Multiple Sclerosis and Other Cns in Ammatory Diseases: Guest Editor: Dean M. Wingerchuk, MD, MSC, FRCPC, Faan

JUNE 2019
VOL. 25 NO. 3 Multiple Sclerosis and

Other CNS Inflammatory
Diseases
Guest Editor: Dean M. Wingerchuk, MD, MSc, FRCPC, FAAN
594 Editor’s Preface

Editor-in-Chief: Steven L. Lewis, MD, FAAN
REVIEW ARTICLES
596 Multiple Sclerosis Risk Factors and Pathogenesis

Bardia Nourbakhsh, MD, MAS; Ellen M. Mowry, MD, MCR, FAAN, FANA
611 Diagnosis, Differential Diagnosis, and Misdiagnosis

of Multiple Sclerosis
Andrew J. Solomon, MD
636 Phases and Phenotypes of Multiple Sclerosis

Orhun H. Kantarci, MD
655 Management of Multiple Sclerosis Relapses

Pavle Repovic, MD, PhD
670 Clinically Isolated Syndrome and Early Relapsing

Multiple Sclerosis
Luanne M. Metz, MD, FRCPC
689 Highly Aggressive Multiple Sclerosis

DENOTES CONTINUUM James D. Bowen, MD
AUDIO INTERVIEW
715 Monitoring, Switching, and Stopping Multiple Sclerosis
Disease-Modifying Therapies
Robert H. Gross, MD; John R. Corboy, MD, FAAN
736 Progressive Multiple Sclerosis

Daniel Ontaneda, MD
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

753 Management of Multiple Sclerosis Symptoms and Comorbidities
W. Oliver Tobin, MBBCh, BAO, PhD
773 Pregnancy and Family Planning in Multiple Sclerosis

Annette M. Langer-Gould, MD, PhD
793 Pediatric Central Nervous System Demyelinating Diseases

Tanuja Chitnis, MD, FAAN
815 Neuromyelitis Optica Spectrum Disorder and Other Non–Multiple

Sclerosis Central Nervous System Inflammatory Diseases
Eoin P. Flanagan, MBBCh
PRACTICE ISSUES
845 Incorporating Clinical Practice Guidelines and Quality Measures

Into High-Quality Cost-Effective Care for Patients With
Multiple Sclerosis
Alexander D. Rae-Grant, MD, FRCPC, FAAN
SELF-ASSESSMENT AND CME
586 Learning Objectives and Core Competencies
851 Instructions for Completing Postreading Self-Assessment and CME

Test and Tally Sheet
853 Postreading Self-Assessment and CME Test
867 Postreading Self-Assessment and CME Test—Preferred Responses
878 Erratum
879 Index
List of Abbreviations (Back Cover)

CONTRIBUTORS
Dean M. Wingerchuk, MD, MSc, Tanuja Chitnis, MD, FAAN

FRCPC, FAAN Professor of Neurology,
Guest Editor Harvard Medical School;
Professor and Chair, Department Senior Neurologist, Brigham
of Neurology, Mayo Clinic, and Women’s Hospital and
Phoenix/Scottsdale, Arizona Massachusetts General Hospital;
Director, Partners Pediatric
Relationship Disclosure: Dr Wingerchuk
serves as co–editor-in-chief of The Multiple Sclerosis Center,
Neurologist; as a consultant for Alexion, MassGeneral Hospital for
Celgene Corporation, and Novartis AG;
and as an adjudication committee member
Children; Director, Translational
for MedImmune. Dr Wingerchuk receives Neuroimmunology Research
research/grant support from Alexion Center, Brigham and Women’s
and Terumo BCT, Inc.
Hospital, Boston, Massachusetts
Unlabeled Use of Products/Investigational
Relationship Disclosure: Dr Chitnis serves
Use Disclosure: Dr Wingerchuk reports
on scientific advisory boards for Biogen,
no disclosure.
Celgene Corporation, F. Hoffmann-La Roche
Ltd, Novartis AG, and Sanofi Genzyme
and as a consultant for Biogen. Dr Chitnis
receives research/grant support from the
James D. Bowen, MD Consortium of Multiple Sclerosis Centers;
Medical Director, Multiple the Department of Defense; EMD Serono, Inc;
Sclerosis Center, Swedish the Guthy-Jackson Charitable Foundation;
Mallinckrodt Pharmaceuticals; the National
Neuroscience Institute; Clinical Institutes of Health; the National Multiple
Associate Professor, Neurology, Sclerosis Society; Novartis AG; Octave
University of Washington, Bioscience; and Verily Life Sciences LLC.
Seattle, Washington Unlabeled Use of Products/Investigation

Use Disclosure: Dr Chitnis discusses the
Relationship Disclosure: Dr Bowen has unlabeled/investigational use of glatiramer
served as a consultant for Biogen; Celgene acetate, interferon beta, natalizumab, and
Corporation; EMD Serono, Inc; Genentech, Inc; rituximab for pediatric multiple sclerosis
and Novartis AG and has received personal and mycophenolate mofetil for myelin
compensation for speaking engagements oligodendrocyte glycoprotein antibody–
from Biogen; EMD Serono, Inc; Genentech, Inc; associated disorders and neuromyelitis
and Novartis AG. Dr Bowen receives optica spectrum disorder in children.
research/grant support from Alexion;
Alkermes; Biogen; Celgene Corporation;
Genentech, Inc; the National Institute of
Allergy and Infectious Diseases (UM1AI110557);
the National Institutes of Health /National
Institute on Aging (U01AG006781); the National
Institutes of Health/National Institute
of Allergy and Infectious Diseases (N01AI15416);
the National Institute of Neurological
Disorders and Stroke (U10NS077309);
and Sanofi Genzyme.

Use Disclosure: Dr Bowen discusses
the unlabeled/investigational use of
cyclophosphamide, high-dose
immunosuppressive therapy with stem
cell transplantation, and rituximab for the
treatment of highly aggressive
multiple sclerosis.
588 JUNE 2019

John R. Corboy, MD, FAAN Robert H. Gross, MD
Professor, Neurology Codirector, Assistant Professor of
Rocky Mountain Multiple Neurology, University of
Sclerosis Center at University Colorado Anschutz Medical
of Colorado, University of Campus, Aurora, Colorado
Colorado School of Medicine,
Relationship Disclosure: Dr Gross reports no
Aurora, Colorado disclosure.
Relationship Disclosure: Dr Corboy serves Unlabeled Use of Products/Investigational

as editor of Neurology Clinical Practice, as a Use Disclosure: Dr Gross discusses
consultant for a legal matter for Mylan NV, the unlabeled/investigational use of
and on the research steering committee cyclophosphamide and rituximab for the
for Novartis AG. Dr Corboy has received treatment of multiple sclerosis.
personal compensation for speaking
engagements from PRIME Education, LLC,
and the Rocky Mountain Multiple Sclerosis
Center and receives research/grant
support from MedDay Pharmaceuticals, the
National Multiple Sclerosis Society, Novartis Associate Professor of
AG, and the Patient-Centered Outcomes Neurology, Mayo Clinic College
Research Institute. Dr Corboy has served as
a consultant on medicolegal proceedings for
of Medicine and Science,
medical malpractice. Rochester, Minnesota
Unlabeled Use of Products/Investigational Relationship Disclosure: Dr Kantarci serves
Use Disclosure: Dr Corboy discusses as a reviewer for Neurology and receives
the unlabeled/investigational use of research/grant support from Biogen.
cyclophosphamide and rituximab for the
treatment of multiple sclerosis. Unlabeled Use of Products/Investigational
Use Disclosure: Dr Kantarci reports no
disclosure.

Consultant in Neurology Annette M. Langer-Gould, MD,
and Laboratory Medicine PhD
and Pathology; Associate Regional Lead for Clinical and
Professor of Neurology, Mayo Translational Neuroscience,
Clinic College of Medicine and Kaiser Permanente/Southern
Science, Rochester, Minnesota California Permanente Medical
Relationship Disclosure: Dr Flanagan Group, Pasadena, California
receives research/grant support from
MedImmune/Viela Bio. Relationship Disclosure: Dr Langer-Gould
receives research/grant support from the
Unlabeled Use of Products/Investigational National Multiple Sclerosis Society and
Use Disclosure: Dr Flanagan discusses the Patient-Centered Outcomes Research
the unlabeled/investigational use of Institute and has provided expert legal
azathioprine, cetirizine, corticosteroids, testimony regarding vaccination.
eculizumab, inebilizumab, IV immunoglobulin,
methotrexate, mycophenolate mofetil, Unlabeled Use of Products/Investigational
plasma exchange, rituximab, SA237, Use Disclosure: Dr Langer-Gould discusses
sivelestat, and tocilizumab for the treatment the unlabeled/investigational use
of neuromyelitis optica spectrum disorder of corticosteroids and plasma exchange
and other non–multiple sclerosis central to treat multiple sclerosis relapse during
nervous system inflammatory diseases. pregnancy, gabapentin to treat neuropathic
pain, natalizumab to treat multiple sclerosis
during pregnancy, and rituximab to treat
multiple sclerosis.
C O N T I N U U M J O U R N A L .C O M 589

CONTRIBUTORS (CONTINUED)
Luanne M. Metz, MD, FRCPC Bardia Nourbakhsh, MD, MAS

Professor, Department Assistant Professor
of Clinical Neurosciences, of Neurology, Johns Hopkins
Cumming School of Medicine, University, Baltimore, Maryland
University of Calgary; Coleader,
Relationship Disclosure: Dr Nourbakhsh has
Multiple Sclerosis Program, served on a scientific advisory board for
Hotchkiss Brain Institute, Jazz Pharmaceuticals Inc and has received
research/grant support from the National
Calgary Alberta, Canada Multiple Sclerosis Society and the Patient-
Centered Outcomes Research Institute.
Relationship Disclosure: Dr Metz receives
research/grant support from Alberta
Innovates Health Solutions (201300669) and
Use Disclosure: Dr Nourbakhsh reports
the Multiple Sclerosis Society of Canada.
no disclosure.
Use Disclosure: Dr Metz was the principal
investigator on a phase 3 study on the use Daniel Ontaneda, MD
of minocycline for the treatment of clinically
isolated syndrome. Assistant Professor of
Medicine/Neurology,
Cleveland Clinic Lerner College
Ellen M. Mowry, MD, MCR, of Medicine of Case Western
FAAN, FANA Reserve University; Staff
Associate Professor of Neurologist, Cleveland Clinic,
Neurology and Epidemiology, Mellen Center for Multiple
Johns Hopkins University, Sclerosis Treatment and
Baltimore, Maryland Research, Cleveland, Ohio
Relationship Disclosure: Dr Mowry serves as Relationship Disclosure: Dr Ontaneda

an editor for Frontiers in Neuroepidemiology, serves as a consultant for Biogen;
ISRN Neuroscience, and Neuroscience Genentech, Inc; and Sanofi Genzyme
Journal. Dr Mowry receives research/grant and receives research/grant support from
support from Biogen, the Department Genentech, Inc; the National Institutes
of Defense, the National Multiple of Health; the National Multiple Sclerosis
Sclerosis Society, Sanofi Genzyme, and Society; Novartis AG; the Patient-Centered
Sun Pharmaceuticals Industries Ltd and Outcomes Research Institute; Race to Erase;
publishing royalties from UpToDate, Inc. and Sanofi Genzyme.
Unlabeled Use of Products/Investigational Unlabeled Use of Products/Investigational

Use Disclosure: Dr Mowry reports Use Disclosure: Dr Ontaneda discusses
no disclosure. clinical trial results for biotin, fingolimod,
ibudilast, mycophenolate mofetil,
natalizumab, and rituximab for the treatment
of progressive multiple sclerosis.
590 JUNE 2019

Alexander D. Rae-Grant, MD, Andrew J. Solomon, MD
FRCPC, FAAN Associate Professor of
Professor of Neurology, Neurological Sciences; Division
Cleveland Clinic Lerner College Chief, Multiple Sclerosis,
of Medicine of Case Western Larner College of Medicine
Reserve University; Staff at The University of Vermont,
Neurologist, Cleveland Clinic, Burlington, Vermont
Cleveland, Ohio
Relationship Disclosure: Dr Solomon has
served as a consultant for Biogen and EMD
Relationship Disclosure: Dr Rae-Grant serves
Serono, Inc, and has received research/grant
as deputy editor for DynamedPlus.
support from Biogen and personal
compensation for speaking engagements
from Med Learning Group, the National
Use Disclosure: Dr Rae-Grant reports
Multiple Sclerosis Society, and RMEI
no disclosure.
Medical Education.

Use Disclosure: Dr Solomon reports no
Pavle Repovic, MD, PhD disclosure.
Medical Director for Neurology
Research, Multiple Sclerosis
Center, Swedish Neuroscience W. Oliver Tobin, MBBCh,
Institute, Seattle, Washington BAO, PhD
Relationship Disclosure: Dr Repovic has Consultant, Division of Multiple
served as a consultant for Biogen; EMD Sclerosis; Assistant Professor
Serono, Inc; Genentech, Inc; Sanofi
Genzyme; and Teva Pharmaceutical
of Neurology, Mayo Clinic
Industries Ltd and has received personal College of Medicine and
compensation for speaking engagements Science, Rochester, Minnesota
from Biogen; EMD Serono, Inc; Genentech,
Inc; and Teva Pharmaceutical Industries Ltd. Relationship Disclosure: Dr Tobin receives
Dr Repovic receives research/grant support research/grant support from Mallinckrodt
from Alexion, the National Institutes Pharmaceuticals .
of Health (5U10NS077309), Novartis AG,
and Genentech, Inc. Unlabeled Use of Products/Investigational
Use Disclosure: Dr Tobin discusses the
Unlabeled Use of Products/Investigational unlabeled/investigational use of amantadine,
Use Disclosure: Dr Repovic reports armodafinil, and modafinil for fatigue;
no disclosure. lacosamide, lamotrigine, and oxcarbazepine
for paroxysmal symptoms; gabapentin
for restless legs syndrome and spasticity;
and nabiximols, oral cannabis extract,
and synthetic tetrahydrocannabinol for the
treatment of spasticity.

CONTRIBUTORS (CONTINUED)
Self-Assessment and CME Test Writers
D. Joanne Lynn, MD, FAAN Allison L. Weathers, MD, FAAN

Associate Dean for Student Associate Chief Medical
Life, Clinical Professor of Information Officer, Cleveland
Neurology, The Ohio State Clinic; Assistant Professor,
University College of Medicine, Cleveland Clinic Lerner College
Columbus, Ohio of Medicine, Cleveland, Ohio
Relationship Disclosure: Dr Lynn receives Relationship Disclosure: Dr Weathers serves
book royalties from Lippincott Williams on the editorial board of Continuum and as
& Wilkins and holds stock in Abbott chair of the adult neurosciences specialty
Laboratories; AbbVie Inc; Amgen Inc; steering board for Epic.
Bristol-Myers Squibb Company; CVS Health
Corporation; Express Scripts Holding Unlabeled Use of Products/Investigational
Company; General Electric; Merck & Co, Inc; Use Disclosure: Dr Weathers reports no
and Zimmer Biomet. disclosure.

