Clinical Neuroimmunology: Multiple Sclerosis and Related Disorders [2nd ed. 2020] 978-3-030-24435-4, 978-3-030-24436-1

Table of contents :
Front Matter ....Pages i-xiii
Front Matter ....Pages 1-1
Introduction to Neuroimmunology (Patricia K. Coyle)....Pages 3-15
Principles of Immunotherapy (Jennifer Joscelyn, Javier Ochoa-Repáraz, Lloyd Kasper)....Pages 17-42
Front Matter ....Pages 43-43
Immunopathogenesis (Patricia K. Coyle)....Pages 45-69
Epidemiology and Genetics (Tina Roostaei, Philip L. De Jager)....Pages 71-87
Clinical Features, Symptom Management, and Diagnosis (Jacqueline F. Rosenthal, James M. Stankiewicz, Guy J. Buckle)....Pages 89-108
Magnetic Resonance Imaging and Analysis in Multiple Sclerosis (Dejan Jakimovski, Deepa P. Ramasamy, Robert Zivadinov)....Pages 109-136
Disease-Modifying Agents (Syed A. Rizvi)....Pages 137-157
Clinical Decision-Making in the Management of Multiple Sclerosis (Syed A. Rizvi, Joshua A. Stone, Saima T. Chaudhry, Nichola Haddad, Brian Wong, Jennifer O. Grimes)....Pages 159-177
Multiple Sclerosis in Children (Charles D. Tyshkov, Leigh Elkins Charvet, Lauren B. Krupp)....Pages 179-196
Vitamin D and Multiple Sclerosis (Michael J. Bradshaw, Michael F. Holick, James M. Stankiewicz)....Pages 197-212
Front Matter ....Pages 213-213
Acute Disseminated Encephalomyelitis (Patricia K. Coyle)....Pages 215-226
Neuromyelitis Optica Spectrum Disorders (Jonathan F. Cahill)....Pages 227-234
Paraneoplastic and Other Autoimmune Disorders (Alexander Mohler, Mayra Montalvo, Julie Roth)....Pages 235-255
Adult and Childhood Vasculitis of the Nervous System (David S. Younger)....Pages 257-281
Front Matter ....Pages 283-283
Immunologic Disorders of Neuromuscular Junction and Muscle (James M. Gilchrist, John E. Donahue)....Pages 285-298
Autoimmune Neuropathies (Jacques Reynolds, George Sachs)....Pages 299-317
Front Matter ....Pages 319-319
Neurologic Manifestations of Systemic Rheumatologic Diseases (Michael J. Bradshaw, Shamik Bhattacharyya, Nagagopal Venna, Jonathan F. Cahill)....Pages 321-342
Back Matter ....Pages 343-353

Citation preview

Current Clinical Neurology Series Editor: Daniel Tarsy

Syed A. Rizvi Jonathan F. Cahill Patricia K. Coyle Editors

Clinical Neuroimmunology Multiple Sclerosis and Related Disorders Second Edition

Current Clinical Neurology Series Editor Daniel Tarsy Beth Israel Deaconness Medical Center Department of Neurology Boston, MA USA

Current Clinical Neurology offers a wide range of practical resources for clinical neurologists. Providing evidence-based titles covering the full range of neurologic disorders commonly presented in the clinical setting, the Current Clinical Neurology series covers such topics as multiple sclerosis, Parkinson’s Disease and nonmotor dysfunction, seizures, Alzheimer’s Disease, vascular dementia, sleep disorders, and many others. Series editor Daniel Tarsy, MD, is professor of neurology, Vice Chairman of the Department of Neurology, and Chief of the Movement Disorders division at Beth Israel Deaconness Hospital, Boston, Massachusetts. More information about this series at http://www.springer.com/series/7630

Syed A. Rizvi  •  Jonathan F. Cahill Patricia K. Coyle Editors

Clinical Neuroimmunology Multiple Sclerosis and Related Disorders Second Edition

Editors Syed A. Rizvi, MD, EMHL Rhode Island Hospital and Alpert Medical School of Brown University Brown Neurology Providence, RI USA

