Multiple Sclerosis: A Mechanistic View

By Alireza Minagar

Multiple Sclerosis: A Mechanistic View provides a unique view of the pathophysiology of multiple sclerosis (MS) and related disorders. As the only book on the market to focus on the mechanisms of MS rather than focusing on the clinical features and treatment of the disease, it describes the role of genetic and environmental factors in the pathogenesis of MS, the role of specific cells in the pathophysiology of the disease, and the pathophysiology of inflammatory and neurodegenerative disorders related to MS.

The book provides discussion of neurodegeneration and neuroregeneration, two critical emerging areas of research, as well as detailed discussion of the mechanisms of action of the approved and investigational drugs for treatment of MS and the emerging role of magnetic resonance spectroscopy (MRI) in investigations into MS.

It is the only book on the market to offer comprehensive coverage of the known mechanisms of MS and related diseases, and contains contributions from physicians and researchers who are worldwide experts in the field of study.

• Focuses on the pathophysiologic mechanisms of multiple sclerosis and the mechanisms of action in agents for the treatment of MS
• Discusses the roles of neurodegeneration and neuroregeneration in MS and related diseases
• Authored and edited by international leaders in the field of MS research

• Language: English
• Publisher: Academic Press
• Release date: Nov 9, 2015
• ISBN: 9780128010051

Book preview

Multiple Sclerosis

A Mechanistic View

Editor

Alireza Minagar

Department of Neurology, LSU Health Sciences Center, Shreveport, LA, USA

Table of Contents

Cover image

Title page

Copyright

Contributors

Preface

Chapter 1. Clinical Manifestations of Multiple Sclerosis: An Overview

Introduction

Motor and sensory manifestations

Fatigue

Cognitive decline

Psychiatric manifestations

Optic neuritis and other neuroophthalmologic manifestations

Uveitis

Uhthoff phenomenon

Pulfrich phenomenon

Brain stem involvement in MS

Transverse myelitis

Cerebellar involvement and tremor in MS

Seizures and other paroxysmal features of MS

Painful syndromes

Bowel and bladder dysfunction

Movement disorders

Chapter 2. Novel Therapies for Multiple Sclerosis: A Mechanistic View

Introduction

Laquinimod

Monoclonal antibodies as novel therapies for MS

Alemtuzumab

Daclizumab

Ocrelizumab

Ofatumumab

Rituximab

The concept of remyelination as therapy for MS

AntiLINGO-1

rHIgM22

Chapter 3. Role of B Cells in the Pathogenesis of Multiple Sclerosis: Mechanisms of Action

Introduction

Evidence of B cell involvement in the pathogenesis of MS and factors pointing to the limits of T cell action

The mechanism of B cell action in the development and progress of MS

The role of clonally expanded B cells

Role of B cells in priming/activating T cells

Regulatory B cells (Bregs)

Memory B cells

The role of MHC in triggering MS

Conclusion

List of abbreviations

Chapter 4. Role of CD4+ T Cells in the Pathophysiology of Multiple Sclerosis

Summary

Traditional CNS inflammation versus neuroinflammation

Etiology of MS

Physiological and pathological roles of CD4+ T cell subsets

Classical Th1/Th2 immunoregulatory axis in MS and its animal models

Novel Th17/Treg immunoregulatory axis in MS and its animal models

Do gain-of-function changes affect susceptibility to MS?

T cell exhaustion as a protective mechanism against immunopathology

Protective roles of PD-1 and TIM-3 in MS and its animal models

Conclusions

Chapter 5. Granulocyte-Macrophage Colony-Stimulating Factor in Central Nervous System Autoimmunity

Introduction

The role of GM-CSF in EAE

GM-CSF production by T cells in MS

Conclusion

Chapter 6. Role of Cytokine-Mediated Crosstalk between T Cells and Nonimmune Cells in the Pathophysiology of Multiple Sclerosis

Introduction

Pathogenic roles of CD4+ T cells

Pathogenic roles of CD8+ T cells

T cell subsets with suppressive functions

Pathogenic role of nonimmune cells: the inflammation amplifier

The mechanism of autoreactive T cell invasion into the CNS

Conclusion

Chapter 7. Vitamin D: Role in Pathogenesis of Multiple Sclerosis

Introduction

Vitamin D and genetic susceptibility to MS

Vitamin D deficiency as a risk factor for MS

Experimental autoimmune encephalitis

Role of vitamin D in disability progression and relapses in MS

Supplementation of vitamin D

Therapeutic potential of vitamin D

Closing remarks

Chapter 8. Role of Genetic Factors in Pathophysiology of Multiple Sclerosis

A genetic component to multiple sclerosis

Identification of genetic risk variants

Missing heritability

Association with disease phenotype and therapy outcome

From gene to function

Concluding remarks

Chapter 9. Neuropathology of Multiple Sclerosis

Introduction

Plaque types

Mechanisms of white matter demyelination

The pathological substrate of MS progression

Cortical demyelination in early MS

Remyelination

Conclusion

Chapter 10. Pathophysiology of Acute Disseminated Encephalomyelitis

Introduction

Epidemiology

Immunopathogenesis of ADEM

Pathology of ADEM

Do ADEM and MS represent a part of immune-mediated spectrum of demyelinating disorders?

Conclusion

Chapter 11. Pathophysiology of Experimental Autoimmune Encephalomyelitis

Introduction

Experimental autoimmune encephalomyelitis

Immunopathogenesis of EAE

Monocytes/macrophages

Concluding remarks

Chapter 12. Pathophysiology of Optic Neuritis

Introduction

ON in relation to the risk of MS

Epidemiology of ON in MS

The afferent visual pathway

Clinical features of optic neuritis

Inflammation in optic neuritis

Demyelination in optic neuritis

Axonal and neuronal degeneration in optic neuritis

Imaging and electrophysiologic correlates of optic neuritis

Conclusions

Disclosures

Chapter 13. Neurodegeneration and Remyelination in Multiple Sclerosis

Introduction

Inflammation and neurodegeneration

Conclusion

Chapter 14. Mechanisms of Action of Glatiramer Acetate in the Treatment of Multiple Sclerosis

Section 1. Introduction

Section 2. Impact on adaptive immune responses

Section 3. Glatiramer acetate as a neuroprotective agent

Conclusion

Chapter 15. Mechanism of Action of Interferon Beta in Treatment of Multiple Sclerosis

Introduction

IFNβ signaling pathway

Association between molecular defects in IFNβ signaling and MS pathogenesis

Modifying the immune response due to effects on multiple cell types

Therapeutic effects of IFNβ through targeting B cells’ functions

Effects of IFNβ on DCs

IFNβ blocks T cell activation

Downregulation of MHC II expression

Inhibition of coactivators interaction

Upregulation of death receptors and CTLA4 on the T cell surface

The effect of IFNβ in cytokine shift

The BBB in the pathogenesis of MS

Mechanisms of action of IFNβ at the BBB

ECAMs and junctional proteins

Chemokines and chemokines receptors

MMPs and CD73 protein

The effect of IFNβ in the CNS

MS and miRNAs

Vitamin D and IFNβ treatments in MS

Chapter 16. Mechanisms of Blood–Brain Barrier Disintegration in the Pathophysiology of Multiple Sclerosis

The blood–brain barrier: normal anatomy and physiology

BBB disintegration in MS: a mechanistic picture

Chemokines and cytokines in MS

Role of cell-derived microparticles in the pathogenesis of MS

MRI and blood–brain disintegration in MS

Conclusion

Chapter 17. Mechanisms and Potentials of Stem Cells in the Treatment of Multiple Sclerosis: The Unpaved Path

Introduction

Neural progenitor/stem cells (NP/SCs): mechanism of function

Mesenchymal stem cells: mechanisms of function

Hematopoetic stem cells

Embryonic stem cells and induced pluripotent stem cells

Allogenic stem cell therapy

Conclusion

List of abbreviations

Chapter 18. Role of Neuroimaging in Multiple Sclerosis

Introduction

Conventional MRI techniques

Nonconventional MRI techniques

Conclusions

List of abbreviations

Chapter 19. Pathophysiology of Lymphatic Drainage of the Central Nervous System: Implications for the Pathophysiology of Multiple Sclerosis

Introduction

Lymphatic drainage of CSF

Lymphatic drainage of ISF from the brain parenchyma

Evidence for lymphatic drainage of the human brain

Age-related deterioration of perivascular lymphatic drainage of the brain

Motive force for perivascular lymphatic drainage

Temporary impairment of perivascular drainage by immune complexes

Pathophysiology of perivascular macrophages

Interrelationship between CSF and ISF

Immunological significance of lymphatic drainage of the brain and implications for MS

Conclusions

Index

Copyright

Academic Press is an imprint of Elsevier

125 London Wall, London EC2Y 5AS, UK

525 B Street, Suite 1800, San Diego, CA 92101-4495, USA

225 Wyman Street, Waltham, MA 02451, USA

The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, UK

Copyright © 2016 Elsevier Inc. All rights reserved.