Use Disclosure: Dr Lynn reports no disclosure.
592 JUNE 2019

EDITOR’S PREFACE
OMG: MS, NMOSD, and MOG

This issue of Continuum is devoted to the diagnosis and management
of our patients with multiple sclerosis (MS) and other central
nervous system (CNS) demyelinating and inflammatory disorders,
including neuromyelitis optica spectrum disorders (NMOSDs) and
the evolving clinical entity of myelin oligodendrocyte glycoprotein
(MOG)–antibody-mediated demyelinating syndromes. My sincere thanks go to
Dr Dean M. Wingerchuk for enthusiastically accepting my invitation to be guest
editor of this issue and for enlisting a team of experts in the field to help keep us
informed of the state of the art of the diagnosis and care of our patients with
these disorders.
The issue begins with the article by Drs Bardia Dr Annette M. Langer-Gould reviews the many
Nourbakhsh and Ellen M. Mowry, who inform us issues that arise regarding pregnancy and family
about the current thinking on the pathogenesis and planning in MS, a complicated topic especially given
risk factors for MS. Next, Dr Andrew J. Solomon the varied current therapeutic options with differing
provides us with an up-to-date review of the risks. Dr Tanuja Chitnis next provides a detailed
diagnosis and differential diagnosis of MS not only review of the issues involved in diagnosis and
to inform our most accurate diagnosis of patients management of the diverse spectrum of disorders
with the disease but to decrease the likelihood of that can be seen in pediatric patients that parallel the
misdiagnosis of MS in patients without the disorder. (MS and non-MS) demyelinating and inflammatory
Dr Orhun H. Kantarci next provides his analysis of disorders seen in adults. In the final review article of
the phases and phenotypes of MS to inform our the issue, Dr Eoin P. Flanagan provides an up-to-date
conception of the disease and its courses. summary of the evolving story of the non-MS CNS
The next articles in this issue relate primarily to inflammatory and demyelinating diseases, including
the management of patients with MS. First, Dr Pavle NMOSD, MOG-IgG disease, and many others.
Repovic provides a detailed review of the current In this issue’s Practice article, Dr Alexander D.
management of MS relapses. Dr Luanne M. Metz Rae-Grant provides a case discussion to describe how
next describes the management of patients with to incorporate clinical practice guidelines and quality
clinically isolated syndrome and early relapsing MS. measures into high-quality cost-effective care for
Dr James D. Bowen then reviews the management of patients with MS.
patients with highly aggressive MS. Drs Robert H. After reading the issue and taking the Postreading
Gross and John R. Corboy discuss the many issues we Self-Assessment and CME Test written by Drs D.
need to be aware of with regard to monitoring, Joanne Lynn and Allison L. Weathers, you may
switching, and stopping MS disease-modifying earn up to 20 AMA PRA Category 1 CreditsTM
therapies. Dr Daniel Ontaneda then discusses clinical toward self-assessment and CME or, for Canadian
features and current therapeutic options for our participants, a maximum of 20 hours toward the
patients with progressive MS. Finally, Dr W. Oliver Self-Assessment Program (Section 3) of the
Tobin discusses the symptomatic management of MS Maintenance of Certification Program of the Royal
as well as its comorbidities. College of Physicians and Surgeons of Canada.
594 JUNE 2019

Additional credit can be obtained by listening to important role in addition to his ongoing role as
Continuum Audio interviews associated with this and Associate Editor of Self-Assessment and CME,
other Continuum issues, available to all subscribers, in which he oversees the SA-CME activities
and completing tests on the Continuum Audio web for Continuum.
platform or app. Continuum Audio is also accredited I would like to thank Dr Wingerchuk for his
by the Royal College of Physicians and Surgeons of expert guest editorship of this multifaceted and
Canada. remarkable issue from its inception, his collaboration
With this issue, I also would like to congratulate in choices of article concepts and titles, his enlisting
Dr Joseph Safdieh, who has graciously accepted my of expert authors, his patience and thoughtfulness in
invitation to take on the overall Associate Editor the many revisions of the title of the issue itself, his
duties for Continuum; he will be performing this skillful review of the detailed content, and his
exceptional responsiveness throughout the process.
The information presented in this issue should be of
great benefit to each of us as we diagnose and manage
My sincere thanks go to Dr Dean M. (and avoid misdiagnosis of) the many patients who
Wingerchuk for enthusiastically present to us with any disorders within the evolving
and awe-inspiring spectrum of demyelinating and
accepting my invitation to be guest
inflammatory disorders of the CNS.
editor of this issue and for enlisting a
team of experts in the field to help
keep us all informed of the state of —STEVEN L. LEWIS, MD, FAAN
EDITOR-IN-CHIEF
the art of the diagnosis and care of
our patients with these disorders. © 2019 American Academy of Neurology.
CONTINUUMJOURNAL.COM 595

REVIEW ARTICLE

Multiple Sclerosis Risk
C O N T I N UU M A UD I O
I NT E R V I E W A V AI L A B L E
ONLINE
Factors and Pathogenesis
By Bardia Nourbakhsh, MD, MAS; Ellen M. Mowry, MD, MCR, FAAN, FANA
ABSTRACT
PURPOSE OF REVIEW: This article summarizes recent advances in the
identification of genetic and environmental factors that affect the risk of
developing multiple sclerosis (MS) and the pathogenic processes involved
in acute relapses and relapse-independent disability progression.
RECENT FINDINGS: The number of single-nucleotide polymorphisms associated

with increased risk of MS has increased to more than 200 variants. The
evidence for the association of Epstein-Barr virus infection, vitamin D
deficiency, obesity, and smoking with increased risk of MS has further
CITE AS: accumulated, and, in cases of obesity and vitamin D deficiency, the evidence
CONTINUUM (MINNEAP MINN) for causal association has strengthened. Interactions between genetic and
2019;25(3, MULTIPLE SCLEROSIS
AND OTHER CNS INFLAMMATORY
environmental factors have been studied more extensively. Dietary factors
DISEASES):596–610. and changes in the gut microbiota are emerging as possible modulators of the
disease risk. Several processes important to MS pathogenesis have been
Address correspondence to
newly investigated or investigated more comprehensively, including the role
Bardia Nourbakhsh, 600 N Wolfe
St, Pathology 627, Baltimore, MD of B cells, innate immune cells, meningeal inflammation, cortical and gray
21287, bnourba1@jhmi.edu. matter demyelination, and early axonal and neuronal loss.
RELATIONSHIP DISCLOSURE:
Dr Nourbakhsh has served on a SUMMARY: MS is a complex disease in which the interaction between genetic
scientific advisory board for and environmental factors causes a cascade of events, including activation
Jazz Pharmaceuticals Inc and
has received research/grant of the adaptive and innate immune system, blood-brain barrier
support from the National breakdown, central nervous system demyelination, and axonal and
Multiple Sclerosis Society and neuronal damage with variable degrees of repair. These events manifest as
the Patient-Centered Outcomes
Research Institute. Dr Mowry potentially reversible focal neurologic symptoms or progressive
serves as an editor for Frontiers nonremitting physical and cognitive disability, or both. Advances in the
in Neuroepidemiology, ISRN
Neuroscience, and Neuroscience
understanding of the risk factors and pathogenic mechanisms of MS have
Journal. Dr Mowry receives resulted in improved therapeutic strategies. The results of ongoing or
research/grant support from future studies are needed to successfully and fully translate these
Biogen, the Department of
Defense, the National Multiple
advances into clinical practice.
Sclerosis Society, Sanofi
Genzyme, and Sun Pharmaceuticals
Industries Ltd and publishing
royalties from UpToDate, Inc.
UNLABELED USE OF INTRODUCTION
M
PRODUCTS/INVESTIGATIONAL ultiple sclerosis (MS) is a chronic disease characterized by
USE DISCLOSURE:
inflammation and demyelination of the central nervous system
Drs Nourbakhsh and Mowry
report no disclosures. (CNS) associated with variable degrees of axonal and neuronal
damage. It usually presents with recurrent, subacute, focal
© 2019 American Academy
neurologic symptoms and signs that improve (at least to some
of Neurology. extent) over several weeks or months. The disease may initially present with (less
596 JUNE 2019

often) or evolve into (more common) a relentless progressive decline of KEY POINT
neurologic functioning, commonly affecting locomotion, bladder function,
● Unlike several other
and cognition.1 common neurologic
Although there is no doubt that immune mechanisms and inflammation are diseases (such as Alzheimer
pivotal to the pathogenesis of MS,2 it is still debated whether the inflammation is disease, Parkinson disease,
the initial event in the cascade of pathophysiologic events or is a secondary and amyotrophic lateral
sclerosis), no mendelian
response to a yet-unknown infectious agent or intrinsic/primary CNS
form of multiple sclerosis
degeneration. Although MS does not have some of the characteristics typical of has thus far been reported.
autoimmune disease,2,3 most MS investigators believe that self-reactive immune
cells gaining access to and attacking components of the myelin sheath in the CNS
is the primary pathogenic event. A breakdown in immune tolerance is posited
to result in the persistence of autoreactive lymphocytes. However, it is less clear
how these cells become activated, proliferate, access the CNS, and orchestrate
the pathologic events that lead to neurologic dysfunction. A complex interaction
among genetic and environmental factors and stochastic events affects not only
the probability of these pathogenic events but also the strength of the CNS repair
mechanisms, functional plasticity, and physical and cognitive reserve. These
factors all affect the probability of a person becoming symptomatic from the
inflammatory demyelination and thus being diagnosed with MS.
Unlike several other common neurologic diseases (such as Alzheimer disease,
Parkinson disease, and amyotrophic lateral sclerosis), no undisputed mendelian
form of MS has thus far been reported.4,5 Also, despite decades of research to
evaluate infectious agents as the cause of MS, no single pathogen has been
determined to be necessary for the development of MS. Data from preclinical
and observational studies (including cohort and case-control studies) have
resulted in the discovery of associations between many genetic loci and several
environmental factors with the risk of developing MS. However, demonstrating
causality of these associations is more difficult, particularly because performing
experimental (interventional) studies in healthy humans is extremely difficult/
infeasible, costly, or unethical. Also, because, in most patients, MS has a long
subclinical period (as evidenced by the presence of silent lesions on MRI at the
time of clinical onset and subtle deficits on clinical testing years before the onset
of symptoms),6 the specific environmental factors that predisposed a given
person to developing MS were probably present many years before the clinical
onset. This makes identifying these factors more difficult. Despite these hurdles,
identifying environmental and genetic risk factors provides mechanistic insights
that can be examined as putative complementary treatments for MS. Discovering
modifiable risk factors also allows for consideration of studies or interventions
related to disease prevention.
OVERVIEW OF MULTIPLE SCLEROSIS PATHOGENESIS

MS, like many other chronic neurologic diseases, has a complex etiopathogenesis.
Both genetic susceptibility and environmental exposures have been
incriminated.7 The concordance rate of MS for northern European monozygotic
twins (with close to 100% genetic similarity) is only 20% to 30%.8 Although
much higher than the risk of MS in the general population (only 0.1% to 0.2% in
northern Europeans), suggesting strong evidence for high degree of heritability
of the disease, this provides evidence that environmental exposures or
nonmendelian genetics must play an important role in MS pathogenesis. Some
experts have proposed that MS develops in a genetically susceptible individual

MS RISK FACTORS AND PATHOGENESIS
who experiences a “sufficient set” of environmental factors. This “sufficient

set” can be different for persons with different genetic backgrounds,9 and even
the constituents of the set may differ from one person to the next. Early life
events in the presence of this predisposing genotype and the interaction of some
of these environmental and genetic factors are hypothesized to result in
defective immune tolerance, with persistence and activation of autoreactive
adaptive immune cells that access the CNS and set off pathologic events that
result in demyelination, axonal and neuronal damage, and gliosis. Over time,
incomplete repair, activation of innate immunity in the CNS, oxidative damage,
abnormal energy metabolism, and possibly the development of lymphoid
follicle–like structures in the meninges are thought to propagate the injury and
exhaust the compensatory mechanisms, resulting in relentless neurologic
worsening.10
No single autoantigen, autoantibody, or infectious agent has thus far been
unequivocally associated with MS. However, as many MS susceptibility genes are
shared by other autoimmune disorders and as immunosuppressive therapies
modify the disease course, most researchers consider MS a primary
organ-specific autoimmune disease. An increased risk of several autoimmune
diseases (including autoimmune thyroid disease, inflammatory bowel disease,
and psoriasis) also exists in patients with MS.11
Autoreactive lymphocytes that gain access to the CNS start a pathogenic
cascade that culminates in demyelination, neuroaxonal degeneration, synaptic
loss, dying-back oligodendrogliopathy, and, eventually, tissue loss and
astrogliosis.12 Relapses are thought to be caused by the subacute development of
inflammatory aggregates in an eloquent area of the CNS. These inflamed areas,
which are also associated with blood-brain barrier breakdown, appear as
gadolinium-enhancing lesions on MRI around the time they develop.13
Downstream immunopathologic events lead to the development of confluent
demyelinated areas in both white and gray matter, indicating the loss of
oligodendrocytes, loss of myelin sheaths, and astrocytic scars, producing the
pathologic markers of MS: demyelinated plaques.12 Demyelination in MS is not
confined to the white matter. Cortical and deep gray matter demyelination can
be detected pathologically and is present even in early stages of the disease.14
Historically, MS was thought to be a T-lymphocyte–mediated disease.
Animal models of MS had provided ample evidence for the role of T cells in the
pathogenesis of neuroinflammation.15,16 However, as clinical trials in patients
with MS demonstrated unequivocal efficacy of B-lymphocyte–depleting
antibodies in decreasing the disease activity and even some effects on slowing
disability accumulation in progressive disease,17,18 it seems that B cells also
play an important role in disease pathogenesis.19,20 The rapid response to
B-cell–depleting antibodies suggests that antigen presentation and production
of proinflammatory chemokines and cytokines by B lymphocytes (as
compared to their role in antibody production) might be more relevant to MS
pathogenesis.21
Although demyelination is the hallmark of the disease, axonal injury is
present, even from the earliest stages of MS, and appears to be an important
contributor to symptoms and disability.22,23 In mouse models of demyelination,
CD8+ T cells have been shown to damage the axons by releasing perforin and
granzyme.24 Other mechanisms underlying neuronal and axonal injury include
glutamatergic excitotoxicity,25 cytokine release,26 hypoxia, and generation of
598 JUNE 2019

reactive oxygen and nitrogen species.27,28 These events lead to calcium influx into KEY POINTS
the axons and neurons, mitochondrial dysfunction, and oxidative stress.
● No single autoantigen,
Ultimately, ion channel redistribution and energy deficiency result in cell autoantibody, or infectious
swelling, activation of degrading enzymes, and eventual apoptotic and necrotic agent has thus far been
neuronal damage.10 unequivocally associated
In progressive stages of the disease, when the acute inflammatory infiltrates with multiple sclerosis.
develop less frequently or completely cease to happen, it is not clear what drives
● Autoreactive
the progressive neurologic disability. Some argue that age-related changes in an lymphocytes that gain
already-injured brain and spinal cord underlie the progression. The more recent access to the central
discovery of meningeal lymphoid follicle–like aggregates,29 which can be imaged nervous system start a
with MRI,30 has raised the possibility that ongoing sequestered intrathecal pathogenic cascade that
culminates in demyelination,
inflammation might be a factor contributing to progression. These lymphoid neuroaxonal degeneration,
aggregates are not accessible to systemically administered anti-inflammatory and synaptic loss, dying-back
immunosuppressive therapies. Another proposed mechanism of continued oligodendrogliopathy, and,
neurodegeneration in the absence of apparent adaptive immune activity is eventually, tissue loss and
astrogliosis.
activation of CNS innate immunity, particularly microglial cells.10 The
development of effective therapies for progressive MS requires better ● Demyelination in multiple
understanding of the relative contribution of each pathogenic mechanism, an sclerosis is not confined to
understanding of when in the disease it is important to disrupt each mechanism, the white matter, and
cortical and deep gray
and the development of medications that cross the blood-brain barrier and target
matter demyelination can be
the mechanisms effectively. Alternatively, medications that protect detected pathologically
mitochondria or target ion channels or antioxidative agents may prove to be and is present even in early
beneficial in slowing the progressive stages of the disease. stages of the disease.
● Both T lymphocytes and B

