Cover
Title page
Copyright page
Contributors
Series Foreword
Preface
1 Etiology
1. Background
2. Genes
3. Gender effects: Genetic or biologic?
4. The role of the environment
5. Combining risk factors
6. Conclusion
7. Acknowledgment
8. References
2 Immunopathogenesis of Multiple Sclerosis
1. What does the neuropathology of MS tell us about its pathogenesis?
2. Gray matter pathology
3. Multiple sclerosis as an autoimmune disease
4. Candidates for the self-antigen in multiple sclerosis
5. Antigen spreading
6. Epitope spreading
7. Outside-in versus inside-out?
8. Lymphocyte trafficking into the CNS
9. Role of T cells in MS
10. Role of B cells and humoral immunity
11. Role of microglia and macrophages
12. Role of other cells: Dendritic cells and astrocytes
13. Role of cytokines
14. What might trigger autoimmunity?
15. Further Reading
3 Diagnostic Process
1. Introduction
2. Clinical features of MS
3. Diagnostic evaluation of MS
4. Conclusion
5. Further Reading
4 MRI in Diagnosis and Disease Monitoring
1. Introduction
2. MRI at presentation
3. MRI diagnostic criteria
4. MRI consensus protocol
5. MRI for monitoring disease and treatment
6. Limitations
7. Nonconventional MRI
8. Conclusions
9. Acknowledgments
10. References
5 Relapsing MS: Disease Staging and Therapeutic Algorithms
1. Introduction
2. Window
3. Prognostic factors
4. Therapy
5. Initiation
6. Suboptimal response
7. Combination therapy
8. Rescue therapy
9. Escalation
10. Rapid advancement
11. Conclusion
12. Newer oral agents
13. Further Reading
6 Progressive MS Treatment Algorithms
1. Background
2. Challenges to clinical trials in progressive MS
3. Clinical trials in progressive MS
4. Monitoring progressive MS in clinical practice
5. Treatment of progressive MS in clinical practice
6. Stopping disease-modifying therapy
7. Neuroprotective strategies
8. Other treatment considerations
9. Further Reading
7 Sex-Determined Issues in Multiple Sclerosis
1. Epidemiology of MS and gender
2. Basic science of sex hormone and chromosome differences seen in MS
3. Reproductive issues in MS
4. Pregnancy and the MS patient
5. Breastfeeding
6. Female cancers
7. Male sex hormones and concerns for the male patient
8. Acknowledgments
9. References
8 Pediatric Multiple Sclerosis
1. Introduction
2. Definitions
3. Clinical outcome following a first demyelinating attack
4. Epidemiology and risk factors
5. Clinical presentation
6. Disease course
7. Diagnostic considerations
8. Differential diagnosis
9. Treatment of acute demyelinating attacks
10. Disease-modifying therapy
11. Escalation of care for severe MS
12. Symptomatic therapy
13. Cognitive dysfunction and quality of life considerations
14. Conclusions and future directions
15. Further Reading
9 Complementary and Alternative Medicine
1. Introduction
2. Terminology
3. Unconventional medicine use
4. CAM therapies
5. Conclusion
6. Further Reading
10 Symptomatic Management of MS
1. Bladder dysfunction
2. Bowel dysfunction
3. Sexual dysfunction
4. Pain
5. Impaired gait
6. Spasticity
7. Tremor
8. Further Reading
11 Invisible Symptoms of MS
1. Introduction
2. Fatigue
3. Cognition
4. Depression
5. Summary
6. Reference
7. Further Reading
12 Rehabilitation
1. Introduction
2. Physical rehabilitation
3. Organ rehabilitation: Bladder and bowel management
4. Cognitive rehabilitation
5. Summary
6. References
13 Psychosocial Adaptation to Multiple Sclerosis
1. Introduction
2. Coping and adaptation
3. Stages and phases in the adaptation process
4. Acknowledgments
5. References
14 Transverse Myelitis and Acute Disseminated Encephalomyelitis
1. Introduction
2. Transverse myelitis
3. Acute disseminated encephalomyelitis (ADEM)
4. References
15 Neuromyelitis Optica
1. Introduction
2. Diagnosis
3. Differential diagnosis
4. Treatment
5. Prognosis and follow-up
6. References
7. Further Reading
16 Neurosarcoidosis
1. Introduction
2. General principles of diagnosis
3. General principles of treatment
4. Dosages
5. Specific presentations
6. Cranial neuropathy
7. Peripheral neuropathy and myopathy
8. Prognosis and long-term monitoring
9. Further Reading
17 Lyme Neuroborreliosis
1. Introduction
2. Borrelia burgdorferi infection
3. Conclusion
4. Acknowledgments
5. References
6. Further Reading
18 Neuro-Behçet Syndrome
1. Introduction
2. Epidemiology
3. Diagnosis and systemic manifestations of Behçet disease
4. Pathology and etiopathogenesis of Behçet syndrome
5. Nervous system involvement in Behçet disease: Neuro-Behçet syndrome
6. Diagnostic studies in NBS
7. Treatment
8. References
Index
End User License Agreement

