Neuroimmunology in Clinical Practice

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Neuroimmunology in Clinical Practice

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Neuroimmunology in Clinical Practice Edited by Bernadette Kalman and Thomas H. Brannagan III

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© 2008 by Blackwell Publishing Ltd BLACKWELL PUBLISHING 350 Main Street, Malden, MA 02148-5020, USA 9600 Garsington Road, Oxford OX4 2DQ, UK 550 Swanston Street, Carlton, Victoria 3053, Australia The right of Bernadette Kalman and Thomas H. Brannagan III to be identified as the Authors of the Editorial Material in this Work has been asserted in accordance with the UK 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 2008 by Blackwell Publishing Ltd 1 2008 Library of Congress Cataloging-in-Publication Data Neuroimmunology in clinical practice / edited by Bernadette Kalman and Thomas H. Brannagan III. p. ; cm. Includes bibliographical references and index. ISBN-13: 978-1-4051-5840-4 (hardback : alk. paper) ISBN-10: 1-4051-5840-9 (hardback : alk. paper) 1. Neuroimmunology. 2. Nervous system—Diseases—Immunological aspects. I. Kalman, Bernadette. II. Brannagan, Thomas H. [DNLM: 1. Autoimmune Diseases of the Nervous System—physiopathology. 2. Nervous System—immunology. WL 140 N49152 2008] RC346.5.N4785 2008 616.8′0479—dc22 2007001113 A catalogue record for this title is available from the British Library. Set in 10/12.5pt Photina by Graphicraft Limited, Hong Kong Printed and bound in Singapore by Fabulous Printers Pte Ltd The publisher’s policy is to use permanent paper from mills that operate a sustainable forestry policy, and which has been manufactured from pulp processed using acid-free and elementary chlorine-free practices. Furthermore, the publisher ensures that the text paper and cover board used have met acceptable environmental accreditation standards. For further information on Blackwell Publishing, visit our website: www.blackwellpublishing.com

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Contents

Preface, vii Foreword, viii Contributing authors, ix Part I: Basic science introduction to clinical neuroimmunology, 1 Editor: Bernadette Kalman 1

2

The basics of cellular and molecular immunology, 3 Amy E. Lovett-Racke, Anne R. Gocke, and Petra D. Cravens Major components of myelin in the mammalian central and peripheral nervous systems, 11 Alexander Gow

Part II: Inflammatory demyelination in the central nervous system, 27 Editor: Bernadette Kalman 3

4

Dévic’s disease, 83 Bernadette Kalman

5

Acute disseminated encephalomyelitis and related conditions, 88 Robert S. Rust

Part III: Autoimmune diseases of the peripheral nervous system and the muscle, 115 Editor: Thomas H. Brannagan III 6

Guillain–Barré syndrome, 117 Eduardo A. De Sousa and Thomas H. Brannagan III

7

Immune-mediated chronic demyelinating polyneuropathies, 123 Thomas H. Brannagan III

8

Immune-mediated autonomic neuropathies, 139 Louis H. Weimer and Mill Etienne

9

Autoimmune myasthenic syndromes: Myasthenia gravis and Lambert–Eaton myasthenic syndrome, 153 Andrew Sylvester and Armistead Williams

10

Polymyositis and dermatomyositis, 169 S. Christine Kovacs

Multiple sclerosis, 29 3.1 3.2 3.3 3.4 3.5

3.6 3.7

3.8

Epidemiology and genetics (Bernadette Kalman), 29 Immunopathogenesis (Thomas P. Leist), 35 Courses and diagnosis of MS (Bernadette Kalman), 38 Clinical features (Bernadette Kalman), 42 The pathology of MS: A quest for clinical correlation (William F. Hickey), 50 Cerebrospinal fluid (Mark S. Freedman), 54 Magnetic resonance imaging characteristics of MS ( Jennifer L. Cox and Robert Zivadinov), 56 Treatment of MS (Sean Pittock), 63

Part IV: Disorders of the central and peripheral nervous systems related to known or assumed system-immune abnormalities, 179 Editor: Bernadette Kalman 11

Neuro-Sjögren’s syndrome, 181 Bernadette Kalman

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CONTENTS

12

Neuro-Behçet’s syndrome, 185 Bernadette Kalman

13

Steroid-responsive encephalopathy associated with Hashimoto’s thyroiditis, 189 Bernadette Kalman

14

Rasmussen’s encephalitis, 191 Bernadette Kalman

15

Susac’s syndrome, 197 Bernadette Kalman

16

Cogan’s syndrome, 200 Bernadette Kalman

17

Neurosarcoidosis, 203 Bernadette Kalman

18

Anti-VGKC syndromes: Isaacs’ syndrome, Morvan’s syndrome, and autoimmune limbic encephalitis, 207 Bernadette Kalman

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Paraneoplastic neurological autoimmunity, 210 Daniel H. Lachance and Vanda A. Lennon

20

Vasculitis and connective tissue diseases, 218 David S. Younger and Adam P.J. Younger

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Poststreptococcal movement disorders, 240 Andrew J. Church and Gavin Giovannoni

22

Neurological manifestations of gluten sensitivity, 251 Marios Hadjivassiliou

23

Anti-GAD associated neurological diseases, 256 Marios Hadjivassiliou

Index, 259

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Preface

Neurology, as many other fields in medicine, has evolved into a framework of rapidly developing subspecialties increasingly dependent on technologydriven advances in clinical and basic sciences. Neuroimmunology is a particularly dynamic subspecialty with daily emergence of new information in imaging, electrophysiology, clinical trials, molecular immunology, neurosciences, and genetics, which necessitates frequent changes in clinical practice. The authors of this book recognize the difficult task that neurology residents and other young medical professionals have to face when preparing for their exams and practicing modern neuroimmunology. With the intention to alleviate this task, here we provide a comprehensive but concise description of

immune-mediated neurological disorders complemented with the most pertinent and up-to-date scientific data. We hope that not only residents, fellows, young neurologists, physician assistants, and nurses, but also scientists working in the area of neuroimmunology will find this volume useful. The editors invited coauthor experts who both teach and study specific aspects of neuroimmunology at academic medical centers. Non-author experts including Drs. John O. Susac, Mark Keegan, Christian G. Bien, Horst Urbach, Alexander G. Khandji, and Fred D. Lublin generously contributed to several chapters with their constructive comments and images of rare disorders.

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Foreword

Neuroimmunology in Clinical Practice provides a useful and comprehensive review of the field of clinical neuroimmunology. In addition to presenting timely updates of such common conditions as multiple sclerosis, autoimmune neuropathies, myasthenia gravis, and polymyositis, it highlights less familiar neuroimmunological entities such as anti-VGKC syndromes, and gluten-induced neurological dysfunction, which can go unrecognized in common clinical practice. It provides a scientific background

for understanding the underlying pathophysiology, and guides the physician through the diagnosis and management of patients with these conditions. The book is a welcome and timely addition to our library of neurological subspecialties. Norman Latov, M.D., Ph.D. Professor of Neurology and Neuroscience Weill Medical College of Cornell University

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Contributing authors

Thomas H. Brannagan, III. M.D. Associate Professor Director, Diabetic Neuropathy Research Center, Peripheral Neuropathy Center Department of Neurology Weill Medical College of Cornell University 635 Madison Avenue, Suite 400 New York, NY 10022, USA [email protected] Andrew Church, Ph.D. Fellow Department of Neuroinflammation National Institute of Neurology University College of London Queen Square London WC1N 3BG, United Kingdom [email protected] Jennifer L. Cox, Ph.D. Assistant Professor Department of Neurology SUNY School of Medicine and Biomedical Sciences The Jacobs Neurological Institute 100 High Street Buffalo, NY 14203, USA [email protected]. Petra D. Cravens, Ph.D. Postdoctoral Fellow Department of Neurology University of Texas Southwestern Medical Center 5323 Harry Hines Blvd Dallas, TX 75390-9036, USA [email protected] Eduardo Adonias De Sousa, M.D. Assistant Professor Department of Neurology Thomas Jefferson University 900 Walnut Street, Suite 200

Philadelphia, PA 19107, USA [email protected] Mill Etienne, M.D. Fellow Department of Neurology College of Physicians and Surgeons Columbia University 710W 168th Street New York, NY 10032, USA [email protected] Mark S. Freedman M.Sc., M.D., FAAN, FRCP(C) Professor of Medicine (Neurology) Director, Multiple Sclerosis Research Unit University of Ottawa The Ottawa Hospital-General Campus Box 601, 501 Smyth Road Ottawa, ON K1H8L6, Canada [email protected] Gavin Giovannoni, M.D., Ph.D. Department of Neuroinflammation Consultant Neurologist National Institute of Neurology University College of London Queen Square London WC1N 3BG, United Kingdom [email protected] Alexander Gow, Ph.D. Associate Professor Center for Molecular Medicine and Genetics Wayne State University School of Medicine 3216 Scott Hall, 540 E Canfield Ave Detroit, MI 48201, USA [email protected] Anne R. Gocke, B.S. Student Department of Neurology

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CONTRIBUTING AUTHORS

University of Texas Southwestern Medical Center 5323 Harry Hines Blvd Dallas, TX 75390-9036, USA [email protected] Marios Hadjivassiliou, M.D. Consultant Neurologist Department of Neurology The Royal Hallamshire Hospital Glossop Road Sheffield S10 2JF, United Kingdom [email protected] William F. Hickey, M.D. Professor of Pathology and Neuropathology Senior Associate Dean for Academic Affairs Department of Pathology Dartmouth-Hitchcock Medical Center One Medical Center Drive Lebanon, NH 03756, USA [email protected] Bernadette Kalman, M.D., Ph.D. Associate Professor of Neurology, Associate Chief of Staff VAMC and SUNY Upstate Medical University 800 Irving Avenue, Research (151) Syracuse, NY 13210, USA [email protected] S. Christine Kovacs, M.D. Assistant Clinical Professor of Medicine Division of Rheumatology Lehay Clinic 41 Mall Road Burlington, MA 01805, USA Tufts Medical School Boston, MA [email protected] Daniel H. Lachance, M.D. Assistant Professor of Neurology Consultant, Neurology and Neuroimmunology Laboratory Mayo Clinic College of Medicine Rochester, MN 55905, USA 200 First St. SW [email protected] Thomas P. Leist, M.D., Ph.D. Associate Professor Director of the Comprehensive MS Center and the

Division of Neuroimmunology Department of Neurology Thomas Jefferson University 900 Walnut Street, Suite 200 Philadelphia, PA 19107, USA [email protected] Vanda A. Lennon, M.D., Ph.D. Director, Neuroimmunology Laboratory, Professor of Immunology and Neurology Director, Autoimmune Neurology Fellowship Program Mayo Clinic College of Medicine 200 First St. SW Rochester, MN 55905, USA [email protected] Amy Lovett-Racke, Ph.D. Assistant Professor Department of Molecular Virology Immunology and Medical Genetics Ohio State University College of Medicine 333 W. 10th Avenue 2166D Graves Hall Columbus, OH 43210, USA [email protected] Sean J. Pittock, M.D. Assistant Professor of Neurology Co-Director Neuroimmunology Laboratory Co-Director Autoimmune Neurology Fellowship Mayo Clinic College of Medicine 200 First St. SW Rochester, MN 55905-0001, USA [email protected] Robert S. Rust Jr., M.D. Thomas E. Worall, Jr. Professor of Epileptology and Neurology and Professor of Pediatrics Department of Neurology and Pediatrics University of Virginia P.O. Box 800394 Charlottesville, VA 22908, USA [email protected] Andrew Sylvester, M.D. Attending Neurologist International Multiple Sclerosis Management Practice 521 West 57th Street, Suite 400 New York, NY 10019, USA [email protected]

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Contributing authors

Louis H. Weimer, M.D. Associate Clinical Professor Department of Neurology College of Physicians and Surgeons Columbia University 710W 168th street, R55 New York, NY 10032, USA [email protected] Armistead Williams, M.D. Fellow International Multiple Sclerosis Management Practice 521 West 57th Street, Suite 400. New York, NY 10019, USA [email protected] Adam P.J. Younger Research Assistant Edgemont Science Scholar Program 300 White Oak Lane Scarsdale, NY 10583, USA

David S. Younger, M.D. Clinical Associate Professor Department of Neurology New York University School of Medicine St. Vincent’s Catholic Medical Center Lenox Hill Hospital 550 First Avenue New York, NY 10016, USA [email protected] Robert Zivadinov, M.D., Ph.D. Associate Professor Department of Neurology SUNY School of Medicine and Biomedical Sciences The Jacobs Neurological Institute 100 High Street Buffalo, NY 14203, USA [email protected]

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1 The basics of cellular and molecular immunology Amy E. Lovett-Racke, Anne R. Gocke, and Petra D. Cravens

The immune system is composed of cells, tissues, and vessels that collectively protect the body from pathogens. In some instances, the immune system can inadvertently cause tissue damage resulting in immune-mediated diseases, and appears to be at least partially responsible for the pathology seen in multiple sclerosis (MS). The immune system provides defenses against pathogens in nonspecific mechanisms, termed innate immunity, and pathogen-specific mechanisms, termed adaptive immunity. Innate immunity is composed of phagocytic cells that engulf and digest microorganisms, natural killer cells that nonspecifically kill infected cells, and physical barriers as a means to eradicate pathogens. Adaptive immunity is composed of cells that specifically recognize components of pathogens and directly target a particular infected cell. It is the adaptive immune response that is believed to be responsible for targeting self-proteins in autoimmunity, but innate immunity plays a critical role in the events that initially condition the environment that ultimately determines the phenotype of the cells of the adaptive immune response. B lymphocytes and T lymphocytes are the key cells that provide adaptive immunity. B cells have multiple functions, including antibody production, antigen presentation, and immune modulation via cytokine expression. The production of antibodies by B cells is the key feature of humoral immunity, which is critical to the defense against extracellular microbes. Cell-mediated immunity is primarily provided by T cells, which recognize antigens of intracellular pathogens displayed on the surface of infected cells. Together, B cells and T cells can usually eradicate an infection in a pathogen-specific manner with minimal damage to the host, and further protect the host from future infections of that pathogen by establishing immunological memory. Humoral immunity B cells express and secrete antibodies that are unique and specific for proteins. This provides humoral

immunity to the host, which was originally described as a form of immunity that could be transferred from immunized to naive hosts via serum. All antibodies, which are also referred to as immunoglobulins (Ig), have a common structure composed of two heavy and two light chains (Edelman et al., 1969). The heavy chain is composed of four sequence domains, three of which are highly conserved and referred to as constant regions (CH) (Hilschman and Craig, 1969). The fourth domain, the variable region (VH), has a unique sequence that provides the specificity of the antibody for its target protein. Two identical heavy chains are linked by disulfide bonds between the CH1 and CH2 domains as shown in Fig. 1.1. In addition, there are two light chains that are each composed of a single constant region (CL) and a single variable region (VL ). The light chain is connected to the heavy chain at CH1 and CL. The VH and VL regions form the antigen-binding site. The V regions of both the heavy and light chains contain three short, highly diverse sequences called the hypervariable or complementary-determining regions (CDR),

Light chain

Heavy chain

Antigenbinding site VH

Complementarydetermining regions (CDR)

VL

CH1

CL

CH2 FC region Fc receptor complement binding site

CH3

Fig. 1.1 Antibodies are composed of two heavy and two light chains that form an antigen-specific binding site.

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which encode the unique binding site for specific antigens (Wu and Kabat, 1970). Antibodies are classified into five isotypes based on the differences in the structure of their heavy chain C regions, IgA, IgD, IgE, IgG, and IgM. IgM and IgD serve as the antigen receptors for the activation of naive B cells. Antigen binding to membrane-bound IgM and IgD results in the secretion of IgM and expression of other Ig isotypes. This process, termed isotype switching, results from a new CH chain being produced by the B cells, while the V regions remain unchanged and thus the specificity of the antibody is the same (Kataoka et al., 1980). Both secreted IgM, which is typically found in a pentameric form, and IgG can utilize the complement system to mediate the lysis of IgM- or IgG-coated targets. IgG can also facilitate the opsonization of microbes by promoting the phagocytosis of IgG-coated targets by binding to the FC (constant region framework of IgG) receptors on phagocytes (Leijh et al., 1981). IgA provides defenses against microbes that enter through mucosal surfaces such as the gastrointestinal and respiratory tracts. IgA is produced by mucosal lymphoid tissues, secreted through the epithelium, binds to pathogens in the lumen, and prevents the entry of pathogens into the host (South et al., 1966). IgE is the antibody isotype that mediates immediate hypersensitivity reactions, as well as defense against helminthic parasites. Mast cells and basophils express an IgE receptor that interacts with antigen-bound IgE, resulting in degranulation of mast cells and basophils, and the expression of immediate hypersensitivity reactions (Schleimer et al., 1986). Eosinophils express IgE receptors and can elicit antibody-dependent cellmediated cytotoxicity (ADCC) of IgE-coated helminthes (Gounni et al., 1994). Thus, antibodies protect the host by providing a very diverse set of antigenspecific antibodies with multiple isotypes to control the numerous pathogens that the host encounters. In addition, antigen-specific memory B cells are established following the initial infection with a particular pathogen. Memory B cells produce antibodies rapidly following re-exposure to a pathogen, protecting the host from a subsequent infection (Uhr and Finkelstein, 1963). Monoclonal antibodies have provided a valuable research tool, as well as a mechanism to develop antigen-specific therapeutic agents. Since each B cell produces an antibody with a unique specificity, immortalized B cells have been generated that can produce an unlimited amount of an antibody specific for an antigen of interest. Immortalized B cells are

generated by fusing B cells with a myeloma cell to form a hybridoma, and then selecting B cell clones that produce an antibody with the desired specificity. Because monoclonal antibodies can be generated for virtually any protein or peptide, and even for polysaccharides and lipids, they have become a major tool in studying many molecules. Some of the in vitro research techniques, which utilize monoclonal antibodies, include ELISA, ELISPOT, western blot, flow cytometry, and immunohistochemistry. Monoclonal antibodies have also been utilized in vivo to study particular molecules, pathways, and the function of a specific cell population. In vivo, monoclonal antibodies that induce complement or ADCC can be used to deplete a particular cell population by targeting a cell-surface molecule specific for that cell population. In addition, monoclonal antibodies administered in vivo can be used to physically block a particular molecule, thus preventing the natural ligand from binding and initiating a signal. It is these in vivo research strategies that have extended into the development of monoclonal antibodies as therapeutic agents. A monoclonal antibody specific for the adhesion molecule, VLA4, expressed on T cells was developed as a therapeutic agent for multiple sclerosis. The anti-VLA4 antibody prevented the binding of VLA4 to VCAM on the vascular epithelium, physically preventing the entry of T cells into the central nervous system (CNS) (Yednock et al., 1992; Miller et al., 2003). Using an alternative strategy, a monoclonal antibody specific for CD20, a molecule expressed specifically by B cells, was developed to treat B cell malignancies (Maloney et al., 1997). Anti-CD20 binds to B cells and elicits an immune-mediated destruction of these cells. Thus, monoclonal antibodies have been an invaluable tool in both the understanding and treatment of diseases. Cell-mediated immunity T lymphocytes are the mediators of cell-mediated immunity. T cells recognize antigens in the context of major histocompatibility complex (MHC) molecules. The human MHC, often referred to as human leukocyte antigens (HLA), contains at least 50 genes on chromosome 6. T cells recognize antigens bound to HLA class I molecules called HLA-A, -B, and -C; and HLA class II molecules called HLADR, -DP, and -DQ. Class I molecules are single-chain glycoproteins that pair with β2-microglobulin. In contrast, class II molecules are heterodimeric, composed of α and β chains.

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MHC molecules bind peptides derived from microbes generated by two distinct processing pathways (Morrison et al., 1986). Endogenous cytosolic proteins from intracellular viruses or tumors are digested into peptides in proteosomes, transported to the endoplasmic reticulum where they bind MHC class I molecules, and presented on the cell surface (Braciale, 1992). Virtually all nucleated cells express MHC class I molecules with one notable exception being neurons ( Joly, Mucke, and Oldstone, 1991). It is also important to note that cell-surface MHC molecules always contain a peptide, usually a selfpeptide, which is not recognized by autologous T cells. Peptides presented by MHC class I molecules are recognized by T cells that express the CD8 molecule. CD8 binds to nonpolymorphic regions of the class I molecule and actively participates in transducing signals necessary for activation in coordination with the T-cell receptor (Emmrich, Strittmatter, and Eichmann, 1986). MHC class II molecules are expressed by a subpopulation of cells called antigen-presenting cells (APC). The primary APC include dendritic cells, macrophages, and B cells. Dendritic cells, which are very efficient at antigen capture and constitutively express class II molecules, are present in lymphoid tissues, blood, epithelia of the skin and gastrointestinal and respiratory tracts, and most parenchymal organs (Steinman and Nussenweig, 1980). Macrophages, which typically express low levels of class I molecules, are phagocytic cells and typically present peptides derived from extracellular pathogens such as bacteria and parasites. Class II expression is significantly increased by interferon-γ (IFNγ ), which is often expressed by immune cells in the presence of infection. B cells, which constitutively express class II molecules, utilize their antigen receptor (membrane-bound antibody) to bind and internalize foreign proteins. Thus, APC internalize extracellular proteins, which are digested into peptides in endocytic vesicles and bound to MHC class II molecules (Cresswell 1995). Peptide–MHC class II complexes are then transported to the cell surface for recognition by CD4+ T cells. Activation requirements for naive T cells are distinct from those from effector T cells. Naive T cells recognize antigens presented by dendritic cells in peripheral lymphoid organs. Activation of naive T cells requires multiple signals other than peptide/MHC engagement, including costimulation and cytokine signaling (Fig. 1.2). Engagement of the peptide/MHC complex by the T-cell receptor is often referred to as signal one

of T-cell activation. T-cell receptors are composed of unique α and β chains that form an antigen-specific binding site. In addition, naive T cells express a molecule called CD28 that binds B7 molecules on the APC and provides essential costimulatory signals necessary for T-cell activation, referred to as signal two. B7 is constitutively expressed on APC and initially engages CD28 on T cells, resulting in proliferation and cytokine expression (Fraser et al., 1991). Activated T cells then differentiate into antigenspecific effector T cells or memory T cells. Effector T cells and memory T cells require signal one, but usually do not require costimulation for activation (Lovett-Racke et al., 1998). Thus, recognition of foreign antigens in peripheral tissues where costimulatory molecules may not be present does not preclude effector T cells or memory T cells from effectively targeting those cells. Once T cells become activated, they proliferate or clonally expand primarily in response to the autocrine growth factor IL-2. After T cell–APC engagement, activation, and proliferation, an additional ligand for B7 called CTLA-4 is induced. CLTA-4 interaction with B7 sends an inhibitory signal to the T cell, resulting in decreased

Produces IFNγ, IL-2 and Iymphotoxin

Th1 cell

IFNγ and IL-12

TCR peptide MHC CD4+ T cell

Dendritic cell

CD4 CD28 IL-4

B7

Th2 cell

Produces IL-4, IL-5 and IL-13

Fig. 1.2 Naive T cells require two signals from the APC for differentiation and activation. T cells that encounter antigen in the presence of IFNγ and IL-12 differentiate into Th1 cells which express IFNγ, IL-2, and lymphotoxin, while IL-4 promotes the differentiation of Th2 cells which express IL-4, IL-5, and IL-13.

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activation and return of the T cell to a resting state (Krummel and Allison, 1995). The other critical factor in the differentiation of naive T cells is the cytokine milieu in which the naive T cells are differentiated. CD4+ T cells are generally classified into T helper 1 (Th1) and T helper 2 (Th2) cells based on the cytokines that are expressed by the CD4+ T cells (Cherwinski et al., 1987) (Fig. 1.2). The cytokines expressed by CD4+ T cells are actually determined by the cytokine present in the lymphoid tissue during the initial activation. IFNγ and IL-12, often expressed by APC and innate immune cells, direct the differentiation of Th1 cells, which subsequently express IFNγ, IL-2, and lymphotoxin (Hsieh et al., 1993; Reynolds, Boom, and Abbas, 1987). Recognition of pathogens occurs partially through a set of evolutionarily conserved proteins, called toll-like receptors (TLR), expressed by macrophages and other cells of the innate immune system. TLR recognize conserved pathogen-associated molecular patters, generating proinflammatory signals that are critical to the generation of an antigen-specific response. TLR signaling directly contributes to the cytokines generated by the APC and therefore effects the cytokine milieu in which antigen-specific T cells differentiate. For example, TLR signaling that induces the expression of IFNγ and IL-12 would promote the development of Th1. Th1 cells express these proinflammatory cytokines, which are often associated with immune-mediated tissue damage. In contrast, IL-4 directs the differentiation of Th2 cells which express IL-4, IL-5, IL-6, IL-10, and IL-13 (Swain et al., 1990). These anti-inflammatory cytokines expressed by Th2 cells can downregulate the effects of Th1 cells. More recently, a small, yet distinct population of CD4+ T cells that express IL-17 has been described. The requirement for the differentiation of this T-cell population is still unclear, but it appears that IL-23 plays a role in at least promoting the expansion of these T cells (Harrington et al., 2005; McKenzie, Kastelein, and Cua, 2006). CD4+ T cells primarily provide help to other immune cells by the cytokines that they express. For example, isotype switching of Ig genes is dependent on IL-4, which is primarily expressed by Th2 cells. Thus, B cells are very dependent on CD4+ T cells for antibody production. Naive CD8+ T cells require the same three signals (T-cell receptor engagement, costimulation, and cytokine signaling) as CD4+ T cells for differentiation into cytotoxic T lymphocytes (CTL). Since most nucleated cells express MHC class I molecules, CD8+ T cells can differentiate in both the lymphoid tissue

and any peripheral tissue that express foreign or tumor antigens. CD4+ T cells often play a critical role in CD8+ T-cell differentiation by producing cytokines or activating APC via CD40–CD40L engagement, which subsequently stimulates CD8+ T cells. CD8+ T cells mediate their effects by two primary mechanisms. CD8+ T cells can function as CTL in which cytoplasmic granules containing perforin and granzymes are released by the CD8+ T cell upon T-cell receptor engagement resulting in the killing of the antigenpresenting cell (Masson and Tschopp, 1987). In addition, CD8+ T cells can produce cytokines, such as IFNγ, lymphotoxin, and TNFα, which can activate phagocytes, increase inflammation, and alter the function of other immune cells (Ramshaw et al., 1992). Trafficking of lymphocytes is key to an effective immune response. Chemokines play a central role in the recruitment of immune cells to the site of infection. Chemokines up-regulate expression of adhesion molecules on the vascular endothelium, which are necessary for lymphocytes to enter tissues when directed by chemotactic signals. The CNS entry of activated lymphocytes, monocytes, and dendritic cells positive for distinct sets of chemokine receptors is also controlled by a gradient of corresponding chemokines between the CNS and the peripheral circulation. The intervening blood–brain barrier is composed of cerebrovascular endothelial cells, pericytes, and astrocytic processes (Carlson et al., 2006). This multifunctional complex structure is involved in the regulation of cell trafficking and the development of CNS autoimmunity (see Chapter 3). Lymphocyte maturation and immunogenetics Lymphocytes arise from pluripotent stem cells in the bone marrow. Early lymphocyte maturation is dependent on rapid proliferation of lymphocyte progenitors promoted by IL-7 (Peschon et al., 1994). The generation of large numbers of immature lymphocytes provides a sizable group of cells with a highly diverse repertoire of antigen receptors necessary to protect the host from diverse pathogens. The diverse repertoire of antigen receptors for both B and T cells is generated by somatic recombination, also termed genetic rearrangement (Okada and Alt, 1994). Human B cell receptor genes are located on three different chromosomes: the heavy chain locus is on chromosome 14; the κ light chain is on chromosome 2; and the λ light chain is on chromosome 22. Each locus contains a set of V (variable) genes, J ( joining) genes, and C (constant) genes. In addition, the heavy

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The basics of cellular and molecular immunology

gene locus contains D (diversity) genes. The number of V, D, and J genes varies between loci and species. For example, the V region of the heavy chain of human B cells contains approximately 45 genes, while the Vκ locus contains about 35 genes and the Vλ locus contains about 30 genes. Although all cells have these loci, these germline genes are not transcribed into messages that encode antigen receptors. In B cells, a gene from each V, (D), and J region is joined by somatic recombination, involving doublestrand DNA breaks within the V, (D), and J regions, and ligating these segments together such that a single V, (D), and J gene form a single exon capable of being transcribed. This V–(D)–J gene codes for the antigen-binding site of antibodies. The diversity of B cell antigen receptors is created by the multiple V, (D), and J genes which can potentially combine, the additions or deletions of nucleotides that can occur during ligation of V, (D), and J genes; somatic mutations within recombined V–(D)–J segments that can occur following B-cell activation; and antigen receptor editing in which a B cell may select a new light chain to pair with an existing heavy chain. Immature B cells that express an antigen receptor then undergo a process of negative selection in the bone marrow in which B cells with antigen receptors specific for selfproteins are deleted or fail to mature (Grandien et al., 1994). These nonself-reactive B cells then migrate into the periphery where they are capable of recognizing and responding to foreign proteins. Maturation of T cells and development of the T-cell receptor is quite similar to B cells. T-cell precursors are derived from stem cells in the bone marrow or fetal liver and migrate to the thymus where these thymocytes proliferate and undergo somatic recombination. The germline configuration of T-cell receptor genes is similar to B-cell receptor genes. T-cell receptors can form from the pairing of an α and β chain or a γ and δ chain, with αβ T-cell receptors expressing significantly more diversity and being expressed by the majority of T cells (Kronenberg et al., 1986). The α, δ locus is located on chromosome 14, the β locus is on chromosome 7, and the γ locus is on chromosome 7. The α and γ loci contain multiple V and J genes, while the β and δ genes also include a set of D genes. The recombination of V–(D)–J genes within thymocytes results in a unique T-cell receptor gene for each T cell. The diversity of T-cell receptors results from combinatorial and junctional diversity similar to that observed in B cells, but somatic mutations and receptor editing have not been observed in T cells. Thymocytes with a T-cell receptor that

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recognize self-MHC are stimulated to survive and thus positively selected (Pardoll and Carerra, 1992). Subsequently, thymocytes that have a T-cell receptor that strongly recognizes self-peptides are programmed to die and thus negatively selected. Therefore, the host’s T cells only recognize peptides in the context of self-MHC and potentially autoreactive T cells are eliminated in the thymus. Mature T cells exit the thymus and migrate to lymphoid tissues, where they await the encounter with antigen-laden APC. Immune privilege, tolerance, and autoimmunity There are several sites in the body, called immunologically privileged sites, in which normal immune responses are not typically elicited. Immune privilege was originally described when tissue grafts placed in some areas of the body failed to elicit an immune response and consequently were not rejected. Immunologically privileged sites include the brain, eye, testis, and uterus. The brain has several features that normally protect it from immune-mediated damage (Steilein, 1993). First, there is limited lymphatic drainage from the brain. Second, there is a blood–brain barrier established by vascular endothelium cells that form tight junctions, preventing the transport of most cells and proteins into the brain. Third, there is limited expression of MHC molecules in the brain, reducing the possibility that T cells can become activated in the brain. Interestingly, antigens sequestered in immunologically privileged sites may be the target of autoimmune diseases. For example, experimental autoimmune encephalomyelitis, a model for multiple sclerosis, is induced by immunization with myelin proteins and the disease can be transferred to naive recipients by transfer of myelin-specific T cells (Martin and McFarland, 1995). In addition, both healthy individuals and multiple sclerosis patients have myelinspecific T cells, but the activation state of these T cells is different (Lovett-Racke et al., 1998). Thus, it appears that autoreactive T cells are not completely eliminated in the thymus during negative selection. The failure to delete some autoreactive T cells may be due to low avidity T-cell receptors on these cells or minimal expression of some selfpeptides in the thymus during T-cell maturation. The realization that all individuals have T cells that recognize self-peptides has led to the discovery that T-cell tolerance is critical to limiting autoimmune disease. Central tolerance is the phenomenon

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described above in which self-reactive T cells are deleted in the thymus during maturation. Peripheral tolerance is obtained through several mechanisms. Naive CD4+ T cells, which normally require both T-cell receptor-peptide/MHC engagement and costimulation for activation, can become anergic (unresponsive to antigen) if they engage peptide/MHC in the absence of costimulation (Gimmi et al., 1993). Since peripheral antigen-presenting cells express few, if any, costimulatory molecules in the absence of infection, autoreactive T cells may commonly engage self-peptide/MHC complexes in the absence of costimulation in the periphery, resulting in clonal anergy. T cells may also become tolerant in the periphery if the T cell expresses CTLA-4, the inhibitory receptor for B7, at the time of T-cell receptor engagement (Perez et al., 1997). Since CTLA-4 binds B7 with a higher affinity, autoreactive T cells that express low levels of B7 may preferentially bind CTLA-4 and become anergic. It has recently been postulated that regulatory T cells, defined as CD4+CD25+Foxp3+ T cells, induce tolerance by blocking the function and activation of effector T cells. Mutation in the human Foxp3 gene results in multisystem autoimmune disease, suggesting that the regulatory T cells are critical for self-tolerance (Patel, 2001). It is speculated that infections may play a critical role in the loss of self-tolerance and the onset of autoimmunity. Infections can induce the expression of costimulatory molecules on cells presenting selfproteins. Thus, peripheral antigen-presenting cells, once incapable of activating self-reactive T cells, may now be capable of eliciting a destructive immune response against self-tissues. This is supported by the observation that mice with a transgenic T-cell receptor for myelin basic protein usually remain healthy in a pathogen-free environment, but frequently develop spontaneous experimental autoimmune encephalomyelitis in a conventional environment (Goverman et al., 1993). Another mechanism by which infections may trigger autoimmunity is molecular mimicry (Fujinami and Oldstone, 1985). Pathogens induce the activation of T cells and B cells that may have antigen receptors that can cross-react with self-proteins. As a result, T cells and antibodies originally expanded by recognition of a foreign protein may target and destroy self-tissues. Summary The immune system is designed to protect the host from pathogens and tumors. The diversity of the

antibody and T-cell repertoire and the selection process that occurs during lymphocyte maturation ensures that the immune system is capable of recognizing and responding to the vast array of potential microbes with minimal damage to the host. However, this does not preclude the possibility that some hosts harbor lymphocytes that may inadvertently recognize self-proteins under some circumstances. Our increasing understanding of lymphocyte maturation, selection, activation, and tolerance will provide insight into the understanding of immune-mediated diseases and potential therapeutic interventions. References Braciale, T.J. 1992. Antigen processing for presentation by MHC class I molecules. Curr Opin Immunol, 4, 59–62. Carlson, M.J., Doose, J.M., Melchior, B., Schmid, C.D. and Ploix, C.C. 2006. CNS immune privilege is not immune isolation. Immunol Rev, 213, 48–65. Cherwinski, H.M., Schumacher, J.H., Brown, K.D. and Mosmann, T.R. 1987. Two types of mouse helper T cell clone. III. Further differences in lymphokine synthesis between Th1 and Th2 clones revealed by RNA hybridization, functionally monospecific bioassays, and monoclonal antibodies. J Exp Med, 166, 1229–44. Cresswell, P. 1995. Assembly, transport and function of MHC class II molecules. Ann Rev Immunol, 12, 259–93. Edelman, G.M., Cunningham, B.A., Gall, W.E., Gottlieb, P.D., Rutihauser, U. and Waxdal, M.J. 1969. The covalent structure of an entire gamma G immunoglobulin molecule. Proc Natl Acad Sci USA, 63, 78–85. Emmrich, F., Strittmatter, U. and Eichmann, K. 1986. Synergism in the activation of human CD8 T cells by cross-linking the T-cell receptor complex with the CD8 differentiation antigen. Proc Natl Acad Sci USA, 83, 8298–302. Fraser, J.D., Irving, B.A., Grabtree, G.R. and Weiss, A. 1991. Regulation of interleukin-2 gene enhancer activity by the T-cell accessory molecule CD28. Science, 251, 313–16. Fujinami, R.S. and Oldstone, M.B. 1985. Amino acid homology between the encephalitogenic site of myelin basic protein and virus: Mechanism for autoimmunity. Science, 230, 1043–5. Gimmi, C.D., Freeman, G.J., Gribben, J.G., Gray, G. and Nadler, L.M. 1993. Human T-cell clonal anergy is induced by antigen presentation in the absence of B7 costimulation. Proc Natl Acad Sci USA, 90, 6586–90. Gounni, A.S., Lamkhioued, B., Ochiai, K. et al. 1984. High-affinity IgE receptor on eosinophils is

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The basics of cellular and molecular immunology

involved in defense against parasites. Nature, 367, 183–6. Goverman, J., Woods, A., Larson, L., Weiner, L.P., Hood, L. and Zaller, D.M. 1993. Transgenic mice that express a myelin basic protein-specific T cell receptor develop spontaneous autoimmunity. Cell, 72, 551–60. Grandien, A., Modigliani, Y., Freitas, A., Andersson, J. and Coutinho, A. 1994. Mechanisms that control antigen receptor variable region gene assembly. Semin Immunol, 6, 185–96. Harrington, L.E., Hatton, R.D., Mangan, P.R. et al. 2005. Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol, 6, 1123–32. Hilschman, N. and Craig, L.C. 1969. Amino acid sequence studies with Bence–Jones proteins. Proc Natl Acad Sci USA, 53, 1403–9. Hsieh, C.S., Macatonia, S.E., Tripp, C.S., Wolf, S.F., O’Garra, A. and Murphy, K.M. 1993. Development of TH1 CD4+ T cells through IL-12 produced by Listeria-induced macrophages. Science, 260, 547–9. Joly, E., Mucke, L. and Oldstone, M.B. 1991. Viral persistence in neurons explained by lack of major histocompatibility class I expression. Science, 253, 1283–5. Kataoka, T., Kawakawi, T., Takahashi, N. and Honjo, T. 1980. Rearrangement of the immunoglobulin γ1-chain gene and mechanism for heavychain class switch. Proc Natl Acad Sci USA, 77, 919–23. Kronenberg, M., Siu, G., Hood, L.E. and Shastri, N. 1986. The molecular genetics of the T-cell antigen receptor and T-cell antigen recognition. Annu Rev Immunol, 4, 529–91. Krummel, M.F. and Allison, J.P. 1995. CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation. J Exp Med, 182, 459–65. Leijh, P.C., van den Barselaar, M.T., Daha, M.R. and van Furth, R. 1981. Participation of immunoglobulins and complement components in the intracellular killing of Staphylococcus aureus and Escherichia coli by human granulocytes. Infect Immun, 33, 714–24. Lovett-Racke, A.E., Trotter, J.L., Lauber, J., Perrin, P.J., June, C.H. and Racke, M.K. 1998. Myelin basic protein-reactive T cells are less dependent on CD28-mediated costimulation in multiple sclerosis patients: A marker of activation/memory T cells. J Clin Invest, 101, 725–30. Maloney, D.G., Grillo-López, A.J., White, C.A. et al. 1997. IDEC-C2B8 (Rituximab) anti-CD20 monoclonal antibody therapy in patients with relapsed low-grade non-Hodgkin’s lymphoma. Blood, 90, 2188–95. Martin, R. and McFarland, H.F. 1995. Immunological aspects of experimental allergic encephalomyelitis and multiple sclerosis. Crit Rev Clin Lab Sci, 32, 121–82.

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Masson, D. and Tschopp, J. 1987. A family of serine esterases in lytic granules of cytolytic T lymphocytes. Cell, 49, 679–85. McKenzie, B.S., Kastelein, R.A. and Cua, D.J. 2006. Understanding the IL-23-IL-17 immune pathway. Trends Immunol, 27, 17–23. Miller, D.H., Khan, O.A., Sheremata, W.A. et al., and the International Natalizumab Multiple Sclerosis Trial Group. 2003. A controlled trial of Natalizumab for relapsing multiple sclerosis. N Engl J Med, 348, 15–23. Morrison, L.A., Lukacher, A.E., Braciale, V.L., Fan, D.P. and Craciale, T.J. 1986. Differences in antigen presentation to MHC class 1 and class II-restricted influenza virus-specific cytolytic T-lymphocyte clones. J Exp Med, 163, 903–21. Okada, A. and Alt, F.W. 1994. Mechanisms that control antigen receptor variable region gene assembly. Semin Immunol, 6, 185–96. Pardoll, D. and Carerra, A. 1992. Thymic selection. Curr Opin Immunol, 4, 162–5. Patel, D.D. 2001. Escape from tolerance in the human X-linked autoimmunity-allergic disregulation syndrome and the Scurfy mouse. J Clin Invest, 107, 155–7. Perez, V.L., van Parijs, L., Biuckians, A., Zheng, X.X., Strom, T.B. and Abbas, A.K. 1997. Induction of peripheral T cell tolerance in vivo requires CTLA-4 engagement. Immunity, 6, 411–17. Peschon, J.J., Morrissey, P.J., Grabstein, K.H. et al. 1994. Early lymphocyte expansion is severely impaired in interleukin 7 receptor-deficient mice. J Exp Med, 180, 1955–60. Ramshaw, I., Ruby, J., Ramsay, A., Ada, G. and Karupiah, G. 1992. Expression of cytokines by recombinant vaccinia viruses: A model for studying cytokines in viral infections in vivo. Immunol Rev, 127, 157–82. Reynolds, D.S., Boom, W.H. and Abbas, A.K. 1987. Inhibition of B lymphocyte activation by interferongamma. J Immunol, 139, 767–73. Schleimer, R.P., MacGlashan, D.W., Petters, S.P., Pinchard, R.N., Adkinson, N.F. and Lichtenstein, L.M. 1986. Characterization of inflammatory mediator release from purified human lung mast cells. Ann Rev Resp Dis, 133, 614–17. South, M.A., Cooper, M.D., Wollheim, F.A., Hong, R. and Good, R.A. 1966. The IgA system. I. Studies of the transport and immunochemistry of IgA in the saliva. J Exp Med, 123, 615–27. Steinman, R.M. and Nussenweig, M.C. 1980. Dendritic cells: features and functions. Immunol Rev, 53, 127–47. Steilein, J.W. 1993. Immune privilege as the result of local tissue barriers and immunosuppressive microenvironments. Curr Opin Immunol, 5, 428–32. Swain, S.L., Weinberg, A.D., English, M. and Huston, G. 1990. IL-4 directs the development of Th2-like helper effectors. J Immunol, 145, 3796–806.

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Uhr, J.W. and Finkelstein, M.S. 1963. Antibody formation. IV. Formation of rapidly and slowly sedimenting antibodies and immunological memory to bacteriophage phi-X 174. J Exp Med, 117, 457–77. Wu, T.T. and Kabat, E.A. 1970. An analysis of the sequences of the variable regions of the Bence– Jones proteins and myeloma light chain and their

implications for antibody complementarity. J Exp Med, 132, 211–50. Yednock, T.A., Cannon, C., Fritz, L.C., Sanchez-Madrid, F., Steinman, L. and Karin, N. 1992. Prevention of experimental autoimmune encephalomyelitis by antibodies against alpha 4 beta 1 integrin. Nature, 356, 63–6.

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2 Major components of myelin in the mammalian central and peripheral nervous systems Alexander Gow

Introduction Insulation of large diameter axons by supporting glia in the nervous system is a feat of evolution that has appeared independently at least three times (Waehneldt, 1990): in worms (Annelida), in crustaceans (Crustacea), and in terrestrial and some marine vertebrates (Gnathostomata). Although each of these incarnations has yielded insulation with distinct morphologies, the critical feature in each instance is a multilayered cellular sheath that confers high-speed neural transmission, enables large reductions in energy expenditure, and allows for compaction of the nervous system. In vertebrates, this insulation takes the form of the myelin sheath, which is a very stable lipid-rich membrane that is wrapped around segments of larger diameter axons in the central nervous system (CNS) and peripheral nervous system (PNS) and some dendrites. In its native state, the myelinated axon is often descriptively likened to link-sausage in lay terms; the sausage portions being analogous to myelin sheaths and the knots in between analogous to short bare regions of the axon, which are called nodes of Ranvier (sites of sodium channel clustering for neural transmission). However, myelin sheaths are not simply blobs of fatty substance along the axon but, rather, are large specialized flattened membrane domains that are spirally wrapped around segments of axons, as illustrated in Fig. 2.1 for a CNS myelin sheath. In further contrast to the humble sausage, myelin sheaths are by no means amorphous or uniform membranes but are highly organized and compartmentalized. At the ultrastructural level, the vertebrate myelin sheath has a very distinct organization. A flattened, cytoplasm-containing membrane process from a myelinating cell contacts and expands radially and longitudinally around an axon, loosely enveloping it in a manner analogous to rolling up a newspaper. The membrane then compacts to tighten around the axon and extrude the cytoplasm. During this process, cytoplasmic membrane surfaces become juxtaposed

and appear to fuse together. In electron micrographs, these fused surfaces are darkly stained by lead salts and the spiral line is known as the major dense line. The extracellular surfaces of the membrane also become juxtaposed; however, these surfaces do not fuse but, rather, maintain a discrete distance to form the minor dense line. Myelinating oligodendrocytes and Schwann cells Myelin sheaths elaborated by oligodendrocytes in the CNS and Schwann cells in the PNS share similar organizations and serve the same functions (Arroyo and Scherer, 2000). Typically, axons are small caliber in the CNS and myelin sheaths may reach 500 µm in length with 50–100 lamellae. In the PNS, myelin sheaths may be over 1000 µm in length and comprise 200 or so lamellae. There is a linear relationship between the diameter of an axon and the size of the myelin sheath. In the CNS and PNS, axons must exceed minimum diameters to be myelinated, which are approximately 0.5 µm and 1 µm, respectively. Several features distinguish CNS and PNS myelin: a Schwann cell establishes a one-to-one relationship around a segment of a single axon while most oligodendrocytes synthesize and maintain multiple myelin sheaths around a number of nearby axons, perhaps as many as 50; a Schwann cell synthesizes a collagenous basement membrane around the outside of the cell to form a tube, oligodendrocytes do not; in the event of axonal transection in the PNS, axons usually regrow through the original basement membrane tube and are reinvested by Schwann cells and remyelinated; in the CNS transected axons generally do not regrow. Major functions of myelin A major function of the myelin sheath is to electrically insulate a segment of axon. In this regard, myelin is analogous to the coating around the outside of

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Outer Loop

A

Internodal Tight Junction

Compact Myelin

Paranodal Tight Junction

Paranodal Loop Node of Ranvier

JP

Axon

Axoglial Junction Paranode

Node of Ranvier

JP

Inner Loop Internode

B

C Tight Junctions Axon

Paranode

Compact Myelin Tight Junctions Axon

Cyt.

JP

Paranode

Node of Ranvier Axoglial Junction

Fig. 2.1 Salient features of a myelin sheath in the CNS. (a) Myelin sheath synthesized by an oligodendrocyte has been “unfurled” from around an axonal segment to reveal the major features of this rhomboidal-flattened membrane process. The central region of the myelin sheath, or internodal myelin, contains no cytoplasm to allow for membrane compaction; however, the perimeter of the sheath maintains a cytoplasmic channel for maintenance of the myelin components and signaling with the cell body. Cytoplasmic channels, or Schmidt–Lantermann incisures, are also observed in compact regions of large myelin sheaths, especially in the PNS. Tight junctions are observed throughout the myelin sheath. They form the radial component of compact myelin that is observed in electron micrographs. At paranodes, tight junctions seal the extracellular space between myelin lamellae, which is analogous to their function in polarized epithelial cell layers. The axonal membrane is segmented underneath each myelin sheath into at least three distinct compartments: paranodes, juxtaparanodes (JP), and an internode. Cytoplasmic scaffolds anchor and maintain boundaries between distinct sets of proteins in each domain. A sodium channel domain is also maintained at nodes of Ranvier between myelin sheaths. (b) Transverse section through the internodal region of a myelinated axon reveals the spiraling, multilamellar structure of myelin and the locations of tight junctions. (c) Longitudinal section through the paranodal region of a myelinated axon reveals the axoglial junction (black dots) that sticks the cytoplasm-filled (Cyt.) paranodal loops of the myelin sheath to the axon. In electron micrographs, these junctions are referred to as transverse bands.

copper wires in underground cables that supply a suburb with electricity. Shielding the conductive fiber (copper wire or axon) dramatically reduces current dissipation to the environment and isolates the signal from interfering with signals in other conductive fibers. In similar fashion to an underground cable, electrical signals traveling along an axon (action potentials) must be boosted at regular distances to maintain signal strength and integrity. This is achieved for the underground cable using step-up transformers at relay stations. In the axon, boosting the signal is achieved at nodes of Ranvier between the myelin sheaths. In these regions of an axon, voltage-sensitive sodium channels are clustered at

high density and open when they detect an approaching action potential. The current that flows into the axon through these ion channels is greater than that flowing along the axon; thus, depolarization at nodes of Ranvier boosts the signal and propagates it toward the nerve terminal. After an action potential has passed through a region of the axon, ATPases in the axonal membrane must pump out the sodium ions that entered through the channels and repolarize the axon in preparation for the next action potential. There are several advantages conferred on neural communication by myelin that are pivotal to the success of the insulated nervous system. First, myelin enables an electrical signal to travel along the axon

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approximately 10 times faster than it would in an unmyelinated axon of similar size; thus, animals can respond to their environment very rapidly. Furthermore, axons can be of smaller diameter and still conduct signals rapidly which enables miniaturization of the nervous system or enhancement of its complexity by increasing the number of axons. Second, myelin dramatically reduces energy consumption. Membrane depolarization/repolarization is an energyintensive process that, in an unmyelinated axon, occurs along its entire length as the action potential moves like a wave to the nerve terminal; however, myelin limits depolarization to nodes of Ranvier as the action potential jumps from node to node (saltatory conduction) and only small regions of the axon need to be repolarized.

regrowth is very limited and is potently inhibited by several components of myelin sheaths that participate in the Nogo ligand–receptor complex. To serve as a guide to molecular components of the myelinated axon, I describe general features of the major proteins and lipids that comprise myelin sheaths in the CNS and PNS as well as important neuronal proteins with which the myelin proteins interact. In addition, I briefly touch on transcriptional regulation of myelin genes and provide some discussion aimed at dispelling the notion of the myelin sheath as an immune-privileged compartment.

Diseases of myelin

Located on the short arm of chromosome 12 in humans (12p13) and on chromosome 6 in mice (6 F2), the CD9 gene yields a single transcript (Boucheix et al., 1991). CD9 is a polytopic membrane glycoprotein with four putative transmembrane domains and the amino and carboxyl termini exposed to the cytoplasm. This protein was initially recognized as an abundant protein on the surface of developing B lymphocytes and platelets but is not required for development of these cell types. The protein is expressed by differentiated Schwann cells and its gene is regulated by the presence of axons in vitro and in vivo in similar fashion to other myelin genes (Banerjee and Patterson, 1995). CD9 is also expressed by oligodendrocytes and localized to myelin paranodes in the CNS (Ishibashi et al., 2004; Nakamura, Iwamoto, and Mekada, 1996). CD9 has been associated with a number of functions. It is the receptor for pregnancy-specific glycoprotein-17 in mice (Waterhouse, Ha, and Dveksler, 2002). CD9 functions in concert with CD81 and integrin-α6β1 to regulate sperm–egg fusion (Le Naour et al., 2000; Miyado et al., 2000) and also appears to interact with this integrin in myelinating cells. Female knockout mice exhibit reduced fertility and both males and females exhibit mild paranodal pathology in the CNS and PNS where axoglial junctions of some paranodes are partially disrupted and important paranodal components including Caspr and NF155 are mislocalized (Ishibashi et al., 2004).

In neurodegenerative disease states myelin sheaths can be direct or indirect targets, which renders vulnerable the critical communication networks in the CNS and between the nervous system and the body. Certain regions of the myelin sheath are more sensitive to damage than others. The myelin paranode is particularly sensitive because it compartmentalizes the axonal membrane to cluster sodium channels at the node and potassium channels at the juxtaparanode, by means of the axoglial junction. Action potentials are slowed or may even fail to reach the nerve terminal (conduction block) if this compartmentalization is compromised. In contrast, internodal myelin is relatively resilient and can enable near normal conduction velocity with only a fraction of the normal number of lamellae around each segment of the axon. Although genetic diseases of myelin may damage specific regions of myelin sheaths, diseases involving the immune system such as multiple sclerosis or Guillain–Barré syndrome usually damage large regions of the nervous system containing hundreds or thousands of myelin sheaths and it is unlikely that the destruction will be localized to specific regions of these sheaths. Nonetheless, it is instructive to understand that myelin repair will be ineffective unless myelin paranodes can reestablish compartmentalization. In the event that axons are transected during the disease process, the CNS and PNS respond very differently. In the PNS, myelin sheaths around degenerating axons are cleared by macrophages and the proximal axon stumps sprout neurites which grow out to reinnervate their targets. In the CNS, axonal

Internodal proteins CD9

Myelin associated glycoprotein, MAG Located on the long arm of chromosome 19 in humans (19q13.1) and on chromosome 7 in mice

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(7 B1), MAG is alternatively spliced at the mutually exclusive exons 2 and 12, which yield the protein isoforms S-MAG and L-MAG, respectively (Schachner and Bartsch, 2000). MAG is a member of the immunoglobulin superfamily (IgSF) and is one of the earliest proteins to be inserted into the myelin membrane during development. This glycoprotein is localized to the inner loop in mature myelin where it can interact with surface lipids or proteins from the axon. One such interacting protein is the Nogo-66 receptor (NgR), which is present at the axolemma and in neurites. MAG is one of a number of myelin proteins that are involved in suppressing axonal outgrowth in the CNS, possibly through its interaction with the Nogo receptor on the surface of growth cones (Hunt, Coffin, and Anderson, 2002). Deletion of the MAG gene in mice causes a subtle late-onset phenotype in the CNS characterized by delayed myelin sheath formation (Bartsch et al., 1997; Li et al., 1994; Li et al., 1998; Montag et al., 1994). The PNS is also abnormal in MAG-null mice with tomaculae forming in some myelin sheaths shortly after birth and increasing in frequency with age, which suggests that MAG may regulate axonal caliber, at least in the PNS (Cai et al., 2002; Yin et al., 1998).

strongly to the headgroups of negatively charged lipids (Smith, 1992). The absence of the MBP gene in naturally occurring mutant mice, shiverer and mld, causes severe disease from an early age which is characterized by whole-body intention tremors and an inability to compact CNS myelin to form the major dense line ( Jacobs, 2005). MBP appears to play a similar role in PNS myelin (Martini et al., 1995a), although this is a minor role because of its low abundance and the presence of the MPZ protein (Giese et al., 1992; Martini et al., 1995a). The functions of Golli-MBP proteins have also been characterized in some detail. These proteins are not only expressed by oligodendrocytes, but also by neurons and in lymphoid tissue during development and autoimmune disease (MacKenzie, Ghabriel, and Allt, 1984; Pribyl et al., 1993). These proteins are localized to cell nuclei (Landry et al., 1996) and negatively regulate Ca2+-mediated signal transduction in T-lymphocytes (Feng et al., 2004) and oligodendrocytes ( Jacobs et al., 2005). Golli-null mice have a subtle phenotype characterized by regional hypomyelination and delayed myelination in the CNS. Myelin-associated oligodendrocyte basic protein, MOBP

Myelin basic protein, MBP Located on the long arm of chromosome 18 in humans (18q23) and on chromosome 18 in mice (18 E2-E4), the MBP gene is alternatively spliced at exons 2, 5, and 6 and gives rise to five major isoforms (de Ferra et al., 1985; Newman, Kitamura, and Campagnoni, 1987; Takahashi et al., 1985). In addition, several promoters are known for MBP; the canonical promoter used by myelinating oligodendrocytes and two upstream promoters that give rise to multiple Golli-forms of MBP by alternative splicing (Campagnoni et al., 1993). MBP is the second most abundant protein in CNS myelin and comprises approximately 35% of total protein by weight (Braun, 1984). MBP is an extrinsic membrane protein which is bound to the cytoplasmic surfaces of the myelin membrane and may serve as an electrostatic adhesive to form the major dense line of compact myelin (Omlin et al., 1982). The protein has a high content of positive charged amino acids and exhibits very little higher-ordered structure even when purified under non-denaturing conditions (Gow and Smith, 1989) and binds very

Located on the short arm of chromosome 3 in humans (3p22.1) and on chromosome 9 in mice (9 F4), the MOBP gene yields at least five isoforms by alternative splicing, with all isoforms sharing a common amino terminus (Holz et al., 1996; McCallion et al., 1999; Yamamoto et al., 1994). MOBP isoforms are small soluble proteins expressed at high levels by oligodendrocytes that are incorporated into compact myelin. Interestingly, one of the MOBP isoforms (MOBP155) includes tandem repeats of a proline-rich domain, suggesting it may interact with other proteins (Yamamoto et al., 1994). The gene is not expressed by Schwann cells. Similar to MBP, MOBP has an unusually high proportion of positively charged amino acids in its primary structure and is hypothesized to function at the major dense line (Yamamoto et al., 1994). Indeed, deletion of the MOBP gene in mice renders the myelin ultrastructure less stable to organic solvents than wild-type controls (Yamamoto et al., 1999). In addition, the organization of tight junctions in the mutant myelin appears to be partially disrupted. However, this disruption does not cause a behavioral

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phenotype, even though absence of the gene products is not compensated (Yoo et al., 2005). Myelin oligodendrocyte glycoprotein, MOG Located on the short arm of chromosome 6 in humans (6p22.1) and on chromosome 17 in mice (17 C), the MOG gene gives rise to six alternatively spliced transcripts in humans and to a single transcript in mice (Ballenthin and Gardinier, 1996; Pham-Dinh et al., 1995a; Pham-Dinh et al., 1995b). MOG is a type I transmembrane glycoprotein and is an IgSF member (Ballenthin and Gardinier, 1996; Kroepfl et al., 1996). The function of MOG is currently unknown; however, this protein is an antigenic component of CNS myelin and has been postulated as a major autoantigen for multiple sclerosis (Bernard et al., 1997). A proportion of the MOG pool in oligodendrocytes is glycosylated with the L2/HNK-1 epitope, suggesting that this protein may be involved in antigen presentation or serve as a co-receptor for T-cell activation (Burger et al., 1993; Steinman, 1993). Neither the absence of the MOG gene (Delarasse et al., 2003), nor overexpression of MOG (unpublished data) in transgenic mice causes a detectable oligodendrocyte phenotype. Several lines of evidence provide tantalizing hints that MOG may be involved in the pathophysiology of multiple sclerosis. First, the MOG gene is located in the major histocompatibility complex (MHC) in humans and mouse and shares homology with three other genes located in this region: butyrophilin, BT2.1, and BT3.2/B7-3 (Linsley et al., 1994; Pham-Dinh et al., 1995b). Second, although a minor component of myelin, MOG is known to be a very immunogenic protein in multiple sclerosis patients and in experimental autoimmune encephalomyelitis, EAE (Sun et al., 1991), and elicits both B- and T-lymphocyte reactivity. Finally, the localization of this protein at the plasma membrane of oligodendrocytes and to the external surfaces of myelin sheaths makes MOG an accessible target for immune interaction. Myelin protein zero, MPZ (P0) Located on the long arm of chromosome 1 in humans (1q22) and on chromosome 1 in mice (1 H3), the MPZ gene yields a single transcript and protein. MPZ is the major structural protein in PNS myelin. It is a type I transmembrane glycoprotein and an IgSF member. Crystallization of the extracellular domain of MPZ has revealed the mechanism by which

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this protein effects myelin membrane adhesion at minor dense lines of compact myelin (Shapiro et al., 1996). Thus, MPZ forms homotetramers in cis at the extracellular surfaces of the membrane, which pack together in a continuous array. Furthermore, these units interact in trans with tetramers on the apposing membrane surface and have been likened to molecular Velcro. At the major dense line, the tail of MPZ carries a net positive charge and appears to stabilize the major dense lines by interacting electrostatically with the negatively charged headgroups of myelin lipids (Giese et al., 1992; Martini et al., 1995a; Martini et al., 1995b), in similar fashion to MBP. Mutations in MPZ are known to cause Charcot– Marie–Tooth disease and Dejerine–Sottas syndrome (Patel and Lupski, 1994) and demonstrate the importance of this protein at the major and minor dense lines. Nogo (reticulon 4, RTN4) Located on the short arm of chromosome 2 in humans (2p16.3-16.1) and on chromosome 11 in mice (11 A3.3), the Nogo gene gives rise to at least 12 mRNAs in humans by alternative splicing of exons 1–5 and alternative use of up to six tissue-specific promoters (Hunt, Coffin, and Anderson, 2002). These mRNAs encode seven distinct proteins, although there are only three major isoforms (Nogo-A, -B, and -C). Nogo appears to be an intrinsic membrane protein with two putative transmembrane domains and the amino and carboxyl termini exposed to the cytoplasm (Teng and Tang, 2005) and is the latest member of the reticulon family (Oertle et al., 2003). Nogo-B and -C are broadly expressed; however, Nogo-A is specific to the CNS and includes a large amino-terminal domain (amino-Nogo) not present in the other isoforms. One of the major functions of Nogo in many regions of the CNS is to suppress neurite outgrowth, and this inhibitory activity is widely believed to account for the virtual absence of regeneration following spinal cord injury. A 66-amino acid peptide located between the transmembrane domains of Nogo-A appears to be extracellular and confers the neurite outgrowth inhibition. This Nogo-66 domain interacts with the Nogo receptor (NgR) on neurons and causes growth cone collapse (Fournier et al., 2001; GrandPre et al., 2000). In addition, the amino-Nogo domain appears to inhibit neurite outgrowth, even though this region of the protein is probably exposed to the cytoplasm (McKerracher and Winton, 2002).

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The NgR is a heteromeric complex expressed by several classes of neurons and includes at least three co-receptors: p75NTR, LINGO-1, and TROY (Park et al., 2005). This protein complex is thought to effect neurite outgrowth through activation of RhoA and protein kinase C (Yamashita et al., 2005). Despite a plethora of evidence in favor of Nogo serving as a regeneration inhibitor, Nogo-null and NgR-null mice generated in several laboratories provide equivocal supporting evidence (Teng and Tang, 2005). Thus, regeneration in the CNS of experimentally injured mice may be enhanced or marginally improved, and these data suggest more complex regulation than, hitherto, has been appreciated. On the other hand, dominant-negative suppression of Nogo-66 binding to neuronal NgR enables neurite sprouting in vivo after spinal cord injury (Li et al., 2005). In this animal model, Li and colleagues use the astrocyte-specific Gfap promoter to drive expression of a soluble NgR fragment, which is secreted into the CNS and blocks Nogo-66 binding to the endogenous receptor on neurons. Oligodendrocyte-myelin glycoprotein, OMG Located on the long arm of chromosome 17 in humans (17q11.2) and on chromosome 16 in mice (16 B1), the OMG gene gives rise to a single mRNA in humans and mouse (Mikol et al., 1993). OMG is a type I membrane glycoprotein attached to the membrane surface via a glycosyl-phosphatidylinositol (GPI) anchor (Mikol et al., 1993) and is a member of a small family of proteins with a conserved leucine-rich repeat domain that is required for function, at least in vitro (Vourc’h and Andres, 2004; Vourc’h et al., 2003). OMG is a potent inhibitor of neurite outgrowth in the CNS (Kottis et al., 2002; Wang et al., 2002). This protein serves as a ligand for the NgR expressed on neurons and appears to compete with Nogo-66 for binding to the NgR (Hunt, Coffin, and Anderson, 2002). Like Nogo-66, OMG is expressed by some neurons and may also interact with the NgR in cis (Hunt, Coffin, and Anderson, 2002). In the CNS, OMG is localized at myelin paranodes but is expressed by NG2-like cells that extend OMG+ processes to encircle nodes of Ranvier (Huang et al., 2005). In this location, OMG is ideally located to inhibit neurite outgrowth. In the PNS, OMG is expressed by Schwann cells and may be localized to microvilli that contact nodes of Ranvier. In OMGnull mice, neurite sprouting at CNS nodes of Ranvier are observed (Huang et al., 2005), which confirms a major function of this protein.

Peripheral myelin protein, PMP22 Located on the short arm of chromosome 17 in humans (17p12-p11.2) and on chromosome 11 in mice (11 B3), the PMP22 gene expression is regulated from two tissue-specific promoters which give rise to distinct 5′ untranslated regions. The distal promoter is utilized by Schwann cells while the proximal promoter is used in non-neural tissues (Bosse et al., 1994; Suter et al., 1994). However, the coding regions encoded by both mRNAs are identical. PMP22 is a polytopic membrane glycoprotein expressed by myelinating Schwann cells that has four transmembrane domains, the first of which is N-glycosylated, and the amino and carboxyl termini are exposed to the cytoplasm (D’Urso and Muller, 1997). PMP22 is also expressed by growth-arrested fibroblasts that have been serum starved or contact inhibited (Manfioletti et al., 1990). Dedifferentiation and resumed proliferation in either cell type downregulates expression of PMP22. Although the specific function of PMP22 remains elusive, it is clear that this protein is involved in the maintenance of myelin thickness and stability as well as regulating Schwann cell proliferation. Overexpression, gene deletion, and coding region mutations have been found to cause several subtypes of Charcot–Marie–Tooth disease, which are motor and sensory peripheral neuropathies in humans. Naturally occurring missense mutations have also been characterized in rodents (Chance et al., 1993; Matsunami et al., 1992; Patel et al., 1992; Roa et al., 1993; Suter et al., 1992) and are thought to cause disease via a toxic gain-of-function mechanism similar to that proposed for PLP1 mutations in the CNS (Gow, 2004). Proteolipid protein, PLP1 Located on the long arm of the X chromosome in humans (Xq22) and on the X chromosome in mice (X F1-F2), PLP1 gene products comprise the major protein component of CNS myelin (Willard and Riordan, 1985). The PLPP1 gene in most terrestrial vertebrate species is alternatively spliced in exon 3, giving rise to two protein products, PLP1 and DM-20, which differ only by the presence or absence (respectively) of a 35-amino acid PLP1 specific peptide in the central cytoplasmic domain of the proteins (Hudson and Nadon, 1992). PLP1 and DM-20 together comprise approximately 50% of total myelin protein by weight (Braun, 1984)

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with PLP1 dominant over DM-20 by 6:1 in adult myelin. Both are intrinsic membrane proteins with identical topologies (Gow et al., 1997). They have four transmembrane domains and their amino and carboxyl termini are exposed to the cytoplasm. A major function of PLP1 is structural, with the protein regulating the spacing between the extracellular surfaces of compact myelin bilayers (Duncan et al., 1989; Klugmann et al., 1997). DM-20 may also function in this capacity; indeed, DM-20 increases the spacing at the extracellular membrane appositions in the absence of PLP1 (Stecca et al., 2000). PLP1 does exhibit functions not shared by DM-20. The molecular basis of these functions is currently poorly understood, but PLP1 serves to promote longterm stability of axon–oligodendrocyte interactions. In the absence of PLP1, fast axonal transport in myelinated fibers is unstable leading to axonal spheroids demyelination and axonal loss (Edgar et al., 2004a; Edgar et al., 2004b) and DM-20 cannot rescue this phenotype (Stecca et al., 2000).

1997), MAL is expressed by oligodendrocytes and Schwann cells during myelinogenesis (Kim et al., 1995; Schaeren-Wiemers et al., 1995). This protein has been shown in several cell types to participate in apically directed vesicular trafficking between the Golgi apparatus and the cell surface (Puertollano and Alonso, 1999) and may be a component of clathrinmediated endocytosis (Martin-Belmonte et al., 2003). Deletion of the MAL gene in mice does not cause any major behavioral phenotype. Nonetheless, this mutation results in abnormal attachment of some CNS myelin paranodal loops to axons with concomitant reductions in the trafficking of several myelinspecific proteins but partial preservation of axoglial junctions (Schaeren-Wiemers et al., 2004). There is no overt phenotype associated with PNS myelin, suggesting that Schwann cells either do not require MAL for normal function or compensate for its absence using another protein(s).

T-lymphocyte maturation-associated protein/myelin and T-lymphocyte protein, MAL

Claudin 11 (OSP)

Located on the long arm of chromosome 2 in humans (2q11.1) and on chromosome 2 in mice (127.147– 127.171 Mb), the MAL gene is alternatively spliced at either or both exons 2 and 3 to yield four isoforms (Rancano et al., 1994). Thus, isoform a includes exons 2 and 3; isoform b lacks exon 3; isoform c lacks exon 2; and isoform d lacks both exons 2 and 3. Because the splice donor sites of both exons are between codons, the reading frame of all four isoforms is maintained to the carboxyl terminus in exon 4. MAL is a small polytopic membrane protein with up to four hydrophobic domains of sufficient length to span the bilayer, depending on the isoform. Each exon encodes one hydrophobic domain and the absence of a cleaved signal peptide indicates that the amino terminus is probably exposed to the cytoplasm. Rancano and colleagues (Rancano et al., 1994) have proposed that hydrophobic domains in the alternatively spliced exons do not span the bilayer, but rather loop in and out of the extracellular surface of the membrane; thus, the protein has two transmembrane domains (encoded by exons 1 and 4) and the carboxyl terminus of all four isoforms is exposed to the cytoplasm. In addition to its expression in mature T lymphocytes where it co-purifies with detergent-insoluble membrane (lipid raft) microdomains (Perez et al.,

Paranodal and juxtaparanodal proteins

Located on the long arm of chromosome 3 in humans (3q26.2-q26.3) and on chromosome 3 in mice (3 12.6 cM), the claudin 11 gene yields a single transcript that is widely expressed inside and outside of the CNS during development and in adult animals (Gow et al., 1999; Morita et al., 1999). Claudin 11 is a polytopic transmembrane protein that is believed to harbor four transmembrane domains with its amino and carboxyl termini exposed to the cytoplasm. This protein is a member of a large family of proteins encoded by almost 30 genes in mammals, which serve as the principal structural components of tight junctions in most, if not all, polarized epithelial cell layers. Typically, these genes have broad and overlapping expression patterns so that most epithelia form tight junctions composed of several claudin family members. Claudin 11 is an exception to this rule in several tissues including testis, cochlea, and CNS myelin where it is the only family member present in the tight junctions (Gow et al., 2004; Gow et al., 1999; Kitajiri et al., 2004). In the absence of claudin 11, mice exhibit no overt behavioral symptoms apart from a mild body tremor that is transiently manifested in some animals and persistent in others. The morphology of CNS myelin appears unperturbed which suggests that these tight junctions, at most, play only a minor role in adhesion. Nevertheless, knockout animals exhibit 20–40%

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increases in the latencies of visual and auditory evoked potentials (Gow et al., 2004; Gow et al., 1999; Kitajiri et al., 2004) as well as sensorineural deafness and male sterility. Claudin 19 Located on the short arm of chromosome 1 in humans (1p34.2) and on chromosome 4 in mice (4 D2.1), the claudin 19 gene yields a single transcript that is highly expressed in the PNS as well as in the distal collecting ducts of the kidney. Claudin 19 is believed to exhibit the same topology as claudin 11, although the most closely related family members are claudins 1 and 7. In an analogous fashion to claudin 11, claudin 19 is the only family member present in Schwann cell tight junctions at the inner and outer mesaxons, and deletion of the claudin 19 gene in mice reduces saltatory conduction in a subpopulation of PNS axons in the absence of morphological disruption to compact myelin or paranodal axoglial junctions (Miyamoto et al., 2005). Thus, claudins 11 and 19 serve similar functions in myelin. Contactin Located on the long arm of chromosome 12 in humans (12q11-q12) and on chromosome 15 in mice (15 F), the contactin gene gives rise to a number of different transcripts in mice by northern blotting (Gennarini et al., 1989). These isoforms likely result from the use of alternate polyadenylation signals or possibly alternative splicing of untranslated regions. Contactin is a type I glycoprotein that lacks transmembrane and cytoplasmic domains and is bound to the cell surface via a glycosyl-phosphatidylinositol (GPI) anchor (Gennarini et al., 1989). This protein is an IgSF member and has six Ig-like domains and four FNIII-like domains. Contactin has been characterized extensively for its role in binding to other adhesion molecules and the extracellular matrix as well as its strong neurite outgrowth activity (Stoeckli et al., 1991). More recently, contactin has been shown to be a major component of axoglial junctions in the CNS and PNS and is expressed by axons, oligodendrocytes, and Schwann cells. Contactin interacts in cis with Caspr in the axonal membrane and in trans with Nfasc in myelin paranodal loops. In the CNS, contactin may also participate in homomeric interactions between the axon and myelin membranes (Tait et al., 2000).

Deletion of the contactin gene in mice causes severe defects in the CNS, characterized by extensive disorganization of Purkinje and cerebellar granular layer neurons; and in the PNS, characterized by the absence of axoglial junctions at myelin paranodes and the mislocalization of juxtaparanodal potassium channels to nodes of Ranvier (Berglund et al., 1999; Boyle et al., 2001). Contactin-associated protein, Caspr Located on the long arm of chromosome 17 in humans (17q21) and on chromosome 11 in mice (11 D), the Caspr gene yields a single transcript that is abundantly expressed in neurons (Einheber et al., 1997; Peles et al., 1997). Caspr is a type I glycoprotein with a single transmembrane domain and is targeted to axons underlying paranodal regions of myelin sheaths in the CNS and PNS (Einheber et al., 1997). This protein participates in axoglial junction assembly by associating in cis with contactin on the axonal surface and in trans with Nfasc and possibly contactin on the surface of myelin paranodal loops. Caspr may also interact with Nogo-A at paranodes (Nie et al., 2003). Deletion of the Caspr gene in mice causes a severe neurological phenotype characterized by widespread CNS and PNS behavioral phenotypes and early death (Bhat et al., 2001). Paranodal axoglial junctions fail to form (also called transverse bands or septate junctions), the targeting of sodium channels to nodes of Ranvier is perturbed, and juxtaparanodal delayed-rectifier potassium channels (Kv1.1 and Kv1.2) diffuse into the nodes and mix with the sodium channels. Neither contactin nor Nfasc are correctly targeted to myelin paranodes. Three additional Caspr family members have been identified. Casp2 is localized to juxtaparanodal regions of myelin sheaths, colocalizes with K+ channels (Poliak et al., 1999), and probably interacts with TAG-1 (Traka et al., 2003). In contrast, Caspr3 and 4 are expressed more regionally in different populations of neurons and Caspr3 is also expressed by oligodendrocytes (Spiegel et al., 2002). Neurofascin, Nfasc Located on the long arm of chromosome 1 in humans (1q32.1) and on chromosome 1 in mice (1 E4), the Nfasc gene gives rise to at least six protein isoforms through alternative splicing. Most of this splicing occurs for exons that encode extracellular regions

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of the protein. Cell-type specific alternative splicing between neurons and myelinating cells accounts for two of the splice isoforms; neuronal isoforms include a mucin domain, while myelinating cells include an additional FNIII domain (Southwood et al., 2004; Tait et al., 2000). At least two promoters have been identified and may confer relative cell-type specific expression in neurons and oligodendrocytes (unpublished). Nfasc is a type I glycoprotein with a single transmembrane domain. It is an IgSF member belonging to the L1 subgroup and typically contains six Ig domains and three FNIII domains in its extracellular region. Although Nfasc has been studied because of its neurite outgrowth promoting activity and participation in axon–axon interactions (Volkmer et al., 1996), it has most recently been characterized with regard to its roles in myelination and node of Ranvier formation. In the CNS, both the neuronal and myelin isoforms of Nfasc are targeted to paranodal regions of myelin sheaths where they participate in formation of axoglial junctions along with contactin and Caspr (Sherman et al., 2005; Tait et al., 2000). Neuronal splicing of the Nfasc gene encodes a 186 kD form of the protein (NF186) while oligodendrocytes and Schwann cells synthesize NF155. NF186 is also targeted to nodes of Ranvier, where it may participate in macromolecular complexes to stabilize the association of astrocyte processes with the nodal axonal membrane. In the PNS, NF155 synthesized by Schwann cells is targeted to myelin paranodes and axons target NF186 only to nodes of Ranvier. Deletion of the Nfasc gene in mice results in the absence of axoglial junctions at myelin paranodes, the failure of Schwann cell microvilli adhesion to the nodal axon, reduced saltatory conduction in a subpopulation of myelinated fibers, and early death (Sherman et al., 2005). Myelin lipids Traditionally, scholarly contributions from brain lipid research to our understanding of the molecular components of the nervous system have been prominent, although a switch to proteinaceous components triggered by recombinant DNA technologies in recent decades has shifted the focus of neurochemistry. A renaissance of lipid biochemistry in the nervous system is in progress and has yielded very important insights into function, particularly at the level of the myelin sheath (Taylor et al., 2004).