Jonathan F. Cahill, MD Rhode Island Hospital and Alpert Medical School of Brown University Brown Neurology Providence, RI USA

Patricia K. Coyle, MD Department of Neurology MS Comprehensive Care Center Stony Brook University Medical Center Stony Brook, NY USA

ISSN 1559-0585     ISSN 2524-4043 (electronic) Current Clinical Neurology ISBN 978-3-030-24435-4    ISBN 978-3-030-24436-1 (eBook) https://doi.org/10.1007/978-3-030-24436-1 © Springer Nature Switzerland AG 2020 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, express or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Humana imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

Preface

Immune activation of the central or peripheral nervous system (CNS or PNS) has been shown to play a key role in the pathogenesis of many neurological disorders. Basic concepts in clinical neuroimmunology have changed significantly during the last 10  years and are constantly evolving. New data has driven treatment concepts for a large number of autoimmune diseases, none more so than multiple sclerosis. As this area of research has become increasingly active and productive, the need for a comprehensive up-to-date second edition of this handbook has become apparent. Clinical Neuroimmunology: Multiple Sclerosis and Related Disorders (Second Edition) has been written with the clinician in mind and targets residents, fellows, internists, nurse practitioners, as well as general neurologists. The aim of this book is to make recent developments in neuroimmunology accessible to the clinicians who feel daunted by such advances and requires a clear explanation of the scientific and clinical issues. The chapters have been written by experts in their field and been extensively revised and updated. Two new chapters have been added. Part I provides a logical and straightforward overview of neuroimmunology. Part II consists of eight chapters focused on multiple sclerosis and includes a chapter on clinical decision-­ making and a chapter on vitamin D in MS. Part III has four chapters and focuses on other CNS inflammatory disorders including neuromyelitis optica, ADEM, vasculitis, autoimmune encephalopathies, and immunological aspects of cancer. Part IV includes two chapters that describe autoimmune disorders of the PNS. Part V, the final part, includes a single chapter that focuses on neurologic manifestation of systemic rheumatologic diseases such as systemic lupus erythematosus (SLE), neuro-sarcoidosis, and Behcet’s. We hope health professionals who are interested in neuroimmunological disorders will find this book useful. Finally, we would like to thank our contributing authors for their hard work and guidance. Providence, RI, USA Providence, RI, USA  Stony Brook, NY, USA

Syed A. Rizvi, MD Jonathan F. Cahill, MD Patricia K. Coyle, MD

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Series Editor’s Introduction

The role of the immune system in the pathophysiology of central and peripheral nervous system disorders continues to be a topic of great interest among clinicians and researchers in the field. As stated by Drs. Rizvi, Cahill, and Coyle, the editors of Clinical Immunology, Second Edition, basic concepts in this field have changed significantly due to a constant evolution of knowledge since the publication of the first edition of this book in 2011. This comprehensive and up-to-date second edition of this useful handbook is therefore a welcome addition to the field. Clinical Immunology, Second Edition, continues to be written primarily for clinicians in the field and targets general neurologists, internists, fellows, residents, and nurse practitioners. Although clinically oriented, the chapters all include updated authoritative information on new understandings of the basic mechanisms of the disorders being discussed. Section 1 begins with two useful chapters which provide an excellent introduction and overview of clinical neuroimmunology and the principles of immunotherapy. Section 2 covers multiple sclerosis and includes new chapters on clinical decision-making in the management of multiple sclerosis and the role of vitamin D in this disease. Section 3 covers other central nervous system inflammatory disorders, such as neuromyelitis optica, acute disseminated encephalomyelitis, and CNS vasculitis, and a new chapter on paraneoplastic disorders. Section 4 covers immunologic disorders of muscle and peripheral nerve, and Section 5 provides a new chapter concerning the neurologic manifestations of systemic rheumatologic disorders. The readers of this volume will discover that the quantity of new knowledge accumulated in the past 10 years is worthy of this new and highly comprehensive summary of the field. Daniel Tarsy, MD Professor in Neurology, Harvard Medical School Beth Israel Deaconess Medical Center Boston, MA, USA