List of Tables

Chapter 03
1. Table 3.1 Common Presenting Symptoms in MS
2. Table 3.2 MRI Features That Suggest Against a Diagnosis of MS
3. Table 3.3 Differential Diagnosis of MS
4. Table 3.4 Historical Features Suggesting Against MS
5. Table 3.5 Examination Findings Suggesting Against MS
Chapter 04
1. Table 4.1 2010 MRI Criteria for Multiple Sclerosis
2. Table 4.2 Consensus Brain MRI Protocol for Clinical Evaluation of MS
3. Table 4.3 Consensus Spinal Cord MRI Protocol for Clinical Evaluation of MS
Chapter 05
1. Table 5.1 Current DMD Administration, MoA, Adverse Reactions, and Pivotal Study
2. Table 5.2 Pre- and Postmedication Laboratory Tests
Chapter 06
1. Table 6.1 Summary of Disease-Modifying Therapy Clinical Trials
Chapter 07
1. Table 7.1 DMTs—Pregnancy Safety Categories^a
2. Table 7.2 Symptom Management Medications—Pregnancy Safety Categories
Chapter 08
1. Table 8.1 MRI Features on Baseline Scan That Predict Subsequent MS Diagnosis in Children
2. Table 8.2 Description of Pediatric-Specific Diagnoses That Can Mimic Pediatric MS
3. Table 8.3 Pediatric Dosing Regimens for Commonly Used Symptomatic Medications in Patients Weighing Less Than 40 kg
Chapter 09
1. Table 9.1 NIH Classification of CAM Therapies with Representative Examples
2. Table 9.2 Risk–Benefit Profiles of MS-Relevant CAM Therapies
Chapter 10
1. Table 10.1 Anticholinergic Agents for Detrusor Hyperreflexia
2. Table 10.2 PDE-5 Inhibitors for ED
3. Table 10.3 TN Treatments
4. Table 10.4 Dysesthesia Treatments
5. Table 10.5 Pharmacologic Management of Spasticity
6. Table 10.6 Pharmacologic Management of Tremor
Chapter 14
1. Table 14.1 Timing of MRI Based on the Last Time a Patient’s Myelopathic Symptoms Progressed
2. Table 14.2 Standard Evaluation of TM Patients
3. Table 14.3 Clinical Presentations of ADEM Patients
Chapter 16
1. Table 16.1 Selected Differential Diagnosis for NS According to Localization
2. Table 16.2 Reported Treatments
3. Table 16.3 CSF in NS versus MS
Chapter 18
1. Table 18.1 Criteria for diagnosis of Behçet’s disease^a
2. Table 18.2 Suggested Diagnostic Criteria for NBS^a
3. Table 18.3 The Neurological Spectrum of Behçet Disease
4. Table 18.4 Classical Presentation and Features of a Patient with Intra-axial (Parenchymal) NBS
5. Table 18.5 The Differential Diagnosis of MS and Intra-axial (CNS) NBS