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To underscore their importance, lipids comprise 37% of total rat brain dry weight, but in purified myelin it exceeds 70% and is more than 50% complex lipids and cholesterol. Indeed, myelin is one of the most protein-poor membranes known (Norton and Cammer, 1984). Recent studies show that, like proteins, myelin lipids do not simply form the amorphous structures that were envisioned in the fluid mosaic model (Singer and Nicolson, 1972), but rather are assembled into highly organized domains that regulate structural protein clustering, receptor signaling activity, protein–protein and cell–cell interactions. The most intensively studied of these domains are lipid rafts, which are detergent resistant and enriched in glycolipids and cholesterol (Taylor et al., 2002). Several knockout mice have been generated to ablate different classes of myelin glycolipids and these have focussed on inactivating key enzymes in the biosynthetic pathways. Thus, ablation of the genes encoding ceramide sulfotransferase (CST), to eliminate sulfated glycolipids, or ceramide galactosyltransferase (CGT) to eliminate galactosyl and sulfated glycolipids, cause axoglial junction phenotypes largely limited to the CNS (Coetzee et al., 1996; Honke et al., 2002). These junctions form during myelinogenesis but eventually dissipate and cause myelin paranodal loops to dissociate from the axon with variable loss of compartmentalization and mixing of nodal and juxtaparanodal ion channels. Elimination of complex gangliosides by ablating GM2/GD2 synthase also causes myelination defects, although the phenotype is mild and appears to be more like a late-onset progressive disorder related more to motorneuron dysfunction and Wallerian degeneration than to myelin sheath abnormalities (Chiavegatto et al., 2000). Myelin glycolipids are also of importance to disease involving the immune system, particularly Guillain– Barré syndrome and other inflammatory neuropathies which lead to PNS myelin or neuromuscular dysfunction (Hughes and Cornblath, 2005; Overell and Willison, 2005). Thus, molecular mimicry stemming from infectious illnesses (often Hemophilus influenzae and Campylobacter jejuni infections) leads to the production of antibodies that cross-react with PNS gangliosides (GD1, GD3, or GQ1b) and myelin proteins that may disrupt myelin paranodes (Kwa et al., 2003). Transcriptional regulation of myelin genes Transcriptional regulation of myelin genes has been an area of study for relatively few laboratories in the myelin field and, in general, the data are relatively

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difficult to obtain. Working with primary oligodendrocyte cultures is difficult because large numbers of cells are not easily obtained, particularly from mice, and transfection efficiencies are low. A few cell lines have been generated for myelinating cells; however, these studies yield data of variable quality and should be interpreted with a healthy dose of skepticism as illustrated below. Accordingly, I only deal with two transcription factors for which in vivo data are available from knockout mouse studies. Importantly, these data provide genetic evidence of genes that are downstream of the transcription factor activity; they do not demonstrate that the transcription factor binds to the promoters/enhancers of those downstream genes. Nkx6-2 (Gtx) The transcription factor, Nkx6-2, is a homeodomain protein expressed in neurons during development and in oligodendrocytes postnatally (Awatramani et al., 1997; Cai et al., 1999; Komuro et al., 1993). From oligodendrocyte cell culture experiments, Nkx6-2 was found to act as a repressor of the PLP1 and MBP genes (Awatramani et al., 2000) and several consensus Nkx6-2 binding sites are present in the proximal promoter regions of these genes. Using an in silico approach, Farhadi and colleagues identified evolutionarily conserved binding sites in the MBP promoter/enhancer (Farhadi et al., 2003). However, expression of these genes is unperturbed in Nkx6-2null mice (Cai et al., 2001; Southwood et al., 2004), indicating that the transfection data are largely in vitro artifact. Consistent with the cell culture experiments, Nkx6-2 appears to act as a repressor in oligodendrocytes in vivo, but this transcription factor actually regulates at least two genes associated with axoglial junction formation, NF155 and contactin (Southwood et al., 2004). Olig1 and Olig2 The transcription factors, Olig1 and Olig2, are basic helix-loop-helix proteins coordinately expressed in neural progenitor cells and oligodendrocytes during development and in oligodendrocytes postnatally. Both proteins appear to regulate expression of the same genes in oligodendrocytes and each can partially compensate for the other. However, Olig1 function is far more important in brain than spinal cord and the converse is true for Olig2 (Lu et al., 2002, Xin et al., 2005).

In Olig1-null mice, oligodendrocyte progenitors born in the brain are able to migrate, proliferate, and differentiate to the point of recognizing and making contact with axons; however, myelinogenesis is arrested at this point which is just prior to expression of major myelin genes such as MAG, PLP1, and MBP (Xin et al., 2005). Arnett and colleagues (Arnett et al., 2004) suggest that Olig1 is only required for remyelination in the brain; however, this partial phenotype likely stems from a technical problem with the knockout construct that masks the developmental phenotype by enabling Olig2 to compensate for the absence of Olig1 during myelinogenesis. Thus, Olig1 is genetically upstream of a number of myelin-specific genes in vivo, although it seems unlikely that these genes are direct targets of Olig1. In contrast, Olig1null oligodendrocytes in primary cell culture can override this arrest in myelinogenesis and can synthesize myelin membrane and at least some myelin proteins (Xin et al., 2005). In Olig2-null mice, spinal cord oligodendrocyte precursor cells are apparently never born so it is unclear if this transcription factor regulates myelin gene expression (Lu et al., 2002). The notion of myelin as an immune-privileged compartment Originally, the concept of immune privilege arose from transplantation studies because of the relative lack of immune system activation toward grafted tissue in specific locations in the body such as the brain and the eye (reviewed by Bechmann, 2005). In light of the discovery that adaptive immunity, to distinguish “self” from “non-self”, is established perinatally in at least some mammals, the immune-privileged compartment concept was expanded to account for the absence of immune activation toward proteins that are not expressed until well after birth. From early morphological studies on Sertoli cells in the testis and subsequently in oligodendrocyte myelin sheaths, a common perception about the function of tight junctions assembled in these cells was that they defined immune-privileged compartments (reviewed in Abraham, 1991; Mugnaini and Schnapp, 1974). Thus, spermatocyte- and myelinspecific proteins that are not expressed in the perinatal period during the establishment of immune self-tolerance require lifelong sequestration from the immune system to avoid recognition as foreign antigens. This notion is consistent with the pathogenesis of autoimmune orchiditis in the testis and multiple

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sclerosis in the CNS, which were postulated to stem from the dysfunction of tight junctions and the release of “protected antigens” into the interstitium where they could be recognized by the immune system. However, the phenotype of claudin 11-null mice, which includes male sterility and reduced saltatory conduction velocity in the CNS, does not include signs of autoimmune disease in the testis or CNS, either in terms of infiltrating immune cells or the production of autoimmune antibodies (Gow et al., 1999). Accordingly, this mutant casts doubt on the longstanding notion that myelin proteins are shielded from the immune system by myelin tight junctions to protect against the induction of multiple sclerosis. Acknowledgments This work was supported by grants from NINDS, NIH (NS43783) and the National Multiple Sclerosis Society (RG2891). References Abraham, M., 1991. The male germ cell protective barrier along phylogenesis. Int Rev Cytol, 130, 111–90. Arnett, H.A., Fancy, S.P., Alberta, J.A. et al. 2004. bHLH transcription factor Olig1 is required to repair demyelinated lesions in the CNS. Science, 306, 2111–15. Arroyo, E.J. and Scherer, S.S. 2000. On the molecular architecture of myelinated fibers. Histochem Cell Biol, 113, 1–18. Awatramani, R., Beesley, J., Yang, H. et al. 2000. Gtx, an oligodendrocyte-specific homeodomain protein, has repressor activity. J Neurosci Res, 61, 376–87. Awatramani, R., Scherer, S., Grinspan, J. et al. 1997. Evidence that the homeodomain protein Gtx is involved in the regulation of oligodendrocyte myelination. J Neurosci, 17, 6657–68. Ballenthin, P.A. and Gardinier, M.V. 1996. Myelin/ oligodendrocyte glycoprotein is alternatively spliced in humans but not mice. J Neurosci Res, 46, 271–81. Banerjee, S.A. and Patterson, P.H. 1995. Schwann cell CD9 expression is regulated by axons. Mol Cell Neurosci, 6, 462–73. Bartsch, S., Montag, D., Schachner, M. and Bartsch, U. 1997. Increased number of unmyelinated axons in optic nerves of adult mice deficient in the myelinassociated glycoprotein (MAG). Brain Res, 762, 231–4. Bechmann, I. 2005. Failed central nervous system regeneration: A downside of immune privilege? Neuromolecular Med, 7, 217–28. Berglund, E.O., Murai, K.K., Fredette, B. et al. 1999. Ataxia and abnormal cerebellar microorganization

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in mice with ablated contactin gene expression. Neuron, 24, 739–50. Bernard, C.C., Johns, T.G., Slavin, A. et al. 1997. Myelin oligodendrocyte glycoprotein: A novel candidate autoantigen in multiple sclerosis. J Mol Med, 75, 77–88. Bhat, M.A., Rios, J.C., Lu, Y. et al. 2001. Axon–glia interactions and the domain organization of myelinated axons requires neurexin iv/caspr/paranodin. Neuron, 30, 369–83. Bosse, F., Zoidl, G., Wilms, S., Gillen, C.P., Kuhn, H.G. and Muller, H.W. 1994. Differential expression of two mRNA species indicates a dual function of peripheral myelin protein PMP22 in cell growth and myelination. J Neurosci Res, 37, 529–37. Boucheix, C., Benoit, P., Frachet, P. et al. 1991. Molecular cloning of the CD9 antigen. A new family of cell surface proteins. J Biol Chem, 266, 117–22. Boyle, M.E., Berglund, E.O., Murai, K.K., Weber, L., Peles, E. and Ranscht, B. 2001. Contactin orchestrates assembly of the septate-like junctions at the paranode in myelinated peripheral nerve. Neuron, 30, 385–97. Braun, P.E. 1984. Molecular organization of myelin. In P. Morell (ed.), Myelin, Plenum Press, New York, pp. 97–116. Burger, D., Steck, A.J., Bernard, C.C. and Kerlero de Rosbo, N. 1993. Human myelin/oligodendrocyte glycoprotein: A new member of the L2/HNK-1 family. J Neurochem, 61, 1822–7. Cai, J., Qi, Y., Wu, R. et al. 2001. Mice lacking the Nkx6.2 (Gtx) homeodomain transcription factor develop and reproduce normally. Mol Cell Biol, 21, 4399–403. Cai, J., St Amand, T., Yin, H. et al. 1999. Expression and regulation of the chicken Nkx-6.2 homeobox gene suggest its possible involvement in the ventral neural patterning and cell fate specification. Dev Dyn, 216, 459–68. Cai, Z., Sutton-Smith, P., Swift, J. et al. 2002. Tomacula in MAG-deficient mice. J Peripher Nerv Syst, 7, 181–9. Campagnoni, A.T., Pribyl, T.M., Campagnoni, C.W. et al. 1993. Structure and developmental regulation of Golli-mbp, a 105-kilobase gene that encompasses the myelin basic protein gene and is expressed in cells in the oligodendrocyte lineage in the brain. J Biol Chem, 268, 4930–8. Chance, P.F., Alderson, M.K., Leppig, K.A. et al. 1993. DNA deletion associated with hereditary neuropathy with liability to pressure palsies. Cell, 72, 143–51. Chiavegatto, S., Sun, J., Nelson, R.J. and Schnaar, R.L. 2000. A functional role for complex gangliosides: Motor deficits in GM2/GD2 synthase knockout mice. Exp Neurol, 166, 227–34. Coetzee, T., Fujita, N., Dupree, J. et al. 1996. Myelination in the absence of galactocerebroside and sulfatide: Normal structure with abnormal function and regional instability. Cell, 86, 209–19.

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de Ferra, F., Engh, H., Hudson, L. et al. 1985. Alternative splicing accounts for the four forms of myelin basic protein. Cell, 43, 721–7. Delarasse, C., Daubas, P., Mars, L.T. et al. 2003. Myelin/ oligodendrocyte glycoprotein-deficient (MOG-deficient) mice reveal lack of immune tolerance to MOG in wild-type mice. J Clin Invest, 112, 544–53. Duncan, I.D., Hammang, J.P., Goda, S. and Quarles, R.H. 1989. Myelination in the jimpy mouse in the absence of proteolipid protein. Glia, 2, 148–54. D’Urso, D. and Muller, H.W. 1997. Ins and outs of peripheral myelin protein-22: Mapping transmembrane topology and intracellular sorting. J Neurosci Res, 49, 551–62. Edgar, J.M., McLaughlin, M., Barrie, J.A., McCulloch, M.C., Garbern, J. and Griffiths, I.R. 2004a. Age-related axonal and myelin changes in the rumpshaker mutation of the Plp gene. Acta Neuropathol (Berl), 107, 331–5. Edgar, J.M., McLaughlin, M., Yool, D. et al. 2004b. Oligodendroglial modulation of fast axonal transport in a mouse model of hereditary spastic paraplegia. J Cell Biol, 166, 121–31. Einheber, S., Zanazzi, G., Ching, W. et al. 1997. The axonal membrane protein Caspr, a homologue of neurexin IV, is a component of the septate-like paranodal junctions that assemble during myelination. J Cell Biol, 139, 1495–506. Farhadi, H.F., Lepage, P., Forghani, R. et al. 2003. A combinatorial network of evolutionarily conserved myelin basic protein regulatory sequences confers distinct glial-specific phenotypes. J Neurosci, 23, 10214–23. Feng, J.M., Fernandes, A.O., Campagnoni, C.W., Hu, Y.H. and Campagnoni, A.T. 2004. The golli-myelin basic protein negatively regulates signal transduction in T lymphocytes. J Neuroimmunol, 152, 57–66. Fournier, A.E., GrandPre, T. and Strittmatter, S.M. 2001. Identification of a receptor mediating Nogo-66 in hibition of axonal regeneration. Nature, 409, 341–6. Gennarini, G., Cibelli, G., Rougon, G., Mattei, M.G. and Goridis, C. 1989. The mouse neuronal cell surface protein F3: A phosphatidylinositol-anchored member of the immunoglobulin superfamily related to chicken contactin. J Cell Biol, 109, 775–88. Giese, K.P., Martini, R., Lemke, G., Soriano, P. and Schachner, M. 1992. Mouse P0 gene disruption leads to hypomyelination, abnormal expression of recognition molecules, and degeneration of myelin and axons. Cell, 71, 565–76. Gow, A. 2004. Protein misfolding as a disease determinant. In R.A. Lazzarini (ed.), Myelin Biology and Disorders Vol. 1, Elsevier, Amsterdam, pp. 877–85. Gow, A., Davies, C., Southwood, C.M. et al. 2004. Deafness in Claudin 11-null mice reveals the critical contribution of basal cell tight junctions to stria vascularis function. J Neurosci, 24, 7051–62. Gow, A., Gragerov, A., Gard, A., Colman, D.R. and Lazzarini, R.A. 1997. Conservation of topology, but

not conformation, of the proteolipid proteins of the myelin sheath. J Neurosci, 17, 181–9. Gow, A. and Smith, R. 1989. The thermodynamically stable state of myelin basic protein in aqueous solution is a flexible coil. Biochem J, 257, 535–40. Gow, A., Southwood, C.M., Li, J.S. et al. 1999. CNS myelin and Sertoli cell tight junction strands are absent in Osp/Claudin 11-null mice. Cell, 99, 649–59. GrandPre, T., Nakamura, F., Vartanian, T. and Strittmatter, S.M. 2000. Identification of the Nogo inhibitor of axon regeneration as a Reticulon protein. Nature, 403, 439–44. Holz, A., Schaeren-Wiemers, N., Schaefer, C., Pott, U., Colello, R.J. and Schwab, M.E. 1996. Molecular and developmental characterization of novel cDNAs of the myelin-associated/oligodendrocytic basic protein. J Neurosci, 16, 467–77. Honke, K., Hirahara, Y., Dupree, J. et al. 2002. Paranodal junction formation and spermatogenesis require sulfoglycolipids. Proc Natl Acad Sci USA, 99, 4227–32. Huang, J.K., Phillips, G.R., Roth, A.D. et al. 2005. Glial membranes at the node of Ranvier prevent neurite outgrowth. Science, 310, 1813–17. Hudson, L.D. and Nadon, N.L. 1992. Amino acid substitutions in proteolipid protein that cause dysmyelination. In R.E. Martenson (ed.), Myelin: Biology and Chemistry, CRC Press, Boca Raton, pp. 677–702. Hughes, R.A. and Cornblath, D.R. 2005. GuillainBarre syndrome. Lancet, 366, 1653–66. Hunt, D., Coffin, R.S. and Anderson, P.N. 2002. The Nogo receptor, its ligands and axonal regeneration in the spinal cord; a review. J Neurocytol, 31, 93–120. Ishibashi, T., Ding, L., Ikenaka, K. et al. 2004. Tetraspanin protein CD9 is a novel paranodal component regulating paranodal junctional formation. J Neurosci, 24, 96–102. Jacobs, E.C. 2005. Genetic alterations in the mouse myelin basic proteins result in a range of dysmyelinating disorders. J Neurol Sci, 228, 195–7. Jacobs, E.C., Pribyl, T.M., Kampf, K. et al. 2005. Regionspecific myelin pathology in mice lacking the golli products of the myelin basic protein gene. J Neurosci, 25, 7004–13. Kim, T., Fiedler, K., Madison, D.L., Krueger, W.H. and Pfeiffer, S.E. 1995. Cloning and characterization of MVP17: A developmentally regulated myelin protein in oligodendrocytes. J Neurosci Res, 42, 413–22. Kitajiri, S., Miyamoto, T., Mineharu, A. et al. 2004. Compartmentalization established by claudin-11based tight junctions in stria vascularis is required for hearing through generation of endocochlear potential. J Cell Sci, 117, 5087–96. Klugmann, M., Schwab, M.H., Puhlhofer, A. et al. 1997. Assembly of CNS myelin in the absence of proteolipid protein. Neuron, 18, 59–70. Komuro, I., Schalling, M., Jahn, L. et al. 1993. Gtx: A novel murine homeobox-containing gene, expressed specifically in glial cells of the brain and germ cells

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3 Multiple sclerosis Bernadette Kalman

The condition recognized today as multiple sclerosis (MS) was first described in the early nineteenth century (Cruveilhier, 1829–42; Carswell, 1838; Frerichs, 1849). Systematic clinical and pathological characterizations of the disease, and the name “la sclerose en plaques” were provided by Charcot (1868). Comprehensive reviews of contemporary clinical and pathological observations were published by Charcot’s pupils, Bourneville and Guerard (1869) and Bourneville (1892). The subsequent development of microscopic techniques resulted in thorough analyses of inflammation, demyelination, and neuronal injury in the central nervous system (CNS), whereas advances in neurophysiology led to a better understanding of the protean clinical presentations of the disease. The etiology of MS, however, appeared elusive and most investigators explored toxic or microbial causes (Dejong, 1970). Autoimmunity as a prevailing hypothesis arose in the early twentieth century, when postvaccinal leukoencephalitis was observed in a proportion of patients who received vaccines against viral diseases, particularly rabies. The complication was initially attributed to the attenuated virus grown in rabbit brains. However, when Rhesus macaques injected with normal rabbit brain homogenate also developed a condition similar to postvaccinal leukoencephalitis, the autoantigen-triggered and T-cell mediated nature of the process gained support (Rivers and Schwentker, 1935). The animal model became known as experimental allergic (or autoimmune) encephalomyelitis (EAE), and it was reproduced in various species for studying immune-mediated pathways of demyelination. After a long-lasting influence of this paradigm, activated myelin-specific T cells are not uniformly accepted any more as a primary cause of lesion development in typical MS. Several alternative hypotheses of etiology are under investigation, but no decisive conclusion has been reached (Lassmann, 2005). The inspiring development of biotechnology and the resultant extraordinary amount of information

in molecular immunology and genetics, clinical neurology, pathology, and imaging, are expected to reveal new correlations of data and a better understanding of MS pathogenesis. Classical natural history data serve today as reference information for evaluating disease heterogeneity and the response to therapy (Krementchutzky et al., 1999, 2006). The first disease-modifying drug was approved by the Food and Drug Administration (FDA) in 1993 (The IFNB Multiple Sclerosis Study Group, 1993). Since then, the methodology of designing, monitoring, and interpreting clinical trials has itself evolved into a new science while numerous new pharmaceutical agents were developed and tested. Novel strategies also continuously emerge in the area of molecular therapies (Imitola et al., 2006; Polman et al., 2006; Rudick et al., 2006a). The following sections summarize the most up-to-date observations concerning epidemiology and genetics, immune pathogenesis, histology, clinical and paraclinical features, and current therapies of MS and related immune-mediated disorders in the CNS. 3.1 Epidemiology and genetics (Bernadette Kalman) Epidemiology Epidemiological data of MS have accumulated since the early twentieth century. Davenport (1922) and Limburg (1950) demonstrated that a geographic distribution of MS exists. A north to south gradient was noted on the northern hemisphere including Europe, North America, and Japan (Kurtzke, 1975a,b, 1993; Kuroiwa et al., 1983), while a south to north gradient was observed in Australia and New Zealand on the southern hemisphere (McLeod et al., 1994; Miller et al., 1990; Skegg et al., 1987). Prevalence surveys from the 1960s to date distinguished high prevalence (30 or more / 100,000, e.g. north, western,

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Table 3.1

Epidemiological studies support both environmental and genetic etiology of MS.

Evidence for environmental factors MS in immigrants occurs with a rate similar to that in the indigenous population when the immigration is before teenage years Epidemics of MS (e.g. on the Faroe Islands) Increasing prevalence and decreasing age of onset of MS in populations with stable genetics

Evidence for genetic factors • • • • • •

and central Europe), medium (5–29/100,000, e.g. south Europe) and low prevalence regions (less than 5/100,000, e.g. most Asian countries) (Kurtzke, 2005). These distributions may be related to both environmental (climate, viruses, UV irradiation, and diet) and genetic factors (Table 3.1). Migration studies, history of epidemics, and serial epidemiological updates support the existence of environmental effects. European immigrants in South Africa develop MS with a similar frequency as the indigenous population, while an opposite trend is observed for offspring of individuals immigrating from India, South Africa, and the West Indies to the United Kingdom (Dean, 1967; Elian et al., 1990). A migration before mid-teenage years seems to confer to the migrant the recipient country’s risk for MS, possibly related to the effects of childhood infections on immune maturation (Alter et al., 1966). MS occurred on the Faroe Islands in four epidemics between 1943 and 1990. These epidemics were attributed to a primary infectious agent imported into the islands by the occupying British forces during World War II, and to its transmission to subsequent generations (Kurtzke 1975a,b, 1993, 2005). Serial epidemiological updates suggest that the relative risk for MS is increasing in certain groups over time (Kurztke, 2005). This observation is well illustrated in Sardinia, where the mean annual incidence rate significantly increased from 1.1/100,000 in 1965–9 to 5.8/100,000 in 1995–9 (Pugliatti et al., 2005). Estimates of MS in cohorts from World War II and the Korean conflict show a relative risk of 0.44 for African American men and 0.22 for other men as compared to white men, while estimates in similar

Ethnic groups (genetic isolates) with varying susceptibility to MS Increased familial recurrence Higher concordance in monozygotic than in dizygotic twins Higher risk for MS in full-sibs than in half-sibs; the presence of a maternal parental effect Highly increased risk of MS in siblings of index cases from consanguineous parents A similar risk of MS for nonbiological relatives and individuals in the general population

ethnic cohorts from the Vietnam war and up to 1994 reveal a relative risk of 0.67 and 0.3, respectively (Kurtzke, 2005). The risk of MS for white women as compared to white men was 1.79 in the earlier cohorts, which also significantly increased in the more recent cohorts. Women of all races now have a risk ratio near to 3:1 as compared to white men (Kurtzke, 2005). Anticipation of age at onset may be another indicator for the involvement of environmental factors. Anticipation was demonstrated in two-generational MS families and longitudinal surveys of sporadic cases in Sardinia, where the mean age of onset decreased from the most remote to the most recent decade of birth from 41 to 21 years (Cocco et al., 2004). Interestingly, in another subset of the Sardinian population an increasing age of onset was noted (Pugliatti et al., 2005). In contrast to data supporting the involvement of environmental effects, ethnic, family, and twin studies suggest the involvement of genetic factors in MS (Table 3.1). While the highest prevalence rates (100/ 100,000 and beyond) correlate with the worldwide distribution of individuals of Scandinavian descent (Poser, 1994), several ethnic isolates with resistance to MS live in geographic locations where the disease is generally common. Examples include gypsies in Hungary (Gyodi et al., 1981), Indians and Orientals in North America (Ebers, 1983; Kurtzki et al., 1979), Lapps in Scandinavia (Gronning and Mellgren, 1985), Maoris in New Zealand (Skegg et al., 1987) and Aborigines in Australia (McLeod et al., 1994). The varying prevalence rates of MS in the genetically distinct but geographically close populations of Malta, Sicily, and Sardinia also implicate genetic factors

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Multiple sclerosis

(Elian et al., 1987; Rosati 1986). In addition, some ethnic groups (e.g. Orientals and African Blacks) are characterized by very low occurrence of MS (Dean, 1967; Poser, 1994). Familial recurrence of MS was recognized long ago (Eichorst, 1896). The observed inheritance patterns are incompatible with Mendelian autosomal dominant, recessive, and X-linked or mitochondrial transmission patterns. MS is a complex trait disorder with the involvement of several genes, each exerting small effect, and probably in an interaction with the environment. There is an excess in the mother-to-child as compared to the father-to-child transmissions in families with vertical concordance (Sadovnick et al., 1991). The age-adjusted empirical recurrence risk for first-degree relatives is 3 to 5%, which is 30 to 50 times the 0.1% rate in the general population (Sadovnick et al., 1991, 1998). Individuals with a greater “genetic loading” have an earlier age of onset, and “genetic loading” is increased in individuals with affected parents (Sadovnick et al., 1998). In a population-based analysis of MS index cases and their siblings whose parents were related, Sadovnick et al. (2001) found a recurrence risk of 9% for sibs, which is significantly higher than the risk for sibs of MS index cases from nonconsanguineous parents. Data from several large twin studies consistently demonstrated a higher concordance rate of MS among monozygotic (21.05% to 40%) as compared to dizygotic twins (0 to 4.7%), strongly suggesting a genetic effect (Bobowick et al., 1978; Hansen et al., 2005; Heltberg and Holm, 1982; Kinnunen et al., 1988; Mumford et al., 1994; Sadovnick et al., 1993). The concordance rate among dizygotic twins (4.7%) is similar to that observed among siblings (5.1%) (Sadovnick et al., 1993).

Table 3.2

Further confirmation of genetic effects is gained from studies on adoptees revealing that the frequency of MS among first-degree nonbiological relatives living with an index case is not greater than expected from the general population (Ebers et al., 1995). The largest half-sib study (Ebers et al., 2004) defines an age adjusted recurrence risk of 3.11% and 1.89% for full-siblings and half-siblings, respectively. The moderately significant excess of maternal vs. paternal half-sibling risk (2.35% vs. 1.31%, respectively) suggests a maternal effect on susceptibility to MS. Early case–control candidate gene association studies Associations of MS with polymorphic alleles of candidate genes involved in immune regulation and myelin production have been extensively investigated based on the autoimmune hypothesis of demyelination (Table 3.2). The first association noted with the haplotype of class I human leukocyte antigen (HLA) A3 and B7 alleles was extended to the Class II DR2 allele in both population and family studies ( Jersild et al., 1973; Stewart et al., 1979). Since then, the association of MS with the HLA A3, B7, DR2, Dw2 haplotype has been the most consistent finding in Caucasians (Francis et al., 1991; Gyodi et al., 1981; Olerup and Hillert, 1991), while HLA DR4 was detected in Sardinians and Jordanian Arabs, and DR6 was described in Japanese and Mexicans (Gorodezky et al., 1986; Kurdi et al., 1977; Marrosu et al., 1988; Naito et al., 1978). Further studies revealed that the DR15, DQ6 alleles define the MSassociated DR2, DW2 haplotype, which is described today in DNA-based terminology as DRB1*1501, DQA1*0102, DQB1*0602 haplotype (Hillert et al.,

Studies in MS.

Case–control association Region of interest Approach Major finding

Linkage

Polymorphic alleles of candidate genes Hypothesis-based

Full genome or regional scans Hypothesis-free

MHC DRB1 alleles define a major proportion of genetic susceptibility and resistance to MS

Multiple susceptibility loci with small effect including 1q44, 2q35, 5p15–5q13, 6p21, 17q11, 17q22, 18p11, 19q13

LD mapping Full genome or regional scans Hypothesis-free or hypothesis-directed Distribution of LD genome wide; identification of chromosomal segments carrying MS susceptibility genes and variants in progress

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BERNADETTE KALMAN ET AL.

Class II

DP DN DO DQ

0

Class III

DR

1000

21-OH Hsp C4 BFC2

Class I

TNF HLA-B HLA-C αβ

2000

HLA-H HLA-G HLA-A HLA-F

HLA-X HLA-E

3000

MOG

4000

kb

Telomere

Centromere

Fig. 3.1 The figure depicts the MHC class II, class III, and class I regions encompassing 4 MB in chromosome 6p21.3. MS-associated haplotypes have been consistently detected in the DRB1–DQB1 subregion in Caucasians.

1994). Whether the primary MS-specific allele is the DRB1*1501 or the DQB1*0602 could not be sorted out because of the strong linkage disequilibrium (LD) in this region. However, recent family and case– control studies in African Americans suggested a selective association of MS with the DRB1*1501 allele and a primary role for the DRB1 locus. This finding appeared unlikely to be secondary to an admixture with Caucasians, since several African American MS susceptibility haplotypes were found within chromosomal segments of African origin (Oksenberg et al., 2004). Additional studies in the major histocompatibility complex (MHC or HLA) region tested the association of polymorphic alleles of HLA DP (Roth et al., 1991), complement C4, Bf, C2 components (MHC III) (Hauser et al., 1989), protein transporters (LMP, TAP1, TAP2) (Bell and Ramachandran, 1995; Liblau et al., 1993) and of the TNF α and TNF β genes with MS (Braun et al., 1996; Roth et al., 1994). A polymorphic CA repeat within the gene of myelin oligodendrocyte glycoprotein (MOG), telomeric to the MHC, was also tested in MS (Malfroy et al., 1995) (Fig. 3.1). However, the overall outcome of these studies reflected inconsistent observations and did not reveal independent associations of MS with genes outside of the MHC class II subregion (Fig. 3.1). Analyses of sequence variations within germline elements of the T-cell receptor (TCR) α and β chain genes as well as tests for a preferential utilization of certain TCR V–J–D gene segments in the rearranged mRNA seemed to reveal promising data in several studies. Nevertheless, the involvement of TCR genes in MS susceptibility could not be consistently supported (Fugger et al., 1990; Hashimoto et al., 1992; Oksenberg et al., 1989; Seboun et al., 1989). Linkage analyses also excluded that a TCR α or β gene would contribute to MS susceptibility (Lynch et al., 1991, 1992). Similarly, both association and linkage studies of immunoglobulin genes

revealed conflicting observations (Feakes et al., 1998; Hashimoto et al., 1993). Additional analyses of immune response genes included ligands and receptors in the cytokine, chemokine, and adhesion molecule networks, but also without unequivoval conclusion (Crusius et al., 1995; Epplen et al., 1997; He et al., 1998a). Candidates related to myelin production included the myelin basic protein (MBP) promoter, MOG on chromosome 6 and genes of oligodendrocyte growth factors or their receptors. However, associations or linkage detected in some studies were not confirmed in subsequent analyses (Boylan et al., 1990; He et al., 1998b; Mertens et al., 1998; Wood et al., 1994). Despite the involved conceptual and technical difficulties (e.g. matching controls to patients in order to avoid population stratification or selecting genetic candidates), the case–control design continues to be a widely used approach in MS. With the recognition of more and more intercellular and subcellular pathways in pathogenesis, the number of molecular candidates permanently grows (Achiron et al., 2004; Chiocchetti et al., 2005; Kantarci et al., 2005; Leyva et al., 2005; Michailova et al., 2005; Oksenberg and Barcellos, 2005). Today, however, both full-genome scans and expression profiling assist a focused selection of candidates, and a comprehensive list of sequence variations is provided for association studies by the Human Genome Project (see below). Linkage studies In contrast to the hypothesis-driven case–control association approach, the method of linkage can identify susceptibility loci genome wide without a preconceived idea of disease pathogenesis (Table 3.2). Four full-genome scans with microsatellite markers in MS families showed linkage to multiple susceptibility loci, each with a minor effect (λs =
2) (Ebers et al., 1996; Kuokkanen et al., 1997; The Multiple

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Sclerosis Genetics Group, 1996; Sawcer et al., 1996). Among the reported provisional sites, the 6p21, 5p15, 5q13, 17q22, and 19q13 regions were consistently positive in more than one study. Additional susceptibility loci at 1q44, 2q35, and 18p11 were recently suggested (Kenealy et al., 2006). A metaanalysis of combined, raw genotype data of three full-genome scans underscored the importance of 17q11 and 6p21 in MS (The Transatlantic Multiple Sclerosis Genetics Cooperative Study, 2001). Within many regions with the highest scores, clusters of immune regulatory genes are encoded (e.g. 6p21 – MHC cluster; 17q11 – β-chemokine cluster). There are, however, also loci likely involved in neurodegeneration. An association of the epsilon 4 allele of the ApoE gene in 19q13 was suggested with both susceptibility and progression rate of MS in several studies, but a recent meta-analysis of available worldwide data showed negative outcome (Burwick et al., 2006; Schmidt et al., 2002). Comprehensive analyses of the MHC region further confirmed its importance in MS. While Haines et al. (1998) proposed that linkage to the MHC was limited to families segregating DR2, Ligers et al. (2001) also detected linkage to this region in a larger cohort of DRB1*15-negative families. This latter observation led to the conclusion that the DRB1*15 may not be the only HLA determinant of MS. The association with DRB1*15 may be secondary to LD with a nearby locus, or disease susceptibility alleles can be present in DRB1*15-negative haplotypes. Analyses of the DRB1 allelic heterogeneity in a large number of MS families showed the involvement of several susceptibility (e.g. DRB1*15 and DRB1*17) and protective (e.g. DRB1*14) alleles suggesting trans interactions among DRB1*15-positive and -negative genotype combinations (Dyment et al., 2005). Altogether, association and linkage studies unambiguously established that MHC class II genotypes determine a major proportion of genetic susceptibility and resistance to MS. Further refinements of MS susceptibility loci by LD mapping The method of linkage in complex disorders usually identifies large (2–20 cM) chromosomal regions of interest, but does not have the power to confine these regions to single candidate genes with small effects. For fine mapping, the use of modern association methods within linkage-defined chromosomal regions or the entire genome may be considered. The Human Genome Project provided the means for this new

33

approach. The data revealed that two human genomes are approximately 99.9% identical, leaving still millions of different base pairs among the total of 3.2 billion. The 0.1% difference is attributed to the presence of a single nucleotide polymorphism (SNP) at approximately every 1000 nucleotides. SNPs are not only responsible for the interindividual phenotypic differences, but also for the variations in susceptibility to common diseases (Table 3.2, Fig. 3.2) (The International SNP MAP Working Group, 2001). Because of the abundance of SNPs, these variations may be used as markers in comprehensive association studies. SNP marker alleles align in haplotypes which tend to be inherited together in a given population. This correlation between paired SNP markers is called LD. The genome-wide distribution of LD is influenced by many factors and varies among ethnic groups. A recent study of selected chromosomal regions revealed that half of the SNP haplotypes are 22 kb or larger in African and African-American samples, and 44 kb or larger in European and Asian samples (Gabriel et al., 2002). However, it is important to note that the distribution of LD shows great regional variations. LD between a marker allele and a disease-specific allele may allow us to identify mutations or variants with pathogenic significance if SNP markers are genotyped with sufficient density in a selected region (e.g. in a linkage-defined susceptibility locus). Fewer markers may be used in a two-stage study, which aims first to identify the disease-associated haplotypes, and then attempts (with a more dense marker distribution) to reveal disease-relevant mutations within or in the proximity of these haplotypes (Fig. 3.2). Using this strategy in the 17q11 region, we first defined and then refined MS-associated haplotypes in two independent sets of families. Sequence analyses of these haplotypes and their flanking regions will reveal if disease-causing mutations are present in the colocalizing CC chemokine genes (Vyshkina et al., 2005; Vyshkina and Kalman, 2005). With a high-density SNP panel encompassing the MHC and flanking genomic regions in over 1100 MS families, Lincoln et al. (2005) detected strong associations with blocks in the class II region, and the strongest association with the DRB1. Conditioning on HLA DRB1 found no additional block or SNP association independent of the class II genomic region. Thus, this study established that MHCassociated susceptibility in MS is defined by HLA class II alleles, their interactions, and closely neighboring variants.

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CHARACTERISTICS OF THE HUMAN GENOME

SNPs

A • 3.2 BILLION BASEPAIRS • 30,000 GENES • EVERY TWO GENOMES ARE 99.9% IDENTICAL • A SNP IS PRESENT AT EVERY 1000 NUCLEOTIDE • SNPs CONTRIBUTE TO PHENOTYPIC DIFFERENCES AND SUSCEPTIBILITY TO COMMON DISEASES HAPLOTYPES B • SNP ALLELES ALIGN IN HAPLOTYPES • WHEN A MUTATION ARISES, ...acgt... ...aTgtac... IT DOES SO IN A SPECIFIC ...acgt... ...acgtac... HAPLOTYPE ...Gcgt... ...aTgtac... • EACH MUTATION CAN BE ...Gcgt... ...aTgtac... TRACKED IN A POPULATION ...Gcgt... ...aTgtac... BY IDENTIFYING THE ...Gcgt... ...acgtac... CORRESPONDING ...Gcgt... ...acgtac... ANCESTRAL CHROMOSOMAL SEGMENT ON WHICH IT AROSE SNPs:A/G C/T

TCAATGTCTGCATA TCCATGACTGCGTA GATCCTGGACTGC GATCGTGAACTGA ACGTTTACGTCGC ACGTATAGGTCGC

...gtacgt... ...Atacgt... ...Ata*Ggt... ...Ata*Ggt... ...Ata*Ggt... ...gtacgt... ...gtacgt... G/A

Full-genome LD mapping studies are also in progress and are expected to identify novel susceptibility genes with small effects. Mapping by admixture linkage disequilibrium (MALD) offers another new approach for the identification of disease-relevant genes with approximately 100 times fewer SNP markers than would be required for whole-genome haplotype scans. This method implies that the genomes of different ethnic groups have chromosomal segments of different origin due to a historic gene flow between them (e.g. African Americans have chromosomal segments of African as well as European origin) (Smith et al., 2004). The strategy involves the identification of a genomic region from one ancestral population with the highest occurrence of the disease. MALD can be particularly powerful in finding genes for a disease that differs profoundly in frequency among populations. Highly informative MALD markers have been recently defined (Smith et al., 2004) and successfully used to identify MS-relevant loci in African Americans (Reich et al., 2005). In summary, recent genetic data reflect a significant increase in power achieved by the use of new association-based methods and densely packed SNP markers in MS. In addition to the identification of disease-associated allelic variants, further explorations of epistatic gene interactions as well as of transcriptional and post-transcriptional regulatory mechanisms are needed to better understand the

*G:disease-related mutation

Fig. 3.2 The Human Genome Project provided the means for LD mapping in complex disorders.

disease pathogenesis and to identify the best targets for therapy. Mitochondrial (mt)DNA in MS A group of corollary studies aimed to clarify mitochondrial genetics in MS. MtDNA is a small (16.5 kb) extranuclear part of the human genome. Numerous point mutations and deletions in mtDNA have been identified in association with neuromuscular and multiorgan disorders. A possible involvement of mtDNA in MS was postulated because there is a higher transmission of the disease from mother to child than from father to child (Sadovnick et al., 1991), and because of the observed association between Leber’s hereditary optic neuropathy (LHON), a mitochondrial disease, and MS (Harding et al., 1992; Lee et al., 1964). The identification of mtDNA mutations at nt 11,778, 3460, and 14,484 with primary pathogenic significance for blindness made possible the objective evaluation of the association between MS and LHON (Howell et al., 1991; Johns et al., 1992; Wallace et al., 1988). Such mutations were reported in a number of patients with prominent optic neuritis (PON) and MS (Flanigan et al., 1993; Harding et al., 1992; Kellar-Wood et al., 1994), while inflammatory demyelination was also found in LHON patients more often than expected by chance (Riordan-Eva et al., 1995). However,

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comprehensive screening and sequencing of mtDNA in large patient cohorts revealed that primary LHON mutations are very rare in typical MS or PON, and no other pathogenic mtDNA mutations contribute to the pathogenesis of MS (Kalman et al., 1995, 1996, 1999). Postgenomics The recently developed cDNA microarray technology led to the identification of hundreds of gene products potentially involved in disease pathogenesis based on their differential expressions in patients and controls. Comparisons between mRNA repertoires in leukocytes as well as brain tissues of MS patients and controls have been carried out in several studies (Lindberg et al., 2004; Mandel et al., 2004; Satoh et al., 2005). In addition, mRNA repertoires in chronic and acute plaques were compared to those in the corresponding normal appearing white-matter regions in patients (Tajouri et al., 2003). The differentially expressed molecules can be groupped into functional clusters that include mediators of inflammation and apoptosis, regulators of cell cycle, nuclear factors, and molecules involved in subcellular signaling, myelin development, and protection against oxidative stress. The cDNA microarray technology has also been used to investigate more clinically oriented questions such as regulation of gene expression by disease-modifying drugs, or differences in gene expression regulation in responders and nonresponders to a drug (Koike et al., 2003). Proteomic identification and quantitation of proteins represent the next level of molecular analyses, which aim to define disease-related changes in various tissues of patients (Newcombe et al., 2005). A simultaneous determination of genetic, transcriptional, and proteomic profiles in correlation with clinical, imaging, and histological phenotypes may represent a comprehensive approach that will enable us to better capture the mechanism and control the natural history of this complex disease. 3.2 Immunopathogenesis (Thomas P. Leist) Lesion characteristics and model systems There have been advances in the understanding of the pathogenesis of MS over recent years. These advances have been fostered by observations in animal models, and by ex vivo studies using specimens of human origin and by development of new imaging techniques. The experimental work done

35

to elucidate the mode of action of the currently available therapies also should not to be underestimated as a source of new insights into the disease process. In turn these advances have pointed to new molecular targets that may warrant development of future therapies. White-matter plaques in the CNS, particularly in the optic nerve, brainstem, spinal cord, and periventricular regions, are a cardinal pathological feature of MS (Ikuta et al., 1976). It is now clear that diseaseinduced changes are not restricted to the white matter alone but also occur in gray matter (Dalton et al., 2004). Inflammation and demyelination are the histological hallmarks of MS, but astrogliosis, neuronoaxonal injury, and degeneration also contribute to the overall pathology (Raine, 1984). There is a considerable heterogeneity of actively demyelinating lesions. A classification to distinguish four lesion types was proposed based on pathological features including myelin protein loss, oligodendrocyte involvement, complement activation, and types of inflammatory infiltrates. Type I is characterized by demyelination, T cell and macrophage infiltration, and presence of macrophage-related products such as tumor necrosis factor. In Type II, immunoglobulin and complement are also present in addition to the mononuclear cell infiltration. Type III lesions are characterized by the dying-back type of oligodendrocytopathy with a preferential loss of myelin-associated glycoprotein but with a preservation of proteolipid lipoprotein and myelin basic protein, and lack of remyelination in the absence of overt inflammation or immunoglobulin and complement deposition. Type IV is characterized by apoptosis oligodendrocytes (Lucchinetti et al., 2000). It is a central issue in MS whether different immunological pathways sequentially active over time result in demyelination in an individual patient or mechanisms of demyelination differ from patient to patient defined by genetic factors. The ultimate answers will have significant therapeutic implications. Barnett and Prineas (2004) have demonstrated that lesions from a given patient can contain features of more than one of the above lesion types. The matter of lesion classification remains therefore a process in evolution. At cellular level, neurons and their projections and oligodendrocytes and the myelin sheets they generate can be damaged and destroyed through a number of immunopathological mechanisms. These mechanisms include direct interactions with cytotoxic immune cells and their products named cyto- and chemokines with cytotoxic potential, and demyelinating antibodies.

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Adhesion

Postcapillary venule Adhesion molecules

Invasion/ Diapodesis

T cell

BBB MMPs microglia

ro

ph

Y Y Y Y Y

ag

Antibodies e

B Cell

Y

ac

age

macroph

IFNγ / IL-17

m

Myelin

Reactivation/Proliferation T cell

Y

IL-12/23

Axon

Oligo

Fig. 3.3

Recruitment of T cells into the CNS.

Remyelination is an important feature of MS lesions and re-expression of oligodendrocyte transcription factor 1 can be seen during remyelination. To what degree apoptosis, signaled through members of the family of tumor necrosis factor receptors, is responsible for oligodendrocyte drop out remains to be elucidated. Molecules associated with recruitment of myelinating cells and remyelination include CXC and CC chemokine receptors, which were recently described on oligodendrocytes (Omari et al., 2005). Recruitmentof oligodendrocyte-precursor cells appears to be normal in MS lesions. There appears to be inhibition of differentiation and growth of these precursors. Several substances have been identified in the gliotic scar that stunt differentiation of oligodendrocytes and local myelin repair. A leucinerich–repeat and immunoglobulin-domain-containing Nogo receptor has been identified which may represent a target for improved myelin repair (Mi et al., 2005). The axonal compromise observed in MS is, however, not just a function of inflammation and demyelination but is also reflective of abnormal expression of ion channels including sodium channels. As a result there is an increased entry of sodium, slowing of nerve conduction, and conduction block. These effector mechanisms have also been shown to be operative in EAE models. Distinct pathological presentations similar to those recognized in active MS lesions can be produced dependent on the animal strain used, and the employed protocol of active or

passive immunization. EAE in rodents predominantly affects the spinal cord, and therefore, the observed clinical deficits almost stereotypically reflect the extent of inflammation and demyelination. In the persistent virus model of inflammatory demyelination induced with Theiler’s virus, the correlation between the distribution of cellular immune mediators and demyelination and the clinical deficit is also limited. However, immunopathological changes that are characteristic of specific mechanisms can be identified during the acute destruction of myelin. Inflammatory characteristics of active lesions include standard elements of inflammation such as CD4+ and CD8+ T cells along with activated microglia, macrophages, and B cells (Fig. 3.3). Induction of an autoreactive immune response It is not known how and when MS is initially induced but there is substantial evidence to support the hypothesis that genetics determines a person’s susceptibility to MS, and that environmental factors modulate the risk. It is not clear when induction of autoreactive immune cells occurs but migration studies suggest that this may occur before or around puberty (Noseworthy et al., 2000). Though these self-reactive cells have the potential to cross-react with CNS antigens, it appears that they remain dormant and sequestered outside of the CNS. In this model, an unidentified external trigger is postulated to deliver a second

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signal that will lead to the activation of resting selfreactive cells. This second signal is believed to be delivered after puberty. Once activated, these cells are capable of traversing the blood–brain barrier (BBB). Characteristics of the inflammatory response In rodent and primate model systems of EAE, CD4+ or CD8+ T cells reactive with constituent proteins of the myelin can induce inflammatory demyelination in the CNS (Ando et al., 1989; Huseby et al., 2001; Pettinelli and McFarlin, 1981). Myelin basic protein is one of these proteins. T cells reactive with myelin basic protein can be demonstrated in individuals with MS and in normal controls. The myelin-specific T cells from patients with MS generally exhibit a memory or activated phenotype, whereas those from healthy persons have a naive phenotype. The most direct evidence that myelin-reactive T cells can induce inflammatory demyelination comes from one of the clinical studies using an altered peptide ligand as a potentially disease-attenuating treatment. While a reduced disease activity was observed on magnetic resonance imaging (MRI) in one of the studies using a low dose of the altered peptide ligand (Kappos et al., 2000), an increased clinical and MRI activity was noted in several patients treated with a higher dose of the altered peptide ligand (Bielekova et al., 2000). Patients exhibited a surge of T cells reactive with the corresponding myelin basic protein peptide at the time of clinical activity. This finding supports the view that a self-reactive inflammatory process directed against myelin constituents plays a central role in MS. The cytokine profile produced by myelin-specific T cells determines the ability of these cells to initiate inflammation in the CNS. Myelin-reactive T cells from patients with MS produce cytokines more consistent with a proinflammatory Th1-mediated response, whereas myelin-reactive T cells from healthy persons are more likely to produce Th2 cytokines which exert immunoregulatory response. Cytokines associated with a Th2 response include interleukin (IL-4) and IL-5. IL-12 is a cytokine that is strongly associated with proinflammatory Th1 responses. It activates the transcription factor Stat-4 in human T cells and promotes their differentiation towards a proinflammatory, pathogenic Th1 phenotype. Some data suggest that interferon-β, which is used to treat MS, causes a shift from a Th1-mediated to a Th2-mediated response. However, microarray studies demonstrate that interferon therapy induces the upregulation of a number

37

of genes which are associated with a differentiation into Th1rather than Th2 phenotype (Wandinger et al., 2001). IL-12 and IL-23 are heterodimers and share the same p40 subunit. They affect regulation of T-cell responses in a way that may be relevant to the disease process of MS (Trinchieri et al., 2003). Development of EAE depends on a sequencial expression of distinct cytokine patterns. Mice deficient in both IL-12 and IL-23 are resistant to EAE, whereas animals deficient in IL-12 alone develop severe disease. Interleukin-23 induces IL-17 production by T cells. IL-17 is expressed in brain lesions and appears to be a regulator of CNS inflammation. T cells have been viewed as central players in the autoimmune process of MS. However, when instructed by T cells, B cells differentiate and produce autoreactive antibodies which contribute to the pathobiology of the disease by binding of antigens and activation of complement. The intrathecal synthesis of immunoglobulins is characteristic of MS: cerebrospinal fluid (CSF)-restricted oligoclonal bands (OCB) and an increased IgG can be observed in most patients. In addition, B-cell clones restricted to the CNS can be found (Monson et al., 2005). The presence of antimyelin oligodendrocyte glycoprotein (MOG) antibodies in patients with clinically isolated demyelinating syndromes was suggested to have predictive value in identifying those patients who will go on to develop clinically definite MS. Further studies are needed to evaluate this finding. There is an interest in targeting B cells as an alternative strategy to the approaches that are directed against T cells and their products. Marcophages and microglia are the primary mediators of the inflammatory response in active early MS plaques. They are generally abundant at the outer rim of the lesion and release cytokines, reactive oxygen species, and nitric oxide, which cause tissue injury including damage to the myelin sheath. In hyperacute and highly destructive lesions, particularly in variant forms such as neuromyelitis optica and Marburg’s type of MS, granulocytes and eosinophils may be part of the inflammatory reaction. Recruitment of inflammatory cells into the CNS Migration of autoreactive leukocytes from the systemic circulation into the CNS is thought to play an important role in the formation of inflammatory MS lesions. The leukocyte extravasation occurs in consecutive steps (Fig. 3.3). The initial step is marked by tethering and rolling of inflammatory cells on the endothelium. E-selectin and sialyl Lewis (SLe) are

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thought to play an important role in this stage. The ensuing firm adhesion is mediated by β2 integrins and includes vascular cell adhesion molecule (VCAM)-1, very late antigen (VLA)-4, intracellular adhesion molecule (ICAM)-1, and lymphocyte function-associated antigen (LFA)-1 (Miller et al., 2003; Yednock et al., 1992). Antibodies against LFA-1 and ICAM-1 were shown suppressing EAE in some studies, and a rise in ICAM-1 levels was seen in the same model just prior to onset of clinical symptoms. Inflammatory cells diapedese through the endothelial layer and the extracellular matrix. Matrix metalloproteases (MMPs) produced by activated leukocytes assist the breakdown of the BBB and invasion of the brain parenchyma. In both EAE and MS, levels of gelatinase B (MMP-9) and matrilysin (MMP-7) are increased in blood, CSF, and brain during periods of inflammatory disease activity associated with enhancing MRI lesions. Chemokines form a chemo-attractant gradient that is perceived by T cells and assists their invasion into the CNS. Chemokines, including interferon γ-inducible protein-10 and its receptor CXCR3, are elevated in patients with disease activity. The sequence of tethering, adhesion, and diapedesis is a choreographed process dependent on a number of interacting molecules each of which may represent a potential target for therapeutic intervention. Macrophage activation antigens, MRP14 and 27E10, hold promise as markers for the identification of actively demyelinating lesions in MS as they are only transiently expressed after emigration from the vasculature. Once in the CNS, lymphocytes interact with antigenpresenting cells (microglia, macrophages, and B cells as well as other antigen-presenting cells) that bear the appropriate antigenic epitope embedded in HLA class I or II molecules, and undergo local clonal proliferation if appropriate costimulatory molecules are expressed. In turn, activated T cells will recruit macrophages and control the synthesis of immunoglobulins that can bind to epitopes on the myelin sheath. T cells reactivated within the CNS also secrete cytokines that in turn stimulate activation of T and B cells as well as monocytes. These immune interactions result in a vitious circle of local inflammation in the CNS.

of these white-matter changes in MS patients with longstanding disease may partly be due to other coincidental diseases affecting the CNS (e.g. vascular or neurodegenerative disorders), findings on MR spectroscopy at the time of a first demyelinating event emphasize that the process of MS itself causes early and significant changes in the “normal appearing white matter”. This diffuse pathology in the “normal appearing white matter” may be explained by a reaction of brain tissue to the chronic inflammation and axonal degeneration, or by a diffuse molecular pathology present in myelin prior to the formation of overt demyelinating lesions. Gray- and white-matter atrophy and gliosis are characteristic features in MS cases with severe or longstanding disease and with significant cognitive involvement. The damage occurring in plaques results in anterograde and retrograde effects along the fiber tracts, and thus contributes to tissue changes remote to the lesion. In addition, the “normal appearing white matter” often contains small focal inflammatory and demyelinating lesions that elude macroscopic detection. The mechanisms of demyelination may vary among patients, and the complexity of MS pathogenesis cannot be explained on the basis of a T-cell mediated immune response alone. The involvement of demyelinating antibodies is suggested by the close similarity between MS and MOG-induced EAE in rodents and primates, by the demonstration of complement activation in active lesions and by the presence of anti-MOG antibodies in some patients. Deposition of anti-MOG antibodies can be observed in MOGinduced EAE. While the destructive nature of inflammation is much appreciated, its tissue protective features are often neglected. Evidence suggests that inflammation can induce removal of debris, which may be a necessary step in the induction of reparative mechanisms. Subsets of activated lymphocytes control inflammation while others produce nerve growth factors. Therefore, a complete abrogation of all inflammatory responses at a given time point in the disease process may not always provide the most effective route towards a maximal treatment efficacy. 3.3 Courses and diagnosis of MS (Bernadette Kalman)

Extent of inflammatory changes 3.3.1 Courses of MS The white-matter regions distant from plaques are frequently abnormal even though usually referred to as “normal appearing white matter”. While some

Analyses of clinical and pathological phenotypes suggest that MS represents a spectrum rather than

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a single entity of inflammatory demyelination and neurodegeneration. Natural history studies confirm heterogeneity of the disease and define discrete clinical subtypes with characteristic course, accumulation of disability, and long-term outcome. While phenotype-specific biomarkers are not yet available, a standardized terminology describes four clinical courses that are routinely used in practice (Lublin and Reingold, 1996). This empirical classification, in agreement with natural history studies, distinguishes relapsingremitting (RR), secondary progressive (SP), primary progressive (PP), and progressive-relapsing (PR) forms of MS (Fig. 3.4). Eighty to eighty-five percent of patients have an RR onset with a substantial proportion converting into SP-MS over time. The remaining patients present with PP-MS characterized by a later onset, less female predominance, and a more rapid deterioration (Cottrell et al., 1999). The median time from disease onset to reach an expanded disability status scale (EDSS) score of 4, 6, and 7 is longer in RR than in PP-MS. However, the time to reach EDSS 6 from EDSS 4 is similar in the SP- and PP-MS groups (Confavreux et al., 2000), and the time to major disability milestones after the onset of progression at DSS2 or less is also similar in all progressive forms (Kremenchutzky et al., 2006). These observations suggest that the rates of accumulation of irreversible pathological changes are different in RR- and PP-MS, but are markedly similar in SP- and PP-MS (Confavreux et al., 2000; Ebers 2004; Kremenchutzky et al., 2006). Analyses of long-term outcomes (time to EDSS 3, 6, 8, and 10) suggest that patients with relapsing-progressive (RP) course can be reassigned either to SP- or PP-MS, and patients with PR-course

PP-MS

PR-MS

Disability

Time

Disability

Time

Time

Fig. 3.4

SP-MS Disability

Disability

RR-MS

Time

Course of MS (after Lublin and Reingold, 1996).

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can be reassigned to PP-MS (Kremenchutzky et al., 1999). The younger the age of onset, the younger the age of reaching disability milestones (Confavreux and Vukusic, 2006). In addition to these patterns of disease course, “benign” and “aggressive” labeling of MS have been used, but with varying definitions. McAlpine (1961) proposed “benign” disease for those patients who, after a follow up of 10 or more years, were without restriction of normal activity in professional and private life, but not necessarily without neurological symptoms. Hawkins and McDonell (1999) identified a subgroup with “benign” MS representing 19.9% of their patient cohort when defining EDSS = 3.0 at least 10 years after onset. Pittock et al. (2004) found that patients with EDSS = 2 or less for 10 years or longer have a greater than 90% chance of remaining stable in the subsequent decade. This subgroup represented 17% of their original (year 1991) prevalence cohort. These studies suggest that approximately a fifth of patients with MS have little or no disability for long periods of time. However, the EDSS-based definitions of benign MS are not without pitfalls, as EDSS is weighted for motor disability without appreciating cognitive impairments, conventional MRI activity of the disease, and nonconventional MRI measures of the disease burden. Overall, a favorable disease course is associated with female gender, early onset, presentation with ON and sensory symptoms. Acute onset, little residual disability after each relapse, and long inter-relapse periods are also indicators of a benign course. Data from the Optic Neuritis Study Group (2004) revealed that 65% of patients, who were enrolled in the Optic Neuritis Treatment Trial (ONTT) between 1988 and 1991 and developed clinically definite MS (CDMS), had an EDSS less than 3.0 at least 10 years after the initial ON, underscoring that ON at onset is a favorable prognostic factor. In contrast, unfavorable prognostic indicators include male gender, later age of onset, progressive course from onset, frequent exacerbations in the first two years, poor recovery from relapses and early development of progressive deficit, involvement of cerebellar and motor pathways, and initial presentation with multisystem involvement. There are also “fulminant” forms of MS that are less well defined than the benign forms, but generally have a rapid progression rate and high mortality. “Marburg type” of MS is reserved for a rapidly progressive monophasic disease reaching severe disability or even death in a few weeks to months, as was the case

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described by Otto Marburg (1906). Patients usually have acute lesions affecting eloquent regions of the brainstem and widespread inflammatory lesions of the optic nerves, spinal cord, and hemispheral white matter. The lesions are usually extensive and show signs of intense inflammation (Johnson et al., 1990; Marburg, 1906). With the currently available antiinflammatory and disease-modifying medications, the management of this subtype became less dismal. The “tumefactive” form of MS typically is related to a single mass-like plaque which is both clinically and radiologically indistinguishable from a brain tumor. The clinical presentation may be a subacute neurological deterioration reflecting the lesion location. A tumefactive lesion may develop in an individual with an established diagnosis, or sometimes as an initial presentation of MS. Response of the lesion to corticosteroid treatment and other paraclinical data including CSF immune work up, conventional magnetic resonance imaging (MRI), and spectroscopy (MRS) monitoring may help to establish the diagnosis without biopsy in some of these patients. However, this presentation often represents a diagnostic challenge and makes brain biopsy unavoidable (Capello et al., 2001; Khoshyomn et al., 2002). Another potentially severe variant, Balo’s disease, is both radiologically and pathologically a distinct one, and has been predominantly observed in Asians. In Balo’s type of concentric sclerosis, large hemispheral lesions occur with alternating rings of preserved and damaged myelin in MRI and pathological studies (Balo, 1928; Stadelmann et al., 2005). Typical MS plaques are also usually present. The clinical course may be fulminant with obscuration of consciousness or even development of coma and death, if not treated aggressively. Recent molecular studies implicate the upregulation of neuroprotective machinery in regions of subtotal, inflammation-induced mitochondrial impairment leading to the preservation of myelinated tissue at the edges of inflammation and demyelination. Inflammation, however, may overcome neuroprotection at the edges of preserved tissue segments, resulting in alternating damaged and preserved tissue layers. This mechanism of hypoxic deconditioning is similar to that described in acute ischemic injury (Stadelmann et al., 2005). 3.3.2 Diagnosis of MS The diagnosis of MS has always relied on objective evidence for a dissemination of clinical events and pathological lesions in time and space, and on

a simultaneous exclusion of alternative diagnoses (Poser et al., 1983; Schumacher et al., 1965). The Poser’s criteria (1983), still in use (particularly in repositories and retrospective data analyses), provide different levels of diagnostic certainty including clinically definite or laboratory-supported definite, and clinically probable or laboratory-supported probable, and possible MS. The more recently developed McDonald’s criteria (2001) omit the terms of “clinically definite” and “probable MS,” and retains only “MS” or “not MS,” leaving diagnostic uncertainties for the category of “possible MS”. A major advantage of the McDonald’s criteria is that by the integration of MRI work up into clinical and paraclinical methods, the diagnosis can be established much earlier than before. When no signs of dissemination in time and space have occurred yet, but are expected with high probability in the future, clinically isolated syndrome (CIS) or monosymptomatic disease may be diagnosed. The McDonald’s criteria allow establishing the diagnosis of MS exclusively based on clinical observations if there is objective evidence of the separation of lesions in time and space. An acute episode of neurological dysfunction that lasts for at least 24 hours in the absence of fever or metabolic disturbance can be called an attack, exacerbation, or relapse. All events within 30 days of the initial event are considered to be part of the same exacerbation. For dissemination in space, the involvement of distinct regions of the CNS needs to be demonstrated. MRI criteria for the demonstration of dissemination in space and time are summarized in Boxes 3.1 and 3.2, respectively. Information from MRI, laboratory analyses of the CSF, and visual evoked potentials (VEP) will become critical when the clinical presentation alone is not sufficient to establish the diagnosis. Among these methods, MRI has the highest degree of specificity and sensitivity. CSF can be supportive when the clinical presentation is unusual and the MRI alterations are insufficient to fulfill the criteria. VEP also can be supportive when the number (e.g. progressive myelopathy in PP-MS) or the specificity (e.g. elderly patients with possible microvascular disease) of MRI lesions is in question. Other evoked potentials contribute little to the diagnosis (McDonald et al., 2001) (Tables 3.3 and 3.4). The distinct characteristics of PP-MS (Cottrell et al., 1999; Montalban 2005) prompted investigators to develop separate diagnostic criteria for this subgroup of patients. Thompson et al. (2000) state that clinical progression from onset at least for one year must be

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Box 3.1 MRI determination of dissemination of lesions in space (McDonald et al., 2001). Three of four of the following requirements:

3 4

1

Note: One spinal cord lesion can be substituted for one brain lesion. After Barkhof et al. (1997) and Tintore et al. (2000). The 2005 revision by Polman et al. (2005) confirmed these criteria and provided clarification for the incorporation of spinal cord lesions into the criteria (see text).

2

One gadolinium-enhancing lesion or nine T2-weighted hyperintense lesions if there is no enhancing lesion. One infratentorial lesion.

One juxtacortical lesion. Three periventricular lesions.

Box 3.2 MRI determination of lesion dissemination in time. (a) MRI criteria for dissemination of lesions in time (McDonald et al., 2001) If the first scan is performed three months or more after the clinical onset, a gadoliniumenhancing lesion (not at the site involved in the original clinical event) is needed; if no enhancing lesion is present, a follow-up scan with new T2- or gadolinium-enhancing lesion in another three months or later is needed to fulfill the criterion for dissemination in time.

Table 3.3

(b) MRI criteria for lesion dissemination in time (Polman et al., 2005) 1 A gadolinium-enhancing lesion at a site not involved in the initial event, and at least three months after the onset of the initial clinical event is needed; or 2 A new T2 lesion at any time compared to the reference scan performed at least 30 days after the clinical onset is needed to fulfill the criterion.

Diagnostic criteria for MS (McDonald et al., 2001; Polman et al., 2005).

Clinical presentation

Additional data needed for MS diagnosis

Two or more attacks Objective clinical evidence of two or more lesions

None required (If MRI or CSF are done, the results should be consistent with MS)

Two or more attacks Objective clinical evidence of one lesion

Dissemination in space demonstrated by MRI (Box 3.1) or Two or more MRI lesions consistent with MS plus positive CSF (OCB by isoelectrofocusing or raised IgG index) or Another clinical attack involving a different site

One attack Objective clinical evidence of two or more lesions

Dissemination in time, demonstrated by MRI (Box 3.2) or Second clinical attack

One attack Objective clinical evidence of one lesion (monosymptomatic presentation)

Dissemination in space, demonstrated by MRI (Box 3.1) or Two or more MRI lesions consistent with MS plus positive CSF (OCB by isoelectrofocusing or raised IgG index) and Dissemination in time demonstrated by MRI (Box 3.2) or Second clinical attack

Notes: The diagnosis is “MS” if the criteria fulfilled; the diagnosis is “possible MS” if the criteria are not completely fulfilled; the diagnosis is “not MS” if the criteria are fully explored and not fulfilled. Table 3.3 is published with the permission of the Legal Department of John Wiley & Sons, Inc.

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Table 3.4

Diagnostic criteria for PP-MS (McDonald et al., 2001; Polman et al., 2005).

Clinical presentation Insidious neurological progression suggestive of MS (PP-MS)

Additional data (Polman et al., 2005)

Additional data (McDonald et al., 2001) Positive CSF (OCB by isoelectrofocusing and raised IgG) and Dissemination in space, demonstrated by – Nine or more T2 lesions in brain or – Two or more lesions in spinal cord or – Four to eight brain lesions plus one spinal lesion; or Abnormal VEP with four to eight brain lesions or with fewer than four brain lesions plus one spinal cord lesion demonstrated by MRI; and Dissemination in time demonstrated by MRI (Box 3.2); or Continued progression for one year

One year of disease progression plus two of the following: – Positive brain MRI (nine T2 lesions or four or more T2 lesions with positive VEP) – Positive cord MRI (two focal T2 lesions) – Positive CSF

Table 3.4 is published with the permission of the Legal Department of John Wiley & Sons, Inc.

documented before the diagnosis of PP-MS is made. Most patients with PP-MS present with spastic paraparesis, while the remaining patients have progressive cerebellar, brainstem, hemiparetic, visual, or cognitive involvement. Based on the Thompson et al. (2000) criteria adopted by McDonald et al. (2001) for the diagnosis of definite PP-MS, the presence of intrathecal IgG synthesis with one of three MRI criteria was required: (i) nine brain lesions; (ii) two spinal cord lesions; or (iii) 4–8 brain lesions and one cord lesion. The McDonald’s criteria were studied in retrospective and prospective analyses, and proven to be superior in sensitivity, specificity, and clinical utility compared to previous criteria, particularly in adult western populations with classical MS. These criteria have not been adequately tested in pediatric populations and in ethnic groups other than western populations (e.g. Asian or Latin American patients). In 2005, the International Panel reviewed available data concerning the McDonald’s criteria and proposed a revision based on refined consensus (Polman et al., 2005). While this revision reiterates the essential clinical requirements for the diagnosis of MS, it simplifies and clarifies the original definitions in three areas. 1 MRI criteria for dissemination in time: A new T2 lesion (not only new enhancing lesion) at any time point after a reference scan performed at least 30 days after the onset of the initial clinical event would meet the imaging criteria of dissemination in time.

2 Incorporation of spinal cord lesions into the imaging requirements: A spinal lesion characteristic of MS (little or no swelling in the cord, hyperintense on T2, at least 3 mm in size, less than two vertebral segment in length and occupies part of the cord’s cross-section) is helpful to eliminate alternative diagnosis or to confirm MS when no dissemination in space is detected on brain MRI. A spinal cord lesion can substitute for a brain infratentorial (but not for periventricular or juxtacortical) lesion. An enhancing cord lesion can count doubly (for both an enhancing lesion and an infratentorial lesion) in fulfilling the criteria. Individual spinal cord and brain lesions together may reach the required nine T2 lesions. Although an MS lesion may occur as a diffuse cord lesion (particularly in PP-MS), for the purpose of diagnostic evaluation, a discrete focal lesion is required. Repeated spinal cord MRI has generally a low yield, and is only recommended when a clinical event suggests a new spinal cord lesion. 3 Diagnosis of PP-MS: A positive CSF finding is no longer necessary for the diagnosis of PP-MS (Polman et al., 2005) (See revised definitions in Box 3.2, Tables 3.3 and 3.4). 3.4 Clinical features (Bernadette Kalman) The stochastic distribution of CNS lesions results in a great variety of clinical symptoms usually reflecting multisystem involvement in MS. Nevertheless,

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macroscopic lesions in noneloquent CNS regions may remain asymptomatic, while a single small lesion in an eloquent region (optic nerve, spinal cord, brainstem) can lead to severe neurological disability. A widespread microscopic lesion load may also remain clinically silent until a critical sum of tissue loss is reached, from which point deficits (e.g. spastic paraparesis or cognitive decline) will progressively accumulate. Among the individually variable neurological phenotypes, there are a number of rather stereotypic presentations in MS. Lhermitte’s sign is often noted at onset or during the course of the disease. Optic neuritis (ON) either alone or in combination with other system involvements is another frequent presentation. The distinct combination of ON with myelitis will be discussed in the separate chapter on neuromyelitis optica. Oculomotor abnormalities and internuclear ophthalmoplegia may present alone, but are often associated with signs of corticospinal, spinothalamic, or spinocerebellar involvement in patients with brainstem lesions. Some MS patients have almost exclusively sensory, while others have predominantly motor disability at onset. Cerebellar symptoms can also dominate the clinical picture. Autonomous dysfunctions rarely occur in isolation at the initial presentation, but commonly develop during the course of disease and accompany other symptoms. A great proportion of patients has central and neuropathic or neuralgiform pain. Cognitive and emotional dysfunctions had been somewhat overlooked until recently, even though they may represent the most significant components of disability. The list of idiosyncratic presentations is endless. Paroxysmal symptoms, dystonia, hearing loss, aphasia, pruritus, hyperpathia, or allodynia may be mentioned among the more frequent ones. Optic neuritis Idiopathic ON is most commonly observed in young adults (20–50 years of age) with an incidence of 3/ 105 in the US (Frohman et al., 2005). ON can be an isolated event, but it is the initial presentation of MS in about a quarter of patients. In its typical forms, a partial or complete unilateral loss of vision develops over a few days up to 7–10 days. Impairment of color vision often occurs in the early stage. The visual loss is painful, particularly with eye movements, in the majority (92%) of patients (Optic Neuritis Study Group, 1991). The recovery usually starts in two weeks and the improvement may proceed for several months. In an acute stage, the ophthalmoscopic exam may

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be unrevealing, but swollen disc (papillitis), typically without hemorrhages or exudates, can be seen in a third of patients. In retrobulbar neuritis, the head of the optic nerve appears normal. Visual field exam usually reveals large central scotoma and centrocecal scotoma (involving the macula and blind spot) or variable field defects. The afferent pupillary defect (APD) is a critical finding. Chronic ON is associated with neuro-ophthalmological abnormalities including disc pallor, pupillary abnormalities, and field defects. Exclusion of superimposed glaucoma or infiltrating lesions may be necessary in some cases. Atrophy of optic nerves may be noticeable on MRI, and the atrophy of the retinal nerve fiber layer (RNFL) can be detected by optical coherence tomography (OCT). Neuro-ophthalmological tests used in the ONTT (Beck et al., 1992) included visual acuity (retroilluminated Snellen charts at 4 m), color vision (pseudoisochromatic Ishihara plates – 11 plates and the Farnsworth–Munsell 100-hue test), contrast sensitivity (Pelli–Robson letter chart at 1 m), and a visual field test (Humphrey Field Analyzer Program 30-2). Most neurologists in bedside settings limit the assessment to acuity, confrontational field evaluation, pupillary light reflexes, color vision assessment, and ophthalmoscopy. VEP studies may be useful in atypical and chronic cases, or when a discrimination of retinal and optic nerve disease is needed (Frohman et al., 2005). While orbital MRI with gadolinium enhancement can support the diagnosis of acute ON, a T2-weighted or FLAIR study of the brain has prognostic values (see below). Likewise, a CSF work up may not only facilitate the diagnosis and differential diagnosis but also serve as a prognostic marker in patients with ON. OCT is a recently introduced method that allows quantifying the axonal loss in the RNFL along with the assessment of secondary retinal ganglion cell loss (Trip et al., 2005). A significant reduction of the RNFL thickness and macular volume was noted in affected eyes with incomplete recovery as compared to the unaffected fellow eyes or to the eyes of normal controls (Trip et al., 2005). While the visual loss completely recovers in about half of patients with ON and significantly improves in most of the remaining cases, atrophy of the optic nerve (optic disc pallor, MRI finding) and of the RNFL (OCT assessment) are usual findings in chronic stages. Approximately, one in every eight patients will have relapsing ON, and a few patients will also have ON in the fellow eye. Relapsing ON is greatly associated with increased risk for CDMS.