No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions.

This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein).

Notices

Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary.

Practitioners and researchers may always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility.

To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein.

ISBN: 978-0-12-800763-1

British Library Cataloguing-in-Publication Data

A catalogue record for this book is available from the British Library

Library of Congress Cataloging-in-Publication Data

A catalog record for this book is available from the Library of Congress

For information on all Academic Press publications visit our website at http://store.elsevier.com/

Publisher: Mica Haley

Acquisition Editor: April Farr

Editorial Project Manager: Timothy Bennett

Production Project Manager: Lucía Pérez

Designer: Victoria Pearson

Typeset by TNQ Books and Journals

www.tnq.co.in

Contributors

Jonathan S. Alexander,     Department of Molecular & Cellular Physiology, LSU Health Sciences Center, Shreveport, LA, USA

Omar Al-Louzi,     Division of Neuroimmunology and Neurological Infections, Johns Hopkins Hospital, Baltimore, MD, USA

Yasunobu Arima,     Molecular Neuroimmunology, Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University, Hokkaido, Japan

Toru Atsumi,     Molecular Neuroimmunology, Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University, Hokkaido, Japan

Hidenori Bando,     Molecular Neuroimmunology, Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University, Hokkaido, Japan

Felix Becker,     Department of Molecular & Cellular Physiology, LSU Health Sciences Center, Shreveport, LA, USA

Mandana Mohyeddin Bonab,     Department of Immunology, College of Medicine, Tehran University of Medical Sciences, Tehran, Iran

Yesica Campos,     Multiple Sclerosis Center of Excellence, Department of Neurology, Miller School of Medicine, University of Miami, Miami, FL, USA

Roxana O. Carare,     Clinical and Experimental Sciences, Southampton University School of Medicine, Southampton, UK

Bogoljub Ciric,     Department of Neurology, Thomas Jefferson University, Philadelphia, PA, USA

Fariba Dehghanian,     Division of Genetics, Biology Department, Faculty of Sciences, University of Isfahan, Isfahan, Iran

Aleksandar Denic,     Department of Neurology, Mayo Clinic, Rochester, MN, USA

Bénédicte Dubois

Laboratory for Neuroimmunology, Section of Experimental Neurology, Department of Neurosciences, KU Leuven - University of Leuven, Leuven, Belgium

Department of Neurology, University Hospitals Leuven, Leuven, Belgium

Ian Galea,     Clinical and Experimental Sciences, Southampton University School of Medicine, Southampton, UK

Steven Gangloff,     School of Medicine, University at Buffalo (UB), Buffalo, NY, USA

Ravindra Kumar Garg,     Department of Neurology, King George’s Medical University, Uttar Pradesh, Lucknow, India

Eduardo Gonzalez-Toledo,     Department of Radiology and Neurology, LSU Health Sciences Center, Shreveport, LA, USA

An Goris,     Laboratory for Neuroimmunology, Section of Experimental Neurology, Department of Neurosciences, KU Leuven - University of Leuven, Leuven, Belgium

Cheryl A. Hawkes,     Clinical and Experimental Sciences, Southampton University School of Medicine, Southampton, UK

Kelly Hilven,     Laboratory for Neuroimmunology, Section of Experimental Neurology, Department of Neurosciences, KU Leuven - University of Leuven, Leuven, Belgium

Zohreh Hojati,     Division of Genetics, Biology Department, Faculty of Sciences, University of Isfahan, Isfahan, Iran

Eric S. Huseby,     Department of Pathology, University of Massachusetts Medical School, Worcester, MA, USA

S.L. Jaffe,     Department of Neurology, Louisiana State University Health Sciences Center, Shreveport, LA, USA

Vijaykumar Javalkar,     Department of Neurology, LSU Health Sciences Center, Shreveport, LA, USA

Jing-Jing Jiang,     Molecular Neuroimmunology, Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University, Hokkaido, Japan

Daisuke Kamimura,     Molecular Neuroimmunology, Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University, Hokkaido, Japan

Maryam Kay,     Genetics Department, Faculty of Sciences, University of Tarbiat Modaress, Tehran, Iran

Channa Kolb,     Jacobs Neurological Institute (JNI), University at Buffalo (UB), Buffalo, NY, USA

Neeraj Kumar,     Department of Neurology, King George’s Medical University, Uttar Pradesh, Lucknow, India

Claudia F. Lucchinetti,     Department of Neurology, Mayo Clinic, Rochester, MN, USA

Hardeep Singh Malhotra,     Department of Neurology, King George’s Medical University, Uttar Pradesh, Lucknow, India

Ashutosh Mangalam,     Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA, USA

Jeanie McGee,     Department of Neurology, LSU Health Sciences Center, Shreveport, LA, USA

Jie Meng,     Molecular Neuroimmunology, Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University, Hokkaido, Japan

Alireza Minagar,     Department of Neurology, LSU Health Sciences Center, Shreveport, LA, USA

Masaaki Murakami,     Molecular Neuroimmunology, Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University, Hokkaido, Japan

Mohammed Nadeem,     Jacobs Neurological Institute (JNI), University at Buffalo (UB), Buffalo, NY, USA

Behrouz Nikbin,     Department of Immunology, College of Medicine, Tehran University of Medical Sciences, Tehran, Iran

Bardia Nourbakhsh,     Department of Neurology, University of California San Francisco, San Francisco, CA, USA

Hideki Ogura,     Molecular Neuroimmunology, Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University, Hokkaido, Japan

Seiichi Omura

Department of Microbiology and Immunology, Louisiana State University Health Sciences Center, Shreveport, LA, USA

Center for Molecular and Tumor Virology, Louisiana State University Health Sciences Center, Shreveport, LA, USA

Istvan Pirko,     Department of Neurology, Mayo Clinic, Rochester, MN, USA

Bogdan F. Gh. Popescu,     Department of Anatomy and Cell Biology and Cameco MS Neuroscience Research Center, University of Saskatchewan, Saskatoon, SK, Canada

Murali Ramanathan,     Jacobs Neurological Institute (JNI), University at Buffalo (UB), Buffalo, NY, USA

Javad Rasouli,     Department of Neurology, Thomas Jefferson University, Philadelphia, PA, USA

Abdolmohamad Rostami,     Department of Neurology, Thomas Jefferson University, Philadelphia, PA, USA

Lavannya Sabharwal,     Molecular Neuroimmunology, Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University, Hokkaido, Japan

Shiv Saidha,     Division of Neuroimmunology and Neurological Infections, Johns Hopkins Hospital, Baltimore, MD, USA

Vasu Saini,     Jacobs Neurological Institute (JNI), University at Buffalo (UB), Buffalo, NY, USA

Fumitaka Sato

Department of Microbiology and Immunology, Louisiana State University Health Sciences Center, Shreveport, LA, USA

Center for Molecular and Tumor Virology, Louisiana State University Health Sciences Center, Shreveport, LA, USA

Yadollah Shakiba,     Department of Immunology, College of Medicine, Tehran University of Medical Sciences, Tehran, Iran

William Sheremata,     Multiple Sclerosis Center of Excellence, Department of Neurology, Miller School of Medicine, University of Miami, Miami, FL, USA

Emily V. Stevenson,     Department of Molecular & Cellular Physiology, LSU Health Sciences Center, Shreveport, LA, USA

Fatemeh Talebian,     Department of Pathology, The Ohio State University, Columbus, OH, USA

Ikuo Tsunoda

Department of Microbiology and Immunology, Louisiana State University Health Sciences Center, Shreveport, LA, USA