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Contents

Part 1 Introduction 1 Introduction to Neuroimmunology������������������������������������������������   3 Patricia K. Coyle 2 Principles of Immunotherapy ��������������������������������������������������������  17 Jennifer Joscelyn, Javier Ochoa-Repáraz, and Lloyd Kasper Part II Multiple Sclerosis 3 Immunopathogenesis ����������������������������������������������������������������������  45 Patricia K. Coyle 4 Epidemiology and Genetics������������������������������������������������������������  71 Tina Roostaei and Philip L. De Jager 5 Clinical Features, Symptom Management, and Diagnosis����������  89 Jacqueline F. Rosenthal, James M. Stankiewicz, and Guy J. Buckle 6 Magnetic Resonance Imaging and Analysis in Multiple Sclerosis ���������������������������������������������������������������������������� 109 Dejan Jakimovski, Deepa P. Ramasamy, and Robert Zivadinov 7 Disease-Modifying Agents �������������������������������������������������������������� 137 Syed A. Rizvi 8 Clinical Decision-Making in the Management of Multiple Sclerosis ���������������������������������������������������������������������������� 159 Syed A. Rizvi, Joshua A. Stone, Saima T. Chaudhry, Nichola Haddad, Brian Wong, and Jennifer O. Grimes 9 Multiple Sclerosis in Children�������������������������������������������������������� 179 Charles D. Tyshkov, Leigh Elkins Charvet, and Lauren B. Krupp 10 Vitamin D and Multiple Sclerosis�������������������������������������������������� 197 Michael J. Bradshaw, Michael F. Holick, and James M. Stankiewicz

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Part III Other CNS inflammatory Disorders 11 Acute Disseminated Encephalomyelitis ���������������������������������������� 215 Patricia K. Coyle 12 Neuromyelitis Optica Spectrum Disorders������������������������������������ 227 Jonathan F. Cahill 13 Paraneoplastic and Other Autoimmune Disorders���������������������� 235 Alexander Mohler, Mayra Montalvo, and Julie Roth 14 Adult and Childhood Vasculitis of the Nervous System �������������� 257 David S. Younger Part IV Peripheral Nervous System Disorders 15 Immunologic Disorders of Neuromuscular Junction and Muscle���������������������������������������������������������������������������������������� 285 James M. Gilchrist and John E. Donahue 16 Autoimmune Neuropathies ������������������������������������������������������������ 299 Jacques Reynolds and George Sachs Part V Systemic Disorders 17 Neurologic Manifestations of Systemic Rheumatologic Diseases �������������������������������������������������������������������������������������������� 321 Michael J. Bradshaw, Shamik Bhattacharyya, Nagagopal Venna, and Jonathan F. Cahill Index���������������������������������������������������������������������������������������������������������� 343

Contents

Contributors

Shamik Bhattacharyya, MD, MS  Department of Neurology, Brigham and Women’s Hospital, Boston, MA, USA Michael  J.  Bradshaw, MD Department of Neurology, Chicago Medical School, Rosalind Franklin University of Medicine and Science, Billings Clinic, Billings, MT, USA Guy  J.  Buckle, MD, MPH  Shepherd Center, Multiple Sclerosis Institute, Atlanta, GA, USA Jonathan F. Cahill, MD  Rhode Island Hospital and Alpert Medical School of Brown University, Brown Neurology, Providence, RI, USA Leigh Elkins Charvet, PhD  Department of Neurology, Multiple Sclerosis Comprehensive Care Center, NYU Langone Health, New York, NY, USA Saima  T.  Chaudhry, MD  MS Fellow, Brown Neurology, Providence, RI, USA Patricia K. Coyle, MD  Department of Neurology, MS Comprehensive Care Center, Stony Brook University Medical Center, Stony Brook, NY, USA Philip  L.  De Jager, MD, PhD Department of Neurology, New York  – Presbyterian Hospital, New York, NY, USA John  E.  Donahue, MD Department of Neuropathology, Rhode Island Hospital, Providence, RI, USA James  M.  Gilchrist, MD Department of Neurology, Southern Illinois University School of Medicine, Springfield, IL, USA Jennifer O. Grimes, MA, MD Candidate  Alpert Warren Medical School of Brown University, Providence, RI, USA Nichola Haddad, BA  Alpert Warren Medical School of Brown University, Providence, RI, USA Michael F. Holick, PhD, MD  Department of Medicine, Boston University Medical Center, Boston, MA, USA Dejan  Jakimovski, MD Department of Neurology, Buffalo General Hospital, University of Buffalo, Buffalo, NY, USA