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The ONTT revealed that patients with no MRI lesions had 16% risk for CDMS, while those with three or more MRI lesions had 51% risk at five years (Optic Neuritis Study Group, 1997). Lack of pain, optic disk swelling, and mild loss of visual acuity were associated with a low risk for CDMS in patients with negative MRI and history of no neurological symptoms or ON in the fellow eye. The analyses of data from the 10-year follow up established that even one brain lesion predicts a risk of 56% for CDMS as compared to the risk of 22% in patients with negative MRI (Optic Neuritis Study Group, 2003). Inflammatory CSF profile with OCB at onset also doubled the risk for CDMS in patients presenting with ON (Nilsson et al., 2005). In less typical cases, ON presents with progressive visual loss over weeks, resembling optic neuropathy of genetic, toxic-metabolic, chronic infectious, or compressive origin. In such cases and in the appropriate clinical setting, Leber’s hereditary optic neuropathy (LHON), Lyme disease, sarcoidosis, syphilis, lupus, West Nile virus, B12 deficiency, toxic causes, and infiltrative processes should be considered. The clinical presentation of anterior ischemic optic neuropathy may also overlap with that of ON. Similarities include the rate and severity of visual deterioration or altitudinal field defect, although this latter is rare in ON. In addition to the appropriate laboratory tests, orbital MRI with gadolinium enhancement around the optic nerve sheaths may clarify diagnostic uncertainties. LHON is a subacute, painless visual loss in young adults, most commonly in men. LHON not only represents a differential diagnostic problem in MS, but can also co-occur with inflammatory demyelination (see Section 3.1). While family history of a maternally transmissed visual loss and neuro-ophthalmological observations raise the suspicion for LHON, commercially available tests for pathogenic mtDNA mutations at nt 11,778, 3460 and 14,484 can unambiguously define the diagnosis (Howell et al., 1991; Johns et al., 1992; Wallace et al., 1988). Uveitis Uveitis is another ophthalmological complication detected more often than expected by chance in MS. The estimated frequency of uveitis varies in the range of 0.4% and 27% in this population due to the use of different diagnostic methods and criteria. The diagnosis of MS may precede, follow, or be concomitant with the diagnosis of uveitis (Zein et al., 2004). Pars planitis (intermediate uveitis) and panuveitis

are the most commonly encountered presentations, but anterior uveitis may also occur in MS (Biousse et al., 1999). Associated symptoms include retinal inflammation presenting as periphlebitis retinae. Bilateral pars planitis without significant visual loss in white females is particularly often associated with MS. Slit lamp exam and dilated fundoscopy need to be included in the routine neuro-ophthalmological work up to reveal the characteristic abnormalities of uveitis when it is suspected in patients with MS. Oculomotor abnormalities associated with brainstem and cerebellar lesions Internuclear ophthalmoplegia (INO) is one of the commonest brainstem signs in MS that is caused by the involvement of the medial longitudinal fasciculi (MLF) within the dorsomedial pontine or midbrain tegmentum. INO is characterized by slowing or paresis of the medial rectus on an attempted lateral gaze and by nystagmus in the abducting eye. During horizontal gaze, burst cells in the pontine paramedian reticular formation (PPRF) innervate the abducens (VI) nucleus. The abducens nerve innervates the ipsilateral lateral rectus muscle, while axons from the abducens interneurons cross to the contralateral side and form the MLF that innervates the medial rectus subnucleus of the oculomotor complex (Frohman et al., 2005). The impairment of binocular fusion may lead to transient oscillopsia, diplopia, reading fatigue, and loss of stereopsis. INO can be unilateral, but it is frequently bilateral in MS. Other forms of ophthalmoparesis (related to oculomotor, abducens, or rarely trochleal nerve lesions) may occur alone or in combination with long tract sensory and motor symptoms. INO in one direction may be associated with horizontal gaze paresis in the other direction, presenting as one-and-a-half syndrome. Many patients with bilateral INO also have abnormal vertical eye movements, impaired vestibulo-ocular reflex, and impaired optokinetic and pursuit responses. Skew deviation is characterized by supranuclear vertical misalignment and changes in ocular torsion, when the eye in the higher position is ipsilateral to the lesion in the pons or midbrain, while the eye in the lower position is usually ipsilateral to a medullary lesion. Unilateral and bilateral horizontal gaze palsy related to lesions in the PPRF can also occur in MS (Frohman et al., 2005). Nystagmus can be caused by lesions in various anatomical locations. Frohman et al. (2005) propose to approach nystagmus as disorders of the

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gaze-holding networks in the brainstem, cerebellum, and the inputs to them (e.g. the vestibular system). Essential structures of this neuronal integrator system are located in the medulla for horizontal gaze (medial vestibular nuclei and the adjacent nucleus propositus hypoglossi) and in the mesencephalon for vertical gaze (the interstitial nucleus of Cajal). The superior vestibular nuclei may also influence vertical gaze by their connections via the MLF to the interstitial nucleus of Cajal (Frohman et al., 2005). The nuclei in the PPRF are important for ocular motor integration. The brainstem components of the gazeholding network are connected to the cerebellar flocculus and paraflocculus involved in fine-tuning of brainstem integrators (Frohman et al., 2005). Gaze-evoked nystagmus is a common finding in MS, and is related to a lesion in the neuronal integrators presenting with a slow drift in one, and a resetting saccade in the other direction. Pendular nystagmus is characterized by a back and forth slow-phase oscillation, and is also frequently seen in MS. Pendular nystagmus may be related to increased conduction time in demyelinated fibers, visual loss, and lesions in the Guillian–Mollaret triangle composed of the dentate nucleus, superior cerebellar peducle, red nucleus, central tegmental tract, inferior olive, and inferior cerebellar peduncle (Frohman et al., 2005). It is often associated with palatal tremor (also called palatal myoclonus). Impaired fixation is caused by saccadic intrusions related to lesions in the pause-cell neurons in the pontine raphe which tonically inhibit saccadic premotor burst neurons in the PPRF. The saccadic intrusions may present as square-wave jerks (1–5 degree eye movements away and back to the neutral position with intersaccadic latency), ocular flutter (horizontal back-to-back saccades without intersaccadic latency), and opsoclonus (both horizontal and vertical back-to-back saccades). Hypermetric or hypometric saccades may be associated with lesions in the cerebellar dorsal vermis and posterior fastigial nuclei. Plaques in the cerebellar peduncules cause hypermetric saccades towards the side of a lateral medullary lesion or away from a lesion in the Hook Bundle region close to the superior cerebellar peduncle. Floccular and para-floccular lesions cause horizontal gaze-evoked nystagmus, neutral-position downbeat nystagmus, impaired pursuit with corrective saccades, rebound nystagmus, postsaccadic drift, and loss of vestibulo-ocular reflex suppression (Frohman et al., 2005). Ocular contrapulsion presents in a triad of abnormalities including:

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(i) hypermetric saccadic eye movements in the direction opposite to the lesion; (ii) hypometric saccades towards the side of the lesion; and (iii) oblique saccades directed away from the lesion on attempted vertical saccades. The relevant pathology is in the uncinate fasciculus at the level of superior cerebellar peduncle (Frohman et al., 2005). The vestibulo-ocular reflex is normally suppressed to allow a concurrent smooth head and eye movement. In case of an impaired suppression, “catch-up” saccades develop to maintain fixation of the target moving with the head while the unsuppressed reflex drives the eyes in the opposite direction of the head movement. Impaired suppression of the vestibuloocular reflex is usually associated with impaired smooth pursuit (Frohman et al., 2005). Parinaud’s syndrome is related to lesions in the dorsal midbrain and is characterized by diminished upward saccades, convergent retraction nystagmus on attempted upward saccades, and near-light dissociation. Other brainstem symptoms Vestibular involvement is rather common but deafness rarely occurs in MS. Dysarthria, dysphasia, and tongue movement difficulties usually develop later during the course of the disease, and can be related to supranuclaer tract lesions or to direct nuclear and fascular lesions in the brainstem. The corticospinal, spinothalamic, and spinocerebellar tracts are frequently affected in brainstem lesions. In most severe forms and advanced disease, communication difficulties may develop in association with extensive brainstem lesions. High cervical–low bulbar lesions rarely have the size to cause respiratory problems in MS, while a life-threatening respiratory arrest is associated with a high mortality in Dévic’s disease. Sensory symptoms Initial presentations of MS frequently include pure sensory symptoms such as paraesthesia (pins and needles), numbness and decreased temperature sensation on the face, extremities, and trunk, or beltlike pain usually at the low thoracic level with or without sensory abnormalities below. The quality of sensory abnormality may be difficult to describe (e.g. “I feel that the bottom of my foot is round shaped” or “cannot stand wearing a shirt”). Abnormalities in proprioception may present with unsteadiness, gait difficulties, clumsiness in fine movements, and

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sensory ataxia. Isolated involvement of the dorsal columns may be present in some patients. Lhermitte’s sign is a classical sign associated with but not specific for MS, and typically indicates a cervical cord lesion causing a stereotypic sharp electric sensation radiating into the upper or lower extremities upon bending forward the neck. Al-Araji and Oger (2005) found that 41% of their 300 MS patients and none of 100 normal controls experienced Lhermitte’s sign. In 53% of those who had Lhermitte’s sign, this abnormality appeared in the first three years. It was an isolated symptom at onset in 64% of patients, and polysymptomatic in 36%. Cervical MRI lesions were highly associated with Lhermitte’s sign. Pain About a third of MS patients describe pain as one of the worst symptoms of the disease (Svendsen et al., 2005), and about half of MS patients experience pain some time during the course of the disease (Osterberg et al., 2005). The clinical presentations are complex and include musculoskeletal pain, painful spasm, neuralgias, neuropathic and central pain. Musculoskeletal pain may be related to associated conditions or develop secondary to immobility. Trigeminal neuralgia is caused by a demyelinatined plaque in the root-entry zone of the sensory division of the V. nerve, leading to ectopic generation of action potentials and/or emphatic neuronal transmission. Similar mechanisms may result in neuralgiform pain in the distribution of other cranial nerves and spinal roots. The mechanism of central pain is the least understood and this pain type is also the most difficult to control. It is detected in about half of MS patients with pain (Svendsen et al., 2005). Disinhibition of pain pathways by an injury to the spinothalamic tract and imbalance of different sensory inputs has been implicated in the pathogenesis, but hyperexcitability caused by a CNS lesion may also contribute to it. Quantitative sensory testing reveals that abnormal pain and temperature sensitivity are frequently present. Allodynia and mechanical and thermal hyperalgesia are sensory qualities associated with central pain. Lesions in the posterior columns, however, are also frequently detected in patients with central pain. Motor symptoms Signs of nuclear and fascicular involvements of the motor divisions of cranial nerves (e.g. VII – Bell’s

palsy, or III, IV, and VI – ophthalmoparesis) may be seen alone or in association with other brainstem symptoms (as described above). Depending on the anatomical location of lesions, the involvement of corticospinal tract may present as a spastic hemiparetic, paraparetic, or tetraparetic syndrome. The weakness occasionally follows a pseudoradicular or pseudoperipheral nerve distribution. Spasticity is a significant component of upper motor neuron syndromes, and is associated with increased responses to rapid stretch, flexor, extensor, and adductor spasms, and simultaneous contraction of agonist–antagonist muscles and clonus. The stretch-reflex response at rest is normally mediated by IA afferents with monosynaptic connection to the spinal motoneuron. Other reflex components, including group II spindle afferents and transcortical pathways, are also evoked when the muscle is activated. Modulation of stretch reflexes by task reflects changes in motoneuronal and spinal inhibitory interneuronal activity that is also controlled by descending supraspinal and peripheral inputs (Thompson et al., 2005). In spasticity, an enhanced and prolonged response to stretch occurs, with the involvement of both group IA and group II afferents via mono- and polysynaptic circuits. Abnormal modulation of stretch reflexes is related to abnormalities in the supraspinal control. In association with spasticity, exaggerated deep tendon reflexes and pathological reflexes (e.g. Babinski) are seen. Fatigue and perceived heaviness of an extremity are also frequently noted. Even mild degrees of spasticity and weakness can significantly interfere with normal daily activity, personal hygiene and mobility, and result in a decreased quality of life. In most extreme conditions, the severe spasticity causes limited range of motion in a joint, contractures, pain, decubitus, and infectious complications (Haselkorn et al., 2005). Cerebellar symptoms Oculomotor abnormalities caused by cerebellar lesions are detailed above. A pure cerebellar presentation is relatively uncommon, and may include vertigo, unsteadiness of gait, and change of speech in addition to nystagmus and eye-movement abnormalities. Over time, many of these patients develop severe intention tremor, coordination difficulties in the extremities, ataxia of trunk, difficulties with alternating movements, overshooting, and scanning speech. The Charcot’s triad includes nystagmus, intention tremor, and scanning speech, and is usually seen in advanced disease. Cerebellar symptoms are often

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associated with brainstem signs including cranial nerve and long tract involvement. Cerebellar symptoms are not only significant contributors to disability, but also are relatively refractory to diseasemodifying as well as symptomatic therapies. Growing evidence suggests that mistuning of Purkinje cells secondary to the abnormal expression of sodium channels (particularly Nav 1.8) may distort the firing of these important cells in MS (Waxman, 2005). Myelitis and myelopathy Many patients with RR-MS present with signs of myelitis, while a progressive myelopathy is the commonest presentation of PP-MS. Acute myelitis, however, often has an infectious, or postinfectious and postvaccinial origin, with different prognosis and therapeutic considerations. In addition, acute noncompressive myelopathy may be the complication of systemic autoimmune diseases, irradiation, and vascular abnormalities or occlusions. In a study of 45 consecutive patients with acute transverse myelitis (ATM), Harzheim et al. (2004) found that 38% of patients had parainfectious etiology, 36% of patients had idiopathic origin, and 22% of patients had ATM as the first manifestation of MS. T1weighted post-gadolinium images typically showed enhancement in ATM. T2-weighted MRI abnormalities were detected in 96% of patients. ATM in MS usually affects parts of the long ascending and descending tracts, the lesions usually are asymmetric and involve a part of the cord shorter than a vertebral segment. In contrast, lesions in neuromyelitis optica show gray–white matter involvement frequently with swelling and extend longer than three vertebral segments. Lesions in parainfectious and idiopathic ATM also tend to extend longer than 1–2 segments. In ATM-MS, there may be one or more well-circumscribed lesions, a diffuse lesion, or the combination of circumscribed and diffuse lesions. The lesions may involve the spinothalamic tracts, dorsal columns, cortico-spinal and spinocerebellar tracts, and autonomous projections. The corresponding clinical symptoms include paraparesis, biparesis, or monoparesis, and sometimes tetraparesis. Increased deep tendon reflexes and Babinski sign are almost always present. Painful band-like sensation or tightness over the trunk with a sensory level and paresthesia below, or difficulties in the discriminative sensations in a patchy, hemisensory, or pseudoperipheral distribution are common. Bowel, bladder, and sexual dysfunction

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frequently develop in combination with sensorymotor signs, and occasionally represent the sole initial presentation of ATM-MS. Brown–Sequard syndrome may develop in association with a unilateral circumscribed plaque and present with contralateral loss of pain and temperature sensation, and ipsilateral corticospinal deficit along with a loss of joint position and vibration sensation (Ozaki et al., 2003). While peripheral nerve involvement occurs in almost a third of patients with infectious, parainfectious, and idiopathic ATM, it is extremely rare in patients with ATM-MS (Harzheim et al., 2004). Inflammatory CSF with pleocytosis, elevated IgG index, and occasionally OCB is seen in the majority of ATM. The most recently proposed diagnostic criteria for idiopathic ATM require the presence of all inclusion criteria (Transverse Myelitis Consortium Working Group, 2002): 1 Clinical sensory, motor, and autonomic dysfunction reflecting spinal cord lesions. 2 Bilateral signs and symptoms. 3 Exclusion of extra-axial compression by neuroimaging. 4 Signs of inflammation on postgadolinium MRI and in the CSF. 5 Progression to nadir between 4 hours and 21 days after the onset. None of the exclusion criteria should be present: History of spinal irradiation in the last 10 years. Thrombosis of a spinal vessel. AVM. CNS complications of bacterial and viral infections (syphilis, Lyme, HIV, HTLV-1, Herpes viruses, etc.). 5 Positive brain MRI consistent with MS. 6 History of ON. 1 2 3 4

Based on these criteria, a retrospective multicenter study of 288 patients with ATM of various origins identified 45 cases (15.6%) with idiopathic disease, indicating that most patients with ATM have identifiable causes of the disease (de Seze et al., 2005). MS represented 10.8% of the entire cohort. The subgroup of patients with idiopathic ATM was homogeneous based on clinical and MRI criteria, but the prognosis was highly unpredictable. However, severe initial symptoms suggesting spinal shock were highly predictive of a poor outcome.

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In the case of a progressive myelopathy that is a frequent presentation of PP-MS, exclusion of a list of similar phenotypes may be necessary in the appropriate clinical setting. This list includes inherited forms of spastic paraparesis and adrenomyeloneuropathy, systemic autoimmune disorders (lupus, antiphospholipid antibody syndrome, Sjögren’s syndrome, Behçet’s syndrome), neurosarcoidosis, Lyme disease, syphilis, or arteriovenosus malformations and dural fistula.

located in the spinal cord, but lesions in the brainstem, basal ganglia, hypothalamus, and the cerebral hemispheres representing widespread autonomic regulatory areas and their connections can also be involved. The severity of these abnormalities does not necessarily correlate with the overall severity of MS, but rather increases with the duration of the disease (McDougall and McLeod, 2003).

Fatigue

Paroxysmal phenomena are more common than generally appreciated in MS, and may be related to ectopic impulses, direct effects of soluble inflammatory products, ion channel dysfunction, and accumulation of extracellular potassium. Eriksson et al. (2002) estimated the frequency of seizures 8%, cranial neuralgias 4%, and other paroxysmal symptoms 4% in MS. Seizures more commonly develop in progressive disease than relapsing disease in association with juxtacortical or cortical lesions. One of the most common paroxysmal signs is painful dystonic posturing (also called paroxysmal dystonia or tonic spasm) precipitated by voluntary movement, tactile stimuli, startle, and hyperventilation (Waubant et al., 2001; Zenzola et al., 2001). Other paroxysmal movement disorders include chorea, kinesigenic choreoathetosis, ballisms, spasmodic torticollis, writers’ cramp, generalized dystonia, palatal myoclonus, and ticks. Corresponding lesions most often are detected in the contralateral thalamus and basal ganglia, but lesions in the spinal cord and other locations have also been implicated. Trigeminal neuralgia and other cranial neuralgias, paroxysmal vertigo and tinnitus, phosphenes, and migraines may also be among the complaints. Paroxysmal pruritus is another complaint noted among the episodic sensory phenomena. A classical feature of MS is a temporary worsening, such as visual blurring (Uhthoff phenomenon) or weakness and paresthesias in the limbs, induced by heat or physical exercise. The pathophysiology of this phenomenon is likely related to the abnormal heat sensitivity and conduction slowing in demyelinated fibers.

While the anatomical localization of fatigue is very complex, fatigue is a frequent and disabling complaint presenting either as an initial onset or a gradually developing problem during the course of MS. Most patients mean physical tiredness under fatigue, but this term is also used to describe mental and emotional deprivation, lack of sleep, and muscle weakness. Primary fatigue is intrinsic to MS (immune dysregulation, anatomical CNS lesions, neuroendocrine and neurotransmitter abnormalities), while secondary fatigue develops due to sleep deprivation, pain, emotional abnormalities, or medications. Recently, fatigue was defined: “A subjective lack of physical and/or mental energy that is perceived by the individual or caregiver to interfere with usual and desired activities” (MS Council for Clinical Practice Guidelines, 1998). Pathological fatigue is present more than 60% of the time and interferes with normal activity. Both acute (newly occurring in the past six weeks) and chronic (has been present more than six weeks) forms are recognized. Several fatigue scales have been developed, many of which became very useful in clinical trials (Krupp, 2004). Reduced sleep, weakness and spasticity, impaired conduction due to demyelination, and depression may contribute to the complex mechanism of fatigue. The involvement of proinflammatory cytokines in mediating fatigue in MS has been both suggested and rejected (Giovannoni et al., 2001; Heesen et al., 2006). Autonomic dysfunction The most commonly noted autonomic dysfunctions include bladder, bowel, and sexual abnormalities during the course of MS and affect more than half of the patients. Cardiovascular, gastrointestinal, and sudomotor changes may also develop. Autonomic abnormality alone is rare at the onset of MS. The responsible anatomical lesions most frequently are

Paroxysmal symptoms

Cognitive and mood disturbance Neuropsychological studies suggest that 45 to 65% of MS patients suffer from some degrees and forms of cognitive impairment that may include slowing of information processing, attention deficit, difficulties with concentration and abstract reasoning, reduced

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manual dexterity, impaired verbal memory and language deficits in all forms of the disease. Cortical aphasia, agnosia, and apraxia are rare in MS, while verbal fluency and verbal memory are often impaired relatively early during the disease. Callosal disconnection as well as alexia without agraphia was described in case reports (Mao-Draayer and Panitch, 2004). Since the observed cognitive abnormalities predominantly affect executive functions, such impairments by themselves may become highly disabling in MS, and significantly interfere with professional and social functioning. The combination of abnormalities in attention, planning, working memory, speed of information processing and visuo-spatial skills, along with physical disability, can significantly interfere with the performance of complex daily tasks. Impairments in all cognitive domains may result from a diffuse distribution of microscopic pathology, while a large lobar lesion can present with a predominant lobar deficit. Extensive cortical pathology accompanying varying loads of subcortical lesions may result in mixed forms of dementia (Buchanan et al., 2005). The severity of cognitive impairment best correlates with the total cerebral disease burden defined by recently developed conventional and nonconventional MRI sequences, and both gray- and white-matter atrophy contributes to cognitive and neuropsychological impairments in MS (Sanfilipo et al., 2006). Metabolic and functional abnormalities detected by PET scan or functional MRI in cortical neurons likely reflect disruption of intercortical and subcortical pathways, lesions directly affecting neurons and toxic effect of soluble inflammatory products (De Souza et al., 2002; La Rocca, 2000; Rao et al., 1991). A trans-synaptic alteration of neuronal activity is also possible. Mapping of compensatory changes and plasticity of the brain represents an important field of functional imaging (Tartaglia and Arnold, 2006). Psychological disability in MS most commonly includes emotional lability, irritability, euphoria, apathy, depression, bipolar disorder, suicidal ideation, antisocial behavior, and psychosis (Figved et al., 2005; De Souza et al., 2002). These symptoms negatively influence the quality of life and add to the disabling effects of cognitive abnormalities. Depression may be caused by the disruption of normal anatomy, changes in neurotransmitter production, and alteration of the neuroendocrine pathways. Reaction to disability and medication side effects may also contribute to depression. Most studies testing the relationship between depression and cognition suggest that

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there is little or no relationship. However, a metaanalysis by Thronton and Naftail (1997) reveals a strong correlation between depression and working memory, but no relationship between depression and short-term or long-term memory (La Rocca, 2000; De Souza et al., 2002). Euphoria is an inappropriate expression of optimism and happiness that is often associated with signs of emotional dysinhibition. Euphoria usually results from a diffuse and severe pathology in patients with advanced physical and cognitive disability. Bedside testing cannot adequately assess cognitive function or mood disorders, and the use of comprehensive neuropsychological batteries may be necessary in a great proportion of MS patients. The increasing availability of immunomodulatory, neuroprotective, antipsychotic, and mood-stabilizer drugs, along with other symptomatic treatments and rehabilitation methods, underscore the importance of early evaluation of cognitive and mood disorders in MS. Variants of MS ON, ATM, Marburg’s type of MS and Balo’s concentric sclerosis are discussed above. Neuromyelitis optica or Dévic’s disease is reviewed in Chapter 4. MS mimics There are several autoimmune, infectious, and granulomatosus disorders which imitate sporadic MS. A short list includes lupus, Sjögren’s syndrome, Behçet’s disease, antiphospholipid antibody syndromes, Susac’s syndrome, Lyme disease, cysticercosis, and sarcoidosis. The history, clinical presentation, MRI characteristics, and a comprehensive laboratory work up usually help to establish the differential diagnosis. Familial forms of MS occasionally present with pseudomendelian inheritance patterns. Therefore, inherited forms of whitematter diseases including leukodystrophies with autosomal dominant, recessive, or X-linked transmission patterns have been misdiagnosed as familial MS. Adrenomyeloneuropathy, an adult-onset variant of X-linked adrenoleukodystrophy, can particularly pose diagnostic difficulties. Alexander’s disease and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) are other rare disorders with features imitating MS. The recently described vanishing white-matter disease only seldom causes confusion

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with MS. With the recent availability of imaging, specific molecular genetic and biochemical tests, the diagnostic dilemma can be easily solved in most of these disorders (Kalman and Leist, 2004). Pregnancy and MS While family planning may profoundly be influenced by the level of disability in MS patients, the effect of pregnancy on the disease has also been a matter of controversy. Korn-Lubetzki et al. (1984) determined in a large retrospective study that the frequency of relapses decreased during pregnancy, increased in the postpartum period, and was similar in the pregnancy year (nine months pregnancy plus three months postpartum) to that of out of pregnancy. The Pregnancy in Multiple Sclerosis (PRIMS) study was a large prospective natural history analysis of MS in pregnant women (Confavreux et al., 1998). This multicenter study confirmed the significant decline of relapse rate during pregnancy, most marked in the third trimester, and the increase of relapse rate in the first three months postpartum. However, no acceleration of disability was noted during the puerperium, and neither breast feeding nor epidural analgesia had negative effects. In an extension of this study, patients were followed up to two years postpartum (Vukusic et al., 2004). This second PRIMS study added that from the second trimester onwards and for the following 21 months, the annualized relapse rate did not significantly differ from that of the prepregnancy year. Despite the increased risk in the first three postpartum months, 72% of women did not have relapses. Increased relapse rate in the prepregnancy year and during pregnancy and a higher disability status score at pregnancy onset, correlated with the postpartum relapses.

highly variable. They differed with the age of the lesion and seemed to correlate poorly with the clinical syndrome exhibited by the patient (Figs. 3.5 and 3.6), except for the fact that if they were situated in the CNS at a specific site, they could be correlated with the resulting neurological deficit. Their histological

A

B

Old plaque with myelin loss gliosis and axonal loss (late)

C

D

Fig. 3.5 The gross photographs (A) of the parietal lobes with totally demyelinated, old MS plaques in the periventricular area on each section. Histological sections were prepared from the brain slice in the lower right, and are depicted in B–D. B is a Holzer stain to demonstrate gliosis that extends well beyond the area of the MS plaque itself. C is a Bodian stain and D is a Bielshowsky stain which identify axons. Both demonstrate the near total axonal loss in the demyelinated zone.

3.5 The pathology of MS: A quest for clinical correlation (William F. Hickey) Introduction Merely a decade ago if one were to delve into the basic pathology of MS, the picture that would emerge was relatively consistent, but it contained great variability. The pathognomonic lesions of MS, called plaques, were chronic inflammatory foci randomly affecting the white matter of the central nervous system that resulted in myelin loss and gliosis (Figs. 3.5 and 3.6). The features of the histological lesions of MS have long been acknowledged to be

Fig. 3.6 The edge of a typical, actively demyelinating MS plaque is shown (hematoxylin and eosin (H&E) stain, X125). The tissue at site “A” is neither inflamed nor demyelinated, and no loss of oligodendroglia has occurred. At site “B” loss of myelin and oligodendroglial cells is nearly complete. As indicated by the arrow, the border of the advancing plaque is hypercellular and contains large numbers of T cells and macrophages.

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appearance neither helped with prognosis, selection of therapy nor insight into etiology or pathogenesis. While there had been steady progress in dissecting the structure of MS plaques using immunohistochemical and ultrastructural techniques, the fundamental links between the microscopic features of the plaque and questions regarding etiology, pathogenesis, and prognosis remained opaque (Hickey, 1999; Lassmann, 2005). The various features of the lesions found in MS were reviewed and analyzed at an international symposium that inspected the complexity of MS plaques varying from their immunological constituents and types of damage to the temporal changes in lesional pathology and clinical correlations (Lassmann et al., 1998). It was obvious that MS was a highly complex, variable, and enigmatic problem. The histopathology of MS has been examined for nearly a century and a half, but progress in understanding the disease has been slow. Pathologists accept that while there are certain general features of the MS lesion that could be expected based on a lesion’s age, inflammatory activity, and the clinical features of the illness, a reliable and informative classification system had not evolved . . . if such a system was ever to prove to be appropriate and useful. Lucchinetti et al. (1996) for the first time proposed a classification schema that apparently permitted MS cases to be characterized and subdivided based upon specific immunohistochemical features of the lesions. The concept that the pathogenesis of MS might fall into a set number of specific patterns, each representing a distinct immunopathological mechanism, was revolutionary. Pathological subtypes – reality or illusion? While there have been some minor modifications in the proposed classification, at this time there are basically four types of MS lesions that are presumed to be histologically, immunophenotypically, and pathogenetically distinct (Lucchinetti et al., 2005). Type I lesions are those characterized by extensive infiltration by T cells and macrophages. The plaques have sharp, distinct edges and the disappearance of the various molecular components of myelin seems to occur simultaneously, not in a selective or sequential manner. In this type of inflammatory focus some oligodendroglial cells survive the insult and remyelination (partial or complete) may be possible. Shadow plaques, areas of incomplete remyelination, can be associated with type I lesions. In many ways type I

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lesions are reminiscent of the pathology found in EAE, a well-established animal model of MS. If so, this MS subtype may represent a true autoimmune attack by T cells against one or more specific myelin components. Type II plaques are in many ways similar to the prior type, but are associated with extensive deposition of antibodies and the presence of activated complement components, including formation of the membrane attack complex from the final elements of the complement cascade. The lesions have sharp edges and the loss of myelin components occurs simultaneously. As before, some oligodendroglial cells are able to survive in the inflammatory foci, thus remyelination can occur and shadow plaques are found. This subtype of MS lesion resembles the pathology of EAE induced by MOG. MOG-induced EAE is distinct in that it requires not only antigenspecific T cells, but also the simultaneous presence of anti-MOG antibodies. Hence, it would seem that in type II lesions the T cells may be permitting leakage of antibodies into the CNS, but it is the binding of antimyelin antibodies and the activation of the complement cascade that actually leads to myelin destruction. Type III lesions are distinct from the former two. While there are T cells and macrophages present, the lesions are irregular and the borders ill-defined. Moreover, in this subtype there seems to be a preferential loss of myelin-associated glycoprotein (MAG) over the other molecular components of compact myelin; in other words, the molecules making up compact myelin are lost selectively. Oligodendroglial cells undergo destruction in what appears to be an apoptotic fashion, their loss is nearly total and remyelination does not seem possible. This MS type is believed to represent a degeneration of oligodendrocytes that starts at their most distal processes. Since at the subcellular level MAG is restricted to the portions of the oligodendroglial processes in the periaxonal area, it has been suggested that type III lesions may represent a “dying-back oligodendrogliopathy”. Such an unusual finding may be parallel to certain features found in hypoxic/ischemic lesions of the white matter. This has led to the hypothesis that demyelinating foci in some forms of MS may represent hypoxia-like tissue injury (Aboul-Enein et al., 2005). Indeed, it is possible that some form of small-vessel vasculitis, possibly one mediated by activated T cells, may underlie this class of MS damage (Kornek and Lassmann, 2003; Lassmann et al., 1998).

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The type IV lesions in MS are a bit more difficult to discern. Those proposing the classification suggest that this subtype may represent a distinct disorder affecting the oligodendroglial cell itself – a so-called primary oligodendrogliopathy. Histologically, the plaques have sharp edges, are infiltrated by T cells and macrophages, and the loss of the various myelin components appears to occur simultaneously. There is abundant apoptotic death of oligodendroglia in the white matter around the edge of the plaque. Yet, the nature of the problem that leads to oligodendroglial death has not been defined. Moreover, this subtype is rare. There are some problems with this proposed classification system. These problems are not necessarily fatal flaws, nor do they reflect negatively on the proponents who advocate immunophenotypically categorizing MS lesions. Certainly, few would expect that an initial classification system based upon a relatively small number of cases would be comprehensive and never need modification or amendment. It is most likely that there will be further refinements of the classification based on yet to be identified parameters. Nevertheless, given the proposed classification system, the current question is whether it should be utilized and broadly applied. It is at this point that we need more data. It is coming, but at this writing, not yet available. The aforementioned classification system was derived from extensive analysis of biopsies from the brains of patients not previously diagnosed with MS who presented acutely with a progressive neurological disorder. Some argue that this represents a highly skewed group of patients, even if the majority (but not all) actually progressed to develop clinical multiple sclerosis. However, following a further analysis of a broader group of patients, the categorization method appears to be sustained (Pittock et al., 2005). Another potential difficulty with the classification system is that it has yet to be replicated and confirmed by a group not associated with the system’s original proponents. Access to MS tissue, the scarcity of MS brain biopsies, the accurate duplication of the reagents and methods used by the original authors, and unfamiliarity with the parameters of analysis of the tissue employed by the authors of the classification method, are all impediments that must be overcome. One of the major questions concerning the categorization of MS lesions which still remains to be resolved is whether MS lesions are homogeneous

and consistent within an individual patient, or if a spectrum of histopathological types coexists simultaneously within one person. There are reports from experienced MS pathologists stating that various forms of inflammatory lesions do coexist within individual MS patients (Prineas et al., 2001). Also, studies of some cases of classic relapsing-remitting MS have shown lesions that do not neatly fit into the above categories (Barnett and Prineas, 2004). Others have reported that there is “notable homogeneity within individual patients” (Morales et al., 2006). The answer is elusive, but should appear in the next few years. At present the topic remains a point of much debate. Another final issue with this categorization method centers on the extent to which the various histological types of lesions correlate with specific clinical types of MS. It is generally recognized that the clinical course of MS typically falls into a relapsingremitting pattern, or the secondary progressive type; the primary-progressive form and the so-called “benign” type are rarer (Lublin, 2005). To date the correlation of histopathological type with clinical subtype is weak at best (Pittock et al., 2005); however, there are ongoing studies that are specifically designed to address this issue of clinical correlation. Can prognosis and therapies be directed by the pathological type? Here there is cause for cautious optimism. A retrospective study by Keegan et al. (2005) predicted that patients with type II lesions – those characterized by extensive antibody and complement deposition – might benefit from therapeutic plasma exchange. This is what they found. Plasma exchange did not seem to benefit those with lesion types I or III, but individuals with type II lesions experienced moderate to substantial neurological improvement. Needless to say, if some correspondence between a specific immunohistological pattern and a predictable clinical syndrome emerges, then the classification of MS based on the lesions’ histopathological features will be both broadly accepted and rapidly applied. Axonal pathology – an unexpected, unifying feature From the earliest days of the microscopic study of MS lesions, it has been known that axons are damaged in such lesions. But the paper by Trapp et al. (1998) still caught those who studied MS unawares. What was so amazing was not that axonal damage existed; rather it was the extent to which it was present in MS lesions. Vast numbers of axons were transected

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in active MS plaques. Even in inactive or marginally active plaques, the axon damage continued. Yet, the most startling observation was that significant axonal damage was occurring in the normal appearing white matter, far away from a site of definable inflammation or demyelination (Bjartmar et al., 2001). While all who study MS agree that axonal damage does occur, the puzzle as to whether axonal damage represents a primary insult versus a secondary phenomenon is unresolved. The work of Trapp and colleagues strongly suggests that the axonal pathology is a unique and primary feature of MS (1998). Axonopathy may be an early feature in MS lesions (Kornek and Lassmann, 2003). Yet some reports have questioned this and proposed that axonal damage occurs in the setting of chronic inflammation and longstanding disease afflicting the CNS, but is not a necessary or acute phenomenon (Kutzelnigg et al., 2005). The potential causes of axonal degeneration are manifold. Obviously, the presence of a chronic inflammatory infiltrate, activated macrophages and reactive microglial cells, and the elaboration of a spectrum of cytokines and reactive oxygen metabolites would create an environment conducive to cell membrane damage (Bjartmar et al., 2000). The specific offending entities, however, have not yet been specified. Alternatively, it has recently been proposed that mitochondrial dysfunction may be the cause of the axonal damage (Dutta et al., 2006). Much effort is being expended to dissect this potentially critical aspect of MS lesions. The great attention currently being paid to this seemingly isolated feature of the pathology of MS derives from the fact that many if not all of the fixed neurological deficits found in longstanding cases of MS may result from axonal loss rather than demyelination (Trapp et al., 1999). In cases of secondary-progressive MS the constant deterioration of neurological function likewise may be attributable to axonal pathology rather than myelin loss. In addition, the relentlessly progressive axonal loss that seems to occur in MS almost certainly provides the pathological substrate for the extensive atrophy afflicting all MS patients as they age. Cortical lesions in MS The existence of focal lesions in the cerebral cortex of MS patients was a relatively new observation (Bo et al., 2003a). These damaged areas do exhibit gliosis, but are relatively difficult to identify due to

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the relative absence of dense myelin in the cortex. Indeed, subpial demyelination can be an extensive, but subtle, feature in some cases of MS (Bo et al., 2003b). While loss of myelin occurs in cortical lesions, there is remarkably little inflammatory infiltrate (Bo et al., 2003a). As such, this would suggest that white matter and cortex operate under different rules when it comes to inflammatory demyelination. Perhaps more importantly, this offers the possibility that lymphocytes might not be essential in producing damage leading to demyelination, gliosis, and axonal loss. Even less certain about these cortical and subpial lesions is what they mean clinically. Occasional MS patients exhibit seizures. Are such lesions the cause? Do they contribute to the unusual affect seen in some cases of MS? Can they cause motor or sensory abnormalities? Again, pathological analysis of the CNS has identified a group of lesions that sporadically do develop in MS, but the clinical phenomena attributable to such foci are unknown. Summary In the past decade a system for categorizing the lesions of pathological MS into four discrete subtypes has been proposed. While it is very attractive, some question its validity. Currently it is not in universal use because of the uncertainty regarding its ability to provide any meaningful correlations with etiology, clinical course, prognosis, or therapeutic options. At a deeper level, if the existence of distinct pathological patterns of MS plaques is verified and can be employed by pathologists, do these patterns bespeak different etiologies, different mechanisms, and different clinical syndromes? Likewise the conundrum of whether the CNS lesions are consistently of the same type within a given patient throughout the course of the disease must be resolved. The most elemental and important question regarding MS that will be answered in the next few years has been brought into focus by recent and ongoing pathological analysis of MS tissue. Is MS one disease with widely varying clinical manifestations, or is it actually a number of distinct neuroinflammatory diseases each with its own etiology, pathogenetic mechanism, and prognosis? It is very possible that the protean disorder called multiple sclerosis represents a final common pathway for distinct disease entities. With questions such as this to be resolved the excitement surrounding the ongoing immunopathological analysis of MS is not likely to abate soon.

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3.6 Cerebrospinal fluid (Mark S. Freedman) The cerebrospinal fluid (CSF) or the brain’s “soup”, unlike the blood, is in direct contact with brain cells, hence sampling its contents can give an indication of what processes may be transpiring in the CNS. In the case of inflammatory conditions such as MS, there are abnormalities that reflect activity arising from within the CNS and help to distinguish them from those due to inflammation penetrating the CNS from without. An understanding of just what the CSF can tell you about inflammatory conditions that affect the CNS demands some basic knowledge about CSF as well as the limitations of the tests used to examine it. First it should be pointed out that the blood–brain barrier (BBB) separating the brain from the vasculature is not the same as the blood–CSF barrier (BCB) that comes between the CSF and the blood. The BBB tends to be “sealed” by the specialized endothelial tight junctions seen in the CNS, whereas the BCB is fenestrated acting as a specialized macrofilter. Anything that originates in the blood must cross either barrier by means of diffusion that is facilitated either by specialized transporters (e.g. proteins) or by active transport (e.g. glucose). Diffusion across the BBB is dependent on lipid solubility whereas more hydrophilic molecules have an easier passage through the BCB. By measuring the amount of molecules that are formed outside the CNS, but found in CSF, it is possible to get some idea of the “leakiness” of these barriers. Albumin is the simplest molecule measured; formed in the liver, any amount found in the CSF had to have traversed the BCB. It has long been known that the ratio of CSF/serum albumin is a direct measurement of BCB permeability (Qalb ) which increases with age. Using a simple scale, it is possible to estimate whether permeability is in excess of that expected for a given age (see Table 3.5).

Table 3.5

Increasing values of Qalb with age.

Age (range) 60

Qalb × 10 −3 5 6 7 8 9

Conditions that are typically associated with mild to moderate increase in Qalb include neuropathic processes (e.g. Guillain–Barré), neuroborelliosis or meningitis. Typically these inflammatory processes are thought to reduce CSF absorption and therefore reduce the natural flow of CSF, which leads to concentration of albumin within the CSF. This reduced CSF flow rate would also lead to intra-CSF accumulation of other molecules such as immunoglobulin (Ig). This is the main reason that any measurement of intrathecal Igs must take into account some measure of BCB leakiness to know if the CSF Ig is simply due to diffusion in from the blood, or is the direct result of synthesis within the CNS. Numerous mathematical formulas have been devised to account for this leakiness, and one of the simplest to use is known as the “Link index” (Link and Tibbling, 1977): Link IgG Index =

IgG[CSF]/Albumin[CSF] IgG[serum]/Albumin[serum]

×

100% (normal range < 70%) Determining that Ig synthesis had to have arisen within the CNS is tantamount to saying that there is an immune process that is taking place locally. Although this is expected in conditions such as MS, it is not specific for that disease; rather localized Ig synthesis is common to any inflammatory CNS condition that leads to humoral immune responses. IgG is the commonest Ig to be evaluated, but similar formulas have been used to assess IgA or IgM, the latter two being of more importance with respect to infectious causes. For instance, in Lyme disease (often considered an important mimic of MS) IgM prevails over IgA or IgG. Usually the Qalb is also markedly elevated beyond that expected for age (see Table 3.5) in the case of CNS infectious conditions, whereas in MS, it is typically normal. Though rarely a concern, as dysfunction of the BCB (indicated by an increase in Qalb ) increases, especially due to conditions outside the CNS such as meningitis, formulas such as the Link index, which are based on a linear relationship become inaccurate, as the relationship becomes hyperbolic in function and more complicated nonlinear formulas are required for accurately assessing localized Ig synthesis (Reiber and Peter, 2001). The commonest cause for a localized increase in Ig is infection. However, nonspecific increases in localized Ig to ubiquitous agents such as measles, rubella or varicella are common in the presence of CNS autoimmune-type conditions and

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this so-called “MRZ reaction” (measles-rubella-zoster) typifies the polyspecific nature of Ig activation that takes place in conditions such as MS (Reiber and Peter, 2001). Qualitative analysis of CSF Ig is key to the diagnosis of conditions such as MS. It is equally important to insure that this assessment be performed in a qualified laboratory in a standardized manner (Freedman et al., 2005). There is a clear consensus as to what constitutes this analysis (Keir and Thompson, 1990) which is to perform isoelectric focusing (IEF) of Ig on agarose gels followed by immunoblotting. This technique separates the Ig present into either distinct “bands” suggesting either a specific infection or autoimmune process or into a smear of protein consistent with a nonspecific increase in Ig. It is imperative that comparison be made of CSF Ig directly with serum Ig, as the presence of bands in CSF that are clearly not in serum is what constitutes the specificity of the intrathecal response. CSF should be applied to gels undiluted, whereas serum is usually diluted empirically 1:400, so as to equate the overall amount of Ig and minimize overloading in the serum lanes which can obscure at times the visibility of “bands”. Five patterns of “banding” will emerge using this methodology (see Fig. 3.7) with types II or III being indicative of intrathecal synthesis of oligcoclonal banding. In most cases, the sensitivity of IEF for detecting oligoclonal bands in MS is >95% (Paolino et al., 1996). It should raise an alarm therefore, if clinical suspicion is high that a patient has MS, but intrathecal synthesis of oligoclonal bands is undetected. This means that more times than not, rather than the test being “falsely negative,” the absence of oligoclonal bands usually suggests a diagnosis other than MS (Zeman et al., 1993). In considering what the CSF can tell you, it is important to consider all aspects of CSF analysis: the cells present (differential or cytology), biochemistry (albumin, glucose, or lactate), as well as the Ig. These features altogether are used to help distinguish between causes of systemic inflammation which spill over into the CNS, such as vasculitis or chronic infection and intrathecal processes such as the autoimmune condition MS. It is also therefore important to draw simultaneously blood for serum analysis alongside the CSF, as well as to send it for biochemical studies, such as glucose. Typically 1–4 partially filled tubes of CSF are required and 1–2 tubes of blood for full analysis. The first tube can sometimes be contaminated with a few red cells from nicking epidural small

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Fig. 3.7 Isoelectric focusing on agarose gels followed by immunoblotting for IgG. Five classic patterns are known: type 1, no bands in cerebrospinal fluid (CSF) and serum (S) sample; type 2, oligoclonal IgG bands in CSF, not in the S sample, indicative of intrathecal IgG synthesis; type 3, oligoclonal bands in CSF (like type 2) and additional identical oligoclonal bands in CSF and the S sample (like type 4), still indicative of intrathecal IgG synthesis; type 4, identical oligoclonal bands in CSF and the S sample illustrative of a systemic not intrathecal immune reaction, with a leaky or normal or abnormal blood–CSF barrier and oligoclonal bands passively transferred in the CSF; and type 5, monoclonal bands in CSF and the S sample; this is the pattern seen owing to the presence of a paraprotein (monoclonal IgG component). Courtesy of H. Reiber.

vessels during the lumbar puncture. The cell count should be performed no later than two hours after obtaining the CSF, otherwise changes in cell shape may hamper the ability to offer a correct and full differential. A red blood cell count that is too high (5–7 × 109/l) probably indicates too much of a traumatic tap, rendering other quantitative measurements more difficult to interpret. If a high number of red cells are noted in the first tube, then the last CSF tube should also be checked for red cells and if the number remains as high as the first tube, then often this is reflective of continued bleeding within the subarachnoid space such as what might be expected in a ruptured cerebral aneurysm of arterio–venous malformation. One only needs 1–2 ml of CSF for cell counts. White blood cell counts in the CSF are typically low (normal 50 × 106/l) are most unusual in MS. In some cases, the presence of unusual looking cells should prompt a full review of cytopathology to exclude the possibility of neoplasia or to look for inclusions that might occur in certain types of chronic infections such as toxoplasmosis. In some cases where a high white count is due to lymphocytes, a full tube of 7–10 ml CSF should be drawn and sent for a cytospin and staining with cell markers in order to know for instance if the lymphocytes are all B cells, strongly suggesting a diagnosis of lymphoma, or T cells, more reflective of either infection or chronic inflammation. For biochemical studies such as glucose, lactate, or angiotensin-converting enzyme (ACE) 3–4 ml of CSF will usually suffice. Low CSF glucose (when compared to serum, CSF/serum ratio 1 g/l) is more consistent with an infectious or neoplastic process. Lactate, where available, is a good substitute and has an advantage over paired CSF–plasma glucose measurements in that only a single CSF measurement is required (Nelson et al., 1986). If infectious causes are considered, then a separate sterile tube for Gram stain and microbial or fungal cultures is required. Special requests should be made in cases of chronic meningitis to look for “acid-fast bacillus” and special cultures requested if tuberculosis is suspected. In all cases, if a specific pathogen is suspected, most times specific antigen testing is available. Regardless, a tube of 3–4 ml of CSF is all that is required for all these analyses. Overall, CSF can be very informative in most cases of suspected CNS disease. A normal CSF in suspected cases of MS or other possible CNS autoimmune entities is often reassuring and indicates that these diagnoses are less likely. A typical CSF picture of specific oligoclonal bands in a patient suspected of MS but who has a MRI that is either normal or shows nonspecific lesions and in whom infection has been ruled out would almost certainly turn out to have MS. On the other hand, the finding of a very high protein, a leaky BCB, or a high cell count in someone who clinically is highly suspected of having MS should raise concern that a different diagnosis is being missed. A lumbar puncture to obtain CSF along with some serum is a minor procedure with high yields in terms of reassurance of not missing more treatable conditions such as infections, and can help to reinforce clinical certainty of a diagnosis of MS, when clinical presentation is somewhat vague or MRI results are nonspecific.

3.7 Magnetic resonance imaging characteristics of MS (Jennifer L. Cox and Robert Zivadinov) Introduction MS is an inflammatory disease of the CNS characterized by demyelinating lesions and axonal loss. The immunopathogenic mechanisms underlying disease initiation and disease course are unknown. Current diagnostic criteria (McDonald et al., 2001; Polman et al., 2005) suggest MRI is the most sensitive and specific of the radiological and laboratory tools used to aid in the diagnosis of MS. Although MS could be diagnosed without MRI by waiting for clinical evidence of a second attack, it is strongly recommended that MRI be used when available to demonstrate dissemination of lesions in space and time. In addition to its diagnostic usefulness, MRI is routinely used to monitor the course of MS disease over time. Although conventional MRI scans such as T2weighted images (WI) and gadolinium (Gd)-enhanced T1-weighted scans have long been used for clinical diagnosis and monitoring of MS, they cannot distinguish between inflammation, edema, demyelination, Wallerian degeneration, and axonal loss. In addition, they do not exhibit a reliable correlation with clinical measures of disability. Some patients have multiple hyperintense lesions on T2-weighted images, yet show few clinical symptoms of MS, while other patients with few hyperintense lesions may have a marked clinical presentation. The lack of a strong correlation between the presence of lesions observed with conventional MRI and clinical symptoms is often referred to as the “clinical–MRI paradox” (Barkhof, 2002; Zivadinov and Leist, 2005). Furthermore, there is increasing evidence that pathological changes in MS can be found in both cortical and subcortical gray-matter structures, yet conventional MRI scans are not able to detect these gray-matter changes. In recent years, the use of nonconventional MRI sequences as well as advanced analysis methods of conventional sequences have allowed the capture of a more global picture of the range of tissue alterations caused by inflammation and neurodegeneration. Newer, nonconventional metrics of MRI analysis include measurement of hypointense lesions on T1-weighted imaging (T1-WI), central nervous system atrophy, magnetization transfer imaging (MTI), magnetic resonance spectroscopy (MRS), diffusion tensor imaging (DTI), high-field MRI, and functional MRI (fMRI).

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When compared to conventional imaging, nonconventional MRI techniques appear to be better surrogate markers for monitoring the destructive pathological processes related to disease activity and clinical progression. The nonconventional techniques can reveal the underlying substrate of intrinsic pathology within lesions and normal appearing brain tissue (NABT) that include edema, inflammation, demyelination, axonal loss, and neurodegeneration (Bakshi et al., 2005; Zivadinov and Bakshi, 2004c). Due to their ability to detect the neurodegenerative aspects of MS, including recent evidence for cortical demyelination (Geurts et al., 2005), these techniques are receiving increased attention as clinically relevant markers of disease progression. This section will discuss both conventional and nonconventional MRI techniques and their role in detecting inflammation and neurodegeneration in MS lesions and NABT. Role of conventional MRI in MS T2-weighted imaging is highly sensitive in detection of hyperintense lesions in the white matter (WM) and, less commonly, the gray matter (GM). The most typical sites for lesions are in the WM: periventricular region, corpus callosum, posterior fossa, and cortical regions (Fig. 3.8). Several MRI sequences are capable of identifying T2 hyperintense lesions; those preferred most often are conventional spin echo, fast spin echo, and fluid-attenuated inversion recovery (FLAIR) (Zivadinov and Bakshi, 2004c). FLAIR provides improved detection over T2-weighted imaging in the evaluation of periventricular and cortical/ juxtacortical lesions, as CSF may mask the visualization of these plaques on T2-WI (Bakshi et al., 2005; Zivadinov and Bakshi, 2004c). Continuous technical improvements in MRI hardware and software over the last decade have led to the development of more efficient and sensitive pulse sequences. Among them, turbo or fast spin-echo (TSE or FSE) and fast-FLAIR have already demonstrated their usefulness in a wide variety of neurological diseases, including MS (Simon et al., 2006; Zivadinov and Bakshi, 2004c). FSE has shown greater sensitivity than conventional spin-echo in detecting areas of T2 prolongation in MS. On the other hand, fast-FLAIR sequences have emerged as especially helpful in evaluating periventricular and cortical/juxtacortical lesions where CSF signal may mask these plaques on T2-WI (Zivadinov and Bakshi, 2004c). Moreover, double-inversion recovery (DIR) imaging has recently shown a further increase over FLAIR in the ability to detect cortical

lesions as well as provide better contrast between GM and WM (Geurts et al., 2005). Due to fat suppression, areas of T2 prolongation can also be detected using short tau inversion recovery (STIR) sequences and, in certain scanning platforms, this sequence may be superior to T2-WI in detecting spinal cord lesions in MS (Campi et al., 2000). An added advantage to using STIR when imaging the optic nerves is increased contrast between lesions and the surrounding retrobulbar fat (Moseley et al., 1998). Recently the Consortium of Multiple Sclerosis Centers (CMSC) proposed MRI consensus guidelines for imaging of the brain and spinal cord in patients with MS (Simon et al., 2006). Recommended for imaging of the brain were sagittal and axial fast spin-echo fluid-attenuated inversion recovery (fastFLAIR), axial FSE with proton density (PD) and T2weighting, and post-Gd-enhanced T1 sequences. An axial T1-weighted pre-Gd scan and T1-weighted 3D volume scan were suggested as optional series to include. Recommended for imaging of the spinal cord were sagittal and axial FSE PD-T2 and Gd-enhanced T1 sequences, with a 3D volume scan as optional.

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Fig. 3.8 Axial T2-weighted FLAIR image from a 26-year-old female with relapsing-remitting MS showing periventricular (a) cortical, (b) pericallosal (Dawson’s fingers), (c) hyperintense white-matter lesions. (d) Axial T2-weighted FLAIR image from a 25-year-old male with secondary-progressive MS showing hyperintense white matter lesions in the cerebellum and pons.

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Similar guidelines have also been provided in Europe by the European Federation of Neurological Science Task Force (Filippi et al., 2006). Despite the sensitivity of T2-WI to reveal disease activity and lesions over time (Paty and Li, 1993), there is only modest correlation between MRI findings and clinical evolution, except in subjects with very early disease (Rudick et al., 2006a; Sailer et al., 1999; Zivadinov et al., 2001b). Several long-term studies have examined the correlation of disability progression and the accumulation of T2-lesion burden. One of the longest MRI studies followed patients with clinically isolated syndrome for up to 14 years (Brex et al., 2002). After five years of follow up, data showed that T2-lesion volume accumulation predicted 25% of the correlation variance in disability, but at 10 years it was down to 16%, and at 14 years, it explained only about 10–12% of the variance. Evidence is increasing that diffuse, and particularly central, brain atrophy as a characteristic of mid-tolate stage MS may influence this relationship. It is possible that T2-lesion volume may be “artificially” lowered by the loss of lesions along with normal appearing tissue. A decrease in the relationship between T2-lesion volume and disability in advanced disease stages cautions against the assumptions that T2-lesion volume progression is a function of disease duration alone and that stabilizing T2-lesion volume indicates a reduction in disease activity (Dwyer et al., 2005; Li et al., 2006). Despite the previously mentioned limits, several strategies for increasing the sensitivity of T2-WI have become available in the last few years. Recent consensus guidelines recommend a ≤3 mm slice thickness on 2D and ≥1.5 mm on 3D acquisition sequences for the evaluation of disease burden in MS patients scanned in clinical routine practice (Simon et al., 2006). Thinner slices provide increased lesion detection and higher measurement consistency. Recent consensus guidelines also recommend that any scanner used in clinical routine practice should operate at a field strength higher than 1.0T. With the introduction of 3T MRI systems into clinical practice, several questions arise, including the comparison of 3T versus 1.5T. It has been previously demonstrated that scanner field strength has a substantial impact on the measured T2 lesion volume (LV), being about 25–40% higher with standard 3T magnets than for lower field scanners (Erskine et al., 2005; Keiper et al., 1998; Sicotte et al., 2003). Higher-field MRI increases specificity in the correlation between detected lesions and clinical disability.

Gadolinium enhancement Gd-enhancement in MS lesions has been connected with histopathological findings of the blood–brain barrier breakdown and active inflammation (Filippi, 2000). Gd-enhancing lesions on T1-WI usually correspond to areas of high signal intensity on T2-WI and low signal intensity on unenhanced T1-WI, probably due to edema and demyelination associated with these lesions (Fig. 3.9) (Zivadinov and Bakshi, 2004c). A transient phenomenon in MS, Gd-enhancement is usually detectable for an average of 3–6 weeks, and typically precedes or accompanies the appearance of a majority of new lesions found on T2-WI in MS patients. Most of the enhancing plaques are not associated with the presentation of clinical symptoms and do not correlate with clinical status in crosssectional, and especially longitudinal, studies in the mid and long term (Kappos et al., 1999; Zivadinov and Leist, 2005). This discrepancy supports the concept that varied factors operate in the occurrence of relapses in MS as well as the development of longterm sustained disability. Nevertheless, the presence of continuing enhancement indicates a higher risk of relapses over the short-to-intermediate term and may contribute to long-term clinical dysfunction (Filippi, 2000; Zivadinov and Bakshi, 2004c). Several strategies have been proposed to increase the sensitivity of Gd-enhanced MRI for the detection of active MS lesions. One analysis strategy examines the pattern of Gd-enhanced lesions and their relationship to lesions found on other MRI sequences. Determination of an enhancement pattern may indicate differences in the histopathology of MS plaques. Concentric ring-enhancing lesions with central contrast pallor arise in previously damaged areas or in areas of accelerated local inflammation (Zivadinov and Leist, 2005). When compared with homogeneously enhancing plaques, ring-enhancing lesions are larger, have a shorter duration of enhancement, lower apparent diffusion coefficient (ADC) and magnetization transfer ratio (MTR) (Minneboo et al., 2005; Morgen et al., 2001). It has also been shown that ring-enhancing lesions are strong predictors for the development of persisting hypointense lesions on T1-W1 and brain atrophy (Bagnato et al., 2003; Minneboo et al., 2005; Zivadinov et al., 2004). Thus, the appearance of ring-enhancing plaques on Gd-enhanced MRI may not only be characteristic of a more aggressive form of MS but also predictive of long-term deterioration. Other strategies that maximize the amount of information that can be obtained through Gd

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a

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Fig. 3.9 Comparison of images from a 25-year-old male with secondary-progressive MS (a, b, c) showing homogeneously enhancing lesions (a) and from a 29-year-old female with relapsing-remitting MS (d, e, f ) showing ring-enhancing lesions (d). (a) and (d): Single dose (0.1 mmol/kg) gadolinium postcontrast axial T1-weighted images. (b) and (e): Axial T1-weighted images (precontrast). (c) and (f ): Axial T2-weighted images.

enhancement include frequent serial monthly scanning, scanning the spinal cord as well as the brain, a delay of five minutes or more between Gd injection and scanning, using doses of higher contrast (e.g., a double or triple dose instead of a standard 0.1 mmol/kg dose), acquiring thinner tomographic slices, co-registration, reducing the background signal by the application of MTI pulses to T1-WI and, finally, use of high-field strength scanners (Filippi, 2000; Zivadinov and Bakshi, 2004c). Role of nonconventional MRI in MS Three-dimensional T1-weighted high resolution imaging The CMSC MRI guidelines suggest the option of collecting high resolution (1 mm × 1 mm × 1.5 mm

voxel size) 3D T1 scans. Although high-quality 3D T1 scans may take longer to acquire than 2D sequences, they are valuable for many advanced measures of neurodegeneration in MS, including evaluation of cross-sectional and longitudinal GM, WM, and CSF volumes estimates, anatomically defined region of interest analyses, and voxel-based morphometry. Mounting evidence supports the idea that brain atrophy is an important biomarker of the disease process in MS (Fig. 3.10) (Bermel and Bakshi, 2006; Miller et al., 2002; Zivadinov and Bakshi, 2004a; Zivadinov and Bakshi, 2004b; Zivadinov and Bakshi, 2004d). Several studies emphasize the usefulness of MRI in assessing CNS atrophy and its relationship to long-term neurodegeneration and disability progression (Fisher et al., 2002; Zivadinov et al., 2001a). It has also been established that CNS atrophy is a moderate but significant predictor of neurological

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Fig. 3.10 Axial view of 3D-SPGR image (a) from a 29-year-old female with relapsing-remitting MS. An automated, crosssectional method (structural image evaluation including normalization of atropy, SIENAX) method was applied to the image to generate separate images of gray matter (b), white matter (c), cerebral spinal fluid (d), and segmented image (e).

impairment (Zivadinov and Bakshi, 2004a; Zivadinov and Bakshi, 2004b; Zivadinov and Bakshi, 2004d). The association between atrophy and disability is independent of the effect of conventional MRI lesions. Studies suggest that CNS atrophy begins in patients with CIS even before the first clinical symptoms, especially in those at high risk for MS. The estimated percentage change of brain atrophy varies across studies in CIS but is estimated to be 0.8% per year (Zivadinov and Bakshi, 2004a). Natural history and therapeutic studies of patients treated with placebo suggest that CNS atrophy is common in patients with RR-MS, even in the earliest stages of the disease. The estimated annual rate of whole-brain atrophy varies across studies but is slightly higher in patients with early RR-MS (range, −0.7% to 1.33%) than in those with advanced RR-MS (range, −0.61% to 1.2%) (Zivadinov and Bakshi, 2004b). Patients with PPMS have a slightly higher annual rate of ventricular enlargement (range, −2.4% to +7.7%) than patients with SP-MS; however, this rate is lower than the rate in patients with RR-MS (range, +2.1% to +29.8%). On the other hand, spinal cord atrophy also develops at a faster rate than brain atrophy in patients with PP-MS (Zivadinov and Bakshi, 2004a; Zivadinov and Bakshi, 2004b). Although initial reports indicated that brain atrophy in MS was primarily due to decreases in WM (Ge et al., 2000), several more recent reports have noted diffuse GM atrophy in the brains of patients with MS (Benedict et al., 2006; Bermel et al., 2003; Chen et al., 2004; Dalton et al., 2004; Fabiano et al., 2003; Valsasina et al., 2005; Zivadinov et al., 2006). These findings suggest that the disease process in MS is not limited to WM and that including GM atrophy in the assessment of patients with MS may

further improve the usefulness of MRI measurements. Preliminary data from several short- and long-term studies suggest that GM atrophy develops at a much faster rate than WM or whole-brain atrophy (Dalton et al., 2004; Valsasina et al., 2005). However, it is not clear whether GM atrophy is a result of the disease process in MS or is secondary to WM atrophy. Recently, our research team used an approach based on regional segmentation called semiautomatic brain region extraction, or SABRE, to detect predilection for brain atrophy development on a region-by-region basis (Carone et al., 2006a). The study compared 66 MS patients and 40 normal controls and found that the regions most affected in the brain were deep gray-matter structures including the posterior basal ganglia and the thalamic regions, as well as the cortical regions in the orbital frontal, superior parietal, superior frontal, and medial superior frontal regions. Similarly, reduced thalamic GM volume in patients with MS was the primary finding in a voxel-based morphometry study of CIS patients (Cox et al., 2006). Taken together, these studies suggest that there is a regional specificity for brain atrophy development, prevalent mostly in GM structures, in areas of the brain that do not usually show WM lesions. Wallerian degeneration and independent neuronal degeneration are proposed mechanisms for GM atrophy in MS. We recently investigated partial correlations between T2 and T1 regional lesion volumes and regional/total GM atrophy in 110 MS patients (Carone, 2006b). After controlling for total GM atrophy, partial correlations between regional lesion volume and regional GM atrophy were not significant for any of the 26 investigated regions. Results suggest that a distinct generalized disease

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process better accounts for GM atrophy than regionally distinct Wallerian degeneration. Furthermore, it is not clear whether GM atrophy contributes to neurological impairment in MS because several reports have failed to find an association between GM loss and neurological impairment (Dalton et al., 2004; Ge et al., 2000; Sastre-Garriga et al., 2005). On the other hand, other studies have found a significant association between GM loss and impairment, in both RR-MS and PP-MS (Chen et al., 2004; Sanfilipo et al., 2005). Magnetization transfer imaging, MTI MTI is an advanced MRI technique that has been widely used to evaluate characteristics and evolution of MS lesions and NABT. It is based on the interactions and exchange between two types of protons: those that are unbound in a free water pool and those where motion is restricted due to binding with macromolecules (Filippi and Rocca, 2004). MT contrast is achieved by applying radio frequency (RF) power only to the proton magnetization of the macromolecules. Tissue damage in MS is usually reflected by a reduction in this exchange of protons and thus a decrease in MTR. Decreases in MTR indicate a reduced capacity of free water to exchange magnetization with the neighboring brain tissue matrix and are not specific to MS pathological substrates. Although MTR decreases are not specific to any of the various MS pathological substrates, a relationship has been shown between MTR and the percentage of residual axons and the degree of demyelination (van Buchem et al., 1997). The most compelling evidence in support of this hypothesis comes from a postmortem study that shows a strong correlation between MTR values from MS lesions and NABT with the percentage of residual axons and the degree of demyelination (Schmierer et al., 2004). MTI can be used to assess tissue injury in lesions, in the whole brain and in specific brain structures (Filippi and Rocca, 2004; Sharma, 2006; Zivadinov et al., 2001a). MTI studies have demonstrated two possible evolution paths for new MS lesions: (i) in some lesions, a moderate decrease in MTR with subsequent complete recovery of MTR within a few weeks may reflect edema, demyelination, and subsequent remyelination (Filippi and Rocca, 2004); (ii) in other lesions, a marked reduction of MTR with only partial recovery at follow up (Dousset et al., 1998). Different MTI studies have revealed clinically relevant pathological changes in areas of WM

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and GM that appear normal on conventional images. Such changes in normal appearing white matter (NAWM) and normal appearing gray matter (NAGM) occur early in the disease process and provide prognostic information pertaining to the risk of MS progression (Filippi et al., 2000; Laule et al., 2003). MTI metrics have been correlated with the degree of disability (Rovaris et al., 2003). In general, modestto-strong correlation was found between baseline MTR and subsequent change in the EDSS disability score. These data support the idea that early MTR abnormalities in NABT can predict the clinical evolution of MS. Magnetic resonance spectroscopy, MRS MRS offers the potential to investigate tissue structure, metabolism, and function. Information about the biochemistry of selected brain tissue volumes provides potential surrogate markers for the pathology underlying MS (Narayana, 2005). MRS imaging allows for the quantitative assessment of inflammation, demyelination, axonal and neuronal injury processes in MS (Tartaglia and Arnold, 2006). The N-acetylaspartate (NAA) peak in an MR spectrum is a putative marker of neuronal and axonal integrity, and axonal and neuronal injury can be quantified through decreases in NAA. The choline peak appears to reflect cell-membrane metabolism (Narayana, 2005). An elevated choline peak represents heightened cell-membrane turnover, as seen in demyelination, remyelination, inflammation, or gliosis. MRS further provides unique information regarding not only structural, but also metabolic changes in the CNS. Other metabolic peaks of interest in the study of MS include the glutamate/glutamine peak and myoinositol peak. The glutamate/glutamine peak represents a mixture of amino acids and bioamines used throughout the CNS as excitatory and inhibitory neurotransmitters (Srinivasan et al., 2005). The myoinositol peak represents a sugar-like molecule thought to be a marker of glial proliferation and now recognized for its importance in osmotic regulation of brain tissue volume (Narayanan et al., 2006). Recent MRS studies have shown that neurodegenerative changes may be detected in cortical lesions and deep GM tissue (Geurts et al., 2006; Inglese et al., 2004). Correlations between disability and decreased NAA–creatine (NAA–Cr) ratio were found in several studies, suggesting that MRS measures of brain metabolites are better predictors of clinical disability than conventional MRI.

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Diffusion imaging DWI (diffusion weighted imaging) and DTI (diffusion tensor imaging) are unique MRI techniques based on the diffusional motion of water molecules, and thus provide an indirect measure of tissue orientation, size, and geometry (Rovaris et al., 2005b). The mobility of water molecules is reduced in highly organized tissue like WM and GM due to interactions with cellular and tissue structures. In the CNS, diffusion is influenced by the microstructural components of tissue, including cell membranes and organelles and, as a result, the ADC is lower in those tissues than in pure water. Furthermore, ADC values depend on the orientation of the tissue relative to the measurement. Thus, conventionally, the average ADC is calculated from three (DWI) or more (DTI) orthogonal directions that provide information on the overall diffusivity in the tissue. Pathological processes that modify tissue organization can cause abnormal water motion, thereby altering ADC values. In MS, the two main pathological processes that affect the brain are demyelination and neurodegeneration, both of which can alter the geometry of brain tissue orientation, resulting in an increase of water diffusivity measurable with different DWI and DTI indices. These measures include mean diffusivity (MD), fractional anisotropy (FA), and entropy. FA is an indirect measure of tissue integrity. In healthy WM, the diffusional movement of water molecules is restricted by the myelin sheath and axon, thus water molecules in healthy WM tend to move along the long axis of the axons. High FA values are associated with healthy WM, whereas low FA values are indicative of a disruption in the microstructural integrity of WM. Changes in FA could be caused by various factors, including demyelination and inflammation. Several DWI-DTI studies have demonstrated abnormal MD or FA values in MS lesions (Werring et al., 2000) that differ between Gd-enhancing vs. nonenhancing lesions. Some studies reported lower MD in Gd-enhancing lesions when compared with nonenhancing lesions (Roychowdhury et al., 2000), whereas others did not observe significant differences (Cercignani et al., 2001). Conversely, the FA studies showed a consistent decrease of FA in Gdenhancing lesions, compared to nonenhancing lesions (Werring et al., 1999). Most of the studies have shown higher MD and lower FA values in lesions than in areas of NAWM, the most abnormal being in the hypointense T1 lesions (Filippi et al., 2001;

Rovaris et al., 2005b; Werring et al., 1999). Numerous diffusion MRI studies have consistently shown increased diffusivity and reduced anisotropy in the NAWM and NAGM of MS patients when compared to normal controls (Rovaris et al., 2005b). Significant cross-sectional correlations between DWI and DTI and clinical findings have been established (Cercignani et al., 2001), indicating that the disease process does not spare either the NAWM or the NAGM (Fabiano et al., 2003; Rovaris et al., 2005a). Diffusion studies have confirmed that the severity of damage within T2-visible lesions and in the NAGM, as well as in clinically eloquent WM regions, might have a significant impact on MS patients’ neurological disability. Functional MRI, fMRI fMRI is an indirect measure of blood flow and neuronal activity based on changes in the local magnetic field (T2*). When neurons are active there is an increase in blood flow to the region, which increases the amount of oxygenated hemoglobin in the capillary beds. The amount of oxygen delivered by the hemodynamic response to neuronal activity exceeds the amount required by the tissue, thus increasing the ratio of oxygenated to deoxygenated hemoglobin in the venous beds compared to the resting state. At rest, deoxygenated hemoglobin causes a slight disturbance in the local magnetic field, which is attenuated by increased presence of diamagnetic oxygenated hemoglobin during neuronal activity, thereby causing a longer T2* and increased signal intensity. The signal change is very small (1–10%), but is reliably measured by subtracting images collected at rest from images collected during activity. Unlike the other measures discussed above, fMRI is not yet used clinically for diagnosis or monitoring of the disease. Rather it has been used in research settings to examine the neural correlates of known motor and neuropsychological deficits in patients with MS. The most commonly used paradigms assess motor ability, processing speed, and working memory. Several studies have found that patients with MS show increased bilateral frontal activation during working memory tasks as compared to healthy controls who show unilateral activation when completing the same task (Pantano et al., 2006). It has been suggested that increased activation in patients with MS is a compensatory mechanism. The relationship between motor disability and functional activation was examined in a serial fMRI

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study (Reddy et al., 2000). In this case study, a patient with MS showed an initial increase in sensorimotor activation on fMRI three weeks after onset of a right hemiplegia. Structural MRI revealed four large confluent lesions in the left hemisphere. fMRI scans completed at six weeks and 24 weeks after presentation showed reduced bilateral activation despite maintained motor performance. These findings suggest that dynamic cortical adaptation occurs in response to disease relapse (Reddy et al., 2000). fMRI has also been used to demonstrate functional changes in connectivity even at the earliest stages of the disease. Decreased functional connectivity between frontal and anterior cingulate regions was found during a working memory task, paced auditory serial addition task (PASAT), in patients with CIS compared to controls (Audoin et al., 2006). Decreased functional connectivity was correlated with T2-lesion load and MTR results in the same study. Indeed, with the heterogeneous lesion load and lesion pattern in MS, it will be important to combine fMRI data with many of the nonconventional measures discussed here. Conclusions Nonconventional MRI scans and analysis methods such as hypointense lesions on T1-WI (“black holes”), MTI, DWI and DTI, MRS, fMRI and high-field MRI are emerging as promising tools for improving our understanding of the pathophysiology of MS. By considering information from multiple neuroimaging methods and analyses, we will gain a better understanding of the relationship between MRI findings and clinical symptoms and disease course. The “clinical–MRI paradox” will not remain such a mystery as we look beyond conventional MRI measures. 3.8 Treatment of MS (Sean Pittock) Introduction Advances have been made in the development of partially effective disease-modifying parenteral therapies for MS in the past decade. These advances have primarily been realized in the management of relapsing remitting MS. This section will focus on the management of the acute MS relapse, the current FDA-approved disease-modifying agents (DMAs), their associated complications and symptomatic management of MS complications. In addition, evolving therapies and current controversies in MS management will be discussed.

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Treatment of the acute relapse Corticosteroid therapy The natural history of most acute relapses is spontaneous resolution with the majority of patients making full to near-full recovery. However, some attacks can be disabling with motor weakness, diplopia, ataxia, or pain. Early treatment with corticosteroids will accelerate recovery from these acute attacks. The debate continues as to the most efficacious type, dose, and route of administration of corticosteroid. A metaanalysis found no difference in EDSS improvement between high-dose and low-dose methylprednisolone regimens (Miller et al., 2000). Most neurologists use high-dose intravenous methylprednisolone (1 g per day) for a short period (usually 3–5 days). Not all patients with an acute relapse should be treated with corticosteroids. A patient with a mild, nondebilitating relapse should be allowed to recover with rest and avoidance of physical and mental stress. In the assessment of an MS patient with new or worsening symptoms, it is important to consider the possibility of pseudoexacerbation or pseudorelapse (a clinical worsening associated with fever, often in the setting of a urinary tract infection), which are not new “attacks” and should not be treated with immunosuppression but with appropriate antibiotic treatment or fever-reducing therapy. In addition, patients may have difficulty in differentiating minor fluctuations in their baseline function from those of a true clinical relapse. Plasmapheresis Patients with acute, severe disabling attacks who do not respond to steroid therapy are considered steroid resistant. Plasmapheresis should be considered the next step for such patients. In 1993, plasmapheresis was first reported (Rodriguez et al., 1993) to benefit patients with steroid-resistant, devastating, acute relapses (either paraplegia or quadriplegia) occurring within days for some patients. Subsequently, a randomized double-blind and sham plasmapheresis control study was done in patients with steroidresistant devastating relapses. This study showed convincing benefit though the study size was limited (Weinshenker et al., 1999). Five of 11 patients who received plasmapheresis demonstrated moderate or marked improvement within days of treatment. In addition, three of eight patients who had failed the sham treatment subsequently had moderate or

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marked improvement when switched to plasmapheresis. Overall, there was a 42% improvement in the plasmapheresis group as compared to the 6% improvement in the sham treatment group.

consider treatment with approved therapy in these patients.

Other medication therapies

Beta interferon (IFNβ) exerts its effect through a variety of mechanisms. These include actions that (i) inhibit T-cell costimulation and/or activation processes; (ii) modulate anti-inflammatory and proinflammatory cytokines; (iii) inhibit interferon gamma-induced class-II expression; (iv) inhibit antigen presentation; and (v) decrease aberrant T-cell migration. IFNβ are administered either by subcutaneous injection (Betaseron and Rebif ) or by intramuscular injection (Avonex). The IFNβ drugs have demonstrated efficacy in relapsing-remitting MS with reduction in relapse rate by approximately one-third and reduction in the accumulation of new and active lesions on brain MRI (The IFBN Multiple Sclerosis Study Group, 1993). Some short- to medium-term studies suggest some small benefit in terms of EDSS reduction though benefit in the long term remains unproven. The relative risk reduction of relapse rate in patients with relapsingremitting MS varied from 20–40%. Absolute risk reduction was even lower with numbers needed to treat (NNT) calculations revealing mild to moderate efficacy. For example, 6–8 patients need to be treated for two years to increase by one the number of patients free of relapse and 8–9 patients must be treated for two years to prevent one patient developing an increase of one point in EDSS (Francis, 2004). It is important to be aware that randomized control trials contain an enriched sample of patients defined by specific inclusion criteria and are likely not representative of patients seen in a population-based sample. Therefore, NNT estimated from drug trials may far underestimate the NNT for patients in communitybased clinical practice (Noseworthy et al., 2005). The role of IFNβ in secondary-progressive MS is vague. A study from the United Kingdom reported slowing of disease progression with Betaseron (European Study Group on interferon-beta-1b in secondary-progressive MS, 1998). A subsequent North American trial did not confirm this finding (Secondary Progressive Efficacy Clinical Trial of Recombinant Interferon-beta-1a in MS (SPECTRIMS) Study Group, 2001). Improvements in some outcome measures (MS functional composite), but not other more standard measures (EDSS), make it difficult to interpret the benefits of Avonex in secondaryprogressive MS (Noseworthy et al., 2005).

There have been disappointing results from studies on the use of monoclonal antibody therapy in acute relapses. A randomized study of the humanized antiCD11/CD18 monoclonal antibody, HU23F2G, in 169 patients with acute relapse failed to show benefit from use of the drug versus placebo (Lublin and the Hu 23F2G MS Study Group 1999). Natalizumab, humanized anti-alpha 4 integrin monoclonal antibody recently licensed for use in relapsing-remitting MS, did not reveal any benefit over placebo in terms of clinical improvement when given within 2–4 days of acute relapse (O’Connor et al., 2004). Randomized studies investigating the use of intravenous immunoglobulin (IVIg) administered with or before intravenous methylprednisolone in patients with acute relapses in MS have been disappointing. These studies were of limited size and larger drug trials are warranted. There are also reports of response to IVIg, methylprednisolone, or plasmapheresis with other inflammatory demyelinating conditions such as acute disseminating encephalomyelitis, neuromyelitis optica, and tumefactive (Marburg’s or Balo’s) forms of MS. Disease-modifying agents Since the mid-1990s, large randomized clinical trials have shown that DMAs reduce the number and severity of relapses as well as the number of lesions appearing on MRI. This has resulted in FDA approval of a number of DMAs for use in MS. Current drugs approved for long-term use by the FDA for MS include: (i) three beta interferon preparations (Avonex, Betaseron and Rebif ); (ii) glatiramer acetate (Copaxone); (iii) mitoxantrone (Novantrone); and (iv) the monoclonal antibody natalizumab (Tysabri). The Medical Advisory Board of the National MS Society recommends initiation of a DMA as soon as possible following a definite diagnosis of relapsing remitting MS and in selected patients with a first attack who are at high risk for MS (clinically isolated syndrome, CIS). The Therapeutics and Technology Assessment Committee of the American Academy of Neurology and the MS Council of Clinical Practice Guidelines also suggest that it is appropriate to

Beta interferon therapies (Avonex, Betaseron, Rebif )

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Adverse effects of beta interferon therapy Injection-site reaction: Injection-site reactions (erythema, bruising, swelling, and pain) are seen more commonly with subcutaneous injections than with intramuscular injections (Wingerchuk, 2006). These reactions usually subside during the first weeks of treatment. Mild to moderate reactions do not require discontinuation of treatment. Management approaches to injection-site reactions include rotation of the injection sites, use of topical anesthetics or corticosteroid, optimization of injection technique, icing the injection site, warming the medication prior to injection, and allowing the alcohol cleanser to dry before injection. The use of nonsteroidal inflammatory drugs (NSAIDS) is not recommended as they may actually increase injection-site reaction. The use of autoinjectors may allow better approximation of a standardized technique and reduce discomfort. Subcutaneous injections should be discontinued if skin necrosis should occur and consideration given to switching to an intramuscular injection. Flu-like symptoms: Flu-like symptoms occur in a majority of patients after IFNβ therapy initiation. Symptoms generally resolve by three months and are characterized by myalgias, fatigue, malaise, headache, fever, and chills. The symptoms generally emerge within 2–6 hours of injection and improve over the following 12–24 hours. Dose titration is often helpful in controlling symptoms. High-dose IFNβ preparation may be started at 25% or less of the target dose and increased incrementally over 2–6 weeks as tolerated. Injections should be administered at night. NSAIDS or acetaminophen may alleviate the symptoms. Laboratory abnormalities: Hematological and hepatic function laboratory values are commonly mildly affected by IFNβ therapy. Complete blood count and liver function tests should be performed before initiation of treatment as a baseline, at one week, one month, and three months after initiation of treatment and then every three to six months thereafter. Depression: Because there is a high prevalence of depression and elevated suicide risk among patients with MS, there has been some concern regarding the possibility of worsening depression with the use of IFNβ drugs. Patients and their caregivers should report any mood changes immediately.