Center for Molecular and Tumor Virology, Louisiana State University Health Sciences Center, Shreveport, LA, USA

Department of Neurology, Louisiana State University Health Sciences Center, Shreveport, LA, USA

Emmanuelle Waubant,     Department of Neurology, University of California San Francisco, San Francisco, CA, USA

Bianca Weinstock-Guttman,     Jacobs Neurological Institute (JNI), University at Buffalo (UB), Buffalo, NY, USA

Roy O. Weller,     Clinical and Experimental Sciences, Southampton University School of Medicine, Southampton, UK

Bharath Wootla,     Department of Neurology, Mayo Clinic, Rochester, MN, USA

J. Winny Yun,     Department of Molecular & Cellular Physiology, LSU Health Sciences Center, Shreveport, LA, USA

Robert Zivadinov,     Department of Neurology, Buffalo Neuroimaging Analysis Center, University at Buffalo, State University of New York, Buffalo, NY, USA

Preface

Multiple sclerosis (MS) is presumably an immune-mediated and neurodegenerative disease of the human central nervous system (CNS), which generally causes irreversible neurologic disability in young adults. As an incurable disease, MS imposes significant medical and financial burdens on patients, their family members, and society, which often leads to devastating outcomes. Despite major leaps in our understanding of the pathophysiology of MS since the 1980s, it remains largely unknown as to why individuals initially develop MS. Such lack of insight into the exact cause of MS translates into our inability to cure MS and, at best, we can only offer certain treatments to slow down disease progression and postpone the beginning the inevitable disability that such a rapidly progressive neurologic ailment creates.

Numerous textbooks and monographs about MS have been published, and the majority of these publications are clinically oriented and target, mainly, clinicians. Few textbooks exist to discuss the fundamental mechanisms involved in MS pathophysiology. The present textbook differs from other traditional books in the sense that it addresses what we know up to now about mechanisms of disease formation and progression in MS. Except for one chapter which briefly addresses the clinical manifestations of MS, the rest of this textbook focuses on pathophysiologic mechanisms involved in MS. The editor and contributors of this unique textbook have intentionally and significantly eliminated the clinical and therapeutic aspects of MS and have concentrated on molecular pathophysiology of this complex and fascinating disease. A panel of brilliant, well-published, and internationally known authors have kindly contributed their magnificent chapters on various aspects of MS pathophysiology. Each chapter addresses a different component of MS pathophysiology and discusses the latest achievements and findings in that field. I am eternally grateful and indebted to these phenomenal neurologists, neuroimagers, neuropathologists, and neuroscientists who made this book a reality.

During the course of preparation of this textbook, we lost a great neurologist and neuroscientist, Dr Istvan Pirko. Dr Pirko was a brilliant neuroimmunologist from the Mayo Clinic, Rochester, MN, USA, whose area of research was imaging of the animal models of MS. After a courageous battle against cancer, he eventually succumbed to this devastating disease. However, during his short life, he achieved much and improved our understanding of MS pathophysiology. I dedicate this book to his name and memory. To a man who devoted his life to a great cause and for years after his untimely death, the scientific world will benefit from his achievements.

I would like to acknowledge Mrs April Farr, Mr Timothy Bennette, and their production team at Elsevier, Inc. for their dedication, hard work, time, and energy which they spent on this book. Thank you for all of your efforts.

At the end, the editor and the contributors to this interesting book wish that our effort will stimulate the scientific curiosity of other younger colleagues to continue the research on the pathophysiology of MS and find a cure for this progressive disease.

Alireza Minagar, MD, FAAN, FANA,     Professor and Chairman, Department of Neurology, LSU Health Sciences Center, Shreveport, LA

Chapter 1

Clinical Manifestations of Multiple Sclerosis

An Overview

Vijaykumar Javalkar, Jeanie McGee,  and Alireza Minagar     Department of Neurology, LSU Health Sciences Center, Shreveport, LA, USA

Abstract

Multiple sclerosis (MS) is a presumably immune-mediated, demyelinating, and neurodegenerative disease of the human central nervous system, which usually affects young adults and causes significant irreversible neurological disability. Up to 85% of newly diagnosed MS patients have relapsing–remitting (RR) disease which is characterized by periods of development of new or worsening of older neurological deficits followed by complete or partial improvement. In most cases, MS manifests between the ages of 20 and 40, with a peak age of 29 and females being predominantly affected, at least in the most common form of MS. MS lesions develop in various areas of the brain and spinal cord which in turn causes development of a wide array of clinical manifestations. In many cases the neurologic manifestations of MS present episodically and then advance to a progressive phase with steady accumulation of neurologic deficits. In many patients the severity and complexity of clinical manifestations of MS are severe and devastating and significantly compromise the patient's quality of life. The present chapter presents an overview of MS clinical features.

Keywords

Cognitive; Demyelinating; Disorder; Motor; Multiple sclerosis (MS)

Introduction

Multiple sclerosis (MS) is a presumably immune-mediated, demyelinating, and neurodegenerative disease of the human central nervous system, which usually affects young adults and causes significant irreversible neurological disability. Up to 85% of newly diagnosed MS patients have relapsing–remitting (RR) disease which is characterized by periods of development of new or worsening of older neurological deficits followed by complete or partial improvement. In most cases, MS manifests between the ages of 20 and 40, with a peak age of 29 and females being predominantly affected, at least in the most common form of MS. MS lesions develop in various areas of the brain and spinal cord which, in turn, lead to the development of a wide array of clinical manifestations. In many cases the neurologic manifestations of MS present episodically and then advance to a progressive phase with steady accumulation of neurologic deficits. In many patients the severity and complexity of clinical manifestations of MS are severe and devastating and significantly compromise the patient’s quality of life. The present chapter presents an overview of MS clinical features.

Motor and sensory manifestations

Weakness is a common finding in MS patients and significantly stems from the involvement of corticospinal tract. Patients describe their weakness as heaviness, stiffness, or giving way under their weight of their extremities. The lower extremities are more commonly and usually earlier affected than the upper extremities. Weakness begins in one lower extremity; however, both lower extremities eventually are affected. The weakness is usually associated with hyperactive reflexes and increased tone in the lower extremities, and many patients present with spastic paraparesis. Clonus is present at the ankle, and examination of these patients also reveals extensor plantar responses. Spasticity of the upper, lower, or four extremities is also a significant finding and may interfere with the patient’s gait and other physical activities.

Sensory symptoms, including numbness, pins and needles sensation, dysesthetic pain, tingling, and burning, are among the most common complaints of MS patients and often present early in its clinical course. These sensory presentations may be more indicative of the demyelination of the posterior columns than spinothalamic tracts. Neurologic examination of these patients may reveal impairment and decrease in feeling of the vibration and abnormalities in fine touch and joint position senses. Pinprick and temperature sensations are less commonly affected over the course of MS. An interesting sensory symptom of MS is Lhermitte’s sign wherein the patient experiences an acute feeling of electric shock sensation which travels down the spine and the extremities. This event occurs when the individual bends the neck forward. A number of painful sensory experiences in MS patients include persistent and painful dysesthesia, burning pain, and painful cramps and spasms of the muscles, particularly in the lower extremities.

Fatigue

Mental and physical fatigue constitutes the most common problem voiced by MS patients. Many report an increase of their fatigue prior to and during the clinical exacerbation. During pathophysiology of MS, the demyelination of the axons leads to tardy and desynchronized transmission of nervous impulses to the point that the impulse conduction may completely cease. Interestingly, exposure to heat intensifies the fatigue in MS patients. They describe fatigue as an unusual and overwhelming feeling of mental and physical exhaustion, which is worse with heat exposure and may slightly improve with rest and sleep. Fatigue significantly restricts patients’ mental and physical activity and adversely affects their performance on neuropsychological evaluations. Fatigue is worse during relapses of MS and does not show any meaningful correlations with brain magnetic resonance imaging (MRI) parameters such as gadolinium-enhancing lesions, lesion load, or any known inflammatory biomarkers. Primary mechanisms for fatigue in MS include pro-inflammatory cytokines, endocrine influences, axonal loss, and altered patterns of cerebral activation (Braley & Chervin, 2010). Secondary mechanisms for fatigue include sleep disorders, depression, disability status, MS subtype, and iatrogenicity (Braley & Chervin, 2010). Alterations in basal ganglia connectivity may contribute to pathophysiology of fatigue in MS (Finke, Schlichting, Papazoglou, et al., 2015). Thalamic involvement in MS may manifest with fatigue, movement disorders, painful syndromes, and cognitive decline (Minagar, Barnett, Benedict, et al., 2013).