GENETIC RISK FACTORS lymphocytes, as well as
Genetic contributions to MS risk were known to exist decades ago. Familial innate immune mechanisms,
clustering of the disease, with increased risk dependent on the degree of genetic participate in multiple
similarity to the proband, and higher prevalence of MS in some racial groups are sclerosis pathogenesis.
strong evidence for a genetic basis of the disease.31 Family and population data ● Although demyelination in
suggested that multiple DNA variants that are relatively frequent in the the central nervous system
population are the basis of MS heritability.32 is the hallmark of multiple
For decades, only several variants of HLA antigen were known to affect MS sclerosis, axonal injury is
present from the earliest
risk. Genes in the HLA antigen locus have the strongest effect on the risk of MS.
stages of the disease and is a
Carrying HLA-DRB1*1501 is associated with about threefold greater odds of major contributor to
developing MS, while carrying HLA-A*02 is associated with meaningfully physical and cognitive
reduced odds of developing MS.33 disability.
In the past 15 years, international collaborations for performing genome-wide
● More than 200 genetic
association studies have studied tens of thousands of MS patients and controls variants have been
and provided strong evidence for the association of approximately 200 discovered to be associated
autosomal susceptibility variants outside of the major histocompatibility with modifying the risk of
complex gene complex. In addition, one variant in chromosome X and 32 multiple sclerosis.
independent variants in the extended major histocompatibility complex region
were discovered.34 Almost all these variants are located in the noncoding regions
of the genome, and many of them are in intergenic regions. These variants are
thought to affect regulatory mechanisms and gene activity. Interestingly, many
MS-associated genetic variants are located close to the genes that regulate innate
or adaptive immunity and are shared by several other autoimmune diseases.
All these variants only explain 20% to 30% of MS heritability, suggesting the
remainder of heritability is likely related to epigenetic factors and gene-gene or
gene-environment interactions.35

ENVIRONMENTAL RISK FACTORS

Dozens of environmental factors and exposures have been reported to be
associated with the risk for developing MS. Only a few, however, have been
studied in adequately powered and less biased studies; even fewer of those
findings have been replicated consistently. This article reviews the factors with
the strongest incriminating evidence for a role in MS, including low sunlight
exposure, vitamin D deficiency, obesity, and smoking, with a focus on those that
have more recently been implicated (TABLE 1-136 and CASE 1-1).
Epstein-Barr Virus
Epstein-Barr virus (EBV) is a ubiquitous human herpesvirus. EBV seropositivity,
or the presence of antibodies indicating prior exposure to EBV, has been
consistently shown to be associated with adult- and pediatric-onset MS in people
of different races and ethnicities.37,38 In fact, almost all adult patients with MS
have serologic evidence of prior EBV infection. People with MS have higher titers
of antibodies to Epstein-Barr nuclear antigen 1 (EBNA1).39 In a nested
case-control study, all adults with MS who were initially EBNA1 antibody
negative had become antibody positive before the disease onset.40 While
childhood infection with EBV is usually asymptomatic, infection with this virus
later in life can be associated with clinical infectious mononucleosis. The risk of
MS in people with a clinical history of infectious mononucleosis is more than
twice that of the general population.41 In fact, it has been suggested that EBV
infection during adolescence or adulthood, perhaps more so than during
childhood, increases the risk of MS.42
TABLE 1-1 Environmental Risk Factors for Multiple Sclerosisa
Odds Ratio Interaction With Strength of

Risk Factor (Approximate) HLA Antigen Gene Evidence
Epstein-Barr virus 3.6 Yes +++

seropositivity
Adolescent obesity 2 Yes +++
Smoking 1.6 Yes +++
Vitamin D deficiency 1.4 Probably +++
Low sunlight exposure 2 Probably ++
Shift work 1.7 No ++
Infectious mononucleosis 2 Yes ++
Passive smoking 1.3 Unknown +
Oral tobacco 0.5 Unknown +
Coffee 0.7 Unknown +
Alcohol 0.6 Unknown +
a
Modified with permission from Olsson T, et al, Nat Rev Neurol.36 © 2016 Springer Nature.
600 JUNE 2019

An otherwise healthy 27-year-old woman presented to the clinic with CASE 1-1
blurred vision in her right eye that had started 5 days earlier. She had no
significant past medical or family history. On examination, she had visual
acuity of 20/200 in her right eye and a right afferent pupillary defect.
Brain and cervical spine MRI showed T2-hyperintense lesions in the
juxtacortical and periventricular white matter and cervical spinal cord in a
pattern suggestive for inflammatory demyelination. Some of the brain
lesions enhanced after gadolinium administration. Her CSF analysis was
notable only for more than five oligoclonal bands that were not present in
the serum.
She was diagnosed with relapsing-remitting multiple sclerosis (MS).
During a clinic visit, she asked about the risk of MS in her 3-year-old son
and 30-year-old sister and if anything could be done to reduce their risks
of developing MS.
Relatives of a person with MS are at increased risk of developing MS. COMMENT

The risk depends on the degree of genetic similarity to the patient. First-
degree relatives have about 2% to 5% chance of developing MS. Many
environmental risk factors for MS seem to be more important in young
adults. Although preventive studies have not been conducted to date, it
stands to reason that, in theory, modifying environmental factors and
exposures might have a more profound effect on MS risk in younger people
(eg, for this patient’s 3-year-old son, as opposed to her 30-year-old sister).
In other words, decreasing the chance of MS development by reducing
exposure to MS risk factors will probably be more effective in children than
older adults.
Despite the lack of interventional data to support lifestyle changes to
prevent MS, avoiding smoking and the prevention and treatment of obesity
and vitamin D deficiency can be considered by most or all those who are at
higher risk of developing MS as these are unlikely to be harmful. In
particular for children, the decision to initiate vitamin D supplementation
with the goal of reducing the risk of MS should be made in concert with the
primary care provider. Ultraviolet radiation exposure, because of its
carcinogenic effects, cannot be routinely recommended. No effective
intervention for prevention of Epstein-Barr virus infection is known. Not
enough evidence exists for other environmental exposures (such as diets,
dietary factors, or nutrients) to be routinely recommended for MS
prevention. Genetic testing (eg, for HLA antigen MS risk alleles) is not
recommended.

A mendelian randomization study has shown that genetic factors associated

with higher EBNA1 titers are positively associated with MS risk (BOX 1-1).46 An
additive interaction also exists between EBNA1 titer (or a self-reported history of
infectious mononucleosis) and HLA antigen MS risk genetic variants as well as
between these EBV markers and obesity. Specifically, having a higher EBNA1
titer or history of infectious mononucleosis is a bigger risk factor in those who
carry HLA antigen MS risk alleles, or among those who are obese, than in those
who do not possess those features.47,48 These results are interpreted as the
evidence for causal association between EBV infection and MS risk. In pediatric
MS, EBV antibodies had a multiplicative interaction with race.49 Positive EBV
antibody is more strongly associated with the odds of pediatric MS development
in whites than in African Americans. Despite the robust epidemiologic evidence
for the importance of EBV infection in the development of MS, the mechanism
by which EBV increases MS risk is not clear. Several mechanisms have been
proposed, including direct infection of the CNS by the virus, molecular mimicry,
and cross-reaction between the virus and human antigens and latent infection
of B cells.
Unlike EBV, the evidence for the association of cytomegalovirus (CMV) and
herpes simplex virus is not compelling. Although positive CMV serology was
reported to be associated with decreased risk of pediatric MS,50 a larger study
did not replicate this result.49 A case-control study also reported a negative
association between CMV seropositivity and MS risk in adults in Sweden,51 but a
2017 study in California showed an association between CMV infection and
decreased risk of MS in Hispanics but not in non-Hispanic whites or African
Americans.52 The results were interpreted as a sign of noncausal association.
Among white children, positive herpes simplex virus serology has been shown to be
associated with higher pediatric MS risk only in those who are negative for the
HLA antigen MS risk allele (HLA-DRB1*15:01).50 These results require replication.
Ultraviolet Radiation Exposure and Vitamin D

MS incidence and prevalence are higher in higher latitudes.53 This observation
was the basis of many studies looking at the effects of sun exposure and
vitamin D on the risk of MS. Ultraviolet radiation synthesizes vitamin D in the
skin, so it is difficult to study the independent effects of these variables on the
odds of developing MS. However, it seems that both ultraviolet radiation and
vitamin D are associated with lower odds of MS and that not all of the effect
of ultraviolet radiation may be entirely explained by its contribution to
vitamin D synthesis.54
Multiple studies have shown the negative association of ultraviolet radiation
exposure and MS, when assessed at the time of MS onset or diagnosis. This
association remains even after adjusting the statistical models for serum
vitamin D levels.55,56 These results are in line with preclinical studies, in which
ultraviolet radiation exposure, independent of vitamin D, is protective in an
animal model of MS. These effects might be mediated by the effects of ultraviolet
radiation on regulatory T cells and antigen-presenting dendritic cells.57
Vitamin D, in part, may mediate some of the protective effects of ultraviolet
radiation on MS. If the effect of ultraviolet radiation was completely independent
of vitamin D, then oral intake of vitamin D should have no effect on the risk
of MS. However, it has been shown that a diet high in fatty fish (a good source of
vitamin D) is associated with lower odds of MS in people with low sun exposure.58
602 JUNE 2019

Further, the apparent association between serum vitamin D levels and MS risk KEY POINTS
remains even when measures of ultraviolet radiation exposure were included in
● Low sunlight exposure,
the models.56 Higher serum vitamin D levels (particularly in young adulthood) vitamin D deficiency,
have been shown to be associated with lower risk of developing MS later in life, obesity, and smoking are
although these analyses did not account for ultraviolet radiation exposure.59 On factors with strong evidence
the other hand, the effect of vitamin D deficiency of a mother during pregnancy for association with multiple
sclerosis risk.
on the MS risk of offspring is controversial.60,61
Several mendelian randomization studies have demonstrated the association ● Many infectious agents
of genetic variants affecting serum vitamin D levels and the risk of MS. These have been reported to be
studies are the strongest evidence of a causal association of vitamin D status and associated with multiple
MS.62,63 However, these conclusions are not undisputed. For example, the sclerosis risk; however, only
Epstein-Barr virus infection
association between serum vitamin D levels and MS has been only shown in has been consistently shown
whites and was not seen in African Americans or Hispanics.54 The absence of to be a risk factor.
association in some racial or ethnic groups has cast some doubt on the causal
association between vitamin D and MS risk, at least as a universally important ● Exposure to several risk
factors for developing
factor. multiple sclerosis (including
Epstein-Barr virus infection
Obesity and obesity) during
Several cohort and case-control studies have demonstrated the association adolescence appears to be
more detrimental than
between obesity and MS risk.64–66 Similar to many other environmental risk
exposure in adulthood.
factors, obesity in adolescence and young adulthood, but not later in adult life,
seems to be associated with subsequent risk of MS.64 The risk is highest in overtly ● Statistical interactions
obese individuals, although a milder degree of being overweight may also between risk factors and
associated with greater risk. mendelian randomization
studies have provided
By showing an association between genetic variants affecting the body mass evidence for the causal
index and the risk of MS, mendelian randomization studies have provided association of several
stronger evidence for causality of the association of obesity and MS.67,68 environmental factors and
Similar to adult-onset disease, obesity has been shown to be associated with the risk of multiple sclerosis.
pediatric-onset MS.69 Obesity may also interact with HLA antigen MS risk ● Lung irritation from
variants: in one study, obesity was a stronger risk factor in individuals carrying inhalation of cigarette
HLA-DRB1*1501.64 smoke is likely the mediator
An interaction between EBV infection and obesity may also exist. In one of association between
smoking and multiple
cohort, while obesity and EBV infection were each associated with about twofold
sclerosis risk.
greater odds of MS, the co-occurrence of both risk factors in the same person
increased the odds 14-fold.48 These interactions are interpreted as providing
stronger evidence for causality of these environmental risk factors.
Smoking
A large case-control study and pooled analysis of several smaller studies have
shown that smoking is a risk factor for MS.70,71 This association is dose
dependent: smoking more cigarettes a day is associated with more substantial MS
risk. Even passive smoking has been incriminated as a risk factor, including in
pediatric-onset MS. In addition to self-reported smoking, elevated serum
cotinine levels (a marker of smoking) in samples obtained before developing MS
has been shown to be associated with increased MS risk.72
One study showed that the use of oral tobacco was associated with lower odds
of MS, particularly among concomitant cigarette smokers.73 This observation
has led to the conclusion that the lung irritation from inhalation of cigarette
smoke is the mediator of association between smoking and MS risk. This is
similar to several other autoimmune diseases, such as rheumatoid arthritis, in

BOX 1-1 Instrumental Variables, Mendelian Randomization Studies, and

Statistical Interaction
Observational studies can provide evidence for the association between

an exposure (eg, a potential risk factor) and an outcome (eg, the
development of multiple sclerosis [MS]). However, to prove causality,
randomized controlled studies are usually needed. Although randomized
controlled trials to demonstrate the efficacy of an intervention for the
purpose of treatment are feasible and commonly performed, randomized
studies of disease risk factors are extremely difficult to undertake, may
be unethical, and often are not feasible. Using instrumental variables in
observational studies has become a rising trend in epidemiology to
demonstrate causal association. An instrumental variable is a factor that is
associated with the exposure of interest but is not associated with the
outcome of interest, either directly or through another pathway. If these
assumptions are correct, then showing the association between the
instrumental variable and the outcome of interest demonstrates the causal
association of the exposure of interest and the outcome.43 For example, when
FIGURE 1-1
Schematic representation of the instrumental variable concept. In this hypothetical
example, if it were demonstrated that imposing a cigarette tax in a geographical area was
associated with decreased MS incidence in that area, since a cigarette tax cannot be
associated with multiple sclerosis risk through any other mechanism aside from changing
(probably reducing) smoking habits, it would provide strong evidence for the causal
association between smoking and multiple sclerosis.
604 JUNE 2019

considering the role of smoking on the risk of MS, case-control or cohort
studies have shown a clear association of smoking with MS. However,
confounding variables might explain this association. Using an instrumental
variable can remove the effect of potential confounders. In this case, if
some areas of the country start imposing a very high tax on cigarettes and
a subsequent decrease in the incidence of MS were observed in those
areas, cigarette tax, as an instrumental variable, would demonstrate
causal association between the smoking and risk of MS (FIGURE 1-1).
Mendelian randomization is one method of using instrumental variables.
Random segregation of alleles during meiosis provides an opportunity to
conduct instrumental variable studies for many different risk factors.44
For example, if the heterogeneity in a gene is shown to be associated
with a trait (such as height) and no plausibility exists that the gene can
be associated with MS risk through any other pathway, showing the
association of the heterogeneity of this gene and MS risk is suggestive of a
causal association between height and MS risk (FIGURE 1-2).
In epidemiology, the effects of an independent variable on an outcome
may depend on the level of another (independent) variable, a phenomenon
known as interaction. Interaction can
be additive or multiplicative.45 In the
additive interaction of two risk factors,
the risk of an outcome in a person
exposed to both factors is higher
(or lower) than the sum of the effects
of each factor in the absence of the
other one. For example, if the baseline
risk of MS in an individual not exposed
to risk factors A and B is x, an individual
exposed to only risk factor A is x + a
and in an individual exposed only to
risk factor B is x + b; if an additive
interaction exists between A and B,
the risk of MS in an individual exposed
to both A and B will be x + a + b + c,
where c is the interaction effect.
Multiplicative interactions between a
risk factor and demographic factor(s)
may also exist. For example, factor FIGURE 1-2
A might be a risk factor for MS in the Mendelian randomization. Mendelian
general population, but it may have a randomization is the use of random
multiplicative interaction with race. segregation of alleles that affect a trait
as an instrumental variable to demonstrate
For example, on further analysis, a the causal association of that trait and a
researcher might find that factor A specific outcome. In this hypothetical
is only a risk factor in one race but example, if genetic variability that is known
not other races. The concepts of to affect height were to be demonstrated
to be associated with the risk of multiple
additive and multiplicative interaction
sclerosis, it would be evidence for a causal
are discussed, when appropriate, in association between height and the risk of
the following sections. multiple sclerosis.

which lung irritation can trigger inflammatory responses and autoimmunity. In

the mouse model of MS (experimental autoimmune encephalomyelitis),
lymphocytes that attack the CNS acquire their migratory abilities in the lungs,
enabling them to enter the CNS.
Similar to EBV infection and obesity, one unreplicated study found that
smoking interacts with HLA antigen MS risk alleles.74 Smoking and harboring
HLA-DRB1*15:01 together increase the odds of developing MS by about 14 times,
much higher than the sum of the absolute effect of each risk factor alone. A
similar interaction was reported with a non–HLA antigen gene (NAT1).75 These
gene-environment interactions increase the likelihood that the association
between smoking and MS is causal.
LIFESTYLE RISK FACTORS