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Gynecological: Other reported adverse effects of IFNβ therapy include menstrual disorders such as alterations in the menstrual cycle and breakthrough bleeding or spotting in premenopausal women. Given that a large proportion of patients using IFNβ therapy are women in their child-bearing years, all women must be advised to utilize effective contraception techniques while taking IFNβ. Although good data is lacking, it is recommended that women planning to become pregnant should discontinue IFNβ at least three months prior to discontinuation of contraception to allow a washout period. Two recent studies have raised some concern regarding use of IFNβ and pregnancy. One study suggested that the risk of spontaneous abortion was higher in women exposed to IFNβ during pregnancy (Sandberg-Wollheim et al., 2005). A Canadian study revealed a significant increase in the rate of miscarriage or still birth in the exposed group as compared with healthy controls (39% versus 5%) with a decrease in mean birth weight in the exposed group (Boskovic et al., 2005). Neutralizing antibodies (NAb): Up to 45% of patients on IFNβ therapy develop NAb (>20–30% with high-dose IFNβ such as Rebif and Betaseron compared with 2–5% with low-dose IFNβ such as Avonex). Persistent high NAbs reduce biological activity and may reverse any effect on frequency of relapses (Kappos et al., 2005). Patients who do not develop NAbs within the first two years of therapy are likely to remain seronegative in the future. If NAbs develop to one IFNβ they will likely develop with exposure to other preparations as well. Some neurologists recommend early testing and, if high titers of antibodies are identified, then discontinuation of IFNβ in favor of one of the other DMAs. Glatiramer acetate Glatiramer acetate (GA), approved for use in relapsing-remitting MS, is a synthetic peptide composed of L-alanine, L-glutamic acid, L-lycine, and L-tyrosine and was designed to mimic the structure of myelin basic protein. GA is administered subcutaneously daily at a dose of 20 mg and has been shown, in large randomized control trials, to reduce the rate of clinical relapse and of development of gadolinium-enhancing MRI lesions and T1-weighted black holes (Comi et al., 2001; Johnson et al., 1995). Multiple mechanisms of action have been described and include: (i) modulation of T-cell activation and proliferation; (ii) modification of dendritic cell

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costimulation processes and inhibition of antigen presentation; (iii) increase of IL-10, IL-4, TNFα, and IL-6 affecting interferon gamma secretion; (iv) induction of regulatory TH2/3 cells with resultant expression of anti-inflammatory cytokines and neurotrophic factors; and (v) enhanced production of brain derived nerve growth factor (Noseworthy, et al., 2005). The benefits of GA on relapse-rate reduction are minimal to moderate with NNT of 14 for two years to generate one person free of relapse (Francis 2004; Johnson et al., 1995). Extensive studies suggest some long-term benefit, but are difficult to interpret due to high patient drop out and concern that those who do relatively well tend to remain in therapy, whereas those who do not tend to discontinue therapy ( Johnson et al., 2000; Noseworthy et al., 2005; Wingerchuk, 2006). Adverse effects Injection-site reactions: GA is generally better tolerated than IFNβ therapy. Injection-site reactions are common and management is similar to management for IFNβ injection-site reactions (Wingerchuk, 2006). Lipoatrophy: Lipoatrophy (for which there is no treatment) occurs in 10–46% of patients on longterm GA therapy. Patients should be advised to avoid injection into an area of lipoatrophy. Lymphadenopathy: Lymphadenopathy (usually painless) has been described in up to 30% of patients in clinical trials and is usually confined to inguinal lymph nodes, but may be generalized. Rotation of injection sites and/or temporary discontinuation of injections may be beneficial. Hematological malignancy should be ruled out by performing complete blood counts and manual blood smears. Long-term treatment with GA does not result in hematological or liver enzyme abnormalities and monitoring is not required. Nearly all patients receiving GA develop binding antibodies to the drug within 3–4 months after initiation of therapy. This does not appear to interfere with efficacy. Systemic reactions: Fewer than 15% of patients experience systemic reaction consisting of flushing, chest tightness, anxiety, palpitations, or dyspnea within a few minutes after GA injection and lasting for 30 seconds to 30 minutes. Although frightening for some patients, this reaction is benign and self-

limiting and patients should be reassured about the benign nature of these reactions. Mitoxantrone (Novantrone) Mitoxantrone, an anthracenedione agent, intercalates DNA, inhibiting both DNA and RNA synthesis with a resultant depression of T- and B-cell immunity. Mitoxantrone reduces relapse frequency and MRI evidence of blood–brain barrier disruption in patients with relapsing-remitting MS or early secondaryprogressive MS who have active inflammatory disease and evidence of substantial disease worsening over short periods of time despite the use of standard DMAs (Hartung et al., 2002; Noseworthy et al., 2005). The benefit for patients with relapse-independent progression is unproven. The Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology, who published a report reviewing the evidence for efficacy and the range of toxicity associated with mitoxantrone, recommend caution with the use of mitoxantrone (Goodin et al., 2003). In a randomized study of either placebo or mitoxantrone therapy in 194 patients with either worsening relapsing-remitting or secondary-progressive MS, the mitoxantrone in the MS Study group reported improvement in the mitoxantrone-treated group (Hartung et al., 2002). The NNT for two years with mitoxantrone were 11 patients with secondaryprogressive MS to prevent one patient from worsening by one EDSS point. The approved dosage of mitoxantrone is 12 mg/m2 administered quarterly by intravenous infusion. Adverse effects Laboratory abnormalities: Leukopenia and neutropenia commonly occur with mitoxantrone. Prior to each infusion, a complete blood count should be obtained and if the neutrophil counts are less than 1500 cells/mm3, mitoxantrone should be held. A complete blood count should be rechecked in one to two weeks and mitoxantrone treatment can be resumed when counts normalize. Liver function tests (LFTs) should also be performed prior to each infusion and if LFTs increase by greater than 2.5 of the upper limits of normal, mitoxantrone therapy should be suspended. Concurrent hepatotoxic medications should be stopped (Wingerchuk 2006). Cardiotoxicity: The risk of cardiomyopathy with this medication is dose-dependent and may be as

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great as 6% in patients receiving up to 140 mg/m2 (Noseworthy et al., 2005). It is, therefore, recommended that duration of treatment be limited to approximately two years at the standard dosage regimen (Wingerchuk, 2006). Mitoxantrone should not be used in patients with pre-existing cardiac disease including cardiomyopathy or coronary artery disease or in those patients who have previously been treated with anthracycline or have had mediastinal radiation therapy. A baseline left ventricular ejection fraction of less than 50% also precludes mitoxantrone treatment. Prior to every infusion, patients should have an echocardiogram or MUGA scan performed to evaluate their left ventricular ejection fraction. A reduction in ejection fraction of more than 10% from baseline should result in permanent discontinuation of mitoxantrone. There appears to be some evidence to suggest that concomitant use of dexrazoxane and the liposomal form of mitoxantrone may reduce cardiotoxicity. Delayed effects of mitoxantrone on cardiac function have been reported. Other: Nausea can be expected during infusion and for up to several days after infusion of mitoxantrone. Antiemetic premedications, such as ondansetron, can be given. Patients should be warned that mitoxantrone may cause a harmless, temporary blue discoloration of the urine and sclerae. In women under the age of 35, 7% may develop secondary amenorrhea, which can be prolonged for up to several months after therapy is complete. In women over the age of 35, the risk of permanent amenorrhea may reach 14%. The drug may also reduce fertility in both men and women. Careful discussion and consultation with a reproductive endocrinologist is appropriate before commencing treatment. Mitoxantrone is teratogenic and women of child-bearing age should be advised to avoid pregnancy. Toxic acute myelogenous leukemia is estimated to occur in approximately 0.07% based on review of more than 1300 treated MS patients (Ghalie et al., 2002). Response to leukemia treatment in these patients is generally favorable.

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molecule (VCAM)-1 on activated vascular endothelium. Natalizumab is administered by monthly infusions at a dose of 300 mg in 100 ml 0.9% sodium chloride over approximately one hour. Natalizumab has been evaluated in two randomized, double-blind, placebo-controlled trials in patients with MS (Polman et al., 2006; Rudick et al., 2006b). The first monotherapy study of patients who had not received any other DMA for at least six months showed a 66% reduction in the annualized relapse rate from 0.74 to 0.25 at one year (Polman et al., 2006). The second study enrolled patients who had experienced one or more relapses while on treatment with Avonex during the year prior to study entry. A combination of natalizumab and Avonex was compared with placebo plus Avonex at one year (Rudick et al., 2006). The annualized relapse rate was reduced by 56% (0.75 to 0.33) and the percentage of patients remaining relapse-free was 54% in the natalizumab plus Avonex group compared to 32% in the placebo plus Avonex group. In addition, natalizumab monotherapy or combination therapy appeared to significantly reduce new enhancing lesions. The NNT estimates for natalizumab are more favorable than the other DMAs with NNT to render one patient relapse free after two years of therapy being 2–2.4 (Pittock et al., 2006). Despite its greater efficacy in terms of relapse rate and MRI lesion load reduction, natalizumab was withdrawn from the market on February 28, 2005, having been approved for use in the relapsing forms of MS in November 2004. This occurred due to the development of a rare, but fatal complication of progressive multifocal leukoencephalopathy (PML) in two patients. Subsequently, however, the drug has become available, but only under a special restricted distribution program called the TOUCH (Tysabri Outreach: Unified Commitment to Health) Prescribing Program. Under the TOUCH Prescribing Program, only prescribers at infusion centers and pharmacies associated with infusion centers registered with the program are able to prescribe, distribute, or infuse the product. Adverse effects

Natalizumab (Tysabri) Natalizumab is a recombinant humanized IgG-4 kappa monoclonal antibody which blocks leukocyte transmigration across the blood–brain barrier by multiple ligand-blocking mechanisms including inhibition of the molecular interaction of alpha 4, beta 1 integrin with the vascular cell adhesion

Progressive multifocal leukoencephalopathy (PML): PML is an opportunistic infection caused by the JC virus that typically occurs in immunosuppressed patients. Two cases of PML have been reported in 1859 MS patients who had been treated with natalizumab for a median of 120 weeks. A third case occurred among 1043 patients with Crohn’s disease

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after the patient received eight doses of natalizumab. The risk for PML in patients treated with natalizumab is roughly 1 in 1000 patients treated for a mean of 17.9 months (Yousry et al., 2006). There are no known interventions that can reliably prevent or adequately treat PML if it occurs. In addition, it is not known whether early detection of PML and discontinuation of the drug might mitigate the disease. Unfortunately, the clinical picture of PML can be difficult to distinguish from MS. It is recommended that patients have a pretreatment brain MRI and regular clinical follow up to allow early detection of changes in neurological status. New or recurrent neurological symptoms should prompt careful evaluation. If PML is suspected, natalizumab dosing should be suspended immediately and further investigation should include brain MRI evaluation. If MRI evaluation reveals lesions suspicious for PML, lumbar puncture with evaluation of the CSF for the detection of JC virus should be undertaken. The reader is referred to the TOUCH prescribing program issued by Biogen Idec and Elan for further guidelines. Infusion-related reactions: Approximately 1–4% of patients may develop acute hypersensitivity reactions within two hours of infusion (Polman et al., 2006). Hypersensitivity reactions consist of a combination of symptoms including urticaria, dizziness, fever, rash, rigors, pruritus, nausea, flushing, hypertension, dyspnea, and chest pain. These types of reactions should be treated by stopping the infusion and initiating therapies such as acetaminophen, antihistamines, corticosteroids, and fluids as necessary. Immunosuppression: The immune-system effects of natalizumab may increase the risk for infection. Pneumonia, urinary tract infections, gastroenteritis, vaginal infections, dental infections, tonsillitis, and herpes infections occurred more frequently in natalizumab-treated patients than in placebo-treated patients in clinical trials. In the monotherapy natalizumab study, the incidence of serious infection was 2.1% in natalizumab-treated patients versus 1.3% in placebo-treated patients (Polman et al., 2006). Concurrent use of antineoplastic immunosuppressant or immunomodulation medication may further increase the risk of infection (including PML and other opportunistic infections) over the risk observed with the use of natalizumab alone. Because of this potential interaction, it is recommended that patients have a washout period if they have been treated with immunosuppressants

or immunomodulatory medications prior to commencement with natalizumab. Laboratory abnormalities: Natalizumab may result in substantial increases in lymphocytes, monocytes, and eosinophils for some weeks to months after commencement of infusion though neutrophil counts generally remain unchanged. Anti-natalizumab antibodies: Data on antinatalizumab antibodies is highly dependent on the sensitivity and specificity of the assay. About 6% of patients will develop persistent antibodies, which are associated with a loss of efficacy and an increased risk of infusion-related adverse events (Polman et al., 2006). Immunosuppressant drugs in the long-term management of MS Azathioprine, cyclosporin, cyclophosphamide, and methotrexate have shown only modest beneficial effects in MS. They are generally not prescribed by neurologists in the management of MS (Noseworthy et al., 2005). Symptomatic treatments in MS MS is commonly associated with significant complications that can result in persistent disability. These complications can be improved by symptomatic therapies (Stolp-Smith et al., 1997). The reader is referred to a larger text for a more comprehensive review of this subject (Noseworthy et al., 2005). Here we will address some of the more common problems affecting MS patients. Fatigue Fatigue is present in up to 90% of MS patients and 40% of patients consider it their most bothersome symptom. It is typically characterized by a diurnal circadian pattern with most prominent fatigue after the middle of the day. Therapeutic options for MS-related fatigue are limited and treatment is indicated when conservative management such as energy conservation, exercise, and optimized sleep hygiene are ineffective. Modest benefit has been reported with amantadine (100 mg orally twice daily). Recent studies have failed to confirm benefit of modafinil or pemoline in MS-related fatigue. A randomized control cross-over trial of aspirin (1300

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mg daily) for fatigue in MS reported favorable results (Wingerchuk et al., 2005). Spasticity Spasticity, a common symptom in MS, interferes with mobility and often results in muscle spasm, pain, and disturbed sleep. Spasticity often worsens in the setting of infection, medication, stress, fatigue, or bladder and bowel retention. The legs are usually more markedly affected than the arms. Extensor spasticity of the legs may be advantageous for standing, walking, or transferring and may compensate for muscular weakness. Treatment of spasticity requires a multidisciplinary approach with careful assessment of the patient’s functional status and identification of treatment goals. Physical therapy should be the firstline approach. Medications such as baclofen, tizanidine HCL, clonazepam, and dantrolene sodium are usually started at a low dose and titrated up as required. Other options include intramuscular injection of botulinum toxin type A (Snow et al., 1990) or baclofen intrathecal pumps (Stolp-Smith et al., 1997). Bladder, bowel, and sexual dysfunction Impaired bladder control affects up to 80% of patients with MS. Bowel and sexual dysfunction are also common. Bladder problems generally precede bowel problems. Bladder symptoms cause much distress and are usually related to lesions in the spinal connection between the pontine and sacral micturition centers with resultant detrusor sphincter externus dyssynergia with simultaneous contractions of both sphincter and detrusor muscles. Medications to consider in the management of urgency and urge incontinence include anticholinergic drugs such as oxybutynin chloride, tolterodine, terazosin hydrochloride, and propantheline bromide. These medications may further compromise bladder emptying and it is recommended that post-micturition residual volume be determined and kept at less than 100 ml, if necessary by intermittent self-catheterization. The combination of anticholinergic medications and clean, intermittent self-catheterization is probably the optimal treatment of MS patients with bladder symptoms caused by detrusor hyperreflexia and incomplete emptying. Desmopressin acetate may benefit nocturia when administered via nasal spray and may reduce urine output for six to eight hours. The most common bowel dysfunction in MS is constipation. Causes are often multifactorial and

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include poor fluid intake, poor mobility, and side effects of medications (e.g., anticholinergic medications). Slow colonic transit in MS may be due to autonomic system failure or other mechanisms. Conservative approaches should include exercise, increasing movement and body fitness, and the use of bran, flax seed, linseed and mineral oils. Medical management includes the use of medications such as Senna (oral or rectal suppositories) or Lactulose. Fecal incontinence can be a difficult symptom to manage and is best referred to a gastroenterologist. MS may compromise sexual function in a number of ways including fatigue, depression, poor self-esteem, pain and sensory loss, neurogenic bladder and bowel symptoms, and need for catheterization. For most patients, the problem is a result of spinal demyelination. Medications that may contribute to sexual dysfunction should be identified and either reduced or substituted. Treatment with oral sildenafil (25– 100 mg orally one hour before sexual activity) (Fowler et al., 2005), alprostadil (urethral suppository, 125– 1000 mcg or injection of the corpora cavernosa of 1.25 mcg) and vildenafil (10–20 mg orally) are often helpful for men. Sexual dysfunction in women is less easy to manage. Vaginal dryness may respond to estrogen creams and water-soluble lubricants are also helpful. Some advocate use of sildenafil (Sipski et al., 2000), but there is no definitive evidence for benefit in women with multiple sclerosis. Pain syndromes Significant acute or chronic pain syndromes are experienced by up to half of MS patients at some time during their illness. Optimal management requires accurate diagnosis. Psychosocial stressors, mechanical stressors, insomnia, and mood disorders need to be identified and addressed. Nonsteroidal antiinflammatory drugs and physical therapy may be adequate. Tricyclic antidepressants such as amitriptyline or nortriptyline (starting at a low nightly dose of 10–25 mg and titrating to 75–100 mg) or gabapentin (maximum 3600 mg daily) are widely used for the management of chronic burning, dysesthetic extremity pain. Paroxysmal symptoms, which are often painful, may occur and are due to spontaneous discharge of partially demyelinated axons. A low dose of carbamazepine, sodium valproate, or other anticonvulsants that increase membrane stability often brings these attacks under control (Solaro et al., 1998). Once paroxysmal episodes resolve, it is often recommended to continue medication for two to

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three months. It would then be reasonable to reduce and stop if the paroxysms do not return. Other medications to consider for management of pain include topiramate, lamotrigine, and misoprostol. Cognition Cognitive impairment occurs commonly in MS. The ability to perform complex cognitive activities and executive functions are affected most. Memory may also be disturbed but language is generally preserved. There are limited treatment options for cognition problems and treatment is multidisciplinary as with other dementing illnesses. Acute worsening cognitive function may accompany a relapse and respond to corticosteroids. Donepezil hydrochloride, a cholinesterase inhibitor, may have some benefits for MSassociated cognitive decline (Krupp et al., 2004). Movement disorders Ataxia and tremor may result in significant disability in patients with MS and can be embarrassing, having a negative impact on social activity. Unfortunately, drug treatment of these symptoms remains unsatisfactory. Management approaches to tremor include physical therapy, use of physical restraint with weight and use of splints and medications (beta blockers (propanolol, metoprolol, nadolol or sotalol), clonazepam, and carbamazepine). Small studies have suggested benefit from isoniazid, ondansetron, and gabapentin. Stereotactic neurosurgical procedures creating lesions in the ventral lateral nucleus of the thalamus and thalamic electrostimulation may benefit some patients (Alusi et al., 2001; Matsumoto et al., 2001). Controversies regarding when to start treatment in MS The currently approved DMAs for treatment of MS have been discussed earlier in this section. Opinions vary as to who and when to treat (Frohman et al., 2006; Pittock et al., 2006). Neurologists suggesting that early initiation of DMAs in all MS patients is warranted (Frohman et al., 2006) contend that: 1 Most patients with MS will become disabled over time and it is not possible to predict early in the course of MS the long-term outcome. 2 Pathological and radiological studies show irreversible axonal injury evident early in the

course of the disease. Patients who appear to be doing well clinically may actually be accumulating new lesions and progressive tissue damage as evidenced by MRI abnormalities. 3 The FDA has suggested that DMAs work best early in the course of the illness, even at the time of the CIS, and work poorly, if at all, later in the progressive phase of the illness. 4 Since there is a suggestion that relapses do translate into more disability, at least early in the illness, DMAs started early make sense since they reduce relapse rate, lesion accrual on MRI, and subsequent progression of disability. 5 Delayed therapy is associated with a larger burden of disease on MRI and more patients developing progressive disability. Those who suggest that not all patients with MS should be started on a DMA (Pittock et al., 2006) contend that: 1 Many patients with MS have a favorable natural history. In fact, approximately one in five patients will have minimal or no disability after 20 years of disease duration. 2 DMAs are only partially effective in the short term and prevention of disability in the long term is unproven. 3 It is difficult to distinguish whether a favorable outcome reflects the favorable natural history or successful treatment in an individual patient. 4 Expense, adverse effects, and neutralizing antibodies are a concern and patients may be reluctant to commit to long-term parenteral medication. Those who argue for a “wait and see” approach for patients who have a clinical and radiological profile suggesting a greater chance of a benign course with a low chance of benefit (low relapse rate and lacking evidence of disease activity on MRI, i.e. lack of gadolinium-enhancing or new T2 lesions), suggest they be watched carefully with yearly neurological examinations and MRI scans. Currently available DMAs are not curative. While they do result in mild to moderate benefit for some patients, their long-term benefit is unproven and conclusions drawn from drug studies may not be applicable to patients in the community. Future directions in treatment of MS There is a major drive to identify better drugs for the management of MS due to the limited efficacy of the

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Table 3.6

Evolving/Investigational treatments for MS (Noseworthy et al., 2005, Kappos et al., 2004).

Category

Agents

CTLA4-Ig (structural homolog of CD28); daclizumab (targets α subunit of the high-affinity interleukin-2 receptor, anti-CD25); alemtuzumab (anti-CD52, Campath 1H); rituximab (anti-CD20); anti-CD40L/-CD154 (IDEC-131); anti-IL-12, anti-CD6; anti-CD3 (OKT3); anti-Vβ5.2/5.3+ T cells; anti-CD4; integrin inhibitors Inhibitors of intracellular Lymphocyte-specific cytoplasmic protein – tyrosine kinase P56lck; zeta-associated activation, signaling and protein (ZAP)-70; protein kinase C theta; mitogen-activated protein kinase; nuclear factor of activated T cells; inhibitors of calcium release – activated Ca channels; T-cell proliferation Janus protein tyrosine kinase (JAK 3) inhibitors; inhibitors of pyrimidine biosynthesis (gemcitabine, leflunomide, and FK778); inosine monophosphage dehydrogenase inhibitor; VX-497; vaccination with T cells or T-cell receptor peptides AMPA/kainite receptor antagonists (talampanel, E2007); riluzole (inhibitor of Neuroprotective and glutamate transmission); Na channel blockers; inhibitors of Na/Ca exchange; repair strategies antioxidants (alpha lipoic acid, tirilazide mysylate, vitamin E); neurotrophic factors; transplantation of stem cells; rHIgM22 (remyelinating monoclonal antibodies); IN-1 (anti-Nogo-A mAb) Pyrimadine synthesis inhibitor (teriflunamide); CCI-779 (ester or sirolimus); FTY720 New oral (inhibits T-cell circulation); xaliproden (inhibits cytokine synthesis); statins (induce immunosuppressant/ T-helper-cell cytokine shift and reduce T-cell migration); chemokine receptor-1 immunomodulators antagonists; mesopram (phosphodiesterase inhibitor); minocycline (inhibition of matrix metalloproteinases); macrophage inhibitors Humanized monoclonal antibodies

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4 Dévic’s disease Bernadette Kalman

The association of a spinal cord disease and blindness was first reported by Albutt (1880). Eugene Dévic described his own patient with bilateral optic neuritis and myelitis, and reviewed 16 similar cases from the literature (Dévic, 1894). His student, Ferdinand Gault, summarized the available knowledge on the subject in his thesis (1894) and introduced the term neuromyelitis optica (NMO) that later also became known as Dévic’s disease. A great proportion of recent clinical and paraclinical studies of NMO was reported by investigators at the Mayo Clinic (Lennon et al., 2003, 2004, 2005; Lucchinetti et al., 2002; Pittock et al., 2005, 2006a,b; Wingerchuck et al., 1999, 2003, 2005, 2006). Clinical phenotype Prior to the availability of a biomarker, the question persisted as to whether the distinct clinical, magnetic resonance imaging (MRI), and pathological features of the NMO phenotype reflect a separate entity or rather a subtype within the spectrum of multiple sclerosis (MS). Clinically, patients with NMO present with isolated or simultaneous symptoms of optic neuritis (ON) and myelitis. The index events at nadir are usually associated with severe visual loss and/or paraplegia, sensory impairment, and loss of bowel and bladder control. Patients, who only have one index event at onset, typically develop all index events (myelitis and bilateral ON) within a few days to a few years. Reviewing medical records and MRI data between 1950 and 1993, and adding personal observations of patients between 1993 and 1997 at the Mayo Clinic, Wingerchuck et al. (1999) summarized demographics and clinical, laboratory, and MRI characteristics of NMO. Seventy-one predominantly Caucasian patients were retained in the analyses based on strict criteria (bilateral ON and myelitis, occurring within two years of one another without signs of disease outside of optic nerves and spinal cord) or not meeting strict criteria

(unilateral ON or development of a second index event in more than two years). In this series, NMO presented with monophasic and relapsing phenotypes in 23 and 48 patients, respectively. The female to male ratio was close to 1:1 in the monophasic and 5:1 in the relapsing group. The median onset age of 29 years in the monophasic cohort was 10 years earlier than that in the relapsing cohort. While there was no difference in the rate of preceding viral illnesses or immunizations, 30% of patients with the relapsing form of NMO also had another autoimmune disorder. In relapsing NMO, optic neuritis or myelitis alone was the index event in 48% and 42% of cases, respectively, while 31% of patients with monophasic NMO presented with simultaneous bilateral optic neuritis and myelitis (Wingerchuck et al., 1999). The clinical severity of index events tended to be more severe at presentation and at recovery in the monophasic as compared to the relapsing form of NMO, but patients with the relapsing form also accumulated severe disability over time. Respiratory failure caused by cervical myelitis was noted 19 times in 16 relapsing patients and twice in two monophasic patients, and contributed to a 93% mortality rate in the relapsing group. The survival rate at five years was 90% in the monophasic and 68% in the relapsing group (Wingerchuck et al., 1999). Predictors of relapsing course included longer interattack intervals between the first two clinical (index) events, older age at onset, female gender, and less severe motor impairment with the myelitis. Mortality due to relapsing NMO was related to the history of other autoimmune disease, higher attack rate in the first two years, and a better motor recovery after the index myelitis (Wingerchuck and Weinshenker, 2003). The original Wingerchuck et al. (1999) criteria proposed that only clinical symptoms and imaging signs of lesions affecting the optic nerves/chiasm and the spinal cord (but not the brain) are compatible with the diagnosis of NMO. These clinical criteria

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agreed with the opticospinal restriction of pathology emphasized by Mandler et al. (1993). However, in a more recent study using newer MRI and laboratory methods, Wingerchuck et al. (2005) found that 20% of their 84 patients with NMO also had neurological symptoms suggesting disease outside of the optic nerves and spinal cord. Variables with high discriminative power included the NMO-IgG (see below) and distinct T2-weighted MRI features of the spinal cord lesion (see below) (Wingerchuck et al., 2005). The possible involvement of the central nervous system (CNS) in addition to lesions in the optic nerves and spinal cord was re-emphasized in the new NMO diagnostic criteria that incorporate the highly disease-specific NMO-IgG biomarker status (Wingerchuck et al., 2006). Cerebrospinal fluid characteristics In the acute cerebrospinal fluid (CSF), a moderate pleocytosis and increased proteins can usually be seen. The presence of oligoclonal bands (OCB) and elevated IgG index are less characteristic in NMO than in MS. In the survey by Wingerchuck et al. (1999), the median values of white blood cells were 12 and 28/mm3 with 50% and 60% neutrophils in the monophasic and relapsing groups, respectively. Generally, >50 white blood cells/ml and >5 neutrophils/ml was proposed to support the diagnosis of NMO. The median CSF protein level was higher (84 mg/dl) in the relapsing as compared to the monophasic group (54 mg/dl). Elevated IgG index was detected in only 20% of each group, and OCBs were found in 43% and 33% of the monophasic and relapsing groups, respectively (Wingerchuck et al., 1999). MRI characteristics Imaging hallmarks of NMO are demonstrated in Fig. 4.1. Typically, a longitudinal cervical lesion (often affecting both the gray and white matter) extending across three or more vertebrae can be seen. Cord swelling and gadolinium enhancement occur in more than half of the patients. Cervical lesions may also extend into the medulla, the high thoracic region or even the entire cord, and eventually show signs of necrosis and cavitation. The diffuse enhancement of optic nerves and chiasm in acute stages is usually followed by atrophy in chronic stages of the disease (Wingerchuck et al., 1999). While the presence of cerebral lesions was previously considered incompatible with the diagnosis of NMO (Wingerchuck et al.,

(a)

(b)

Fig. 4.1 MRI images of Dévic’s disease. The lesion extends across the entire cervical and upper thoracic cord with swelling of the cervical cord on the T2-weighted scan (a). The axial T1-weighted postgadolinium image (b) shows enhancement of the optic nerves.

1999), Pittock et al. (2005) found in a follow-up study of 60 patients that 50% of them also had positive brain MRI with nonspecific lesions in most, and with features suggestive of MS in 10%. A small subgroup (8%, mostly children) had atypical, confluent cerebral hemispheral, brainstem or diencephalic (thalamic/hypothalamic) lesions, uncharacteristic of MS (Pittock et al., 2005). The revised diagnostic criteria reflect these observations (Wingerchuck et al., 2006). Magnetization transfer and diffusion tensor imaging techniques also revealed that microscopic pathology may be present in the normal appearing gray matter in the brain of patients with NMO (Rocca et al., 2004). Pathological characteristics A modern and comprehensive pathological evaluation of NMO was reported by Mandler et al. (1993) using hematoxylin-eosin, Luxol fast blue-hematoxylin, periodic acid-Schiff and Bodian’s silver staining. Five of the studied eight patients died between one and four years after the onset. The spinal cord was affected throughout most of its length. Microscopically, cavitation and necrosis were noted in both the gray and white matter. Necrotic lesions were associated with the presence of macrophages and prominent blood vessels. Vessel walls were thickened and hyalinized with scarce nuclei. The perivascular and parenchymal infiltrate included macrophages but no lymphocytes or plasma cells. The anterior optic pathway showed signs of demyelination, gliosis, and cavitation (Mandler et al., 1993). Using a panel of markers for immunohistochemistry, Lucchinetti et al. (2002) characterized 82 lesions from nine autopsy cases of clinically definite NMO. All patients had extensive demyelination

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associated with cavitation, necrosis and acute axonal spheroids across multiple vertebral levels in both the gray and white matter. The depletion of oligodendrocytes was profound. In addition to macrophages, large numbers of neutrophils and eosinophils were seen in acute parenchymal and meningeal infiltrates, with a rare appearance of CD3 and CD8 positive T cells. Striking deposition of immunoglobulins (mostly IgM) and complement C9 neoantigen was associated with vascular fibrosis and hyalinization in active and inactive lesions (Lucchinetti et al., 2002). The involvement of humoral immunity in the pathogenesis of NMO was further confirmed by demonstrating the increased numbers of myelinoligodendrocyte glycoprotein (MOG)-specific B cells that produced increased amounts of IL-5, IL-6, IgG, and IgM in the CSF (Correale and Fiol, 2004). The number of IgM-secreting B cells was much higher than that of the IgG-producing cells. Chemokines chemoattractant for eosinophils were also increased in the CSF of patients with NMO. Genetics NMO presents as a sporadic disease and has been observed in both Caucasians and non-Caucasians. Nevertheless, its preferential occurrence in ethnic groups (i.e. Asians, Africans, Canadian Aboriginals, and French Afro-Caribbeans) with lower prevalence rates of typical MS was recognized (Cabre et al., 2001; Kuroiwa, 1985; Mirsattari et al., 2001; Misu et al., 2002; Osuntokun, 1981). While the relative risk for developing MS is 0.64 in African Americans (AA) compared to that in Caucasian Americans (CA), AAs are more likely to present with the opticospinal form or with transverse myelitis and have a more aggressive disease course than Caucasians (Cree et al., 2004). The DRB1*1501 and DRB5*0101 alleles associated with Western-type of MS are absent in patients with NMO or Asian-type of the disease in Japan (Kira et al., 1996). In contrast, these patients have an increased frequency of the HLA-DPB1*1501 allele (Yamasaki et al., 1999). Whole-genome admixture analyses using polymorphic markers in AA individuals aimed to differentiate chromosomal segments of African and European origin, and defined that 79% of the composite ancestry is African and 21% is European in origin. The association of MS with both the HLA-DRB1*1501 allele of Caucasian origin and the DRB1*1503 allele of African origin revealed that MS susceptibility was not simply related to the Northern-European gene influx into the AA

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population (Oksenberg et al., 2004). Genetic markers associated with the opticospinal disease in AA individuals, however, remain to be identified. Full sequence analyses of mitochondrial DNA in three Caucasian NMO patients excluded the possibility that the necrotic nature of pathology was related to inherited point mutations or deletions in this extranuclear part of the genome (Kalman and Mandler, 2002). NMO-IgG, a biomarker for NMO In accordance with histological data, recent serological studies also add support to the involvement of a humoral mechanism by identifying a new immunoglobulin specific for NMO (Lennon et al., 2003). Sera from patients with NMO, MS, and other autoimmune disorders were used against mouse brain sections in an indirect immunofluorescence assay. A distinct IgG binding pattern associated with capillaries and the blood–brain barrier in the cerebellar cortex, midbrain, pia, and a subpial mesh (prominent in the midbrain) was noted in 54% of patients with NMO. This pattern of staining was also identified with sera from eight patients among several thousands screened in a blinded fashion at the Mayo Clinic. Breaking the code revealed that all these eight patients had definite or possible NMO. Follow-up studies using this assay confirmed a sensitivity of 83% and a specificity of 91% for NMO, and a sensitivity of 58% and specificity of 100% for the Asian form of opticospinal MS (Lennon et al., 2004). This study, thus, established that the NMO-IgG is a biological marker that distinguishes NMO from typical (or western-type of ) MS, and confirmed the immunological similarity between NMO and the Asian form of opticospinal MS. The NMO-IgG is positive in about 40% of longitudinally extensive transverse myelitis at the first event and predicts recurrence in 50% of patients in one year (Weinshenker et al., 2006). Lennon et al. (2005) recently identified the aquaporin-4 water channel as the antigenic target of NMO-IgG. Aquaporin-4 is a component of the dystroglycan protein complex located in the abluminal surface of blood vessels and the foot processes of astrocytes at the blood–brain barrier. Pittock et al. (2006a) observed in a subgroup of NMO patients that the distribution of MRI abnormalities in the hypothalamic and periventricular areas corresponds to cerebral regions with high aquaporin-4 water channel expression. These findings raise the possibility that NMO may belong to a new class of autoimmune channelopathies and is biologically distinct from

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MS. Nevertheless, the direct pathogenic role of antiaquaporin-4 IgG remains to be experimentally evaluated. Of note, this antibody frequently coexists with other antineuronal and antimuscle autoantibodies, and the occurrence of several autoimmune diseases including myasthenia gravis (2.6%) has been observed in Dévic’s disease (Pittock et al., 2006b).

2005). Six of eight patients were relapse free and the median relapse rate dropped from 2.6 to 0 attack/ patient/year. Seven patients experienced significant improvement during the one-year follow up. The pretreatment EDSS of 8.5 improved to 5.5. Rituximab was well tolerated and no major adverse event occurred.

Diagnostic criteria

Summary

The revised diagnostic criteria for definite NMO (Wingerchuck et al., 2006) invariably require the presence of optic neuritis and myelitis, but allow the presence of clinical and MRI evidence for neurological disease outside of the optic nerves and spinal cord. In addition to optic neuritis and myelitis, the best diagnostic combination (with 99% sensitivity and 90% specificity for NMO) also consists of at least two of the three following supportive criteria: a continuous spinal cord lesion extending over three or more vertebral segments on T2-weighted MRI; onset brain MRI nondiagnostic for MS; or NMO-IgG seropositivity.

Based on clinical, imaging, laboratory, and histological characteristics, NMO has always been considered to be a distinct entity with a molecular pathogenesis different from that of MS. This view recently gained firm support by the identification of a new biomarker, the NMO-IgG specific for the aquaporin-4 water channel. The NMO-IgG has moderate sensitivity and high specificity for NMO, and is absent in typical MS. Clinical data suggest a distinct, but not exclusive, optic nerve and spinal cord distribution of lesions. The pathology involves both the gray and white matter and shows demyelination, cavitation, necrosis, hyalinization of small vessels, and a presence of macrophages, neutrophils and eosinophils, along with the deposition of IgM and IgG classes of immunoglobulins and activated complement components in the proximity of blood– brain barrier. MRI correlates of these histological changes are T2-weighted lesions affecting more than three segments of the spinal cord and optic nerves with more frequent than previously appreciated cerebral involvement. A moderate pleocytosis typically without OCB or increased IgG synthesis may be seen in the CSF. The identification of NMOIgG has significantly reduced diagnostic ambiguities and raised the possibility that NMO may belong to a new class of autoimmune channelopathies. Further refinements of the diagnostic evaluations may be necessary to capture the true spectrum of NMO including inaugural symptoms and other limited variants such as recurrent myelitis with negative brain MRI, recurrent isolated optic neuritis, and isolated longitudinal myelitis with or without systemic autoimmunity (e.g. Sjögren’s syndrome or SLE) associated with NMO-IgG seropositivity.

Treatment of NMO Corticosteroids remain the choice of treatment in acute attacks, and corticosteroid dependence has been noted in relapsing patients (Wingerchuck et al., 1999). Plasma exchange is recommended for corticosteroid unresponsive patients (Keegan et al., 2002). For long-term treatment, azathioprine and cyclophosphamide have been used with some benefit (Mandler et al., 1998; Wingerchuck et al., 1999). In a prospective pilot trial, Mandler et al. (1998) treated eight newly diagnosed NMO patients with prednisone and azathioprine. The Expanded Disability Status Scale (EDSS) score significantly improved in all patients and no relapse occurred during the 18 months follow up. The involvement of immunoglobulins and complement in the pathogenesis of NMO suggests that immunosuppression and plasma exchange should be used for these patients rather than immunomodulation approved for MS patients. Targeting the B-cell lineage may also modify the natural history of the disease. Initial data from an open-label uncontrolled trial using rituximab, a chimeric murine/ human monoclonal antibody directed against the CD20 antigen on precursor and mature B cells (Biogen-Idec, Cambridge, MA and Genentech, South San Francisco, CA), revealed promising results in eight patients with worsening NMO (Cree et al.,

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5 Acute disseminated encephalomyelitis and related conditions Robert S. Rust

Acute disseminated encephalomyelitis (ADEM) and multiple sclerosis (MS) are nonvasculitic inflammatory diseases of the central nervous system (CNS) that bear striking clinical, pathological, and pathophysiological resemblance not only to one another, but also to the research model, experimental allergic encephalomyelitis (EAE). Some of the pathophysiological features that these three entities share are listed in Box 5.1. Detailed discussion of the considerable amount of information that is known about pathogenesis of ADEM and MS falls outside of the scope of this clinical review; many current sources for that information are available (Hohlfeld and Wekerle, 2001; Johnson, 1998; Lucchinetti et al., 2001; Poser, 2000; Pouly and Antel, 1999; Pouly et al., 2000; Rust, 2000; Rust and Fleming, 1996; Tellis, 1998). Despite a large and increasing body of literature, it is not yet clear why ADEM is an inflammatory illness with a generally favorable outcome that usually remains monophasic, while MS is an inflammatory illness that follows a chronic degenerative course (Poser, 2000; Pouly and Antel, 1999; Pouly et al., 2000).

Box 5.1

ADEM must be considered in relationship not only to MS, but also to other designated clinical entities that appear to constitute a spectrum between ADEM and MS. As is true of ADEM and MS, most of these have no specific diagnostic test, although recent development of a specific test for neuromyelitis optica (NMO) suggests that in the future the current classification will be replaced by a less equivocal system incorporating specific tests and greater understanding of the pathophysiological differences of the various entities. It is of particular importance to keep in mind that the collections of illnesses currently labeled “ADEM” or “childhood MS” likely contain some subtypes for which distinctive names will in time be selected as biomarkers for these particular subtypes are identified. This likelihood is supported by the fact that many examples of one clinical subtype that has formerly been included under either of these collective headings, neuromyelitis optica, are now discretely identified by the diagnostic biological marker, NMO-IgG. This is true for the clinical entities such as those shown in Box 5.2 that are currently without discrete biomarkers. These are

Similarities between ADEM and MS.

1. Earliest stages of inflammation mediated by stimulated clones of T-helper cells sensitized to autoantigens such as myelin proteins (Oleszak et al., 2001). 2. Ensuing complex inflammatory cascade entails the local action of lymphokines as well as lymphokine-induced chemotaxis of other cellular mediators of inflammation (other T-cell lines, B cells, microglia, phagocytes). 3. Tumor necrosis factor (TNF)-α, soluble TNF receptor 1, and interleukins (IL) 10 and 6, each of which may be elevated

4.

5. 6. 7. 8.

in cerebrospinal fluid (CSF), likely involved in pathogenesis. IL-6 and TNF-α are likely proinflammatory and TNF-α may play a particular role in demyelination (Ichiyama et al., 2002). Disturbance of blood–brain barrier function is likely to be very important. Lymphocytic perivenular inflammation is prominent. Patchy perivenular demyelination occurs with relative preservation of axons. Microglial cells are characteristic elements of the inflammatory exudate.

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Box 5.2 • • • • • • • •

89

Syndromes – some examples of which may be or are ADEM or MS variants.

Acute hemorrhagic leukoencephalopathy (AHLE) Acute multiple sclerosis Acute necrotic encephalomyelitis ADEM without prodromal phase Bickerstaff’s encephalitis Childhood limbic encephalomyelitis Concentric sclerosis, Balò type Dévic syndrome (neuromyelitis optica)

clinical syndromes that in some instances occur as types of ADEM while in others as types of MS. ADEM usually arises in close association with some exogenous stimulus, such as a febrile illness suggestive of viral infection, sometimes rendering the distinction of ADEM from “viral meningoencephalitis” troublesome. There are many other conditions that sometimes produce a clinical appearance so suggestive of ADEM as to be mistaken for it. These conditions constitute the differential diagnosis for ADEM, listed in Box 5.3 (Rust, 2000; Hartung and Grossman, 2001). Many of these conditions are also in the differential diagnosis of MS and will be termed in this chapter “other neurological diseases,” or ONDs. It is possible that some of the conditions in Box 5.3 may share certain pathophysiological mechanisms with ADEM or MS, accounting for similarities not only in clinical manifestations but also in imaging appearance and in various laboratory results including cerebrospinal fluid (CSF) immune profile testing. These CSF tests, shown in Box 5.4, are of considerable importance in the evaluation of patients suspected of having MS, since approximately 95% of all individuals who have MS can be expected to show abnormalities of most or all of these tests upon their second clinical bout and thereafter. Although CSF myelin basic protein (MBP) is not, strictly speaking, an immune profile test, it is included because it is a very useful indicator of inflammatory injury to white matter. ADEM, which produces abnormalities of the other tests in only a minority of cases, is usually associated with an abnormal MBP value. Abnormalities of the CSF immune profile may be seen in some of the conditions listed in Box 5.2 as well as in some ONDs – as is shown in Box 5.5 (Trotter and Rust, 1989).

• • • • • • • •

Encephalomyeloradiculoneuriopathy Miller–Fisher syndrome Optic neuritis “Recurrent” or “multiphasic” ADEM Recurrent herpes encephalitis Schilder disease Steroid-dependent hyper-recurrent disseminated encephalomyelitis Transverse myelitis

As will be seen, similar caution must be exerted in the interpretation of imaging findings obtained in children or adolescents who may have ADEM or its possible variants, MS, or various ONDs. The fact that there are indeterminate boundaries between these various conditions, which give rise to uncertainties concerning the results of immune profile testing or brain imaging, should not be surprising given the probability that there are areas of mechanistic overlap between these conditions. This is to be expected, considering the overlap in pathophysiological mechanisms. Additional specific tests are available for refinement of diagnosis of conditions that resemble ADEM or MS, with the particularly important recent addition of the Wingerchuk assay for neuromyelitis optica. Acute disseminated encephalomyelitis (ADEM) What might be termed “typical ADEM” is an acute monophasic, multifocal CNS disturbance arising in the wake of an exogenous stimulus (e.g. febrile illness or vaccination). It is chiefly encountered in prepubertal children, although it may occur in adults. Strictly speaking, it is a pathologically defined entity, consisting of inflammatory perivenular demyelination with relative sparing of axons. Nonetheless, as is the case with MS, it is a disease that affects both white matter and gray matter. The gray matter manifestations of ADEM tend to be much more prominent during an acute bout of ADEM than one of MS. However, these ADEM manifestations tend to resolve with typical ADEM, while MS is, as has recently become clear, a progressive gray matter degeneration. The MRI manifestations of typical ADEM tend to be characteristic and quite supportive

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Box 5.3 • • • • • • • • • • • • • • • • • • • • • • • • • • •

Other ADEM/MS differential considerations.

Acute cerebellar ataxia Aicardi–Goutieres syndrome AIDS Atlanto-occipital instability Behçet syndrome Childhood ataxia with cerebral hypomyelination Chronic fatigue syndrome Cysticercosis Echinococcosis Embolic/thrombotic vascular disease Encephalitis Glioblastoma multiforme/other glial tumors Hashimoto encephalopathy Heritable leukodystrophies Hereditary spastic paraplegia Hypersensitivity vasculitides Leber’s hereditary optic atrophy Leukemia/lymphoma, other cerebral tumors Lyme encephalomyelitis/neuroborreliosis Marchiafava–Bignami disease Medium-chain acyl dehydrogenase deficiency Mesencephalic leukoencephalopathy/SC cysts Meningitis Migraine Monoclonal gammopathy Moyamoya Neurobrucellosis

Box 5.4 • •

• • • • • • • • • • • • • • • • • • • • • • • • •

• •

Neuroaxonal dystrophy Opsoclonus-myoclonus Paraneoplastic syndromes Pelizaeus–Merzbacher disease Primary CNS vasculitis Progressive multifocal leukoencephalopathy Progressive rubella panencephalitis Rabies Sarcoidosis Schilder’s myelinoclastic diffuse sclerosis Schindler disease Sinovenous thrombosis Sjögren syndrome Spinal stenosis Spinocerebellar degenerations Subacute sclerosing panencephalitis Sydenham chorea/PANDAS Syphilis Syringomyelia Systemic lupus erythematosus Chiari malformation/tethered cord Toluene leukoencephalopathy (“glue sniffing”) Toxic subacute myelopticoneuropathy Toxoplasmosis Tropical spastic paraparesis (HTLV-1-associated myelopathy TSP/HAM)) Vascular malformations – brainstem or spinal cord Whipple disease

CSF immune profile tests.

CSF IgG synthetic rate (Tourtellotte, 1970) CSF IgG/Albumin ratio

of diagnosis, as are those of typical MS, from which they differ. Although pathological confirmation is seldom obtained, “typical, monophasic ADEM” is not so difficult to recognize and will be the chief subject of this review. Should an ADEM-like illness recur, as in some of the conditions listed in Box 5.2 (excepting NMO-IgG positive Dévic syndrome), it is currently

• • •

CSF oligoclonal bands CSF: serum IgG index Myelin basic protein

unsettled as to whether to classify such an illness as ADEM, MS, or something else (Cole et al., 1995). The discussion that follows is based not only on cited references, but also on more than 300 cases of various forms of the conditions considered in this review that we have studied including approximately 150 cases of “typical” ADEM.

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Box 5.5 • • • • •

Diseases that may provoke abnormalities of the CSF immune profile.

Acute bacterial, viral, parasitic, tuberculous, fungal meningitis/encephalitis Acute or chronic inflammatory demyelinating polyneuropathy ADEM Chronic rubella panencephalitis CNS tumor

Clinical aspects Data from our patient series and another large recent series (Tenembaum et al., 2002) show that although ADEM may develop at any point from the first year of life to late middle age, most cases occur in children 3–10 years of age (mean age approximately 6 ± 4 years). Contrary to what is seen in either childhoodor adult-onset MS and possibly adult-onset ADEM

Box 5.6 • • • • • • • • • • • • • • • • • • • • • •

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• • • • • • •

Lyme disease MS Neurosyphilis Sarcoidosis SSPE Stroke Systemic lupus erythematosus

(Hollinger et al., 2002) boys are at higher risk than girls for childhood-onset ADEM (boy:girl ratio 1.3– 1.8:1). It is not clear whether the white:black ratio of approximately 6:1 in our series merely reflects referral bias (Rust et al., 1989a). A wide variety of possible exogenous provocations have been identified, many of which are listed in Box 5.6 (Campistol et al., 2001; Miller et al., 1956; Rust, 2000; Shintani et al., 2001; Tselis, 2001). In

Infections and other exogenous stimuli associated with ADEM.

Antihelminthic medication treatments Bartonella henselae BCG vaccine Campylobacter Chlamydia pneumoniae Clostridium tetani and tetanus vaccine Corynebacterium diphtheria Coxsackie B virus Cryptococcus neoformans (Jaing et al., 2001) Cytomegalovirus Echoviruses Enteroviruses Epstein–Barr virus Hepatitis A or B Human herpes virus 1 or 6 Influenza A or B viruses/vaccines Japanese B virus/vaccine (Plesner et al., 1998) Legionella (Sommer et al., 2000) Lyme disease Malaria Measles virus/vaccine Mumps virus/vaccine

• • • • • • • • • • • • • • • • • • •

Mycoplasma pneumoniae (Hasegawa, 2001) Organ/bone marrow transplant (Au et al., 2002) P. malusia (J Am Phys Ind 49:756, 2001) Parainfluenza virus (Au et al., 2002) Periodic acid-Schiff treatment Pertussis Polio virus/Salk or Sabin vaccines (Arya, 2001) Puumala virus (Toivanen et al., 2002) Rabies virus/Pasteur rabies vaccine Rickettsia rickettsiae (Rocky Mountain Spotted Fever) Rubella virus and vaccine Rubeola virus and vaccine Serum administration Streptococci, Group A beta-hemolytic (Ito, 2002) Streptococci, pyogenes Sulfonamide treatment Typhoid and paratyphoid vaccines Vaccinia virus/vaccine Varicella virus Variola virus

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our series slightly more than half of all cases occur in the wake of respiratory infections, 15–20% follow gastroenteritis, while the remainder are due to nonspecific febrile illnesses, vaccines, or no clearly identifiable provocation. It is presumed that most ADEM cases are provoked by viruses, although specific viruses are seldom identified. Increased prevalence of ADEM in winter months (Dale et al., 2000; Rust et al., 1989; Tenembaum et al., 2002) may be due to increased prevalence during that time of year of particularly provocative pathogens, particularly large envelope-bearing viruses. Fortunately most of the various childhood illnesses due to viruses, which figured prominently in older series of ADEM, are currently prevented by immunization in large parts of the industrialized world. Some of these viruses (e.g. measles, mumps, rubeola, rubella, varicella, variola) were capable of provoking severe and sometimes fatal encephalomyelitis. However, it must be remembered that these same potentially lethal agents continue to cause widespread and severe childhood illnesses including ADEM in less medically favored regions of the world. Antibiotic therapy or changes in immunogenicity may account for reduced prevalence of streptococcal infection as the cause of illnesses prodromal to the development of ADEM, at least in many industrialized nations. Agents for which serological or other evidence can most often be found in contemporary series include Epstein–Barr virus, Bartonella, and Mycoplasma. The statistical prominence of the last of these is due in part to the unsatisfactory specificity of available serological tests. “Recurrent” herpes encephalitis is at least in some instances a severe form of ADEM from which recovery is slow but may be complete. Particularly severe and permanent manifestations of an ADEM-like illness continue to arise in the wake of Lyme disease and Brucellosis. It is possible that the hyperergic and severe illnesses such as cerebral malaria and Dengue fever, which account for millions of cases yearly around the world, share elements of ADEM pathogenesis. Various vaccines have been suggested, sometimes quite controversially, as the exogenous provocations of cases of ADEM, most clearly older versions of the Pasteur rabies vaccine. Currently immunizations account for no more than 3–6% of ADEM cases (Dale et al., 2000; Hynson et al., 2001; Rust et al., 1989; Tenembaum et al., 2002). As many as 14–26% of all ADEM cases are “cryptogenic” with no definite antecedent cause. Neurological dysfunction of ADEM usually arises 1–30 days after exogenous stimulation, typically with

a fever-free interval of hours to weeks separating the two phases of illness (Croft, 1969; de Vries, 1960; Miller et al., 1957; Scott, 1967; Tenembaum et al., 2002). The outside limit of 30 days is an artificial one as it remains unclear whether longer latencies between febrile prodrome and ADEM occur, although experience with herpes and other infections of vaccines suggests that it is possible (Sacconi et al., 2001). However, the more remote the presumed provocation the more difficult to prove cause and effect (Rust et al., 1989; Tenembaum et al., 2002). Very short intervals, on the other hand, may obscure the distinction between possible exogenous stimulus and inflammatory results, which may in turn prompt diagnosis of infectious meningoencephalitis rather than ADEM. Interestingly, however, a hiatus of at least a few hours is usually found between a febrile prodrome and onset of ADEM, even in cases where the febrile prodromal illness was of many weeks’ duration. It remains to be determined what percentage if any of cases of presumed meningoencephalitis without identifiable pathogen are actually cases of ADEM. The question is important since as many as 70% of all cases of clinically diagnosed meningoencephalitis in North America occur without an identifiable pathogen. Similar diagnostic problems arise in cases of presumed postinfectious vasculitis, cases which must themselves be distinguished from ADEM. Approximately 15% of cases in our series thought to represent ADEM have no clearly defined prodrome. Irritability, lethargy, fever recurrence, vomiting, and various other neurological manifestations mark the onset of most cases of ADEM. These features and other features listed in Table 5.1 readily distinguish most first bouts of ADEM from MS. The approximate prevalence of various specific clinical findings of ADEM is shown in Table 5.2. In bouts of either ADEM or childhood MS, neurological manifestations may evolve very dramatically over intervals as short as minutes. However, slower evolution is more common, usually involving 2–6 days, although in some less common instances abnormalities unfold over intervals as long as 6–8 weeks. The evolution of abnormalities tends to proceed longer in ADEM than in a discrete bout of childhood-onset MS. Improvement tends to occur only after the abnormalities have fully developed. ADEM seldom if ever manifests the fluctuation in degree of certain dysfunctions that is characteristic of MS, such as Uthoff ’s phenomenon (transient heat-induced worsening of vision, other sensory or motor abnormalities). On the other hand, findings

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Table 5.1

Prevalence of various features, first bout childhood or adolescent MS or ADEM.

Prevalence of features in first disease bout – Childhood Disease Features MS >11 No Rare Often unilateral Common Common Common Rare Common

Age Febrile illness/vaccination precedes Seizure/encephalopathy Optic neuritis Nonvisual sensory symptoms Posterior column signs Abnormal CSF immune profile Abnormal EEG Transient sensory paroxysms

ADEM > focal) is found in 75–80% of ADEM cases. Abnormalities of sleep architecture may be found. Sharp waves, rhythmic

Approximate rates of positivity, various CSF immune profile tests.

CSF immune profile tests

Diseases CDMS

P/PMS

ADEM

NMSI/I

OND

CSF IgG/Albumin ratio CSF/Serum IgG index IgG synthetic rate Oligoclonal bands

60–80% 88–94% 88–96% 83–100%

21–24% 44–55% 27–67% 24–89%

16–20% 15–20% 16–18% 10–12%

14–42% 43–57% 29% 27–72%

6–10% 3–18% 4–12% 2–29%

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delta, or spikes may be found in the waking state during the early stages of as many as 2–7% of ADEM cases, features that also distinguish ADEM from childhood-onset MS. The absence of such abnormalities during the first bout of acute disseminated demyelinating illness in a child significantly increases the risk for ultimate MS diagnosis (Rust et al., 1989). EEG abnormalities are not found in adult ADEM (Hollinger et al., 2002). Imaging studies Focal low-density abnormalities are found in the brain computed tomography (CT) scans of 60–80% of cases of ADEM. These abnormal areas always correspond to much larger areas of abnormality detectable on MRI scans. Due to the fact that the CT technique is far less sensitive than MRI for the detection of the lesions associated with ADEM, MRI usually identifies numerous additional smaller areas of abnormality. MRI scans detect abnormalities of various size on T2, proton density, and fluid attenuation inversion recovery weighted sequences in more than 90% of ADEM cases. CT scans are superior to MRI scans only in the detection of hemorrhagic changes that define acute hemorrhagic leukoencephalopathy. Unlike MS plaques, the characteristic lesions of ADEM are centrifugal. Nearly 90% of individuals with

ADEM are found to harbor lesions at the junction of deep cortical gray and subadjacent white matter. The indistinct and irregular margins of childhood ADEM lesions tend to suggest a “smudge” rather than the clearly demarcated plaque margin characteristic of MS. Lesions similar to those characteristic of childhood ADEM are found in less than 40% of cases that are labeled as “adult” ADEM – a diagnosis that often changes to MS as time goes on. In childhood or adolescent ADEM, additional unilateral or bilateral lesions may be found in deeper white matter, optic nerves, basal ganglia (30–40%), thalamus (12–40%), brainstem (45–55%), cerebellum (30–40%), and spinal cord. Periventricular lesions (30–45%) and corpus callosum lesions (10–15%) are much less common in childhood ADEM than in MS where they are so characteristic. Various unusual lesions identified by MRI imaging in the nervous system of individuals with ADEM are listed in Box 5.7. Diseases that produce changes on MRI that have been misdiagnosed as ADEM are shown in Box 5.8. In approximately two-thirds of ADEM cases lesions are small (2 months after first bout*

Great Great Moderate Moderate to great? Moderate to great?

Factors that decrease risk

Degree of risk decrease

Clear febrile prodrome within 30 prior days Normal CSF immune profile Moderately abnormal EEG at onset (slow or paroxysmal) Fever and constitutional signs/symptoms at onset Elevated platelet count or sedimentation rate

Moderate Moderate Great Great Moderate

*As has been noted in the text, the appearance of new lesions within two months after an initial bout is of uncertain significance.

immune profile studies have just one recurrence. Therefore, the suggestion based upon a single case (Hahn et al., 1996) that such children should be treated after the first relapse with IVIg in order to assure that there will be no further relapses remains tentative. Most children with a single relapse will have no further disease if treated instead with steroids, although it is also unclear whether either medication influences the ensuing natural history of disease. However, where there are more than three relapses, a situation that arises chiefly postpuberty and without prodromal fever, it is highly likely that the CSF immune profile will be positive and in the absence of some OND, MS is the most likely diagnosis. However, in very rare instances, a single bout of prepubertal ADEM-like illness (febrile prodrome, ADEM-like imaging results, normal CSF immune indices) may be followed, after a latency as long as eight years, by a postpubertal bout of MS (no febrile prodrome, MS-like imaging results, abnormal CSF immune indices). Factors that influence the likelihood of an MS diagnosis in prepubertal children are shown in Table 5.5. Several additional prebupertal illnesses of uncertain standing vis-à-vis the diagnosis of MS or ADEM are to be considered below. Postpubertal relapses render the diagnosis of MS much more likely – as does the occurrence of any illness suggesting differentiation between MS and ADEM. In most if not all of these individuals, the recurrence is not preceded by fever, is usually not associated

with abnormalities of higher cortical functions or EEG, and CSF immune profile results are abnormal. A system for classifying the various entities that fall into something on an “ADEM-MS spectrum” is shown in Box 5.10. Hyper-recurrent ADEM (steroid mediated inflammatory leukoencephalopathy) There is a very rare syndrome of toddlers or young children whose initial ADEM-like bout of illness with febrile prodrome is followed by a persistent “hyperrecurrent” course. The CSF immune profile remains normal despite recurrence. However, myelin basic protein is usually elevated in the CSF. Mental status changes accompany recurrences (which tend to occur when the chronic oral prednisone treatment is tapered to some particular threshold, such as alternate day doses of between 12 and 16 mg of prednisone). Progressive visual loss may occur and epilepsy may develop. Some children tolerate steroid taper after an initial bout but develop “steroid dependency” after the second or third bout (Campistol et al., 2001). IVIg administration may lead to temporary improvement during a recurrence, but does not alleviate the “steroid dependency.” However, these children do respond to chronic cyclophosphamide or to immunomodulatory treatment. MRI scans more closely resemble the classic findings of ADEM, than MS. In some instances the

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Box 5.10

Descriptive categories of recurrent illness resembling ADEM or MS.

1 Monophasic, nonrecurrent 1A Clearly identifiable febrile prodromal illness 1B No clearly identifiable febrile prodromal illness 2 Recurrent during taper of anti-inflammatory therapy (usually corticosteroids) 2A Resolution without recurrence after slower corticosteroid recurrence (“steroid-withdrawal ADEM”) 2B Obligate recurrence each time oral corticosteroid dose is tapered below

a “minimum controlling dose” (MCD). “Hyper recurrent ADEM” 3 Remotely recurrent (i.e. not related to taper of anti-inflammatory therapy) 3A Clearly identifiable febrile prodromal illness associated with recurrence 3A* CSF IgG index or oligoclonal band abnormalities found 3B No clearly identifiable febrile prodromal illness associated with recurrence 3B* CSF IgG index or oligoclonal band abnormalities found

scan appearance suggests the diagnosis of Schilder disease. Whether this group represents MS or some other illness is unclear, although in some instances an inflammatory angiopathy may be identified on biopsy. ONDs must be particularly scrupulously excluded. We are aware of cases of sarcoidosis, “CNS vasculitis,” histiocytic lymphangiomatosis, leukodystrophies, and glioblastoma multiforme that have exhibited a similar pattern of recurrence and “steroid responsiveness/dependency.”

ADEM are applied, no prodrome is found at the onset of more than 30% of adolescent or 45% of adult “ADEM” cases (Schwarz et al., 2001). Possible reasons why initial or recurrent bouts of presumed ADEM should not have such identifiable provocations are listed in Box 5.11. There is likely a considerable risk in such cases for the ultimate diagnosis of MS (Schwarz et al., 2001).

ADEM without prodrome

The first bout of acute demyelinating CNS illness in the prepubertal child may be associated with unusually severe or even bizarre presentations, sometimes labeled “acute MS” (Cole et al., 1995). Similar cases in adults have rarely been reported (Vliegenthart et al., 1985). Acute encephalopathy is typically associated with mental status changes ranging from confusion to coma; convulsions and prominent pyramidal tract abnormalities are usually found (Shaw and Alvord, 1987). More common in very young children, the ensuing course may be one of rapidly progressive

Categories 1B and 3B in Box 3.10 suggest the importance of prodromal illness in assigning diagnosis of ADEM as compared to MS or OND and in estimating the risk of subsequent diagnosis of MS. Approximately 15% of childhood cases for which the diagnosis of ADEM is suggested by clinical features and imaging lack the history of a prodromal illness or vaccination (Dale et al., 2000; Hynson et al., 2001; Rust, 2000). Depending upon what definitions of

Acute MS

Box 5.11 Possible reasons why an ADEM-like illness can occur without identifiable infectious prodrome (or potentially provocative vaccination). • • •

Milder/subclinical or more remote infectious illnesses may provoke ADEM Post-vaccination ADEM may occur after a long latency ADEM may occur without a preceding infectious illness or vaccination

•

The illness in question is not ADEM; even where there is no further recurrence it is rather an example of monophasic MS or some other form of illness other than ADEM

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deterioration that may prove fatal within days to weeks. Survivors almost universally manifest profound, permanent psychomotor and visual deficits. Brain images differ from those typical of juvenile MS in that they tend to manifest large confluent symmetrical (“butterfly pattern”) bright signal abnormalities emphasized in subcortical white matter on T2 weighted sequences. Ring enhancement after contrast administration may be found. Malignant brain edema may be present, manifested by sulcal and ventricular effacement and increased intracranial pressure (Ishihara et al., 1984; Maeda et al., 1989; Morimoto et al., 1985). The proper classification of these rare severe cases remains in doubt. They have clinical and radiographic changes difficult to distinguish from other cases to which hyperacute ADEM, Schilder disease, acute toxic encephalopathy, encephalitis, and other labels have been applied (Bye et al., 1985; Hanefeld et al., 1991; Shaw and Alvord, 1987). Pathological changes of MS were found in one fatal childhood case (Shaw and Alvord, 1987) but in many instances, including most nonfatal cases, pathological studies have not been performed. Many presumed examples were reported prior to the identification of such alternative diagnostic entities as Reye syndrome or encephalitis (e.g. herpes, measles), or the availability of various laboratory tests for such entities. It is of interest that the prevalence of acute MS and similar illnesses has declined since children have been immunized against a number of potentially encephalitogenic viruses. Schilder disease In 1912 Schilder described a severe and fulminating acute demyelinating syndrome of adolescence (Schilder, 1912). During the ensuing 90 years, the pathogenesis has remained uncertain and the term has been applied, often incorrectly and usually not helpfully, to a heterogeneous collection of more than 100 additional possible cases (Poser and van Bogaert, 1956; Rust, 2003). It has been clear for some time that “Schilder disease” (SD) is an entity of uncertain standing that must be set apart from various subsequently defined alternative diagnoses (Kepes, 1993; Mehler and Rabinowitz, 1988, 1989; Poser et al., 1986). The pathology of the index case and the rare subsequent examples of the condition is extensive demyelination of both cerebral hemispheres. Although axons are relatively spared, Wallerian axonal degeneration may be found. The hemispheric lesions are

101

usually somewhat asymmetrical, have sharp margins, and spare the immediate subcortical rim of white matter. Similar demyelinative changes are often found in brainstem and cerebellum. The Wallerian axonal degeneration may occur throughout the nervous system, but is especially marked in the spinal cord. Thus, the pathology including the sharp margin and subcortical sparing tends to resemble MS more closely than ADEM. Poser, who has proposed useful diagnostic criteria, has convincingly estimated only nine of the more than 100 cases that have been reported as Schilder disease represent examples of that condition, including just one of Schilder’s three cases. Seven were prepubertal boys (7–10 years old) and two (including Schilder’s index case) were postpubertal women. The clinical and laboratory features of these cases are shown in Box 5.12. The diagnosis of SD should be reserved for cases whose lesions are, in keeping with the known pathology, large confluent spin-echo bright white matter lesions with sharp margins and sparing of the gray–white junction. Generally there is one lesion in each hemisphere, one somewhat larger than the other. The sharp margin and sparing or cortical ribbon distinguish SD from “typical” ADEM, and the absence of additional smaller lesions or lesions of “varying age” distinguish it from “typical” MS. CSF in these nine cases of SD may be normal or may contain 10–60 monocytic cells (lymphs and monocytes). Elevation of CSF protein is encountered more frequently than in MS, but is seldom higher than 100 mg/dl. Elevation of CSF IgG is found in 50–60% of cases, a prevalence for this abnormality that is higher than in ADEM, lower than in MS or adrenoleukodystrophy, and especially subacute scelrosing panencephalitis (SSPE). There is very little data on the IgG index and oligoclonal bands have been found in just one case of Schilder disease. The diagnosis of SD is now most frequently considered when the MRI scan of a patient with an acute or subacute CNS disease of unknown etiology discloses otherwise unexplained large uni- or bihemispheric areas of confluent bright signal on spinecho sequences. In some instances these lesions may appear to be cavitated. Lesions may also appear to exert mass effects, although these effects are characteristically mild in relationship to their size. Most of these cases have not been biopsied and the diligence with which alternative diagnoses have been excluded has varied greatly. Approximately 70% of chiefly adolescent or adult cases are likely the form of MS that Poser termed

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Box 5.12 • •

•

•

•

Clinical and laboratory features of Schilder disease.

Usually subacute in onset, although may develop abruptly in wake of febrile illness Headache, fevers of unclear etiology, malnutrition, and cachexia are commonly associated with the ensuing chronic course Cortical blindness is common and various field cuts may be found, particularly hemianopsia Hemiparesis, cortical sensory deficits, aphasia, memory disturbances, mental dullness, irritability, changes in personality, confusion, disorientation, behavioral and psychiatric changes are other cortical deficits not infrequently encountered Seizures may occur but are not common. Progressive deterioration of EEG background with appearance of high

“transitional sclerosis” (Poser, 1985). MRI scans disclose multiple lesions typical in appearance and distribution for MS, with one rather large lesion in each hemisphere and CSF findings consistent with MS. In all cases where it is appropriate the consideration of SD should entail excluding such diagnoses as SSPE or other forms of encephalitis, adrenoleukodystrophy, acute MS, ADEM, or tumor. Prepubertal children who present with lesions suggestive of SD may rarely manifest recurrent bouts, some of which are associated with epileptic seizures. The clinical signs in such cases have typically been milder than would be anticipated for the size of the lesions, and apparent cavitation of at least one large lesion is often found. The nature and outcome of these cases remain uncertain. Although individual bouts have responded to high doses of intravenous corticosteroids, the disease may not resolve even with various long-term anti-inflammatory or immunomodulatory forms of treatment. Acute hemorrhagic leukoencephalitis (AHLE, Weston–Hurst disease, hemorrhagic brain purpura) AHLE is a pathological entity consisting of numerous small fairly symmetrically distributed hemorrhages mainly in white matter of the cerebral hemispheres. Hemorrhage is due to vascular necrosis,

• • •

• •

voltage irregular slowing, paroxysmal slowing or spikes (focal, unilateral, bilateral, or generalized) may be observed Some patients manifest psychosis Extrapyramidal manifestations are rare but have been described Deafness is common. Other brainstem or cerebellar deficits that are encountered include vertigo, ophthalmoparesis, nystagmus, facial palsy, dysarthria, or dysphagia Peripheral cranial nerve abnormalities may include optic neuritis and optic atrophy Generalized spasticity and incontinence of bowel and bladder function often develop

which occurs in association with inflammatory perivenular demyelination. The demonstration of typical ADEM pathology in association with the severe necrotic changes of AHLE by Russell permitted AHLE to be classified as a “hyperacute” form of ADEM (Russell, 1955), a theory supported by experimental evidence (Levine and Wenk, 1965). However, changes of both AHLE and ADEM may develop in association with infectious encephalitis due to HSV, VZV, HHV6 and possibly other viruses. Clinical settings in which AHLE has been found are listed in Box 5.13. Although cases do occur in adults, most postinfectious/post-vaccination cases of AHLE have occurred in young individuals (infancy to adolescence). AHLE is usually sporadic, although occurrence in siblings has very recently been reported (McLeod, 2002). Girls and boys are at equal risk. Clinical manifestations of severe cases include abrupt onset of high fever and constitutional symptoms suggestive of sepsis, with rapid development of coma and meningismus with seizures (including tonic seizures) and other “encephalitic” abnormalities. Intracranial pressure elevation may be marked and CSF typically shows increased protein (sometimes in excess of 400 mg/dl), red cells or hemoglobin breakdown products. Elevation of CSF white blood cell count with polymorphonuclear predominance occurs, although white cell counts may prove difficult to interpret due to the

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Box 5.13 •

• • • •

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Etiological association of acute hemorrhagic leukoencephalitis.

Para-infectious (e.g. Influenza A, RSV, mycoplasma, varicella, measles and other exanthematous illnesses) Postvaccination (especially Pasteur rabies vaccine; hepatitis B) Encephalitis (HSV, HHV6, VZV) Fungal cerebritis (e.g. Scopulariopsis phaeohyphomycosis) Drug or toxin exposure (e.g. intrathecal methotrexate)

presence of red blood cells (Leake and Billman, 2002). Imaging studies disclose fairly symmetrically distributed hemorrhages in deep white matter, some of which may coalesce into large somewhat asymmetrical hemorrhagic areas. Thalami, hypothalamus, brainstem, cerebellum, and spinal cord may also be involved, while cerebral cortex and basal ganglia tend to be spared. Involved tissues may be quite edematous. The disease is fulminant with death usually ensuing within hours to days. A number of reports of favorable response to high doses of intravenous corticosteroids (Seales and Greer, 1991) and appropriate additional treatments of increased intracranial pressure suggest that AHLE may be treatable if recognized quickly. Plasmapheresis and cyclophosphamide have also been employed with apparent effectiveness in a few cases. Rapid and effective treatment requires recognition of the presence of AHLE, a diagnosis that has been confirmed in some instances by urgent brain biopsy, followed by successful treatment (McLeod, 2001). Craniectomy appears to have been beneficial in some cases with severe elevation of intracranial pressure. Severe cases have become rarer due to the availability and increased safety of vaccines, permitting children to be effectively vaccinated against many illnesses associated with the possibility of AHLE. However, small quantities of red blood cells (10–500 /mm3) that are often found in lumbar CSF of children with ADEM suggests the possibility that milder degrees of AHLE, falling below the resolution of scan techniques, continue to occur. Moreover, it has been compellingly suggested that cerebral malaria is the result of a hyperergic host response with the production of AHLE (Toro and Roman, 1978).

• • • • • •

•

Blood dyscrasias (e.g. acute myeloid leukemia) Fat embolism Nutritional deficiencies Ulcerative colitis Acute rheumatic fever Membranoproliferative glomerulonephritis, acute tubular necrosis Asthma

Concentric sclerosis, Balò type (CSBT; encephalitis periaxialis concentrica) This illness, which may be a peculiar hyperacute variant of MS, may in addition be influenced by genetic factors that may admix features of both MS and ADEM (Caracciolo et al., 2001; Itoyama et al., 1985; Kira et al., 1996; Moore et al., 1985; Sotgiu et al., 2001). The rarity of this illness appears to be on the order of Schilder disease and its etiological basis similarly uncertain. Peak incidence is in the third decade of life, although cases may arise as early as the second and as late as the sixth decade. The male to female ratio is about 1:2. CSBT appears to have higher incidence in Taiwan, Japan, or the Philippines (Tabira and Nishizawa, 1990; Tabira, 1994). Mild prodromal fever, malaise, and headache are noted in approximately half of CSBT cases, followed by behavioral withdrawal. The acute behavioral change is associated with weakness and numbness, initially on one side of the body (face, limb, or trunk) that then worsens in extent and degree. Development of pyramidal or cerebellar signs and deterioration of higher cortical and oropharyngeal functions ensue. A Dévic syndrome phenotype is occasionally found (Currie et al., 1970). Generalized convulsions occur in approximately 25% of cases. The clinical course may suggest ADEM, especially in younger individuals with this condition. Blood and CSF tests reveal little information of diagnostic importance; mild CSF pleocytosis may be found (Tabira, 1994). Historically, diagnosis was ascertained in severe cases by postmortem or brain biopsy. Pathological study of the concentric layers of greater or lesser degrees of demyelinative and remyelinative inflammation suggest similarities with the appearance of the

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edge of MS plaques (Courville and Cooper, 1970; Moore et al., 1985; Yao et al., 1994). MRI scans have proven useful in identification of milder cases of CSBT. Between 3–5 fairly symmetrical lesions 1.5–5 centimeters in diameter are typically found, more commonly in the deep cerebral (frontoparietal > temporal) or cerebellar white matter than in other rarer locations, such as spinal cord (Currie et al., 1970). During the early acute stage of CSBT gadolinium enhancement may clearly delineate alternating concentric zones of greater or lesser inflammation, quite distinct from what is seen in typical ADEM or MS. In the late acute stage only a single ring of enhancement at the outer margin of lesions may be found more closely resembling MS (which the age at presentation usually suggests) or ADEM (which the febrile prodrome may suggest). The concentric rings may reappear during the ensuing subacute phase of illness (Caracciolo et al., 2001; Chen et al., 1999; Chen, 2001; Ghatak et al., 1989). MR spectroscopic abnormalities of CSBT resemble those found in MS plaques, although similar changes are found in other diseases, including mitochondrial cytopathies (Chen, 2001). In addition to ADEM and MS, tumor, vasculitis, or infection may resemble CSBT (Caracciolo et al., 2001). Caution is especially important where the pattern of alternating enhancement is less centrifugal and more irregular in arrangement. Biopsy may sometimes prove misleading. Reported CSBT cases, chiefly from the pre-MRI era, have generally proved fatal within 2–60 weeks. Early deaths are due to herniation, late deaths to inanition and secondary infections (Courville and Cooper, 1970; Tabira, 1994). Milder cases identified by MRI and increased availability of supportive therapies have modestly improved the overall outlook for this condition. Early provision of immunosuppressive treatments may ameliorate clinical and imaging abnormalities. Some cases arising in fourth–sixth decades have longer survival and more prominent gliosis of demyelinated layers. Optic neuritis (ON) Optic neuritis is considered in detail elsewhere in this volume. In this section childhood ON and its relationship to ADEM and MS will briefly be reviewed. ON may also occur in association with various inflammatory illnesses other than ADEM or MS (Kazarian and Gager, 1978; O’Halloran et al., 1998; Riedel et al., 1998). ON is rare prior to six years of age and more common from six years of age to puberty.