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Jennifer Joscelyn, MS, OT  Thought Leader Liaison, Hooksett, NH, USA Lloyd Kasper, MD  Department of Microbiology/Immunology, Dartmouth College, Hanover, NH, USA Symbiotix Biotherapies, Boston, MA, USA Lauren  B.  Krupp, MD Department of Neurology, Multiple Sclerosis Comprehensive Care Center, NYU Langone Health, New York, NY, USA Alexander  Mohler, MD Alpert Medical School of Brown University, Providence, RI, USA Department of Neurology, Rhode Island Hospital, Providence, RI, USA Mayra  Montalvo, MD  Department of Neurology, Rhode Island Hospital, Providence, RI, USA Javier Ochoa-Repáraz, PhD  Eastern Washington University, Cheney, WA, USA Deepa  P.  Ramasamy, MD Department of Neurology, Buffalo General Hospital, University of Buffalo, Buffalo, NY, USA Jacques Reynolds, MS/DO  Department of Neurology, Midcoast Hospital, Brunswick, ME, USA Syed  A.  Rizvi, MD, EMHL Rhode Island Hospital and Alpert Medical School of Brown University, Brown Neurology, Providence, RI, USA Tina  Roostaei, MD, MPH Department of Neurology, Center for Translational and Computational Neuroimmunology, Columbia University Medical Center, New York, NY, USA Jacqueline F. Rosenthal, MD  Shepherd Center, Multiple Sclerosis Institute, Atlanta, GA, USA Julie  Roth, MD Alpert Medical School of Brown University, Providence, RI, USA Department of Neurology, Rhode Island Hospital, Providence, RI, USA George Sachs, MD, PhD  Department of Neurology, Warren Alpert Medical School of Brown University, Rhode Island Hospital, Providence, RI, USA James  M.  Stankiewicz, MD  Partners Multiple Sclerosis Center, Harvard Medical School, Boston, MA, USA Joshua A. Stone, MD  MS Fellow, Brown Neurology, Providence, RI, USA Charles D. Tyshkov, MD  Department of Pediatrics/Child Neurology, New York Presbyterian Weill Cornell Medical Center/Brooklyn Methodist Hospital, New York, NY, USA Nagagopal  Venna, MD, MRCP(I), MRCP (UK) Neuro-Infectious Diseases, Harvard Medical School, Boston, MA, USA

Contributors

Contributors

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Division of Neuroimmunology, Department of Neurology, Massachusetts General Hospital, Boston, MA, USA Brian Wong, MD  Department of Neurology, Hartford Healthcare, University of Connecticut School of Medicine, Southington, CT, USA David S. Younger, MD, MPH, MS  Department of Neurology, White Plains Hospital, New York, NY, USA Robert  Zivadinov, MD, PhD  Department of Neurology, Buffalo General Hospital, University of Buffalo, Buffalo, NY, USA

Part 1 Introduction

1

Introduction to Neuroimmunology Patricia K. Coyle

Introduction The nervous system can be considered the single most important body organ. It encompasses both the central nervous system (CNS) (brain, spinal cord, and optic nerve) and the peripheral nervous system (PNS) (peripheral nerves, neuromuscular junction, skeletal muscle). The autonomic nervous system can be considered a functional subdivision, with both CNS and PNS components. Historically, the CNS has been described as a sequestered compartment protected from the systemic immune system. However, more recent studies not only support clear communication links between the CNS and specific extraneural systems, but the existence of a brain innate immune system (Table  1.1) [1, 2]. The CNS is more accurately characterized as an immunologically privileged site [3]. Neuroimmunology is the neuroscience specialty that focuses on interactions between the nervous system and immune system. It includes both basic science fields and clinical disciplines which deal with a special set of CNS and PNS disorders (Table  1.2) [4–6]. These disorders result from immune-mediated damage and require diagnostic and therapeutic approaches