Multiple biases (including recall bias, measurement bias, and, particularly,
confounding) can affect the study of association between different nutrients or
dietary factors and the risk of a disease. It is particularly difficult to convincingly
show the causality of the observed associations. Randomized controlled trials of
diets, nutrients, and dietary factors may be unethical or infeasible. Nonetheless,
the more commonly studied dietary factors are briefly reviewed here.
Diet
In vitro and experimental autoimmune encephalomyelitis (a mouse model of
MS) studies demonstrated that high salt conditions induce a proinflammatory
state and worsening of the disease in the animal model.76 Among those with
existing MS, a study in Argentina reported increased clinical and radiologic
disease activity in patients with higher salt intake,77 an observation that was not
replicated in subsequent studies.78,79 A pediatric case-control study also did not
show an association between higher dietary salt intake and MS risk.80 Thus, the
evidence for salt intake being a major contributor to MS risk (or prognosis) is
still lacking.
Two population-based studies reported that high coffee consumption reduces
the risk of MS.81 This observation is in line with the preclinical observation of
the neuroprotective and anti-inflammatory activity of caffeine. Similarly, a
case-control study demonstrated that alcohol, in a dose-dependent fashion,
decreases the risk of MS.82 However, a prospective study did not show an
association between alcohol or coffee consumption and MS.83 Unknown and
unmeasured confounders, such as conditions that are often comorbid with MS
(eg, migraine) influencing intake of caffeine or alcohol, could readily explain
the disparity in the results of these studies.
Shift Work
At least two studies have suggested that shift work increases the risk of MS.84,85
Melatonin has been implicated in inhibiting pathogenic T-cell differentiation and
reducing the disease severity in the experimental autoimmune encephalomyelitis
model. Dysregulation of melatonin may be the mediator of the effects of shift
work on the risk of MS.
MICROBIOTA
The observation that germ-free mice are resistant to the development of
neuroinflammation86 sparked an interest in studying the association between
606 JUNE 2019

the human microbiota and MS. About 1014 microbes live on or in the human
body.87 Rapid advances in nucleic acid sequencing technology have allowed
identification of these microorganisms. Most studies have focused on the most
abundant microbial population in the body: the gut microbiota. Preliminary
studies in both adult and pediatric populations have reported differences in the
composition of the gut microbiota between MS patients and healthy controls.88,89
It is not clear if changes in the gut microbiota had a causal role in development of
MS or if having MS causes changes in the gut microbiota. Nonetheless, a strong
scientific rationale exists for more definitive studies. Several mechanisms have
been proposed for this association, including the effect of the gut microbiota on
the immune system, production of neuromodulatory and immunomodulatory
compounds and metabolites by these organisms, and altered gut permeability.
Several ongoing studies of the human microbiota, including of the respiratory
and other site-specific microbiota, are expected to shed light on the role of these
microorganisms in the pathogenesis of MS in upcoming years.
CONCLUSION
MS is a disease with a complex etiopathogenesis. Despite tremendous advances
in the discovery of genetic and environmental risk factors of the disease, the
mechanisms by which these factors change the risk of MS remain largely
unknown. Understanding these mechanisms may lead to the discovery of
pathogenic pathways and new and more specific treatment targets. Many of
the incriminated genetic variants and environmental factors are thought to affect
the immune system, highlighting the importance of peripheral immune response
in initiating the neuroinflammation. The formidable tasks ahead of MS
epidemiologists are studying how the known genetic and environmental factors
interact to change the MS risk, studying how the gut microbiota and human
epigenetics affect the risk of the disease, and determining how to translate
these data into preventive strategies, particularly for those at high risk of
developing MS.
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610 JUNE 2019

Diagnosis, Differential REVIEW ARTICLE

Diagnosis, and C O N T I N U UM A U D I O
I NT E R V I E W A V A I L AB L E
ONLINE
Misdiagnosis of
Multiple Sclerosis
By Andrew J. Solomon, MD
ABSTRACT
PURPOSE OF REVIEW: The diagnosis of multiple sclerosis (MS) is often
challenging. This article discusses approaches to the clinical assessment
for MS that may improve diagnostic accuracy.
Contemporary diagnostic criteria for MS continue to
RECENT FINDINGS:
evolve, while knowledge about diseases that form the differential
diagnosis of MS continues to expand. Recent data concerning causes of
MS misdiagnosis (the incorrect assignment of a diagnosis of MS) have
further informed approaches to syndromes that may mimic MS and the
accurate diagnosis of MS. CITE AS:
CONTINUUM (MINNEAP MINN)
SUMMARY: This article provides a practical update on MS diagnosis through a
discussion of recently revised MS diagnostic criteria, a renewed AND OTHER CNS INFLAMMATORY
consideration of MS differential diagnosis, and contemporary data DISEASES):611–635.
concerning MS misdiagnosis.
Dr Andrew J. Solomon, Larner
College of Medicine at the
University of Vermont,
INTRODUCTION University Health Center—
M
ultiple sclerosis (MS) is a complex disease, and its clinical and Arnold 2, 1 S Prospect
radiologic heterogeneity1 often make its diagnosis challenging. St, Burlington, VT 05401,
Andrew.Solomon@uvm.edu.
No highly specific and sensitive biomarker for MS has been
identified,2 and many diseases can mimic its appearance. RELATIONSHIP DISCLOSURE:
Efforts to develop MS diagnostic criteria commenced over Dr Solomon has served as a
consultant for Biogen and EMD
50 years ago,3 and the continued refinement of criteria, including the 2017 Serono, Inc, and has received
revisions to the McDonald criteria,4 have enabled earlier diagnosis of MS. research/grant support from
Biogen and personal
However, MS misdiagnosis (the assignment of an incorrect diagnosis of MS),
compensation for speaking
remains an important contemporary problem, with considerable consequences engagements from Med
for patients.5,6 A clinical approach combining knowledgeable attention to the Learning Group, the National
Multiple Sclerosis Society, and
appropriate application of 2017 McDonald criteria, thoughtful consideration of RMEI Medical Education.
the differential diagnosis of MS and the presence of potential red flags for
alternative diagnoses, and an understanding of common contemporary causes of UNLABELED USE OF
PRODUCTS/INVESTIGATIONAL
MS misdiagnosis will improve accuracy of MS diagnosis. USE DISCLOSURE:
Dr Solomon reports no disclosure.
DIAGNOSIS OF RELAPSING-REMITTING MULTIPLE SCLEROSIS
Beginning with the Schumacher criteria3 in 1965, diagnostic criteria have relied © 2019 American Academy
on five principles to confirm of the diagnosis of MS: (1) the identification of a of Neurology.

DIAGNOSIS, DIFFERENTIAL DIAGNOSIS, AND MISDIAGNOSIS OF MS
syndrome “typical” of MS-related demyelination, (2) objective evidence of

central nervous system (CNS) involvement, (3) demonstration of dissemination
in space, (4) demonstration of dissemination in time, and (5) “no better
explanation” other than MS.
Over the past 20 years, evolving data have supported the incorporation of
laboratory and radiologic assessments to complement what were previously
solely clinical assessments to fulfill these principles. The revisions to the
McDonald criteria have enabled earlier diagnosis of MS.7 Yet MS diagnosis,
including the application of the 2017 McDonald criteria,4 continues to rely on the
fulfillment of these five key principles.
Typical Syndromes
The evaluation for a diagnosis of MS begins with an assessment of whether a
patient’s clinical presentation is typical for MS-related demyelination.8 A broad
spectrum of neurologic symptoms may prompt a clinical evaluation for MS.
Similarly, patients with a confirmed MS diagnosis may have an assortment of
chronic and paroxysmal symptoms that are sequelae of the CNS damage
associated with the disease. However, confirmation of a diagnosis of MS using
the current diagnostic criteria requires first the identification of the presentation
of a one of a limited number of syndromes typical for an MS-related
demyelinating attack or relapse.4,8 Typical syndromes include optic neuritis,
brainstem syndromes such as internuclear ophthalmoplegia and trigeminal
neuralgia, cerebellar syndromes, and transverse myelitis. Clinical acumen and
experience are often necessary for this first critical step in approaching the
diagnosis of MS, as distinguishing a noninflammatory optic neuropathy or
myelopathy from optic neuritis or myelitis may be challenging at times (refer to
the section “No Better Explanation”: the Differential Diagnosis of Relapsing-
Remitting Multiple Sclerosis later in this article).
Importantly, the McDonald criteria were validated only in cohorts of patients
presenting with attacks or relapses consisting of these typical syndromes. Since
the specificity for MS of the McDonald criteria has not been evaluated in other
syndromes, their application alone for diagnosis of MS in patients with other clinical
presentations is not recommended. If a patient’s clinical presentation is determined
to be atypical, further clinical, laboratory, and radiologic assessments beyond the
minimum requirements of the McDonald criteria are necessary to confirm a
diagnosis of MS (refer to the section Atypical Syndromes, Typical Syndromes
With Red Flags, and Evaluation of Long-standing Diagnoses later in this article).
Objective Evidence
Objective clinical evidence of at least one CNS lesion corresponding to the
presentation of an attack typical for MS-related demyelination is also necessary
to fulfill MS diagnostic criteria.4 Objective evidence may include a relative
afferent pupillary defect in a patient presenting with visual symptoms suggestive
of optic neuritis, internuclear ophthalmoplegia in a patient presenting with
diplopia, or detection of a hemisensory level in a patient with sensory or motor
symptoms suggestive of myelitis.
The authors of the 2017 revisions to the McDonald criteria also affirm that
paraclinical or radiographic evidence of a CNS abnormality that corresponds to
the anatomic location suggested by symptoms may substitute for clinical
objective evidence for diagnosis of MS. For example, P100 latency prolongation
612 JUNE 2019

on a visual evoked potential or a T2 hyperintensity on MRI in the optic nerve KEY POINTS
might provide objective evidence of an episode of optic neuritis, or a T2
● Diagnosis of relapsing-
hyperintensity in the spinal cord might provide objective evidence of an episode remitting multiple sclerosis
of myelitis. begins with confirmation of
In patients presenting with symptoms concerning for a syndrome typical for objective evidence of a
MS but without objective clinical, paraclinical, or radiographic evidence of a syndrome typical for
multiple sclerosis.
corroborating CNS lesion, caution is especially warranted before making a
diagnosis of MS. For example, patients often present for MS evaluation with ● Knowledge of the recent
neurologic symptoms accompanied by a normal neurologic examination and a revisions to the 2017
brain MRI with abnormalities that would not explain the presenting symptoms. McDonald criteria is
The McDonald criteria have not been tested in such patients, and their essential for the proper use
of paraclinical (ie, visual
application without objective evidence would likely diminish specificity for MS. evoked potentials, CSF
Further clinical evaluation and radiographic monitoring is often necessary in examination) and
such patients to avoid misdiagnosis and to accurately confirm a diagnosis of MS. radiographic data to
substitute for a second
clinical attack for the
Dissemination in Space and Time demonstration of
Confirmation of objective evidence for a single attack typical for MS-related dissemination in space and
demyelination is the first step in an evaluation for a diagnosis of MS. Such a dissemination in time for
patient has a clinically isolated syndrome4,9 if the patient has no further fulfillment the diagnosis of multiple
sclerosis.
of MS diagnostic criteria. Subsequent assessment for evidence of both
dissemination in space and dissemination in time of CNS involvement
characteristic of MS is the next step toward the confirmation of a MS diagnosis.
Evidence of dissemination in space is defined as detection of lesions in more than
one distinct anatomic location within the CNS.4 Multifocal CNS involvement is
characteristic of MS. Fulfillment of dissemination in time requires confirmation
of new CNS lesions over time, suggesting an ongoing disease process typical of
MS rather than a monophasic disease.
Objective evidence of a second attack typical for MS in a different location
than the first would fulfill dissemination in space and dissemination in time
criteria. The authors of the 2017 revisions to the McDonald criteria reaffirm
that prospective confirmation of objective clinical findings for two attacks
disseminated in both space and time typical for an MS diagnosis remains most
secure.4 However, in a patient with objective evidence of a single typical attack,
evolving data10,11 have suggested that the results of CSF and MRI assessments
may substitute for clinical evidence to demonstrate dissemination in space and
dissemination in time without diminishing specificity and sensitivity for the
diagnosis of MS.
MRI Demonstration of Dissemination in Space

Recent studies continue to support11,12 the 2017 McDonald criteria recommendations
for MRI demonstration of dissemination in space4 by detection of the presence
of T2-hyperintense MRI lesions in four areas of the CNS, including (1)
periventricular, (2) cortical or juxtacortical, and (3) infratentorial brain regions
and (4) the spinal cord. The presence of at least one T2-hyperintense MRI lesion
in two of these regions demonstrates dissemination in space.
As a result of new data,13 the 2017 revisions to the McDonald criteria now
include symptomatic lesions for demonstration of dissemination in space.4 For
example, in a patient presenting with myelitis and MRI evidence of a
corresponding spinal cord lesion (objective evidence of a “symptomatic lesion”),
a single additional T2-hyperintense MRI lesion in the periventricular, cortical or

juxtacortical, or infratentorial region would demonstrate MRI dissemination in

space. Of note, although MRI may provide paraclinical objective evidence of an
attack of optic neuritis, the anterior visual system was not included as a region
for demonstration of MRI dissemination in space in the 2017 criteria. In a patient
presenting with optic neuritis, evidence of lesions in two of the four
aforementioned regions remains necessary to demonstrate MRI dissemination
in space.
The 2017 McDonald criteria also for the first time include cortical lesions
(considered equivalent to juxtacortical lesions) as a region that may provide MRI
demonstration of dissemination in space.4 The detection of cortical lesions
remains challenging, particularly using MRI scanners and sequences typically
employed in clinical practice. Recent studies12 and consensus guidelines14
TABLE 2-1 The 2017 McDonald Criteria for Diagnosis of Multiple Sclerosis in
Patients With an Attack at Onseta,b
Number of
Clinical Number of Lesions With Objective Additional Data Needed for a Diagnosis of
Attacks Clinical Evidence Multiple Sclerosis
≥2 ≥2 Nonec
≥2 1 (as well as clear-cut historical evidence of a Nonec

previous attack involving a lesion in a distinct
anatomic locationd)
≥2 1 Dissemination in space demonstrated by an additional

clinical attack implicating a different central nervous
system site or by MRI
1 ≥2 Dissemination in time demonstrated by an additional

clinical attack or by MRI or demonstration of CSF-specific
oligoclonal bandse
1 1 Dissemination in space demonstrated by an additional

clinical attack implicating a different central nervous
system site or by MRI
And
Dissemination in time demonstrated by an additional
clinical attack or by MRI or demonstration of CSF-specific
oligoclonal bandse
CSF = cerebrospinal fluid; MRI = magnetic resonance imaging.