Cognitive decline

Cognitive dysfunction in MS occurs in 30–70% of patients (Rao, Leo, Bernardin, & Unverzagt, 1991; Kujala, Portin, & Ruutiainen, 1996). Patients develop reduced information processing speed causing intellectual slowing, attention problems, impairment in abstract reasoning, problem solving, and memory dysfunction (Piras, Magnano, Canu, et al., 2003). Patients with progressive MS may commonly exhibit language and visuospatial deficits (Connick, Chandran, & Bak, 2013). Cognition is more impaired in patients who smoke cannabis than in those who do not (Pavisian et al., 2014). A study using 7 Tesla (T) MRI revealed that leukocortical (type I) and subpial (III–IV) cortical lesions identified on 7T FLASH-T2 sequences are potential cortical biomarkers of the cognitive status in MS (Nielsen et al., 2013). Atrophy of the corpus callosum is strongly associated with cognitive impairment in MS (Granberg, Martola, Bergendal, et al., 2014; Yaldizli, Penner, Frontzek, et al., 2014). Meticulous neuropsychological assessment of MS patients reveals that up to 65% of these patients suffer from cognitive decline.

Psychiatric manifestations

About 20–40% of patients with MS present with personality changes characterized by irritability and apathy (Stathopoulou, Christopoulos, Soubasi, & Gourzis, 2010). The frequency of depression in MS patients and their family members is up to three times higher than the general population. The depression of MS patients is a potential psychiatric presentation of MS. In addition, depression may be a reactive response to the devastating impact of MS on one’s life or it may be a side-effect of treatment with β-interferons. Clinicians should bear in mind that treatment of MS patients with β-interferons, in a minority of patients, is associated with depression, and attention to this side-effect is important. Patients with MS have a higher tendency to attempt suicide and such a devastating event is more frequent in these patients. In addition to personality changes and depression, other psychiatric disorders and symptoms such as bipolar disorder, pseudobulbar affect, euphoria, and anxiety are also over presented in patients with MS (Iacovides & Andreoulakis, 2011).

Optic neuritis and other neuroophthalmologic manifestations

The optic nerve is an extension of the brain within the orbit and is commonly affected in the course of MS. A significant portion of MS patients present with optic neuritis (ON) as the initial manifestation or at one point in the course of their disease develop ON. The other neuroophthalmological manifestations include internuclear opthalmoplegia, nystagmus, saccadic dysmetria, ocular convergence spasm, Pulfrich phenomenon, Uhthoff phenomenon, and retrogeniculate visual field defects (Torres–Torres & Sanchez-Dalmau, 2015). Patients with ON usually develop monoocular subacute visual loss. The scotoma significantly affects central visual field, and patients report a dark patch in the center of their visual field. Other visual capabilities such as color perception and contrast sensitivity are compromised and patients report significant decrease in light intensity perception. Up to 90% of patients with ON present with retroorbital pain upon eye movement (Optical Neuritis Study Group, 1991). Neurologic examination of patients with ON reveals the presence of relative pupillary afferent defect (RAPD or Marcus Gunn pupil). Funduscopic examination demonstrates blurring of the optic disc margin or swelling of the disc (papillitis). In one study the optic disc appeared swollen in 35% of the patients and normal in 65% (Optical Neuritis Study Group, 1991). Bilateral ON is uncommon and when present should alert the examining physician to consider other causes of optic neuropathy (Torres–Torres & Sanchez-Dalmau, 2015). In one study, the simultaneously appearing bilateral ON was seen only 0.42% of cases (Burman, Raininko, & Fagius, 2011), therefore, the presence of bilateral ON should concern the clinician about other differential diagnoses. Other signs of ocular inflammation noted in patients with MS include uveitis, periphlebitis retinae, cells in the anterior chamber, and pars planitis (Torres–Torres & Sanchez-Dalmau, 2015).

Uveitis

Intermediate uveitis is commonly seen in patients with MS (Messenger et al., 2014). Patients with intermediate uveitis have an 8–12% risk of being diagnosed with MS and this risk is higher in females and in those with bilateral disease (Gordon & Goldstein, 2014). One study suggested that uveitis might be used as a good prognostic factor, Expanded Disability Status Scale (EDSS), and progression index scores of MS patients with uveitis were significantly lower than those without uveitis (Shugaiv, Tuzun, Kurtuncu, et al., 2014). Uveitis is one of the common autoimmune disease in patients prior to the diagnosis of MS (odds ratio  =  3.2, 95% confidence interval  =  1.7–5.7) (Langer-Gould, Albers, Van Den Eeden, & Nelson, 2010).

Uhthoff phenomenon

Transient visual blurring in patients with exercise in MS patients occurs occasionally. The exact pathophysiology remains unknown. Other triggers include emotional events, altered temperature, menstruation, smoking, and altered lighting (Rae-Grant, 2013).

Pulfrich phenomenon

The Pulfrich phenomenon is a stereoillusion resulting from latency disparities in the visual pathways (Diaper, 1997). A moving object viewed binocularly in front of a patient appears to travel in an elliptical orbit rather than in a line. This phenomenon can be demonstrated in a healthy individual when a light-attenuating filter is placed over one eye. In MS it may be seen during or after an episode of ON, which by unilaterally reducing light perception acts as a light-attenuating filter (Rae-Grant, 2013).

Brain stem involvement in MS

The human brain stem is composed of cranial nerves nuclei and their axons and an extensive network of myelinated neuroanatomic pathways. The brain stem is commonly affected in MS and even a small demyelinating lesion may cause significant functional impairment. Of the various brain stem syndromes manifesting in MS patients, abnormalities of the ocular movements are the most common. Brain stem lesions can cause a variety of neurological findings such as internuclear ophthalmoplegia, ocular motor palsy, ocular misalignment, pathologic nystagmus, impaired saccades, saccadic intrusions, and impaired pursuit (Prasad & Galetta, 2010). A significant number of MS patients develop nystagmus (Roodhooft, 2012). The nystagmus in MS patients is usually horizontal. Central nystagmus is purely a torsional or upbeat nystagmus and is not suppressed by fixation, no latency, or fatigability (Javalkar & Davis, 2014). Other types of nystagmus described in MS include pendular nystagmus and gaze evoked nystagmus (Tilikete et al., 2011). Primary position upbeat nystagmus is rare and in one series noted only in 5% of cases (Kim, Jeong, Lim, & Kim, 2014). MS patients also suffer from dizziness and vertigo due to demyelinating lesions near the intrapontine eighth nerve fascicle (Pula, Newman-Toker, & Kattah, 2013). In some patients nystagmus is asymptomatic; however, many patients complain of jumping of the images in front of the eyes (oscillopsia), double vision, and blurry vision.

Internuclear ophthalmoplegia (INO) is an interesting brain stem syndrome which stems from the development of demyelinating lesions involving medical longitudinal fasciculus (MLF). This is an intrinsic brain stem sign. Any brain stem syndrome can interrupt the MLF and result in impaired horizontal eye movement, but the most frequent underlying cause is MS (Hassen & Bhardwaj, 2013). MLF are highly organized myelinated axons within human brain stem that serves a central canal for a number of brain stem neuroanatomic pathways that coordinate all groups of conjugate ocular movements such as saccades, smooth visual pursuit, and vestibule–ocular reflexes. The MLF interconnects the paramedian pontine reticular formation–abducens nucleus of the opposite side with the oculomotor nucleus on the same side. Clinically, and as an abnormality of conjugate lateral gaze, INO manifests with limited adduction of the affected eye and nystagmus of the abducting eye. The location of INO is named based on the side where the third nerve function is impaired. Many MS patients develop bilateral INO. Many MS patients with INO complain of horizontal double vision. However, convergence is usually intact. It was reported that dalfampridine may improve internuclear ophthalmoparesis in MS (Serra, Skelly, Jacobs, Walker, & Cohen, 2014). In one study, T2-weighted axial imaging through the MLF region resulted in the greatest overall diagnostic efficacy in terms of the identification of INO-causing lesions (McNulty, Lonergan, Bernnan, et al., 2014).