List of Illustrations

Chapter 03
1. Figure 3.1 Disease courses of MS. These drawings illustrate how disability evolves with time in the different courses of the disease. (a) In RRMS, subjects may have complete recovery from intermittent relapses, or they may have partial recovery with some residual disability. (b) Subjects may have progressive disability without relapses in SPMS, or they may have some continuing relapses early in SPMS superimposed on an underlying progressive course. (c) PPMS can progress at a steady rate or may fluctuate in terms of rate of decline, in either event without any clear relapses. (d) In PRMS, there are both relapses and progressive decline from the onset of the disease, and recovery from relapses may be partial or complete.
Chapter 04
1. Figure 4.1 Brain images of a 43-year-old man with active relapsing–remitting MS, performed on a 3 T scanner. (a) Proton density. (b) T2-FLAIR. (c) T1 without contrast. (d) T1 after injection of 0.1 mmol/kg gadobutrol. The arrows denote an enhancing lesion that was not present on the prior scan 1 month earlier. Note that the plane of section for the proton density image (a) is slightly different from that of the other images.
2. Figure 4.2 Cervical spinal cord images of a 55-year-old woman with secondary progressive MS, performed on a 3 T scanner. (a) Sagittal T2. (b) Sagittal STIR. (c) Sagittal T1. (d) Axial T2* at the C1–C2 disk level. The arrows denote a lesion in the right lateral column on all images.
3. Figure 4.3 Brain images of a 51-year-old woman with active relapsing–remitting MS, performed on a 3 T scanner. (a) T2-FLAIR. (b) T1 after injection of 0.1 mmol/kg gadopentetate dimeglumine. Note the presence of four enhancing lesions, one of which is denoted by an arrow. (c) T2-FLAIR after contrast injection. Enhancing lesions are brighter than their nonenhancing counterparts. (d) MTR. Both enhancing and nonenhancing lesions are hypointense, probably due to a combination of demyelination and increased water content (edema).
4. Figure 4.4 Brain images of a 64-year-old woman with primary progressive MS, performed on a 3 T scanner. (a) T2-FLAIR after injection of 0.1 mmol/kg gadobutrol showing an enhancing periventricular lesion. (b) T2* (susceptibility) image showing the presence of a vein (arrow) within the lesion. (c) Mean diffusivity map showing facilitated diffusion of water within the enhancing lesion. (d) Relative cerebral blood volume map showing elevated perfusion within the enhancing lesion.
Chapter 05
1. Figure 5.1 MS: Pathology versus clinical course of the disease.
Chapter 06
1. Figure 6.1 Approach to treatment of progressive MS.
Chapter 07
1. Figure 7.1 ARR in the year before pregnancy, during pregnancy, and in the 2 years after delivery among 227 women with MS (vertical bars represent means and 95% confidence intervals).
Chapter 08
1. Figure 8.1 MRI in ADEM. (a) Axial FLAIR image showing bilateral cerebellar and brainstem lesions with patchy, indistinct borders. (b) Axial FLAIR image showing left thalamic and occipital lesions. (c) Axial FLAIR image showing large hyperintense lesions that are patchy and without periventricular predominance.
2. Figure 8.2 MRI in pediatric MS. (a) Axial FLAIR image with distinct, small brainstem hyperintense lesions. (b) Axial FLAIR image with numerous hyperintense lesions that have a periventricular predominance and distinct borders. (c) Axial T1 contrast-enhanced image showing a small left juxtacortical contrast-enhancing lesion. (d) Axial T1 imaging with several periventricular T1 hypointense lesions (black holes) that correlate with image (b).
3. Figure 8.3 Treatment algorithm.
Chapter 10
1. Figure 10.1 Algorithm for management of bladder symptoms in MS. ISC, intermittent straight catheterization.
2. Figure 10.2 Algorithm for management of TN in MS.
3. Figure 10.3 Abnormal gait.
Chapter 11
1. Figure 11.1 Algorithm for the treatment of fatigue.
Chapter 12
1. Figure 12.1 Common gait abnormalities in MS patients. (a) Foot slap due to mild ADF weakness, (b) knee instability with buckling leading to a fall, (c) Trendelenburg (compensated on the right) finding secondary to hip abduction weakness, and (d) steppage gait with moderate to severe ADF weakness. Each abnormality is aligned with its corresponding phase of the gait cycle.
2. Figure 12.2 AFOs. (a) Posterior leaf spring, (b) double metal upright, (c) ground reaction force, and (d) carbon fiber AFOs.
3. Figure 12.3 ADs for ambulation. (a) Single-point canes, (b) quad cane, (c) forearm crutches, (d) axillary crutches, (e) four-point folding walker, (f) front-wheeled walker, (g) four-wheeled walker with seat and active braking system, and (h) four-wheeled walker with seat and passive braking system (U-Step walker).
Chapter 13
1. Figure 13.1 Time phases of MS.
Chapter 14
1. Figure 14.1 Categorization of CNS demyelinating conditions based on temporal course and lesion distribution.
2. Figure 14.2 Recommended diagnostic pathway for myelopathic patients.
3. Figure 14.3 FLAIR MRI sequence from a pediatric patient with ADEM.
Chapter 15
1. Figure 15.1 Sagittal spinal cord MRI T2-weighted sequence of an NMO patient with acute myelitis. A longitudinally extensive thoracic lesion is present.
2. Figure 15.2 Coronal brain MRI T1-weighted sequence after gadolinium administration of an NMO patient with acute bilateral ON. Swelling and gadolinium enhancement of the optic nerves and optic chiasm is visible.
Chapter 16
1. Figure 16.1 Algorithm for diagnosis of neurosarcoidosis.
2. Figure 16.2 FLAIR MRI of a patient initially diagnosed as MS with a history of steroid-responsive optic neuritis in 1989 followed 2 years later by a right internuclear ophthalmoplegia. The patient developed biopsy-proven pulmonary sarcoidosis 6 years after her optic neuritis and stopped beta-interferons at that time due to a strong suspicion of NS. The patient was then followed long term for a total of 19 years from onset without further relapse or change in MRI.
Chapter 17
1. Figure 17.1 The distribution of pareses.
2. Figure 17.2 Antibody responses to the I. dammini spirochete in 41 serial serum samples from 12 patients with different clinical manifestations of Lyme disease, as compared with the responses found in 40 control subjects, determined by ELISA. Antibody titers were determined by serial dilutions of each serum (left), and antibody responses, shown in units, were calculated from a single dilution compared with a standard curve (right). The horizontal bar indicates the geometric mean response for each group, and the shaded areas indicate the range of responses generally observed in controls. Arth = arthritis, mono = infectious mononucleosis.
Chapter 18
1. Figure 18.1 (a–d) Flair MR images of a patient with intra-axial NBS showing a brainstem lesion involving the dorsal pons and midbrain and extending to the diencephalic–basal ganglia region on the left.
2. Figure 18.2 T1W images with gadolinium of the same patient showing sparse enhancement in the lesion.
3. Figure 18.3 (Experience-based) Treatment algorithm for intra-axial neuro-Behçet disease.MP: methylprednisolone; IVMP, intravenous methylprednisolone.