a
Modified with permission from Thompson AJ, et al, Lancet Neurol.4 © 2017 Elsevier Ltd.
b
If the 2017 McDonald criteria are fulfilled and no better explanation exists for the clinical presentation, the diagnosis is multiple sclerosis. If
multiple sclerosis is suspected by virtue of a clinically isolated syndrome but the 2017 McDonald criteria are not completely met, the diagnosis is
possible multiple sclerosis. If another diagnosis arises during the evaluation that better explains the clinical presentation, the diagnosis is not
multiple sclerosis.
c
No additional tests are required to demonstrate dissemination in space and time. However, unless MRI is not possible, brain MRI should be
obtained in all patients in whom the diagnosis of multiple sclerosis is being considered. In addition, spinal cord MRI or CSF examination should be
considered in patients with insufficient clinical and MRI evidence supporting multiple sclerosis, with a presentation other than a typical clinically
isolated syndrome, or with atypical features. If imaging or other test (eg, CSF) is undertaken and is negative, caution needs to be taken before
making a diagnosis of multiple sclerosis, and alternative diagnoses should be considered.
d
Clinical diagnosis based on objective clinical findings for two attacks is most secure. Reasonable historical evidence for one past attack, in the
absence of documented objective neurologic findings, can include historical events with symptoms and evolution characteristic for a previous
inflammatory demyelinating attack; at least one attack, however, must be supported by objective findings. In the absence of residual objective
evidence, caution is needed.
e
The presence of CSF-specific oligoclonal bands does not demonstrate dissemination in time per se but can substitute for the requirement for
demonstration of this measure.
614 JUNE 2019

recommend the use of advanced imaging techniques available at specialized KEY POINT
centers for cortical lesion detection. MRI evaluation for cortical lesions to meet
● Objective evidence of a
dissemination in space may be best limited to physicians experienced in using demyelinating syndrome
such techniques. typical for multiple sclerosis
demonstrating both
MRI and CSF Demonstration of Dissemination in Time dissemination in space and
dissemination in time must
Similar to previous revisions, the 2017 McDonald criteria specify that MRI
be accompanied by a search
dissemination in time can be demonstrated on a single MRI scan by the presence for “no better explanation”
of any gadolinium-enhancing and nonenhancing lesions or by the appearance of to confirm a diagnosis of
a new T2-hyperintense or gadolinium-enhancing lesion on a follow-up MRI multiple sclerosis.
compared to a baseline scan, irrespective of the timing of either scan.4 In a change from
the 2010 criteria, previously excluded gadolinium-enhancing symptomatic lesions
often responsible for the syndrome prompting evaluation (eg, a gadolinium-
enhancing brainstem lesion in a patient with internuclear ophthalmoplegia) may
now be included for consideration of fulfillment of MRI dissemination in time.
In a change from previous revisions and based on recent data10 suggesting
CSF-specific oligoclonal bands are an independent predictor of a second clinical
attack, the 2017 McDonald criteria recommend that demonstration of two or
more oligoclonal bands may substitute for demonstration of clinical or MRI
dissemination in time. This notable revision enables earlier diagnosis of MS in a
patient with objective evidence of a single clinical attack typical for MS with an
MRI that only demonstrates dissemination in space. The authors of the 2017
McDonald criteria emphasize that the accuracy of oligoclonal band testing
depends on the methodology employed, and a laboratory that performs
agarose gel electrophoresis with isoelectric focusing and immunoblotting
or immunofixation for IgG is recommended.4
Patients presenting for evaluation for MS often report a history of prior
neurologic symptoms that may, at times, aid in diagnosis. When objective
evidence exists of a single clinical attack typical for MS, the description of
historical symptoms compatible with an additional prior syndrome typical for
MS may support demonstration of dissemination in time. In such instances,
evaluation for objective evidence of a CNS lesion to confirm a suspected prior
syndrome by neurologic examination or paraclinical testing such as evoked
potentials or by MRI identification of a lesion is highly recommended.
Consideration of prior symptoms alone for the demonstration of dissemination
in time may increase the risk of MS misdiagnosis.5 The authors of the 2017
criteria recommend caution when considering historical symptoms for the
demonstration of dissemination in time in the absence of supportive objective
evidence of a CNS lesion.4 TABLE 2-1 summarizes the 2017 McDonald criteria for
the diagnosis of relapsing-remitting MS, including requirements of
demonstration of dissemination in space and dissemination in time. CASE 2-1
and CASE 2-2 demonstrate application of the revised criteria.
“No Better Explanation”: the Differential Diagnosis of Relapsing-Remitting

Multiple Sclerosis
Objective evidence of a demyelinating syndrome typical for MS demonstrating
dissemination in space and dissemination in time is insufficient for the diagnosis
of MS. As no single biomarker for MS exists, each revision of MS diagnostic
criteria has also specified that there must be a determination of “no better
explanation”4 for the clinical presentation under consideration. This final key

CASE 2-1 A 21-year-old woman presented for evaluation after 5 days of vision loss
in her right eye. She described gradual onset and progression of
symptoms and reported periocular pain worsened by eye movements.
She had no additional history of medical problems or prior neurologic
symptoms.
Her neurologic examination was notable for a relative right afferent
pupillary defect and visual acuity of 20/70 in the right eye. The remainder
of her ophthalmic and neurologic examination was normal. Brain MRI
revealed enhancement of the right optic nerve and four ovoid T2
hyperintense lesions. One of these was a juxtacortical lesion, while the
remaining three lesions were in the subcortical or deep white matter. MRI
of the cervical and thoracic spinal cord demonstrated a small T2-
hyperintense lesion at the C6 disk level located posteriorly. The thoracic
spinal cord was normal. None of the lesions demonstrated contrast
enhancement. Subsequent CSF evaluation demonstrated nine oligoclonal
bands restricted to the CSF and a white blood cell count of 11 cells/mm3
with lymphocytic predominance; the CSF was otherwise normal. Serum
and CSF evaluation for inflammatory, metabolic, and infectious
diagnoses other than multiple sclerosis (MS) was nonrevealing. No
clinical or radiographic red flags suggested diagnoses other than MS.
COMMENT This patient presented with objective evidence of an attack of optic

neuritis, a syndrome typical for MS. Vision loss alone would have been
inadequate to make this diagnosis; the presence of an afferent pupillary
defect and an MRI demonstrating enhancement of the optic nerve served
as objective evidence of this single attack typical for MS. Her clinical
history and presentation did not demonstrate dissemination in space by
two clinical attacks. Brain MRI only fulfills one (juxtacortical) out of four
regions for MRI dissemination in space according to the 2017 McDonald
criteria, as the optic nerve is excluded from consideration.
This case highlights that spinal cord lesions are not always symptomatic.
The patient had no prior history of neurologic symptoms or neurologic
examination findings that localized to the spinal cord. The case also
demonstrates the importance of baseline spinal cord imaging to aid in MS
diagnosis. Inclusion of the cervical spinal cord lesion results in MRI
demonstration of dissemination in space. The clinical history and
presentation did not demonstrate dissemination in time by two clinical
attacks, and the patient’s brain MRI did not demonstrate enhancing and
nonenhancing T2 lesions to fulfill dissemination in time, as the optic nerve
is excluded according to 2017 McDonald criteria. However, her positive
CSF substituted for clinical or MRI dissemination in time based on the 2017
McDonald criteria revisions. The case also highlights that CSF evaluation
may now facilitate earlier diagnosis of MS in some patients.
This patient had objective evidence of a single attack typical for MS and
fulfilled 2017 McDonald criteria for demonstration of dissemination in
space and dissemination in time, and, as no better evidence for her clinical
presentation existed, she was diagnosed with MS.
616 JUNE 2019

A 34-year-old man presented with 3 days of gradual worsening CASE 2-2
paresthesia starting at his right chest and ending at his toes on his right
side. He had no additional history of medical problems or prior neurologic
symptoms.
Neurologic examination revealed diminished pinprick from the T4
dermatome and below on the right side and mild diminished vibration in
the right first toe. General and neurologic examinations were otherwise
unremarkable. MRI of his thoracic spinal cord demonstrated a T2-
hyperintense contrast-enhancing lesion at the T4 vertebral disk level
visualized on both sagittal and axial images. Brain MRI demonstrated six
T2-hyperintense lesions, including one ovoid periventricular lesion, with
the remainder located in the subcortical or deep white matter. None
demonstrated contrast enhancement. Cervical spinal cord MRI was
normal. Serum evaluation for inflammatory, metabolic, and infectious
diagnoses other than MS was nonrevealing. CSF evaluation demonstrated
four oligoclonal bands restricted to the CSF, a white blood cell count of
3 cells/mm3 with lymphocytic predominance, and protein elevation to
65; the CSF was otherwise normal. No clinical or radiographic red flags
suggested diagnoses other than MS. Serum and CSF evaluation for
inflammatory, metabolic, and infectious diagnoses was nonrevealing.
This patient presented with objective evidence of a single attack of COMMENT

myelitis, a syndrome typical for multiple sclerosis (MS). Neurologic
examination revealed a sensory level, and MRI provided objective
corroboration of the central nervous system lesion responsible for his
symptoms. His presentation demonstrated MRI dissemination in space and
dissemination in time according to 2017 McDonald criteria, because the
symptomatic thoracic spinal cord lesion can count toward both MRI
demonstration of dissemination in space and dissemination in time
(reflecting a change from prior criteria); the periventricular and spinal cord
lesions demonstrated MRI dissemination in space, and the presence of
contrast-enhancing and nonenhancing lesions demonstrated
dissemination in time. CSF evaluation was most suggestive of myelitis
caused by MS, rather than alternative inflammatory or infectious
diagnoses, based on the presence of CSF-restricted oligoclonal bands,
a normal white blood cell count, and mildly elevated protein.
This patient had objective evidence of a single attack typical for MS
and fulfilled 2017 McDonald criteria for dissemination in space and
dissemination in time. After evaluation, no better evidence for his
presentation was identified, and he was diagnosed with MS.

element of MS diagnosis requires an astute consideration of the differential

diagnosis of MS, with particular attention to the presence of red flags, before the
confirmation of MS diagnosis.
Better Explanation for Typical Syndromes

A variety of disorders may present with objective evidence of a syndrome typical
for MS and demonstrate clinical or radiographic dissemination in space and
dissemination in time, thus appearing to fulfill MS diagnostic criteria. Disorders
such as neuromyelitis optica spectrum disorder (NMOSD), syndromes associated
with myelin oligodendrocyte glycoprotein (MOG) antibody (anti-MOG),
neurosarcoidosis, and CNS manifestations of systemic rheumatologic and
oncologic disease may present with optic neuritis or transverse myelitis.15–18 Yet in
many instances, these disorders are accompanied by a red flag,19,20 that is, clinical,
laboratory, or radiographic findings atypical for MS and suggestive of
an alternative diagnosis that may offer a better explanation than MS for the
clinical presentation. Thoughtful assessment for such red flags may avoid a
misdiagnosis of MS.
Although optic neuritis or transverse myelitis may be typical for MS, specific
characteristics atypical for MS may alert the astute clinician that an alternative
diagnosis should be investigated. For example, severe or bilateral optic neuritis
may suggest NMOSD. Longitudinally extensive transverse myelitis may
suggest NMOSD, neurosarcoidosis, anti-MOG–associated myelitis, systemic
rheumatologic disease, or a paraneoplastic disorder. Complete spinal cord lesions
or a history of intractable vomiting may also suggest NMOSD. Transverse
myelitis associated with prodromal symptoms or MRI T2 signal abnormality
confined to spinal cord gray matter may suggest anti-MOG–associated myelitis.21
Multiple cranial nerve involvement might suggest neurosarcoidosis. Transverse
myelitis or optic neuritis accompanied by high CSF pleocytosis should also
prompt investigation into infectious or inflammatory disorders other than MS.
Systemic symptoms such as joint pain, skin changes, and weight loss might
suggest either rheumatologic or paraneoplastic disease. A variety of additional
non-neurologic red flags accompanying a typical syndrome might also suggest
specific alternative diagnoses.18
A comprehensive review of red flags suggesting alternative diagnoses in
patients presenting with syndromes otherwise typical for MS is beyond the scope
of this article. Several excellent review articles expand further on the differential
diagnosis that should be considered in such patients before determining that a
typical syndrome has no better explanation other than MS.15–19
Validation of the 2017 McDonald Criteria

Knowledge of the characteristics of patients included in the studies on which
the 2017 revisions to the McDonald criteria relied is also important for the
consideration of “no better explanation” in an evaluation for MS. These studies
included predominantly white patients from Europe, the United States, and
Canada who were younger than 50 years old. The authors of the 2017 McDonald
criteria also recommend application with caution in diverse populations4 and
patients younger than 11 years of age, in whom the 2017 McDonald criteria have
not been evaluated.
Thus, a presentation of optic neuritis, a brainstem or cerebellar syndrome, or
transverse myelitis in a very young, older, or nonwhite patient would be a
618 JUNE 2019

potential red flag that should prompt further evaluation before a diagnosis of MS. KEY POINTS
Alternative diagnoses may be more common in patients with this demographic
● A syndrome typical for
profile. For instance, MS is less common in nonwhites, whereas NMOSD22 and multiple sclerosis may also
neurosarcoidosis23 are comparatively more common in such populations.1 Although exhibit characteristics
children may present with MS, evaluation for other pediatric demyelinating atypical for multiple
syndromes, particularly acute disseminated encephalomyelitis (ADEM),24,25 is sclerosis, suggesting a
specific alternative
essential in young children. A first clinical attack typical of MS demyelination is less
diagnosis.
common after the age of 50. In an older patient, vascular disease or a neoplasm
might prove a better explanation than MS for neurologic syndromes or MRI ● The demographic profile
abnormalities that appear to fulfill MS diagnostic criteria. of patients presenting with
syndromes typical for
multiple sclerosis may
Expanding the Differential Diagnosis and Red Flags to provide an important red
Noninflammatory Disorders flag prompting evaluation
Some disorders often included in the broad differential diagnosis of MS do not for alternative diagnoses.
usually present with syndromes typical for demyelination. The explanation for
● Noninflammatory
this is that the symptoms caused by these syndromes (eg, visual or sensory conditions may also be
symptoms) may be mistaken for symptoms typical of MS. The determination mistaken for a typical
that objective evidence exists of a syndrome typical for MS, a clinical assessment presentation of multiple
reliant on the expertise of the examining neurologist, can often be challenging. sclerosis. Knowledge of
broad red flags suggesting a
Nondemyelinating and noninflammatory syndromes are frequently mistaken for
structural, functional,
a presentation typical of MS.5 metabolic, infectious,
Knowledge of the specific disorders frequently mistaken for optic neuritis26,27 neoplastic, or other disease
and myelitis28,29 and the skills to facilitate their diagnosis are critical in the may lead to a specific
alternative diagnosis.
evaluation for MS. Nonarteritic anterior ischemic optic neuropathy may
frequently be mistaken for optic neuritis26,27; other optic neuropathies,
migrainous visual symptoms, functional vision loss, retinal or macular disorders,
and neoplasms must also often be differentiated from optic neuritis.27 Patients
with myelopathies with vascular, spondylotic, or compressive etiology
frequently present for evaluation of myelitis,28,29 and infectious, metabolic, or
neoplastic myelopathies may also mimic transverse myelitis.15 Several recent
large cohort studies26–29 have provided guidance on a number of clinical,
paraclinical, or radiographic red flags that may help identify a noninflammatory
diagnosis in patients with ophthalmic or spinal cord syndromes. FIGURE 2-1,
FIGURE 2-2, and TABLE 2-2 present approaches and the differential diagnosis of
clinical presentations that may mimic syndromes typical for MS.
Studies spanning 30 years that evaluated the characteristics of patients
referred to MS subspecialty centers30–32 and data concerning MS misdiagnosis5,33
have identified migraine and functional neurologic disorders as diagnoses
frequently prompting MS evaluation. Diagnosis requires special attention to
history and clinical examination, as MRI abnormalities accompanying
nonspecific neurologic symptoms often prompt an initial evaluation for MS
in such patients. White matter abnormalities associated with migraine34 or
small vessel ischemia may demonstrate MRI dissemination in space, and
interval symptoms may appear to demonstrate dissemination in time if
attention to an initial confirmation of an MS-specific typical syndrome is
neglected. The presence of migraine or risk factors for small vessel ischemia
in any patient seen for an evaluation for MS should prompt caution for the
interpretation of MRI abnormalities. Important initial red flags that should
prompt further evaluation for common noninflammatory diagnoses that may
result in brain MRI abnormalities and neurologic symptoms include the

FIGURE 2-1
An approach to the evaluation of a brainstem syndrome.
CSF = cerebrospinal fluid; MRI = magnetic resonance imaging; MS = multiple sclerosis.
Modified from Miller DH, et al, Mult Scler.19 © 2008 SAGE Publications.
absence of clinical or radiographic spinal cord involvement or of CSF-restricted

oligoclonal bands.
Comprehensive knowledge of every red flag for the disorders that may mimic
MS19,20 is not easy, and misdiagnosis of a rare syndrome presenting with an
infrequently seen red flag may be difficult to avoid. TABLE 2-3 presents a list of
important red flags that may suggest diagnoses other than MS, including a
number of rare syndromes. A stepwise clinical approach to MS differential
diagnosis, such as that suggested by FIGURE 2-1, FIGURE 2-2, and TABLE 2-2 and
recent authors,35 may aid in the initial identification of alternative broad
categories of disease other than MS before ultimately leading to the confirmation
of a specific diagnosis. CASE 2-3 demonstrates an approach to the evaluation for
MS incorporating the consideration of red flags.
Atypical Syndromes, Typical Syndromes With Red Flags, and Evaluation of

Long-Standing Diagnoses
The authors of the 2017 McDonald criteria reaffirmed that the criteria “were not
developed to differentiate MS from other conditions”4 but to confirm the
620 JUNE 2019

FIGURE 2-2
An approach to the evaluation of a spinal cord syndrome.
CSF = cerebrospinal fluid; MRI = magnetic resonance imaging; MS = multiple sclerosis.
diagnosis of MS in patients presenting with typical demyelinating syndromes.