Other brain stem presentations of MS include impairment of extraocular motility which manifest with horizontal and vertical gaze weakness, one-and-a-half syndrome, skew deviation, and dysfunction of each of the cranial nerves III, IV, or VI.

Many patients with MS present with dysarthria and dysphagia (Hartelius & Svensson, 1994). One particular form of dysarthria, recognized as scanning speech is common in MS patients. Many MS patients have difficulties drinking and swallowing solid food. These disorders partially originate from the generalized weakness of the lower cranial nerves as well as the head and neck muscles which are innervated by them.

Trigeminal and glossopharyngeal neuralgias are two relatively uncommon brain stem painful syndromes which are discussed in this chapter. Bilateral trigeminal neuralgia (TN) may be seen in up to 14% of trigeminal neuralgia patients with MS. In patients with MS-related TN, diffusion tensor imaging reveals microstructural changes within the trigeminal nerve not only on the affected side but also on the clinically nonaffected side (Lummel, Mehrkens, Linn, et al., 2014). The most likely cause of MS-related TN is a pontine plaque damaging the primary afferents (Cruccu, Biasiotta, Di Rezze, et al., 2009). A study has shown that dalfampridine may activate latent trigeminal neuralgia in patients with MS (Birnbaum & Iverson, 2014). Gamma knife radio surgery is a safe and effective treatment for trigeminal neuralgia in patients with MS. In one study, 91% were pain-free initially (Tuleasca, Carron, Resseguier, et al., 2014). Facial pain outcomes after microvascular decompression (MVD) in patients with suspected MS-related TN are poor compared with outcomes for patients with idiopathic TN (Ariai, Mallory, & Pollock, 2014). Surgical interventions are less effective for the treatment of MS-related TN compared with classic TN, and higher recurrence rates are observed (Mohammad-Mohammadi, Recinos, Lee, Elson, & Barnett, 2013).

Facial paresis of central type, facial myokymia, blepharospasm, and facial hemispasm are among other clinical presentations of brain stem involvement in MS. Palatal myoclonus may be a presentation symptom in patients with MS.

Transverse myelitis

Involvement of the spinal cord in MS is usually a short segment unlike neuromyelitis optica (NMO) where longitudinally extent transverse myelitis (more than three vertebral segments) is seen. Patients can present with motor, sensory, and autonomic dysfunction. Motor symptoms include weakness of the extremities depending on the level of the lesion. The existence of a reproducible sensory level is common. Other prevalent sensory symptoms include paresthesias and dysesthesias. Bladder and bowel involvement is also common in the course of MS. About 10% of patients may convert to MS as per one study (Bruna, Martinez-Yelamos, Martinez-Yelamos, Rubio, & Arbizu, 2006) and in another study the conversion rate was high (Gajofatto, Monaco, Fiorini, et al., 2010; Bourre, Zephir, Ongagna, et al., 2012). Those who develop MS may do so within 24  months of onset and have oligoclonal bands or elevated cerebrospinal fluid immunoglobulin G index and abnormal brain MRI scans (Bourre et al., 2012; Perumal, Zabad, Caon et al., 2008).

Cerebellar involvement and tremor in MS

Cerebellar ataxia is a common feature in patients with MS and tremor is the most common manifestation. Early cerebellar findings are a predictor of disability and disease progression (Tornes, Conway, & Sheremata, 2014). Cerebellar cortex may be extensively involved in particular in patient with primary or secondary progressive MS (SPMS) (Kutzelnigg, Faber-Rod, Bauer, et al., 2007). In a study into purkinji cell loss, purkinji axonal spheroids and changes in neurofilament phosphorylation states within Purkinje cells were noted (Redondo et al., 2014). Studies have shown reduced fiber coherence in the main cerebellar connections utilizing tractography and volumetric analysis (Anderson, Wheeler-Kingshott, Abdel-Aziz, et al., 2011).

Seizures and other paroxysmal features of MS

Seizures occur in about 2–3% of all patients with MS (Koch, Uyttenboogaart, Polman, & De Keyser, 2008). Primary or secondary generalized seizures have roughly the same prevalence and account for approximately two-thirds of all seizures in MS. Among the partial seizures, however, simple partial seizures are about twice as common as complex partial seizures in MS (Koch et al., 2008). Rare epilepsy forms like dysphasic status epilpeticus (Spatt, Goldenberg, & Mamoli, 1994) and musicogenic epilepsy (Newman & Saunders, 1980) have been described in patients with MS. Patients with MS with seizures are usually younger and may have an earlier onset of symptoms (Uribe-San-Martin et al., 2014). Cortical and juxtacortical involvement may significantly increase the risk of seizures (Martinez-Lapiscina, Ayuso, Lacruz, et al., 2013). Seizure may be a presenting symptom in MS patients treated with natalizumab (Tysabri®) who have developed progressive multifocal encephalopathy (Clifford et al., 2010). The choice of medication to treat seizures and prognosis of seizures in patients with MS has not been fully investigated (Kelley & Rodriguez, 2009; Koch, Polman, Uyttenboogaart, & De Keyser, 2009).

Painful syndromes

MS is a painful disease and pain in MS may be of central or peripheral origin. Uncommonly, the initial clinical manifestation of MS may be a painful syndrome; however, painful tonic spasms or Lhermitte’s sign may precede clinical relapses of MS. Many MS patients present with pseudoradicular pain, neuropathic pain, increased frequency of headaches, particularly migraine, and trigeminal and glossopharyngeal neuralgias. Compared with the general population, MS patients experience more migraines and, in some cases, persistent migraine may be the initial clinical presentation of MS. Migraine headache may occur as a result of MS or may be cooccur with MS. Alternatively, headaches can be an adverse effect of therapy with β-interferons (Kenner, Menon, & Elliott, 2007). Trigeminal neuralgia is relatively uncommon in MS; however, when it occurs cannot be distinguished from idiopathic trigeminal neuralgia. Both trigeminal and glossopharyngeal neuralgias can be so severe that they interfere with daily living activities such as swallowing, talking, or brushing the teeth and significantly compromise the patient’s quality of life. Patients with MS complain off and on of paroxysmal bouts of involuntary muscle spasms and contractions that move to adjacent regions of the body and cause significant pain. In addition, MS patients with a history of myelitis suffer from tonic spasms and painful spasticity of the extremities. Commonly, MS patients describe dysesthetic pain in back and extremities. A minority of MS patients may develop glossopharyngeal neuralgia which is another extremely painful syndrome which requires aggressive pain management.

Bowel and bladder dysfunction

A significant portion of the MS population suffers from bladder and bowel dysfunction. Frequent bladder abnormalities in MS patients consist of neurogenic detrusor over activity and detrusor sphincter dyssynergia. Hyporeflexia of the bladder which translates into inability to empty the bladder stems from brain stem/pontine demyelinating lesions, while detrusor sphincter dyssynergia may originate from cervical spinal cord lesions. Bladder and sexual dysfunction are associated with poor health-related quality of life in patients with MS patients (Vitkova, Rosenberger, Krokavcova, et al., 2014) and need to be addressed promptly. Similar to the neurogenic bladder, MS patients may develop bowel dysfunction. Constipation is the most common bowel dysfunction and may be due to pelvic floor spasticity, improper hydration, medications, immobility, poor physical conditioning, and weak abdominal muscles (Hawker and Frohman, 2001). In a population-based cohort study, 57.5% reported some to major bladder dysfunction, 41% reported bowel dysfunction, and 51% of cases reported sexual dysfunction (Bakke, Myhr, Gronning, & Nyland, 1996).

Movement disorders

Tremor is frequently seen in patients with MS and other less frequently described movement disorders include parkinsonism, dystonia, chorea, hemiballism, paroxysmal dystonia, paroxysmal chorea, myoclonus, tourettism, restless leg syndrome, and hemifacial spasm (Mehanna & Jankovic, 2013).

References

Anderson V.M, Wheeler-Kingshott C.A, Abdel-Aziz K, et al. A comprehensive assessment of cerebellar damage in multiple sclerosis using diffusion tractography and volumetric analysis. Multiple Sclerosis. 2011;17:1079–1087.