Prior to puberty it usually occurs in association with ADEM or NMO. In approximately 70% of cases, acute visual loss occurs days to weeks after a nonspecific viral illness (especially measles, mumps, and varicella) or immunization (Kazarian and Gager, 1978; Kline et al., 1982; Purvin et al., 1988; Riikonen, 1989). After puberty, it may occur in isolation or in association with NMO or MS and the association with a prodromal illness is less common. In isolated postpubertal cases the risk for subsequent diagnosis of MS is approximately 50%. Visual loss of childhood ON may be preceded by headache (frontal or ocular), scintillating scotomata, or painful eye movements. Visual loss may be unilateral or bilateral. Three-quarters of prepubertal cases develop bilateral changes either simultaneously or sequentially, the changes in the second eye lagging behind the first by weeks to months. Degree of visual loss is usually fairly symmetrical in bilateral cases, however, in a significant minority of cases it is asymmetrical (Riikonen et al., 1988). Initially the visual disturbance may be limited to visual blurring with progression over several days to partial to complete visual loss. In cases with partial visual field loss there may be a particularly dense central scotoma. Swelling of the optic nerve head (papillitis) is more common in children than it is in adults with ON, occurring in at least two-thirds of cases (Kriss et al., 1988; Parkin et al., 1984). Quite striking abnormalities, including fiber layer hemorrhages at the optic nerve margin, vascular tortuosity, or sheathing of veins, are readily observable on funduscopy in many cases (Riikonen et al., 1988). These changes may suggest papilledema, however, the visual loss of ON can, in most cases, readily be distinguished from that due to malignantly increased intracranial pressure (ICP). Increased ICP is usually associated with additional neurological signs (e.g. sixth nerve palsy, meningismus). It manifests slower onset and as it usually provokes less profound degree of visual loss is less frequently associated with an afferent pupillary defect. As in many cases of adult ON, childhood ON may occur without observable funduscopic changes, in which case the term retrobulbar ON is applied. The diagnosis of ON is made on the basis of a combination of clinical and laboratory findings. In subtle cases, diagnosis can be clinically supported by loss of red vision (“red desaturation”), or by loss of duration or variety of the “flight of colors” that are apprehended in a dark room immediately after 60 seconds of stimulation of a retina with bright light. Greater

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degrees of visual loss are signified by the presence of an afferent papillary defect (APD – loss of the reflexive constriction of the contralateral pupil when the retina of the affected eye is illuminated). Visual evoked responses (VER) are particularly useful where visual loss is mild enough to be uncertain. ON results in increased latency of the positive component of this cortical response (Feinsod et al., 1975). Delayed VER may persist for several years in patients who have shown excellent clinical recovery (Aicardi, 1992). Abnormalities of other portions of the nervous system should be sought and if found a more general diagnosis (e.g. ADEM, Dévic syndrome, Guillain– Barré syndrome (GBS), MS) should be applied on the basis of clinical features and history. Positivity of the CSF immune profile studies noted above (excepting myelin basic protein) or of other studies such as CSF free kappa chains (Rudick et al., 1986; Riikonen et al., 1988a) favors the diagnosis of MS but does not exclude the diagnosis of ADEM. MRI scanning of brain and brainstem with appropriate weighting (T1, T2, balanced, and with gadolinium administrations) and special orbital views is important. MRI demonstrates swelling of the optic nerve in most cases; the extent of optic nerve enlargement may be alarming in some children who nevertheless experience good recovery. MRI is the most important tool in excluding alternative diagnoses such as lesions compressing the optic nerve. Disseminated T2 bright lesions may be found by MRI elsewhere in the brain in as many as 70% of patients (Riikonen et al., 1988), interpretation of such changes in children is difficult and may not indicate MS. Where such abnormalities are at the gray–white junction and the patients are younger, ADEM is suggested. Periventricular plaques (especially if perpendicular to the ventricular surface) are more suggestive of MS (Ormerod et al., 1986). SSPE, intoxications (e.g. methanol), leukodystrophies, and stroke must occasionally be considered. Malingering may be excluded on the basis of inconsistencies on examination or with VER testing. Generally, recovery from idiopathic childhood ON is excellent, although the rate of recovery may be slow (Good et al., 1992). The most common residua include optic nerve atrophy and impairments of color and stereoscopic vision (Parkin et al., 1984; Purvin et al., 1988). Permanent severe visual loss is quite exceptional. Bilateral presentation after an antecedent illness or immunization usually (although not always) implies good prognosis for visual recovery

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(Parkin et al., 1984; Riikonen et al., 1988b; Good et al., 1992). Postpubertal ON is more likely to have residual deficits. In adults, treatment with intravenous high-dose methylprednisolone of first bout of ON hastens recovery and may prolong the time to diagnostic recurrence of MS. Oral prednisone provides no benefit and may heighten odds of early recurrence of a bout diagnostic of MS (Beck et al., 1992; Beck et al., 1993; Silberberg, 1993). These cases were chiefly first bouts of MS and the relevance of this data to children, many of whom do not go on to develop MS, is unclear. Recovery occurs with or without anti-inflammatory therapy in most children and there is little evidence that final recovery is favorably influenced by treatment. High-dose intravenous treatment for 3–5 days in cases of quite profound optic nerve swelling may prevent ischemic injury and other childhood ON may manifest more rapid recovery with such treatment. Limited data suggests treatment may reduce chances for ultimate diagnosis of MS ( Jacobs et al., 1994). ON may recur. Various studies, following up for 2–18 years, have estimated a 0–60% risk for MS if a bout of ON occurs before 18 years of age (Kriss et al., 1988; Parkin et al., 1984; Riikonen et al., 1988). A more refined estimate suggests 15–30% overall risk (ON Study Group, 1997), chiefly sustained by those over 12 years of age, in whom there is about a 50% risk. Poor or incomplete visual recovery, itself chiefly a postpubertal phenomenon, also implies a 50% risk for ultimate diagnosis of MS (Good et al., 1992). The presence of lesions consistent with MS plaques in typical locations (periventricular, forceps major and minor) on MRI increases the risk for subsequent diagnosis of CD-MS to at least 75–80%. The presence of oligoclonal bands in the CSF also increases the risk for diagnosis of MS within five years, although not so decisively as the MRI features just noted. Oligoclonality increases risk even where the MRI is normal (Cole et al., 1998). Risk of MS is high in unilateral ON (which is mostly postpubertal) and trivial in bilateral prepubertal cases (Parkin et al., 1984). In cases where ON is associated with ADEM, GBS, or Dévic syndrome, the prognosis should be determined on the basis of the more disseminated illness, but visual recovery is usually good. Acute transverse myelitis (ATM) Various causes for acute childhood/adolescent myelopathy are listed in Box 5.14. The most common

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Box 5.14 •

•

Causes of acute transverse myelitis.

Isolated ATM – Abscess* – Hemorrhage – Stroke (vascular malformation, compressive, embolic*) – Radiation – Tumor (spinal,* spinal root, meningeal, vascular, bone) – Trauma* More widespread neurological disease – Dévic syndrome (see below)*** – Encephalomyeloradiculoneuropathy*** – Multiple sclerosis*** – ADEM*** – Guillain–Barré syndrome – Neurosarcoidosis**

causes are inflammatory, traumatic, or vascular. In children, post-infectious/post-vaccination inflammatory myelitis is a particularly important category. These cases are often a form of ADEM, including Lyme myelitis (Kerr and Ayetey, 2002; Rousseau et al., 1986; Tyler et al., 1986). Infections precede ATM by days to several weeks in 60% of cases (Paine and Byers, 1953). The additional history of blunt trauma to the spine is not infrequently recalled. The cervical location is a common one as is thoracic. Many more levels of the spine may be involved than is typical of MS. In some instances the entire spine is involved as well as some of the brainstem. In some instances the inflammatory sensitization involves both central and peripheral (e.g. spinal root) myelin (Abramsky and Teitelbaum, 1977). The irreversible injury with myeloclasia that complicates severe ATM is likely to be vascular: due to the ischemia induced by cord swelling within the confined space of the spinal canal. ATM that occurs in the first few years of life may be particularly malignant, but most cases occur in children more than five years of age (Aicardi, 1992; Berman et al., 1981). Pain and dysaesthesiae in the region of the developing ATM are the most common early symptoms. Fever and meningismus may then follow. Paraplegia, sensory loss, and sphincter dysfunction may develop slowly over days to many weeks or paroxysmally within several hours. The rate of onset is often proportional to the intensity of the initial discomfort.

•

– Tropical spastic paraparesis** (Link et al., 1989) In association with systemic disease – AIDS vascular myelopathy*,** (Rosenblum et al., 1989) – Chronic progressive (third stage) Lyme neuroborreliosis**,*** – Systemic lupus erythematosus** – Syphilis

*Seldom if ever found in children; **Imaging changes may resemble ADEM or MS; ***May be manifestation of ADEM or MS. Interferon beta-1b in the treatment of multiple sclerosis: final outcome of the randomized controlled trial. The IFNB Multiple Sclerosis Study Group and The University of British Columbia MS/MRI Analysis Group, Neurobrucellosis.

Intense pain in neck presaging hyperacute cervical ATM is a medical emergency that may have a fatal outcome due to cardiorespiratory compromise. In most instances bilateral flaccid areflexic paraparesis with a sensory level and sphincter dysfunction develop, followed in a few days by spastic weakness in the same distribution. Superficial reflexes (abdominal, cremasteric, bulbocavernosus) are usually absent. Partial spinal cord syndromes (e.g. Brown–Sequard syndrome) or Dévic syndrome may be found. Rarely ATM presents with the isolated complaint of urinary retention (Ropper and Poskanzer, 1978). ATM with febrile infectious prodrome and associated constitutional symptoms is more common in prepubertal patients and suggests ADEM. ATM without these associated features is more common in adolescents and is suggestive of MS. MS tends to provoke a less complete form of myelitis than ADEM. The MRI of patients with MS-related myelitis typically demonstrates T2 bright signal abnormality of some, but not all, areas of the cord that are enriched with myelinated fibers. The outlook for recovery may be poorer and that for severity of MS may be greater in adolescents that are found to have signal abnormality through many rather than few levels of the spinal cord. Adolescent patients with purely spinal manifestations suggesting MS should be screened for tropical spastic paraparesis/HTLV-1 associated myelopathy (TSP/HAM), while men should be evaluated for adrenomyeloneuropathy (Walther and Cutler, 1997).

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Some combination of history, examination, imaging studies, and CSF and serum tests discloses an etiological diagnosis (from among those listed in Box 5.14) for ATM in approximately two-thirds of the cases encountered in children and adolescents. MS-associated ATM is almost entirely confined to postpubertal individuals, ADEM-related ATM to prepubertal individuals. Imaging studies of brain and spinal cord are important in order to disclose distribution and in some instances cause of disease, as well as lesions or edema that require urgent therapy in order to prevent irreversible ischemic injury. Unsuspected brain lesions may be found in MS, ADEM, neurosarcoidosis, and other diagnoses (Miller et al., 1987; Sanders et al., 1990). Myelography is sometimes helpful (Narciso et al., 2001). CSF pleocytosis is present in 25%, increased CSF protein in 50% of presumed ATM cases (Aicardi, 1992). No therapy, including corticosteroids, has been rigorously proven to be efficacious in the treatment of ATM. Management is largely symptomatic, with particular attention to careful management of such associated problems as urinary retention and impaired breathing. Pain and dysaesthesiae may be troublesome and vigorous attempts should be made to treat these symptoms, particularly where they interfere with sleep. Some degree of recovery occurs in 80–90% of children, requiring weeks to months. Approximately half of children with ATM will show excellent recovery; 10–20% develop cord necrosis and do not recover. Most of the remainder have variable residua (Ropper and Poskanzer, 1978; Berman et al., 1981). The most important prognostic factor is acuteness of onset; recovery is poor after hyperacute onset (Dunne et al., 1986). A very small number of children with cervical ATM die from cardiorespiratory arrest or upwards herniation. Despite the lack of established efficacy, very high doses of anti-inflammatory agents may be tried in cases of progressive cervical ATM, particularly those with hyperacute and potentially lifethreatening presentation. Ultimate diagnosis of MS is made in only about 10% of adults who experience ATM; the diagnosis of MS after isolated childhood ATM is probably even more exceptional (Aicardi, 1992). Neuromyelitis optica (NMO, Dévic syndrome) In children with NMO the signs of ATM and ON may develop simultaneously or in rapid succession. Most prepubertal cases develop within days to weeks

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after a viral illness or immunization. The transverse myelitis is typically sudden and severe, producing paraplegia. ON often develops in both eyes bilateral, onset in the second eye occurring days to months after the first. Funduscopic changes of papillitis are usually, but not always, present. The prodromal illness is less commonly discerned in postpubertal cases, the myelitis less complete, and there is a greater tendency for the ON to be unilateral. More detailed description of this entity and recent advances in understanding of pathogenesis, classification, differential considerations and diagnostic testing are considered elsewhere in this volume. There is no generally accepted therapy for DS. However, very high doses of intravenous corticosteroids may be considered where optic nerve or spinal cord swelling is particularly alarming, in order not only to attenuate the inflammatory process, but also to close blood– brain barrier and prevent swelling that may lead to tissue ischemia. Encephalomyeloradiculoneuropathy (Miller–Fisher/Bickerstaff encephalitis) Some cases of ADEM with prominent myelitis will have peripheral nerve signs, representing clinical overlap with GBS. This overlap is particularly prominent in patients with AIDS. Tumors with involvement of the cauda equina or nerve roots must also be considered. The anti-Hu-associated paraneoplastic syndromes that should also be considered in adults have not yet been shown to occur in children (Dalmau et al., 1992). Acute necrotic encephalitis (ANE) The pathogenesis of this early childhood illness that has chiefly been reported in Japanese and Taiwanese (Mizuguchi et al., 1995; Voudris et al., 2001) remains obscure. Although some type of inflammatory encephaloclasia is a likely explanation, it is unclear whether this might be due to a primary infectious process. As with ADEM, there is a male predominance (boy to girl ratio = 2:1). Most cases arise between 6–24 months of age, although cases have occurred in children as old as five years. The onset is typically marked by fever and rapid deterioration of mental status in association with convulsive seizures and brainstem signs. Abnormalities of liver enzyme testing may be found. MRI scans of severely affected children disclose symmetrical bright lesions on T2 weighting that

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involve the thalami, hypothalamus, brainstem tegmentum, and cerebellum. Bright signal may also be found in cerebral white matter. Some of these abnormalities (particularly those representing edema) and clinical status may improve with high doses of intravenously administered corticosteroids. Some particularly malignant cases appear to have favorably responded to heroical treatment with surgical decompression of intracranial pressure. The gray matter lesions may become cavitary and death has occurred in approximately half of recognized cases. This severe disease must be differentiated from those cases of presumed ADEM whose imaging manifestations may be confined to or emphasized in white matter and thalami. The patients with these ADEM-related manifestations tend to be older (0.4– 6 years of age) and their disease evolution is much less severe than is observed by the infants with ANE. The outcome is favorable, with resolution of scan changes once recovery occurs (Cusmai et al., 1994; Marcu et al., 1979; Suwa et al., 1999; Tenembaum et al., 2002). It is not entirely clear whether some reports of milder cases of ANE from which infants recover without subsequent relapse are cases of mild ANE or of ADEM. ANE must not be confused with some cases that fall within the ADEM/childhood MS/“recurrent ADEM” spectrum that manifest large pseudo-cavitary lesions of deep white matter sparing basal ganglia or thalamus, or with AHLE or Balò disease, all diseases for which high doses of intravenous corticosteroids may prove beneficial. The differential diagnosis also includes tumor, infectious, metabolic, or vascular (e.g. sinovenous thrombosis) diseases of brain. Subacute-onset disseminated CNS illnesses that may be forms of ADEM Considerable recent interest has focused on the possibility that certain complex subacute-onset illnesses with extra pyramidal, psychiatric, and behavioral manifestations may represent post-infectious diseases that have mechanisms similar to ADEM or might respond to therapies advocated for ADEM and related illnesses. The basis for such speculation derives in part from the strong evidence that one such illness, Sydenham chorea, is a post-infectious condition that is known to be provoked by certain strains of Group A β-hemolytic streptococci. Recent studies have attempted to characterize another entity, termed pediatric autoimmune neuropsychiatric disorder (PANDAS). Attention has also been directed to the

study of the neuropsychiatric disturbances that may develop in patients with rheumatic fever without associated chorea, observations that some believe will have pertinence to the development of isolated psychiatric disturbances (Mercandonte, 2000) or such controversial entities as “chronic fatigue syndrome.” During the past two decades, a number of cases of indolent psychiatric disturbances associated with “ADEM-like” MRI abnormalities have been reported, as has the gradual improvement of images and affect with corticosteroid treatment. Investigators have suggested that these are examples of “subacute” limbic or disseminated encephalomyelitis ( Johnson et al., 1985). These cases have tended to have no clear association of deterioration with a preceding febrile illness or vaccination and CSF immune profile studies if obtained have been normal. Meningoencephalitic encephalitis and other infections with possible ADEM-related complications The role that inflammatory dysregulation plays in the pathogenesis of CNS infectious conditions has received increasing scrutiny in the past decade and falls outside of the scope of this review. The extent to which mechanisms closely resemble those of ADEM or MS, the role of genetics, and the pertinence of anti-inflammatory therapy for these conditions are as yet incompletely understood. These conditions constitute part of the differential diagnosis of ADEM and MS, and may produce similar imaging or CSF abnormalities. The presence of pial or cortical gadolinium enhancement on T1-weighted images is suggestive of encephalitis rather than ADEM. The borderland between HSV2 encephalitis and ADEM is especially unclear when there are widespread lesions, some such cases responding very well to acyclovir treatment (Chu et al., 2002), some apparently benefiting from the addition of antiinflammatory therapy. Acute or “relapsing” HSV2 encephalitis may be especially difficult to distinguish from ADEM (Chu et al., 2002). Some widespread HSV2 “recurrence” is a form of ADEM, responsive to corticosteroid treatment with a good outcome (Tulyapronchote and Rust, 1992). Chronic progressive Lyme encephalomyelitis or third-stage neuroborreliosis may also be a form of ADEM (Braune, 1991; Pavlovic et al., 1993; Reik et al., 1985). Japanese B, measles, and mumps encephalitides, cerebral malaria, and the CNS manifestations of Dengue all likely entail immuno

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dysregulation that may involve ADEM-related mechanisms and may prove responsive to therapies aimed at this form of pathogenesis. The presence of pial enhancement, which is not a finding in ADEM, suggests active meningoencephalitis. Metazoal parasitic diseases of brain (e.g. cysticercosis) may produce imaging changes that closely resemble ADEM,

Box 5.15 I

II

although the pathogenic mechanisms of ADEM are probably not involved. Summary Box 5.15 includes hypothetical criteria for various ADEM spectrum diagnoses in children.

Criteria for various suggested diagnostic groupings of ADEM family.

Tentative ADEM (T-ADEM) 1 Preceding exogenous provocation (required) a Febrile, likely infectious illness or vaccination within 28 days b At least 12 hours afebrile improvement prior to ADEM-related deterioration 2 Neurological deterioration: required a At least two separate clinical lesions, otherwise unexplained b At least three of the following: (1) Recurrence of fever, irritability, or lethargy at onset (2) Bilateral optic neuritis (3) MRI typical for ADEM (see text) (i) Cortical ribbon– subcortical white matter junction (ii) Indistinct margins (“smudge” appearance) (4) Focal or generalized EEG slowing (5) Elevated myelin basis protein with normal CSF immune profile (6) Clear improvement ≤24 hours after high-dose intravenous steroids 3 Other relevant diagnoses, including MS, excluded by appropriate testing Probable ADEM (P-ADEM): Meet T-ADEM criteria without recurrence in 2 years*

III

Definite ADEM (D-ADEM): Meet P-ADEM criteria, no recurrence for additional 10 years

IV

Tentative Recurrent ADEM (TR-ADEM): Initial bout + ≤ four total bouts* each meeting criteria for diagnosis T-ADEM

V

Probable recurrent ADEM (PR-ADEM): Meet TR-ADEM criteria followed by a hiatus of ≥ 2 years without further recurrence* Not treated with immunomodulatory prophylaxis during those 2 years without bouts

VI

Definite recurrent ADEM (DR-ADEM): Meet PR-ADEM criteria followed ≥ 10 additional years without recurrence Not treated with immunomodulatory prophylaxis during those 10 additional years (*Excepting taper-related recurrences)

VII

Type 1 steroid-dependent idiopathic demyelinating illness (SDIPI) 1 Recurrent cases not satisfying CD-MS or ADEM diagnostic categories 2 Unavoidable recurrences provoked at same approximate threshold of steroid taper unless replaced with at least monthly high dose intravenous corticosteroids 3 Excludes alternative diagnoses

VIII

Type 2 steroid-dependent idiopathic demyelinating illness (SDIPI) 1 Recurrent cases not satisfying CD-MS or ADEM diagnostic categories continued

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Box 5.15

(Cont’d)

2 Unavoidable recurrences provoked at same approximate threshold of steroid taper unless replaced with immunomodulatory interferon therapy 3 Excludes alternative diagnoses IX

Other idiopathic recurrent demyelinating illness (OIRDI) 1 Recurrent cases not satisfying CD-MS, ADEM, R-ADEM, T-ADEM, or SDIDI criteria

References Abramsky, O. and Teitelbaum, D. 1977. The autoimmune features of acute transverse myelopathy. Ann Neurol, 2, 36– 40. Aicardi, J. 1992. Diseases of the Nervous System in Childhood. MacKeith Press, London. Apak, R.A., Anlar, B. and Saatci, I. 1999. A case of relapsing acute disseminated encephalomyelitis with high dose corticosteroid treatment. Brain Dev, 21(4), 279– 82. Arya, S.C. 2001. Acute disseminated encephalomyelitis associated with poliomyelitis vaccine. Pediatr Neurol, 24(4), 325. Atlas, S.W., Grossman, R.I., Goldberg, H.I. et al. 1986. MR diagnosis of acute disseminated encephalomyelitis. J Comp Assist Tom, 10(5), 798– 801. Au, W.Y., Li, A.K., Cheung, R.T. et al. 2002. Acute disseminated encephalomyelitis after para-influenza infection post bone marrow transplantation. Leuk Lymphoma, 43(2), 455– 7. Baum, P.A., Barkovich, A.J., Koch, T.K. et al. 1994. Deep gray matter involvement in children with acute disseminated encephalomyelitis. AJNR Am J Neuroradiol, 15(7), 1275–83. Beck, R.W., Cleary, P.A., Anderson, M.M., Jr. et al. 1992. A randomized, controlled trial of corticosteroids in the treatment of acute optic neuritis. The Optic Neuritis Study Group (see comments). N Engl J Med, 326(9), 581–8. Beck, R.W., Cleary, P.A., Trobe, J.D. et al. 1993. The effect of corticosteroids for acute optic neuritis on the subsequent development of multiple sclerosis. The Optic Neuritis Study Group (see comments). N Engl J Med, 329(24), 1764–9. Berman, M., Feldman, S., Alter, M. et al. 1981. Acute transverse myelitis: incidence and etiologic considerations. Neurology, 31(8), 966–71.

2 Alternative diagnoses excluded by specific testing X

Idiopathic progressive disseminated encephalomyelitis 1 Requires exogenous stimulus 2 Excludes cases with identifiable toxic, heritable, infectious condition (e.g. heritable leukodystrophy, Aicardi-Goutieres, TORCH infection, AIDS, etc.)

XI

Special cases 1 Lyme neuroborreliosis

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6 Guillain–Barré syndrome Eduardo A. De Sousa and Thomas H. Brannagan III

Guillain–Barré syndrome (GBS) is the most common cause of nontraumatic acute and subacute generalized paralysis in adults in the industrialized world. It is an acute acquired inflammatory neuropathy that usually affects the motor nerve roots or its axons. GBS probably represents several distinct diseases that are grouped within a single syndrome. Typically GBS presents with acroparesthesias or numbness, and evolves to ascending weakness within days to weeks. Areflexia is a hallmark. As the weakness progresses, the patient may become completely paralyzed, requiring assisted ventilatory support. Typically there is normal cerebrospinal fluid (CSF) cellularity with an increased CSF protein level. Several variants have been reported. Epidemiology Throughout the world, the annual incidence of GBS is 1.3 cases for 100,000, affecting children and adults. GBS is the most common acute acquired neuropathy of childhood. In adults the prevalence is higher in older patients (>75 years) as compared to younger patients (6 months CSF protein >45 g/dl, nerve biopsy (demyelination/ remyelination), NCS: motor conduction velocity may be normal but more commonly slowed

Progression Diagnostic studies

Diagnostic certainty

Reflexes

Tendency to symmetric, proximal, and distal weakness, though some have predominantly motor, sensory, or autonomic involvement Large-fiber sensory involvement Hyporeflexia or areflexia

Dyck, 1975

Definite: clinical phenotype, NCS, CSF, and biopsy Probable: clinical phenotype, NCS, and CSF Possible: clinical phenotype and NCS

Definite: clinical major, NCS, and CSF Probable: clinical major, NCS or CSF, and biopsy Possible: (1) clinical major and one out of three diagnostic studies, or (2) clinical minor and two out of three diagnostic studies

>2 months Mandatory: CSF protein >45 g/dl, nerve biopsy (demyelination), NCS (Table 7.2) Supportive: CSF 2 months Mandatory: CSF (2 months Inclusion criteria: CSF 2 months Elevated CSF protein is supportive, nerve biopsy (demyelination) may be supportive, NCS (Table 7.2) seen in most patients with weakness, though not in all patients

Classic CIDP: symmetric, progressive, proximal, and distal weakness and predominantly large-fiber sensory impairment Variants: purely motor, predominantly sensory, asymmetric or multifocal weakness or sensory loss, cranial nerve involvement, only proximal or distal weakness Hyporeflexia or areflexia

Neuropathy Association, 2003

Definite: clinical criteria (typical or atypical) and definite NCS (Table 7.2); or probable + at least one supportive criterion; or possible + at least two supportive criteria Probable: clinical criteria and probable NCS (Table 7.2); or possible CIDP + at least one supportive criterion Possible: clinical criteria and possible NCS (Table 7.2); or CIDP (definite, probable, possible) associated with concomitant diseases

Typical: chronically progressive, stepwise, or recurrent symmetric proximal and distal weakness and sensory dysfunction of four extremities. Cranial nerves may be affected Atypical: predominantly distal weakness; purely motor or purely sensory; asymmetric; focal; CNS involvement Typical: hyporeflexia or areflexia Atypical: normal in unaffected limbs >2 months Supportive criteria: elevated CSF protein with 80% LLN

Same as AAN

Same as AAN

If CMAP amplitude ≥75% LLN

Same as AAN

If CMAP amplitude ≥20% LLN

Same as AAN

DML ≥150% @ULN

DCMAP duration ≥9.0 ms DCMAP duration ≥9.0 ms

Same as AAN

>30% (median, ulnar, and peroneal nerves)

Definite CB: ≥50% if CMAP amplitude ≥20% LLN¶ Probable CB: ≥30% if CMAP amplitude ≥20% LLN

Definite: ≥1 of the following (a–g): (a) prolonged DML ≥2 nerves; (b) CVS ≥2 nerves; (c) prolonged F-min ≥2 nerves; (d) absent Fs ≥2 nerves plus §; (e) definite CB ≥2 nerves, or definite CB in 1 nerve plus §; (f) TD ≥2 nerves; (g) prolonged DCMAP duration in one nerve plus §. Probable: either probable CB ≥2 nerves, or probable CB in one nerve plus §. Possible: As in definite, but in only one nerve. CV ≤70% LLN¶

ENFS/PNS, 2005

>30% (median, ulnar, and peroneal nerves)

≥30% (forearm segment for median and ulnar, lower leg segment for peroneal nerves)

Same as AAN

Nerve conduction abnormalities ≥3 nerves with ≥1 nerve with demyelinating abnormalities (CVS, CB, TD, DCMAP duration, DML, or F-waves)

Neuropathy Association, 2003

¶: LLN: lower limit of normal; @ULN: upper limit of normal; §: plus another demyelinating parameter in one other nerve; ¥: CVS, prolonged DML, absent or prolonged F-min.

Distal CMAP (DCMAP) dispersion Severely prolonged distal motor latency (DML) Severely prolonged F-wave minimal latency (F-min) Absent F-waves Same as AAN

>30% (median, ulnar, radial, tibial, and peroneal nerves)

Temporal dispersion (TD)

Same as AAN

>15% (median, ulnar, and peroneal nerves)

>40–60% amplitude drop, or >40 –50% area drop

(1) DML >150% @ULN if CMAP amplitude 125% ULN if CMAP amplitude >80% LLN (1) F-min >150% @ULN if CMAP amplitude 120% ULN if CMAP amplitude >80% LLN

≥30% for the median, ulnar, and peroneal nerves, or ≥50% with Erb’s point stimulation

Same as AAN

(1) CV 65), CIDP typically has a slowly progressive distal pattern, unlike in younger patients, where proximal weakness is more common and a relapsing course is seen more frequently. Predominantly sensory (31%) or equal sensory and motor involvement (51%) is more common in the elderly, and a pure motor syndrome is less common (17%). In contrast, adults (20–64) or juveniles (50%), the initial symptoms involve the ocular muscles with patients complaining of symptoms related to ptosis or oculomotor dysfunction or both (Grob, 1953). Approximately 15% of patients present with bulbar symptoms: dysphagia (6%), dysarthria (5%), and difficulty chewing (4%). Isolated proximal limb weakness is the presenting symptom less than 5% of the time (Grob, 1953). Rare presentations include neck, respiratory, or distal limb weakness. Weakness remains localized to the ocular muscles in 15% of patients, termed ocular MG. In 85% of cases, signs of generalized weakness develop, usually within the first two years of the disease. With generalized MG, the weakness often begins in a few muscle groups and, over the course of weeks to several months, extends to other parts of the body. Almost all patients with MG experience ocular symptoms during the course of the disease, usually within the first year or two. The diagnosis of MG ultimately is made clinically, the characteristic signs and symptoms often suggesting the diagnosis. Patients may report that they are weaker later in the day. Weakness is typically bilateral and asymmetric, but can be relatively symmetric. Some describe worsening with significant heat exposure or severe stress. Patients with ptosis typically notice the degree fluctuating throughout the day. Some may not notice drooping of their eyelids until it obscures their vision. Weakness of the extraocular muscles causes intermittent or persistent diplopia or the perception of blurred vision, which resolves when one eye is covered. Symptoms in the limb muscles are typically more proximal than distal, so common complaints include fatigability and weakness

with tasks such as brushing hair, walking long distances, or climbing stairs. Localized muscle atrophy occurs in roughly 6 to 10% of patients usually in muscles with longstanding weakness (Oosterhuis and Bethlem, 1973). There are several forms of dysarthria: the nasal speech of palatopharyngeal weakness, the articulation disturbances of tongue or facial weakness, and the hypophonic or “breathy” quality of weakness of laryngeal muscle. With dysphagia, mild involvement may present as the feeling of food “getting stuck in the throat,” and when more severe as nasal regurgitation of liquids or frank aspiration. Masticatory muscle weakness presents with diminishing chewing force, often worse towards the end of the meal or with solid foods. If weakness is severe, the lower jaw may sag open. Facial muscle weakness can cause diminished facial expressions, inability to whistle, or even difficulty keeping liquids in the mouth when drinking. Involvement of the orbicularis oculi causes difficulty with eye closing. Neck weakness usually affects the flexors more than the extensors. When neck extensor weakness is severe, patients may assume a characteristic pose with their hand under their chin to hold their head upright. The most ominous symptoms are those of respiratory muscle weakness. With myasthenic dyspnea, breathing is usually shallow, worse lying flat, and more pronounced with exertion. Patients also may note a weak cough. “Myasthenic crisis” is a life-threatening condition, and occurs when patients develop weakness of respiration or swallowing so severe as to require mechanical ventilation or feeding. Patients with antibodies to muscle specific tyrosine kinase (MuSK) may display slightly different features than other myasthenics. Most reports note a greater tendency to develop bulbar or neck weakness and less limb weakness. They have a tendency to develop facial muscle atrophy (Evoli et al., 2003; Zhou et al., 2004). These patients are more prone to myasthenic crisis. The clinician should consider this when devising a treatment plan. The majority of these patients are female, and the mean age tends to be younger than patients seropositive for AchR antibodies. Natural history Early in the course of the disease, symptoms can be persistent or transient, with periods of remission for days, months, or even years. About 20% of patients experience full or nearly full clinical remissions lasting for at least six months (Grob, 1953; Grob, 1958). Most patients (84%) suffer recurrent relapses. Before

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current treatments and therapeutic strategies were commonplace, patients often reached maximum disease severity within the first one to three years (Grob et al., 1981; Grob et al., 1987). Later in the course of the disease, many patients’ symptoms become more chronic. Exacerbations can be triggered by systemic illness, infection, physical or emotional stress, drugs that impair neuromuscular transmission, thyroid dysregulation, pregnancy, delivery, or rarely from an overdose of cholinergic medication. Often, exacerbations have no identifiable precipitant. A list of drugs known to inhibit neuromuscular transmission is readily available on the Myasthenia Foundation website (www.myasthenia.org). Mortality from MG is usually related to respiratory or bulbar weakness. Death rates have declined dramatically over the decades with the advent of immunotherapy and supportive therapies. Mortality was 31% from 1949 to 1957, 15% from 1958 to 1965, 6% from 1966 to 1985, and these days quite rare (significantly below 5%) (Grob et al., 1981; Grob et al., 1987). With proper treatment, most patients today can attain a high functioning status and lead productive lives. Epidemiology Myasthenia is an uncommon disease with a prevalence of approximately 10 per 100,000. Over the last 50 years, epidemiological studies show a rising prevalence (Phillips et al., 1996). Most likely, this is due to longer lifespans for patients with myasthenia, improved surveillance and diagnostics, and an increasing proportion of society in the age range at risk for myasthenia gravis (Zhou et al., 2004). As with some other autoimmune diseases, the typical age of onset differs with gender. Women tend to develop MG in the second or third decade of life, while men have a higher incidence over the age of 50. The overall incidence is similar in women and men, but since men tend to develop MG later in life, the prevalence in women is approximately twofold higher (Poulas et al., 2000). About 10% of myasthenic patients have a thymoma, and their syndrome represents a paraneoplastic syndrome. Thymomas tend to spread locally. They are rarely invasive. The incidence of a co-occurring autoimmune disorder is approximately 10%, particularly thyroid disease, lupus, and rheumatoid arthritis (Cristensen et al., 1995; Thorlacius et al., 1989). About 10–20% of newborns from mothers with myasthenia gravis develop transient myasthenic

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symptoms due to transplacental transfer of the mother’s autoantibodies, termed “transient neonatal myasthenia”. Pathophysiology The following line of evidence, a parallel to Koch’s postulates for infectious agents, supports the autoimmune antibody-driven nature of MG. Most cases have an associated antibody. The antigen is relevant to the clinical symptoms and pathology. Symptoms and signs of the disease can be transferred to experimental animals by the transferal of affected serum or IGg. An animal model of the disease can be made by immunizing an animal with the antigen. Removing the antibody improves symptoms. To treat myasthenia, the clinician should have a good understanding of physiology and pathophysiology of the neuromuscular junction, especially the significance of the safety factor. The motor nerve stimulates muscle with acetylcholine, which it synthesizes and stores in vesicles at the presynaptic terminal. A normal action potential releases 150–200 of these vesicles into the synaptic cleft; each containing approximately 10,000 molecules of ACh. The postsynaptic membrane contains muscle endplate zones with nicotinic ACh receptors aggregated on the crests of specialized folds. The AChR is a transmembrane ion channel that opens to allow an influx of ions when ACh is bound. Within milliseconds of the transmission, synaptic acetylcholinesterase hydrolyzes the ACh. When a sufficient number of AChRs in the endplate zone are simultaneously opened, the depolarizing end-plate potential (EPP) reaches a threshold and triggers muscle contraction. Under normal circumstances, the number of ACh receptors opened by a volley of ACh creates an end-plate potential that well exceeds the threshold required to make a muscle action potential. This excess end-plate potential is a “safety factor” that ensures neuromuscular transmission. With sustained firing of a motor nerve, the number of ACh vesicles available for release diminishes. The safety factor ensures successful muscle depolarization despite this decline in released ACh. The predominant form of MG is an autoimmune destruction of both the ACh receptors and the postsynaptic end-plate region. Both the humoral and cellular arms of the adaptive immune system are involved in sustaining the disease, but antibodies mediate the final pathology. Eighty-five percent of patients with generalized myasthenia and 55% of

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patients with ocular myasthenia have antibodies directed towards the AChR. While anti-AChR antibodies are heterogeneous, their target antigens tend to be located on an extracellular sequence of the alpha subunit called the main immunogenic region (Tzartos and Lindstrom, 1980). These autoantibodies exert three pathophysiological effects: blocking the receptor; cross-linking receptors which stimulates their degradation; and most significantly, stimulating complement-mediated lysis of the end-plate region. The cumulative immunological damage reduces the number of available receptors, flattens the postsynaptic folds of the end-plate region, and widens the synaptic cleft (Woolf, 1966). The reduction in available ACh receptors narrows the safety factor for neuromuscular transmission. Seronegative myasthenia is a subset of MG with no detectable anti-AChR antibody. This group comprises approximately 15% of the patients with generalized MG, and 40–50% with ocular MG. Nearly 50% of patients with seronegative MG have antibodies to MuSK, a component of the complex that aggregates and anchors ACh receptors in the end-plate zone (Hoch et al., 2001). MG negative for MuSK and AChR antibodies is presumed antibodymediated, but the antibody or antibodies have not yet been identified. The pathogenesis of MuSK antibody-positive myasthenia is currently obscure, but is a matter of active research. In patients with MuSK antibodies, biopsies of affected muscles do not show a significant decrease in AChR density, and no significant IgG or complement binding (Selcen et al., 2004; Shiraishi et al., 2005). One report found MuSK antibodies may have an antiproliferative effect on muscles, and downregulate NMJ-related genes (Boneva et al., 2006). MuSK-associated MG has either minimal or no associated thymus pathology, theoretically arguing against a pathogenic role for the thymus in these patients (Lauriola et al., 2005). MuSK antibodies are not seen in seropositive patients (McConville et al., 2004). There is one known case report of a MuSKpostive, AChR Ab-negative patient with a thymoma. This is unusual both in that almost all patients with thymomas and MG are AChR Ab-positive and that MuSK patients do not typically have any thymus pathology, much less a thymoma (Saka et al., 2005). The role of the thymus in MG The thymus, the organ responsible for maturing and differentiating T cells while selecting for immuno-

tolerance, is usually abnormal in seropositive MG. About 70% of patients have thymic lymphoid follicular hyperplasia (TFH) and another 10–15% have thymoma. In TFH, lymphoid follicules and germinal centers form at the corticomedullary junction. This architecture brings AChR-bearing myoid cells into intimate contact with antigen-presenting cells, the major histocompatibility complex (MHC)-II positive interdigitating cells. The myasthenic thymus has all the cellular components required for autoantibody production: MHC-II positive antigen-presenting cells, B cells, T-helper cells and AChR antigen. Thymomas in MG are functionally similar to normal thymus in their ability to home and differentiate T cells. Additional evidence for a primary role of TFH in seropositive MG comes from animal models. When rat models of MG are created by passive transfer of antibodies or after immunization with AChR, the rats do not develop any of the thymic changes typical of human MG (Meinl, 1991). This implies that TFH is not a secondary effect of another pathogenic process. Conversely, when a piece of a myasthenic patient’s thymus is implanted into mice with severe combined immunodeficiency (SCID), the mice produce AChR antibodies for sustained periods. Diagnostic testing and evaluation Serology The standard serological test is the AChR antibodybinding test. The most commonly used laboratory method for this test is an immunoprecipitation test that uses ACh receptors radiolabeled with alphabungarotoxin. The binding antibody is positive in nearly 85% in generalized myasthenia, 50–70% in ocular myasthenia, and 100% of patients with thymoma. False positives are rare but have been reported with motor neuron disease, and polymyositis. Ten percent of patients with Lambert–Eaton syndrome have positive AChR antibodies. These can be differentiated by testing for the P/Q-type calcium channel receptor antibody if the electrophysiological studies or physical examination raise a suspicion for LEMS (Lennon, 1997). Additional AChR antibody tests include modulating and blocking antibodies. AchR-modulating antibodies bind to external segments of the AChR, cross-linking them on the cell surface and triggering their degradation. They are positive in approximately 86% of MG patients and only 3–4% of AChR-binding antibody negative patients (Howard et al., 1987). AchR-blocking anti-

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bodies bind directly to or near the AChR site. They are positive in 52% of myasthenic patients but only 1% of patients without AChR-binding antibodies (Howard et al., 1987). Seronegative patients should be tested for MuSK antibody, present in approximately 50% of this group. Anti-striated muscle Abs (titin and ryanodine antibodies) are present in 30% of patients, but their significance is a matter of active research. Ideally, antibody tests should be sent prior to immunotherapy, to avoid suppressing a diagnostic test. The Tensilon test The Tensilon test can give immediate supportive evidence for MG. Tensilon, a short-acting antiacetylcholinesterase, causes a transient improvment in myasthenic symptoms by increasing available ACh. The drug’s onset is 30 seconds and effects last 5–10 minutes. An initial dose of 2 mg is given intravenously. If no response is seen by 45–60 seconds, another 3 mg is given, and if no response is seen after another 45–60 seconds, the last 5 mg is given. A positive response is unequivocal improvement in a weak muscle. The most reliable signs are improvements of ptosis and extraocular muscles. False positives occasionally occur with other diseases, but more often arise from human errors of patient suggestibility or the physician’s attempt to interpret an effort-dependent weakness. The test is neither 100% sensitive nor specific but provides rapid supportive evidence of the clinical diagnosis. In MuSk-antibody patients, approximately one-third of patients have no response to the Tensilon test. Tensilon should be given in a monitored setting with atropine available in case of the rare side effects of bradycardia or asystole. Asthma and cardiac conduction disease are relative contraindications to this test. Electrophysiological testing Electrodiagnostic studies are an important part of the evaluation of MG, especially in patients who do not possess AChR- or MuSK-antibodies. The test requires patience and a specially trained clinician who can tailor the study to symptomatic muscles. Repetitive nerve stimulation and single-fiber electromyography (SFEMG) can confirm a defect in neuromuscular transmission and help rule out other nerve and muscle diseases. Repetitive nerve stimulation (RNS) at 3 Hz typically shows a decremental response of the compound muscle action potential.

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This is characteristic of a postsynaptic defect in neuromuscular transmission. This test is more helpful in generalized myasthenia, with a sensitivity of 60%, and less sensitive in ocular myasthenia (Preston and Shapiro, 2005). Single-fiber EMG has the highest sensitivity for detecting an abnormality of NMJ transmission and typically demonstrates increased jitter in almost all patients with MG, particularly if a weak muscle is checked (Preston and Shapiro, 2005). The test lacks specificity, however, as patients with peripheral neuropathy, myopathies, and motor neuron disease may also display increased jitter. In MuSK-antibody positive patients, the repetitive stimulation test is often normal, whereas SFEMG is sensitive but the abnormalities are present in a more limited distribution than in other myasthenics (Evoli et al., 2003). Imaging and ancillary tests In addition to confirming myasthenia, the clinician should review a computed tomography (CT) or magnetic resonance imaging (MRI) scan of the chest in order to evaluate for thymic hyperplasia or thymoma. It should be noted that CT contrast may rarely exacerbate the myasthenic symptoms. Thymoma may not appear on initial imaging, so the clinician should consider follow-up screening if the patient does not have a thymectomy. Other autoimmune disorders sometimes co-occur with MG: consider testing for thyroid disease, rheumatoid arthritis, systemic lupus erythematosis, and other autoimmune diseases based on index of suspicion. Differential diagnosis The classic myasthenia presentation, with fluctuating extraocular, bulbar, and limb weakness that worsens with exercise and improves with rest, is often readily differentiated from other diseases. However, when the symptoms are particularly focal or do not involve eye muscles, other diseases should be considered. These include diseases of the neuromuscular junction such as Lambert–Eaton myasthenic syndrome or botulism, as well as other nerve or muscle diseases such as amyotrophic lateral sclerosis (ALS), progressive external opthalmoplegia (PEO) muscular dystophies, myopathies, and inflammatory neuropathies. Hyperthyroidism with Grave’s ophthalmoparesis can also mimic myasthenia. In young seronegative patients, a congenital myasthenic syndrome should be considered.

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Treatment The management of MG is individualized and requires diligence and attentiveness on the part of the physician and the patient. The goal is to find the safest regimen that will adequately treat the disease while minimizing side effects. While the best guides for therapeutic choices are sound empiric clinical studies, these do not exist for many situations and we must rely on our scientific knowledge of the pathogenesis of MG and the therapeutic properties of medications. Choosing appropriate therapy for an MG patient begins with deciding how fast the patient needs to improve. The safety of the patient is paramount. Respiratory or bulbar involvement, severe weakness, and a propensity for acute worsening indicate greater risk. Degree of disability and neurological impairment should be considered. The risks of immunotherapy should be assessed with the duration of therapy as important as the intensity of therapy. The practitioner should work diligently to minimize chronic steroid exposure by adding other immunotherapies for patients who require steroids. Some practitioners feel that the goal of treatment should be an early induction of clinical remission using aggressive immunotherapy, often with combinations of medications. The rationale for this approach includes evidence for advancing complement-induced destruction of the end plate at the postsynaptic membrane, experimental evidence for epitope spreading over the course of time, and the observation that some exacerbations may not fully reverse with treatment and can pose significant risk to the patients. Before initiating nonemergent therapy, there are several important considerations. First, identify and minimize or eliminate all agents that can worsen MG. Infections should be treated empirically and vigorously. Evaluate the necessity for any medications that block neuromuscular transmission and potentially cause worsening of MG. Screen for endocrine abnormalities (such as thyroid) and electrolyte disturbances. Consider conditions that can cause secondary MG such as penicillamine therapy, interferon-alpha, and chronic graft versus host disease associated with bone marrow transplant. Screen for other associated autoimmune disorders as their presence may complicate therapy or decision making and may add to the picture of immune dysregulation. In addition, autoantibodies may be masked once immunotherapy has been initiated.

Screen for disorders that may complicate certain immunosuppressive therapies such as tuberculosis, peptic ulcer disease, gastrointestinal bleed, renal disease, obesity, and hypertension. In appropriate patients, anticipate and weigh the potential effects of immunosuppressive therapies on fertility and pregnancy. Explore with the patient their likelihood to adhere to therapy and follow-up with necessary monitoring for safety measurements. It is imperative to record the baseline severity of the disease to allow later evaluation of the outcome of therapeutic endeavors. For this, the MGFA Clinical Classification of Myasthenia Gravis or the Modified Osserman Scale grade disease severity functionally and regionally. Quantitative strength testing should include endurance testing such as the timed forward abduction test for the upper extremities and respiratory function testing (forced vital capacity, negative inspiratory pressure, and positive expiratory pressure), dynometry of selected weak muscle, and eye muscle function. Endurance testing is as important as strength testing. Symptomatic treatment of autoimmune MG Cholinesterase inhibitors (CIs) are generally used as the initial treatment for most MG patients. CIs enhance neuromuscular transmission by inhibiting acetylcholinesterase, the enzyme that hydrolyzes acetylcholine at the neuromuscular junction, increasing the available Ach to bind to AChRs. The most commonly used CI is pyridostigmine bromide (Mestinon R). Initial dosages are usually 30–60 mg in intervals of 3–6 hours. The onset of action is about 30 minutes, with peak effects around 2 hours. The benefits decline gradually over a few hours thereafter. Dosing schedules can be individualized based on the patient’s symptoms, side effects, and lifestyle. In most instances, improvements are incomplete and often wane over many months. Thus, most patients require additional treatments. Of note, patients with anti-MuSK antibodies appear to have a variable response to pyridostigmine (Sanders et al., 2003). Two rarely used symptomatic treatments are ephedrine (Sieb and Engel, 1993) and 3,4-diaminopyridine (Lundh et al., 1985). These drugs increase the release of ACh from the presynaptic nerve terminal. Limited data is available regarding their use, and safety and availability issues exist. These drugs may be considered in the rare patient unable to tolerate pyridostigmine.

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Immunotherapy Immunotherapy is necessary for most patients with MG and is generally more effective than symptomatic therapy. Immunotherapy targets the autoimmune pathophysiology: either by reducing pathogenic antibody production or by reducing damage to the end plate caused by pathogenic antibodies. Immunotherapies in MG can be divided into two groups based on their onset and duration of response: those that provide rapid improvement but have short-lived benefits; and those that have relatively slower onset but provide long-term benefits. The therapeutic responses of the various therapies dictate their strategic use in the treatment of patients with MG. Long-term immunotherapy Thymectomy Thymectomy has two roles in the management of MG. Thymectomy is indicated for all patients with thymoma in order to prevent local spread and invasion of the tumor. Thymectomy also is an accepted therapy for nonthymomatous MG. The rationale is based on the presumed role of the thymus gland in the initiation and/or maintenance of the immune dysfunction in MG. Numerous studies give support for beneficial effects of thymectomy on the clinical course of MG. An evidenced-based review of 21 studies conducted between 1953 and 1998 found that thymectomy led to clinical improvements and two times the likelihood of achieving a medication-free clinical remission (Gronseth and Barohn, 2000). The onset of benefit tends to occur 6 to 12 months following surgery, and the maximal benefit may require 2 to 5 years (Masaoka et al., 1996). Unfortunately, all studies have suffered from significant confounding factors: none were randomized, many were not controlled. Thus, significant limitations and controversies exist regarding their interpretations. Currently, most practitioners consider thymectomy more effective if performed within the first years of symptom onset for patients who are younger (usually less than 60 years old), and if more invasive and “complete” operative procedures are performed (Durelli et al., 1991; Maggi et al., 1989). Seronegative patients may benefit from thymectomy but small retrospective series suggest that anti-MuSK positive patients may not benefit from thymectomy (Sanders et al., 2003). The therapeutic response to thymectomy

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may not be as favorable for patients with thymoma compared to patients with thymic hyperplasia, but the myasthenic symptoms of thymoma-related MG are similarly responsive to medical therapy. Immunosuppressants Corticosteroids (usually prednisone) are the most commonly used form of maintenance immunotherapy in patients with MG. Steroids have numerous immunosuppressive effects on the immune system. They provide a reliable and rapid onset of action, but produce the most side effects of the immunosuppressive therapies. They are typically indicated for patients whose symptoms respond inadequately to AChE inhibitors and are significantly disabling or in danger (i.e., have respiratory or bulbar weakness) so as to warrant the high risk of side effects that occur with chronic steroid use. Prednisone can be initiated at 60 to 100 mg per day with the expectation of an initial response within two to four weeks and a maximal response in about six months. With this regimen, transient steroid-induced weakness can occur in about one-third of patients. Lower dose, slowly escalating regimens reduce this risk but take longer to induce a response. After adequate improvement is achieved, the dose should be minimized very slowly and cautiously. Aggressive measures should be taken to prevent and monitor for the side effects common to chronic steroid use. Several immunosuppressant drugs are commonly used in the management of MG. These therapies typically take a few months to achieve a response, and many more months to reach maximum benefit. They are usually employed in combination with corticosteroids as steroid-sparing agents or to produce a greater response than corticosteroids alone. Patients who are mildly disabled and stable enough to wait several months for treatment effect may be able to use immunosuppressant monotherapy. Patients who tolerate corticosteroids poorly, such as diabetics or patients with gastric ulcer disease, also may benefit from this option. While side effects can occasionally be significant, they are usually better tolerated than long-term corticosteroid therapy. Azathiopurine is a general immune suppressant that is beneficial for MG (Kuks et al., 1991). This purine analog inhibits DNA synthesis and thus reduces T- and B-cell proliferation. Its onset of action takes a few months, with maximal benefit sometimes requiring up to one to two years. Mycophenolate

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mofetil is becoming increasingly popular due to its efficacy and favorable side-effect profile (Meriggioli et al., 2003). Its predominant action is blocking purine synthesis selectively in activated T and B lymphocytes by blocking the de novo pathway of purine synthesis upon which only lymphocytes rely. Patients sometimes show improvement within two months (Ciafaloni et al., 2000) but typically require many more months to achieve maximum benefits. Cyclosporine A is an immunosupressant that blocks interleukin-2 activation of T-helper cells by inhibiting calcineurin. While a controlled, double-blind clinical trial has shown its effectiveness in MG (Tindell et al., 1993), significant side effects and drug interactions usually render it less preferable than azathioprine and mycophenolate mofetil for most patients. Onset of action is often four to eight weeks, with benefits increasing over many months. Other immunosuppressive agents sometimes considered for severe treatment-resistant MG patients include cyclophosphamide (Gustavo De Feo et al., 2002), tacrolimus (Evoli et al., 2002), and rituximab (Zara et al., 2000). Short-term immunotherapy The two short-term immunotherapies used in the treatment of MG are plasmapheresis (therapeutic plasma exchange) and intravenous immunoglobulin ( IVIg). These treatments have a rapid onset of action, usually within one week, and short durations of benefit, usually between one and two months. They are used in four clinical settings: 1 in myasthenic crisis or severe exacerbations to produce rapid improvement; 2 prior to surgery (including thymectomy) in order to maximize strength and reduce postoperative morbidity; 3 as bridging therapy for treatment-resistant MG or steroid-intolerant patients, administered every month or so until slow-onset long-term therapy takes effect 4 when initiating corticosteroid therapy to minimize the risk of transient steroid-induced weakness. The efficacy of plasmapheresis has been demonstrated in several uncontrolled studies (Pinching et al., 1976, 1977). Plasma exchanges typically remove one to two plasma volumes roughly every other day for a total of five to six treatments. The mechanism of action of plasmapheresis is the bulk removal of

pathogenic antibodies and immune complexes. Small series of patients with anti-MuSK antibodies report good response to plasmapheresis (Evoli et al., 2003). With IVIg, polyclonal human Ig is administered at 2 g/kg over two to five days. Efficacy has been demonstrated in several nonplacebo-controlled studies (Arsura, 1989; Cosi et al., 1991). While IVIg is known to have numerous effects on the immune system, those responsible for the therapeutic response in MG have not been established. A randomized study comparing IVIg to plasmapheresis showed equal efficacy, but IVIg had fewer and less severe side effects (Gajdos et al., 1997). Lambert–Eaton myasthenic syndrome Introduction Lambert–Eaton syndrome (LES) is a rare disease that causes fatigable muscle weakness and mild autonomic dysfunction. It is caused by an immune-mediated attack against the voltage-gated calcium channels (VGCC) on the presynaptic motor nerve terminal. In about 40–50% of patients, LES occurs as a paraneoplastic syndrome (P-LES), usually associated with small-cell lung cancer (SCLC). Although paraneoplastic syndromes are rare in neurology, LES is the most common and one of the best characterized. Nonparaneoplastic LES (NP-LES) accounts for approximately 50–60% of LES cases and occurs as an idiopathic autoimmune disease of unknown etiology. History In 1953, Anderson and colleagues described a patient with oat cell lung cancer who had myasthenic symptoms (Anderson et al., 1953). From 1956 to 1961, Lambert and his colleagues described a series of patients who suffered from fatigable muscle weakness that differed from myasthenia gravis. These patients had a different distribution of weakness, areflexia, and autonomic dysfunction. Their neurophysiological profile was also distinctive with facilitation of both muscle strength after exercise and the amplitude of compound muscle action potential (CMAP) after high-frequency repetitive electrical stimulation (Eaton and Lambert, 1957; Lambert et al., 1956, 1961). In most of these patients (10 out of 17), their myasthenic syndrome was associated with malignancies, especially small-cell lung cancer. Elmqvist and Lambert were the first to identify that the pathophysiology of LES involved dysfunction

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of the presynaptic motor nerve terminal with reduction of quantal release of acetylcholine (Elmqvist and Lambert, 1968; Lambert and Elmqvist, 1971). In 1972, Gutmann noted an association of autoimmune disorders in patients with LES without malignancies, and theorized an autoimmune etiology for LES (Gutman et al., 1972). The autoimmune basis for LES was supported by the development of clinical and physiological features of LES in mice receiving IgG from patients with LES (Fukunaga et al., 1983; Kim, 1986; Lambert and Lennon, 1988; Lang et al., 1981), the discovery that serum IgG from patients with LES interacts with VGCC in cell cultures of human small-cell carcinoma (Roberts et al., 1985), and, in 1989, the development of a diagnostic radioimmunoassay that binds the pathogenic VGCCdirected autoantibodies in LES (Lennon and Lambert, 1989). Based on its known pathophysiology, several treatments have been developed that positively impact the lives of patients with LES. These treatments include those that enhance the release of acetylcholine from the presynaptic motor nerve terminal, plasmapheresis, IVIg, and immunosuppressive medications, as well as surgical removal of associated malignancies. Clinical features The characteristic clinical presentation of patients with LES consists of subacute progressive proximal limb muscle weakness and fatigability, diminished or reduced muscle stretch reflexes, and autonomic dysfunction. The diagnosis is often delayed for months or even years because the symptoms often begin insidiously and findings on physical examination may go undetected early in the course of the disease. The typical distribution of weakness involves the hip flexors and other hip girdle muscles, the proximal muscles of the upper extremity, neck muscles, and the interossei muscles. The hip girdle muscles usually are affected more prominently than those of the upper extremities, and account for the majority of disability. In one series of 50 patients, weakness began in the lower limbs in 65% (O’Neill et al., 1988); 12% began with generalized weakness, but with hip girdle muscles involved more than other muscles of the body. Patients often complain of difficulty arising from a sitting position and climbing stairs, and sometimes even fall. Patients commonly report that the weakness transiently worsens on repeated muscle exertion and improves with rest. Occasionally, patients experience transient improvement of strength following brief exertion, followed by increasing weakness

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with continued exertion; eliciting this history, though, is not common. Muscle atrophy is rare. Enhancement of depressed reflexes after brief exercise or repeated elicitation of the reflex is strongly suggestive of the diagnosis and is more readily demonstrated at the bedside than facilitation of muscle strength. Patients may experience aching pain in their hips and posterior thigh. Approximately 25% have cranial nerve involvement. Ptosis, facial weakness, dysphagia, dysarthria, and difficulty chewing can occur but are usually milder and tend to occur later in the disease course than in MG. Respiratory involvement is less common and usually significantly milder than in MG. Respiratory failure is rare. Approximately 80% of patient with LES have symptoms of autonomic dysfunction. In 6%, autonomic dysfunction is the presenting symptom (O’Neill et al., 1988). The most common autonomic symptoms are erectile dysfunction in men and xerostoma (dry mouth) in both sexes. Other features include slow pupillary reaction to light, gastrointestinal dysmotility, orthostatic hypotension, and urinary retention. Autonomic testing may reveal abnormalities in sweating, cardiovagal reflexes, and salivation. As mentioned earlier, early medical description noted a clear association of malignancy in approximately 40–50% of patients diagnosed with LES. The majority of the patients had small-cell lung cancer (SCLC). While several other types of cancer have been reported in patients with LES, only lymphoma has shown a possible paraneoplastic association with LES. The symptoms of LES can precede the diagnosis of malignancy by several years, but not usually more than five years. Symptoms of lung cancer itself are uncommon at the time of diagnosis of LES. The sensory system is always spared in LES. If sensory deficits are present, their origin may lie in the presence of an additional paraneoplastic disease such as sensory neuronopathy, peripheral neuropathy, or myelopathy. Other paraneoplastic syndromes associated with LES include subacute cerebellar ataxia and encephalomyelitis. Organ-specific autoimmune diseases such as pernicious anemia and autoimmune thyroid disease are common in patients with NP-LES. Natural history The course of LES tends to be slowly progressive in the first year. Fluctuations of symptoms are less pronounced and spontaneous remissions are less common than with MG. The course of NP-LES can vary considerably. Approximately half of NP-LES

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patients achieve sustained remissions, usually with chronic immunotherapy but sometimes spontaneously (Maddison et al., 2001). The other half suffers various degrees of long-term disability. Immunotherapy is effective in reducing disability, however, less so than with MG. In patients with P-LES, the course may be more heterogeneous compared to those with NP-LES. The symptoms of P-LES often improve following effective treatment of the underlying cancer, with 70% of patients achieving clinical remission (Chalk et al., 1990; Maddison et al., 2001). The overall prognosis for these patients is related to that of the underlying cancer, which for SCLC is usually fatal. One report notes SCLC in patients with LES tends to be less aggressive and has a greater response to therapy than patients without LES (Maddison et al., 1999). When coexisting paraneoplastic syndromes of peripheral neuropathy and subacute cerebellar ataxia occur, their symptoms tend to be more prominent and disabling than LES. Epidemiology Figures for the incidence and prevalence of LES are unknown due to its rarity. Idiopathic LES occurs more often in females and can occur at any age (Maddison et al., 2001). There is a frequent association with organspecific autoimmune disorders in these patients and family members. Certain HLA-gene products are found in higher prevalence than in patients with P-LES (Parsons et al., 2000; Willcox et al., 1985). P-LES occurs more often in men and in older populations at higher risk of cancer. Cancer is found in 45% of patients with LES, with SCLC accounting for 90% (O’Neill et al., 1988). Other cancers reported include lymphoproliferative disorders, thymoma, renal cell cancer, and tumors of the reproductive tract (Argov et al., 1995; Burns et al., 1999; Collins, 1999; Gutmann et al., 1992; O’Neill et al., 1988; Oyaizu, 2001). Occasionally patients with these cancers harbor occult SCLC as well. Primary smallcell carcinoma of extrapulmonary locations can occur in patients with LES, especially when no risk factors for lung cancer are present. In patients with SCLC, LES occurs in approximately 6% (Croft and Wilkinson, 1965; De La Monte et al., 1984; Hawley et al., 1980). Eighteen percent of patients with SCLC are seropositive for antibodies to the P/Q-type calcium channel without clinical evidence of LES. Pathophysiology The Lambert–Eaton myasthenic syndrome is an

immune-mediated disease caused by antibodies directed at the α1A subunit of the VGCC located on the presynaptic nerve terminal. As described in the pathophysiology section on myasthenia gravis, a nerve impulse induces presynaptic calcium influx via VGCCs, which triggers the release of acetylcholine into the synaptic cleft. Electrophysiological studies of LES patients show a presynaptic abnormality in neuromuscular transmission (Lambert et al., 1961). The miniature end-plate potentials (MEPP) have normal amplitude and frequency in LES. There is a reduced number of ACh vesicles released, leading to a reduction of end-plate potential (EPP) amplitude. This produces a decrease in the safety margin of neuromuscular transmission. High-frequency repetitive nerve stimulation or bathing a muscle sample in high-calcium solutions increases the EPP amplitude. These features support the concept that VGCC antibodies in LEMS patients reduce calcium flux through VGCCs on the presynaptic membrane. While the specific disruptive mechanism or mechanisms of these antibodies requires further study, significant evidence implicates VGCC antibodies that bind and cross-link adjacent VGCCs. This causes an acceleration in the rate of VGCC degradation, known as antigenic modulation (Fukuoka, 1987; Prior, 1985). This reduces the number of available VGCCs. This process is IgG-mediated, and does not involve complement. Significant ultrastructural abnormalities occur in the presynaptic membrane in patients with LES that further reduce the safety margin of neuromuscular transmission. Several types of VGCC exist which are distinguished by differences in their biomolecular and pharmacological properties. The P/Q-type VGCC are normally arranged in parallel arrays in the active zones of the presynaptic motor nerve terminal and some preganglionic autonomic synapses. Most patients with LES have antibodies directed at the P/Q-type VGCC. In patients with LES, there is a reduction in the density of active zones in the motor nerve terminals and the normally formed parallel arrays of P/Q-type VGCCs become disordered (Fukunaga et al., 1982). These anatomical changes reduce the number of functional calcium channels leading to a decrease in the release of acetylcholine. The autonomic symptoms involved in LES may be mediated by a similar immunological process (Waterman, 2001). The neurons of the autonomic nervous system contain a different array of VGCCs. The subtype of VGCCs varies among specific tissues and the neurotransmitters utilized. The predominant

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subtype found in the autonomic nervous system is the N-type VGCC, but P/Q-type and R-type VGCCs are present to lesser degrees. Autoantibodies from patients with LES may impair neurotransmitter release through downregulation of one or more subtypes of VGCCs at the presynaptic sympathetic and parasympathetic autonomic nerve terminal. This inhibition of autonomic nervous system transmission likely is the basis for their autonomic symptoms. Interestingly, most patients with autonomic symptoms in LES do not possess antibodies to the N-type VGCC, whereas the majority possess antibodies to the P/Q-type receptor. The degree of autonomic dysfunction does not seem to correlate with the presence of the P/Q-type or the N-type VGCC. In P-LEMS, evidence supports the hypothesis that antigens expressed on the underlying neoplasm may provoke and maintain the autoimmune response towards the VGCCs. First, P/Q-type VGCCs are expressed in SCLC cells (McCann et al., 1981; Roberts et al., 1985). Immunoglobulins obtained from LEMS patients with SCLC bind to P/Q-type VGCCs and produce downregulation of these channels in SCLC cells. Patients with LEMS often experience improvements in muscle strength with effective treatment of the underlying cancer. This evidence suggests that VGCCs on the SCLC cells trigger an autoimmune process in which pathogenic antibodies cross-react with VGCCs on the SCLC cells and the presynaptic nerve terminals. In NP-LES, the etiology of the autoimmune dysregulation has not been elucidated. Patients with NP-LES are known to have an increased frequency of autoimmune disease and autoantibodies in their personal or family history compared to patients with P-LES (Lennon et al., 1982; O’Neill et al., 1988). Clinically, no major features differ between NP-LES and P-LES except the age and sex differences noted above and the presence of P/Q-type VGCCs is more commonly found in P-LES. While an immunemediated process has been established as the cause, the primary cause of this immune dysregulation has not been found. Diagnosis Clinical manifestations The basis for the diagnosis of LES is the clinical triad of fatigable proximal limb muscle weakness, reduced or absent muscle stretch reflexes, and autonomic dysfunction. Ancillary tests for LES are distinctive and

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usually provide reliable confirmation of the diagnosis. Cases of prolonged apnea following surgery with exposure to neuromuscular blocking agents should prompt suspicion of LES (as well as MG). LES should also be considered in patients with another lung cancer associated paraneoplastic syndrome who develop significant weakness or have antibodies to the P/Q-type calcium channel. Sometimes LES is diagnosed in patients previously misdiagnosed with seronegative MG. Electrodiagnostic studies Electrodiagnostic studies provide the most specific and rapid confirmation of the diagnosis of LEMS. The distal hand muscles often provide the most pronounced findings. CMAPs have a low amplitude at baseline. CMAPs display a decremental response at slow rates of repetitive nerve stimulation and marked postactivation facilitation of greater than 100–200% following high-frequency repetitive nerve stimulation (at rates of 20–50 Hz) or about 10 seconds of brief exercise (Harper, 1999). Single-fiber electromyography demonstrates increased jitter and blocking that transiently improve with high firing rates. This combination of findings is the hallmark of LES. Serum testing Antibodies directed towards the P/Q-type VGCC are detectable in greater than 90% of patients with LES (Lennon et al., 1995). In LES patients with SCLC, up to 100% have antibodies to VGCC, whereas 50–90% of LES patients without associated cancer have antibodies to VGCC. In P-LEMS, antibodies directed to the N-type VGCC are present in 75% of patients with SCLC and generally not seen in patients with other types of cancer. Forty percent of NP-LES have antibodies to the N-type VGCC. Antibody titers tend to diminish with improving disease severity, the administration of immunotherapy, and effective treatment of an underlying malignancy. It is, thus, imperative to test for VGCC antibodies early in the evaluation of all patients under consideration for LES. The interpretation of positive serum antibody tests requires correlation with the clinical picture. Antibodies to VGCC can occur in other conditions not in association with clinical LEMS. In SCLC patients without LEMS, 18% have P/Q-type VGCC antibodies and 22% have N-type VGCC antibodies. VGCC antibodies occur in 15–40% of patients with paraneoplastic cerebellar ataxia, and rarely in autoimmune

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MG or other autoimmune disorders (Yu et al., 2001). In 13% of patients with LEMS, muscle or ganglionic nicotinic AChR antibodies or striational antibodies are present. Differential diagnosis While the characteristic clinical features of LES are quite distinctive, LES is frequently misdiagnosed initially due to its insidious onset and rarity. The differential diagnosis of LES includes such disorders as MG, myopathies, polymyalgia rheumatica, and botulism. Several features distinguish LES from these disorders. With MG, the distribution of weakness and fatigability with early involvement of ocular and bulbar muscles, as well as typical electrodiagnostic and autoimmune serological profile differentiate it from LES. Myopathies may present with a similar distribution of weakness. However, the lack of autonomic dysfunction, different electrodiagnostic findings, and reflexes which are proportional to the degree of weakness and do not exhibit potentiation after brief voluntary exertions, distinguish them from LES. Botulism causes progressive weakness, autonomic dysfunction, and some similar electrodiagnostic features. The course, however, is more fulminant, and prominent respiratory involvement, early pupillary involvement, and a descending progression of weakness are not typical features of LEMS. Polymyalgia rheumatica can present with muscle pain, but an elevated erythrocyte sedimentation rate (ESR) and the lack of true muscle weakness and fatigability differentiate it from LEMS. Treatment and management Once the diagnosis of LES has been established, an extensive investigation for an underlying malignancy should be implemented. For patients with an underlying malignancy, symptoms of LES often improve with treatment of the malignancy. If the evaluation detects no malignancy, repeated testing should be performed at regular intervals for at least five years, especially in persons with significant risk factors for cancer. In patients with P-LES, treatment should be directed towards the underlying malignancy. Patients in whom the underlying malignancy is not effectively treated tend not to improve substantially with immunotherapy. Conversely, effective treatment of the underlying malignancy usually leads to significant improvement of the neurological symptoms, and, in some cases, to complete remission. Some of these

patients may not require further treatment for LES. Immunotherapy should be considered for patients whose malignancies respond to therapy but their neurological symptoms not improve adequately. It is also indicated for patients without malignancy who suffer from significant disability despite symptomatic therapy. Therapy of LES must be individualized, with consideration given to the degree of disability, associated underlying medical conditions, and life expectancy. The therapeutic strategies for immunotherapy are generally similar to those used with MG, although the response to treatment is often less dramatic. Symptomatic treatment 3,4-Diaminopyridine (3,4-DAP) has been shown to improve symptoms in patients with LES in placebocontrolled prospective trials (Lundh, 1990; McEvoy, 1989). Many practitioners consider 3,4-DAP firstline therapy for LES. 3,4-DAP blocks voltage-gated potassium channels in the nerve terminal, which leads to prolongation of the action potential and opening of VGCC, increased calcium entry and, ultimately, to enhanced ACh release. Dosing schedules vary, and repeated dosages are titrated to optimize patient response (Lundh et al., 1993; Sanders, 1998). 3,4DAP is usually well tolerated but it is not approved for clinical use in the United States. Thus, it is available only for compassionate use as an investigational drug. Guanidine hydrochloride also enhances the release of ACh from the presynaptic nerve terminal. Guanidine increases calcium within the nerve terminal by inhibiting uptake of calcium by subcellular organelles (Kamenskaya et al., 1975). While guanidine is occasionally utilized in the management of LES, its use has been significantly limited due to potential hematopoietic and renal toxicity. Cholinesterase inhibitors are sometimes administered in LES. Potential benefits are limited, perhaps because it is an attempt to slow the metabolism of an already-reduced amount of ACh. Clinically, CIs are not particularly effective as monotherapy. Enhanced benefits can occur when CIs are combined with medications that facilitate the release of acetylcholine, such as the 3,4-diaminpyridine or guanidine. Immunotherapy For patients who fail to respond adequately to symptomatic treatments, immunotherapy is an option.

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Therapeutic plasma exchange and IVIg are both used for short-term immunotherapy because they provide relatively quick onset but short-term benefits (Bain et al., 1996; Newsom-Davis and Murray, 1984). Clinical response to plasma exchange occurs around 10 days and for IVIg around 2 weeks, somewhat slower than with MG. The benefit of both lasts about 6–8 weeks. Plasma exchange and IVIg both are typically utilized for patients with severe weakness, or bulbar or respiratory muscle involvement. Repeated treatments sometimes have been employed for maintenance therapy or until long-term immunotherapy takes effect. Patients with long-standing disabling symptoms should consider chronic immunosuppressive therapy. In patients with known malignancy or at high risk for malignancy, it is important to be contemplative of the theoretical risk of immunosuppression promoting tumor growth. Although not considered high risk, some practitioners reserve immunosuppressive therapy only for the most disabled patients who fail to respond to other therapies. Prednisone is often the choice immunosuppressive (Lundh et al., 1990). It is administered at dosages of 0.75–1 mg/kg/day, typically 60–80 mg per day. After clinical response occurs, the dosing schedule may be converted to alternate days (i.e. 100–120 mg every other day). Starting on alternate-day dosing usually delays the onset of the clinical response. The dose of prednisone should be gradually tapered over many months to the minimal dose required for adequate disease control. The administration of an additional immunosuppressive agent may help minimize steroid exposure and is usually better tolerated than steroids. Azathioprine is often utilized and has shown benefit in this role in a retrospective study (Lee et al., 2001). Azathioprine also can be used as monotherapy for those patients who can wait months for clinical response. The therapeutic efficacies of mycophenolate mofetil, cyclosporine, and other immunosuppressive agents have not been adequately investigated for use in patients with LES. Some practitioners have employed these medications on the theoretical basis that treatments efficacious in MG should show similar efficacy in LES. References Anderson, H.J., Churchill-Davidson, H.C. and Richardson, A.T. 1953. Bronchial neoplasm with myasthenia: Prolonged apnea after administration of succinylcholine. Lancet, 2, 1291–3.

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Selcen, D., Fukuda, T., Shen, X.M. and Engel, A.G. 2004. Are MuSK antibodies the primary cause of myasthenic symptoms? Neurology, 62, 1945–50. Shiraishi, H., Motomura, M., Yoshimura, T., et al. 2005. Acetylcholine receptors loss and postsynaptic damage in MuSK antibody-positive myasthenia gravis. Ann Neurol, 57, 289– 93. Sieb, J.P. and Engel, A.G. 1993. Ephedrine: Effects on neuromuscular transmission. Brain Res, 623, 167–71. Thorlacius, S., Aarli, J.A., Riise, T., Matre, R. and Johnsen, H.J. 1989. Associated disorders in myasthenia gravis: Autoimmune diseases and their relation to thymectomy. Acta Neurol Scand, 80(4), 290–5. Tindell, R.S., Phillips, J.T., Rollins, J.A., Wells, L. and Hall, K. 1993. A clinical therapeutic trial of cyclosporine in myasthenia gravis. Ann NY Acad Sci, 681, 539– 51. Tzartos, S.J. and Lindstrom, J.M. 1980. Monoclonal antibodies used to probe acetylcholine receptor structure: Localization of the main immunogenic region and detection of similarities between subunits. Proc Natl Acad Sci USA, 77, 755–9. Waterman, S. 2001. Autonomic dysfunction in Lambert–

Eaton myasthenic syndrome. Clin Autonom Res, 11, 145–54. Willcox, N., Demaine, A.G., Newsom-Davis, J., Welsh, K.I., Robb, S.A. and Spiro, S.G. 1985. Increased frequency of IgG heavy chain marker Glm(2) and of HLA-B8 in Lambert–Eaton myasthenic syndrome with and without associated lung carcinoma. Hum Immunol, 14, 29–36. Wilson, A. and Stoner, H.B. 1944. Myasthenia gravis: A consideration of its causation in a study of fourteen cases. Q J Med, 13, 1–18. Woolf, A.L. 1966. Morphology of the myasthenic neuromuscular junction. Ann NY Acad Sci, 135(1): 35–59. Yu, Z., Kryzer, T.J., Griesmann, G.E., Kim, K., Benarroch, E.E. and Lennon, V.A. 2001. CRMP-5 neuronal autoantibody: Marker of lung cancer and thymoma-related autoimmunity. Ann Neurol, 49, 146–54. Zara, F., Russo, D., Fuga, G., Perella, G. and Baccarani, M. 2000. Rituximab for myasthenia gravis developing after bone marrow transplant. Neurology, 55, 1062–3. Zhou, L., McConville, J., Chaudhry, V. et al. 2004. Clinical comparison of muscle-specific tyrosine kinase (MuSK) antibody-positive and negative myasthenic patients. Muscle Nerve, 30, 55–60.

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10 Polymyositis and dermatomyositis S. Christine Kovacs

Idiopathic inflammatory myopathies share the histopathological feature of inflammation in striated muscle. The three major subgroups are dermatomyositis (DM), polymyositis (PM), and inclusion body myositis (IBM). This chapter focuses on dermatomyositis and polymyositis. Dermatomyositis was first noted in the literature when Wagner (1863) published a description of a patient with the disease. Several other clinical descriptions followed in the late nineteenth century and were further classified as dermatomyositis, polymyositis, pseudotrichinosis, and myositis universalis acute infectiosa ( Jackson, 1887; Unverricht, 1887; Wagner, 1887). It seems that the criteria for classification of the inflammatory myopathies are “a work in progress”. A general schema based on clinical features and disease associations was used until the landmark article written by Bohan and Peter (1975) was published. In their description of the disease they ascribed the probability of having the disease based on a number of clinical features being present (Box 10.1). New efforts in further defining the disease have included exhaustive search for myositisassociated antibodies and pathological findings. Bohan and Peter’s criteria have been criticized for being inadequate in excluding other conditions presenting as polymyositis. Additionally, muscle biopsy was considered to be the gold standard in the diagnosis and

now it has been shown that a muscle biopsy may not distinguish polymyositis from some toxic, necrotizing, or dystrophic myopathies (Dalakas, 2002). More recently interest has centered on the presence of MHC-I/CD8 complex as an immunopathological marker which seems to be specific for polymyositis and inclusion body myositis, as well as central to the immunopathogenesis (Dalakas, 2004). The latest criteria for diagnosis are shown in Box 10.2. Clinical phenotype The clinical manifestations of polymyositis are representative of all idiopathic inflammatory myopathies. Patients with polymyositis usually present with gradual onset of proximal muscle weakness involving both the upper and lower extremities. Patients often note trouble with their daily activities. The muscles of the oropharynx, esophagus, diaphragm, and intercostals can also be involved, resulting in dysphagia and dyspnea. Involvement of the neck flexors may make it difficult for the patient to lift his or her head. Ocular and facial muscles are spared, and there is no involvement of the nerves (Dalakas, 1991). Extramuscular manifestations such as fever, anorexia, and weight loss may be prominent. The development of pulmonary and cardiac symptoms

Box 10.1 Diagnostic criteria for dermatomyositis (Bohan and Peter, 1975). 1

2 3 4

Proximal symmetric muscle weakness, progressing weeks to months. Muscle biopsy evidence of an inflammatory myopathy. Elevation of serum muscle enzymes. Electromyographic features of a myopathy.

5

Cutaneous eruption typical of dermatomyositis.*

Definite PM/DM: Fulfill four criteria. Probable PM/DM: Fulfill three criteria. Possible PM/DM: Fulfill two criteria. *Criterion 5 must be one of the stated number of criteria in patients with definite, probable, or possible dermatomyositis.