Application of the McDonald criteria in patients presenting with atypical
syndromes (presentations other than optic neuritis, brainstem/cerebellar
syndromes, or myelitis) likely diminishes their accuracy.36 The criteria were not
validated in patients with atypical syndromes or in patients presenting with
typical syndromes accompanied by red flags. However, a small proportion
of patients eventually diagnosed with MS do present with such atypical
syndromes or a clinical, paraclinical, or radiographic red flag.37 In such
patients, further data complementing fulfillment of the McDonald criteria
are advised to confirm a diagnosis of MS. Monitoring for new radiographic
changes suggestive of MS, repeating CSF evaluation to confirm the
subsequent appearance of CSF-restricted oligoclonal bands, or waiting for an
additional attack typical for MS-related demyelination may be necessary to
confirm a diagnosis of MS in patients presenting with atypical syndromes or
red flags.
Clinicians also often encounter patients presenting for evaluation with a
previous diagnosis of MS made by another provider. Evidence of a remote attack

typical for MS can be difficult to confirm as symptom history may be challenging

to recall, and symptoms, neurologic examination findings, and radiologic
abnormalities may change, evolve, or even resolve over time. The McDonald
criteria have not been evaluated in patients with a prior long-standing diagnosis
of MS. Yet some proportion of such patients presenting to establish care for a
preexisting diagnosis of MS may not have MS.5,38 The hindsight potentially
provided by a duration of time since initial diagnosis in such patients may reveal
red flags for alternative diagnoses.5,38 Although clinicians may be reluctant to
reevaluate a preexisting MS diagnosis, particularly if it is long-standing,33,39
confirmation is necessary before proceeding with care. If objective evidence of a
prior attack is no longer present, radiographic or paraclinical (eg, visual evoked
potential) confirmation of a historical episode is an important first step in
evaluation. Records and prior imaging confirming the presence of spinal cord
lesions and CSF-specific oligoclonal bands also make a diagnosis of MS more
TABLE 2-2 Differential Diagnosis of Optic Neuritisa
Usual Clinical Features in Each

Diagnosis Category Tests to Consider in Each Category
Corticosteroid-responsive optic
neuropathies
Sarcoidosis, systemic lupus Progressive severe visual loss; may be MRI orbits and brain with contrast;
erythematosus, autoimmune optic very painful; often bilateral lumbar puncture; anti–aquaporin-4
neuritis, chronic relapsing (simultaneous or sequential); isolated or antibodies; anti–myelin oligodendrocyte
inflammatory optic neuropathy, optic as part of a multisystem disorder; more glycoprotein antibodies; antinuclear
perineuritis, Behçet disease, frequent in Africans or Afro-Caribbeans antibodies; serum angiotensin-
neuromyelitis optica (NMO, Devic (sarcoidosis); relapse when converting enzyme; chest radiograph;
67
disease) corticosteroids withdrawn Gallium scan; biopsy of accessible
tissue (sarcoid)
Other inflammatory optic neuropathies
Postinfectious, postvaccination, acute Bilateral and simultaneous; often in MRI orbits and brain with contrast;
disseminated encephalomyelitis childhood; usually excellent prognosis lumbar puncture
(ADEM)
Neuroretinitis Swollen optic disc and macular star; Bartonella, borrelia, and syphilis
spontaneous recovery serology
Compressive optic neuropathies
Primary tumors (eg, meningiomas, Painless (rarely painful—eg, aneurysms CT or MRI orbits and brain with contrast;
gliomas, and pituitary tumors), and mucoceles); progressive visual biopsy if appropriate
metastases, tuberculomas, thyroid loss; optic atrophy at presentation;
ophthalmopathy, arterial aneurysms, past history of, or evidence for, primary
sinus mucoceles tumor (metastases)
Infectious optic neuropathies
Syphilis, tuberculosis, Lyme disease, Progressive visual loss with exposure to Appropriate serology, lumbar puncture,
viral optic neuritis infectious agent; severe optic disc chest radiograph, tuberculin test
edema; cellular reaction in vitreous
CONTINUED ON PAGE 623
622 JUNE 2019

likely but require consideration of alternative inflammatory disorders. TABLE 2-4
summarizes an approach to the diagnosis of MS in patients with atypical and
challenging clinical presentations.40
DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS OF PRIMARY

PROGRESSIVE MULTIPLE SCLEROSIS
Approximately 10% to 15% of patients with MS have a progressive course from
the onset of symptoms.1 The diagnostic criteria for primary progressive MS differ
from the criteria for relapsing-remitting MS. A small proportion of patients with
primary progressive MS may have infrequent attacks or relapses. The diagnosis
of primary progressive MS first requires confirmation of at least 1 year of gradual
disability progression, independent of any disability associated with a clinical
relapse, determined either retrospectively or prospectively. In addition to 1 year
of progression, primary progressive MS diagnostic criteria require fulfillment of
CONTINUED FROM PAGE 622
Usual Clinical Features in Each

Diagnosis Category Tests to Consider in Each Category
Ischemic optic neuropathies
Anterior ischemic optic neuropathy, Usually older age groups; sudden onset; Erythrocyte sedimentation rate
posterior ischemic optic neuropathy, painless (except giant cell arteritis);
giant cell arteritis, diabetic papillopathy swollen optic disc (except posterior
ischemic optic neuropathy); altitudinal
field defect
Toxic and nutritional optic neuropathies
Vitamin B12 deficiency, copper Bilateral and symmetric; painless; poor Serum vitamin B12, copper
deficiency, tobacco-alcohol prognosis
amblyopia, methanol intoxication,
ethambutol toxicity, Cuban and
Tanzanian epidemic optic
neuropathies
Inherited optic neuropathies
Leber hereditary optic neuropathy Family history; sequential (or Genetic testing for Leber mutation
simultaneous) bilateral painless;
visual loss
Ocular causes
Posterior scleritis Severe pain; fewer visual symptoms B-mode ultrasound of orbits
Maculopathies and retinopathies, Painless; metamorphopsia; preserved Electroretinogram, fluorescein

including central serous retinopathy color vision angiogram
Big blind spot syndrome and acute Visual field loss and photopsias; normal ECG
zonal occult outer retinopathy fundus; preserved color vision
CT = computed tomography; ECG = electrocardiogram; MRI = magnetic resonance imaging.

a
Modified with permission from Hickman SJ, et al, Lancet.18 © 2002 Elsevier Ltd.

TABLE 2-3 Clinical or MRI Red Flags That May Suggest Diagnoses Other Than
Multiple Sclerosisa
Sign, Symptom, or Finding Red Flaga Examples of Alternative Diagnosis
Bone lesions Major Histiocytosis, Erdheim-Chester disease
Lung involvement Major Sarcoidosis, lymphomatoid granulomatosis
Multiple cranial neuropathies or Major Chronic meningitis, including sarcoidosis and tuberculosis; Lyme
polyradiculopathy disease
Peripheral neuropathy Major Vitamin B12 deficiency, adrenoleukodystrophy, metachromatic

leukodystrophy, Lyme disease
Tendon xanthomas Major Cerebrotendinous xanthomatosis
Cerebral venous sinus thrombosis Major Behçet disease, vasculitis, chronic meningitis, antiphospholipid or
anticardiolipin antibody syndromes
Cardiac disease Major Multiple cerebral infarcts, brain abscesses with endocarditis or
right-to-left cardiac shunting
Myopathy Major Mitochondrial encephalomyopathy (eg, MELAS), Sjögren syndrome
Renal involvement Major Vasculitis, Fabry disease, systemic lupus erythematosus
Cortical infarcts Major Embolic disease, thrombotic thrombocytopenic purpura, vasculitis
Hemorrhages/microhemorrhages Major Amyloid angiopathy, moyamoya disease, CADASIL, vasculitis
Meningeal enhancement Major Chronic meningitis, sarcoidosis, lymphomatosis, central nervous

system (CNS) vasculitis
Extrapyramidal features Major Whipple disease, multisystem atrophy, Wilson disease
Livedo reticularis Major Antiphospholipid antibody syndrome, systemic lupus

erythematosus, Sneddon syndrome
Retinopathy Major Mitochondrial encephalomyopathy, Susac syndrome and other

vasculitides (retinal infarction), neuronal ceroid lipofuscinosis
Calcifications on CT Major Cysticercosis, toxoplasmosis, mitochondrial disorders
Diabetes insipidus Major Sarcoidosis, histiocytosis, neuromyelitis optica (NMO)
Increased serum lactate level Major Mitochondrial disease
Selective involvement of the anterior Major CADASIL

temporal and inferior frontal lobe
Hematologic manifestations Major Thrombotic thrombocytopenic purpura, vitamin B12 deficiency,

Wilson disease (hemolytic anemia), copper deficiency
Lacunar infarcts Major Hypertensive ischemic disease, CADASIL, Susac syndrome
Persistent gadolinium enhancement and Major Lymphoma, glioma, vasculitis, sarcoidosis

continued enlargement of lesions
Mucosal ulcers Major Behçet disease
Myorhythmia Major Whipple disease
Hypothalamic disturbance Major Sarcoidosis, NMO, histiocytosis
624 JUNE 2019

Recurrent spontaneous abortion or Major Antiphospholipid antibody syndrome, thrombotic

thrombotic events thrombocytopenic purpura, metastatic cancer with
hypercoagulable state
Simultaneous enhancement of all lesions Major Vasculitis, lymphoma, sarcoidosis
Rash Major Systemic lupus erythematosus, T-cell lymphoma, Lyme disease,

Fabry disease
T2 hyperintensity in the dentate nuclei Major Cerebrotendinous xanthomatosis
Arthritis, polyarthralgia, myalgia Major Systemic lupus erythematosus, Lyme disease, fibromyalgia
Amyotrophy Major Amyotrophic lateral sclerosis, syringomyelia, polyradiculopathy
Headache or meningismus Major Venous sinus thrombosis, chronic meningitis, lymphoma or glioma,
vasculitis, systemic lupus erythematosus
T1 hyperintensity of the pulvinar Major Fabry disease, hepatic encephalopathy, manganese toxicity
Persistently monofocal manifestations Major Structural lesion (eg, Chiari malformation), cerebral neoplasm
Large and infiltrating brainstem lesions Major Behçet disease, pontine glioma
Predominance of lesions at the cortical/ Major Embolic infarction, vasculitis, progressive multifocal
subcortical junction leukoencephalopathy
Hydrocephalus Intermediate Sarcoidosis or other chronic meningitis, lymphoma or other CNS

neoplasm
Punctiform parenchymal enhancement Intermediate Sarcoidosis, vasculitis
Sicca syndrome Intermediate Sjögren syndrome
T2 hyperintensities of U fibers at the Intermediate CADASIL

vertex, external capsule, and insular
regions
Gastrointestinal symptoms Intermediate Whipple disease, celiac disease, and other malabsorptive states
that lead to vitamin B12 or copper deficiency
Regional atrophy of the brainstem Intermediate Behçet disease, adult-onset Alexander disease
Diffuse lactate increase on brain Intermediate Mitochondrial disease

magnetic resonance spectroscopy
Marked hippocampal and amygdala Intermediate Hyperhomocysteinemia

atrophy
Loss of hearing Intermediate Susac syndrome, glioma, vertebrobasilar infarction
Fulminant course Intermediate Thrombotic thrombocytopenic purpura, intravascular lymphoma,

acute disseminated encephalomyelitis (ADEM)
Symmetrically distributed lesions Intermediate Leukodystrophy
T2 hyperintensities of the basal ganglia, Intermediate Behçet disease, mitochondrial encephalomyopathies, Susac
thalamus, and hypothalamus syndrome, ADEM


Diffuse abnormalities in the posterior Intermediate Vitamin B12 deficiency, copper deficiency, paraneoplastic disorder
columns of the cord
Increased serum angiotensin-converting Intermediate Sarcoidosis, histiocytosis

enzyme level
Prominent family history Intermediate Depending on pattern of inheritance suggested by family history:
hereditary spastic paraparesis, leukodystrophy, Wilson disease,
mitochondrial disorders, CADASIL
Constitutional symptoms Intermediate Sarcoidosis, Whipple disease, vasculitis
Lesions across gray matter/white matter Intermediate Hypoxic-ischemic conditions, vasculitis, systemic lupus
boundaries erythematosus
T2 hyperintensities of the temporal pole Intermediate CADASIL
Complete ring enhancement Intermediate Brain abscess, glioblastoma, metastatic cancer
Progressive ataxia alone Intermediate Multisystem atrophy, hereditary spinocerebellar ataxia,

paraneoplastic cerebellar syndrome
Central brainstem lesions Intermediate Central pontine myelinolysis, hypoxic-ischemic conditions, infarct
Predominant brainstem and cerebellar Intermediate Behçet disease, pontine glioma

lesions
Neuropsychiatric syndrome Intermediate Susac syndrome, systemic lupus erythematosus, Wilson disease,
GM2 gangliosidosis
Lesions in the center of corpus callosum, Intermediate Susac syndrome

sparing the periphery
Seizure Intermediate Whipple disease, vasculitis, metastases
Dilation of the Virchow-Robin spaces Intermediate Hyperhomocysteinemia, primary CNS angiitis
Uveitis Intermediate Sarcoidosis, lymphoma, Behçet disease
Cortical/subcortical lesions crossing Intermediate Ischemic leukoencephalopathy, CADASIL, vasculitis

vascular territories
Pyramidal motor involvement alone Intermediate Primary lateral sclerosis variant of amyotrophic lateral sclerosis,
hereditary spastic paraparesis
626 JUNE 2019


Large lesions with absent or rare mass Intermediate Progressive multifocal leukoencephalopathy
effect and enhancement
Gradually progressive course from onset Intermediate Human T-cell lymphotrophic virus type I (HTLV-I)–associated
myelopathy, adrenomyeloneuropathy, adrenoleukodystrophy,
metachromatic leukodystrophy, vitamin B12 deficiency
No “occult” changes in normal- Intermediate Lyme disease, isolated myelitis, CADASIL

appearing white matter
Brainstem syndrome Minor Pontine glioma, cavernous malformation, vertebrobasilar ischemia
No enhancement Minor Progressive multifocal leukoencephalopathy, ischemic lesions,

metachromatic leukodystrophy
Myelopathy alone Minor Chiari malformation type 1, cord compression (including cervical
spondylosis), vitamin B12 or copper deficiency, HTLV-I
No optic nerve lesions Minor Metastatic carcinoma, gliomatosis cerebri, toxoplasmosis
Onset before age 20 Minor Mitochondrial encephalomyopathy, leukodystrophy, Friedreich

ataxia
No spinal cord lesions Minor Multiple infarcts, vasculitis, progressive multifocal

leukoencephalopathy
Abrupt onset Minor Cerebral infarction, cerebral hemorrhage, cerebral venous sinus
thrombosis
Large lesions Minor Glioblastoma, lymphoma, progressive multifocal

leukoencephalopathy
No T1-hypointense lesions (black holes) Minor Ischemic degenerative leukoencephalopathy, progressive

multifocal leukoencephalopathy
Onset after age 50 Minor Cerebral infarction, amyloid angiopathy, lymphoma
Marked asymmetry of white matter Minor Glioblastoma, lymphoma, cerebral infarction

lesions
CADASIL = cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy; CT = computed tomography;
MELAS = mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes; MRI = magnetic resonance imaging.
a
b
Red flags are ordered from the most “major” to the most “minor” as per subgroup rankings. Major red flags point fairly definitively to a non–
multiple sclerosis (MS) diagnosis; minor red flags may be consistent with MS or an alternative diagnosis. Intermediate red flags are those for which
there was poor agreement and uncertainty among raters about the weighting of the flag for differential diagnosis in MS, especially in isolation of
other informative symptoms, signs, and assays. Minor red flags suggest that a disease other than MS should be considered and fully explored, but
an MS diagnosis is not excluded.