Ariai M.S, Mallory G.W, Pollock B.E. Outcomes after microvascular decompression for patients with trigeminal neuralgia and suspected multiple sclerosis. World Neurosurgery. 2014;81:599–603.

Bakke A, Myhr K.M, Gronning M, Nyland H. Bladder, bowel and sexual dysfunction in patients with multiple sclerosis–a cohort study. Scandinavian Journal of Urology and Nephrology Supplementum. 1996;179:61–66.

Birnbaum G, Iverson J. Dalfampridine may activate latent trigeminal neuralgia in patients with multiple sclerosis. Neurology. 2014;83:1610–1612.

Bourre B, Zephir H, Ongagna J.C, et al. Long-term follow-up of acute partial transverse myelitis. Archives of Neurology. 2012;69:357–362.

Braley T.J, Chervin R.D. Fatigue in multiple sclerosis: mechanisms, evaluation, and treatment. Sleep. 2010;33:1061–1067.

Bruna J, Martinez-Yelamos S, Martinez-Yelamos A, Rubio F, Arbizu T. Idiopathic acute transverse myelitis: a clinical study and prognostic markers in 45 cases. Multiple Sclerosis. 2006;12:169–173.

Burman J, Raininko R, Fagius J. Bilateral and recurrent optic neuritis in multiple sclerosis. Acta Neurologica Scandinavica. 2011;123:207–210.

Clifford D.B, De Luca A, Simpson D.M, Arendt G, Giovannoni G, Nath A. Natalizumab-associated progressive multifocal leukoencephalopathy in patients with multiple sclerosis: lessons from 28 cases. The Lancet Neurology. 2010;9:438–446.

Connick P, Chandran S, Bak T.H. Patterns of cognitive dysfunction in progressive MS. Behavioural Neurology. 2013;27:259–265.

Cruccu G, Biasiotta A, Di Rezze S, et al. Trigeminal neuralgia and pain related to multiple sclerosis. Pain. 2009;143:186–191.

Diaper C.J. Pulfrich revisited. Survey of Ophthalmology. 1997;41:493–499.

Finke C, Schlichting J, Papazoglou S, Scheel M, Freing A, Soemmer C, et al. Altered basal ganglia functional connectivity in multiple sclerosis patients with fatigue. Multiple Sclerosis. 2015;21(7):925–934. doi: 10.1177/1352458514555784.

Gajofatto A, Monaco S, Fiorini M, et al. Assessment of outcome predictors in first-episode acute myelitis: a retrospective study of 53 cases. Archives of Neurology. 2010;67:724–730.

Gordon L.K, Goldstein D.A. Gender and uveitis in patients with multiple sclerosis. Journal of Ophthalmology. 2014;2014:565262.

Granberg T, Martola J, Bergendal G, et al. Corpus callosum atrophy is strongly associated with cognitive impairment in multiple sclerosis: results of a 17-year longitudinal study. Multiple Sclerosis. 2014;21(9):1151–1158.

Hartelius L, Svensson P. Speech and swallowing symptoms associated with Parkinson’s disease and multiple sclerosis: a survey. Folia phoniatrica et logopaedica: Official Organ of the International Association of Logopedics and Phoniatrics. 1994;46:9–17.

Hassen G.W, Bhardwaj N. Images in clinical medicine. Bilateral internuclear ophthalmoplegia in multiple sclerosis. The New England Journal of Medicine. 2013;368:e3.

Hawker K.S, Frohman E.M. Bladder, bowel, and sexual dysfunction in multiple sclerosis. Current Treatment Options in Neurology. 2001;3:207–214.

Iacovides A, Andreoulakis E. Bipolar disorder and resembling special psychopathological manifestations in multiple sclerosis: a review. Current Opinion in Psychiatry. 2011;24:336–340.

Javalkar V.K.K.M, Davis D. Clinical manifestations of cerebellar disease. Neurologic Clinics. 2014;32:871–879.

Kelley B.J, Rodriguez M. Seizures in patients with multiple sclerosis: epidemiology, pathophysiology and management. CNS Drugs. 2009;23:805–815.

Kenner M, Menon U, Elliott D.G. Multiple sclerosis as a painful disease. International Review of Neurobiology. 2007;79:303–321.

Kim J.A, Jeong I.H, Lim Y.M, Kim K.K. Primary position upbeat nystagmus during an acute attack of multiple sclerosis. Journal of Clinical Neurology. 2014;10:37–41.

Koch M.W, Polman S.K, Uyttenboogaart M, De Keyser J. Treatment of seizures in multiple sclerosis. The Cochrane Database of Systematic Reviews. July 8, 2009;8(3):CD007150.

Koch M, Uyttenboogaart M, Polman S, De Keyser J. Seizures in multiple sclerosis. Epilepsia. 2008;49:948–953.

Kujala P, Portin R, Ruutiainen J. Memory deficits and early cognitive deterioration in MS. Acta Neurologica Scandinavica. 1996;93:329–335.

Kutzelnigg A, Faber-Rod J.C, Bauer J, et al. Widespread demyelination in the cerebellar cortex in multiple sclerosis. Brain Pathology. 2007;17:38–44.

Langer-Gould A, Albers K.B, Van Den Eeden S.K, Nelson L.M. Autoimmune diseases prior to the diagnosis of multiple sclerosis: a population-based case-control study. Multiple Sclerosis. 2010;16:855–861.

Lummel N, Mehrkens J.H, Linn J, et al. Diffusion tensor imaging of the trigeminal nerve in patients with trigeminal neuralgia due to multiple sclerosis. Neuroradiology. 2014;57(3):259–267.

Martinez-Lapiscina E.H, Ayuso T, Lacruz F, et al. Cortico-juxtacortical involvement increases risk of epileptic seizures in multiple sclerosis. Acta Neurologica Scandinavica. 2013;128:24–31.

McNulty J.P, Lonergan R, Brennan P.C, et al. Diagnostic efficacy of conventional MRI pulse sequences in the detection of lesions causing internuclear ophthalmoplegia in multiple sclerosis patients. Clinical Neuroradiology. 2014;25(3):233–239.

Mehanna R, Jankovic J. Movement disorders in multiple sclerosis and other demyelinating diseases. Journal of the Neurological Sciences. 2013;328:1–8.

Messenger W, Hildebrandt L, Mackensen F, Suhler E, Becker M, Rosenbaum J.T. Characterisation of uveitis in association with multiple sclerosis. The British Journal of Ophthalmology. 2014;99(2):205–209.

Minagar A, Barnett M.H, Benedict R.H, et al. The thalamus and multiple sclerosis: modern views on pathologic, imaging, and clinical aspects. Neurology. 2013;80:210–219.

Mohammad-Mohammadi A, Recinos P.F, Lee J.H, Elson P, Barnett G.H. Surgical outcomes of trigeminal neuralgia in patients with multiple sclerosis. Neurosurgery. 2013;73:941–950 discussion 950.

Newman P, Saunders M. A unique case of musicogenic epilepsy. Archives of Neurology. 1980;37:244–245.

Nielsen A.S, Kinkel R.P, Madigan N, Tinelli E, Benner T, Mainero C. Contribution of cortical lesion subtypes at 7T MRI to physical and cognitive performance in MS. Neurology. 2013;81:641–649.

Optic Neuritis Study Group, . The clinical profile of optic neuritis. Experience of the optic neuritis treatment trial. Archives of Ophthalmology. 1991;109:1673–1678.

Pavisian B, MacIntosh B.J, Szilagyi G, Staines R.W, O’Connor P, Feinstein A. Effects of cannabis on cognition in patients with MS: a psychometric and MRI study. Neurology. 2014;82:1879–1887.

Perumal J, Zabad R, Caon C, et al. Acute transverse myelitis with normal brain MRI: long-term risk of MS. Journal of Neurology. 2008;255:89–93.

Piras M.R, Magnano I, Canu E.D, et al. Longitudinal study of cognitive dysfunction in multiple sclerosis: neuropsychological, neuroradiological, and neurophysiological findings. Journal of Neurology, Neurosurgery, and Psychiatry. 2003;74:878–885.

Prasad S, Galetta S.L. Eye movement abnormalities in multiple sclerosis. Neurologic Clinics. 2010;28:641–655.