P. K. Coyle (*) Department of Neurology, MS Comprehensive Care Center, Stony Brook University Medical Center, Stony Brook, NY, USA e-mail: [email protected]

that recognize and address this fact. Some are truly autoimmune, with a recognized pathogenic neural autoantigen target, while others are not. Most will be covered in subsequent chapters. Sometimes unusual diseases are characterized as neuroimmune based on their pathology and/or therapeutic response. Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is a recently described rare disorder that predominantly targets brainstem, cerebellum, and spinal cord. The MRI pattern is suggestive, with punctate (10 ms) or as bound to complex macromolecules (750 cases of PML in 177,000 patients exposed to the drug with almost a 20% mortality rate. The risk of developing PML is higher in patients who are positive for JCV antibody (high titers associated with highest risk), with duration of exposure >24  months and prior exposure to

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immunosuppressive agents. PML is extremely rare in treated patients who remain JCV negative (five cases) [39]. Natalizumab may cause PML by reactivation of latent JC virus found in greater than 80% of individuals [40, 41]. Although the exact mechanism is unknown, evidence points to impairment of immune surveillance. PML usually occurs in immunocompromised individuals such as patients infected with HIV and patients treated with aggressive immunosuppressive agents and some monoclonal antibodies including rituximab [42–44]. Although PML in general carries a grave prognosis, most of the data comes from the HIV literature. Early recognition and discontinuation of natalizumab resulting in accelerated removal of natalizumab from the circulation may lead to a better outcome [45].

B-Cell-Depleting Therapies (Rituximab and Ocrelizumab) Rituximab is a chimeric monoclonal antibody targeting CD20-positive B lymphocytes [46, 47], resulting in rapid and sustained depletion of B cells (6–9  months). Rituximab is currently approved in the treatment of non-Hodgkin’s lymphoma (NHL) [48], refractory rheumatoid arthritis [49], and diffuse B-cell lymphoma but has been used extensively for the treatment of MS (off-label). Several case reports and smaller open-label studies have found rituximab to be beneficial in the treatment of a range of autoimmune neurological disorders including neuromyelitis optica (NMO), where it is now considered standard of care [50]. Treatment of RMS patients with rituximab results in selective depletion of CD20-positive B cells resulting in significant reduction of gadolinium-enhancing lesions (91%) and clinical relapses (44%), as demonstrated in a phase II trial with 104 patients with relapsing multiple sclerosis treated with rituximab compared to placebo [51]. Even though the existence of a humoral component in MS has been implicated for decades, the results of this trial provided solid evidence regarding the role of B cells in the i­ mmunopathology of multiple scle-

S. A. Rizvi

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rosis [52, 53]. Rituximab may be useful in patients with aggressive RRMS who have failed to respond to other conventional therapies [54] and offers superior efficacy when compared to other commonly used agents in newly diagnosed RRMS patients [55]. Ocrelizumab a humanized (90–95%) has a similar mode of action as rituximab but is expected to produce less side effects. Ocrelizumab was recently approved (March 2017) for the treatment of RMS and PPMS. In two identical RRMS trials (OPERA I and OPERA II), patients on ocrelizumab had 46% reduction in annualized relapse rate and significant reduction in MRI lesions and disability progression when compared to interferon beta-1a [56]. As of July 2019, approximately 100,000 patients have been infused with ocrelizumab. It appears to be well tolerated with no serious unexpected adverse events. Both rituximab and ocrelizumab were tested in the PPMS population, and while rituximab failed to meet its primary endpoint of confirmed disability progression, ocrelizumab became the first disease-modifying agent approved for PPMS by reducing the relative risk of disability progression by 25% when compared to placebo [57]. In general, B-cell-depleting therapies when used as a monotherapy in patients with MS appear to be relatively safe [58]. As with several other monoclonal antibodies, both rituximab and ocrelizumab have been associated with serious infusion reactions. Treatment with rituximab has been associated with serious infections, including PML in patients with other autoimmune and neoplastic disease [59]. No cases of PML have been reported in MS patients treated with B-cell-­ depleting therapies. There appears to be an increased risk of herpes reactivation and a possible increased risk of breast cancer (ocrelizumab). The safety of long-term repeated fixed dose use of B-cell-depleting therapies is unknown. Individualized dosing based on CD19 counts is a possibility but would need to be confirmed in a clinical trial [60, 61]. B-cell-depleting therapies offer an effective and completely different approach for treatment of MS.  These monoclonal antibodies have sev-

eral advantages including superior efficacy, acceptable risk profile, infrequent dosing (1–2 infusions every 6 months), and a documented effect on patients with progressive disease.