CASE 2-3 A 56-year-old woman presented with episodes of nausea and vertigo
accompanied by visual obscuration involving both eyes. She described a
mild unilateral throbbing headache that accompanied these episodes.
She had several episodes lasting less than 24 hours over the week before
evaluation. The patient also described a prior history of intermittent right
leg numbness radiating from the buttocks to the toes that had occurred
approximately 3 years earlier and had resolved after a month. She did not
seek care for this symptom at the time. Her past medical history was
significant for hypertension and chronic tobacco use.
General and neurologic examinations were normal. MRI of the brain
demonstrated numerous T2-hyperintense lesions located predominantly
in the subcortical and deep white matter, but several periventricular and
juxtacortical lesions were noted. None demonstrated contrast
enhancement. MRI of the cervical and thoracic spinal cord was normal,
and CSF examination was normal.
COMMENT The age of this patient should prompt caution in the evaluation for multiple
sclerosis (MS) as an initial presentation of MS is less common in patients of
this age. Application of McDonald criteria may also result in diminished
specificity, as the criteria were not tested in patients older than the age of
50 and such patients are known to have an increased risk for comorbidities
causing MRI white matter abnormalities. This patient did not present with a
syndrome typical of MS and also, despite MRI abnormalities, had no
objective evidence of a central nervous system lesion that correlated with
present or prior symptoms. Despite MRI demonstration of dissemination in
space, the McDonald criteria cannot be applied.
This patient also presented with numerous clinical red flags, including
brief duration of symptoms atypical for demyelination; a normal neurologic
examination; no MRI lesions corresponding to vision loss, vertigo, or prior
leg symptoms; and comorbid conditions that included suspected migraine
by current history, hypertension, and tobacco use—all known to cause MRI
abnormalities that may mimic the appearance of MS. Although normal
spinal cord imaging and CSF do not rule out MS, they should be considered
red flags suggesting evaluation for a diagnosis other than demyelination in
a patient presenting with an atypical syndrome.
This patient presented with historical neurologic symptoms without
objective evidence on neurologic examination of the prior sensory
disturbance or on MRI of a spinal cord lesion corresponding to symptoms.
Prior symptoms without such objective corroborating evidence of a central
nervous system lesion should prompt caution before inclusion for
demonstration of dissemination in time. This patient had a better
explanation than MS for her symptoms and MRI abnormalities, including
migraine and vascular disease, especially after a thorough evaluation
including CSF and spinal cord imaging.
628 JUNE 2019

two of the following: (1) at least one T2-hyperintense MRI lesion in the
periventricular, cortical or juxtacortical, or infratentorial brain regions; (2) two
or more T2-hyperintense spinal cord lesions; or (3) detection of CSF-specific
oligoclonal bands. The criteria for the diagnosis of primary progressive MS
remain the same in the 2017 McDonald criteria as in the previous criteria, with
the exception of the incorporation of cortical and symptomatic lesions as discussed
for the criteria for relapsing MS. TABLE 2-5 presents the updated criteria for
primary progressive MS.
The differential diagnosis for primary progressive MS41 is considerably
shorter than that of relapsing-remitting MS and includes compressive myelopathy
and a limited number of hereditary, metabolic, inflammatory, infectious,
neuromuscular, vascular, paraneoplastic, and toxic disorders (TABLE 2-6). In
many cases, completion of laboratory, radiographic, and CSF evaluation may
provide red flags suggesting these alternative diagnoses.
MISDIAGNOSIS OF MULTIPLE SCLEROSIS

Misdiagnosis of MS (the incorrect assignment of a MS diagnosis) remains a
contemporary problem.5,6,33,38,42 MS misdiagnosis is associated with unnecessary
long-term risk and morbidity for patients and considerable costs to health care
systems.5 Although the prevalence of MS misdiagnosis is unknown, neurologists
endorse having frequently evaluated patients who had been previously
misdiagnosed with MS.33 Recent data concerning the characteristics of
misdiagnosed patients5,38 provide important guidance on its prevention.
Accurate diagnosis of MS relies on an initial clinical assessment to
determine if a presentation is typical for MS in order to proceed with the
diagnostic process described above. If objective evidence of a syndrome
typical for MS is not seen, the 2017 McDonald criteria do not apply. However,
many of the clinical diagnoses mistaken for MS are diagnoses that do not
Recommended Approach to Diagnosis of Multiple Sclerosis in Patients TABLE 2-4

With Atypical and Challenging Clinical Presentationsa
◆ Fulfillment of more than the minimum requirements of the McDonald criteria is necessary to
avoid misdiagnoses in the setting of red flags or an atypical presentation
◆ Evaluation for CSF-restricted oligoclonal bands or spinal cord lesions in patients with migraine,
vascular risk factors, or examination findings suggestive of a functional neurologic disorder
◆ In oligoclonal band–negative patients, consider repeat CSF evaluation at a later date
◆ Consider a lesion threshold of 6 mm for MRI criteria in patients with atypical syndromes and
advanced age
◆ Presence of callososeptal lesions may help differentiate MRI demyelination from vascular
changes
◆ Reevaluate preexisting diagnoses of multiple sclerosis in patients who transfer care from
another provider
◆ Additional clinical and radiographic monitoring for objective evidence supporting at least
two episodes of demyelination typical for multiple sclerosis may be necessary

a
Reprinted with permission from Solomon AJ, et al, Neurology.40 © 2018 American Academy of Neurology.

usually present with such typical syndromes.5 These include migraine,

functional neurologic disorders, fibromyalgia, and nonspecific symptoms that
do not localize to the CNS.5 This suggests either that, in some cases, the
evaluating providers are either unaware that MS diagnostic criteria require
objective confirmation of a limited number of specific syndromes for their
application or that patient syndromes are often incorrectly identified as
typical of MS-related demyelination. Thus, the first step in the prevention of
MS misdiagnosis may be broader education surrounding the diagnosis of
presentations typical for MS.
Abnormal brain MRI findings prompt an evaluation for MS in many patients.
Overreliance on such MRI abnormalities, particularly in patients with atypical,
nonspecific, or non–CNS-localizing clinical presentations, is an important
contributor to MS misdiagnosis.5 Demonstration of MRI dissemination in space is
possible in a number of common disorders, such as migraine34 and small vessel
ischemic disease, and lack of attention to the presence of atypical syndromes in
patients with these diagnoses leads to misdiagnosis.5 Furthermore, studies have
suggested that some providers either misunderstand34 or have difficulty
correctly applying MRI dissemination in space criteria to juxtacortical and
periventricular lesions.5 Careful and correct application of MRI dissemination
in space criteria, now further specified in 2017 McDonald criteria,4,5,34 would
likely also prevent many cases of MS misdiagnosis.
Although the identification of prior episodes of demyelination may aid
in the demonstration of dissemination in time and confirm a diagnosis of
MS, the assessment of historical episodes of neurologic symptoms without
objective evidence of a lesion has been noted to be a frequent contributor to
MS misdiagnosis.5 Authors of the 2017 criteria state that if such historical
events include “symptoms and evolution characteristic for a previous
inflammatory demyelinating attack,”4 they may be considered for demonstration
of dissemination in time in the absence of objective evidence. Determining
TABLE 2-5 2017 McDonald Criteria for Diagnosis of Multiple Sclerosis in Patients With
a Disease Course Characterized by Progression From Onset (Primary
Progressive Multiple Sclerosis)a
Primary progressive multiple sclerosis can be diagnosed in patients with:

◆ 1 year of disability progression (retrospectively or prospectively determined) independent
of clinical relapse
Plus two of the following criteria:
◆ One or more T2-hyperintense lesionsb characteristic of multiple sclerosis in one or more of
the following brain regions: periventricular, cortical or juxtacortical, or infratentorial
◆ Two or more T2-hyperintense lesionsb in the spinal cord
◆ Presence of CSF-specific oligoclonal bands
CSF= cerebrospinal fluid.

a
Reprinted with permission from Thompson AJ, et al, Lancet Neurol.4 © 2017 Elsevier Ltd.
b
Unlike the 2010 McDonald criteria, no distinction between symptomatic and asymptomatic MRI lesions is
required.
630 JUNE 2019

Differential Diagnosis of Progressive Multiple Sclerosisa TABLE 2-6
Cord Compression
◆ Cervical spondylosis
◆ Intrinsic or extrinsic tumor
Hereditary
◆ Hereditary spastic paraplegia
◆ Friedreich ataxia
◆ Leukodystrophies (adrenomyeloneuropathy, Krabbe disease)
Metabolic
◆ Vitamin B12 deficiency
◆ Phenylketonuria
◆ Copper deficiency
Inflammatory
◆ Neurosarcoidosis
◆ Central nervous system vasculitis
Infection
◆ Human T-cell lymphotrophic virus type I (HTLV-I)
◆ Schistosomiasis
◆ Syphilis
◆ HIV
◆ Brucellosis
Degenerative
◆ Motor neuron disease
Toxic
◆ Lathyrism
◆ Nitrous oxide
Vascular
◆ Dural arteriovenous malformation
◆ Cerebral autosomal dominant arteriopathy with subcortical infarcts and
leukoencephalopathy (CADASIL)
Paraneoplastic
HIV = human immunodeficiency virus.

a
Reprinted with permission from Miller DH, Leary SM, Lancet Neurol.41 © 2007 Elsevier Ltd.

TABLE 2-7 Recommendations for Prevention of Multiple Sclerosis Misdiagnosis When

Applying the 2017 McDonald Criteriaa
Typical Demyelinating Syndromes

◆ Multiple sclerosis (MS) diagnostic criteria should be applied only in the typical demyelinating
syndromes in which they have been validated
◆ Caution should be taken in patients older than 50 years of age (or younger than 11 years of
age) and in nonwhite populations
◆ Continue to consider a broad differential diagnosis, with vigilance for red flags, even in
patients with typical syndromes
Use of Prior Symptoms for Fulfillment of Dissemination in Time Criteria
◆ Objective evidence on neurologic examination or as the result of paraclinical testing (visual
evoked potentials, MRI, optical coherence tomography) must corroborate symptoms
◆ Objective evidence specific for central nervous system demyelination, such as internuclear
ophthalmoplegia or afferent pupillary defect, is preferred over nonspecific evidence such
as hyperreflexia
MRI Lesions and Their Characteristics
◆ Juxtacortical lesions must abut the cortex, without intervening white matter
◆ Periventricular lesions must abut the ventricles, without intervening white matter
◆ Lesions should be 3 mm or larger in diameter
◆ Small punctate lesions should not be used to fulfill MRI criteria
◆ Use of intracortical and subpial cortical lesions to fulfill criteria should be restricted to
experienced imaging centers
Symptomatic MRI Lesions for Fulfillment of Dissemination in Space and Dissemination
in Time
◆ In patients with monophasic syndrome of a single symptomatic brainstem or spinal cord
lesion where only one additional MRI dissemination in space region is satisfied, consider
awaiting appearance of an additional MRI lesion or additional clinical event to meet
dissemination in space criteria, especially when comorbidities are present
CSF Evaluation
◆ CSF evaluation is recommended before finalizing a diagnosis of primary progressive MS
◆ Oligoclonal bands restricted to the CSF should be used with caution in the presence of high
numbers of polymorphonuclear cells or highly elevated protein
◆ Positive oligoclonal bands should be used to substitute for dissemination in time criteria only
in patients younger than 50 presenting with optic neuritis, brainstem, or spinal cord
syndromes typical for MS and without evidence of another inflammatory central nervous
system condition
◆ If CSF is negative for findings typical of MS, a diagnosis of MS should be made with caution

a
Reprinted with permission from Solomon AJ, et al, Neurology.40 © 2018 American Academy of Neurology.
632 JUNE 2019

if remote and subsequently resolved symptoms (eg, a history of visual KEY POINTS
disturbance, vertigo or diplopia, or sensory and motor impairment in an
● The McDonald criteria
extremity) are indeed typical of MS-related demyelination can be especially have not been evaluated in
difficult. Without corroborating objective CNS findings on neurologic patients presenting with
examination, visual evoked potentials, or MRI, consideration of such atypical syndromes or
historical symptoms for the demonstration of dissemination in time warrants typical syndromes with red
flags, and additional clinical,
caution given its association with misdiagnosis. In some cases, waiting to
paraclinical, or radiographic
confirm a diagnosis of MS until interval imaging demonstrates MRI evaluation and monitoring is
dissemination in time may be prudent. In the majority of patients who do not necessary to confirm a
demonstrate clinical or MRI dissemination in time but have a high likelihood diagnosis of multiple
sclerosis.
of developing MS, evaluation for the presence of CSF-restricted oligoclonal
bands may now provide fulfillment of dissemination in time according to the ● In patients presenting to
2017 criteria.4 establish care with a
In the absence of a highly specific biomarker for MS, misdiagnosis may not preexisting diagnosis of
always be avoidable. In some cases, the passage of time after an initial multiple sclerosis,
reassessment of the
diagnosis may be necessary to reveal subsequent red flags for clinical features accuracy of multiple
atypical for MS and raise suspicion for alternative diagnoses. For this reason, it sclerosis diagnosis is
is necessary to continue to reassess any diagnosis of MS. Yet, as detailed above, prudent.
many causes of MS misdiagnosis reflect inappropriate application of MS
● The diagnosis of primary
diagnostic criteria. Although the McDonald criteria necessitate clinical
progressive multiple
assessments that, by definition, may be susceptible to error, a detailed sclerosis and its mimics
knowledge of the criteria and their various caveats and strict adherence to differs from that of
their application would likely prevent many cases of MS misdiagnosis. The relapsing-remitting multiple
sclerosis and requires a
2017 McDonald criteria now provide detailed discussion of MS misdiagnosis
thorough understanding of
and its avoidance and a helpful glossary defining the fundamental clinical, the assessment of clinical
paraclinical, and radiologic terms necessary for its correct application.3 progression.
TABLE 2-7 summarizes recommendations for the prevention of MS misdiagnosis
in the application of 2017 McDonald criteria.40 ● Misdiagnosis of multiple
sclerosis is often caused by
misapplication of the
McDonald criteria in
CONCLUSION patients with atypical
The skilled confirmation of a syndrome typical for MS demyelination is required syndromes, overreliance on
or misunderstanding of MRI
to maintain accuracy for the initial clinical assessment for a diagnosis of MS. dissemination in space, or
Meticulous knowledge of MS diagnostic criteria and their careful application is consideration of historical
necessary to confirm demonstration of dissemination in space and time episodes of symptoms
suggestive of MS. Vigilance for clinical, paraclinical, and radiographic red flags without objective evidence
of a central nervous system
and an understanding of the causes of MS misdiagnosis ensures that no better
lesion for demonstration of
explanation exists other than a diagnosis MS. dissemination in time.
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REVIEW ARTICLE