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Library of Congress Cataloging-in-Publication Data

Multiple sclerosis and CNS inflammatory disorders / edited by Lawrence M. Samkoff, Andrew D. Goodman.
p. ; cm.
Includes bibliographical references and index.

ISBN 978-0-470-67388-1 (pbk.)
I. Samkoff, Lawrence M., 1958– editor. II. Goodman, Andrew D., 1952– editor.
[DNLM: 1. Multiple Sclerosis. 2. Central Nervous System Diseases–immunology. 3. Neurogenic Inflammation–physiopathology. WL 360]
RC377
616.8′34–dc23
2014007073

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

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Cover design by Sarah Dickinson Design

Contributors

Brenda Banwell MD
Department of Pediatrics (Neurology)
The Hospital for Sick Children
Toronto, Ontario, Canada

Allen C. Bowling MD
Colorado Neurological Institute
Englewood, CO, USA

Leigh E. Charvet PhD
Department of Neurology
Stony Brook Medicine
Stony Brook, NY, USA

Jeffrey A. Cohen MD
Mellen Center for Multiple Sclerosis Treatment and Research
Neurological Institute, Cleveland Clinic
Cleveland, OH, USA

Anne H. Cross MD
Department of Neurology
Washington University School of Medicine
St Louis, MO, USA

Mark Freedman MSc, MD, FAAN, FRCP(C)
Multiple Sclerosis Research Unit
University of Ottawa
Ottawa, Ontario, Canada