Alemtuzumab Alemtuzumab, a humanized MCA-targeting CD52 (expressed on circulating T and B cells), is approved for relapsing forms of MS.  It has a unique dosing schedule given as two annual courses (initial 5 days of IV infusion followed by 3  days at the end of 1 year). In phase III trials alemtuzumab was compared to SC IFN beta-1a in naïve MS patients (CARE-MS-I) and patients who had inadequate response to prior treatment (CARE-MS II). In both clinical trials, alemtuzumab reduced relapses by approximately 50% when compared to IFN beta-1a [62, 63]. Long-­ term follow-up data reveals excellent retention rates (CARE-MS I 86%, CARE-MS II 79%) and sustained long-term efficacy with the majority of patients treated with alemtuzumab not requiring any further treatment for up to 6  years (CARE-MS 1 64%, CARE-MS II 55%) [64, 65]. The effect on disability was significant in CAREMS-II but did not reach significance in CARE-MS I.  Alemtuzumab had a beneficial impact on all MRI measures and significantly reduced brain volume loss when compared to IFN beta-1a. The proportion of patient achieving no evidence of disease activity (NEDA) was consistent throughout the extension period of up to 6  years (CARE-MS I 57% at 6  years, CARE-MS II 60% at 6 years). The proportion of patients treated with alemtuzumab who had 6-month clinical definite improvement (CDI) was 34–43%. Very low number of patients in the CARE-MS trials converted to SPMS over the 6-year follow-up period (CARE-MS I 1.1%, CARE-MS II 3.7%). MSBase, an international registry conversion rates for a similar period was about 18% [66]. Treatment-related risk included infusion reactions which were common and in some cases severe as well as several documented cases of pneumonitis. Several infections related to an

7  Disease-Modifying Agents

immunocompromised state have been documented including herpetic (10%), nocardia, and several cases of listeria monocytogenes. Alemtuzumab has also been associated with secondary autoimmune diseases including autoimmune thyroid disease (42% at 6 years), immune thrombocytopenic purpura (ITP) (2.3%), and several cases of autoimmune nephropathy. Most patients with adverse events were easily managed with either observation or first-line interventions [67]. Several recent cases of cervical arterial dissection as well as ischemic and hemorrhagic strokes have also been reported. Alemtuzumab is highly efficacious but because of its risk profile, it is generally used in patients who have failed to respond to other agents. The clinical development program for alemtuzumab includes several steps to mitigate risk and facilitate early detection of any side effects. Alemtuzumab (as well as mitoxantrone and cladribine) can be used as an induction agent early in the treatment of RRMS with potentially long-­term benefits.

Daclizumab Daclizumab was the first FDA-approved humanized monoclonal antibody for clinical use, initially for prevention of renal transplant rejection and eventually for relapsing–remitting MS. It is a humanized IgG1 monoclonal antibody that binds to CD25, the alpha subunit of the high-affinity IL-2 receptor, resulting in upregulation of immunoregulatory CD56 NK cells, inhibition of IL-2 trans-presentation on dendritic cells, and downregulation of effector and lymphoid inducer T cells [68]. Notably, the FDA-approved formulation of subcutaneous daclizumab beta differs from the original humanized form of daclizumab in terms of the extent of glycosylation, and this may have as yet unknown implications for mechanistic differences [69]. After several smaller studies reported a beneficial effect of IV daclizumab on MS patients, three major clinical trials have evaluated subcutaneous daclizumab in combination with IFN beta-­1a or as monotherapy [70–72]. The CHOICE study was a phase II trial involving 230 patients with RRMS