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Box 10.2 Diagnostic criteria of polymyositis (adapted from Dalakas, 2004). 1

2

Myopathic weakness, which: a evolves over weeks to months b spares facial and eye muscles c is manifested in patients above the age of 18 Patient does not have: a rash, characteristic of dermatomyositis b a family history of neuromuscular diseases c exposure to myotoxic drugs (D-pencillamine, zidovudine, statins) d endocrine disease (hypothyroid, hyperthyroid, hypoparathyroid, hyercortisolism) e neurogenic disease (excluded by electromyographic (EMG) and neurological exam) f dystrophies and metabolic myopathies (excluded by history and muscle biopsy) g IBM (excluded by clinical examination and muscle biopsy)

has been well described (Box 10.3). Primary pulmonary involvement can take the form of a diffuse alveolitis or a more slowly evolving interstitial lung disease. Dyspnea in these patients may be related to respiratory muscle weakness, aspiration, cardiac process, or drug-induced (such as with methotrexate) (Dickey, 1984; Tazelaar et al., 1990). The most

3

4 5

Disease can be associated with: a another autoimmune disease or viral infection Polymyositis is rare, as a standalone entity Reconsider polymyositis if: a disease onset below the age of 18 years b myopathy has slow onset and evolves over months to years (think of IBM or dystrophy) c patient has fatigue and myalgia, without muscle weakness, even if a transient creatine kinase elevation is seen (such patients may have fibromyalgia or fasciitis and their muscle biopsy is either normal or nonspecific) d there are no typical histologic features of polymyositis, expecially when there is an absence of MHC-1 or MHC-1/CD8 complex

frequent cardiac abnormalities are conduction disturbances (Yale et al., 1993). Gastrointestinal involvement with dysphagia and heartburn secondary to pharyngeal dysfunction and esophageal dysmotility is common. Primary renal involvement is unusual, but renal failure from massive deposition of myoglobin in the renal tubules can occur. The arthritis

Box 10.3 Noncutaneous manifestations of dermatomyositis. Respiratory manifestations: Interstitial lung disease (bronchiolitis obliterans organizing pneumonia, interstitial pneumonia, diffuse alveolar damage); aspiration pneumonia; ventilatory insufficiency; drug-induced reaction (secondary to methotrexate use); malignancy; pleural effusions; opportunistic infection; pulmonary hypertension; spontaneous penumothorax; pulmonary alveolar proteinosis (Dickey, 1984; Tazelaar et al., 1990). Cardiac manifestations: Conduction abnormalities; arrhythmias; myocarditis;

congestive heart failure; hyperkinetic state, pericardial tamponade; pericardial effusions; pericarditis (Yale et al., 1993). Gastointestinal manifestations: Esophageal reflux; delayed gastric emptying; dysphagia; esophageal dysmotility; decreased intestinal motility; rectal incontinence. Ocular manifestations: Conjunctival edema; nystagmus; extraocular muscle imbalance; iritis; cotton-wool spots; optic atrophy; conjunctival pseudopolyposis.

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associated with the anti-Jo-1 antibody tends to be prominent, chronic and deforming, but lacks the extensive bone erosions that characterize rheumatoid arthritis. Although dermatomyositis and polymyositis differ in immunopathogenesis, clinically dermatomyositis is phenotypically polymyositis with typical skin changes. The primary skin lesion is a violaceous

Fig. 10.1 Gottron’s sign. (a) Violaceous plaques over the dorsal surface of the metacarpal phalangeal joints and interphalangeal regions. (b) Gottron’s papules and plaques over knee joint.

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macular erythema distributed symmetrically that over time becomes more poikilodermatous and indurated secondary to mucin depositon. The pathognomonic skin lesions are Gottron’s papules (violaceous papules overlying the dorsal surface of the interphalangeal, metacarpophalangeal (MCP), elbow, or knee joints), Gottron’s sign (atrophic macules or plaques in the same distribution) (Fig. 10.1), heliotrope rash (erythematous/violaceous rash with associated edema of the eyelids) (Fig. 10.2), shawl sign (erythematous poikilodermatous macules distributed in a “shawl” pattern involving the shoulder, arms, and upper back) (Fig. 10.3), and the V sign (same changes in a V pattern on the anterior neck and chest). Nonspecific findings include mechanic’s hands (scaly, fissured lesions involving the hands), cuticular changes, and photosensitivity. The rash is often the presenting complaint and may precede the onset of muscular symptoms by more than a year. The severity of the skin findings does not always correlate with the extent of muscle involvement (Euwer and Sontheimer, 1996; Kovacs and Kovacs, 1998). The presentation of muscle involvement in dermatomyositis is clinically indistinguishable from that of polymyositis, with symmetrical weakness involving the proximal muscles that develops over weeks to months. Myalgias can occur with an acute onset, but the hallmark presentation is that of weakness. Patients with classic skin changes of dermatomyositis without weakness or laboratory evidence of muscle disease are described as having amyopathic dermatomyositis (ADM) (also called dermatomyositis sine myositis). “Hypomyopathic DM” (HDM) refers to patients with the presence of skin disease for at least six months who have no muscle weakness, but on testing are found to have some evidence of muscle involvement. Clinically amyopathic DM (CADM) has been proposed by Gerami et al. (2006) to emphasize the clinically active component at that time – the

Fig. 10.2 Heliotrope rash of dermatomyositis demonstrating violaceous erythema overlying the upper eyelids with associated periorbital edema.

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Fig. 10.3 Shawl sign. Erythematous macules distributed on the neck, upper back, shoulders, and arms.

skin involvement. In the review by Gerami et al. (2006), patients with CADM, as well as, patients with classic DM have a similar association with malignancy and interstitial lung disease. Anti-Jo-1 antibodies are rarely found in CADM patients even if they have interstitial lung disease. The other interesting finding in this review is that in adult-onset CADM calcinosis is very uncommon. Juvenile dermatomyositis differs from the adult form both histologically and clinically (Pachman and Dooke, 1980; Reed and Mason, 2005). The histological finding on muscle biopsy of perifascicular atrophy is much more common in the pediatric population. The skin lesions are similar in both populations, but there is a higher incidence of calcinosis in the pediatric group. The calcific deposits tend to occur over the elbows, knees, buttocks, or other pressure point regions and have been shown to correlate with disease activity and duration. The incidence of calcinosis ranges between 30–70% in children

compared to adults where the occurrence of this finding is less than 10% (Bowyer et al., 1986; Martini et al., 1987). Vasculitis involving the gastrointestinal tract has a predilection for the pediatric population. The Gower’s sign describes how a child with proximal muscle weakness is able to get up off the floor without relying on his or her lower extremity strength. Laboratory evaluation Serum creatine kinase (CK) assay is a good initial screening test in patients suspected of having an inflammatory myopathy. Muscle enzymes used as markers for muscle damage include CK, aldolase, lactic dehydrogenase (LDH), aspartate aminotransferase (AST), and alanine aminotransferase (ALT). The most sensitive marker is CK, which has three isoforms: muscle type (CK-MM); brain type (CK-BB); and hybrid type (CK-MB). The major source of CK is

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skeletal muscle where the CK-MM predominates, but CK-MB may be present in smaller concentrations. Although disease states may be associated with elevations in CK levels, exercise, intramuscular injections, and EMG testing may be responsible for such elevations and they may remain elevated for up to 48 hours. Medications such as morphine, benzodiazepines, and barbiturates impair the excretion of CK from circulation and may cause a mild elevation. In addition, racial differences in CK levels exist; with healthy African American men having higher levels than Caucasians or Hispanics. Autoantibodies Antinuclear antibodies can be identified in 40–80% of patients with an idiopathic inflammatory myopathy. Attention has focused in particular on myositisspecific antibodies (MSAs). The categories of MSAs that have been identified include antibodies directed against aminoacyl-transfer RNA synthetase (antisynthetases), antibodies directed against signal recognition particle proteins (anti-SRP), and antibodies directed against the nuclear protein complex Mi-2 (anti-Mi-2). The antisynthetases are the most common MSAs, with anti-SRP and anti-Mi-2 occurring considerably less often. The presence of MSAs appears to be associated with a particular clinical subset of patients with myositis. Anti-Mi-2 antibodies are usually specific for dermatomyositis, whereas anti-SRP antibodies are specific for polymyositis and portend a poor prognosis (Targoff, 1990). The antisynthetases are seen in half of the patients with dermatomyositis or polymyositis but are neither sensitive nor specific for either disease. Miller et al. (2002) described clinical and histopathological features of a group of seven anti-SRP positive patients. Interestingly, the results did not show the SRP antibody to be associated with PM, but with a rapidly progressive course. The patients in this study tended to respond poorly to steroids. Hengstman et al. (2006) collected samples from 417 patients with myositis – 23 patients were anti-SRP positive. This study confirmed the lack of response to treatment and the rapidly progressive course. Interstitial lung disease was present in onefourth of the patients. The muscle biopsy demonstrated the presence of a necrotizing myopathy without the typical features seen with an inflammatory myositis. Several biopsies showed staining of necrotic fibers to membrane-attack complex (MAC) (which is also seen in the muscle in paraneoplastic myositis biopsies), but only two patients in this group had neoplastic disease.

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The most common antisynthetase is antihistidyltransfer RNA synthetase (anti-Jo-1); it is most specific for the antisynthetase-myositis syndrome. The presence of anti-PM-Scl, a nonspecific antibody, helps define a unique subset of patients with scleroderma and dermatomyositis or polymyositis (Miller, 1993; Oddis et al., 1992; Targoff, 1990, 1994). Electromyographic (EMG) evaluation EMG testing is useful in differentiating a neurogenic from a myogenic process. EMG is useful in confirming an active myopathic process, but is of no help in distinguishing between the inflammatory myopathies. EMG of affected muscles in inflammatory myopathies demonstrates short duration motor unit potentials; polyphasic motor unit potentials, which may have long duration, bizarre, high-frequency repetitive discharges; and fibrillation potentials, positive sharp waves and insertional irritability (Barkhaus et al., 1990). There is full recruitment, despite weakness, which some term early recruitment. It is typically used to aid in the localization of an active site for biopsy. Noninvasive diagnostic modalities MRI evaluation Magnetic resonance imaging (MRI) offers a noninvasive technique that can identify muscle edema, edema in myofacial distribution, subcutaneous change, muscle calcification, and fatty infiltration (Adams et al., 1995). MRI may be helpful in identifying “occult” muscle disease or to aid in localizing an active site for potential biopsy to optimize the yield of obtaining a meaningful biopsy result. It also may be helpful in distinguishing active inflammation from atrophy. The MRI techniques used include T1and T2-weighted images with T2 being sensitive for detecting muscle edema in acute myositis. Additionally, short tau inversion recovery (STIR), and gadolinium may provide additional information (Childs, 1997). Studies using MRI in patients with dermatomyositis have shown prior to treatment that the vastus lateralis muscle is the most severely involved and that changes in the hamstrings occur in only the extremely weak. Images early in the disease course show preservation of muscle architecture without extensive fat replacement or atrophy, but studies have shown that the inflammation may resolve fairly rapidly over weeks to months

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with fatty change usually occuring after three to five months. Ultrasound evaluation Conventional ultrasound evaluation of muscle can be helpful in detecting muscle edema in the acute inflammatory stage of these disorders and shows up as areas of increased echogenicity. This finding, however, is not specific and can be found in other conditions. A recent study has demonstrated that contrastenhanced ultrasound is able to noninvasively detect increased perfusion in the involved muscle groups in patients with myositis. This study showed a high correlation between increased perfusion on contrastenhanced ultrasound and increased signal intensity on T2-weighted images. The results are preliminary and suggest further analysis in the future (Weber et al., 2005). Muscle biopsy Biopsy should be performed on a clinically affected muscle, which is usually a proximal muscle group such as the biceps or quadriceps. Because of the chance of sampling error, MRI can be useful in localizing an affected area for biopsy. Care must be taken to avoid muscles where electromyography has already been done or where injectable anesthetics have been used, both of which can cause alterations in histopathological features. Arahata and Engel (1984) reported inflammatory cells infiltrating non-necrotic muscle fibers as the hallmark of polymyositis. Interpretation of muscle biopsy results has been reviewed (Dalakas, 2002). The main feature in PM is the presence of endomysial lymphocytic infiltration. Unfortunately, similar findings can also be found in patients with certain muscular dystrophies (Amato and Griggs, 2004). Thus screening for immunocytochemical staining for proteins known to be associated with muscular dystrophies is appropriate. The main finding in DM is perivascular B-cell-predominant inflammation associated with microinfarcts and perifascicular atrophy. Though perifascicular atrophy is specific for DM, sometimes the diagnosis of DM or PM cannot be made on the basis of histopathology alone. Immunopathological markers such as the MHC-I/ CD8 complex may be more specific for polymyositis in addition to inclusion myositis and may be helpful in distinguishing antigen-driven inflammatory cells that characterize PM and IBM from secondary

inflammation seen in other disorders, such as dystrophies (Dalakas, 2004). Also, the presence of the MAC on these specimens may be helpful (Greenberg and Amato, 2004). It has been identified in patients with DM but also in necrotizing myopathies. Association with malignancy Literature reviews have demonstrated that certain cancers (e.g. ovarian, stomach, and lymphoma) are highly associated with DM and PM relative to the normal population. The most common malignancies in the general population (breast, lung, colorectal, and prostate) are seen in these patients, but a strong statistical association does not necessarily exist, however, these reports are conflicting (Buchbinder et al., 2001; Hill et al., 2001; Sigurgeirsson et al., 1992). A continuing question in managing this group of patients is what kind of evaluation should be undertaken to screen for occult malignancy. Unfortunately, large controlled prospective studies are not available to adequately research this question. At this point, age-appropriate cancer screening and perhaps pelvic imaging to evaluate for ovarian cancer in women is reasonable. A recent study looking at tumor antigen markers (CEA, CA15-3, CA19-9, and CA125) for detection of solid cancers did identify both the CA125 and CA19-9 as useful markers in determining a patient’s risk of developing tumors in this population of patients (especially if they did not have interstitial lung disease) (Amoura et al., 2005). This risk was most notable in the first year following the increased CA125 and CA19-9 levels. Immunogenetics and pathogenesis The exact cause of the idiopathic inflammatory myopathies is unknown, but they are generally accepted to be the result of an immune-mediated process. Evidence supporting this hypothesis includes the association of idiopathic inflammatory myopathies with other autoimmune diseases such as thyroiditis, vitiligo, myasthenia gravis, and other connective tissue disease; the high prevalence of circulating autoantibodies in patients with polymyositis and dermatomyositis; and the pathological changes seen in the muscle of affected patients. The myopathies appear to have an environmental component as suggested by geographic clustering of cases and the seasonal onset of disease (Sarkar et al., 2005). Genetic factors seem to play an important role, with the association with certain histocompatability genes

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(Chinoy et al., 2004). Viral infections like influenza, mumps, cytomegalovirus, and Epstein–Barr have been inconclusively implicated in the pathogenesis, perhaps as a trigger for the immune response. Dermatomyositis in general is felt to be a B-cell mediated process with microangiopathy. Antibodies are directed against the endothelium of the endomysial capillaries leading to a prominent vascular reaction. Eventually, it is hypothesized that the complement system is activated and the MAC is formed (Greenberg and Amato, 2004). Polymyositis on the other hand appears to be secondary to cytotoxic T-cell response directed against the muscle fibers and the histology shows invasion of the muscle fibers by inflammatory cells. Treatment Regardless of the pharmacological treatment, all patients with myositis and/or calcinosis require extensive physical therapy to prevent joint contractures and disuse atrophy of the muscle tissue. This may include gentle, passive stretching and splinting in the initial stages of the disease and more aggressive strength building once the muscle inflammation has subsided (Dalakas, 1991). In regard to dermatomyositis topical therapy consists of the routine use of class I or II steroids for the pruritis and inflammatory erythematous skin changes. Hydroxychloroquine also has been used in the treatment of the rash. Treatment of calcinosis cutis is difficult and anecdotal reports of diltiazem (Oliveri et al., 1996), probenicid (Skuterud et al., 1981), warfarin (Berger et al., 1987), colchicine (Taborn et al., 1978), aluminum hydroxide (Wang et al., 1988), EDTA (Herd and Vaughn, 1964), and more recently successful reports with the use of bisphonates have been published (Ambler et al., 2005). Steroids have been the mainstay in the treatment of myositis. Unfortunately, many patients have an inadequate response and need more aggressive therapy. Additionally, treatment tends to be long term and the side effects of steroids are compounded over time. A variety of steroid-sparing agents have been tried including azathioprine, methotrexate, cyclosporine, cyclophosphamide, mycophenolate (Edge et al., 2006; Majithia and Harisdangkul, 2005), and tacrolimus (Mitsui et al., 2005). High-dose intravenous immunoglobulin (IVIg) infusions as treatment for dermatomyositis have been shown to be beneficial in a placebo-controlled double-blind randomized trial (Dalakas et al., 1993). Other studies have

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shown similar positive results, but cost and availability is an issue for some (Dalakas, 2005, 2006; Illa, 2005; Wetter et al., 2005). Rapamycin (sirolimus) has been reported to be useful in the treatment of DM, and appears to also have some antineoplastic activity which makes it appealing in this patient population that appears to have increased risk for the development of malignancy (Nadiminti and Arbiser, 2005). With the burgeoning field of biologics in the treatment of inflammatory arthritis clinicians are now interested in the use of biologics in the inflammatory myopathies in terms of treatment response and better understanding of the underlying pathogenesis. It is generally well accepted that DM is humorally mediated and B cells may play a significant role in the pathogenesis. An open-labeled trial of seven adult patients with DM with inadequate response to current available therapies underwent four intravenous infusions of rituximab (Levine, 2005). Rituximab is a CD20+ B-cell depleting antibody. Six of the patients had clinical improvement in muscle strength over baseline by 36–113%. The maximal improvement occurred 12 weeks after the initial infusion. CD20 B cells were effectively depleted by 12 weeks. Other small studies and case reports have shown that rituximab is effective (Chiappetta et al., 2005; Noss et al., 2005). Tumor necrosis factor (TNF) alpha is a proinflammatory cytokine, which appears to play a role in mediating many inflammatory conditions. Anecdotal reports of its use in patients with refractory DM/PM have been promising (Efthimiou et al., 2004). The largest report has been a retrospective study of eight patients with refractory disease, six of whom had a dramatic decline in the serum CK and significant improvement in fatigue and muscular strength (Norman et al., 2006). The patients that did not respond did not have significant elevations in the pretreatment CK levels. It has been suggested that TNF blockers may be more effective in the initial acute inflammatory phase (as induction therapy). A theoretical concern with the use of these agents long term would be the potential to enhance the development of malignancy in a population of patients that already appear to be at high risk. Prognosis It has been well recognized that the long-term outcome in patients with PM and DM is rather dismal. The mortality rate ranges from 4–45% of patients. The morbidity is also quite high. Hopefully, with

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newer agents available to treat these patients these rates will decline. Several variables have been identified as being useful in predicting worse outcomes including older age, male sex, dysphagia, longstanding symptoms prior to diagnosis, pulmonary or cardiac involvement, presence of antisynthetase or anti-SRP antibodies, and type of myositis (Devere and Bradley, 1975). A more recent study has shown that these patients have a more than 10% chance of dying of a cause related to their disease, mostly cancer, especially in the first year to onset (Bronner et al., 2006). The majority of the surviving patients have a chronic course or polycyclic disease. At two years follow up of the patients in the study 65% had normal strength, 34% had slight or no disability, and only 16% had normal scores on the quality of life scale. A retrospective cohort study of 53 medical records of patients with PM, DM, CTD-associated myositis, and malignancy-associated myositis demonstrated that PM and CTD-associated myositis had a higher rate of relapse rate compared to the other groups (Agarwal et al., 2005). Seventeen patients had multiple relapses and tended to occur within the first two years. Advanced age and duration of symptoms seemed to be associated with a higher relapse rate. In juvenile dermatomyositis the outcomes prior to the introduction of corticosteroids were poor with a mortality rate greater than 30%, and 50% were left with serious disabilities. After steroids were used in the 1960s, the mortality rate dropped to less than 10%. Huber and Feldman (2005) conducted a longterm follow-up study and contacted 65 of 80 children 3–19 years after their diagnosis. Calcinosis was present in 34% and contributed to reduced function. Continuing disease activity was a problem: 40% had ongoing rash, 10% reported weakness, 22% had ongoing pain, and 35% still required medication to control their disease. Conclusion With the many advancements in biological treatments for a variety of immune-mediated disorders, in addition to the ongoing identification of newer antibody profiles, immunohistopathological and genetic testing, it is likely that we will gain further insight into the pathogenesis and hence treatment of the inflammatory myopathies. Future work will need to focus on a universally accepted and validated classification schema so that these newer therapies are applied and tested to a homogeneous patient population to obtain the most meaningful results.

References Adams, E.M., Chow, C.K., Premkumar, A. and Plotz, P.H. 1995. The idiopathic inflammatory myopathies: Spectrum of MR imaging findings. Radiographics, 15, 563–74. Agarwal, S.K., Monach, P.A., Docken, W.P. and Coblyn, J.S. 2005. Characterization of relapses in adult idiopathic inflammatory myopathies. Clin Rheumatol, 3, 1–6. Amato, A.A. and Griggs, R.C. 2003. Unicorns, dragons, polymyositis and other mythical beasts. Neurology, 61, 288–9. Ambler, G.R., Chaitow, J., Rogers, M., McDonald, D.W. and Ouvrier, R.A. 2005. Rapid improvement of calcinosis in juvenile dermatomyositis with alendronate therapy. J Rheumatol, 32, 1837–9. Amoura, Z., Duhaut, P., Houng du, L.T. et al. 2005. Tumor antigen markers for the detection of solid cancers in inflammatory myopathies. Cancer Epidemiol Biomarkers Prev, 14(5), 1279–82. Arahata, K. and Engel, A.G. 1984. Monoclonal antibody analysis of mononuclear cells in myopathies. I: Quantitation of subsets according to diagnosis and sites of accumulation, and demonstration and counts of muscle fibers invaded by T cells. Ann Neurol, 16, 193–208. Barkhaus, P.E., Nandedkar, S.K. and Sanders, D.B. 1990. Quantitative EMG in inflammatory myopathy. Muscle Nerve, 13, 247–53. Berger, R.B., Featherstone, G.L., Raasch, R.H., McCartney, W.H. and Hadler, N.M. 1987. Treatment of calcinosis universalis with low-dose warfarin. AM J Med, 83, 72–5. Bohan, A. and Peter, J.B. 1975. Polymyositis and dermatomyositis (first of two parts). N Engl J Med, 292, 344–7. Bowyer, S.L., Clark, R.A., Ragsdale, C.G., Hollister, J.R. and Sullivan, D.B. 1986. Juvenile dermatomyositis: Histological findings and pathogenetic hypothesis for the associated skin changes. J Rheumatol, 13, 753–8. Bronner, I.M., van der Meulen, M.F., de Visser, M. et al. 2006. Long-term outcome in polymyositis and dermatomyositis. Ann Rheum Dis, in press. Buchbinder, R., Forbes, A., Hall, S., Dennett, X. and Giles, G. 2001. Incidence of malignant disease in biopsy-proven myopathy. Ann Intern Med, 134, 1087–95. Chiappetta, N., Steier, J. and Gruber, B. 2005. Rituximab in the treatment of refractory dermatomyositis. J Clin Rheumatol, 11, 264–6. Childs, N.D. 1997. STIR-MRI goes past fat to detect myopathies. Intern Med News, 1, 37. Chinoy, H., Ollier, W.E. and Cooper, R.G. 2004. Have recent immunogenetic investigations increased our understanding of disease mechanisms in the idiopatic inflammatory myopathies? Curr Opin Rheumatol, 16, 707–13.

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Dalakas, M.C. 1991. Polymyositis, dermatomyositis, and inclusion-body myositis. N Engl J Med, 325, 1487–98. Dalakas M.C. 2002. Muscle biopsy findings in inflammatory myopathies. Rheum Dis Clin North Am, 28, 779–98. Dalakas, M.C. 2004. Inflammatory disorders of muscle: progress in polymyositis, dermatomyositis and inclusion body myositis. Curr Opin Neurol, 17561–7. Dalakas, M.C. 2005. Intravenous immunoglobulin in patients with anti-GAD antibody-associated neurological diseases and patients with inflammatory myopathies. Effects on clinicopathological features and immunoregulatory genes. Clin Rev Allergy Immunol, 29, 255–68. Dalakas, M.C. 2006. The role of high-dose immune globulin intravenous in the treatment of dermatomyositis. Int Immunopharmacol, 6, 550–6. Dalakas, M.C., Illa, I., Dambrosia, J.M. et al. 1993. A controlled trial of high dose intravenous immunoglobulin infusions as treatment for dermatomysotis. N Engl J Med, 329, 1993–2000. DeVere, R. and Bradley, W.G. 1975. Polymyositis: Its presentation, morbidity and mortality. Brain, 98, 637–66. Dickey, B.F. 1984. Pulmonary disease in polymyositis/ dermatomyositis. Semin Arthritis Rheum, 14, 60– 76. Edge, J.C., Outland, J.D., Dempsey, J.R. and Callen, J.P. 2006. Mycophenolate mofetil as an effective corticosterid-sparing therapy for recalcitrant dermatomyosits. Arch Dermatol, 142, 65–9. Efthimiou, P., Schwartzman, S. and Kagen, L.J. 2006. Possible role for TNF-inhibitors in the treatment of resisitant dermatomyosits and polymyositis. A retrospective study of eight patients. Ann Rheum Dis, in press. Euwer, R.L. and Sontheimer, R.D. 1996. Dermatomyositis. In R.D. Sontheimer and T.T. Provost (eds.), Cutaneous Manifestations of Rheumatic Disease, Williams & Wilkins, Baltimore, pp. 73–114. Gerami, P., Schope, J.M., McDonald, L., Walling, H.W. and Sontheimer, R.D. 2006. A systematic review of adult-onset clinically amyopathic dermatomyositis (dermatomyositis sine myositis): A missing link within the spectrum of the idiopathic inflammatory myopathies. J Am Acad Dermatol, 54(4), 597–613. Greenberg, S.A. and Amato, A.A. 2004. Uncertainties in the pathogenesis of adult dermatomyositis. Curr Opin Neurol, 17, 359–64. Hengstman, G.J., Ter Laak, H.J., Vree Egberts, W.T. et al. 2006. Anti-SRP autoantibodies, marker of a necrotizing myopathy. Ann Rheum Dis, in press. Herd, J.K. and Vaughan, J.H. 1964. Calcinosis universalis complicating dermatomyositis. Arthritis Rheum, 7, 259. Hill, C.L., Zhang, Y., Sigurgeirsson, B. et al. 2001. Frequency of specific cancer types in dermatomyo-

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sitis and polymyositis: a population-based study. Lancet, 357, 96–100. Huber, A. and Feldman, F.M. 2005. Long-term outcomes in juvenile dermatomyositis: How did we get here and where are we going? Curr Rheum Reports, 7, 441–6. Illa, I. 2005. IVIg in myasthenia gravis, Lambert–Eaton myasthenic syndrome and inflammatory myopathies: Current status. J Neurol, 252(1), 14–18. Jackson, H. 1887. A case of acute, infectious universal myositis. Boston Med Surg J, 116, 498. Kovacs, S.O. and Kovacs, S.C. 1998. Dermatomyositis. J Am Acad Dermatol, 39, 899–922. Levine, T. 2004. Rituximab in the treatment of dermatomyositis. An open-label pilot study. Arthritis Rheum, 52, 601–7. Majithia, V. and Harisdangkul, V. 2005. Mycophenolate mofetil (CellCept): An alternative therapy for autoimmune inflammatory myopathy. Rheumatology, 44, 386–9. Martini, A., Ravelli, A., Viola, S., Sambugaro, R. and De Benedetti, F. 1987. Calcinosis as the presenting sign of juvenile dermatomyositis in a 14-month old boy. Helv Paediatr Acta, 42, 181–4. Miller, F.W. 1993. Myositis-specific autoantibodies: Touchstones for understanding the inflammatory myopathies. JAMA, 270, 1846–9. Miller, T., Al-Lozi, M.T., Lopate, G. and Pestronk, A. 2002. Myopathy with antibodies to the signal recognition particle: clinical and pathological features. J Neurol Neurosurg Psychiatry, 73, 420–8. Mitsui, T., Kuroda, Y., Kunishige, M. and Matsumoto, T. 2005. Successful treatment with tacrolimus in a case of refractory dermatomyositis. Internal Med, 44, 1197–9. Nadiminti, U. and Arbiser, J.L. 2005. Rapamycin (sirolimus) as a steroid-sparing agent in dermatomyositis. J Am Acad Dermatol, 52, S17–19. Norman, R., Breenber, R.G. and Jackson, J.M. 2006. Case reports of etanercept in inflammatory dermatoses. J Am Acad Dermatol, 54, S139–42. Noss, E.H., Hausner-Sypek, D.L. and Weinblat, M.E. 2005. Rituximab as therapy for refractory polymyositis and dermatomyositis. J Rheumatol, 33, 1021–6. Oddis, C.V., Okano, Y., Rudert, W.A., Trucco, M., Duquesnoy, R.J. and Medsger, T.A. Jr. 1992. Serum autoantibody to the nucleolar antigen PM-Scl. Arthritis Rheum, 35, 1211–17. Oliveri, M.B., Palermo, R., Mautalen, C. and Hubscher, O. 1996. Regression of calcinosis during diltiazem treatement in juvenile dermatomyositis. J Rheumatol, 23, 2152–5. Pachman, L.M. and Dooke, N. 1980. Juvenile dermatomyositis: A clinical and immunologic study. J Pediatr, 96, 226–34. Reed, A.M. and Mason, T. 2005. Recent advances in juvenile dermatomyositis. Curr Rheum Reports, 7, 94–8.

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Sarkar, K., Weinberg, C.R., Oddis, C.V. et al. 2005. Seasonal influence on the onset of idiopathic inflammatory myopathies in serologically defined groups. Arthritis Rheum, 52, 2433–8. Sigurgeirsson, B., Lindelof, B., Edhag, O. and Allander, E. 1992. Risk of cancer in patients with dermatomyositis or polymyositis. A population based study. N Engl J Med, 326, 363–7. Skuterud, E., Sydnes, O.A. and Haavik, T.K. 1981. Calcinosis in dermatomyositis treated with probenicid. Scand J Rheumatol, 10, 92–4. Taborn, J., Bole, G.G. and Thompson, G.R. 1978. Colchicine suppression of local and systemic inflammation due to calcinosis universalis in chronic dermatomyositis. Ann Intern Med, 89, 648. Targoff, I.N. 1990. Immune mechanisms in myositis. Curr Opin Rheumatol, 2, 882–8. Targoff, I.N. 1994. Immune manifestation of inflammatory muscle disease. Rheum Dis Clin North Am, 20, 857–80. Tazelaar, H.D., Viggiano, R.W., Pickersgill, J. and Colby, T.V. 1990. Interstitial lung disease in polymyositis and dermatomyositis. Am Rev Respir Dis, 141, 727.

Unverricht, H. 1887. Ueber eine eigenthumliche form von acuter muskelentzundung mit einem der trichinose ahnelnden krankheitsbilde. Munchener Med Sochnschrf, 34, 488. Wagner, E. 1887. Ein Fall von acuter polymyositis. Dtsch Arch Med, 40, 241. Wagner, E. 1863. Falleiner Seltnen Muskelkrankheit. Dtsch Arch Heilk, 4, 282. Wang, W.J., Lo, W.I. and Wong, C.K. 1988. Calcinosis cutis in juvenile dermatomyositis: remarkable response to aluminum hydroxide therapy (letter). Arch Dermatol, 124, 1721. Weber, M.A., Krix, M., Jappe, U. et al. 2005. Pathologic skeletal muscle perfusion in patients with myositis: detection with quantitative contrast-enhanced USinitial results. Radiology, 238, 640–9. Wetter, D.A., Davis, M.D., Yiannias, J.A. et al. 2005. Effectiveness of intravenous immunoglobulin therapy for skin disease other than toxic epidermal necrolysis: A retrospective review of Mayo Clinic experience. Mayo Clin Proc, 80, 41–7. Yale, S.H., Adlakha, A. and Stanton, M.S. 1990. Dermatomyositis with pericardial tamponade and polymyositis with pericardial effusion. Am Heart J, 126, 997.

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11 Neuro-Sjögren’s syndrome Bernadette Kalman

Sjögren’s syndrome (SS) is an autoimmune disease first described in female patients with arthritic problems, dry eyes and mouth by a Swedish physician, Henrik Sjögren (1933). SS can present in any age and gender, but it predominantly occurs in middleaged women (female:male ratio = 9:1). It may present as an isolated syndrome (primary or P-SS) or be associated with other connective tissue disorders (secondary S-SS). P-SS is characterized by lymphocytic infiltration of exocrine glands and epithelia at multiple sites. The characteristic involvement of lachrymal and salivary glands results in xerophthalmia and xerostomia. About a third of patients also have extraglandular manifestations with polyarthralgia, Raynaud’s phenomenon, and interstitial pulmonary fibrosis occurring most frequently. A revised version of the European classification criteria for SS was recently published by the AmericanEuropean Consensus Group (2002) (Box 11.1). The proposed evaluation process facilitates establishing the diagnosis with high specificity and sensitivity. Clinical features of neuro-SS Neurological complications may be seen in about 40% of patients with P-SS. Diagnostic difficulties may arise when the neurological abnormalities precede systemic signs of P-SS. The involvement of the nervous system in P-SS is dominated by abnormalities in the peripheral nervous system (PNS). The PNS dysfunction may include distal sensory or sensorymotor, usually axonal, polyneuropathy. The abnormality more often involves temperature and light touch sensation than proprioception. In addition to a painful sensory polyneuropathy, however, ataxic polyneuropathy may also develop. Demyelinating polyneuropathy can be seen in a smaller proportion of patients, and bilateral carpal tunnel syndrome is not uncommon. Dysautonomia with tonic pupils, paralytic ileus, upper gastrointestinal dysfunction, neurogenic bladder and hypohydrosis have also

been noted in relationship with the involvement of autonomous nerves and antibodies to the ganglionic acetylcholine receptor (Lafitte et al., 2001; Mori et al., 2003). Sural nerve biopsy usually shows axonal degeneration, demyelination, remyelination, and variable degrees of large or small fiber depletion. T-cell infiltration in the dorsal root ganglia may be found in patients with ataxic sensory neuropathy. Perivascular infiltration (vasculitis) is not a frequent histological finding, but microangiopathy in the endoneurium is believed to contribute to polyneuropathy, particularly in older patients. The involvement of the central nervous system (CNS) can present with progressive multifocal neurological symptoms, spinal cord dysfunction, motoneuron disease (with the involvement of upper and lower mononeurons), and cortical or subcortical cognitive decline (Lafitte et al., 2001). The spinal cord pathology may cause transverse myelitis with paraparesis and sphincter abnormalities or progressive myelopathy. The cognitive deficits frequently involve frontal executive functions, and manifest as dysinhibition and difficulties with attention and abstraction. Memory deficit and visuospatial dysfunction are also often present. Combined CNS and PNS abnormalities occur in a subgroup of patients (Lafitte et al., 2001). Primary progressive multiple sclerosis (MS) and P-SS There has been an ongoing debate about the occurrence of P-SS in patients presenting with primary progressive (PP-) MS. de Seze et al. (2001) assessed clinical and laboratory criteria for SS in 60 consecutive patients with PP-MS. Patients were questioned about xerostomia, xerophthalmia, and underwent a minor salivary gland biopsy, Schirmer test, salivary gland scintigraphy, and tests for SSA and SSB serology. Ten out of 60 patients with PP-MS met four or more criteria for P-SS (Box 11.1). The authors

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Box 11.1 A revised version of the European classification criteria for SS proposed by the American-European Consensus Group (after Vitali et al., 2002). I

II

III

IV

Ocular symptoms: the response is positive if the patient has at least one of the following: – Daily, persistent, troublesome dry eyes for more than three months – A recurrent sensation of sand or gravel in the eyes – Use tear substitutes more than three times a day Oral symptoms: a response is positive if the patient has at least one of the following: – A daily feeling of dry mouth for more than three months – Had recently or persistently swollen salivary glands as an adult – Frequently drinks liquids to aid in swallowing dry food Ocular signs: objective evidence of ocular involvement defined as a positive result for at least one of the following tests: – Schirmer’s I test without anesthesia (
5 mm in 5 min) – Rose Bengal score or other ocular dye score (= or >4 according to van Bijsterveld’s scoring) Histopathology: focal lymphocytic sialoadenitis in minor salivary glands with a focus score 1, defined as

suggest that P-SS can mimic PP-MS. While the remarkable resemblance of P-SS-related myelopathy to PP-MS is well documented (Alexander et al., 1986; Noseworthy et al., 1989; Pericot et al., 2003), the current diagnostic and classification criteria for MS and P-SS (McDonald et al., 2001; Polman et al., 2005; Thompson et al., 2000; Vitali et al., 2002) (Box 11.1) should help to differentiate the two conditions in most cases. Ambiguities are only expected in a small subgroup of patients that meet both the criteria of PP-MS and P-SS. In these cases the question arises as to whether an association occurred between two autoimmune conditions or P-SS caused

V

VI

a number of lymphocytic foci per 4 mm2 of glandular tissue. Salivary gland pathology: objective evidence of salivary gland involvement defined by a positive result for at least one of the following tests: – Unstimulated salivary flow (
1.5 ml in 15 min) – Parotid sialography revealing diffuse sialectasias without obstruction in major ducts – Salivary scintigraphy demonstrating delayed uptake, reduced concentration, and/or delayed excretion of tracer Autoantibodies: The presence of antibodies to SSA (Ro) or SSB (La) antigens or to both in the serum

For P-SS: presence of any four of six items is indicative of P-SS, if either IV or VI is positive; presence of any three of items III, IV, V, and VI. For S-SS: in patients with connective tissue disease, the presence of items I and II plus two from items III, IV, and V may be consistent with S-SS. Exclusion criteria: past head and neck irradiation; hepatitis C infection; AIDS; lymphoma; sarcoidosis; graft versus host disease; use of anti-cholinergics

a myelopathic phenotype indistinguishable from PP-MS (de Seze et al., 2001; Pericot et al., 2003). Immunopathogenesis The etiology of SS is unknown. Involvement of exogeneous microbial agents (e.g. retroviruses) in the initiation of an abnormal immune response against self-antigens has been postulated but not proven (Konttinen and Kasna-Ronkainen, 2002). Immune abnormalities of epithelial cells include an increased expression of HLA Class II and costimulatory molecules, which facilitate antigen presention to

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and activation of the infiltrating, predominantly CD4 lymphocytes. The presented antigens include SSA (Ro), SSB (La), α-fodrin, β-fodrin, and muscarinic cholinergic receptors. The helper T-cell activation leads to B-cell stimulation and antibody production. Anti-SSA may occur alone, while anti-SSB is usually present in association with anti-SSA. An association of P-SS with the HLA A1, B8, DR3, DQ2 haplotype was suggested (Fei et al., 1991; Rischmueller et al., 1998), but this association may be restricted to antiSSA and anti-SSB positive forms of P-SS (Gottenberg et al., 2003). The CSF can be completely normal, or have mildly elevated proteins and lymphocytic pleocytosis. Intrathecal IgG synthesis and oligoclonal bands may occur, but are not typical in P-SS. MRI imaging T2-weighted and FLAIR MRI of the brain may reveal punctate hyperintensities in the periventricular white matter, deep gray matter, and the brainstem, but normal imaging is not rare even in cognitively affected patients. Spinal imaging in patients with spinal cord syndromes usually reveals abnormalities compatible with transverse myelitis, myelopathy, or discrete MS-like lesions (Fig. 11.1).

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Treatment High-dose corticosteroids have been used in acute exacerbations and low-dose steroids in chronic stages of P-SS. In progressive cases, azathioprine, cyclophosphamide, and other immune-suppressive regimens have been tried. Most recently rituximab, a chimeric human–mouse antibody to CD20 positive B cells (90% of all B cells), has been successfully used in P-SS and lymphoma (Somer et al., 2003). Summary Sjögren’s syndrome is a systemic autoimmune disorder that may occasionally overlap with other connective tissue diseases. A great proportion of patients with SS will develop neurological abnormalities most commonly affecting the PNS. A progressive multifocal CNS involvement can also be seen in P-SS which may mimic PP-MS. Recently developed diagnostic criteria for SS and MS provide important guidance for the diagnostic evaluation which should direct disease-specific therapeutic decisions. Patients with P-SS require long-term treatment and laboratory monitoring with alertness for a potential development of a lymphoproliferative condition. References

Fig. 11.1 MRI images of the spinal cord from a patient with Sjögren’s syndrome. T2-weighted images of a cervical cord lesion at the level of C2–C3. The patient presented with progressive myelopathy imitating primary progressive MS.

Complications The underlying lymphoproliferative process increases the risk 44 times for a malignant lymphoma in patients with P-SS. Therefore, patients with P-SS require regular monitoring and laboratory testing.

Alexander, E.L., Malinow, K., Lejewski, J.E., Jerdan, M.S., Provost, T.T. and Alexander, G.E. 1986. Primary Sjögren’s syndrome with central nervous system disease mimicking multiple sclerosis. Ann Intern Med, 104, 323–30. de Seze, J., Devos, D., Castelnovo, G. et al. 2001. The prevalence of Sjögren’s syndrome in patients with primary progressive multiple sclerosis. Neurology, 57, 1359–63. Fei, H.M., Kang, H., Scharf, S., Erlich, H., Peebles, C. and Fox, R. 1991. Specific HLA-DQA and HLA-DRB1 alleles confer susceptibility to Sjögren’s syndrome and antibody production. J Clin Lab Anal, 5, 382–91. Gottenberg, J.E., Busson, M., Loiseau, P., et al. 2003. In primary Sjögren’s syndrome, HLA class II is associated exclusively with autoantibody production and spreading of the autoimmune response. Arthritis Rheum, 48, 2240–5. Konttinen, Y.T. and Kasna-Ronkainen, L. 2002. Sjögren’s syndrome: Viewpoint on pathogenesis. One of the reasons I was never asked to write a textbook chapter on it. Scan J Rheumatol Suppl, 116, 15–22. Lafitte, C., Amoura, Z., Cacoub, P. et al. 2001. Neurological complications of primary Sjögren’s syndrome. J Neurol, 248, 577–84.

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McDonald, W.I., Compston, A., Edan, G. et al. 2001. Recommended diagnostic criteria for multiple sclerosis: Guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol, 50, 121–7. Mori, K., Iijima, M., Sugiura, M. et al. 2003. Sjögren’s syndrome associated painful sensory neuropathy without sensory ataxia. J Neurol Neurosurg Psychiatry, 74, 1320–2. Noseworthy, J.H., Bass, B.H., Vandervoort, M.K., et al. 1989. The prevalence of primary Sjögren’s syndrome in a multiple sclerosis population. Ann Neurol, 25, 95–8. Pericot, I., Brieva, L., Tintore, M. et al. 2003. Myelopathy in seronegative Sjögren’s syndrome and/or primary progressive multiple sclerosis. Mult Scler, 9, 256–9. Polman, C.H., Reingold, S.C., Edan, G. et al. 2005. Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald Criteria”. Ann Neurol, 58, 840–6.

Rischmueller, M., Lester, S., Chen, Z. et al. 1998. HLA class II phenotype controls diversification of the autoantibody response in primary Sjögren’s syndrome. Clin Exp Immunol, 111, 365–71. Sjögren, H. 1933. Zur kenntnis der keratoconjunctivitis sicca. Acta Opthalmol, 11(2), 1–151. Somer, B.G., Tsai, D.E., Downs, L., Weinstein, B., Schuster, S.J.; American College of Rheumatology ad hoc Committee on Immunologic Testing Guidelines. 2003. Improvement in Sjögren’s syndrome following therapy with rituximab for marginal zone lymphoma. Arthritis Rheum, 49, 394–8. Thompson, A.J., Montalban, X., Barkhof, F., et al. 2000. Diagnostic criteria for primary progressive multiple sclerosis: A position paper. Ann Neurol, 47, 831–5. Vitali, C., Bombardieri, S., Jonsson, R. et al.; European Study Group on Classification Criteria for Sjögren’s Syndrome. 2002. Classification criteria for Sjögren’s syndrome: A revised version of the European criteria proposed by the American-European Consensus Group. Ann Rheum Dis, 61, 554–8.

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12 Neuro-Behçet’s syndrome Bernadette Kalman

Behçet’s disease is a multisystem disorder with oral and genital ulcerations and uveitis first described by a Turkish dermatologist, H. Behçet (1937). Additional pathology with cardiovascular, pulmonary and gastrointestinal involvement, and erythema nodosum, pustular skin lesions, or pseudofolliculitis may occur. Oligoarthropathy affecting large joints is also relatively common. Constitutional symptoms include fatigue, fever, nausea, and weight loss. The etiopathogenesis is unknown. Viral and bacterial infectious origins have been investigated but not proven. The postulated autoimmune etiology of the episodic vasculitic process is supported by the association with the HLA B51 allele, neutrophil hyperactivity, and increased CD8/CD4 cell ratio. However, in contrast to the usual female predominance in autoimmunity, males develop Behçet’s disease more frequently. Behçet’s disease is most commonly seen in the eastern Mediterranean countries, the Middle East, and East Asia, but Caucasians are also affected (Kidd et al., 1999). The prevalence is estimated to be 37/105 in rural and 8/105 in urban regions of Turkey (Yurdakul et al., 1988). In contrast, 0.4/105 prevalence rate was estimated in the UK (Chamberlain, 1977). The first autopsy case with neurological involvement was reported by Berlin (1944). A large series of autopsy cases with Behçet’s disease revealed histological evidence of neurological involvement in 20% of patients (Lakhanpal et al., 1985). Diagnosis of Behçet’s disease Based on the criteria defined by the International Study Group for Behçet’s disease (1990), the prerequisite for diagnosis is the presence of recurrent oral ulcerations plus any two of the following: recurrent genital ulcerations, erythema nodosum, pseudofolliculitis, papulopustular eruption, acneiform nodules, positive pathergy test, anterior or posterior uveitis, and retinal vasculitis. In the pathergy test, the forearm is pricked with a sterile needle. The

test is positive if a small red bump or pustule appears 1–2 days after the needle insertion. Clinical presentation of neuro-Behçet Early studies (Pallis and Fudge, 1956; Wadia and Williams, 1957) classified three forms of neurological complications: 1 Subacute brainstem involvement with cranial neuropathy, oculomotor abnormalities, nystagmus, gaze palsy, dysarthria, ataxia and bulbar weakness, accompanied by systemic symptoms of fever, skin lesions, and arthropathy. 2 Meningomyelitis with signs of meningeal inflammation and spinal cord lesions. 3 A confusional syndrome caused by meningoencephalitis initially without focal neurological signs, but with dementia, quadriparesis, pseudobulbar palsy, and Parkinsonism in chronic stages. Subsequent studies pointed to the involvement of blood vessels, particularly with venous sinus thrombosis and intracranial hypertension. Arterial thrombosis and aneurism formation appeared less frequently (Akman-Demir et al., 1996; Bienenstock and Margulies, 1961; Bousser et al., 1980; Wechsler et al., 1989). Idiosyncratic presentations including tumefactive neuro-Behçet disease have been reported (Bennett et al., 2004). While the involvement of optic nerves is relatively rare, isolated optic neuritis may occur (Kocer et al., 1999). Further, neuroBehçet’s disease may imitate multiple sclerosis (MS) (Ashjazadeh et al., 2003). The involvement of peripheral nervous system appears to be rare. In a recent report, Akmar-Demir et al. (1999) reviewed the records of 558 patients with neuroBehçet in Turkey. After the exclusion of patients who did not fulfill the diagnostic criteria, the records of 200 predominantly male patients were analyzed. Of these 200, 162 patients had parenchymal disease,

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51% of them presenting with brainstem involvement alone or in combination with other parenchymal lesions, 14% had spinal cord lesion, 15% had hemispheric involvement, and 19% had isolated pyramidal signs. The remaining 38 patients had either secondary or nonparenchymal involvement. In this latter subgroup, 34 patients had increased intracranial pressure due to dural sinus thrombosis, superior vena cava occlusion, or unknown reasons. Aseptic meningitis was noted in one, and arterial involvement with dissection, occlusion, or aneurism was noted in three patients. In the parenchymal group, pyramidal, hemispheral, behavioral, and sphincter abnormalities were most commonly recorded, while in the secondary and nonparenchymal cohort raised intracranial pressure was the most common clinical finding. The most frequent location of lesions in the parenchymal group was the brainstem and basal ganglia on magnetic resonance imaging (MRI), and 60% of these patients had pleocytosis with elevated protein in the cerebrospinal fluid (CSF). In the nonparenchymal group, elevated pressure but normal chemistry was noted in the CSF. The majority (79%) of patients had a single relapse, a few relapses with remissions or relapsing-progressive course, while 10% had primary progressive course and 21% had silent neurological lesions. A similar study of 50 predominantly Caucasian patients with neuro-Behçet was reported by Kidd et al. (1999) in the UK. Half of these patients presented with meningoencephalitis and brainstem involvement, 14% with spinal cord disease, 10% hemispheral involvement, 8% with meningitis and 8% with intracranial hypertension. In those with hemispheral signs, five had motor or sensory involvement and three patients also developed seizures. The spinal cord involvement varied and the presentation included severe transverse myelitis with paraplegia, Brown–Sequard syndrome or isolated sensory disturbance, hyperreflexia and sphincter abnormality without paresis. There were only two cases (4%) with cerebral venous thrombosis, but eight patients (16%) presented with cranial neuropathy (optic, vestibulo-cochlear, facial, or trigeminal+facial). The prognosis was generally good, and the majority of patients had only one attack over a median of three years. Repeated attacks, incomplete recovery, progressive course, and inflammatory CSF usually indicated poor prognosis. Among patients followed for a median of three years (1–19 years), complete recovery from attacks

without residual disability was seen in the majority with parenchymal lesions. Only a few patients made no improvement after the acute attacks of spinal cord and brainstem lesions. Patients with intracranial hypertension did well following shunting. However, both repeated relapses and progressive deterioration were also noted in patients with parenchymal involvement. Varying figures of mortality have been reported. The mortality rate was as high as 25% in the first year of disease in the 1960s (Wolf et al., 1965). Although the currently used more aggressive medications changed the outcomes, an 11% mortality rate was still estimated in a median follow-up period of five years in the recent study by Akman-Demir et al. (1999). Mortality predominantly occurred in patients with brainstem lesions due to aspiration. Imaging The most common lesion localization on T2-weighted and FLAIR imaging is in the mesencephalon and diencephalon and in the ponto-bulbar region with or without multiple periventricular white-matter involvement, followed by spinal cord lesions. However, hemispheral white-matter lesions without periventricular involvement have also been noted, particularly in those patients with hemispheral syndromes. Severe tissue atrophy was described in patients with progressive disease. Patients with neuro-Behçet and nonparenchymal involvement (cranial neuropathy, increased intracranial pressure) may have normal MRI (Kidd et al., 1999). The mesodiencephalic lesions are often associated with significant edema extending along longitudinal tracts in the brainstem and diencephalon. In acute stages, lesions often enhance on T1-weighted postcontrast images. The anatomical distribution of lesions supports the hypothesis of a small-vessel vasculitis with a predominantly venous involvement (Kocer et al., 1999). In contrast to MS, magnetization transfer imaging does not show significant lesion load in the normal appearing tissue compartment of patients with neuro-Behçet (Rovaris et al., 2000). Cerebrospinal fluid, CSF A mild to moderate pleocytosis (10–360 cells/µl) with up to 10% polymorphonuclear cells, 90–100% lymphocytes and a few monocytes can usually be seen in the CSF. The protein level may be normal or slightly elevated in the majority of cases. Patients with meningeal involvement have more inflammatory

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cells and elevated proteins. Intrathecal synthesis of immunoglobulins and the occurrence of oligoclonal bands are not characteristic of neuro-Behçet (Kidd et al., 1999). Pathology Chronic meningoencephalitis with inflammatory cell infiltration around the blood vessels in the meninges and the parenchyma, and regions of necrosis, gliosis and accumulation of lipid-laden macrophages are usually noted (Berlin, 1944; Kidd et al., 1999; McMenemey and Lawrence, 1957). Neutrophils, eosinophils, and lymphocytes may dominate the inflammatory infiltrate. Lesions are distributed in both the white and gray matter, and significant neuroaxonal loss develops in chronic cases. Treatment Administration of corticosteroids is the choice of treatment in acute attacks. Immunosuppression (azathioprine, cyclophosphamide) may be tried in patients with frequent relapses or progressive disease. Recent studies suggest that infliximab, an antitumor necrosis factor (TNF)-α specific antibody, may be of benefit in some forms of neuro-Behçet’s disease (Sarwar et al., 2005). For symptomatic treatment of nonstructural headaches tricyclic antidepressants or valproid acid are recommended. Topiramate has a carbonic anhydrase inhibitor activity, and may effectively reduce CSF production in the case of intracranial hypertension (Chin and Latov, 2005). Summary Behçet’s disease is a multi-organ disorder presenting with a characteristic oral ulceration accompanied by various combinations of genital ulcers, uveitis, and dermatological symptoms. In addition to meningoencephalitis and meningomyelitis, recent observations emphasize the involvement of cerebral blood vessels, particularly venous sinuses in neuroBehçet’s disease. While a complete neurological recovery from an acute attack is seen in the majority of cases, repeated relapses and progressive deterioration with relatively high mortality have been noted. The etiology of Behçet’s disease remains uncertain. Nevertheless, new therapeutic strategies seem to successfully target molecular pathways involved in the development of systemic inflammation and neuropathology.

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References Akman-Demir, G., Serdaroglu, P. and Tasci, B. 1999. Clinical patterns of neurological involvement in Behçet’s disease: Evaluation of 200 patients. The Neuro-Behçet Study Group. Brain, 122, 2171–82. Ashjazadeh, N., Borhani Haghighi, A., Samangooie, Sh. and Moosavi, H. 2003. Neuro-Behçet’s disease: A masquerader of multiple sclerosis. A prospective study of neurologic manifestations of Behçet’s disease in 96 Iranian patients. Exp Mol Pathol, 74, 17–22. Behçet, H. 1937. Uber residivierende, aphtose durch ein Virus verursachtes Geschwure am Mund, am Auge und an der Genitalien. Derm Wschr, 105, 1152–7. Bennett, D.L., McCabe, D.J., Stevens, J.M., Mifsud, V., Kitchen, N.D. and Giovannoni, G. 2004. Tumefactive neuro-Behçet’s disease. Neurology, 63, 709. Berlin C. 1944. Behçet’s syndrome with involvement of the central nervous system. Arch Derm Syph, 49, 227–33. Bienenstock, H. and Marguiles, M.E. 1961. Behçet’s syndrome: Report of a case with extensive neurologic manifestations. N Engl J Med, 264, 1342– 5. Bousser, M.G., Bletry, O., Launay, M., Portier, E., Guillard, A. and Cataigne, P. 1980. Thromboses veineuses cerebrales au cours de la maladie de Behçet. Rev Neurol (Paris), 136, 753–62. Chamberlain, M.A. 1977. Behçet’s syndrome in 32 patients in Yorkshire. Ann Rheum Dis, 36, 491– 9. Chin, E.L. and Latov, N. 2005. Central nervous system manifestations of rheumatologic diseases. Cur Opin Rheumatol, 17, 91– 9. International Study Group for Behçet’s Disease. 1990. Criteria for diagnosis of Behçet’s disease. (Review), Lancet, 335, 1078–80. Kidd, D., Steuer, A., Denman, A.M. and Rudge, P. 1999. Neurological complications in Behçet’s syndrome. Brain, 122, 2183–94. Kocer, N., Islak, C., Siva, A., Saip, S., Akman, C., Kantarci, O. and Hamuryudan, V. 1999. CNS involvement in neuro-Behçet syndrome: An MR study. AJNR Am J Neuroradiol, 20, 1015– 24. Lakhanpal, S., Tani, K., Lie, J.T., Katoh, K., Ishigatsubo, Y. and Ohokubo, T. 1985. Pathologic features of Behçet’s syndrome: A review of Japanese autopsy registry data. Hum Pathol, 16, 790–5. McMenemey, W.H. and Lawrence, B.J. 1957. Encephalomyelopathy in Becket’s disease: Report of necropsy findings in two cases. Lancet, 273, 353–8. Pallis, C.A. and Fudge, B.J. 1956. The neurological complications of Behçet’s syndrome. AMA Arch Neurol Psychiatry, 75, 1–14. Rovaris, M., Viti, B., Ciboddo, G. et al. 2000. Brain involvement in systemic immune mediated diseases: Magnetic resonance and magnetization transfer

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imaging study. J Neurol Neurosurg Psychiatry, 68, 170–7. Sarwar, H., McGrath, H. Jr. and Espinoza, L.R. 2005. Successful treatment of long-standing neuroBehçet’s disease with infliximab. J Rheumatol, 32, 181–3. Wadia, N. and Williams, E. 1957. Behçet’s syndrome with neurological complications. Brain, 80, 59– 71.

Wechsler, B., Huong, L.T., de Gennes, L.C., et al. 1989. Arterial involvement in Behçet’s disease. Rev Med Interne, 10, 303–11. Wolf, S.M., Schotland, D.L. and Phillips, L.L., 1965. Involvement of nervous system in Behçet’s syndrome. Arch Neurol, 12, 315–25. Yurdakul, S., Gunaydin, I., Tuzun, Y. et al. 1988. The prevalence of Behçet’s syndrome in a rural area in northern Turkey. J Rheumatol, 15, 820– 2.

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13 Steroid-responsive encephalopathy associated with Hashimoto’s thyroiditis Bernadette Kalman

Hashimoto’s thyroiditis is caused by a chronic lymphocytic inflammation in 3–4% of the population. It typically occurs in middle-aged women. Affected individuals may be hypo-, hyper- or euthyroid. Multiple antithyroid antibodies, most commonly including those to thyroid peroxidase and thyroglobulin, are present. Ultrasonogram shows hypoechoic thyroid tissue, and fine-needle biopsy reveals infiltration by T lymphocytes, plasma cells, and colloid accumulation and cell detritus in the thyroid gland (Seipelt et al., 2005). The first patient with Hashimoto’s thyroiditis and altered consciousness, myoclonus, and strokelike episodes was reported by Brain et al. (1966). “Hashimoto’s encephalopathy” was soon coined for the central nervous system (CNS) disorder associated with autoimmune thyroiditis and varying thyroid function. The existence of Hashimoto’s encephalopathy as an entity, however, has been debated because of the lack of evidence indicative of a causative relationship between thyroid autoimmunity and encephalitis (Sunil and Mariash, 2001). Mahmud et al. (2003) recently proposed using the term “Steroid responsive encephalopathy associated with Hashimoto’s thyroiditis” (SREHT), which is being adopted here. SREHT is a rare, potentially life-threatening but treatable condition characterized by intermittent confusions, impaired consciousness, psychosis, hallucinations, seizures, stroke-like episodes, myoclonus, and tremor (Shaw et al., 1991). The seizures may be myoclonic, tonic-clonic generalized, or nonconvulsive status epilepticus that is difficult to control. Less common presentations of SREHT include isolated global amnesia or amnesia with other features of encephalopathy ( Jacobs et al., 2006). The clinical presentation has been attributed to an underlying vasculitic process. The pathogenic significance of antithyroid antibodies remains uncertain. These antibodies are detected in 3–4% of the general

population, and their presence may only indicate a predisposition to developing multiple autoantibodies (McKnight et al., 2005). The electroencephalogram (EEG) typically shows slowing and elevated proteins may be present in the cerebrospinal fluid (CSF). Magnetic resonance imaging (MRI) may show multifocal abnormalities in the cerebral white matter or brain atrophy, but imaging is unrevealing in about half of the patients. Autopsy reports usually reveal perivenular and arteriolar infiltration by predominantly T lymphocytes throughout the brain including the hemispheral gray and white matter, basal ganglia, brainstem, and the leptomeninges. Diffuse gliosis is present in the cortical and deep gray matter, hippocampi, and the parenchymal white matter (Duffey et al., 2003; Nolte et al., 2000; Shibata et al., 1992). The extent of inflammatory changes in postmortem studies is often influenced by the preceding high-dose corticosteroid therapy. The recent observation that euthyroid patients with autoimmune thyroiditis have impaired brain perfusion on single photon emission computed tomography further supports the relationship between a cerebral involvement and Hashimoto’s thyroiditis (Zettinig et al., 2003). The short list of differential diagnosis for SREHT includes Creutzfeld–Jakob disease, Sjögren’s syndrome, CNS complications of other connective tissue disorders and vasculitides, which usually can be sorted out based on EEG, serological and CSF studies, and thyroid work up. A nonvasculitic autoimmune inflammatory meningoencephalitis has also been described in patients with Hashimoto’s thyroiditis, Sjögren’s syndrome, and systemic lupus erythematosus ( Joseph et al., 2004). Despite the obscure etiology, SREHT is a treatable condition. Thyroid replacement therapy alone may improve some aspects of the cognitive abnormalities, while the neurological condition best responds to corticosteroids or plasma exchange.

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Summary Hashimoto’s thyroiditis may be associated with a life-threatening but treatable encephalopathy characterized by altered consciousness, memory disturbances, seizures, myoclonus, psychosis, and stroke-like episodes. The causative relationship between thyroid autoimmunity and encephalitis remains uncertain, but the CNS pathology displays signs of a T-cell mediated vasculitic process affecting both the gray and white matter. A thorough diagnostic work up is necessary to distinguish SREHT from other encephalopathies of immune and nonimmune etiology, and to implement effective treatments as early as possible. References Brain, L., Jellinek, E.H. and Ball, K. 1966. Hashimoto’s disease and encephalopathy. Lancet, 2, 512–14. Duffey, P., Yee, S., Reid, I.N. and Bridges, L.R. 2003. Hashimoto’s encephalopathy: Postmortem findings after fatal status epilepticus. Neurology, 61, 1124–6. Jacobs, A., Root, J. and van Gorp, W. 2006, Isolated global amnesia associated with autoimmune thyroiditis. Neurology, 66, 605. Josephs, K.A., Rubino, F.A. and Dickson, D.W. 2004. Nonvasculitic autoimmune inflammatory meningoencephalitis. Neuropathology, 24, 149–52.

Mahmud, F.H., Lteif, A.N., Renaud, D.L., Reed, A.M. and Brands, C.K. 2003. Steroid-responsive encephalopathy associated with Hashimoto’s thyroiditis in an adolescent with chronic hallucinations and depression: Case report and review. Pediatrics, 112, 686–90. McKnight, K., Jiang, Y., Hart, Y. et al. 2005. Serum antibodies in epilepsy and seizure-associated disorders. Neurology, 65, 1730–6. Nolte, K.W., Unbehaun, A., Sieker, H., Kloss, T.M. and Paulus, W. 2000. Hashimoto encephalopathy: A brainstem vasculitis? Neurology, 54, 769– 70. Seipelt, M., Zerr, I., Nau, R. et al. 1999. Hashimoto’s encephalitis as a differential diagnosis of CreutzfeldtJakob disease. J Neurol Neurosurg Psychiatry, 66, 172–6. Sunil, G.S. and Mariash, C.N. 2001. Hashimoto’s encephalitis. J Clin Endocrinol Metab, 86, 947. Shaw, P.J., Walls, T.J., Newman, P.K., Cleland, P.G. and Cartlidge, N.E. 1991. Hashimoto’s encephalopathy: A steroid-responsive disorder associated with high anti-thyroid antibody titers – Report of 5 cases. Neurology, 41, 228–33. Shibata, N., Yamamoto, Y., Sunami, N., Suga, M. and Yamashita, Y. 1992. Isolated angiitis of the CNS associated with Hashimoto’s disease. Rinsho Shinkeigaku, 32, 191– 8. Zettinig, G., Asenbaum, S., Fueger, B.J. et al. 2003. Increased prevalence of subclinical brain perfusion abnormalitis in patients with autoimmune thyroiditis: Evidence of Hashimoto’s encephalitis? Clin Endocrinol, 59, 637–43.

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14 Rasmussen’s encephalitis Bernadette Kalman

Rasmussen et al. (1958) reported three patients with focal seizures associated with chronic encephalitis. Subsequently, the occurrence of chronic focal encephalitis with seizures was named Rasmussen’s encephalitis (RE) or Rasmussen’s syndrome (Piatt et al., 1988). A European consensus statement recently summarized the accumulated knowledge concerning the pathogenesis, diagnosis, and treatment of RE (Bien et al., 2005). RE is a sporadic disorder with unknown etiology. Because of the lymphocytic infiltration and microglial activation in the brain lesions, a viral cause was proposed (Rasmussen et al., 1958). However, subsequent studies failed to unequivocally support a viral etiology. The cause of immune activation remains to be determined. Clinical characteristics RE usually presents in childhood with six years the average age of onset, but approximately 10% of patients have adult onset (Oguni et al., 1991). Typically, partial motor seizures arise to affect various parts in the same side of the body and gradually expand over time. A focal motor deficit follows the onset of seizures and gradually progresses to hemiparesis. The electroencephalogram (EEG) correlate of these abnormalities is a unilateral deterioration of the background activity with focal repetitive rhythmic discharges migrating from one area of the cortex to another one, but only in the same side. The question has been raised if the seizures directly contribute to neuronal loss and dysfunction or indirectly contribute to further pathological damage and neurological deterioration by opening the blood–brain barrier to immune mediators (Bien et al., 2005). The time course and natural history of RE greatly vary among patients. In the initial “prodromal stage,” patients typically have low seizure frequency and occasionally mild hemiparesis with a median duration of 7.1 months (0 month to 8.1 years). In the

“acute stage,” the seizures usually present as simple partial motor seizures or epilepsia partialis continua (EPC) with rising frequency, and a progressive neurological deterioration develops with severe hemiparesis, hemianopia, cognitive decline, and aphasia, if the dominant hemisphere is involved. In one-third of patients, this is the initial presentation of RE. The median duration of this stage is 8 months (4– 8 months). In the third or “residual stage,” patients still have frequent seizures but also suffer from permanent neurological deficits (Bien et al., 2005). The seizures in RE are characterized by polymorphism, frequent occurrence of EPC, and resistance to therapy. In the series of Oguni et al. (1991), simple partial motor seizures with unilateral motor deficits was the most common presentation noted in 77% of cases. Secondary generalized tonic-clonic seizures were detected in 42%, complex partial seizures with automatisms in 19%, and with subsequent unilateral motor spread in 31% of patients, while postural seizures were noted in 24% and somatosensory seizures in 21% of their 48 patients. EPC was observed in 56–92% of patients (Granata et al., 2003; Oguni et al., 1991). RE is very rarely associated with bilateral cerebral involvement with secondary spread of focal seizures or interictal activity and atrophy in the contralateral hemisphere (Hart and Andermann, 2000). Immune abnormalities The original observation implicating antibodies to the subunit 3 of the ionotropic glutamate receptor (GluR3) in RE was made in rabbits, which developed RE-like pathology and seizures after immunization with a GluR3 fusion protein for raising antibodies. Rogers et al. (1994) detected anti-GluR3 antibodies in the sera of three out of four patients with RE, one of whom responded to plasma exchange. Plasmapheresis or selective IgG immunoabsorption then became the standard treatment, but with varying success (Andrews et al., 1996; Antozzi et al., 1998). While

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evidence suggests that anti-GluR3 antibodies mediate cytotoxic activation of the glutamate receptor in vitro and in vivo (Levite and Hermelin, 1999; Twyman et al., 1995) with or without complement activation in neurons and glial cells (He et al., 1998; Whitney and McNamara, 2000), recent studies argue against the specificity of GluR3 antibodies in RE. GluR3 antibodies are not present in the sera and cerebrospinal fluid (CSF) of all patients with RE, while they are detected in the sera and CSF of patients with other types of epilepsy syndromes in a proportion similar to that found in RE (Mantegazza et al., 2002; Wiendl et al., 2001). Therefore, the pathogenic significance and diagnostic relevance of anti-GluR3 antibodies in RE have been rejected. However, observations support an immunoglobulin and complement-mediated pathogenesis, and ongoing research is investigating the role of antibodies other than anti-GluR3 in RE (Lang et al., 2004; Yang et al., 2002). Most recently, antibodies to human α7 nicotinic acetylcholine receptors (α7nAChR) were detected in two patients with acute phase disease out of nine patients with RE (Watson et al., 2005). These antibodies blocked acetylcholine-induced increase in intracellular free calcium and inhibited 125I-α-bungarotoxin binding in cells expressing α7nAChR. The authors postulate that these antibodies may act by blocking the α7nAChR that influence the release of a variety of excitatory neurotransmitters in the brain. In addition, these antibodies themselves may mediate immune attacks on neurons. A study of inflammatory infiltrates in brains of RE patients revealed T cells with restricted T-cell receptor (TCR) Vβ utilization and CDR3 (complementarity determining region 3) conservation, suggesting the expansion of a few T-cell clones in RE lesions (Li et al., 1997). It was also proposed that cytotoxic T lymphocytes with granzyme B granules may attack neurons expressing major histocompatibility complex (MHC) class I antigens and induce neuronal apoptosis (Bien et al., 2002). Cleavage of the GluR3 molecule by granzyme B may generate immunogenic epitopes for further cellular and humoral activation (Gahring et al., 2001). However, in the light of conflicting observations concerning the role of GluR3-specific antibodies in the pathogenesis of RE, this latter observation needs to be interpreted with caution, and the antigen specificity of cytotoxic T cells remains to be determined (Bien et al., 2005). Nevertheless, these studies suggest that RE is a primarily T-cell driven and immunoglobulin-mediated autoimmune condition.

Pathology Robitaille (1991) classified the cortical pathology of RE into four stages that were recently adapted and further refined by Pardo et al. (2004) based on a comprehensive work up of 45 patients who underwent hemispherectomy for the treatment of RE. The four stages are characterized by the following changes: 1 Early stage: Focal inflammation, focal microglial and astroglial reaction, minimal or no neuronal injury, and perivascular or perineural T lymphocytes in the superficial and deep neuronal layers of the cerebral cortex. 2 Intermediate stage: Increase in the magnitude of lymphocytic infiltration as well as in the microglial and astroglial reactions from focal to panlaminar distribution. Neuronal injury is evidenced by the presence of cytoplasmic and nuclear changes and by the increased amounts of perineuronal satellitosis. Neuronal degeneration, patchy neuronal dropout, and cytoarchitectural changes are also present. The lymphocytes are predominantly CD3+ T cells with predominantly CD8, but also CD4 expression. The presence of B cells and plasma cells is not characteristic. 3 Late stage: Significant decrease in the neuronal population in large focal or panlaminar distribution along with gemistocytic astroglial reaction and microglial activation. Cortical atrophy and focal spongiosis are present. 4 End stage: Extensive destruction of the cerebral cortex with signs of cortical vacuolation or complete panlaminar neuronal dropout. Residual astrogliosis with minimal or no inflammatory changes are characteristic. These histological observations are consistent with a progressive immune-mediated process of neuronal damage associated with T lymphocytic and neuroglial responses similar to that noted in other autoimmune central nervous system (CNS) diseases. This study also emphasizes the multifocal distribution of pathology and the intraindividual heterogeneity of stages in cortical lesions. The patchy nature of pathology implies that the site of biopsy, if needed, has to be carefully determined in early suspected RE, and that partial cortical resection cannot be therapeutic. The earlier the onset and the longer the duration of RE the heavier is the disease burden, which underscores the importance

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of aggressive and early therapeutic interventions (Pardo et al., 2004). Electroencephalogram, EEG Polymorphic delta waves mixed with epileptiform activity can be detected early during the course over the affected hemisphere in most patients. In later stages, the background activity further deteriorates, and epileptiform discharges may occur not only over the ipsilateral but also over the contralateral hemisphere. Multifocal ictal discharges are usually seen only in the affected side. Subclinical ictal activity may also occur.

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and occasional swelling in the cortical/subcortical regions may be noted. In addition to the hemispheral atrophy, the head of the caudate nucleus may also be diminished. The atrophic changes gradually progress across the hemisphere. No calcification develops in the chronic atrophied lesions. In correlation with these images, Bien et al. (2002) also noted higher numbers of T lymphocytes and activated glial cells in the earlier as compared to later surgical specimens in 10 patients who were serially scanned and underwent surgical procedures. In another serial MRI study of seven children with pathology-proven RE between 12 months before and nine months after the onset of EPC, Kim et al. (2002) identified three patterns:

Imaging Despite the inflammatory nature of pathology, gadolinium enhancement on T1-weighted MRI is very rare in RE (Bien et al., 2002; Granata et al., 2003). A progressive tissue loss is the predominant feature noted in longitudinal MRI monitoring (Fig. 14.1) (Bien et al., 2002, 2005; Chiapparini et al., 2003). Initially, a unilateral enlargement of CSF compartments, particularly in the peri-insular/peri-Sylvian region, with T2-weighted and FLAIR hyperintensity

(a)

1 Normal initial MRI followed by hyperintensity and cortical atrophy over time. 2 Initial focal hyperintensity followed by decrease in extent and degree of signal intensity. 3 Sustained hyperintensity on all follow-up scans. Positron emission tomography (PET) and single photon emission computer tomography (SPECT) typically show decreased metabolism in the interictal, and hypermetabolism in the ictal scans. These

(b)

Fig. 14.1 Axial FLAIR images of a patient with RE. The onset of RE started with EPC initially affecting the right side of the face at age 7.5 years in this patient. MRI image (a) at age 8.5 years shows slight atrophy with hyperintense signal in the left hemisphere. The second image (b) four years later reveals marked left hemiatrophy. A few months later, the patient underwent hemispheral deafferentation. Histology showed typical features of RE. Since surgery, the patient has been free of seizures. The MRI studies were performed by Horst Urbach, M.D., Department of Radiology/Neuroradiology, University of Bonn, Germany, and generously provided by Christian G. Bien, M.D., Department of Epileptology, University of Bonn, Germany.

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images may guide brain biopsy, if needed, for supporting the diagnosis. Cerebrospinal fluid, CSF CSF studies are primarily needed to exclude the possibility of encephalitis of infectious etiology. Half of the patients with RE have normal CSF, while the remaining patients have mild lymphocytic pleocytosis, mildly elevated protein, and occasionally oligoclonal bands. Diagnostic criteria for RE Clinical, EEG, and MRI characteristics usually make the diagnosis of RE straightforward (Box 14.1) and leave only a short list of differential diagnoses. The alternative diagnoses may include viral, paraneoplastic, or other autoimmune forms of encephalitides (e.g. anti-voltage-gated potassium channel (VGKC) antibody-mediated limbic encephalitis, Hashimoto encephalitis, vasculitides), unihemispheric epileptic syndromes (cortical dysplasia, tuberous sclerosis, stroke, Sturge–Weber syndrome), inherited metabolic disorders (mitochondrial encephalopathies, Alpers syndrome, Kufs disease), and acquired metabolic disorders associated with EPC (ketotic or nonketotic hyperglycaemia, type I diabetes and anti-GAD65 antibodies, renal and hepatic encephalopathies) (Bien et al., 2005).

Treatment To prevent the progressive tissue loss and clinical deterioration, an early diagnosis with immune modulatory (corticosteroids, plasma exchange, immunosuppression) intervention or epilepsy surgery is necessary as soon as possible. Symptomatic treatments with antiepileptic drugs alone have consistently failed to control seizures in RE. Corticosteroids, plasmapheresis, IVIg, IgG immunoabsorption techniques, immunosuppression with tacrolimus, and the combination of these methods have resulted in variable outcomes, but only delayed the inevitable hemispherectomy (Bien et al., 2005). The effectiveness of immune ablative therapies is currently being investigated. Epilepsy surgery is eventually needed in all cases. Focal cortical resections are ineffective. Hemispherectomy or modern disconnective techniques are the only treatments that efficiently control seizures in RE. The latter techniques are superior because of the low procedure-related morbidity and no mortality. The timing of surgery has to be individually evaluated taking into account potential consequences of surgery (hemiparesis, hemianopia, and language dysfunction in the case of the dominant hemisphere) and the damage caused by the ongoing pathology and seizure activity. Earlier surgery is advocated when the pathology is in the left hemisphere and the child approaches the teenage years (Freeman,

Box 14.1 Diagnostic criteria for RE (after Bien et al., 2005). A 1 Clinical: Focal seizures with or without EPC and unilateral cortical deficits 2 EEG: Unilateral slowing with or without epileptiform discharges and unilateral seizure onset 3 MRI: Unilateral focal cortical atrophy and at least one of the following: – Hyperintense T2/FLAIR signal in gray and white matter – Hyperintense T2/FLAIR signal or atrophy in the ipsilateral caudate head B 1 Clinical: EPC or progressive unilateral cortical deficits 2 MRI: Progressive unilateral focal cortical atrophy

3 MRI: Histopathology: T-cell dominated encephalitis, activated microglial cells and reactive astrogliosis; no significant presence of parenchymal macrophages, B cells or plasma cells and absence of viral inclusion bodies RE can be diagnosed if all three criteria of part A or two of three criteria in part B are present. Consideration of Part B is recommended only if the criteria in part A are not fulfilled. MRI needs to be performed with gadolinium to exclude enhancement, and a CT scan is necessary to exclude calcification. Gadolinium enhancement and calcification are features noted in unihemispheric vasculitis but not in RE.