María I. Gaitán MD
National Institute of Neurological Disorders and Stroke
National Institutes of Health
Bethesda, MD, USA
and
Dr. Raúl Carrea Institute for Neurological Research
FLENI, Buenos Aires, Argentina

Barbara Giesser MD
Department of Neurology, MS Division
UCLA School of Medicine
Los Angeles, CA, USA

Andrew D. Goodman MD
Neuroimmunology Unit
Department of Neurology
University of Rochester School of Medicine and Dentistry
Rochester, NY, USA

Benjamin M. Greenberg MD, MHS
Department of Neurology and Neurotherapeutics
and
Department of Pediatrics
University of Texas Southwestern
Dallas, TX, USA

Megan H. Hyland MD
Neuroimmunology Unit
Department of Neurology
University of Rochester School of Medicine and Dentistry
Rochester, NY, USA

Mohsen Khoshnam MD
Multiple Sclerosis Research Unit
University of Ottawa
Ottawa, Ontario, Canada

Benzi Kluzer MD
Department of Neurology
University of Colorado
Denver, CO, USA

George H. Kraft MD, MS
Department of Rehabilitation Medicine
and Neurology
Institute for Stem Cell and Regenerative Medicine
University of Washington
Seattle, WA, USA

Lauren B. Krupp MD
Department of Neurology
Stony Brook Medicine
Stony Brook, NY, USA

Eric Logigian MD
Department of Neurology
University of Rochester Medical Center
Rochester, NY, USA

Marcelo Matiello MD, MSc
Department of Neurology
Massachusetts General Hospital and Brigham and Women’s Hospital
Harvard Medical School
Boston, MA, USA

Nesanet S. Mitiku MD, PhD
Departments of Rehabilitation Medicine and Neurology
and
Corinne Goldsmith Dickinson Center for Multiple Sclerosis
Icahn School of Medicine at Mount Sinai
New York, NY, USA

Callene Momtazee MD
Department of Neurology, MS Division
UCLA School of Medicine
Los Angeles, CA, USA

Ellen M. Mowry MD, MCR
Department of Neurology
Johns Hopkins University
Baltimore, MD, USA

Paul O’Connor MD
Division of Neurology
Institute of Medical Science
and
St Michael's Hospital
University of Toronto
Toronto, Ontario, Canada

Erica Patrick MD
Department of Neurology
University of Rochester Medical Center
Rochester, NY, USA

Laura Piccio MD, PhD
Department of Neurology
Washington University School of Medicine
St Louis, MO, USA

Daniel S. Reich MD, PhD
National Institute of Neurological
Disorders and Stroke
National Institutes of Health
Bethesda, MD, USA

David J. Rintell EdD
Partners Multiple Sclerosis Center
Brigham and Women’s Hospital
and
Partners Pediatric MS Center
Massachusetts General Hospital
Harvard Medical School
Boston, MA, USA

Jessica Robb MD
Neuroimmunology Unit
Department of Neurology
University of Rochester School
of Medicine and Dentistry
Rochester, NY, USA

Dalia Rotstein MD
Division of Neurology Institute of Medical Science
and
St Michael’s Hospital University of Toronto
Toronto, Ontario, Canada

Sabahattin Saip MD
Department of Neurology
Cerrahpaşa School of Medicine
Istanbul University
Cerrahpaşa, Turkey

Lawrence M. Samkoff MD
Neuroimmunology Unit
Department of Neurology
University of Rochester School of Medicine and Dentistry
Rochester, NY, USA

Alexius E. G. Sandoval MD
Maine Rehabilitation Outpatient Center
Bangor, ME, USA

Thomas F. Scott MD
Department of Neurology
Drexel University College of Medicine
and
Allegheny MS Treatment Center
Pittsburgh, PA, USA

Aksel Siva MD
Department of Neurology
Cerrahpaşa School of Medicine
Istanbul University
Cerrahpaşa, Turkey

Sonya U. Steele MSc
Department of Neurology
Johns Hopkins University
Baltimore, MD, USA

Robert Thompson Stone MD
Department of Neurology
University of Rochester Medical Center
Rochester, NY, USA

Brian G. Weinshenker MD, FRCP(C)
Department of Neurology
Mayo Clinic
Rochester, MN, USA