Pula J.H, Newman-Toker D.E, Kattah J.C. Multiple sclerosis as a cause of the acute vestibular syndrome. Journal of Neurology. 2013;260:1649–1654.

Rae-Grant A.D. Unusual symptoms and syndromes in multiple sclerosis. Continuum. 2013;19:992–1006.

Rao S.M, Leo G.J, Bernardin L, Unverzagt F. Cognitive dysfunction in multiple sclerosis. I. Frequency, patterns, and prediction. Neurology. 1991;41:685–691.

Redondo J, Kemp K, Hares K, Rice C, Scolding N, Wilkins A. Purkinje cell pathology and loss in multiple sclerosis cerebellum. Brain Pathology. November 20, 2014 doi: 10.1111/bpa.12230.

Roodhooft J.M. Summary of eye examinations of 284 patients with multiple sclerosis. International Journal of MS Care. 2012;14:31–38.

Serra A, Skelly M.M, Jacobs J.B, Walker M.F, Cohen J.A. Improvement of internuclear ophthalmoparesis in multiple sclerosis with dalfampridine. Neurology. 2014;83:192–194.

Shugaiv E, Tuzun E, Kurtuncu M, et al. Uveitis as a prognostic factor in multiple sclerosis. Multiple Sclerosis. 2014;21(1):105–107.

Spatt J, Goldenberg G, Mamoli B. Simple dysphasic seizures as the sole manifestation of relapse in multiple sclerosis. Epilepsia. 1994;35:1342–1345.

Stathopoulou A, Christopoulos P, Soubasi E, Gourzis P. Personality characteristics and disorders in multiple sclerosis patients: assessment and treatment. International Review of Psychiatry. 2010;22:43–54.

Tilikete C, Jasse L, Vukusic S, et al. Persistent ocular motor manifestations and related visual consequences in multiple sclerosis. Annals of the New York Academy of Sciences. 2011;1233:327–334.

Tornes L, Conway B, Sheremata W. Multiple sclerosis and the cerebellum. Neurologic Clinics. 2014;32:957–977.

Torres-Torres R, Sanchez-Dalmau B.F. Treatment of acute optic neuritis and vision complaints in multiple sclerosis. Current Treatment Options in Neurology. 2015;17:328.

Tuleasca C, Carron R, Resseguier N, et al. Multiple sclerosis-related trigeminal neuralgia: a prospective series of 43 patients treated with gamma knife surgery with more than one year of follow-up. Stereotactic and Functional Neurosurgery. 2014;92:203–210.

Uribe-San-Martin R, Ciampi-Diaz E, Suarez-Hernandez F, Vasquez-Torres M, Godoy-Fernandez J, Carcamo-Rodriguez C. Prevalence of epilepsy in a cohort of patients with multiple sclerosis. Seizure. 2014;23:81–83.

Vitkova M, Rosenberger J, Krokavcova M, et al. Health-related quality of life in multiple sclerosis patients with bladder, bowel and sexual dysfunction. Disability and Rehabilitation. 2014;36:987–992.

Yaldizli O, Penner I.K, Frontzek K, et al. The relationship between total and regional corpus callosum atrophy, cognitive impairment and fatigue in multiple sclerosis patients. Multiple Sclerosis. 2014;20:356–364.

Chapter 2

Novel Therapies for Multiple Sclerosis

A Mechanistic View

Emily V. Stevenson¹, Jeanie McGee², Jonathan S. Alexander¹,  and Alireza Minagar²     ¹Department of Molecular & Cellular Physiology, LSU Health Sciences Center, Shreveport, LA, USA     ²Department of Neurology, LSU Health Sciences Center, Shreveport, LA, USA

Abstract

Multiple sclerosis (MS) is presumed to be an autoimmune disease of human brain and spinal cord which mainly affects young adults. MS pathophysiology contains two neuroinflammatory and neurodegenerative arms which run concurrently; however, it is the neurodegeneration that eventually leads to loss of neurons and axons and permanent disability. Presently, MS remains incurable and we present a mechanistic review of the present and emerging therapies for this fascinating disease.

Keywords

Mechanistic; Monoclonal antibody; Multiple sclerosis; Therapies

Introduction

Multiple sclerosis (MS) is an assumed immune-mediated disease of the human central nervous system (CNS) that causes inflammatory-mediated loss of myelin sheath/oligodendrocyte complex and axonal and neuronal loss (Frohman, Racke, & Raine, 2006; Noseworthy, Lucchinetti, Rodriguez, & Weinshenker, 2000). The specific cause (or causes) for MS remains undiscovered, and a cure currently remains beyond our grasp. However, several disease management strategies for MS have been developed, beginning in 1993 with the approval of interferon-β1b (Betaseron®) and continuing with the approval of many more treatments by the Food and Drug Administration (FDA), such as interferon (IFN)-β1a (Avonex® and Rebif®), glatiramer acetate (Copaxone®), and mitoxantrone. Unfortunately, none of these approved therapies can fundamentally alter the course of MS disease, and each has its own unique profile of potential adverse side-effects. One factor that has expanded our understanding of the pathogenesis of MS is the introduction and routine application of magnetic resonance imaging (MRI) of brain and spinal cord for diagnosis and follow-up of MS patients. Nowadays, we utilize MRI of the CNS to qualitatively analyze the patient response to the therapy. As we have learned more about the pathogenesis of MS, we have begun to develop more potent treatments for this incurable disease. However, this achievement has come with a significant price, which, in general, is the compromise of the safety of the medication. In general, the more powerful the medication’s ability to suppress disease activity in MS is, the more serious and even deadly the adverse effects may be. The focus of the present chapter is to provide readers with an overview of the mechanisms of action of novel therapies for MS that are presently under clinical trials for patients with relapsing–remitting MS (RRMS).

Laquinimod

Laquinimod, an oral synthetic derivative of linomide, is presently being assessed for treatment of patients with RRMS in clinical trials. Studies on mice with experimental autoimmune encephalomyelitis (EAE) have revealed that laquinimod decreases inflammation within the CNS, reduces demyelination, and circumvents axonal injury (Brück & Wegner, 2011). While laquinimod has shown certain efficacy in the treatment of these patients, its precise and detailed mechanism of action in MS remains incompletely understood. It is believed that laquinimod possesses anti-inflammatory properties and works by shifting the cytokine profile in the CNS from a pro-inflammatory Th1 state to an anti-inflammatory Th2 state (Zou et al., 2002). In addition, laquinimod inhibits the nuclear factor κ-light-chain-enhancer of activated B cell signaling and reduces the expression of major histocompatibility complex class II molecules on human cell cultures (Figure 1). Interestingly, the laquinimod molecule induces the generation of brain-derived neurotrophic factors, which may serve as the basis for the neuroprotective effect of the drug (Thöne et al., 2012).

Monoclonal antibodies as novel therapies for MS

Since the mid-1990s, neurologists have witnessed a march of new therapies for MS which, unlike the first-generation treatments that exerted a global impact on the immune system, target a molecule within the inflammatory cascade of MS. These agents are commonly monoclonal antibodies that target specific molecules without impacting other components of the immune system. Monoclonal antibodies have gained increasing attention as treatment options for MS, and their efficacy is being explored in the context of a number of ongoing clinical trials. These include the most-well known monoclonal antibody treatment for MS, natalizumab (Tysabri®), which blocks the adhesion between VLA4 and α4-integrin (Figure 1), thereby restricting the trans-endothelial migration of activated leukocytes into the CNS milieu. Another potent monoclonal antibody, alemtuzumab, which is by far one of the most potent therapies ever developed for the treatment of MS, was approved by the FDA for the treatment of specific subgroups of MS patients and acts by targeting the CD52 molecule and significantly suppresses the immune system function (Minagar, Alexander, Sahraian, & Zivadinov, 2010). Some monoclonal antibodies that are still under investigation for treatment of MS include daclizumab, ocrilizumab, and ofatumumab. Although these monoclonal antibodies are relatively effective in the treatment of MS, serious concerns exist over some of their unusual and potentially devastating adverse effects, particularly the immune suppression-related development of opportunistic infections.