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or SPMS who were given daclizumab plus IFN or IFN and placebo and used imaging as the primary endpoint. Add-on daclizumab treatment reduced the number of GAD-enhancing lesions compared to IFN beta alone, but it did not significantly reduce the adjusted annualized relapse rate [73]. The SELECT trial was a phase II study with 621 RRMS patients randomized to either daclizumab monotherapy or placebo. Compared with placebo, there was a 54% reduction in annualized relapse rate with daclizumab 150 mg and a 50% reduction with daclizumab 300  mg [74]. Two extension studies (SELECTION and SELECTED) importantly showed no rebound effect during a washout period and made further observations on safety up to 6.5  years of treatment [75, 76]. Lastly, the DECIDE trial was a phase III study involving 1841 RRMS patients comparing daclizumab 150 mg directly to IFN. There was a 45% relative risk reduction in terms of annualized relapse rate for patients receiving daclizumab compared to IFN [77]. The most common adverse events include nasopharyngitis, upper respiratory infection, and headache. Serious adverse events include liver function testing abnormalities, cutaneous reactions, infections, and autoimmune phenomena. In a pooled analysis of the major clinical trials including a total of 2236 patients, 16% of patients experienced a severe adverse event other than MS relapse. Most adverse events were mild or moderate in severity; 13% of patients had to discontinue daclizumab due to an adverse event other than MS relapse [78]. Unfortunately, due to several serious adverse events, daclizumab was withdrawn from the market in March 2018.

Fingolimod Fingolimod (Gilenya) was the first oral disease-­ modifying therapy for the treatment of RRMS. It is a sphingosine-1-phosphate receptor modulator which binds to four out of five S1P receptors on lymphocytes resulting in receptor internalization [79]. These receptors deliver a recognition signal for lymphocytes to egress the thymus and

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s­ econdary lymphoid tissue. Lymphocytes, including Th17 central memory T cells, are retained in the lymphoid tissue and prevented from reaching sites of inflammation [80]. Fingolimod can enter the CNS and may have a beneficial neuroprotective effect on glial cells [81]. A small study described strong expression of S1P receptor 1 and 3 in reactive astrocytes in active and chronic inactive MS lesions [82]. A 6-month phase II study showed that once daily oral treatment with Fingolimod (1.25 or 5 mg) had a significant benefit on inflammatory measures of disease activity (MRI and relapse rate), and the effect seems to persist for at least 24  months [83]. In the TRANSFORMS study, patients treated with FTY720 had a 52% greater reduction of RR compared to IFN beta-1a (I/M) [84]. Side effects of FTY720 include two deaths from disseminated herpes, several skin malignancies, macular edema, initial dose bradycardia, decrease in FEV, elevated liver enzymes, and a single case each of posterior reversible encephalopathy syndrome (PRES) and focal encephalitis. In the FREEDOMS trial, which involved >1200 patients, FTY720 reduced the relapse rate by 54% in the 0.5 mg group and 60% in the 1.25 mg group compared to placebo (p  =  65 years old Ocrelizumab

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Treatment of Radiologically Isolated Syndrome (RIS) Several recent studies have raised awareness of patients with incidentally discovered MRI lesions suggestive of multiple sclerosis, the socalled radiologically isolated syndrome (RIS). These studies have documented a conversion rate to CIS of about one-third within a 5-year period. Many more patients (59%) continue to have radiological progression [118, 119]. Furthermore, the risk of an alternate diagnosis with characteristic MRI finding suggestive of MS seems to be extremely low. Patients with evidence of ongoing disease activity may be candidates for treatment [120].

 reatment of Clinically Isolated T Syndrome (CIS) and Newly Diagnosed Mild RRMS Several natural history and long-term longitudinal studies have provided useful information regarding progress in individual patients with multiple sclerosis. An increased rate of relapses in the first few years, poor recovery from relapses, high lesion burden on MRI, spinal cord lesions, and African-American race are all associated with a relatively poor long-term outcome. On the other hand, lack of poor prognostic indicators may not necessarily point toward a benign outcome. Benign MS is mostly a relapsing disease either mild RRMS or CIS without further episodes [121]. Rare cases of benign PPMS have also been documented [122]. Patient with an EDSS