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2005). Complications of surgery potentially include intraoperative bleeding, hydrocephalus usually following surgery by a few days to weeks, and superficial cortical hemosiderosis with hydrocephalus 10–20 years after the surgery. With the advent of computer tomography (CT) and MRI, early recognition and surgical treatment (shunting) of these complications became possible (Freeman 2005). Summary RE is considered to be a T-cell driven and immunoglobulin-mediated disorder of the brain with progressive unihemispheral tissue loss, accumulation of contralateral motor deficits, and seizures. The seizures are characterized by polymorphisms, EPC, and resistance to therapy. The multifocal distribution of pathology and the various stages of cortical lesions suggest that the site of biopsy, if needed, has to be carefully chosen in an early disease and that a partial resection cannot be therapeutic. Immune modulatory treatments may delay but do not circumvent the ultimately always necessary hemispherectomy or disconnective surgical interventions. References Andrews, P.I., Dichter, M.A., Berkovic, S.F., Newton, M.R. and McNamara, J.O. 1996. Plasmapheresis in Rasmussen’s encephalitis. Neurology, 46, 242–6. Antozzi, C., Granata, T., Aurisano, N. et al. 1998. Longterm selective IgG immuno-adsorption improves Rasmussen’s encephalitis. Neurology, 51, 302–5. Bien, C.G., Granata, T., Antozzi, C., et al. 2005. Pathogenesis, diagnosis and treatment of Rasmussen encephalitis: A European consensus statement. Brain, 128, 454–1. Bien, C.G., Urbach, H., Decker, M. et al. 2002. Diagnosis and staging of Rasmussen’s encephalitis by serial MRI and histopathology. Neurology, 58, 250–7. Bien, C.G., Widman, G., Urbach, H. et al. 2002. The natural history of Rasmussen’s encephalitis. Brain, 125, 1751–9. Chiapparini, L., Granata, T., Farina, L. et al. 2003. Diagnostic imaging in 13 cases of Rasmussen’s encephalitis: Can early MRI suggest the diagnosis? Neuroradiology, 45, 171–83. Freeman, J.M. 2005. Rasmussen’s syndrome: Progressive autoimmune multi-focal encephalopathy. Review Article. Pediatr Neurol, 32, 295–9. Gahring, L.C., Carlson, N.G., Meyer, E.L. and Rogers, S.W. 2001. Cutting edge: Granzyme B proteolysis of a neuronal glutamate receptor generates an autoantigen and is modulated by glycosylation. J Immunol, 166, 1433–8.

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Granata, T., Gobbi, G., Spreafico, R. et al. 2003. Rasmussen’s encephalitis: Early characteristics allow diagnosis. Neurology, 60, 422–5. Hart, Y. and Andermann, F. 2000. Rasmussen syndrome. In J.M. Oxbury, C.E. Polkey and M. Duchowny (eds.), Intractable Focal Epilepsy, WB Saunders, London, pp. 233–48. He, X.P., Patel, M., Whitney, K.D., Janumpalli, S., Tenner, A. and McNamara, J.O. 1998. Glutamate receptor GluR3 antibodies and death of cortical cells. Neuron, 20, 153–63. Kim, S.J., Park, Y.D., Pillai, J.J., Lee, M.R. and Smith, J.R. 2002. A longitudinal MRI study in children with Rasmussen syndrome. Pediatr Neurol, 27, 282–8. Lang, B., Watson, R., Bermudez, I., Sattelle, D., Jepson, J. and Vincent, A. 2004. Antibodies to neuronal alpha7 acetylcholine receptor in patients with Rasmussen’s encephalitis. (Abstract). J Neuroimmunol, 154, 192. Levite, M. and Hermelin, A. 1999. Autoimmunity to the glutamate receptor in mice-a model for Rasmussen’s encephalitis? J Autoimmun, 13, 73–82. Li, Y., Uccelli, A., Laxer, K.D. et al., 1997. Local-clonal expansion of infiltrating T lymphocytes in chronic encephalitis of Rasmussen. J Immunol, 158, 1428– 37. Mantegazza, R., Bernasconi, P., Baggi, F. et al., 2002. Antibodies against GluR3 peptides are not specific for Rasmussen’s encephalitis but are also present in epilepsy patients with severe, early onset disease and intractable seizures. J Neuroimmunol, 131, 179–85. Oguni, H., Andermann, F. and Rasmussen, T.B. 1991. The natural history of the syndrome of chronic encephalitis and epilepsy: A study of the MNI series of forty-eight cases. In F. Andermann (ed.), Chronic Encephalitis and Epilepsy. Rasmussen’s Syndrome, Butterworth-Heineman, Boston, pp. 7–35. Pardo, C.A., Vining, E.P.G., Guo, L., Skolasky, R.L., Carson, B.S. and Freeman, J.M. 2004. The pathology of Rasmussen syndrome: Stages of cortical involvement and neuropathological studies in 45 hemispherectomies. Epilepsia, 45, 516–26. Piatt, J.H. Jr., Hwang, P.A., Armstrong, D.C., Becker, L.E. and Hoffman, H.J. 1988. Chronic focal encephalitis (Rasmussen syndrome): Six cases. Epilepsia, 29, 268– 79. Rasmussen, T., Olszewski, J. and Lloyd-Smith, D. 1958. Focal seizures due to chronic localized encephalitis. Neurology, 8, 435–45. Robitaille, Y. 1991. Neuropathologic aspects of chronic encephalitis. In F. Andermann (ed.), Chronic Encephalitis and Epilepsy. Rasmussen’s Syndrome, Butterworth-Heineman, Boston, pp. 79–110. Rogers, S.W., Andrews, P.I. and Gahring, L.C. et al. 1994. Autoantibodies to glutamate receptor GluR3 in Rasmussen’s encephalitis. Science, 265, 648–51. Twyman, R.E., Gahring, L.C., Spiess, J. and Rogers, S.W. 1995. Glutamate receptor antibodies activate a subset of receptors and reveal an agonist binding site. Neuron, 14, 755–62.

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Watson, R., Jepson, J.E.S., Bermudez, I., et al. 2005. α7Acetylcholine receptor antibodies in two patients with Rasmussen encephalitis. Neurology, 65, 1802–4. Whitney, K.D. and McNamara, J.O. 2000. GluR3 autoantibodies destroy neural cells in a complementdependent manner modulated by complement regulatory proteins. J Neurosci, 20, 7307–16.

Wiendl, H., Bien, C.G., Bernasconi, P. et al. 2001. GluR3 antibodies: Prevalence in focal epilepsy but no specificity for Rasmussen’s encephalitis. Neurology, 57, 1511–14. Yang, R., Puranam, R.S., Butler, L.S. et al. 2000. Autoimmunity to munc-18 in Rasmussen’s encephalitis. Neuron, 28, 375–83.

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15 Susac’s syndrome Bernadette Kalman

Susac et al. (1979) described the triad of encephalopathy, branch retinal artery occlusion, and deafness as a microangiopathy syndrome of the brain, retina, and cochlea; and Hoyt coined the term “Susac’s syndrome” (Neuroophthalmological Symposium, San Francisco, 1986). The prevalence of Susac’s syndrome is unknown, but numerous cases, predominantly women aged 16–58, have been reported. The female to male ratio is 3:1. The disorder is often misdiagnosed as multiple sclerosis (MS) or acute disseminated encephalomyelitis (ADEM) (Susac, 1994; Susac et al., 2003). Clinical characteristics The course is usually relapsing-remitting or less frequently progressive, and becomes self-limited after 2–4 years with usually mild residual visual, hearing, or cognitive symptoms. A proportion of patients develop the sequelae of severe deafness and moderate dementia. Patients may not be aware of their hearing loss or visual impairment, particularly when the first symptom is encephalopathy. Some affected individuals present with incomplete triad (Susac, 1994). Encephalopathy Headaches frequently precede by a month or several months or coincide with the onset of a subacute encephalopathy. Migraine headaches are most frequently seen in those patients who present with branch retinal artery occlusion or hearing loss. The subacute encephalopathy usually presents with confusion, memory disturbances, bizarre or paranoid behavioral changes, and other psychiatric features. The encephalopathy occasionally progresses to stupor. The most characteristic neurological abnormalities include bilateral extensor plantar responses and pseudobulbar speech. Myoclonus and seizures also may develop. Some patients have focal neurological

signs reflecting brainstem or cerebellar lesions, or transient paresthesias and hemiparesis not to be confused with transient ischemic attacks. Branch retinal artery occlusion The sequence of index events varies. The branch retinal artery occlusion may be a presenting symptom or follow the onset of the encephalopathy. The arterial occlusions are usually bilateral, and the infarcts involve varying segments of the retina with striking or unnoticed subjective visual impairment, depending on the central or peripheral location of infarcts (Fig. 15.1). Fluorescein angiography is a helpful tool for the diagnosis of branch retinal artery occlusions. In chronic stages, silver streaks replace the appearance of occluded arterioles in the fundus. Retinal artery wall (Gass) plaques may preferentially occur in the mid-segments of retinal arterioles. Hearing loss Bilateral hearing loss, tinnitus, vertigo, and nystagmus may also be the presentation of Susac’s syndrome. The underlying pathology includes microinfarcts in the apical part of the cochlea and in the semicircular canals resulting in hearing loss predominantly for the low to moderate frequency tones and prominent jerk nystagmus, respectively (Susac, 1994). Paraclinical studies Electroencephalogram (EEG) may reveal diffuse slowing during an acute episode of encephalopathy. T2-weighted and FLAIR (fluid-attenuated inversion recovery) MRI (magnetic resonance imaging) images demonstrate microinfarcts in the periventricular white matter, centrum semiovale, corpus callosum, as well as in the deep and cortical gray matter, cerebellum, and brainstem (Fig. 15.2). In acute and subacute phases, the lesions may enhance on T1-weighted

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(a)

Fig. 15.1 Branch retinal artery occlusion. (a) Right fundus with branch retinal artery occlusion. The picture shows multiple retinal infarcts including the macular region (partial cherry-red spot). (b) Left fundus with asymptomatic branch retinal artery occlusion. The patient was left with 20/30 and dense nasal field defect in the right eye, but 20/20 and full field in the left. Courtesy of Dr. John O. Susac, Winterhaven, FL.

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Fig. 15.2 Brain MRI in Susac’s syndrome. Coronal (a) and sagittal (b) FLAIR images of the brain show multiple hyperintense lesions in the periventricular and subcortical white matter, centrum semiovale, and the deep nuclei and cortical gray matter. Note the snowball-like lesions on both the coronal and sagittal MRI. The images are from a 24-year-old male patient who developed encephalopathy and headaches, followed by hearing loss and branch retinal artery occlusion. He was treated with steroids and IVIg, and went back to work a year after the onset of symptoms. Courtesy of Dr. John O. Susac, Winterhaven, FL.

postgadolinium images. Leptomeningeal enhancement may also be seen. The typically 3–7 mm in size, or occasionally larger, snowball-type of central callosal lesions are distinct from the undersurface plaques of MS and ADEM, and follow the distribution of the microvasculature with infarcts and holes in the central fibers. The inclusion of thin, sagittal T1 and T2/FLAIR-weighted images may facilitate the detection of lesions. Nevertheless, small cortical lesions noted in biopsied specimens are usually missed by current imaging techniques. Infarcted regions undergo atrophy in chronic stages. Increased protein levels in the range of 100 mg to 3 g and mild

pleocytosis have been noted in the cerebrospinal fluid (CSF). The pathology of microangiopathy is usually undetectable by conventional angiography. Laboratory tests for connective tissue disorders, coagulapathy, or infectious diseases are unrevealing. The sedimentation rate is elevated in some cases. Pathological evaluations of biopsied brain tissues revealed chronic stages of angiitis with thickening and sclerosis in the media and adventitia of precapillary arterioles, multiple infarcts, gliosis, and neuronal loss (Bogousslavsky et al., 1989; Monteiro et al., 1985; Susac et al., 1979). Necrosis is not present in the vessel walls, therefore, the use of term “vasculopathy” is

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more correct than “vasculitis” in this condition. The hypothesis of an immune-mediated etiology recently gained support by the identification of antiendothelial cell antibodies in these patients (Susac et al., 2005). Therapy The course of Susac’s syndrome is usually selflimited and patients have been empirically treated. Nevertheless, there is now sufficient experience to treat the disease with immunosuppression. Steroids are the mainstay in conjunction with intravenous immunoglobulins and cyclophosphamide (Rennebohm and Susac, 2005; Susac, 1994, 2004). Patients with severe hearing loss may benefit from cochlear implants. Summary Susac’s syndrome is a recently described triad of encephalopathy, branch retinal artery occlusion, and deafness associated with an immune-mediated microangiopathy of the brain, retina, and cochlea. While its distinct imaging characteristics have been well described, its immune pathogenesis is the subject of active ongoing research. Recommended empirical treatment modalities include corticosteroids, intravenous immunoglobulins, and cyclophosphamide.

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References Bogousslavsky, J., Gaio, J.M., Caplan, L.R. et al. 1989. Encephalopathy, deafness and blindness in young women: A distinct retinocochleocerebral arteriolopathy? J Neurol Neurosurg Psychiatry, 52, 43–6. Monteiro, M.L., Swanson, R.A., Coppeto, J.R., Cuneo, R.A., DeArmond, S.J. and Prusiner, S.B. 1985. A microangiopathic syndrome of encephalopathy, hearing loss, and retinal arteriolar occlusions. Neurology, 35, 1113–21. Rennebohm, R.M. and Susac, J.O. 2005. Treatment of Susac’s syndrome. Presented at the Fourth International Congress on Vascular Dementia. Porto, Portugal, October 21. Susac, J.O. 1994. Susac’s syndrome: The triad of microangiopathy of the brain and retina with hearing loss in young women. Neurology, 44, 591–3. Susac, J.O. 2004. Susac’s syndrome. Am J Neuroradiol, 25, 351–2. Susac, J.O., Egan, R.A. and Rennebohm, R.M. Susac’s syndrome: 1975–2005. 2005. Microangiopathy/ Autoimmune endotheliopathy. Presented at the Fourth International Congress on Vascular Dementia. Porto, Portugal, October 21. Susac, J.O., Hardman, J.M. and Selhorst, J.B. 1979. Microangiopathy of the brain and retina. Neurology, 29, 313–16. Susac, J.O., Murtagh, F.R., Egan, R.A. et al., 2003. MRI findings in Susac’s syndrome. Neurology, 61, 1783–7.

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16 Cogan’s syndrome Bernadette Kalman

David Cogan (1945) reported four patients with nonsyphilitic interstitial keratitis (IK) and Ménière’slike syndrome including vertigo, ataxia, tinnitus, nausea, vomiting, and hearing loss; and recognized the constellation of these abnormalities as an entity. Haynes et al. (1980) and Vollertsen et al. (1986) reviewed their own case series of 13 and 18 patients with Cogan’s syndrome (CS) along with those in the literature. St. Clair et al. (1999) reviewed epidemiological, clinical, and basic science data of the disorder. Grasland et al. (2004) reported 32 patients with typical and atypical CS from a multicenter series along with reviewing the literature. Haynes et al. (1980) and Grasland et al. (2004) proposed that the definition of CS should be extended to include patients not only with IK and audiovestibular symptoms, but also with additional ocular and systemic manifestations. Up to date, fewer than 250 cases with CS have been reported, but the figure continues to grow (Cundiff et al., 2006; Grasland et al., 2004). Clinical characteristics CS predominantly affects young adults without gender predominance. Occasionally, children and elderly people may also be affected. IK is associated with pain, photophobia, blurred vision, and redness of the eye. Slit-lamp examination is necessary to reveal the granular corneal infiltrates. In early stages, the corneal finding may resemble viral keratitis. In most cases, IK is bilateral. In atypical cases, conjunctivitis, episcleritis, scleritis, uveitis, retinal vasculitis and hemorrhage, optic neuritis, glaucoma, central retinal artery trombosis, xerophthalmia, ptosis, or papilla edema may develop with or without IK (Haynes et al., 1980; Grasland et al., 2004; St. Clair et al., 1999; Vollertsen et al., 1986). The vestibulocochlear dysfunction presents with acute Ménière’s-like symptoms including vertigo, nausea, vomiting, tinnitus, and hearing loss. Oscillopsia occurs secondary to the vestibular dysfunction.

The vestibular abnormalities may be assessed by caloric, electronystagmographic, and rotational tests. Audiometry usually shows sensorineural hearing loss and poor speech discrimination (St. Clair et al., 1999). The hearing loss is often bilateral. The symptoms may fluctuate, but eventually permanent hearing loss develops in a great proportion of patients. While the involvement of eyes and ears is typically isolated, a subgroup of patients develops signs of systemic vasculitis resembling Takayasu’s arteritis and polyartheritis nodosa. Systemic manifestations have been reported in up to 78% of patients with CS (Grasland et al., 2004). Active vasculitis may be associated with constitutional features such as fever and weight loss. Secondary occlusions of the coronary arteries, aortic aneurism and stenosis, or aortic valve regurgitation may develop. Veins can also be affected by inflammatory changes. Systemic necrotizing vasculitis can cause a severe multiorgan disorder with gastric ulcers, claudication in the limbs, mesenteric insufficiency, stenosis, and spontaneous ruptures of major vessels. CS may occur in association with Crohn’s disease and ulcerative colitis. Central and peripheral nervous system involvement such as cerebellar or meningeal syndromes and peripheral neuropathy is detected in up to 50% of patients (Albayram et al., 2001). Diagnostic criteria The current diagnostic criteria for typical CS include: (i) ocular symptoms of nonsyphilitic IK that may be associated with conjunctivitis, conjuctival or subconjuctival bleeding, or iritis; (ii) audiovestibular symptoms similar to those of Ménière’s syndrome usually progressing to deafness in 1–3 months; and (iii) a less than two-year interval between the index events. Diagnostic criteria for atypical CS include: (i) additional inflammatory ocular symptoms – as detailed above; (ii) typical ocular manifestation associated in two years with an audiovestibular

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symptom different from Ménière’s-like episodes; and (iii) an episode longer than two years between the typical index events (Grasland et al., 2004; Haynes et al., 1980). Paraclinical findings Cranial MRI and CT typically show normal brain structures, but reveal abnormal soft tissues and calcification in the vestibular system and cochlear labyrinth. Gadolinium enhancement may be seen in these structures in acute stages. The pathology of CS shows chronic inflammation with lymphocytic infiltration in early stages, and neovascularization and scarring in late stages in the corneal tissue. Histologic exams of the temporal bones reveal lymphocytic infiltrates in the spiral ligament, endolymphatic hydrops, and degenerative changes of the sensory receptors and supporting structures in the cochlea and the vestibular apparatus. The inflammatory process in the extracellular matrix of the inner ear leads to endolymphatic hydrops. The degree of matrix accumulation correlates with the severity of hearing loss in animal studies. Ossification of the cochlea is a late and severe complication that develops if the inflammatory process is not treated early and aggressively (St. Clair et al., 1999). Demyelination and degeneration may be seen in the vestibular and cochlear branches of the VIIIth nerve. Although the onset of CS is often preceded by upper respiratory tract infections, the etiology remains unknown. Because of the similarities between syphilis and CS, investigators implicated spirochetes such as Borrelia burgdorferi in the pathogenesis, but no direct proof was found. Similarly, the involvements of Chlamydia trachomatis, pneumoniae and psittaci remain uncertain. Based on histologic changes in the affected tissues, an underlying immune mechanism has been postulated. The detection of humoral and cellular immune response to inner ear and corneal or retinal antigens supported the autoimmune hypothesis of CS (St. Clair et al., 1999), which was further strengthened by the presence of rheumatoid factor and antineutrophil antibodies in some patients (Hughes et al., 1983; Ikeda et al., 2002). Using pooled immunoglobulins of eight patients with CS for the screening of a random peptide library, Lunardi et al. (2002) identified an immunodominant peptide similar to autoantigens such as SSA/Ro and reovirus III major core protein lambda I. The peptide sequence shared similarities with the cell-density enhanced

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protein tyrosine phosphatase-1 (DEP-1/CD148), which is expressed by the sensory epithelia in the inner ear and by endothelial cells. IgG purified from patients’ sera recognized the DEP-1/CS148 protein, bound to connexin 26 and human cochlea, and exerted antiproliferative effects on cells expressing DEP-1/CD148. These antibodies also had the capacity to induce a disease resembling CS in mice. By computer-assisted search, Benvenga et al. (2003) further explored the concept of molecular mimicry and identified additional potential antigenic determinants mostly including adhesion molecules expressed in the inner ear. Therapy Systemic corticosteroids for the vestibulocochlear and topical corticosteroids for the ocular inflammation remain the mainstay of treatment. Occasionally, azathioprine or cyclophosphamide is necessary in steroid-resistant cases. For patients with permanent hearing loss, cochlear implants may offer some benefit. Summary CS is a rare disorder characterized by nonsyphilitic IK and Ménière’s-like syndrome. Additional ocular and systemic manifestations of the disease were also recognized leading to a wider definition of CS. The pathology of affected organs includes lymphocytic infiltrates in early and degenerative changes in late stages of the disease. While the etiology remains unknown, recent studies implicate molecular mimicry in the pathogenesis, and identify adhesion molecules expressed in the inner ear as potential antigenic determinants of autoreactive immunoglobulins. References Albayram, M.S., Wityk, R., Yousem, D.M. and Zinreich, S.J. 2001. The cerebral angiographic findings in Cogan syndrome. AJNR Am J Neuroradiol, 22, 751–4. Benvenga, S. and Trimarch, F. 2003. Cogan’s syndrome as an autoimmune disease. Lancet, 361, 530–1. Cogan, D.S. 1945. Syndrome of nonsyphilitic interstitial keratitis and vestibuloauditory symptoms. Arch Ophthalmol, 33, 144–9. Cundiff, J., Kansal, S., Kumar, A., Goldstein, D.A. and Tessler, H.H. 2006. Cogan’s syndrome: A cause of progressive hearing deafness. Am J Otolaryngol, 27, 68–70.

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Grasland, A., Pouchot, J., Hachulla, E., Bletry, O., Papo, T. and Vinceneux, P.; Study Group for Cogan’s Syndrome. 2004. Typical and atypical Cogan’s syndrome: 32 cases and review of the literature. Rheumatology (Oxford), 43, 1007–15. Haynes, B.F., Kaiser-Kupfer, M.I., Mason, P. and Fauci, A.S. 1980. Cogan syndrome: Studies in thirteen patients, long-term follow-up, and a review of the literature. Medicine, 59, 426–41. Hughes, G.B., Kinney, S.E., Barna, B.P., Tomsak, R.L. and Calabrese, L.H. 1983. Autoimmune reactivity in Cogan’s syndrome: a preliminary report. Otolaryngol Head Neck Surg, 91, 24– 32.

Ikeda, M., Okazaki, H. and Minota, S. 2002. Cogan’s syndrome with antineutrophil cytoplasmic autoantibody. Ann Rheum Dis, 61, 761–2. Lunardi, C., Bason, C., Leandri, M. et al. 2002. Autoantibodies to inner ear and endothelial antigens in Cogan’s syndrome. Lancet, 360, 915– 21. St. Clair, E.W. and McCallum, R.M. 1999. Cogan’s syndrome (Vasculitis syndromes). Curr Opin Rheumatol, 11, 47–52. Vollertsen, R.S., McDonald, T.J., Younge, B.R., Banks, P.M., Stanson, A.W. and Ilstrup, D.M. 1986. Cogan’s syndrome: 18 cases and a review of the literature. Mayo Clin Proc, 61, 344–61.

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17 Neurosarcoidosis Bernadette Kalman

The recognition of sarcoidosis started with the description of a skin lesion (Hutchinson, 1869). Boeck (1899) reported the histological characteristics of lesions in a patient with skin involvement and lymphadenopathy. Subsequently, Heerford (1909) discussed three patients with iridocyclitis and parotitis, plus optic neuritis in one case; facial paresis and dysphagia in another one; and facial paresis and sensory symptoms in the third case, giving rise to the eponym of Heerford’s syndrome for the set of uveitis, parotitis, fever, and facial palsy. Schumann (1916) emphasized the multiorgan nature of pathology and established sarcoidosis as an entity. Colover (1948) presented in detail the most common neurological manifestations of the disease, and Delaney (1977) identified 244 patients with neurosarcoidosis among 5092 patients with sarcoidosis in the literature (5%). The etiology of sarcoidosis is unknown. The peak age of onset is between 20 and 40 years with a slight female predominance. The lifetime risk for sarcoidosis is 0.85% for whites and 2.4% for blacks in the US. Scandinavian whites, however, have a risk for sarcoidosis similar to that of US blacks. While the disease is generally considered sporadic, a genetic susceptibility to certain environmental factors is possible. Several viruses and bacteria have been implicated in lesion development, but the findings remain to be replicated. Even though the pathology of sarcoidosis shows great similarities to those of granulomatous infections, particularly tuberculosis, the presence of microbes could not be demonstrated. Associations of human leukocyte antigen (HLA) and protein transporter gene alleles with sarcoidosis have been extensively investigated (Burns, 2003; Zajicek, 2000). By fine mapping of the HLA region identified as a susceptibility locus in a full-genome scan (Schurmann et al., 2001), recently a variant of the butyrophilinlike 2 (BTNL2) gene was found to be associated with the disease in German, North-American white, and African American cohorts (Rybicki et al., 2005; Valentonyte et al., 2005). This association appeared

to be independent of the DRB1 gene locus. A BTNL2 single nucleotide polymorphism (G->A) leads to the introduction of a cryptic splice site and results in a premature stop in the spliced mRNA. The protein product is lacking its transmembrane part and has disturbed membrane localization, thereby preventing the costimulatory function of the molecule. Although further studies are needed to better understand the role of the BTNL2 molecule in the development of sarcoidosis, the above finding appears to be another break through in the elucidation of how a genetic variant can contribute to a disease phenotype. Clinical characteristics Sarcoidosis is a multiorgan granulomatous disorder with a predominant involvement of the lung and lymphoid system. Uveitis, iridocyclitis, parotitis, and polyarthritis are also relatively common, but any organ may be affected. The most frequently affected parts of the nervous system include the anterior optic pathway (retina, optic nerves, chiasm, and tracts) and cranial nerves VII, IX, and X. However, pathological changes may develop in any other cranial nerves. In the fundus, optic disc pallor, edema or granuloma, periphlebitis or vascular sheathing may be seen. Less frequent ophthalmoscopic findings include disc hemorrhage, optic disc telangectasia, macular exudates, optic disc shunt vessels, and vitreous “snowballs” (Frohman et al., 2003). The granulomatous infiltrate can also invade the pars intermedia of the pituitary gland and pituitary stalk, and cause meningoencephalitis and meningomyelitis or tumor-like growth in various axial or extra-axial central nervous system (CNS) structures. Consequently, patients present with diabetes insipidus, abulia, visual field defects, seizures, cognitive decline, dementia, focal neurological symptoms, myelopathy, or cauda equine syndrome. Pachymeningitis or tumor-like lesions can lead to the development of communicating and noncommunicating (obstructive) hydrocephalus. Polyradiculitis,

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plexopathies, polyneuritis, mononeuritis, and mononeuritis multiplex result from granulomas localized in the perineurium and the epineurium with local effects of demyelination and axonal damage. However, granulomas in the muscle, vasa nervorum, or the arterioles to the muscle may also cause nerve damage. The muscle pathology is often asymptomatic and overlooked, but muscle biopsy may reveal positive findings in a great proportion of cases. Fatigue is a frequent nonlocalizing complaint of patients with neurosarcoidosis (Burns, 2003; Kellinghaus, 2004). Paraclinical findings The lesions are composed of noncaseating epithelioid cell granulomas surrounded by lymphocytes. An

extensive general work up is necessary to define the distribution of pathology. Biopsy of systemic or central and peripheral nervous system (CNS and PNS) lesions is usually needed to establish the diagnosis and to exclude the possibility of other granulomatous disorders. X-ray of the chest is frequently false negative (Kellinghaus et al., 2004). Chest computerized tomography (CT) and fiberoptic bronchoscopy with bronchoalveolar lavage usually better support the diagnosis. A positive mediastinal or total-body gallium scan can be particularly helpful, but it should be performed before corticosteroid treatment. The Kweim test (a skin reaction elicited by intradermal inoculation of sarcoid lymph node tissue) is not in use anymore (Kweim, 1941). Hypercalcemia and elevation of the angiotensinconvertase enzyme (ACE) in the serum can support

(a)

(b)

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Fig. 17.1 Brain MRI of a patient with sarcoidosis. Parenchymal infiltration and pachymeningitis in neurosarcoidosis. The axial FLAIR image (a) shows an extensive lesion in the medulla that enhances on the postgadolinium T1-weighted sagittal scan (c) and extends into the upper cervical cord. Similar to the sagittal image (c), the axial (b) and coronal (d) postgadolinium T1-weighted scans also show extensive dural/meningeal enhancement. Enhancement of the fifth nerve (arrow) can be seen on the axial image (b). The sagittal scan (c) suggests the involvement of the anterior optic pathways.

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the diagnosis. The cerebrospinal fluid (CSF) proteins may be moderately elevated while glucose is normal or slightly decreased in neurosarcoidosis. The spinal and adhesive arachnoiditis variants may be associated with a significant elevation of CSF proteins. A moderate, predominantly lymphocytic pleocytosis is present in about 80% of patients. Intrathecal IgG synthesis and oligoclonal bands are less frequent. Recent data suggest that an elevated CSF ACE can support the diagnosis of neurosarcoidosis with high specificity (94–95%) but the test has low sensitivity (24–55%) (Dale and O’Brian, 1999; Tahmoush et al., 2002). Therefore, the CSF ACE result should be interpreted with caution and in the context of clinical findings (Kellinghaus et al., 2004; Zajicek, 2000). T2-weighted and FLAIR magnetic resonance images (MRI) of the brain and spinal cord can reveal the anatomical distribution of granulomatous lesions, while postgadolinium T1-weighted images may indicate meningeal, parenchymal, or radicular enhancement (Fig. 17.1). MRI with gadolinium provides a sensitivity rate of 80–90%, but with a low specificity (Zajicek, 2000). Multiple white-matter lesions caused by neurosarcoidosis in the CNS are sometimes misclassified as MS. Diagnostic criteria Zajicek et al. (1999) proposed a diagnostic classification for neurosarcoidosis based on a retrospective analysis of 68 patients. Diagnosis of definite neurosarcoidosis requires: (i) clinical symptoms suggesting neurosarcoidosis; (ii) exclusion of other diseases; (iii) histology of granuloma in the nervous system in the absence of mycobacterium or other causes of granuloma; (iv) the histology should indicate noncaseating granuloma with epithelioid cells and macrophages, without central necrosis, surrounded by lymphocytes, plasma cells and mast cells, and variable connective tissue reaction. Probable cases of neurosarcoidosis have (i) and (ii) from above, and (iii) laboratory results suggesting inflammation in the CNS (increased protein, oligoclonal bands in the CSF, and MRI suggesting inflammatory lesions) and (iv) tissue evidence of systemic sarcoidosis or at least two of the following indicators: positive gallium scintigraphy, elevated ACE in the serum, and positive chest imaging. Patients with symptoms of neurosarcoidosis who do not qualify for the definite or probable diagnostic criteria may be classified as possible neurosarcoidosis, if other disorders were excluded.

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Treatment Corticosteroids usually effectively control the disease activity in most tissues including lung, skin, liver, lymph nodes, lachrymal and parotid glands, eye, and the CNS or PNS. While acute lesions generally respond well to corticosteroids, it remains uncertain whether or not this regimen changes the natural history of the disease. In chronic and steroid-resistant cases, azathioprine, cyclophosphamide, methotrexate, cyclosporine, and chloroquine have been tried. Lowdose methotrexate may be effective in panuveitis, and can be used in combination with steroids and hydroxychloroquine (Zajicek, 2000). Recent data suggest that refractory neurosarcoidosis may also be successfully treated with agents possessing antitumor necrosis factor α (TNF-α) activity such as thalidomide, pentoxyfilline and infliximab. Infliximab is a chimeric human-murine antibody directed against TNF-α, which holds great promises in the treatment of sarcoidosis (Pettersen et al., 2002). Summary Sarcoidosis is a granulomatous multiorgan disorder that also affects the nervous system in a small proportion of patients. While the disease is typically sporadic, evidence supports the existence of genetic susceptibility factors. In neurosarcoidosis, any part of the neuroaxis may be affected with most frequent involvement of the anterior optic pathways, cranial nerves, and the pituitary gland. Other presentations include meningoencephalitis and meningomyelitis or granulomatous changes in the peripheral nervous system. Sarcoidosis in the muscle appears to be underestimated. The diagnostic evaluation of neurosarcoidosis is well assisted by recently established diagnostic criteria. Most patients respond to corticosteroids, but more aggressive and newer therapeutic modalities are also available. References Boeck, C. 1899. Multiple benign sarkoid of the skin. J Cutan Genitourin Dis, 17, 545–50. Burns, T.M. 2003. Neurosarcoidosis. Arch Neurol, 60, 1166–8. Colover, J. 1948. Sarcoidosis with involvement of the nervous system. Brain, 71, 451–75. Dale, J.C. and O’Brian, J.F. 1999. Determination of angiotensin-converting enzyme levels in cerebrospinal fluid is not a useful test for the diagnosis of neurosarcoidosis. Mayo Clin Proc, 74, 535.

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Delaney, P. 1977. Neurologic manifestations in sarcoidosis: review of the literature, with a report of 23 cases. Ann Intern Med, 87, 336–45. Frohman, L.P., Guirgis, M., Turbin, R.E. and Bielory, L. 2003. Sarcoidosis of the anterior visual pathway: 24 new cases. J Neuro-ophthalmol, 23, 190–7. Heerfordt, C.F. 1909. Uber eine “Febris uveo-parotidea subchronica,” an der Glandula parotis und der Uvea des Auges lokalisiert und haufig mit Paresen cerebrospinaler Nerven kompliziert. Graefes Arch Ophthalmol, 70, 254–73. Hutchinson, J.A. 1877. Illustrations of Clinical Surgery, J&A Churchill, London, pp. 42–3. Kellinghaus, C., Schilling, M. and Ludemann, P. 2004. Neurosarcoidosis: Clinical experience and diagnostic pitfalls. Eur Neurol, 51, 84–8. Kweim, A. 1941. En ny og spesifikk kutan-reaksjon ved Boescks sarcoid. Nord Med, 9, 169–72. Pettersen, J.A., Zochodne, D.W., Bell, R.B., Martin, L. and Hill, M.D. 2002. Refractory neurosarcoidosis responding to infliximab. Neurology, 59, 1660–1. Rybicki, B.A., Walewski, J.L., Maliarik, M.J., Kian, H. and Iannuzzi, M.C.; ACCESS Research Group. 2005.

The BTNL2 gene and sarcoidosis susceptibility in African Americans and Whites. Am J Hum Genet, 77, 491–9. Schumann, J. 1916. Etude sur le lupus pernio et ses rapports avec les sarcoides et la tuberculose. Ann Dermatol Syphilol, 6, 357–73. Schurmann, M., Reichel, P., Muller-Myhsok, B., Schlaak, M., Muller-Quernheim, J. and Schwinger, E. 2001. Results from a genome-wide search for predisposing genes in sarcoidosis. Am J Respir Crit Care Med, 164, 840–6. Tahmoush, A.J., Amir, M.S., Connor, W.W. et al. 2002. CSF-ACE activity in probable CNS neurosarcoidosis. Sarcoidosis Vasculitis and Diffuse Lung Disease, 19, 191–7. Valentonyte, R., Hampe, J., Huse, K. et al. 2005. Sarcoidosis is associated with a truncating splice site mutation in BTNL2. Nat Genet, 37, 357–64. Zajicek, J.P. 2000. Neurosarcoidosis. Curr Op Neurol, 13, 323–5. Zajicek, J.P., Scolding, N.J., Foster, O. et al. 1999. Central nervous system sarcoidosis – diagnosis and management. QJM, 92, 103–17.

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18 Anti-VGKC syndromes: Isaacs’ syndrome, Morvan’s syndrome, and autoimmune limbic encephalitis Bernadette Kalman

Morvan’s syndrome, Isaacs’ syndrome, and limbic encephalitis are immune-mediated disorders of either paraneoplastic or autoimmune etiology. The paraneoplastic variants are discussed in detail in Chapter 19. Isaacs’ and Morvan’s syndromes Morvan (1890) described a patient with myokymia, pain, excessive sweating and sleep disorder, a condition named after him Morvan’s fibrillary chorea. A similar disorder with widespread myokymia, muscle cramping and delayed muscle relaxation but without central nervous system (CNS) involvement was later reported as neuromyotonia or Isaacs’ syndrome (Isaacs, 1961). While motor nerve hyperexcitability (muscle stiffness, cramps, fasciculations, myokymia, and neuromyotonia) dominates, sensory symptoms may also be present in one-third of patients with these acquired peripheral nerve hyperexcitability syndromes. The sensory symptoms are described as numbness, tingling or paroxysmal electric sensations in generalized or focal distribution in the extremities, trunk or neck in usually brief episodic presentations lasting for weeks to years (Herskovitz et al., 2005). Multiple Tinel’s signs may be elicited. The electrophysiological correlate of motor hyperexcitability is a spontaneous firing of single motor units as doublet, triplet, or multiple discharges with high intraburst frequency. Nerve conduction studies may show compound muscle action potential repetitive afterdischarges usually without polyneuropathy. The hyperexcitability in Isaacs’ and Morvan’s syndromes is related to the presence of antibodies to the α-dendrotoxin-sensitive peripheral voltagegated potassium channels (VGKCs) in about 40% of patients. The VGKCs are formed of heterooligomers of various subunits in the CNS and peripheral nervous system (PNS). The cross-linking of VGKCs by antibodies results in decreased K+ currents which inhibit repolarization and lead to hyperexcitability in the

preterminal motor and sensory axons (Herskovitz et al., 2005; Tomimitsu et al., 2004). Patients with Morvan’s syndrome carry antibodies targeting both PNS- and CNS-specific subtypes of the VGKCs (Hart et al., 2002; Vernino and Lennon, 2002). These patients not only have peripheral (neuromyotonia) but also CNS symptoms (personality changes, hallucinations, sleep disturbances, spatial and temporal disorientation, memory problems and confusion), signs of dysautonomia (cardiac arrhythmias, excessive sweating, severe constipation, urinary incontinence, bronchial secretion, lacrymation and salivation), and weight loss (Liguori et al., 2001). Patients with peripheral nerve hyperexcitability syndromes often have additional antibodies including those to the neuronal acetylcholine receptor. Paraneoplastic forms of neuromyotonia may be associated with thymoma and co-occur with myasthenia gravis, but lung or other cancers may also be involved (Liguori et al., 2001). The anti-VGKC antibodies in the idiopathic forms are believed to be related to an autoimmune pathogenesis. Patients with Isaacs’ and Morvan’s syndromes usually respond well to plasma exchange and other immune modulatory therapies, particularly when the immunopathogenesis is idiopathic. Gabapentin and phenytoin have been successfully used to control the hyperexcitability symptoms. Idiopathic limbic encephalitis Limbic encephalitis (LE) is most commonly recognized as a paraneoplastic disorder, but it seems to be related to an idiopathic or autoimmune etiology in a subgroup of patients. The paraneoplastic form has a poor prognosis. It is most commonly associated with small-cell lung cancer or less commonly with breast, testicular cancer, thymoma, and other tumors. The list of pathognostic paraneoplastic antibodies includes anti-Hu (in half of the patients with LE), anti-Ma2, and anti-CRMP5 (CV2). In anti-Hu negative

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patients with LE and cancer, the pathology is usually limited to the limbic system, and improves more often after the removal of the primary cancer than in anti-Hu positive patients, but even in the anti-Hu negative cases the overall prognosis is poor. The presentation of autoimmune form is both clinically and radiologically indistinguishable from the paraneoplastic variant, and usually is associated with the presence of anti-VGKC antibodies. The clinical symptoms of LE include subacute development of short-term memory loss, complex partial, generalized tonic-clonic or other seizure types, behavioral abnormalities and confusion. T2weighted and FLAIR MRI images usually demonstrate hyperintense lesions in the mesial temporal lobe involving the hippocampus and amygdale (Fig. 18.1). Postgadolinium enhancement may be seen on T1-weighted imaging. The histopathology includes perivascular inflammatory infiltrates, neuronal loss and gliosis in the mesio-temporal regions. An electroencephalogram (EEG) may demonstrate bitemporal spikes and slowing or generalized slowing. The cerebrospinal fluid (CSF) can be normal, but the protein level may be elevated and oligoclonal bands occur occasionally. A thorough work up and long-term monitoring cannot detect primary tumors in patients with idiopathic LE.

Fig. 18.1 Axial FLAIR MRI image of the brain of a patient with idiopathic LE and anti-VGKC antibody. The bilateral hyperintense signals in the hippocampal regions indicate the distribution of pathology in such a patient. Courtesy of Dr. Mark Keegan, Department of Neurology, Mayo Clinic, Rochester, MN.

Antibodies to the VGKCs were first identified in two anti-Hu negative patients who presented with cognitive and behavioral changes, excessive salivation, sweating and bronchial secretion but without signs of neuromyotonia (Buckley et al., 2001). One of these patients had thymoma and myasthenia gravis, while the other patient was tumor free during a two-year follow up. Anti-VGKC antibodies in the serum of patients with LE bind to α-dendrotoxinsensitive potassium channels including the Kv1.1, 1.2, and 1.6 subtypes that are expressed throughout the brain and PNS. It is not completely understood why the clinical phenotype includes limbic and autonomous symptoms without PNS hyperexcitability (neuromyotonia) in these patients. In immunohistochemical studies, the anti-VGKC antibodies from the serum of LE patients bind to the middle onethird of the molecular layer of the dentate gyrus in the hippocampus, a pattern similar to that observed with the commercial anti-Kv1.2 antibody. While the detection of these antibodies in patients with LE supports the diagnosis, evidence for a direct pathogenic significance of these antibodies remains to be presented. Screening 15 patients with LE, Pozo-Rosich et al. (2003) found four patients with anti-VGKC. Two patients had idiopathic LE with high levels of the antibody that correlated with a clinical response to immunotherapy. Two additional patients with lower levels of the anti-VGKC antibodies had lung cancer, and one of them improved on immunotherapy. The remaining 11 patients with LE and without antiVGKC had either anti-Hu or anti-Ma2. Thieben et al. (2004) identified seven patients with LE and anti-VGKC antibodies. The clinical and imaging characteristics of LE were similar in these patients with and without tumors, allowing no distinction between paraneoplastic and idiopathic forms. Four patients had additional antibodies to the muscle acetylcholine receptor, striational, P/Q type of calcium channel or GAD65, and two patients had antithyroperoxidase antibodies. Cancer was detected in two patients. There was one spontaneous improvement. Three patients of the six treated with IV methylprednisolone improved significantly. Vincent et al. (2004) reviewed clinical, immunological, and neuropsychological features of 10 patients with history of memory loss, confusion and seizures, low plasma sodium concentrations initially resistant to correction, and MRI suggestive of LE. All these patients tested negative for paraneoplastic antibodies, but had increased anti-VGKC serum levels.

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One of these patients had neuromyotonia, while the others had no electrophysiological signs of peripheral involvement. Neuropsychological work up revealed severe and global memory impairment with relatively preserved general intellect in most patients. The clinical improvement was paralleled by the fall of anti-VGKC drop following various combinations of steroids, plasma exchange or IVIg in seven patients. However, cerebral atrophy and some residual cognitive impairment were commonly noted in late stages of the disease. Altogether, these studies demonstrate that antiVGKC antibodies are a valuable marker of a potentially reversible autoimmune LE, but may also be detected in the paraneoplastic variant. The temporal correlation between the serum antibody levels and the neurological symptoms suggests the involvement of anti-VGKCs in the pathogenesis of LE. Patients with idiopathic LE and anti-VGKC antibodies generally respond well to high-dose corticosteroid therapy or plasma exchange, particularly if administered early after the onset of clinical symptoms. Summary Patients with Isaacs’ syndrome, Morvan’s syndrome, or LE may carry anti-VGKC antibodies of paraneoplastic or autoimmune etiology. The two forms cannot be distinguished on clinical, radiological, and immunological basis. Therefore, a thorough work up is necessary for the exclusion of cancer, and even tumor-negative patients need periodic tumor screening. VGKCs represent a heterogeneous group of molecules with numerous tissue-specific subtypes which may explain the various anti-VGKC antibodymediated PNS and CNS disease phenotypes. The presence of autonomous symptoms in patients with LE may suggest the presence of anti-VGKC antibodies particularly in anti-HU negative patients. The antiVGKC antibodies are frequently associated with other autoantibodies. While their functional importance is supported by in vitro patch clamp studies, their

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pathogenic significance remains to be further investigated (Tomimitsu et al., 2004). Early high-dose corticosteroid treatment, plasma exchange and IVIg can significantly improve the clinical, radiological, and electrophysiological features of these disorders in correlation with the reduction of the anti-VGKC antibody serum levels. References Buckley, C., Oger, J., Clover, L. et al. 2001. Potassium channel antibodies in two patients with reversible limbic encephalitis. Ann Neurol, 50, 73–8. Herskovitz, S., Song, H., Cozien, D. and Scelsa, S.N. 2005. Sensory symptoms in acquired neuromyotonia. Neurology, 65, 1330–1. Isaacs, H. 1961. A syndrome of continuous musclefiber activity. J Neurol Neurosurg Psychiatry, 24, 319–25. Liguori, R., Vincent, A., Clover, L. et al. 2001. Morvan’s syndrome: Peripheral and central nervous system and cardiac involvement with antibodies to voltagegated potassium channels. Brain, 124, 2417–26. Morvan, A. 1890. de la choree fibrillaire. Gaz Hebd Med Chir, 27, 173–200. Pozo-Rosich, P., Clover, L., Saiz, A., Vincent, A. and Graus, F. 2003. Voltage-gated potassium channel antibodies in limbic encephalitis. Ann Neurol, 54, 530–3. Thieben, M.J., Lennon, V.A., Boeve, B.F., Aksamit, A.J., Keegan, M. and Vernino, S. 2004. Potentially reversible autoimmune limbic encephalitis with neuronal potassium channel antibody. Neurology, 62, 1177–82. Tomimitsu, H., Arimura, K., Nagado, T. et al. 2004. Mechanism of action of voltage-gated K+ channel antibodies in acquired neuromyotonia. Ann Neurol, 56, 440–4. Vernino, S. and Lennon, V.A. 2002. Ion channel and striational antibodies define a continuum of autoimmune neuromuscular hyperexcitability. Muscle Nerve, 26, 702–7. Vincent, A., Buckley, C., Schott, J.M. et al. 2004. Potassium channel antibody-associated encephalopathy: A potentially immunotherapy-responsive form of limbic encephalitis. Brain, 127, 701–12.

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19 Paraneoplastic neurological autoimmunity Daniel H. Lachance and Vanda A. Lennon

Definition Paraneoplastic disorders are cancer-associated conditions that cannot be explained by a tumor’s direct invasion of tissue, or by its treatment or consequences. Skin, bone marrow, endocrine, and nervous systems are most often affected. Some paraneoplastic disorders reflect ectopic secretion of hormones by the tumor, but most paraneoplastic neurological disorders reflect a nervous system-specific autoimmune attack initiated by onconeural antigens released to peripheral lymphoid tissues from an unsuspected primary or recurrent neoplasm (Darnell, 1996). Presentation In most cases, autoimmune neurological disorders that are recognized today as paraneoplastic complicate relatively few types of cancer. The neurological illness typically precedes discovery of the tumor or its recurrence and is subacute in onset. It often progresses rapidly to affect more than one level of the nervous system. Historically, several well-characterized neurological syndromes were described in association with certain cancers, and in the early years of paraneoplastic autoantibody discovery, one or more serological markers were defined in the context of discrete neurological syndromes. However, experience in the past two decades has revealed that the patient’s symptoms, in most cases, do not fulfill classic syndromic criteria. Multiple levels of the nervous system are usually affected and multiple autoantibody markers are detectable in the patient’s serum (Table 19.1). It is now recognized that presentation as a classical neurological syndrome associated with a single autoantibody marker in a patient with cancer is the exception rather than the rule. A patient’s past medical history or family history of any form of autoimmunity is a valuable clue to the diagnosis of paraneoplastic autoimmunity. The diagnosis of cancer (usually malignant) sometimes

requires an exhaustive search, and continued surveillance over an extended period. If the cancer found is of a type other than that predicted by the patient’s autoantibody profile (Table 19.2), the search for the predicted cancer should not be abandoned. In 15% of patients, a coexisting neoplasm will be found that is more obvious but unrelated to the predicted cancer (Lucchinetti et al., 1998; Yu et al., 2000). The failure to find a neoplasm, even at autopsy, occurs in less than 15% of patients with an autoantibody profile that strongly predicts cancer. Those cases likely represent patients in whom the immune response has successfully eradicated the cancer. Seronegativity for all currently recognized autoantibody markers of neurological autoimmunity does not exclude the diagnosis of cancer in a patient with a subacute neurological presentation, with or without known risk factors for cancer or recognizable stigmata of autoimmunity (e.g., Graves ophthalmopathy, hypothyroidism, or vitiligo). Although the number of autoantibodies recognized as markers of paraneoplastic (and idiopathic) neurological autoimmunity has greatly increased in the past two decades, many more clearly remain to be described. Recent reports affirm this concept (Ances et al., 2005; Bataller and Dalmau, 2004; Lachance et al., 2006; Vitaliani et al., 2005). The factors determining the occurrence of autoimmunity in the context of cancer are complex and only partly understood (Darnell et al., 2003). These include genes influencing the patient’s immune responsiveness, a multitude of potential onconeural antigens and endogenous “adjuvant” molecules in individual neoplasms, as well as environmental and therapeutic modulating factors. It is not the intent of this chapter to describe the syndromic neurological disorders traditionally recognized with paraneoplastic autoimmunity (listed in Table 19.1). Such descriptions are readily accessed in recent reviews (Bataller and Dalmau, 2004; Shams’ili and Sillevis Smitt, 2005). The subacute

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Table 19.1 Neurological manifestations of paraneoplastic autoimmunity by level of neuraxis.

Level Cerebral cortex

“Syndromic” disorder Limbic encephalitis Encephalopathy

Diencephalon Basal ganglia

Cerebellum Brainstem

Cranial nerves

Spinal cord

Peripheral somatic nerves and ganglia

Autonomic and enteric nervous system Neuromuscular junction

Hypothalamic dysfunction Chorea Hemi-ballismus Parkinsonism Myoclonus Cerebellar ataxia Brainstem encephalitis Opsoclonus/Myoclonus Stiff-person phenomena Bulbar motor neuropathies Optic neuropathy Hearing loss Retinopathy Myelopathy Transverse myelitis Myoclonus Sensory neuronopathy Sensorimotor neuropathies Motor neuropathy Brachial plexopathy Hyperexcitability syndromes Dysautonomias Gastrointestinal dysmotilities Lambert–Eaton syndrome Myasthenia gravis

Muscle

Polymyositis/Dermatomyositis

presentation of most patients with paraneoplastic autoimmunity initially mimics common disorders such as stroke, a peripheral neuropathy, or multiple sclerosis. Others present with a bizarre constellation of symptoms and signs that is mistaken for hysteria. The correct diagnosis therefore requires a high index of suspicion. The clinician is best advised to analyze a patient’s illness by the localization of neurological signs and symptoms, to inquire routinely about personal and family history of autoimmunity and cancer, and to utilize appropriate laboratory and radiological tests. If the central nervous system is involved, these tests should include cerebrospinal fluid (CSF) analysis for inflammatory cells, protein, evidence of

Serological associations (see Table 19.2) CRMP-5; AGNA-1; ANNA-1,3; VGKC; PCA-2; Ma2; neuropil AGNA-1; ANNA-1,2,3; PCA-2; amphiphysin; CRMP-5; ganglionic AChR; VGCC (P/Q or N); striational; GAD65; EFA6A Ma2; ANNA-1 CRMP-5

VGKC PCA-1,2,Tr; CRMP-5; AGNA-1; ANNA-1,2,3; VGCC (P/Q>N-type); GAD65; Zic4; GluR1 AGNA-1; ANNA-1,2,3; PCA-2; Ma2; CRMP-5; VGCC (P/Q>N-type) Amphiphysin CRMP-5; ANNA-1; 2, PCA-2

CRMP-5; recoverin CRMP-5; VGCC; amphiphysin; ganglionic AChR; VGKC; ANNA-1,2 ANNA-1; CRMP-5; ganglionic AChR; muscle AChR; amphiphysin; VGKC; paraproteins

Ganglionic AChR; VGKC; CRMP-5; muscle AChR Ganglionic AChR; VGCC (N>P/Q-type); CRMP-5; ANNA-1; striational; VGKC; muscle AChR; GAD65 VGCC (P/Q>N-type); muscle AChR; striational; ganglionic AChR; AGNA-1/ANNA-4 Muscle AChR; striational; ganglionic AChR; VGKC; GAD65 Anti-Jo

intrathecal IgG synthesis and autoantibody profile. Table 19.1 organizes neurological and serological associations as one would approach the anatomic localization of the patient’s deficits. Serological markers of paraneoplastic autoimmunity and nomenclature Table 19.2 lists the currently recognized antibody markers of paraneoplastic autoimmunity, their associated tumors, and the frequency of coexisting autoantibodies. These autoantibodies are classified by their reactivity with predominantly nuclear, cytoplasmic, or plasma-membrane components of cells

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Table 19.2 Oncological associations of paraneoplastic autoantibodies.

Antibody

Neoplasm predicted by autoantibody

Neuronal and glial nuclear antibodies ANNA-1 Small-cell lung cancer (SCLC), (Lucchinetti et al., 1998) neuroblastoma, thymoma ANNA-2 Lung or breast carcinoma (Pittock et al., 2003) ANNA-3 Lung or upper airway carcinoma (Chan et al., 2001) AGNA-1/ANNA-4 SCLC (Lachance et al., 2006; Graus et al., 2005) Zic 4 SCLC (Bataller et al., 2004) Neuronal, glial and muscle cytoplasmic antibodies PCA-1 Ovarian, fallopian, endometrial, (Peterson et al., 1992) breast carcinoma PCA-2 SCLC (Vernino and Lennon, 2000) PCA-Tr Hodgkin’s lymphoma (Bernal et al., 2003) Amphiphysin Breast or lung carcinoma (Pittock et al., 2005) CRMP-5-IgG SCLC, thymoma, thyroid, or renal (Yu et al., 200; Cross et al., 2003) carcinoma Striational (sarcomeric proteins) SCLC, thymoma, breast carcinoma Neuronal and muscle plasma membrane antibodies VGCC, N Lung, breast or ovarian carcinoma (Lennon et al., 1995) VGCC, P/Q SCLC (Lennon et al., 1995) AChR, muscle Thymoma, SCLC (Vernino and Lennon, 2004) AChR, ganglionic Thymoma, SCLC, others (Vernino et al., 1998) (Pittock et al., 2004) VGKC Thymoma, SCLC (Thieben et al., 2004) (Vincent et al., 2004) GluR1 Hodgkin’s lymphoma (Sillevis-Smitt et al., 2000) “Neuropil” Thymoma, teratoma, thymic, (Ances et al., 2005) thyroid carcinoma EFA 6A Ovarian teratoma (Vitaliani et al., 2005)

Neoplasm found (%)

Frequency of coexisting antibodies (%)

81

43

86

73

90

30

90

50

92

27

90

9

80

63

90

Unknown

80

38

80

57

Unknown

Unknown

Unknown*

Unknown

Unknown*

Unknown

Unknown

Unknown

Unknown

Unknown

Unknown

Unknown

Unknown

Unknown

Unknown

Unknown

Unknown

Unknown

*Commonly accompanies other paraneoplastic autoantibodies, but not found in the context of thymoma. N-type VGCC Ab alone raises suspicion for carcinoma (usually lung or breast). Cancer-predictive value of P/Q-type VGCC alone is less certain.

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in the central or peripheral nervous system. Autoantibody profiles are defined by a combination of findings in an algorithmic cascade of immunofluorescence and immunoprecipitation assays, bioassays, western blot analyses, and an ELISA assay (Fig. 19.1). The nomenclature of paraneoplastic autoantibodies is confusing because different names have been promoted by different authors. The generic scheme for naming cytoplasmic and nuclear autoantibodies is based on immunostaining characteristics and relates to chronological order of publication (Lennon, 1994). The autoantibody originally named generically as an anti-Purkinje cell cytoplasmic antibody (APCA) (Greenlee and Brashear, 1984) was later renamed arbitrarily by an independent group of authors as Anti-Yo. To retain a generic scheme of nomenclature, we favor the name “PCA-1.” The authors who identified the antibody sometimes called anti-Hu, originally described it as an anti-neuronal nuclear antibody (ANNA). Six years later they renamed this antibody to coincide with their assignment of the name “Hu” to the family of specific protein antigens they defined by molecular cloning. The generic name for this antibody, ANNA-1 (Altermatt et al., 1991; Lucchinetti et al., 1998), refers to a well-characterized

pattern of immunofluorescence in a composite substrate of mouse cerebellum and gut tissues. A second, and much rarer, ANNA was initially named “anti-Ri,” and in accordance with generic classification was renamed “ANNA-2” (Pittock et al., 2003). CRMP-5-IgG and amphiphysin antibody have been fully characterized at the molecular level and have unambiguous western blot and immunostaining patterns of reactivity. ANNA-3, AGNA-1/ANNA-4, PCA-2, and PCA-Tr antibodies were described generically based on their distinctive patterns of immunofluorescence staining. A specific protein antigen has not yet been defined in these instances, however, ANNA-3 and PCA-2 proteins are identifiable by neuronal and small-cell carcinoma western blots (Chan et al., 2001; Vernino and Lennon 2000). The antigen of anti-Ma has been defined at the molecular level, but the antibody has not been well characterized immunohistochemically. Pathophysiology Paraneoplastic neurological disorders are the manifestation of a multifaceted immune response initiated by multiple onconeural antigens that are presented

Serological Evaluation for Neurological Autoimmunity Screening Assays

Immunofluorescence (IgG) ANNA-1 ANNA-2 ANNA-3 ANNA-4 PCA-1 PCA-2 PCA-Tr AGNA-1/ANNA-4 Amphiphysin Ab CRMP-5-IgG

If pattern suggests GAD65 Ab

If pattern suggests CRMP-5-IgG

ELISA Striational Ab, Radioimmunoprecipitation VGCC (P/Q-Type) Ab VGCC (N-Type) Ab ACh Receptor (Muscle) Ab AChR (Ganglionic) Ab VGKC Ab

If pattern indeterminate due to coexisting Abs

If VGCC (P/Q-type or N-type), ganglionic AChR, VGKC or striational Abs detected

CRMP-5 Western Blot GAD65 Radioimmunoprecipitation assay

CRMP-5 Recombinant Western Blot

Native or recombinant neuronal Western Blot

If AChR (muscle) or striational Abs detected

AChR (Muscle) modulating Ab bioassay

If positive

AChR (Muscle) blocking Ab assay

Fig. 19.1 Cascade evaluation of paraneoplastic autoantibody profiles.

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to the immune system as the result of tumor cell death. These can be broadly conceptualized as: (i) Neurological disorders that are mediated immunopathologically by a plasma-membrane-directed effector antibody. In the case of the Lambert–Eaton syndrome (Harper and Lennon, 2002) this antibody is the same one as identified to be the principal serological marker of the disorder (namely the P/Q-type voltagegated calcium channel antibody; Lennon et al., 1995). Autoantibodies directed at specific plasmamembrane ion channel proteins have been demonstrated to cause loss or dysfunction of muscle and neuronal acetylcholine receptors and neuronal calcium channels and potassium channels, in both the peripheral nervous system and the central nervous system. The mechanisms by which a peripherally generated humoral immune response might involve the central nervous system are largely unknown. Examples include cerebellar ataxia associated with P/Q-type voltagegated calcium channel antibodies (Fukuda et al., 2003; Lennon et al., 1995), encephalitides related to voltagegated potassium channel antibodies (Thieben et al., 2004; Vincent et al., 2004), and neuronal acetylcholine receptor antibodies (Vernino and Lennon, 2004). (ii) Neurological disorders associated with neuronal nuclear or cytoplasmic autoantibodies. These antibodies serve as serological markers for cytotoxic CD8+ Tcell-mediated mechanisms. They reflect an immune response triggered by peptides derived from an intracellular nuclear or cytoplasmic onconeural protein that is expressed in both the tumor and the nervous system (Albert et al., 1998; Pittock and Lennon, 2006). It is not yet known how a peripheral immune

response initiated against the tumor leads to upregulation in the nervous system of major histocompatibility (MHC) class 1 proteins that display these antigenic peptides on the surface of neurons and glia. This event renders those cells accessible to attack by activated T cells which readily cross the blood–brain barrier. Further discussion of these issues is beyond the scope of this chapter. Diagnosis Figure 19.2 illustrates the approach to diagnosis of a suspected paraneoplastic autoimmune neurological disorder. This diagnosis should be considered as the potential basis for any disorder of subacute onset or insidious progression that lacks a clear alternative diagnosis. The finding of a formally characterized paraneoplastic autoantibody, or a combination of several, is an important guide to the underlying tumor pathology. If the patient has a past history of cancer, the antibody profile may on one hand mandate a search for recurrent cancer or on the other hand direct a search for a different primary malignancy (Pittock et al., 2004). Extensive imaging may be required to establish the true nature of the neurological illness and to locate the underlying tumor, which usually is limited in metastatic spread. Comprehensive electrophysiological and autonomic testing as well as spinal fluid evaluation may be indicated. The finding of CSF pleocytosis supports the diagnosis of an autoimmune inflammatory process and the paraneoplastic autoantibody profile in CSF may be informative (Yu et al., 2001). In most cases of paraneoplastic autoimmunity, the neuropathological

Neurological syndrome

Autoantibody profile

Predicts cancer

Tumor Detected

Pathology confirmed

Non-informative

Tumor Not Detected

Tumor Detected

Long-term cancer surveillance and periodic autoantibody evaluation indicated

Syndrome likely paraneoplastic; marker autoantibody not yet known

Tumor Not Detected

Consider alternative diagnosis

Fig. 19.2 Diagnostic approach for interpreting the autoantibody profile in patients with a suspected paraneoplastic neurological disorder.

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findings are nonspecific consisting of gliosis, neuronal loss, microglial proliferation, and variable infiltrates of CD8+ T lymphocytes (Scaravilli et al., 1999). Thus, biopsy of indeterminate brain lesions is not advised except to exclude alternative pathology. The search for a tumor rests primarily on traditional laboratory and computed tomographic imaging. However, in cases where there is a high index of suspicion, and the cancer search is uninformative, positron emission tomography (PET) scanning is advised (Linke et al., 2004). In cases with suspected mediastinal pathology, mediastinoscopy or endoscopic ultrasound-guided biopsy are helpful to establish a pathological diagnosis. In PCA-1-positive cases with negative mammography, gynecological cancer is strongly predicted, and exploratory laparotomy is justifiable (Hetzel et al., 1989). We have, in one case, encountered coexisting breast and ovarian adenocarcinomas. An abdominal (presumed colonic) adenocarcinoma has been encountered in rare male PCA-1-positive cases (99% are female).

immunosuppressive strategies, such as prednisone, azathioprine, or mycophenolate mofetil. Episodic use of a B-lymphocyte-targeted therapeutic monoclonal IgG (e.g. rituximab) is a consideration. 2 Cytotoxic T-cell-mediated inflammation in the central nervous system and peripheral sensory, autonomic and enteric ganglia may cause severe and irreversible neuronal injury. 3 The goal of long-term immunosuppression is prevention of disease progression which may require immunosuppression for years. Agents employed most commonly today include pulse high-dose methylprednisolone, oral or pulse intravenous cyclophosphamide, mycophenolate mofetil, or azathioprine. 4 Neurological paraneoplastic autoimmunity can be severely disabling. Coordinated strategies are needed to address neurological symptoms, psychiatric symptoms, rehabilitation, nutrition, management of pain, and palliative and hospice care.

Therapy

Summary

The cornerstones of treatment for paraneoplastic neurological autoimmune disorders are removal of the inciting antigen (i.e. tumor ablation), immunotherapy, and supportive care. In theory, the patient is afforded the best chance for abrogation of the immune response if a tumor can be removed surgically in its entirety. For highly malignant tumors like small-cell lung carcinoma, this is usually not possible. A concern therefore arises when myelotoxic chemotherapy is employed to eliminate the cancer because it may abrogate the effector immune response that has limited the tumor’s growth and metastasis. Until the immunological mechanisms determining a beneficial anti-tumor immune response can be defined by monitoring appropriate biomarkers, myelotoxic chemotherapies should be employed judiciously in patients with neurological autoimmunity who have limited-stage cancer. Plasma exchange and intravenous immune globulin (IVIg) therapy, when combined with therapies directed primarily at the tumor, have yielded variable and limited success (Keime-Guibert et al., 2000; Vernino et al., 2003). In treating these patients, the clinician needs to keep in mind the following principles:

Paraneoplastic neurological disorders are the manifestation of a multifaceted immune response to a neoplasm. These disorders can be broadly conceptualized as being mediated immunopathologically by a plasma-membrane-directed effector antibody, or as being associated with neuronal or glial nuclear or cytoplasmic autoantibodies that serve as serological markers for cytotoxic CD8+ T-cell-mediated mechanisms. Multiple levels of the nervous system can be affected and multiple autoantibody markers may be detected at diagnosis or as the neoplasm evolves over time. While the autoantibody profile may predict the cancer, an extensive evaluation over time may be required to establish the true nature of the neurological illness and to locate an often limited stage underlying tumor. Treatment, tailored to the individual patient, should include removal of the inciting antigen, immunotherapy, and supportive care. The best approaches to immunotherapy remain to be defined.

1 Antibody-mediated dysfunction in the central or peripheral nervous system is most amenable to plasma exchange or IVIg coupled with long-term

References Albert, M.L., Darnell, J.C., Bender, A., Francisco, L.M., Bhardwaj, N. and Darnell, R.B. 1998. Tumor-specific killer cells in paraneoplastic cerebellar degeneration. Nat Med, 4, 1321–4. Altermatt, H.J., Rodriguez, M., Scheithauer, B.W. and Lennon, V.A. 1991. Paraneoplastic anti-Purkinje

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and type 1 anti-neuronal nuclear autoantibodies bind selectively to central, peripheral, and autonomic nervous system cells. Lab Invest, 65, 412–20. Ances, B., Vitaliani, R., Taylor, R. et al. 2005. Treatment-responsive limbic encephilitis identified by neuropil antibodies: MRI and PET correlates. Brain, 128, 1764–77. Bataller, L. and Dalmau, J.O. 2004. Paraneoplastic disorders of the central nervous system: Update on diagnostic criteria and treatment. Semin Neurol, 24, 461–71. Bataller, L., Wade, D.F., Graus, F., Stacy, H.D., Rosenfeld, M.R. and Dalmau, J. 2004. Antibodies to Zic4 in paraneoplastic neurological disorders and small-cell lung cancer. Neurology, 62, 778–82. Bernal, F., Shams’ili, S., Rojas, I. et al. 2003. Anti-Tr antibodies as markers of paraneoplastic cerebellar degeneration and Hodgkin’s disease. Neurology, 60, 230–4. Chan, K.H., Vernino, S. and Lennon, V.A. 2001. ANNA-3 anti-neuronal nuclear antibody: Marker of lung cancer-related autoimmunity. Ann Neurol, 50, 301–11. Cross, S.A., Salomao, D.R., Parisi, J.E. et al. 2003. Paraneoplastic autoimmune optic neuritis with retinitis defined by CRMP-5-IgG. Ann Neurol, 54, 38–50. Darnell, R.B. 1996. Onconeural antigens and the paraneoplastic neurologic disorders: At the intersection of cancer, immunity, and the brain. Proc Natl Acad Sci USA, 93, 4529–36. Darnell, R.B. and Posner, J.B. 2003. Paraneoplastic syndromes involving the nervous system. N Engl J Med, 349, 1543–54. Fukuda, T., Motomura, M., Nakao, Y. et al. 2003. Reduction of P/Q-type calcium channels in the postmortem cerebellum of paraneoplastic cerebellar degeneration with Lambert–Eaton myasthenic syndrome. Ann Neurol, 53, 21–8. Graus, F., Vincent, A., Pozo-Rosich, P. et al. 2005 Antiglial nuclear antibody: Marker of lung cancer-related paraneoplastic neurological syndromes. J Neuroimm, 165, 166–71. Greenlee, J.E. and Brashear, H.R. 1983. Autoantibodies to cerebellar Purkinje cells in patients with paraneoplastic cerebellar degeneration and ovarian carcinoma. Ann Neurol, 14, 609. Harper, C.M. and Lennon, V.A. 2002. Lambert–Eaton syndrome. In H.J. Kaminski (ed.), Current Clinical Neurology: Myasthenia Gravis and Related Disorders, Humana Press, Inc., Totowa, NJ, pp. 269–91. Hetzel, D.J., Stanhope, C.R., O’Neill, B.P. and Lennon, V.A. 1990. Gynecologic cancer in patients with subacute cerebellar degeneration predicted by anti-Purkinje cell antibodies and limited in metastatic volume. Mayo Clin Proc, 65, 1558–623. Keime-Guibert, F., Graus, F., Fleury, A. et al. 2000. Treatment of paraneoplastic neurological syndromes with antineuronal antibodies (anti-Hu, anti-Yo) with

a combination of immunoglobulins, cyclophosphamide, and methylprednisolone. J Neurol Neurosurg Psychiatry, 68, 479–82. Lachance, D.H., Kryzer, T.J., Pittock, S.J., Chan, K.H. and Lennon, V.A. 2006. Anti-neuronal nuclear antibody type 4 (ANNA-4), a novel paraneoplastic marker of SCLC. Abstract. Neurology, 66(2), A340. Lennon, V.A. 1994. Paraneoplastic autoantibodies: The case for a descriptive generic nomenclature. Neurology, 44, 2236–40. Lennon, V.A. 1996. Calcium channel and related paraneoplastic disease autoantibodies. In J.B. Peter and Y. Schoenfeld (eds.), Textbook of Autoantibodies, Elsevier Science, The Netherlands, pp. 139–47. Lennon, V.A., Kryzer, T.J., Griesmann, G.E., O’Suilleabhain, P.E., Windebank, A.J., Woppmann, A., Miljanich, G.P. and Lambert, E.H. 1995. Calciumchannel antibodies in the Lambert–Eaton syndrome and other paraneoplastic syndromes. N Engl J Medicine, 332, 1467–74. Linke, R., Schroeder, M., Helmberger, T. and Voltz, R. 2004. Antibody-positive paraneoplastic neurologic syndromes: value of CT and PET for tumor diagnosis. Neurology, 63, 282–6. Lucchinetti, C.F., Kimmel, D.W. and Lennon, V.A. 1998. Paraneoplastic and oncological profiles of patients seropositive for type 1 anti-neuronal nuclear auto antibodies. Neurology, 50, 652–7. Peterson, K., Rosenblum, M.K., Kotanides, H. and Posner, J.B. 1992. Paraneoplastic cerebellar degeneration. I. A clinical analysis of 55 anti-Yo antibodypositive patients. Neurology, 42, 1931–7. Pittock, S.J., Kryzer, T.J. and Lennon, V.A. 2004. Paraneoplastic antibodies coexist and predict cancer, not neurological syndrome. Ann Neurol, 56, 715–19. Pittock, S.J. and Lennon, V.A. 2006. Paraneoplastic autoimmunity affecting the nervous system. In J. Baehring (ed.), Brain Tumors – A Practical Guide to Diagnosis and Management. Informa Healthcare. Pittock, S.J., Lucchinetti, C.F. and Lennon, V.A. 2003. Anti-neuronal nuclear autoantibody type 2: Paraneoplastic accompaniments. Ann Neurol, 53, 580–97. Pittock, S.J., Lucchinetti, C.F., Parisi, J.E. et al. 2005. Amphiphysin autoimmunity: Paraneoplastic accompaniments. Ann Neurol, 58, 96–107. Scaravilli, F., Shu, F.A., Groves, M. and Thom, M. 1999. The neuropathology of paraneoplastic syndromes. Brain Pathology, 9, 251–60. Shams’ili, S. and Sillevis Smitt, P. 2005. Paraneoplasia. In M. Strauss, N. Fernando and L. Sheinis (eds.), Principles of Neuro-Oncology, McGraw-Hill, New York, pp. 649–72. Sillevis Smitt, P., Kinoshita, A., De Leeuw, B. et al. 2000. Paraneoplastic cerebellar ataxia due to autoantibodies against a glutamate receptor. N Engl J Med, 342, 21–7. Thieben, M.J., Lennon, V.A., Boeve, B.F., Aksamit, A.J., Keegan, M. and Vernino, S. 2004. Potentially reversible autoimmune limbic encephalitis with neuronal

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potassium channel antibody. Neurology, 62, 1177– 82. Vernino, S., Adamski, J., Kryzer, T.J., Fealey, R.D. and Lennon, V.A. 1998. Neuronal nicotinic ACh receptor antibody in subacute autonomic neuropathy and cancer-related syndromes. Neurology, 50, 1806–13. Vernino, S. and Lennon, V.A. 2000. New Purkinje cell antibody (PCA-2): Marker of lung cancer-related neurological autoimmunity. Ann Neurol, 47, 297– 305. Vernino, S. and Lennon, V.A. 2004. Autoantibody profiles and neurological correlations of thymoma. Clin Can Res, 10, 7270–5. Vernino, S., O’Neill, B.P., Marks, R.S., O’Fallon, J.R. and Kimmel, D.W. 2003. Immunomodulatory treat-

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ment trial for paraneoplastic neurological disorders. Neuro-Oncology, 6, 55–62. Vincent, A., Buckley, C., Schott, J.M. et al. 2004. Potassium channel antibody-associated encephalopathy: A potentially immunotherapy-responsive form of limbic encephalitis. Brain, 127, 701–12. Vitaliani, R., Mason, W., Ances, B., Zwerdling, T., Jiang, Z. and Dalmau, J. 2005. Paraneoplastic encephalitis, psychiatric symptoms, and hypoventilation in ovarian teratoma. Ann Neurol, 58, 594–604. Yu, Z., Kryzer, T.J., Griesmann, G.E., Kim, K., Benarroch, E.E. and Lennon, V.A. 2001. CRMP-5 neuronal autoantibody: Marker of lung cancer and thymoma-related autoimmunity. Ann Neurol, 49, 146–54.

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20 Vasculitis and connective tissue diseases David S. Younger and Adam P.J. Younger

Introduction

veins (Fig. 20.1). The diverse forms of vasculitis and autoimmune diseases are summarized in Box 20.1.

Vasculitis, defined by inflammation of arteries and veins of varying caliber, results in a variety of clinical neurological manifestations and neuropathological changes of the central and peripheral nervous system (CNS and PNS). There have been several recent reviews of this topic (Collins and Kissel, 2005; Younger, 2003, 2004, 2005b; Younger and Kass, 1997).

This category of systemic necrotizing arteritis includes polyarteritis nodosa (PAN), microscopic polyangiitis (MPA) syndrome, and Churg–Strauss syndrome (CSS).

Classification and overview

Polyarteritis nodosa

Vasculitis in its various forms affects blood vessels of varying caliber from the aorta to capillaries and

The first American patient with PAN was described at the turn of the twentieth century by Longcope

VESSELS INVOLVED

Systemic necrotizing arteritis

CLINICAL SYNDROME

VEINS

VENULES

CAPILLARIES

ARTERIOLES SMALL MUSCULAR ARTERIES (Intraorgan vessels) MEDIUM MUSCULAR ARTERIES (Coronary, hepatic, intracerebral) LARGE ARTERIES (Vertebral, temporal, carotld) AORTA Usually Involved Sometimes Involved

Eales’ Dlstase

sitivity Angiitis

Wegener’s LymphoGranulomatoid matosis Granulomatosis

Allergic Granulomatosis

Microscopic Polyangiitis

Polyarteritis Nodosa

CNS Vascuiitis

Temporal Tnkarnsu’s Arteritis Arteritis

Fig. 20.1 The pathological spectrum of the major vasculitides. Reproduced from Younger et al., 2003, with permission of the publisher.

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Box 20.1 Classification of vasculitis. Systemic necrotizing arteritis Polyarteritis nodosa Microscopic polyangiitis Churg–Strauss syndrome Hypersensitivity vasculitis Drug-related vasculitis Serum sickness Henoch–Schönlein purpura Hypocomplementemic vasculitis Cryoglobulinemia Systemic granulomatous vasculitis Wegener granulomatosis Lymphomatoid granulomatosis Lethal midline granuloma Giant cell arteritis Temporal arteritis Takayasu arteritis Granulomatous angiitis of the nervous system Connective tissue disorders associated with vasculitis Systemic lupus erythematosus

(Longcope, 1908). His patient was a 35-year-old man with constitutional symptoms and subacute leg pains. Postmortem examination showed widespread necrotizing arteritis and nodules along small and medium sized vessels of the heart, liver, kidney, pancreas, testicles, brain, nerves, and skeletal muscles, sparing the lungs and spleen. The histological lesions consisted of mononuclear cell infiltration, necrosis of internal and external elastic lamina of the media, fibrin deposition, aneurismal dilatation, perivascular inflammation of the adventitia, and intimal proliferation resulting in narrowing of arterial lumina. Later investigators (Kernohan and Woltman, 1938) summarized the clinical and pathological aspects of PAN. The dominant neurological picture was a peripheral neuritis that occurred in one-half of patients early in the illness with a predilection for the legs. At postmortem examination, all had arteritic lesions along nutrient arteries of the peripheral nerves, and threequarters had lesions in arteriae nervorum. The combination of acute and chronic lesions correlated with known exacerbations. Brain infarcts resulted from occlusion of cerebral vessels, but only 10% of lesions were clinically apparent.

