago, the diagnosis of a progressive polyneuropathy was greeted with pessimism. Discovery of the etiology was uncertain, disease mecha­nisms were largely unknown, and treatment was ineffective. In 1970, for example, Prineas analyzed a large series of polyneuropathy patients presenting on the wards at Newcastle-Upon-Tyne. Of the 278 patients, 107 (36%) were classed as idiopathic. Without some understanding of disease mechanisms, physicians could offer these idiopathic neuropathy patients little, and they could expect, for the most part, progressive loss of motor power and sensation, painful paresthesias, and, in many cases, autonomic failure.

Over the last two decades, however, polyneuropathies, like other neurologic diseases, are beginning to yield to systematic scientific study, and major advances in the understanding of the biology, pathology, and natural history of these diseases have occurred. Injust the last decade, a number of texts (Dyck et al., 1984; Schaumburg, et al., 1983; Asbury and Gilliat, 1984) devoted solely to polyneuropathies and reflecting this new knowledge have been published. As a result, more recent studies have shown that skilled clinicians, when armed with new and sophisticated diagnostic tools, are now able to diagnose the majority of patients. Dyck and colleagues (1981), for example, reviewed 205 patients referred for idiopathic neuropathy seen over seven years and were able

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xii Preface

to find a likely cause in 75% of these. They stressed recognition of chronic inflammatory and of inherited polyneuropathies as important contributions to improved diagnostic efficiency. McLeod and associates (1984) were able to find a cause for almost 90% of their 519 polyneuropathy patients seen over a 14-year period. The undiagnosed patients had relatively minor and slowly progressive disease. Painstaking evaluation of all neuropathy patients and prolonged follow-up of the idiopathic cases were important determinamts of success in their series. It seems reasonable now to expect that at least 80% of polyneuropathy patients presenting in the clinics of major teaching centers with modern morphologic and electrophysiologic techniques can be diagnosed. Only a few polyneuropathies, mostly mild, chronic axonopathies, now escape the application of advanced diagnostic methods.

This improvement in our ability to diagnose peripheral nerve disease has been largely due to the maturation of a number of disciplines. The more traditionally related fields, such as peripheral nerve morphometry, histopatho­logy, and electrophysiology, have helped to clarify the nature of nerve dysfunction in neuropathies. A number of experimental models of peripheral nerve disease have been developed which have shed light on the mechanisms of nerve damage and dysfunction. Some of the immunological mechanisms of these diseases have been clarified. These advances, when combined with careful studies of disease natural history, have led to a better understanding of pathogenesis and have set the stage for improved diagnosis and therapy.

One category of neuropathies that has emerged from the previously large number of amorphous idiopathic cases and that has benefited greatly from this new knowledge is that associated with plasma cell dyscrasias. In just the last few years, it has become evident that these polyneuropathies are an important cause of peripheral nerve disease. Although numerically infrequent, they can be very disabling and some are potentially treatable. They have a readily iden­tifiable laboratory marker and may give valuable clues to the pathogenesis of other obscure neuropathies. The emergence of these syndromes has been due to multidisciplinary contributions by neurologists, hematologists, oncologists, epidemiologists, neurochemists, and neuroimmunologists. Our understand­ing of these diseases is still evolving, but already a considerable body of know 1-edge has accumulated on the natural history, pathology, electrophysiology, disease mechanisms, and treatment. Although much information is available, it is widely distributed in the literature and no concise summary of the state of knowledge exists. Therefore, we feel that it is now appropriate for a mono­graph summarizing this information.

This monograph will be multiauthored, featuring information from clinical neurology, neurophysiology, hematology/oncology, and neurochemistry/ neuroimmunology. This book presupposes a knowledge of neuromuscular testing, such as the essentials of electromyography, nerve biopsy techniques, and histopathologic interpretation. Readers unfamiliar with these areas are

xiii

referred to standard texts. Although always a difficult and risky task, this book is designed to reach several audiences. It will serve as a guide to the general neurologist and neuromuscular specialist in approaching individual patients. This book will also appeal to the hematologist/oncologist in day-to-day deal­ings with individual patients with plasma cell dyscrasias and neurological syndromes. Description of the syndromes outlined in this book will help the clinician to understand the multiple questions which arise in the management of these complicated patients. This monograph will also appeal to the re­searcher who requires a source for clinical and basic information in this area and will serve as an up-to-date compendium of knowledge in this rapidly changing area, as well as an indicator of where more work and clarification are needed.

In chapter 1, we describe the essential nature of monoclonal gammopathies and the various plasma cell proliferative disorders. The necessary criteria for diagnosis of the hematologic syndromes are included in this chapter. Some of the confusion in the literature to date concerning these diseases stems from loose criteria for diagnosis of amyloidosis, myeloma, and macroglobulinemia. This chapter will provide guidelines for classifying patients in subsequent clinical and research reports. Chapter 2 discusses the frequency of plasma cell dyscrasia syndromes in the larger mix of all patients with polyneuropathies. This chapter reviews some of the important statistical and epidemiological issues involved in attempting to prove an association between these disorders. Chapter 3 reviews some of the complex neurochemical and neuroimmuno­logic issues which confront investigators and clinicians dealing with these syndromes. The eventual clarification of the nature of nerve fiber injury in these disorders will be a major aid in the understanding of disease mechanisms in all polyneuropathies.

The middle chapters (4-8) summarize current knowledge concerning the natural history, epidemiology, pathology, electrophysiology, pathogenesis, and treatment of these syndromes. These chapters are spiced with case reports to illustrate the syndromes with clinical material and with ample figures and tables to summarize clinical points. Chapter 9 summarizes our recommended approach to individual patients in recognizing and evaluating a plasma cell dyscrasia. This chapter provides practical information about which tests to order, what to do with the results obtained, and when and how to attempt treatment in these patients. A final chapter (10) attempts to put this topic in perspective and includes speculation about the role of monoclonal proteins in polyneuropathies and about future avenues for research.

We believe that an understanding of the mechanisms of these polyneuro­pathies will shed light on all obscure polyneuropathies, including those associated with malignancies and the idiopathic axonopathies which still bedevil physicians. In addition, it will serve as a ready reference to the practicing neurologist and hematologist/oncologist.

xiv Preface

REFERENCES

1. Asbury AK, Gilliat RW: Peripheral Nerve Disorders, a Practical Approach. London: Butterworths, 1984.

2. Dyck PJ, Thomas PK, Lambert EH, Bunge R (cds): Peripheral Neuropathy. (2d ed). Philadelphia: Saunders, 1984.

3. DycR PJ, Oviatt KF, Lambert EH: Intensive evaluation of referred unclassified neuropathies yields improved diagnosis. Ann Neurol 10:222-226, 1981.

4. McLeod JG, Tuck RR, Pollard JD, Cameron J, Walsh JC: Chronic polyneuropathy of undetermined cause. J Neurol Neurosurg Psychiatry 47: 530-535, 1984.

5. Prineas J: Polyneuropathies of undetermined cause. Acta Neurol Scand 46:4-72, 1970. 6. Schaumburg HH, Spencer PS, Thomas PK: Disorders of Peripheral Nerves. Philadelpha: FA

Davis, 1983.