Figure 1  Schematic figure explaining the potential and proposed mechanisms of action of existing and emerging therapies for multiple sclerosis (MS). Following massive activation of the immune system, the activated immune cells (T and B lymphocytes as well as macrophages) cross the disrupted blood-brain barrier (BBB) and the presentation of the proposed central nervous system (CNS) antigen(s) (in this case members of the myelin basic protein family) to the activated T lymphocytes by the antigen-presenting cells (APC) continues. This leads to further differentiation of the naïve T lymphocytes to other groups such as Th1 and Th2 lymphocytes. One particular action of glatiramer acetate (GA) is to alter this scenario as well as by displacing the putative myelin antigen(s). Mechanisms of action of existing and emerging monoclonal antibodies for the treatment of MS such as alemtuzumab, daclizumab, rituximab, and ofatumumab are demonstrated. One point of interest is that daclizumab increases the natural killer (NK) regulatory effect on T lymphocytes and causes amplified lysis of activated T lymphocytes by CD56 bright natural killer lymphocytes. On another front, the LINGO-1 and rHIgM22 affect the oligodendrocytes (ODC) and enhance the remyelination process. CEC, cerebral endothelial cell; Mϕ, macrophage; N, nucleus; MHC II, major histocompatibility complex class II.

Alemtuzumab

Alemtuzumab (CAMPATH-1H) is a CD52-specific humanized monoclonal antibody that was constructed by combining the six hypervariable loops from the rat immunoglobulin (Ig)G2b CAMPATH-1G with a human IgG1 (consisting of the κ light chain of the Bence-Jones protein REI and the heavy chain of a new immunoglobulin) (Cheetham, Hale, Waldmann, & Bloomer, 1998; Riechmann, Clark, Waldmann, & Winter, 1988). CD52 is a cell-surface glycosylphosphatidylinositol-anchored glycoprotein that is expressed on human lymphocytes, monocytes, and eosinophils, and also on epididymis epithelial cells and mature spermatozoa. CD52 is the smallest known surface-expressed glycoprotein at 12 amino acids, which has been suggested as a potential reason for why CD52-specific antibodies are very good at inducing complement-mediated cell lysis. In addition to its extremely effective ability to induce cell lysis via complement activation (Bindon, Hale, & Waldmann, 1988), this antibody can also induce antibody-dependent cell-mediated cytotoxicity as well as cellular apoptosis (Stanglmaier, Reis, & Hallek, 2004).

Alemtuzumab is typically given to patients as an initial 5-day infusion, followed by an additional 3-day infusion 12  months later (Investigators et al., 2008; Zhang et al., 2013). The treatment causes profound lymphocyte and monocyte depletion that is observed in the bloodstream within minutes of initial dosing and that is maintained for up to one year posttreatment. Importantly, due to the absence of CD52 on hematopoietic stem cells, immune cells are able to reconstitute following treatment. However, following alemtuzumab treatment, the lymphocyte profile resulting after immune reconstitution is markedly different than that seen prior to treatment, indicating that alemtuzumab’s mode of action is more complex than the initial immune cell depletion (Figure 1). Peripheral blood monocytes were shown to return to baseline levels within one month in MS patients treated with alemtuzumab (Freedman, Kaplan, & Markovic-Plese, 2013), and B cell populations returned to baseline levels within 3–7  months posttreatment (Cox et al., 2005; Hill-Cawthorne et al., 2012). However, T cell subsets remained depleted for a much longer length of time, with CD8+ T cells requiring from 11 to 20  months and CD4+ T cells requiring from 12 to 35  months to reach the lower limits of the normal range (Coles et al., 2012; Hill-Cawthorne et al., 2012). Further, the pool of T cells that begins to reconstitute from 1 to 3  months posttreatment (although at much lower levels than observed in untreated patients) is predominantly made up of memory T cells that are characterized as CD4+CD25high (Havari et al., 2014) and CD127low, classifying them as T regulator (Treg) cells. This initial phase of Treg reconstitution is followed by a later phase of T cell reconstitution around 6–12  months posttreatment that represents a more normal distribution of T cell subsets (Cox et al., 2005). The change in the T cell subset profile is also associated with a differential T cell cytokine production profile, characterized by decreased production of pro-inflammatory cytokines, like IFN-γ and interleukin (IL)-17, and increased production of anti-inflammatory cytokines, like transforming growth factor-β, IL-4, and IL-10 (Cox et al., 2005; Havari et al., 2014; Zhang et al., 2013).

Daclizumab

Daclizumab (Zenapax®) (anti-CD25) is a humanized neutralizing monoclonal antibody of IgG1 class, which is attached to the Tac epitope on the α-chain of the interleukin-2 receptor (CD25). Daclizumab successfully ceases the generation of the high-affinity Il-2 receptor. Signaling via the high affinity Il-2 receptor, when activated, stimulates the expansion of activated T lymphocytes. Therefore, by inhibiting the Il-2 receptor, daclizumab blocks the expansion and activation of T lymphocytes, which can ameliorate MS disease. Although daclizumab is known for its activity against the α-chain subunit of the Il-2 receptor, treatment with daclizumab also confers other effects on the immune system, suggesting that the mechanism(s) of action of daclizumab remain only partially recognized. For example, daclizumab treatment has been correlated with the expansion of CD56bright natural killer cells (Wynn, Kaufman, Montalban, et al., 2010), which have been shown to regulate the immune system by lyzing activated T lymphocytes via a perforin-dependent pathway (Figure 1). Presently, daclizumab is FDA-approved as an add-on agent to immunosuppressive agents to prevent rejection of allograft transplanted kidneys. The efficacy, safety, and tolerance of daclizumab in the treatment of patients with RRMS have been assessed in a number of clinical trials (Bielekova, 2013; Kreutzkamp, 2014).

Ocrelizumab

Ocrelizumab is a recombinant humanized monoclonal antibody that targets CD20, a molecule that is expressed only on B lymphocytes (specifically, precursor B lymphocytes, mature B lymphocytes, and memory B lymphocytes, but not on plasma cells) (Figure 1). Therefore, ocrelizumab targets only B lymphocytes for depletion, which occurs by enhanced antibody-dependent cell-mediated cytotoxicity, rather than by complement-dependent cell lysis. This humanized monoclonal antibody is less immunogenic than another CD20-specific monoclonal antibody, rituximab (described below), and is generally better tolerated.

Ofatumumab

Ofatumumab (Arzerra® or HuMax-CD20) is another humanized monoclonal that targets CD20 (Barth & Czuczman, 2013) (Figure 1). This monoclonal antibody attaches to a dissimilar region of the CD20 molecule than the other two CD20-specific monoclonal antibodies, rituximab and ocrelizumab. It suppresses the activation of B lymphocytes and is presently approved by the FDA for treatment of certain cases of chronic lymphocytic leukemia, which are refractory to therapy with alemtuzumab and fludarabine and has been used experimentally for the treatment of RRMS.

Rituximab

Rituximab (Rituxan) is a chimeric IgG1 monoclonal antibody that targets CD20 and is currently approved for the treatment of diffuse B cell lymphomas and refractory low-grade or follicular nonHodgkin’s lymphomas. This monoclonal antibody targets the humoral arm of the immune system, inducing the prolonged depletion of B lymphocytes through apoptosis, antibody-dependent cell-medicated cytotoxicity and complement-dependent cytotoxicity (Grillo-López, 2000; Waubant, 2008) (Figure 1).

The concept of remyelination as therapy for MS

The myelin sheath insulates axons of the CNS neurons to ensure that rapid transmission of electric impulses occurs across the nervous system. Within the CNS, the central myelin is generated by oligodendroyctes. MS lesions affect both gray and white matters, and both the inflammatory and degenerative arms of MS pathogenesis destroy the myelin sheath, oligodendrocytes, neurons, and their axons. Loss of the oligodendrocyte–myelin complex is a cardinal feature of MS neuropathology, which occurs continuously and relentlessly in MS (Compston & Coles, 2002). This demyelinating process is massive and widespread, and over time, overwhelms the remyelination process, which is intermediated by oligodendrocyte precursors. Restoration of the myelin sheath may save the neuronal–axonal unit from further degeneration and could improve impulse conduction. Therefore, the concept of activating or potentiating the process of remyelination in MS has fascinated many neuroscientists, and attempts have been made to develop agents which can facilitate remyelination. However, none of the