Scleroderma Rheumatoid arthritis Sjögren syndrome Mixed connective tissue disease Behçet disease Nonsystemic vasculitic neuropathy Infection-associated vasculitis Bacterial meningitis Mycobacterium tuberculosis Spirochetes Treponema pallidum Borrelia burgdorferi Varicella zoster virus Fungi Human immunodeficiency virus type 1 CNS vasculitis associated with amphetamine abuse Paraneoplastic vasculitis Inflammatory diabetic vasculopathy

In PAN the vasculitic lesion proceeds in a characteristic manner, commencing with invasion of the intima, media, and adventitia by polymorphonuclear (PMN), plasma cells, eosinophils, and lymphocytes, and leading to swelling of the media, and fibrinoid necrosis that clusters around the vasa vasorum, with fragmentation of the internal elastic lamina (Fig. 20.2). There is focal deposition of perivascular connective tissue, vascular necrosis, and denuding of the endothelium, followed by vascular thrombosis, ischemia, aneurysm formation, rupture, and hemorrhage. Healed lesions coexist with active lesions. Neuroimaging reveals areas of focal cerebral infarction (Fig. 20.3). Arteriography and biopsy of involved vascular tissue, such as a segment of nerve or muscle in a suspected patient, is the only certain means of histological diagnosis. Microscopic polyangiitis At about the same time as PAN were being delineated, the essential features of MPA were being described (Davson et al., 1948). This disorder differed from PAN in the affliction of small arterioles, capillaries, and

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vessel involvement is considered the definite diagnostic criterion of MPA, and is of the caliber involved in epineurial arteries leading to polyneuropathy in up to a quarter of patients, usually of the MNM type, and in skin nodules and purpura, which occur in the majority of patients. Churg–Strauss syndrome

Fig. 20.2 This small muscular artery from muscle is from a patient with polyarteritis nodosa. In the third, or proliferative, phase illustrated here, chronic inflammatory cells replace the neutrophils of the second phase; there is evidence of necrosis of the media (arrows), early intimal proliferation (arrowheads), and fibrosis. The lumen is almost completely occluded. Ultimately, in the healing phase, this process is replaced by dense, organized connective tissue (stain, hematoxylin and eosin; original magnification, ×250). Reproduced from Younger et al., 2003, with permission of the publisher.

The disorder delineated by Churg and Strauss, and later named in their honor, included asthma, eosinophilia, extravascular granulomas, and necrotizing vasculitis of small and medium arteries, arterioles, capillaries, and veins (Churg and Strauss, 1951). The essential lesions of CSS include angiitis and extravascular necrotizing granulomas with eosinophilic infiltrates. The vasculitis may be granulomatous or nongranulomatous, and characteristically involves arteries and veins, as well as pulmonary and systemic vessels. The granulomas are located near small arteries and veins, and characterized by pallisading epithelioid histiocytes arranged around central necrotic zones in which eosinophils predominant. Pulmonary lesions reflect the combination of necrotizing vasculitis and areas resembling eosinophilic pneumonia. There are three phases of the disease. The first is a prodromal period of constitutional symptoms that includes rhinitis and asthma. This is followed by the second phase of peripheral blood and tissue eosinophilia, and the third phase of systemic vasculitis, wherein neurological involvement occurs, typically peripheral neuropathy of the MNM type, stroke and hemorrhage in up to three-quarters of patients similar to PAN. The laboratory diagnosis is ascertained by serological investigation, primarily ANCA myeloperoxidase, MPO or p-ANCA, and tissue biopsy. Hypersensitivity vasculitis

Fig. 20.3 MRI scan of a case of polyarteritis nodosa with cerebral involvement. Multiple small cortical and subcortical regions of increased signal reflect infarcts in the distribution of small, unnamed branch arteries. Reproduced from Younger et al., 2003, with permission of the publisher.

venules of the lungs and kidney with necrotizing glomerulonephritis. Circulating antinuclear cytoplasmic autoantibodies (ANCA), usually myeloperoxidase (MPO) or p-ANCA, are seen in up to 80% of patients, but are rarely if ever seen in PAN. Small-

This group of vasculitis with a unique predilection for the dermis was defined by Zeek (Zeek et al., 1948). The inflammatory infiltrates in hypersensitivity vasculitis (HSV) (Fig. 20.4) commences with extravasation of erythrocytes, pronounced endothelial swelling, and infiltration by PMN and later mononuclear cells, with resultant fibrosis, and typical involvement of arterioles, capillaries, and postcapillary venules that leaves nuclear fragments or leukocytoclasia with variable necrosis and fibrinoid material termed leukocytoclastic vasculitis (LCV) and circulating immune complexes that deposit in the skin and in the vasculitic lesions. In contrast to PAN, the lesions are all

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that deposit in the skin, eliciting the dermal vasculitic response. Serum sickness

Fig. 20.4 This arteriole from muscle is from a patient with leukocytoclastic vasculitis. The entire vessel and perivascular tissue is infiltrated with polymorphonuclear leukocytes and some chronic inflammatory cells with necrosis and nuclear debris. The vascular lumen is nearly obliterated (stain, hematoxylin and eosin; original magnification, ×400). Reproduced from Younger et al., 2003, with permission of the publisher.

in the same stage of evolution. Other organ involvement includes the peripheral nerves, kidney, lungs, spleen, liver, heart, and rarely the CNS or intestines, wherein microinfarction and hemorrhage can occur. The group of HSV includes drug-related vasculitis, serum sickness, Henoch–Schönlein purpura (HSP), hypocomplementemic, and cryoglobulinemic vasculitis.

Serum sickness leads to vasculitis with varying degrees of infiltration of arterioles, capillaries, and venules, with interstitial inflammation by PMN cells, eosinophils, and mononuclear inflammatory cells, with variable fibrinoid necrosis and perivascular granuloma formation. Urticaria, noted in the majority of patients, is followed by erythematous or maculopapular rash, petechiae, palpable purpura, and lymphadenopathy, first at the site of injection site, and later generalized with arthralgia, edema, headache, and lethargy. Nervous system involvement includes brachial plexus neuritis, mononeuritis simplex and multiplex, Guillain–Barré syndrome, cranial nerve palsies, blurring of vision, retinal and palpebral hemorrhages, meningismus, stroke, and myelopathy. The clinical presentation of serum sickness parallels the appearance of protein antigen and antibody excess and persists until immune complexes are eliminated. The reaction to injection of heterologous serum and many drugs is a complex one, and its multiple neurological manifestations may be explainable on the basis of the immune complex disease with incipient cytotoxic and humoral and cell-mediated immune mechanisms. Henoch–Schönlein purpura

Drug-related vasculitis Drug reactions are responsible for about 20% of cases of dermal vasculitis. They are classified clinically and temporally according to the extent of the allergic reaction, and according to the time that elapses from exposure to the observed reaction. There is a spectrum from urticaria, wheezing, and rhinitis, and variable serum sickness to laryngeal edema, and hypotension, respectively, over minutes, hours, or days. The rash is most often maculopapular or vesicular, less often palpable purpura, along the arms and legs without systemic involvement, and abates after drug withdrawal. More severe drug reactions develop multiple organ involvement, especially the heart, liver, kidneys, gastrointestinal tract, lungs, PNS, and CNS. This disorder results mainly from the focal deposition of immune complexes, which result from the covalent binding of the offending drug, or its metabolites, with native or foreign proteins to produce hapten molecules. The latter forms hapten–antibody complexes

This disorder consists of nonthrombocytopenic purpura, arthralgia, abdominal pain, and leukocytoclastic vasculitis of skin lesions in an affected child with fever, headache, and anorexia. Palpable purpuric lesions arise along extensor surfaces of the lower extremities and buttocks, sometimes in association with migratory angioneurotic edema of the hands, scalp, face, lower legs, and genitalia. The presence of LCV suggests an immune complex-mediated pathogenesis; in that regard, deposits of immunoglobulins, particularly IgA, and C3 have been demonstrated in the kidney and blood vessel walls, and some affected patients had hereditary C2 deficiency. Hypocomplementemic vasculitis Hypocomplementemic or urticarial vasculitis includes urticaria, migratory arthralgia, and persistent or intermittent hypocomplementemia. Affected patients develop urticarial, bullous, and purpuric skin lesions,

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sometimes severe angioneurotic edema and lifethreatening laryngeal edema, accompanied by arthralgia, conjunctivitis, episcleritis, uveitis, mild renal disease, pericarditis, abdominal pain, and splenomegaly. Pseudotumor cerebri is the most common associated neurological manifestation. Hypocomplementemic vasculitis resembles a forme fruste of systemic lupus erythematosus (SLE). Immunological studies show a binding of IgG antibody to C1q along basement membranes, in which it activates the complement cascade. It is not known whether the autoantibody is more than a marker of the disease. Cryoglobulinemia Cryoglobulins are antibodies that reversibly precipitate at temperatures below 37°C. They are composed of IgG and IgM, complement, lipoprotein, and antigenic protein moieties. They are classified into three types with implications for clinical and etiologic specificity. Type I is composed of a single monoclonal IgM or IgG antibody; type II, mixed, has monoclonal IgM, possessing activity against polyclonal IgG; and type III has mixed polyclonal and nonimmunoglobulin molecules in the form of immunoglobulin–anti-immunoglobulin immune complexes. Types I and II cryoglobulins are associated with lymphoproliferative diseases, particularly multiple myeloma and Waldenström macroglobulinemia. Type III cryoglobulins are associated with infection and collagen vascular diseases; one subgroup, termed essential mixed cryoglobulinemia (EMC), harbors circulating HCV RNA and corresponding antibodies in the cryoprecipitate. Type I cryoglobulins cause the hyperviscosity syndrome. Four vascular lesions are noted in cryoglobulinemia: (i) occlusion of small and large vessels in those with high levels of cryoglobulins of type I or II; (ii) bland thrombosis of small arteries and arterioles; (iii) endothelial swelling, proliferation, and basement membrane thickening; and (iv) LCV. Peripheral nerves demonstrate chronic axonopathy of large myelinated fibers. True vasculitis is occasionally seen, mainly in those with associated PAN. Dermatitis is the most conspicuous feature accompanied by palpable purpura that persists for a week to 10 days, heralded by a sharp or burning sensation. Purpura is noted in all types but is more common with type III and in EMC. PNS and CNS manifestations are more common with types II and III. Renal disease is a major feature of EMC. Hepatic disease is far more common with this syndrome by virtue of its association with HCV.

The appearance of high levels of cryoglobulins in the blood of patients reporting cold sensitivity and vasomotor symptoms led to the presumption that cryoprecipitation was the cause of ischemia of arterioles and capillaries due to hyperviscosity and the direct plugging of small vessels. However, it is now known that the cryoprecipitate, when present, may be tangential to the pathogenesis of the clinical syndrome and even an artifact for several reasons. First, cryoprecipitation occurs in systemic organs of normal temperature. Second, the temperature at which precipitates occur in vitro is far below that achieved in the body. Third, symptoms do not correlate with serum cryoglobulin levels, viscosity, or cryoprecipitate concentration. Fourth, in EMC in which levels of cryoglobulins are typically quite low, the pathology can still be explained on the basis of immune complex deposition. Several factors that may contribute to the clinical manifestations of cryoglobulinemia include intravascular activation of complement and the clotting cascade by aggregated immunoglobulin and immune complexes, secondary vessel wall damage; cold agglutination of erythrocytes; local tissue reaction to precipitated proteins; and VEC proliferation. Central nervous system manifestations in types I and II disease are related to vascular occlusion with or without vasculitis. Peripheral neuropathy is associated more frequently with epineurial vasculitis, cryoprecipitate deposition, and microvascular ischemia with resultant secondary axonopathy. In those studied, the inflammatory cell infiltrate in the nerve was mainly T cell with lesser numbers of B lymphocytes, in accordance with T-cell-dependent vasculitis. The isolation of HCV RNA in peripheral nerve biopsies has been unsuccessful in marked contrast to cutaneous lesions. Cryoglobulinemia should be considered in patients with features of characteristic skin lesions, MNM, hyperviscosity, easily coagulable blood, IgM monoclonal paraproteinemia, and risk factors for HCV infection. If found, the presence of cryoglobulinemia will direct the performance of bone marrow studies, nerve biopsy, and studies for HCV and HIV-1 infection, AIDS, occult cancer, infection, plasma cell dyscrasia, and collagen vascular disease. Systemic granulomatous vasculitis This group of systemic granulomatous vasculitis includes Wegener granulomatosis (WG), lymphomatoid granulomatosis (LG), and lethal midline granuloma.

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Wegener granulomatosis Although first considered a form of PAN, WG was later termed rhinogenic pneumogenic granulomatosis by the investigator for whom it was later named. It differed in fact from PAN in the triad of necrotizing granulomatous lesions of the sinuses and lower respiratory tract, systemic necrotizing vasculitis of small arteries and veins, and glomerulonephritis (Godman and Churg, 1954). Nervous system involvement was appreciated almost a decade later (Drachman, 1963). Vasculitic lesions in WG begin as small foci of granular necrosis and fibrinoid degeneration with PMN cells followed by histiocytes and giant cells along the margins of granulomas of the upper airways and in renal glomeruli. Necrotizing granulomatous lesions secondarily involve small arteries, arterioles, capillaries, and venules with segmental fibrinoid necrosis in involved tissues (Fig. 20.5). Affected patients present with multifocal pain, sensory loss, and weakness due to MNM that ultimately can become disabling. Circulating c-ANCA directed against proteinase 3 (PR3) is predictive of the disease in the majority of patients even in the initial phase of illness. A quarter of patients demonstrate CNS and PNS involvement due to direct destruction of nerve or brain tissue by necrotizing granulomas, locally or remote from upper or lower respiratory tract granulomas, and necrotizing arteritis of cerebral and arteriae

Fig. 20.5 Wegener granulomatosis. This small muscular artery is nearly completely destroyed. A large confluent area of fibrinoid degradation (arrows) is surrounded by neutrophils, palisading histiocytes, lymphocytes, plasma cells, and some giant cells (stain, hematoxylin and eosin; original magnification, ×250). Reproduced from Younger et al., 2003, with permission of the publisher.

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nervorum of peripheral nerves. CNS manifestations, in particular, appear to depend upon whether there is vasculitic, contiguous extension, or remote granulomatous spread. Stroke, intracerebral and subarachnoid hemorrhage, and optic neuritis result from vasculitis of anterior and posterior ciliary and retinal vessels. Contiguous extension results from nasal and paranasal sinus cavity granulomas through the orbit leading to pseudotumor with exophthalmos, extraocular muscles, optic and oculomotor nerve involvement, whereas extension through the temporal bone can destroy the middle ear. Lymphomatoid granulomatosis This malignant lymphoreticular disorder has a strong affinity for the CNS. Patients present with constitutional symptoms and skin lesions resembling erythema nodosum. Focal neurological involvement occurs early including MNM, unilateral cranial nerve palsies, hemiparesis, ataxia, seizures, spinal and radicular syndromes, and even myopathy. In particular, CNS complication occurs by the invasion of unifocal and multifocal necrotizing angiocentric and angiodestructive lesions of small- and medium-sized muscular arteries and their endothelia by masses of T cells, plasma cells, histiocytes, and atypical lymphoreticular cells (Fig. 20.6) with immunoblast formation in the cerebrum, brain stem, cerebellar parenchyma, and meninges.

Fig. 20.6 Lymphomatoid granulomatosis. The characteristic invasion of the vessel wall (arrow) and the perivascular tissue by a polymorphocellular infiltrate consists of lymphocytes, plasma cells, and atypical reticuloendothelial cells. The vessel lumen is markedly narrowed. Notice the absence of well-formed granulomas and fibrinoid necrosis (stain, hematoxylin and eosin; original magnification, ×250). Reproduced from Younger et al., 2003, with permission of the publisher.

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Lethal midline granuloma Historically, this disorder was likened to WG but systemic disease is not a major feature of lethal midline granuloma, and WG rarely if ever causes such extensive facial mutilation. It is now known to be a relentlessly invasive necrotizing process of the nose and palate that causes destruction of sinuses and all major midline structures of the head, producing grotesque facial mutilation and ultimately death. The disorder is associated with idiopathic midline granuloma, poorly differentiated diffuse small or large B-cell lymphomas, plasmacytomas, and other polymorphic reticuloses mediate the damage. CNS complications most often result from direct invasion of the orbit and face, jugular vein, sigmoid and cavernous sinuses leading to vascular thrombosis, sepsis, meningitis, and exsanguinations.

sized arteries at autopsy in some cases warranted the diagnosis of generalized giant cell arteritis. The pathological heterogeneity of temporal arteritis was further demonstrated by the finding of intracranial lesions in several patients who also qualified for the diagnosis of granulomatous angiitis. Peripheral nervous system lesions in GCA are exceedingly rare. The earliest lesions of GCA consist of vacuolization of smooth muscle cells of the media, with enlargement of mitochondria, infiltration of lymphocytes, plasma cells, and histiocytes. With progression, there is extension inflammation into the intima and adventitia leading to segmental fragmentation and necrosis of the elastic lamina, granuloma formation, and proliferation of connective tissue along the vessel wall. This eventuates in vascular thrombosis, intimal proliferation and fibrosis (Fig. 20.7). Temporal arteritis and Takayasu arteritis

Giant cell arteritis (GCA) The concept of temporal arteritis was first described by Horton (Horton et al., 1932) and then named by Jennings ( Jennings, 1938) for the site of granulomatous giant cell inflammation and vessel involvement. Patients with biopsy-proven temporal arteritis and associated blindness due to vasculitic involvement of ophthalmic and posterior ciliary vessels were originally classified as cranial arteritis. Other patients had prominent constitutional and musculoskeletal complaints and typical polymyalgia rheumatica. The occasional finding of giant cell lesions along the aorta, its branches, and in other medium- and large-

Two forms of giant cell arteritis, temporal and Takayasu arteritis, are of clinical importance to neurologists. They differ epidemiologically and in the size of vessels involved. Temporal arteritis occurs in elderly Caucasians of either gender, and involves medium and large arteries. Takayasu arteritis affects the aorta and its branches in young Asian women. The clinical manifestations of temporal arteritis namely headache, scalp tenderness, thickened nodular and pulseless superficial temporal artery, unilateral visual loss, and jaw claudication are related primarily to disease along branches of the external carotid artery, and arteritis of the vertebral and carotid

Fig. 20.7 Temporal arteritis. (a) In an early lesion of a large muscular artery, necrosis, inflammation, and giant cell formation (single arrow) can be seen immediately adjacent to the internal elastic lamina (arrowhead), which is undergoing degenerative changes, and there is some intimal proliferation (double arrows) (stain, hematoxylin and eosin; original magnification, ×100). (b) This more advanced lesion has complete segmental destruction of the internal elastic lamina and virtually the entire media (arrows). Marked intimal proliferation has nearly occluded the lumen, and few inflammatory cells remain (stain, hematoxylin and eosin; original magnification, ×50). Reproduced from Younger et al., 2003, with permission of the publisher.

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arteries typically at end points of dural investment. The characteristic involvement of obliterative lesions in large arteries such as the aorta and its major branches in Takayasu arteritis, especially late in the disease, leads to other symptoms, not typically seen in temporal arteritis, due to chronic ischemia such as dizziness, syncope, subclavian steal, carotid sinus syndrome, stoke, amaurosis fugax, corneal opacification, cataracts, claudication and gangrene of the limbs, chest and abdomen angina. Whereas biopsy of the temporal artery is easily performed in clinically suspected patients before commencing therapy with long-term corticosteroids or other agents, similar arterial biopsy is impractical in Takayasu arteritis. Granulomatous angiitis of the nervous system (GANS) This rare vasculitic disorder has captured the attention of generations of neurologists and neuropathologists. The first two patients with this disorder described by Harbitz (Harbitz, 1922) had a previously unrecognized vasculitis with progressive headaches and mental change culminating in stupor, spastic paraplegia, coma, and death. Postmortem examination showed granulomatous vasculitis of the meninges composed of lymphocytes, multinucleate giant cells, and epitheliid cells, with vessel necrosis and extension into the brain involving veins and arteries of varying caliber. The clinicopathological syndrome was delineated and so named for the distinctive pathology (Cravioto and Fegin, 1959). For two more decades, rare affected cases were reported, but there was no effective treatment. Fauci and coworkers (Fauci, 1978) transformed prevailing concepts of the disorder by suggesting angiographic criteria for the antemortem diagnosis of so called “primary angiitis” or “isolated angiitis” of the CNS, and emphasized the clinically restricted nature of the vasculitis rather than the granulomatous histology (Cupps et al., 1983). The rationale was that giant cells and epithelioid cells, described at autopsy, were an inconsistent finding in a meningeal and brain biopsy, and therefore not necessary for antemortem diagnosis, and furthermore, that treatment with prednisone and cyclophosphamide was a given necessity. This unfortunately led to difficulty in comparisons of treatment efficiency and long-term prognosis of cases in the literature, which persisted for two decades until the enthusiasm for the empirical treatment of cerebral vasculitis waned as a result of several influences. First, there was recognition of

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the unreliability of beading in a cerebral angiogram in histologically proven cases of granulomatous angiitis of the brain (Younger et al., 1988); similar beading was demonstrated by young women with the prior diagnosis of primary angiitis of the CNS who were later diagnosed as benign angiopathy of the CNS but differed in spontaneous resolution (Calabrese et al., 1993). Second, interest in empirical therapy with cyclophosphamide waned with the recognition of permanent side effects in up to 40% of patients so treated with WG. Subsequent historical analyses demonstrated an equivalent efficacy of corticosteroids and cyclophosphamide in the initial treatment of this disorder (Younger et al., 1997). There are at least 140 well-described cases of GANS in the literature (Younger, 2003). Diagnostic biopsy of the brain and overlying meninges and postmortem examination shows granulomatous giant cell and epithelioid cell inflammation with necrotizing arteritis of cerebral vessels of all calibers from named cerebral vessels to medium and small leptomeningeal vessels (Fig. 20.8). The disorder has nearly exclusive neurological manifestations including headache, mental change, and pleocytosis and elevated protein content in the cerebrospinal fluid (CSF), with signs of angiographic beading; which precedes focal seizure and stroke (Fig. 20.9), and if untreated, coma and death. The clinical heterogeneity is manifested by the occurrence of GANS in association with cell arteritis, sarcoidosis, varicella zoster virus, lymphoma, amyloid angiopathy, and human immunodeficiency virus (HIV) infection. Collagen vascular diseases The collagen vascular diseases associated with vasculitis of the nervous system include systemic lupus erythematosus, scleroderma, rheumatoid arthritis (RA), Sjögren syndrome, mixed connective tissue disease (MCTD) and Behçet disease, each with recognizable clinical neurological and histopathological syndromes. Systemic lupus erythematosus (SLE) The earliest concepts of connective tissue diseases stemmed from the appreciation of fibrinoid necrosis using collagen staining in patients with SLE. Once thought to be an important cause of cerebral lupus, true vasculitis is present in only about 10% of patients at postmortem examination. The vasculitis of SLE shows fibrinoid necrosis of small arteries,

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Fig. 20.8 Central nervous system vasculitis. (a) The media and adventitia of this small leptomeningeal artery have been almost completely replaced by multinucleated giant cells (arrowheads). There is intimal proliferation with obliteration of the vascular lumen, and a dense, perivascular, mononuclear inflammatory infiltrate can be seen (stain, hematoxylin and eosin; original magnification, ×250). (b) A somewhat larger leptomeningeal vessel shows necrosis of the media and internal elastic lamina with multinucleated giant cell formation (arrows), intimal proliferation (arrowhead), and lymphocytic infiltration of the adventitia and neighboring meninges (stain, hematoxylin and eosin; original magnification, ×250). Reproduced from Younger et al., 2003, with permission of the publisher.

Fig. 20.9 MRI (FLAIR sequence) of a patient with biopsy-proven, unifocal central nervous system vasculitis that is largely confined to the left temporal and basal frontal regions. Reproduced from Younger et al., 2003, with permission of the publisher.

arterioles, and capillaries (Fig. 20.10). As collagen swells and fragments in the course of SLE, it dissolves to form a homogeneous hyaline and granular PAS positive material. The fibrinoid material contains immunoglobulins, antigen–antibody complexes, complement, and fibrinogen. The organ-specific responses of the CNS, PNS, and systemic organs of this fibrinoid necrosis lead to recognizable clinical sequela. A number of fluorescent antibody tests provide serological support of SLE. The antinuclear antibody (ANA) screen produces a homogeneous pattern in the majority of cases; with antibodies

Fig. 20.10 Systemic lupus erythematosus. This small vessel within brain parenchyma is largely necrotic. Abundant fibrin (darkly stained) is evident in vessel walls and surrounding tissues. There are a few chronic inflammatory cells indicating the presence of vasculitis, which may be seen in 20% of patients (stain, fibrin; original magnification, ×250). Reproduced from Younger et al., 2003, with permission of the publisher.

to native double-stranded DNA (anti-ds-DNA), reactivity to Sm and ribonuclear proteins (RNP), the combination of which constitutes the extractable nuclear antigen (ENA), providing the strongest supportive evidence of SLE. Circulating IgG and IgM antibodies with an affinity for charged phosopholipids (APA), some of which have procoagulant activity, the s-called lupus anticoagulant (LAC), and the generic anticardiolipin (aCL) antibody assay using cardiolipin as the antigen probe for APA, are an important determinant of prothrombotic events especially in the CNS wherein there is a propensity

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Fig. 20.11 (a)–(c) Thrombotic-embolic cerebral microangiopathy in a patient with antiphospholipid antibody syndrome (see text for details). Reproduced from Younger et al., 2003, with permission of the publisher.

for occlusive microangiopathy. In particular, elevation of the serum aCL antibody titer appears to be an independent risk factor for stroke, especially in young patients due to vasculopathy and in situ thrombosis. To illustrate, one previously reported 22-year-old man (Younger et al., 1994a) with lupus glomerulonephritis and hypertension developed right frontal headache followed by left hemiplegia. Brain CT showed a large superficial and deep infarct in the territory of the upper and lower divisions of the right middle cerebral artery (MCA). Follow-up brain scan showed hemorrhagic transformation in the absence of clinical worsening. Magnetic resonance angiography (MRA) revealed a proximal right MCA occlusion. Serum aCL titer was 60 GPL (normal range 0 to 10) with a serum ANA titer of 1:320 (homogeneous), and anti-dsDNA titer was 371 unit/ml (normal positive active range 0 to 249). Selective angiography showed total occlusion of the right proximal MCA with retrograde filling of distal branches (Fig. 20.11). He was given intravenous heparin followed by long-term anticoagulation with warfarin.

fibrosis of the adventitia, and intima; duplication and fraying of the internal elastic membrane, with progressive luminal obliteration (Fig. 20.12). The microvascular lesions in scleroderma appear to be mediated by three autoantibodies – anticentromere, anti-SCL-70 or topoisomerase, and anti-RNA polymerase III – and the HLA-DQB1 haplotype, accompanied by autoreactive lymphocytes that produce interleukins 4 and 6, which are chemotactic for dermal fibroblasts and capable of inducing collagen synthesis. Necrotizing vasculitis with prominent neurological involvement can be indolent

Scleroderma Scleroderma or systemic sclerosis is recognized by widespread microvasular changes and diffuse fibrosis affecting first the skin, and later systemic organs and the nervous system. Vascular lesions include increased collagen deposition, sclerosis, and hyalinization, followed by proliferation of the endothelium,

Fig. 20.12 Progressive systemic sclerosis. This digital artery has severe intimal hyperplasia and greater than 90% luminal narrowing. There is also severe adventitial fibrosis and marked telangiectasia of the vasa vasorum, but the media and internal elastic lamina are relatively spared (stain, trichrome; original magnification, ×60). Reproduced from Younger et al., 2003, with permission of the publisher.

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or fulminant, and even resemble PAN, with CREST syndrome of calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia of the skin and face. Rheumatoid arthritis (RA) There are three forms of vasculitis in RA with affliction of blood vessels ranging in size from dermal postcapillary venules to the aorta, usually in association with circulating IgM and IgG rheumatoid factor (RF) as measured by the latex fixation test, decreased complement, and positive ANA. The first is a proliferative endarteritis of a few organs particularly the heart, muscle, and nerves characterized by inflammatory infiltration of all layers of small arteries and arterioles, with intimal proliferation, necrosis, and thrombosis. The second is a fulminant vasculitis indistinguishable from PAN with less severe leukocytosis, myalgia, renal and gastrointestinal involvement, and bowel perforation. The third is an LCV with palpable purpura, arthritis, cyroglobulinemia, and low complement levels. Nonvasculitis spinal and epidural involvement leads to vertebral collapse, subluxation, and direct narrowing of the spinal canal due to rheumatoid pannus that leads to myelopathy, radiculopathy, and stenosis. Sjögren syndrome Sjögren syndrome is recognized by keratoconjunctivitis sicca and xerostomia. Two types of vasculitis occur, LCV of the skin with palpable purpura, urticaria, erythematous macules, and papules; and another that resembles PAN with muscle, nerve, CNS and visceral vascular involvement, without aneurysm formation. Humoral and cell-mediated mechanisms underlie hypergammaglobulinemia, CD4 infiltration of exocrine glands with blast transformation, and association with extractable RNA proteins Ro or Sjögren syndrome (SS)-A and intranuclear RNAassociated antigen La or SS-B. Vasculitis is best confirmed by skin, muscle, and sural nerve biopsy as in PAN and HSV. Mixed connective tissue disease This group of disorders, also known as an overlap syndrome, has clinical and histopathological features of SLE, scleroderma, and polymyositis along with proliferative vascular changes, capillary involvement, and mild tissue fibrosis.

Behçet disease This disorder is characterized by the trial of oral and genital ulcers and uveitis, and is associated with cutaneous, retinal, and CNS vasculitis. Large-artery involvement resulting from smoldering vasculitis along the carotid, radial, and subclavian arteries, and less commonly cerebral veins and arteries without aneurysm formation leads to secondary vascular thrombosis and pseudotumor cerebri. Neurological inflammatory involvement also results from direct inflammation of the neuraxis, for example in the occurrence of focal brainstem meningoencephalitis. Nonsystemic vasculitic neuropathy As originally defined, this disorder encompassed patients with necrotizing arteritis in a nerve biopsy specimen sparing the muscle tissue in the absence of a definable systemic connective tissue and inflammatory disease (Dyck et al., 1987). Affected patients demonstrate all forms of peripheral neuropathy. The legitimacy of this diagnosis has been called into question for at least three reasons. First, two-thirds or more of patients with the initial diagnosis of nonsystemic vasculitic neuropathy are eventually found to have causative systemic disorders after intensive evaluation including PAN, WG, RA, Sjögren syndrome, SLE, scleroderma, diabetes mellitus, plasma cell dyscrasia, lymphoproliferative cancers, occult malignancy, and other disorders. Second, arteritis and nonarteritic inflammatory foci are occasionally found in tandem muscle specimens. Third, there is only a single well-defined postmortem case in the literature that was reported more than 60 years ago (Kernohan and Woltman, 1938). Infection-associated vasculitis The group of infection-related vasculitis includes acute purulent meningitis, tuberculosis, syphilis, Lyme neuroborreliosis, varicella zoster virus ( VZV), fungal infection, seropositivity to human immunodeficiency virus type 1 (HIV-1) infection and acquired immunodeficiency syndrome (AIDS). Recognition of an infection is important because prompt treatment averts or lessens the severity of vasculitis. Purulent bacterial meningitis causes arteritis and thrombophlebitis of vessels due to infiltration of blood vessels as they traverse sites of exudation at the base of the brain and across foci of cerebritis, leading to vascular narrowing, cerebral ischemia,

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infarction, hemorrhage, and abscess formation. Host and immune factors are equally important determinants of whether mycobacterial tubercules rupture in cisterns of the brain with a similar outcome of arteritis. Treponema pallidum, the agent of syphilis, and Borrelia burgdorferi, the agent of Lyme neuroborreliosis, have particular attraction for blood vessels. Untreated, acute syphilitic meningitis leads to arteritis and meningovascular disease, endarteritis, and later general paresis and tabes dorsalis. Vasculitis also occurs in Lyme neuroborreliosis after meningitis, with characteristic encephalopathy, stroke, peripheral neuropathy, and cranial nerve palsy (Younger et al., 1995). Cerebral vasculitis follows VZV ophthalmicus with a characteristic syndrome of contralateral hemiplegia owing to ipsilateral vasculitis of the anterior and middle cerebral arteries. Pathological studies of the vasculitic lesions show necrotizing granulomatous angiitis with demonstrable viral particles. Four fungal agents, Aspergillums, Candida, Coccid oides, and Mucormycosis, lead to opportunistic infection in immunocompromised and severely disabled hosts and have the capacity to invade arteries of the CNS. Vasculitis of the nervous system occurs in association with HIV-1 infection alone or with AIDS, including primary granulomatous angiitis of the brain, eosinophilic temporal arteritis, vasculitic meningoencephalitis, and mononeuritis multiplex and myositis resembling PAN, although these are all rare occurrences (Younger et al., 1994b; Younger et al., 1996b). The pathogenesis of HIV-associated vasculitis appears to result from direct infection of vascular endothelial cells (VEC) by HIV and other infectious agents, in association with immune complex deposition, upregulation of cytokine section and adhesion molecules in native cerebral and peripheral nerve vessels. Peripheral neuropathy can arise as an immune response to HIV infection mitigated by retroviral antigens that stimulate a humoral and cell-mediated immune response. To illustrate, a previously reported (Younger et al., 1996b) 45-year-old homosexual man with lymphadenopathy was found to be HIV-1 seropositive and treated with azido-dideoxythymidine (AZT), and afterward developed painful asymmetric paresthesia of the feet indicative of sensory mononeuritis multiplex. Peripheral blood contained 361 CD4 cells/mm3 (normal 537–1571), with a CD4/CD8 ratio of 0.34 (normal 1.2–3.8). There was no clinical or laboratory evidence of systemic vasculitis. Electrodiagnostic studies showed mild generalized sensory axonal neuropathy. Nonetheless, sural nerve

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biopsy was performed that showed mononuclear infiltration of endoneurial and epineurial blood vessels associated with fibrinoid necrosis, thrombosis, and recanalization of vessel lumina. Immunoperoxidase and alkaline phosphatase stained sections showed infiltrating macrophages that expressed p24 and gp41 HIV-related antigens as well as interleukins, tumor necrosis factor, and strongly reactive C3d, C5b-9, and IgM in the affected vessel wall. Substance abuse Parenteral drug use as a cause of CNS vasculitis was first reported in 1970 among drug addicts who suffered strokes and intracranial hemorrhage in association with multiple amphetamine and narcotic drug use (Citron et al., 1970). Necrotizing arteritis of the polyarteritis type was found in cerebral arteries and arterioles (Fig. 20.13). Many of the patients had complicating factors including severe hypertension and hepatitis B antigenemia. Similar histologically proven cases have been described in other users of amphetamine, cocaine, and opioids, alone or in combination. However, four observations cast doubt on the frequent association of substance abuse including

Fig. 20.13 Cerebral vasculopathy in a case of intracerebral hemorrhage associated with the use of phenylpropanolamine as an aid to weight loss. The profound intimal hyperplasia all but obliterates the vascular lumen. Polymorphonuclear leukocytes are in all three vascular layers but particularly the intima. The media are remarkably well preserved compared with cases of polyarteritis nodosa and leukocytoclastic vasculitis (stain, hematoxylin and eosin; original magnification, ×100). Reproduced from Younger et al., 2003, with permission of the publisher.

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amphetamine with true cerebral vasculitis. First, most cases have been diagnosed by beading alone on a cerebral angiogram, without pathological verification. Second, the vascular insult associated with drug abuse is likely due to contributory factors including HIV-1, opportunistic bacterial, fungal, viral, and spirochete infection. Third, necrotizing arteritis itself is not a feature of an experimental animal model in which vessel beading develops within two weeks of potential administration of amphetamine, postmortem examination of which shows perivascular cuffing, not arteritis. Paraneoplastic vasculitis Several patients with sensory neuropathy and microvasculitis in a sural nerve biopsy and at postmortem examination were described in association with small-cell lung cancer (SCLC) (Johnson et al., 1979). Their observations laid the groundwork for the modern appreciation of current cell-marker immunohistochemistry and the available assays for paraneoplastic autoantibodies, especially anti-Hu antibody, which recognizes nuclei of SCLC or other malignant cells, as defined by their specificity, and cross-react with dorsal root ganglia and other neurons (Dalmau et al., 1990; Dalmau et al., 1992). However, the recognition of microvasculitis of the nerve and muscle as a valid paraneoplastic disorder was firmly established in a patient with paraneoplastic systemic capillary leak syndrome (SCLS) associated encephalomyelitis and sensory neuronopathy, high anti-Hu antibody titers, and transmural inflammation of epimysial and epineurial vessels of muscle and nerve biopsy (Younger et al., 1994a). Successful treatment of malignancy led to improvement in the neurological disorder and a sustained fall in the anti-Hu antibody titer. Other patients with paraneoplastic vasculitis have been reported in association with cancer of the lung, kidney, prostate, and lymphoma. Inflammatory diabetic vasculopathy The vasculopathy and autoimmune sequela of diabetes mellitus has recently come to the attention of neurologists. The views supporting an ischemic pathogenesis stemmed from anecdotal observations of diseased blood vessels and nerve trunks at autopsy from amputated limbs more than a century ago (Pryce, 1887), and much later, systematic studies of peripheral nerve microvessels stained with the periodic acid-Schiff method that showed the

collective features of diabetic microangiopathy (Fagenberg, 1959). Frank inflammation of the nerves of diabetic patients has been recognized in one form or another for decades. Early investigators noted the presence of inflammation in diabetic nerves, but their significance was not fully appreciated, partly because routine histology with hematoxylin and eosin probably underestimated the number of infiltrating cells, and it was not known whether the observed infiltrates exceeded the expected number of cells in normal nerves. Several patients with painful lumbosacral plexopathy were described in association with elevation of the erythrocyte sedimentation rate (ESR), three of whom were diabetic, and showed perivasculitis in sural nerve biopsies, defined as inflammation around the walls of epineurial vessels (Bradley et al., 1984). Other patients with diverse forms of diabetic neuropathy were reported with vascular inflammation or frank arteritis which improved with immunosuppressive and immunomodulating therapy (Krendel et al., 1995; Said et al., 1994). Younger and coworkers (Younger et al., 1996c) characterized the nature of the inflammatory lesions and related clinical and pathological findings in 20 patients with insulin and non-insulin dependent diabetes mellitus (IDDM, NIDDM) and diverse forms of neuropathy. Axonal neuropathy was noted in all patients confirmed by semi-thin plastic sections and teased nerve fiber analysis. A CD8 cytotoxic suppressor cell predominant microvasculitis, defined as inflammation of the epineurial vessel walls (Fig. 20.14), was seen in 40% of nerves, with expression of interleukins, tumor necrosis factor, and abnormal activation of C5b-9 membrane attack complex (MAC). Direct counting of immunoperoxidase-stained T cells was performed in the vascular lesions and in the endoneurium of the diabetic nerves, and compared to normal controls. The diabetic nerves overall contained 129 endoneurium CD3 cells per tissue section compared with 0–5 cells in normal controls. With increasing grades of perivasculitis and microvasculitis, there was a greater predilection for larger vessels. Several patients had differential fiber loss, more severe in some fascicles or others, or localized to the center of the fascicle and occlusion of microvessels by an organized thrombus, also suggestive of an ischemic inflammatory mechanism. There are few modern series of diabetic neuropathy confirmed by nerve tissue to allow assessment of the different clinicopathological types including those associated with vasculitis. Among 110 patients with diabetic neuropathy who underwent sural nerve

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Fig. 20.14 Inflammatory diabetic vasculopathy. A focalintense collection of CD8+ T cells efface the wall of a small epineurial blood vessel (arrowheads) (stain, hematoxylin and eosin; original magnification, ×400). Reproduced from Younger et al., 2003, with permission of the publisher.

or superficial peroneal sensory nerve biopsy between 1992 and 2002 because of progressive weakness and disability, three patients had histopathological evidence of necrotizing arteritis in arteriae nervorum (Younger, 2005a; Younger and Hays, 2006). Two of the three, one with diabetic MNM and the other with diabetic lumbosacral radiculoplexus neuropathy (DLRPN), died of an intervening illness, and were further examined at postmortem examination respectively three weeks and two years after onset of the neurological disorder. Neither patient had evidence of systemic or peripheral nerve vasculitis found in systemic organs or sections of nerve taken at postmortem examination, although the patient with DLRPN had perivasculitis composed of CD8 T cells in sections of femoral nerve, lumbar plexus, and anterior root consistent nonetheless with a vascular ischemic pathogenesis related to microscopic vasculitis as suggested by Dyck and colleagues (Dyck et al., 1999). The frequency of microvasculitis of 3% in this cohort was lower than the frequency of 40% described earlier by Younger and coworkers (Younger et al., 1996a), reflecting the lesser sensitivity of routine hematoxylin and eosin studies as compared to immunoperoxidase-staining methods used in the earlier analysis by Younger and coworkers (Younger et al., 1996a). Patients with various forms of inflammatory diabetic vasculopathy generally complain of pain, weight loss, debilitating sensory and motor deficits typically beginning in one leg with later involvement of the other, and a rapid, stepwise, or insidious progression over weeks to months or longer. Nerve biopsy is the only means of confirming the underlying morphology and the altered cell and humoral dysimmunity. Treat-

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ment with immunosuppressive and immunomodulating medication is effective in proven cases. The frequency of vascular and endothelial inflammation in diabetic nerves is not known probably for several reasons. Few patients overall with diabetic neuropathy are ever referred for nerve biopsy since the disorder has been previously considered untreatable. The inflammation may be highly focal and obvious only with serial sectioning of the tissue block. Cell-marker immunohistochemistry, which is generally required to recognize mononuclear cell types, is not routinely performed at all centers. The significance of the cellular infiltrates and occasional vasculitis is not well understood, however, several observations suggest underlying autoimmunity. First, patients with diabetes appear to be more susceptible to other autoimmune disorders including Graves, Addison disease, pernicious anemia, and chronic inflammatory demyelinating polyneuropathy (CIDP). Second, IDDM itself results from autoimmune mechanisms directed against insulinproducing pancreatic beta cells. Third, the BB rat, serves as a model of IDDM in which cellmediated immunity precedes and accompanies the onset of diabetes and is prevented by immunosuppressant medication. Fourth, the pancreas of newly diagnosed diabetics reveals an insulitis, composed of infiltrating lymphocytes and other cellular elements where they are believed to mediate destruction of pancreatic islets; in that regard, at least two autoantibodies to islet cell antigens have been described. Lastly, one membrane-bound superantigen was described in infiltrating T cells of two juvenile patients who died suddenly of other causes. The initiating factors in cell- and humoral-mediated autoimmunity are also not known, however, it is possible that T-cell clones could become sensitized early in the course of diabetes by superantigen expressed in pancreatic islets. Possible candidate regulatory proteins appear to contribute to the observed humoral dysimmunity in the walls of microvessels, including complement receptor (CR1), decay accelerating factor (CD55), membrane cofactor protein (CD46), and membrane inhibitor of reactive lysis (CD59) that normally protects cells by limiting activation of the complement cascade. Laboratory diagnosis General principles Most authorities agree upon four principles in the diagnosis of vasculitis:

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1 Vasculitis is a potentially serious disorder with a propensity for permanent disability owing to tissue ischemia and infarction; recognition of the neurological manifestations is important in developing a differential etiological diagnosis. 2 Undiagnosed and untreated, the outcome of vasculitis is potentially fatal. 3 A favorable response to an empirical course of immunosuppressive and immunomodulating therapy should never be considered a substitute for the absolute proof of the diagnosis of vasculitis. 4 Histolopathological confirmation of vasculitis in the nervous system is essential for accurate diagnosis, such as by analysis of nerve and muscle biopsy tissue when PNS involvement is postulated, and by brain and meninges where there is CNS involvement. Recommended laboratory evaluation The laboratory evaluation of vasculitis of the nervous system is summarized in Box 20.2. Blood studies are useful in the initial diagnosis of vasculitis, however,

the choice should be guided by the clinical presentation and postulated etiological diagnosis to avoid excessive cost and spurious results. Electrodiagnostic studies are useful in the initial investigation of systemic vasculitis because they can identify areas of asymptomatic involvement and sites for muscle and nerve biopsy and distinguish the various neuropathic syndromes associated with peripheral nerve and muscle involvement. A wide sampling of nerves and muscles should be examined, both distal and proximal, using standard recording and needle electrodes for the performance of nerve conduction studies (NCS) and needle electromyography (EMG), at skin temperatures of 34°C, with comparison to normative data. Most patients with peripheral nerve vasculitis show evidence of active axonopathy acutely in an MNM pattern and over time in a distal symmetric or asymmetric pattern. Quantitative motor unit potential analysis can delineate whether proximal wasting and weakness are caused by myopathic or neurogenic disease. CSF analysis, electroencephalography (EEG), and neuroimaging studies are integral to the diagnostic evaluation of most CNS disorders, including vasculitis.

Box 20.2 Laboratory evaluation of vasculitis. Blood studies Complete blood count (CBC) Erythrocyte sedimentation rate (ESR) Chemistry panel including creatine phosphokinase (CPK) Antinuclear antibody (ANA) Complement levels Rheumatoid factor (RF) Cryoglobulins Immunofixation electrophoresis Quantitative immunoglobulins T and B cell panels Antibodies (selectively) to: Ro (SS-A), La (SS-B), Sm, SCL-70, hepatitis B and C virus Human immunodeficiency virus type 1 (HIV-1), Borrelia burgdorferi (ELISA, eestern blot), c-ANCA and p-ANCA Radiographic studies Chest Body computed tomography (CT) Magnetic resonance imaging (MRI)

Magnetic resonance angiography and venography (MRA and MRV) Single photon emission computed tomography (SPECT) Positron emission tomography (PET) Systemic and cerebral angiography Other neurodiagnostic dtudies Electroencephalography (EEG) Electromyography and nerve conduction studies (EMG-NCS) Lumbar puncture for CSF analysis: protein, glucose, cell count, IgG level, cytology, VDRL, Gram stain, culture, India ink, viral antigens, Lyme Ab and PCR (as indicated) Histopathological studies (as indicated) Muscle and nerve biopsy Temporal artery biopsy Meningeal and cortex Skin Systemic organs Lymph nodes

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Properly performed, lumbar puncture carries minimal risk and provides potentially useful information regarding possible underlying vasculitis so suggested by CSF pleocytosis in excess of 5 cells/mm3, protein content greater than 100 mg/dl, and evidence of intrathecal synthesis of immunoglobulin and present oligoclonal bands. Molecular genetic, immunoassay, and direct staining techniques to exclude spirochetal, fungal, mycobacterial and viral infections, as well as cytospin examination of CSF for possible malignant cells, should be performed. There are no typical EEG findings in CNS vasculitis. Magnetic resonance imaging (MRI) is more sensitive than computed tomography (CT), but both methods lack specificity in histologically confirmed cases. The most common MRI findings are multiple bilateral cortical and deep white-matter signal abnormalities and enhancement of the meninges after gadolinium. MRA and functional imaging of the brain provide complementary findings to conventional MRI. The former is useful in the evaluation of medium and large vessel disease, but misses fine vessel contours better seen on cut-film or digital subtraction angiography. The abnormal diffuse and focal perfusion patterns seen on single photon emission CT (SPECT) do not always correlate with neurological symptoms or distinguish vasculitic from nonvasculitic vasculopathy. Some authorities claimed that cerebral angiography showed diagnostic features, but that assertion was later modified. Beading of vessels is found in only about a third of patients with histologically proven CNS vasculitis, as well as in CNS infection, atherosclerosis, cerebral embolism, and vasospasm of diverse cause (Fig. 20.15). Multiple microaneurysms, often seen on visceral angiography in systemic vasculitis, are distinctly rare in CNS vessels. Brain and meningeal biopsy are still the gold standard for the diagnosis of CNS vasculitis, but false negatives occur because of focal lesions and sampling errors. Radiographic studies that guide the biopsy site toward areas of abnormality probably improve the sensitivity, but this has not been formally studied. The risk of serious morbidity related to biopsy is less than 2% at most centers, which is probably less than the cumulative risk of an empirical course of long-term immunosuppressive therapy. There are no certain guidelines as to when to proceed to brain and meningeal biopsy. However, it would certainly be warranted if there were no other explanation for the progressive syndrome of fever, headache, encephalopathy, and focal cerebral signs,

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Fig. 20.15 Radiographic features of cerebral vasculitis. Ectasia and beading in the M1 segment and lack of flow in the A1 segment of the right anterior cerebral artery (arrow). Reproduced from Wynne P.J., Younger D.S., Khandji A., et al. 1997. Radiographic features of central nervous system vasculitis. Neurologic Clin, 15, 787; with permission from Elsevier.

in association with CSF pleocytosis, and protein content elevation greater than 100 mg/dl, which is suggestive of GANS. The importance of nerve and muscle biopsy in the diagnosis of vasculitis cannot be overemphasized. It can be approached with confidence when a neurologist or surgeon skilled in nerve and muscle biopsy techniques at centers performs the procedure with neuropathologists trained to process and examine the specimens for all of the diagnostic possibilities. The nerve and muscle should be clinically and electrophysiologically affected. However, the muscle should not be so affected, or end stage, as to preclude interpretation. A segment of the sural, superficial peroneal sensory, or femoral intermedius sensory nerve can be surgically removed without incurring a serious deficit, along with pieces of muscle tissue respectively from the soleus, peroneus brevis, or rectus femoris muscle, thereby providing potentially useful information regarding the severity of the underlying neuropathy and increasing the yield of vasculitic lesions (Fig. 20.16). Commercially available monoclonal and polyclonal antibodies directed against T- and B-cell subsets, macrophages, immunoglobulins, C3d, C5b-9 MAC proteins, cytokines and other

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(a)

(b)

(c)

(d)

Fig. 20.16 Muscle and nerve biopsy technique. (a) The superficial peroneal sensory nerve is palpated laterally along the distal third of the leg along a line between the fibular head and lateral malleolus providing markings for the incision. (b) An incision is made and the area is dissected revealing the nerve obliquely traversing the field. (c) Incising the muscle aponeurosis reveals underlying peroneus brevis muscle tissue in addition to nerve available for biopsy. (d) After the specimens are removed and the site is irrigated, a subcuticular closure is performed using absorbable sutures. Reproduced from Younger, D.S. (ed.), Motor Disorders, Peripheral Nerve Pathology, Lippincott Williams & Wilkins, 1999, with permission of the publisher.

inflammatory mediators, and main histocompatibility class (MHC) I and II antigens add precision to the analysis of peripheral nerve specimens with suspected necrotizing and non-necrotizing peripheral nerve vasculitis. Punch skin biopsy for the analysis of epidermal nerve fibers (ENF) in a 3 mm piece of skin is a less invasive procedure to determine the presence of clinically significant neuropathy and dermal vasculitis. The density of ENF ascertained in five 1 mm areas of the tissue specimen is compared to mean reference values and the histology of both unmyelinated and myelinated nerve fibers respectively of the epidermis and dermis can be assessed (Lauria et al., 2005; McArthur et al., 1998). Skin biopsy has been suggested in the evaluation of vasculitic neuropathy (Lee et al., 2005). Patients with clinically significant peripheral neuropathy, connective tissue disease, and

suspected vasculitis, and severe skin denervation, as reflected in a very low density of ENF or absence of detectable fibers, accompanied by pronounced inflammatory cell infiltration especially including perivascular T cells and macrophages on immunohistochemistry, should be considered for conventional nerve biopsy to clearly establish the underlying pathology. Immunopathogenesis Early progress in the understanding of vasculitis took the first major turn during a discussion of the Kernohan and Woltman paper on PAN (Kernohan and Woltman, 1938). At that time, there was no effective treatment and antemortem diagnosis was rarely possible. Harry Lee Parker conceptualized nerve and muscle biopsy when he commented,

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It occurs to me that in any case in which polyarteritis nodosa may be suspected, it is advisable to take a biopsy from a peripheral nerve, muscle, or artery.

Several years later, cases of polyarteritis were ascertained by calf muscle biopsy (Garcin et al., 1955) and nerve biopsy (Lovelace, 1964). Only recently has the utility of peripheral nerve biopsy been accepted as standard medical practice in the diagnosis of all forms of systemic and peripheral nerve vasculitis (Wees et al., 1981). World War II provided an opportunity for an understanding of the blood supply of the peripheral nerves, and these findings in turn guided our thoughts on vasculitis. Detailed accounts of neurovascular anatomy were made possible by dissection of amputated limbs after injection of India ink to opacify the vessels (Sunderland, 1945). Those findings were summarized in a concluding statement, Each of the major nerves is generally abundantly vascularized throughout its entire length by a succession of vessels, which by their repeated division and anastomosis within the nerve outline an unbroken vascular net.

Some nerves such as the median and ulnar nerve between the axilla and elbow and along the sciatic in the gluteal region had few or no entering nutrient vessels but vascular insufficiency was still an unlikely occurrence as stated by Sunderland, Admittedly there are instances, though uncommon, in which one vessel supplies long stretches of a nerve without reinforcement, but it has been demonstrated in sectioned and injected material that even under such apparently adverse conditions of supply, the anastomosis is of such dimensions at the peripheral limits of the solitary channel that segmental ischemia due to the blocking of such a single vessel is a remote possibility.

Based on the aforementioned studies, there was no convincing evidence for the presence of watershed zones of poor vascular supply along major nerves of the arm or leg, a contention that has permeated the literature with regard to the clinical sequela of vasculitis. Nonetheless, investigators ascribed centrofascicular nerve fiber loss in one reported patient with necrotizing vasculitis to poor vascular perfusion along presumed watershed zones of the upper arm and proximal thigh regions (Dyck et al., 1972). Twenty

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years later, there was an account of flail weakness and mid-level sensory loss of the arms ascribed to vasculitis of arteria nervorum, even though the patient was not studied pathologically (Moore et al., 1981). It is now known that under normal circumstances, the nervous system is protected from systemic immunological reactions by the blood–brain and blood–nerve barriers. Tight junctions between neighboring cells and a paucity of micropinocytotic vessels are unique to the blood–brain barrier, and, along with other local determinants, contribute to the prevention of early involvement of the CNS in the course of systemic inflammation. Immune activation requires the interaction of a specific autoantigen, an MHC class II antigen-presenting cell (APC), and an antigen-specific T cell. Macrophages are the principal APCs of the PNS, and their role appears to be that of a local surveillance system, taking up and processing protein antigens and presenting them on their surface. Their interaction with native antigen and antigenspecific T cells leads to a proliferation of specific helper (CD4) and cytotoxic suppressor (CD8) T cells with the expression of human leukocyte antigen (HLA)DR, interleukins (IL)-2 receptor, and tumor necrosis factor (TNF)-α secretion. T cells that become sensitized early in the course of systemic illness probably later contribute to the cellular immune response directed against cross-reacting epitopes present in peripheral nerve and brain. Vascular endothelial cells play an important role in the pathobiology of vascular inflammation along the blood–nerve and blood–brain barriers because of their potential interaction with elements of the systemic immune system. They are potentially active participants in vasculitis, not simply passive targets of injury. They satisfy the criteria for an APC because of their native ability to express MHC class I molecules for interaction with cytotoxic T cells; and under certain conditions, they express MHC class II molecules and the necessary costimulatory factors to induce T-cell proliferation in vivo and in vitro. The function VEC is regulated mainly by IL, TNF, and endotoxins derived from immigrant or resident mononuclear cells. Their action, by virtue of binding to specific receptors, is alteration of the transcription of an array of endothelial genes that program cellular inflammatory secretion; local expression of leukocyte adhesion molecules; the balance of prothrombotic and antithrombotic vascular functions; the synthesis of matrix molecules and their receptors; and the secretion of growth factors, secondary cytokines, and enzymes related

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to matrix degradation. The localization and propagation of leukocytes along VEC depend on local production of IL-1, IL-6, and IL-8; expression of cell adhesion molecules (CAMs), namely integrins, selectins, and the immunoglobulin superfamily molecules (intercellular (ICAM-1), vascular (VCAM-1), platelet-endothelial CAM (PECAM-1) ) constitutively expressed or induced after cellular activation; and expression of autoantigens such as antineutrophil cytoplasmic autoantibody (ANCA) and antiendothelial cell antibodies (AECA). Other substances that contribute to vascular integrity include free radical nitric oxide, Von Willebrand factor, tissue plasminogen activator inhibitor, thrombomodulin, and plateletactivating factors. Humoral mechanisms also contribute to the development of vasculitis and nervous system damage through complement-mediated injury of microvessels. The complement system is composed of 11 proteins that sequentially interact in the activated state to form an assembly of five proteins referred to as C5b-9 or MAC. Activation of C5b-9 along peripheral nerve microvessels leads to increased local permeability, edema, and inflammatory cell infiltration. Complement-mediated injury appears to be an important mechanism in the etiopathogenesis of inflammatory diabetic vasculopathy, however, the initiating factors are still speculative. One possibility is a defect in the expression of certain regulatory membrane proteins in the walls of microvessels, including complement receptor (CR10), decay-accelerating factor (CD55), membrane cofactor protein (CD46), and membrane inhibitor of reactive lysis (CD59), which normally protect cells by limiting activation of the complement cascade. Interest in the role of specific pathogenic autoantibodies has evolved over the past two decades, as, for example, in our understanding of WG and related disorders in the elucidation of ANCA. The pathobiology of ANCA was understood through use of animal models, human neutrophil studies, and monolayers of cultured human umbilical vein endothelial cells. MPO and PR3 antigens, so named for the patterns of staining of normal ethanol-fixed neutrophils with indirect immunofluorescence, granular cytoplasmic (c-ANCA), and perinuclear (p-ANCA), were found to correlate with disease activity in WG and MPA, respectively. The MPO and PR3 antigens are accessible for binding with circulating ANCA and Fc receptors; ANCA-augmented chemotaxis and adhesion bring circulating neutrophils and mononuclear phagocytes into close contact with endothelial cells

and induce neutrophil-mediated endothelial cell lysis and vascular permeability. Treatment Physicians managing vasculitis must choose from among the many available immunosuppressant and immunomodulating therapies, recognizing the possible beneficial and adverse effects, while providing multidisciplinary rehabilitation, pain, and psychotropic therapy. Immunosuppressant therapy The usefulness of corticosteroids in the treatment of systemic vasculitis has been appreciated for over 50 years. Untreated, patients with PAN had a fiveyear-survival rate of 10%; treatment with corticosteroids increased survival to 48% (Frohnert and Sheps, 1967). Although the effectiveness of corticosteroids is well established, there is uncertainty even among experts as to the optimal regimen. For example, in one analysis sustained benefit in PAN was obtained in patients with a minimum equivalent dosage of 31 mg of prednisone daily for seven months (Leib et al., 1979). The beneficial effects of corticosteroids are attributed to a multiplicity of effects on the cell and humoral immune system, including inhibition of activated T and B cells, APCs, and leukocytes at sites of inflammation, IFN-γ, induced MHC class II expression, macrophage differentiation, pathogenic cytokine expression, complement interactions, and immunomodulating CAM. Patients receiving long-term corticosteroid therapy for vasculitis should be monitored closely for hypertension, fluid retention, glucose intolerance, cataracts, myopathy, avascular necrosis, osteoporosis, infection, gastric and duodenal ulcers, and psychosis, and followed empirically for the need of short-acting insulin coverage as needed, physiotherapy, calcium supplementation, and bone densitometry. The effectiveness of a daily oral regimen of cyclophosphamide and prednisone in WG has served as a template for the treatment of virtually all types of systemic vasculitis for decades (Fauci et al., 1971). Its favorable affect on vasculitis derives from the preferential T-cell lysis resulting from the inhibition of hematopoietic precursors in the bone marrow, leaving stem cells unharmed. At high doses, this inhibition favors repopulation of the marrow and thus the cellular immune system. After an intravenous dose of cyclophosphamide, the nadir of peripheral

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leukocytopenia, which corresponds with peak marrow suppression, occurs in 7 to 18 days. Less than 20% of labeled cyclophosphamide is excreted unchanged in the urine, with the remainder metabolized to the active products phosphor amide mustard and acrolein, both of which are believed to exert toxic side effects, which include hemorrhagic cystitis, bladder cancer, bone marrow suppression with risk of fatal infection and gonadal toxicity. Bladder toxicity may be reduced by administration of the drug in a single daily oral morning dose followed by hydration; and administration of the drug intravenously as pulse therapy, adjusting the dose to renal function. Monthly pulse intravenous cyclophosphamide at doses of 500 to 1000 mg per square meter of body surface area, one half the full dose therapy for maximal marrow suppression in malignancy, probably achieves similar effectiveness in peripheral nerve vasculitis. The purine analog azathioprine, which metabolizes to the cytotoxic derivative 6-mercaptopurine, exerts favorable action in vasculitis by the inhibition of T-cell activation and T-cell-dependent antibody-mediated responses. Azathioprine is generally considered a safe alternative to prednisone and cyclophosphamide in virtually all forms of vasculitis. However, there are three drawbacks to its use. First, idiosyncratic side effects, most often gastrointestinal and flu-like, occur in approximately 10% of patients and rarely necessitate permanent withdrawal of the medication. However, pancreatitis and gastritis severe enough to warrant hospitalization can occur. Second, bone marrow suppression occurs in nearly all patients, usually manifested by mild pancytopenia. Third, there is typically a long delay in the onset of the therapeutic effect of three months or more. Taking all of these factors into account, most clinicians concur with the slow advancement of the dose over weeks, commencing with 50 mg/day and achieving maintenance levels of 2 to 3 mg/kg/day with careful monitoring of liver and marrow function. Immunomodulating therapy High-dose intravenous immunoglobulin (IVIg) therapy is the most widely employed immunomodulating agent for autoimmune neurological disorders (Dalakas, 2004). It is indicated in the treatment of systemic and peripheral nerve vasculitis, connective tissue disorders, diabetic inflammatory vasculopathy and neuropathy, paraneoplastic and postinfectious neurological disorders. The first IVIg preparation, a

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5% IgG concentration formulated in a 10% maltose and 0.1 molar glycine solutions, was licensed in the United States in 1981 for combined immunodeficiency syndrome. It was prepared by the classic Cohn cold water alcohol fractionation processing of pooled plasma from at least 1000 normal donors and chemically modified by selective reduction with dithiothreitol, and alkylation with iodoacetamide. Continuing research led to the development of a native 5% IVIg preparation in which the IgG molecule was chemically unmodified and stabilized in solution at pH 4.25 with 10% maltose added to provide isotonicity; a 10% IVIg solution using the same manufacturing method was licensed in 1992. Solvent detergent treatment, including partitioning steps and incubation at low pH in the final container has been effective in the removal and inactivation of enveloped viruses. A new chromatographic purification process alleviates many labor-intensive and time-consuming intermediate steps with a more closed manufacturing process to reduce risk of contamination, and provides a glycine-stabilized, purer final IVIg product that more closely reflects the IgG subclass distribution found in plasma. The immunomodulating and anti-inflammatory actions of IVIg are provided by monthly doses of 2000 mg/kg/body weight given 400 mg/kg/day for five days each month at a slow drip with acetaminophen and diphenhydramine pretreatment to prevent the commonest side effects including fever, chills, rash, erythema, flushing, headache, nausea, myalgia, arthralgia, abdominal cramps, chest and back pain. True anaphylactic reactions to IVIg can occur in recipients with documented prior allergies to immune globulins or antibodies, especially IgA type. Transient reversible renal insufficiency occurs in individuals with preexisting renal disease. Susceptible individuals can be identified by less than normal expected 24-hour creatinine clearance rates for age and abnormal vascular perfusion on radionuclide scans. Aseptic meningitis rarely occurs several hours after treatment and resolves over several days with discontinuation of therapy. Supportive therapy A multidisciplinary approach to vasculitis requires a team of health professionals and caregivers to optimize recovery while initiating immunotherapy. Physical therapy and orthosis may be warranted for disabling motor and cognitive disorder impairments to maintain range of motion and strength, to improve

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function status, and to maintain ambulation. Effective pain management may be an important aspect of their care, not only to provide overall well being but to permit more aggressive physiotherapy. Agents such as tricyclic antidepressants, gabapentin, mexiletine, opioids, clonazepam, and topical anesthetic creams have all been used with varying success. Finally, efforts should be made to limit ischemicenhancing effects of other conditions, such as with diabetes mellitus through improved glycemic control, regulation of blood pressure and hyperlipidemia, alone or as a side effect of concomitant corticosteroids, and the cessation of cigarette smoking. Summary This chapter describes heterogeneous disorders that fall in the spectrum of vasculopathy and vasculitis, typified by characteristic clinical syndromes, often with serologically specific autoantibodies, confirmed by angiographic and histological analysis of diseased vessels. Peripheral and central nervous system vasculitis may be primary disorders or overlap when due to a systemic etiopathogenesis with incipient multiorgan involvement. The clinician must choose from among available immunomodulatory and immunosuppressant agents, alone, in sequence, or in combination depending upon the stage or severity of the insult with the hope of arresting the disorder and providing slow recovery. References Bradley, W.G., Chad, D., Verghese, J.P. et al. 1984. Painful lumbosacral plexopathy with elevated erythrocyte sedimentation rate. A treatable inflammatory syndrome. Ann Neurol, 15, 457–64. Calabrese, L.H., Graff, L.A. and Furlan, A.J. 1993. Benign angiopathy: a distinct subset of angiographically defined primary angiitis of the central nervous system. J Rheum, 20, 2046–50. Churg, J. and Strauss, L. 1951. Allergic granulomatosis, allergic angiitis, and periarteritis nodosa. Am J Pathol, 27, 277–302. Citron, B.P., Halpern, M., Mccarron, M. et al. 1970. Necrotizing angiitis associated with drug abuse. N Engl J Med, 283, 1003–11. Collins, M.P. and Kissel, J.T. 2005. Peripheral nerve vasculitis. In D.S. Younger (ed.), Motor Disorders, 2nd edn, Lippincott Williams and Wilkins, Philadelphia, pp. 349–62. Cravioto, H. and Fegin, I. 1959. Non-infectious granulomatous angiitis with a predilection for the nervous system. Neurology, 9, 599–607.

Cupps, T., Moore, P. and Fauci, A. 1983. Isolated angiitis of the central nervous system: Prospective diagnostic and therapeutic experience. Am J Med, 74, 97–105. Dalakas, M.C. 2004. Intravenous immunoglobulin in autoimmune neuromuscular diseases. JAMA, 291, 2367–75. Dalmau, J., Furneaux, H.M., Rosenblum, M.K. et al. 1990. Detection of the anti-Hu antibody in the serum of patients with small cell carcinoma: A quantitative western blot analysis. Ann Neurol, 27, 544–52. Dalmau, J., Graus, F., Rosenblum, M.K. et al., 1992. Anti-Hu associated paraneoplastic encephalomyelitis/ sensory neuronopathy: A clinical study of 71 patients. Medicine, 71, 59–72. Davson, J., Ball, J. and Platt, R. 1948. The kidney in periarteritis nodosa. Q J Med, 17, 175. Drachman, D.A. 1963. Neurological complications of Wegener’s granulomatosis. Arch Neurol, 8, 145–55. Dyck, P.J., Benstead, T.J., Conn, D.L. et al. 1987. Nonsytemic vasculitis neuropathy. Brain, 110, 843–54. Dyck, P.J., Conn, D.L. and Okazaki, H. 1972. Necrotizing angiopathic neuropathy. Three-dimensional morphology of fiber degeneration related to sites of occluded vessels. Mayo Clin Pro, 47, 461–75. Dyck, P.J.B., Norell, J.E. and Dyck, P.J. 1999. Microvasculitis and ischemia in diabetic lumbosacral radiculoplexus neuropathy. Neurology, 53, 2113–21. Fagenberg, S.E. 1959. Diabetic neuropathy-clinical and histological study of the significance of vasculitic affections. Acta Med Scand, 164(345), 1–97. Fauci, A.S. (Moderator). 1978. The spectrum of vasculitis: Clinical, pathologic, immunologic, and therapeutic considerations. Ann Intern Med, 89, 660–76. Fauci, A.S., Wolff, S.M. and Johnson, J.S. 1971. Effect of cyclophosphamide upon the immune response in Wegener’s granulomatosis. N Engl J Med, 285, 1493. Frohnert, P.P. and Sheps, S.G. 1967. Long-term followup study of periarteritis nodosa. Am J Med, 43, 8–14. Garcin, R., Godlewski, W., Gruner, J. et al. 1955. Sur les formes multinevritiques et polynevritiques de la periarterite noueuse: Etude de 7 observations inedites. Ann Med, 56, 113. Godman, G.C. and Churg, J. 1954. Wegener’s granulomatosis: Pathology and review of the literature. Arch Pathol, 58, 533. Harbitz, F. 1922. Unknown forms of arteritis with special referene to their relation to syphilitic arteritis and periarteritis nodosa. Am J Med Sci, 163, 250–72. Horton, B.T., Magath, B.T. and Brown, G.E. 1932. An undescribed form of arteritis of the temporal vessels. Proc Staff Meet Mayo Clin, 7, 700–1. Jennings, G.H. 1938. Arteritis of the temporal vessels. Lancet, 1, 424. Johnson, P.C., Rolak, L., Hamilton, R.H. et al. 1979. Paraneoplastic vasculitis of the nerve: A remote effect of cancer. Ann Neurol, 5, 437–44.

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Kernohan, J.W. and Woltman, H.W. 1938. Periarteritis nodosa: A clinicopathologic study with special reference to the nervous system. Arch Neurol Psychiatry, 39, 655–86. Krendel, D.A., Costigan, D.A. and Hopkins, L.C. 1995. Successful treatment of neuropathy in patients with diabetes mellitus. Arch Neurol, 52, 1053–61. Lauria, G., Cornblath, D.R., Johansson, O. et al. 2005. EFNS guidelines on the use of skin biopsy in the diagnosis of peripheral neuropathy. European J Neurol, 12, 747–58. Lee, J.E., Shun, C.T., Hsieh, S.C. et al. 2005. Skin denervation in vasculitis neuropathy. Arch Neurol, 62, 1570–3. Leib, E.S., Restivo, C. and Paulus, H.E. 1979. Immunosuppressive and corticoteroid therapy of polyarteritis nodosa. Am J Med, 67, 941. Longcope, W.T. 1908. Periarteritis nodosa, with report of a case with autopsy. Bull Ayer Clin Lab, Pennsylvania Hosp, 5, 1. Lovelace, R.E. 1964. Mononeuritis multiplex in polyarteritis nodosa. Neurology, 14, 434. MacArthur, J.C., Stocks, E.A., Hauer, P. et al. 1998. Epidermal nerve fiber density. Normative reference range and diagnostic efficiency. Arch Neurol, 55, 1513–20. Moore, P.M. and Fauci, A.S. 1981. Neurologic manifestations of systemic vasculitis. A retrospective and prospective study of the clinicopathologic features and response to therapy in 25 patients. Am J Med, 71, 517–24. Pryce, T.D. 1887. Perforating ulcers of both feet associated with diabetes and ataxia symptoms. Lancet, 2, 11–12. Said, G., Goulon-Goeau, C., Lacroix, C. et al. 1994. Nerve biopsy findings in different patterns of proximal diabetic neuropathy. Ann Neurol, 35, 559–69. Sunderland, S. 1945. Blood supply of the nerve of the upper limb in man. Arch Neurol Psychiatry, 53, 91–115. Wees, S.J., Sunwood, L.N. and Oh, S.J. 1981. Sural nerve biopsy in systemic necrotizing vasculitis. Am J Med, 71, 525–32. Younger, D.S. 2003. Vasculitis and connective tissue disorders. In R. Griggs and R. Joynt R. (eds.), Baker and Joynt’s Clinical Neurology on CD-ROM, Lippincott Williams and Wilkins, Philadelphia.

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Younger, D.S. 2004. Vasculitis and the nervous system. Curr Opin Neurol, 317–36. Younger, D.S. 2005a. The diabetic neuropathies. In D.S. Younger (ed.), Motor Disorders, 2nd edn, Lippincott Williams and Wilkins, Philadelphia, pp. 281–8. Younger, D.S. 2005b. Central nervous system vasculitis. In D.S. Younger (ed.), Motor Disorders, 2nd edn, Lippincott Williams and Wilkins, Philadelphia, pp. 615–27. Younger, D.S., Calabrese, L.H. and Hays, A.P. 1997. Granulomatous angiitis of the nervous system. Neurol Clin, 15, 821–34. Younger, D.S., Dalmau, J., Inghirami, G. and Hays, A.P. 1994a. Anti-Hu-associated peripheral nerve and muscle micro vasculitis. Neurology, 44, 181–3. Younger, D.S. and Hays, A.P. 2006. Nerve pathology in diabetic neuropathy a ten-year experience in 110 patients. Muscle and Nerve, 34, 509. Younger, D.S., Hays, A.P., Brust, J.C.M. and Rowland, L.P. 1988. Granulomatous angiitis of the brain: an inflammatory reaction of nonspecific etiology. Arch Neurol, 45, 514–18. Younger, D.S. and Kass, R.M. 1997. Vasculitis and the nervous system: Historical perspective and overview. Neurol Clin, 15, 737–58. Younger, D.S., Rosoklija, G. and Hays, A.P. 1994b. Sensory neuropathy in AIDS: Demonstration of vasculitis and HIV antigens in peripheral nerve. J Neurol, 241, 17. Younger, D.S., Rosoklija, G. and Hays, A.P. 1995. Lyme polyradiculoneuritis: Immunohistochemical findings in sural nerve. Muscle Nerve, 18, 359–60. Younger, D.S., Rosoklija, G. and Hays, A.P. 1996a. Peripheral nerve immunohistochemistry in diabetic neuropathy. Semin Neurol, 16, 139–42. Younger, D.S., Rosoklija, G., Hays, A.P., Neinstedt, L., Latov, N. and Jaffe, I.A. 1996b. HIV-1 associated sensory neuropathy; a patient with peripheral nerve vasculitis. Muscle Nerve, 19, 1364–6. Younger, D.S., Rosoklija, G., Hays, A.P., Trojaborg, W. and Latov, N. 1996c. Diabetic peripheral neuropathy: A clinical and immunohistochemical analysis of sural nerve biopsies. Muscle Nerve, 19, 722–7. Zeek, P.M., Smith, C.C. and Weeter, J.C. 1948. Studies on periarteritis nodosa, III: The differentiation between the vascular lesions of periarteritis nodosa and of hypersensitivity. Am J Pathol, 24, 889.

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21 Poststreptococcal movement disorders Andrew J. Church and Gavin Giovannoni

Abstract A potentially new group of autoimmune diseases of the central nervous system (CNS), occurring in the setting of recent streptococcal infection, and characterized by the presence of antibasal ganglia antibodies (ABGA), has been described. At present it has not been possible to establish whether or not this group of disorders fulfills contemporary criteria for autoimmunity (Rose and Bona, 1993). The spectrum of neuropsychiatric disorders associated with ABGA and streptococcal infection includes Sydenham’s chorea (prototype), PANDAS, a subset of cases with Tourette’s syndrome (TS) and obsessive-compulsive disorder, adult-onset tics, dystonia, and some cases with postencephalitic Parkinsonism or encephalitis lethargica. ABGA recognize four main bands of 40, 45, 60, and 98 kDa. These antigens have been identified as glycolytic enzymes and are involved in energy homeostasis and as expected are found in the cytosol. These proteins are also located on the neuronal surface, where they may have alternative functions. These “putative autoantigens” have homologous proteins in Streptococci, which raise the possibility that they are induced by molecular mimicry. These findings have clinical implications for the diagnosis and management of this group of disorders. Basal ganglia disorders The basal ganglia are involved in fine control of movement with behavioral and emotional processing (Alexander et al., 1986; Bhatia and Marsden, 1994; Brown et al., 1999; Nakano, 2000; Rolls, 1994). Lesions in the basal ganglia are related to extrapyramidal movement disorders in addition to abulia, depression, disinhibition, and confusion (Bhatia and Marsden, 1994). Psychiatric symptoms such as obsessive-compulsive and behavioral abnormalities have also been described in association with

basal ganglia lesions (Laplane et al., 1989). These abnormalities might be due to damage or interruptions in basal ganglia circuits that have functional roles in oculomotor, prefrontal, and cingulate pathways which are central to attention, learning, and behavioral control (Brown et al., 1999; Gerfen, 1984; Haber et al., 1995; Yamashiro et al., 1997). Sydenham’s chorea (SC), an extrapyramidal movement disorder, is useful as a model for basal ganglia disorders as both movement and psychiatric symptoms are prevalent. SC has been proposed as having an immune-mediated and perhaps autoimmune pathogenesis (Dale, 2003). Sydenham’s chorea Sir Thomas Sydenham first described the extrapyramidal movement disorder (chorea) named after him in 1686 (Sydenham, 1848). Chorea was described as “unsteadiness and convulsions of movements,” which mainly affected the arms and legs. The movements were reported to be difficult to control or stop, and distinguished the disease from the form of religious dancing mania prevalent at the time (St. Vitus dance) (Dale, 2003; Jummani and Okun, 2001). There was speculation until the nineteenth century that Sydenham’s chorea (SC) was similar to Huntington’s disease (HD) but they were subsequently recognized as different diseases (Aron et al., 1965; Dale, 2003; Jummani and Okun, 2001). It was not until the nineteenth century, however, that a link between infection and SC was made, with the discovery that a large number of patients with SC had rheumatic fever (RHF) (Bouteille, 1810). Epidemiological studies have confirmed the relationship between group A beta-hemolytic streptococcal (GABHS) infection, RHF, and SC (Aron et al., 1965; Ayoub and Wannamaker, 1966; Jones and Bland, 1935; Taranta and Stollerman, 1956). In common with other streptococcal pathologies there appears to be a limited number of strains associated with

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most cases of SC, typically M5, M6, M19, and M24 (Bronze and Dale, 1993), although other strains or groups may be involved. Throat culture for GABHS is positive in 25–40% of patients with SC (Moore, 1996; Special Writing Group of the Committee of Rheumatic Fever, 1992). Serotyping and strain

20 18

Controls Acute SC Persistent SC RHF

16

ASOT IU/mL

14 12 10 8 6 4 2

Fig. 21.1 Antistreptolysin O titers in 40 acute, 24 persistent Sydenham’s chorea and 40 normal and 25 rheumatic fever controls. P