Phases and Phenotypes
ONLINE
of Multiple Sclerosis
By Orhun H. Kantarci, MD
ABSTRACT
PURPOSE OF REVIEW: This article describes the dynamic evolution of multiple
sclerosis (MS) through its phases and the impact of this understanding on
treatment decisions.
RECENT FINDINGS: MS consists of three phases: (1) the high-risk phase, (2) the
relapsing-remitting phase, and (3) the progressive phase. Increasingly,
subclinical disease activity is becoming an integral part of our definition of
disease course in MS. In many patients, the relapsing-remitting phase
starts as subclinical activity, likely long before they present with a
clinically isolated syndrome. Differentiating progressive MS subgroups is
also becoming less relevant. This is illustrated by comparing progressive
MS that evolves from an asymptomatic state in individuals with
radiologically isolated syndrome (primary progressive MS) and
symptomatic individuals with relapsing-remitting MS (secondary
progressive MS). In each case, the background disease activity and
pathology can be indistinguishable. These phases evolve on a continuum
and largely follow the aging process with little influence by the preceding
clinical activity level. Recently, it also became evident that one or a few
poorly recovered relapses at the beginning of clinical manifestations of MS
CITE AS:
predict much earlier progressive MS onset.
AND OTHER CNS INFLAMMATORY SUMMARY: These findings suggest that interventions to prevent progressive
DISEASES):636–654.
MS, when they become available for clinical practice, may need to be
Address correspondence to considered as early as when the asymptomatic radiologically isolated
Dr Orhun H. Kantarci, syndrome is detected. This early treatment approach is being evaluated
Department of Neurology, Mayo
Clinic, 200 First St SW,
with ongoing trials with available disease-modifying therapies. In contrast,
Rochester, MN 55905, continuing the use of disease-modifying therapy beyond a certain age
kantarci.orhun@mayo.edu. may have little benefit. However, being in the progressive phase of MS is
not, in itself, an argument against disease-modifying therapy use in active
Dr Kantarci serves as a reviewer disease in younger patients.
for Neurology and receives
research/grant support from
Biogen.
UNLABELED USE OF INTRODUCTION
H
PRODUCTS/INVESTIGATIONAL eterogeneity in clinical, radiologic, biological, and pathologic
USE DISCLOSURE:
Dr Kantarci reports no
presentations of multiple sclerosis (MS) has been well documented,
disclosure. beginning with Dr Charcot himself. Even the immunopathology of
MS has significant heterogeneity.1 This phenotypic variability is, at
© 2019 American Academy minimum, confusing and, at worst, leads to frustrating difficulties
of Neurology. with interpreting and applying clinical trial results in the real world. This is
636 JUNE 2019

further complicated by the fact that early clinical trials of disease-modifying KEY POINT
therapies largely focused on relapse reduction, whereas natural history studies
● Current disease course
completed before the advent of disease-modifying therapies showed that the classification in multiple
progressive phase is the key determinant of poor long-term disability in MS.2–5 sclerosis consists of three
These studies also documented that, other than progressive disease, determinants phases: the multiple
of worse long-term disability were male sex, older age at MS onset, spinal cord sclerosis high-risk phase,
the relapsing-remitting
syndrome at MS onset, and high early relapse rate.2–5
phase, and the progressive
Clinical definitions of MS phenotypes should be complemented by subclinical phase.
observations obtained with MRI. For example, in radiologically isolated
syndrome, classic MS findings are detected on MRI studies in patients who have
no typical symptoms of the disease. This situation was originally described as
asymptomatic MS as it had also been observed in autopsy studies. This article
discusses how understanding this asymptomatic phase of MS shed light onto MS
phenotypes such as primary progressive MS. We have also learned that all
progressive MS phenotypes, including primary progressive MS, have striking
similarities in pathology, imaging, and clinical presentations. Aging, through
yet-to-be-identified mechanisms, plays a major role in development of a
progressive clinical phenotype of MS. Recent findings also document that gray
matter atrophy in brain starts in the preclinical asymptomatic phase of MS, and
spinal cord atrophy is already detectable at the time of clinical manifestation of
progressive MS.6,7
Why does all this matter? The currently available disease-modifying therapies
that work through immunomodulation seem to be mostly ineffective once the
relapsing phase of MS is over. While mild to moderate disability in MS can be
driven by clinical relapses and partial remissions, most of the moderate to severe
disability in MS is associated with progressive disease. But, if the progressive
gray matter and spinal cord atrophy started much earlier than the clinical
manifestations, is it already too late to intervene with currently available
disease-modifying therapies at the time of clinical MS diagnosis? It seems natural
to think that when nervous system reserve is building earlier in life, it provides a
better opportunity to actively intervene with a disease such as MS to prevent
ensuing damage or harness the natural recovery process so that as one reaches an
age where the reserve plateaus or starts declining, neurodegeneration is less likely
to occur. While thinking about starting disease-modifying therapies earlier in life
(not just earlier in clinically observable disease course), the decision is further
complicated by the risks associated with prolonged exposure to disease-
modifying therapies. The future potential of regenerative medicine approaches
should also be considered. Understanding the clinical and radiologic phases of
MS as they relate to pathology will be necessary to make the individualized
treatment decisions of today and tomorrow.
PHENOMENOLOGY OF MULTIPLE SCLEROSIS

Interaction between two phenomena, relapses and progression, describe the
disease course in MS. These phenomena can overlap at different stages in the
disease. Current disease course classification in MS consists of three phases:
the MS high-risk phase, the relapsing-remitting phase, and the progressive
phase. About 80% of patients ultimately evolve to the progressive phase of the
disease.8 Each phase is further defined as active or inactive at any given time.
Understanding how MS phenomenology is defined will help the reader follow
the figures in this article. While diagnostic criteria are referred to in this

PHASES AND PHENOTYPES OF MS
article, it is important for readers to recognize that diagnostic criteria are

ever-evolving.
Relapses, Remissions, and Pseudorelapses

New events in a patient with MS are described as symptomatic or asymptomatic.
A symptomatic relapse refers to a distinct, acute to subacute (peaking over hours
to days), generally focal, sometimes multifocal and rarely diffuse, central
nervous system (CNS) syndrome. However, a patient may also present with
subclinical “activity” as new MRI lesions without symptoms, which is referred
to as an asymptomatic relapse. Pathologically, whether symptomatic or
asymptomatic, relapses reflect an acute inflammatory demyelination event
with or without axonal injury. Currently, the biological basis of why some
presentations remain asymptomatic in MS is unclear.
A symptomatic relapse generally plateaus over days to weeks, and a recovery
phase ensues. Remission refers to this recovery phase, with some level of
restoration of myelin and axonal integrity. Maximum clinical recovery after a
relapse generally stabilizes within the first 3 months and rarely continues beyond
6 months following a relapse. Most patients clinically recover completely or
almost completely back to baseline; some recover partially, but, rarely, patients
may not recover at all.9
Recovery in MRI lesions (symptomatic or asymptomatic) can be defined as
resolution of enhancement, restoration of diffusion characteristics, and
shrinkage in size of the MS lesion(s) on MRI. Rapidly developing imaging
technologies will likely give a better characterization of lesion recovery in the
future, so the definition of subclinical recovery may change.
Clinicians should be aware of and able to identify a pseudorelapse. A
pseudorelapse is a recurrence of symptoms from a previous clinical relapse
or a subclinical lesion. A pseudorelapse likely indicates incomplete recovery
from the previous CNS insult. Any stress to the nervous system (eg, heat,
infection, exercise, fatigue) exceeding a threshold that the damaged nervous
system can sustain can trigger a pseudorelapse. The sustained threshold is
likely determined not just by the damage and limited recovery alone but also
by the nervous system reserve. The latter is evident from many patients who
may develop pseudorelapses years later in a CNS location previously affected
by MS. The author of this article believes that this is due to aging and loss of
reserve that affects the damaged nervous system areas disproportionally.
Future studies looking into the age sensitivity of pseudorelapses can potentially
provide indirect proof of this concept. Once the trigger is eliminated,
symptoms are supposed to recover, often noted by the patients themselves
(eg, self-limited worsening during a hot shower or during a urinary tract
infection). If symptoms attributed to a pseudorelapse exceed the arbitrary
cutoff of 24 hours or do not start improving within a few days despite identifying
and intervening with a potential trigger (eg, treatment of a urinary tract
infection), an MRI should be obtained to differentiate it from a symptomatic
relapse recurrent in the same location or close vicinity on the same neural
pathway. Two potential scenarios can otherwise arise that are problematic:
(1) the patient is treated with steroids for a relapse because of strict adherence
to the 24-hour rule when he or she actually has an ongoing infection or (2)
the patient may be having a real relapse that cannot be differentiated from
an existing deficit by history or examination alone (eg, a slight change in
638 JUNE 2019

sensory level due to a new transverse myelitis), and a delay in steroid treatment KEY POINTS
may ensue. This is one area in which the development of cost-effective precise
● Progression is the
serologic markers of a relapse in MS can significantly help clinical practice in insidious and irreversible
the future. worsening of neurologic
function due to multiple
Progression and Pseudoprogression sclerosis over years.
Progression is the insidious and irreversible worsening of neurologic function
● Active disease in multiple
due to MS over years. The main corresponding pathology is one of progressive sclerosis is defined as new
axonal injury or loss. Imaging technology is evolving, and in the future, detection symptomatic relapses or
of subclinical progression will be an important component of the treatment asymptomatic MRI activity
decision-making process in MS. (contrast-enhancing
T1-hyperintense lesions,
In some patients, the term pseudoprogression is used to describe accumulating new T2-hyperintense
insidious disability due to factors indirectly related or unrelated to MS. Examples lesions, or enlarging
are deconditioning, degenerative joint diseases, other concomitant medical T2-hyperintense lesions).
illnesses associated with progressive fatigue, other causes of structural
● Worsening disability can
myelopathy (CASE 3-1), and other concomitant neurodegenerative diseases (eg, be due to the stepwise
Parkinson disease) and peripheral nervous system disorders that can increase accumulation of neurologic
in frequency with age. deficit from partially
recovered relapses, the
insidious accumulation of
Active Versus Inactive Multiple Sclerosis
neurologic deficit from a
Operationally, MS activity is defined clinically and subclinically. Active disease progressive disease course,
is defined as new symptomatic relapses or asymptomatic MRI activity a combination of both, or
(contrast-enhancing T1-hyperintense lesions, new T2-hyperintense lesions, or other multiple sclerosis or
non–multiple sclerosis-
enlarging T2-hyperintense lesions).11 The absence of active disease for an
related factors.
arbitrarily determined time cutoff of 1 year or more11 is referred as “no evidence
of disease activity” (NEDA).12 The NEDA definition also includes absence of
any progression in MS; however, active status, as used in this article and
supported by the author, implies what can be clinically and radiologically
demonstrated as potential ongoing immunologic activation. In the author’s
opinion, because of the differing biological phenomena discussed below,
inactive progression should be differentiated from an active progression within
the NEDA definition.
Disability Worsening
Worsening disability can be due to the stepwise accumulation of neurologic
deficit from partially recovered relapses, the insidious accumulation of
neurologic deficit from progressive disease course, a combination of both, or
other MS or non–MS-related factors.
Worsening disability sometimes is referred to as disability progression, but this
term should be avoided. Disease-modifying therapies can impact disability
worsening (the more appropriate term)11 by preventing symptomatic relapses
and asymptomatic subclinical activity. However, especially considering most
recent studies of CD20-depleting monoclonal antibodies that interfere with
disease activity (expectedly more so in younger individuals) without any clear
impact on inactive progressive MS, caution should be exercised in setting patient
expectations.10 Hence, the term progression should only be used to indicate
progressive MS and disease-modifying therapy should be described as decreasing
the likelihood of disability worsening due to active MS in the setting of
progressive MS. The concept of active versus inactive progressive MS is further
discussed in the next section.

CASE 3-1 A 40-year-old left-handed woman presented for a neurologic

consultation because of right-sided numbness and weakness. Three
weeks earlier, she had the abrupt onset of right-sided lower extremity
numbness and tingling below the upper chest wall, which peaked over
the course of a week. Over the week before presentation, she had
noticed the numbness had improved somewhat, but she had also
developed weakness on that side. She stated that starting at about age
37, she had noticed right hip problems, which were thought to be
mechanical in nature. She also noted right leg weakness and stiffness that
was chronic at onset and had been insidiously progressive since. After hip
surgery at age 39, she noticed a continued worsening and drag in her right
lower extremity and experienced falls. She described heat-induced
episodic worsening of her symptoms as well. She reported no bladder,
bowel, or upper extremity problems. She had no other significant
past medical history and no family history of neurologic disease or
autoimmune disease. She had never smoked, drank, or used drugs and
had always been athletic.
On examination, the patient was asymmetrically spastic and
paraparetic with right lower extremity dominance with brisk right lower
extremity deep tendon reflexes and an upgoing toe on the right side. She
had a sensory level around T8 on the right. MRI of the brain and cervical
and thoracic spinal cord showed cortical, juxtacortical, subcortical,
cervical medullary junction, C2-C3, left C4-C5, and right C5-C6 spinal
cord lesions, with mild atrophy associated with the right C5-C6 lesion
without enhancement. She also had moderate cervical spondylosis,
without central canal compromise, throughout most of the cervical spine.
All lesions were at a location and orientation typical of multiple sclerosis
(MS). She also had a faintly enhancing right anterolateral thoracic cord
lesion at T6-T7 and a small nonenhancing left posterolateral T8 lesion. A
lumbar puncture was performed, which showed 12 oligoclonal bands
unique to CSF; IgG index was elevated to 2.3. In retrospect, an MRI of her
brain obtained at age 35 for headaches reported similarly described brain
lesions, although she did not have any other symptoms at that time.
Although the images were not available for review, the report suggested a
diagnosis of pre–radiologically isolated syndrome or radiologically
isolated syndrome at that time.
The rest of the workup was negative for alternative diagnoses, and a
diagnosis of clinically active primary progressive MS was established.
Methylprednisolone 1 g/d IV for 5 days was given, but the patient failed to
have sufficient recovery within the next 4 weeks. Her sensory level
remained prominent, and, overall, her improvement from motor function
was, at best, 50% from her peak deficit 4 weeks after treatment. She then
received five plasma exchange treatments over the course of 10 days,
640 JUNE 2019

with rapid further recovery to 75% from the peak deficit overall. At the
same time, subcutaneous interferon beta was initiated since the patient
had active disease on top of a progressive course.
Over the next 3 years, the patient tolerated medications and stayed
active, with mild progression in the right leg weakness and spasticity
limiting her walking distance further, although she did not need any
support. Yearly imaging revealed no new lesion formation, and she had no
other new symptoms. The patient returned to clinic at age 44 with a
6-month history of progressively worsening bowel incontinence,
increased spasticity, and symmetric upper extremity numbness from her
midarms down that was provoked mainly by prolonged lying down and
improved after standing or sitting up for a while. Examination revealed
worsened right lower extremity spasticity compared to 1 year earlier.
Repeat MRI of the brain, cervical spine, and thoracic spine revealed no
evidence of new demyelinating lesions. However, the cervical central
canal stenosis had worsened, with bilateral C5-C6 foraminal stenosis.
She was referred to neurosurgery for intervention consideration.
This case illustrates the full spectrum of disease evolution, from COMMENT
asymptomatic findings on MRI to the development of progressive MS at a
relatively early age complicated by ongoing active MS on a background of
primary progressive MS. While a small percentage of patients with primary
progressive MS can have active disease, this generally happens at a
younger age. This patient would, in the old terminology, be described as
having relapsing-progressive or progressive-relapsing MS. Disease-
modifying treatments available for intervening with relapses would
therefore be indicated with the caveat that they will not necessarily impact
the insidious progression but may prevent any further cumulative deficits
that could arise from incomplete recovery from relapses in the future. The
progressive loss of nervous system reserve due to primary progressive
MS also makes this patient even more prone to a life-altering cumulative
deficit from a future relapse. In this author’s opinion, as this patient is still
at an age to have potentially active disease in the future (as discussed
further in the next section), the preventive treatment was indicated.
Indeed, most recent evidence from clinical trials with CD20-depleting
agents clearly confirm this approach.10 This case further illustrates a
relatively rapid change in progressive phenotype that led to a suspicion of
another neurologic problem. As the patient was monitored with cervical
MRIs, it became clear that the cervical canal stenosis was leading to a
pseudoprogression. After surgery, patient recovered back to her baseline
of about a year prior and resumed an active lifestyle.

PHASES AND DISEASE COURSE IN MULTIPLE SCLEROSIS

FIGURE 3-1 illustrates the dynamic phases of MS and diagnostic categories as a
patient evolves from one step to the other.13 Each step where a patient can
present is represented with a box outlining the diagnostic nomenclature. Some of
these concepts will be familiar as they are used in MS diagnostic criteria and
some not, such as the pre–radiologically isolated syndrome or solitary sclerosis
concepts; these conceptually fill the missing links in our understanding of
MS phases.
Relapsing-Remitting Phase
The relapsing-remitting MS diagnosis that most clinicians are familiar with
requires the presence of multiple clinically distinct events affecting different
parts of the CNS separated in time (arbitrarily defined as at least 1 month apart).
This operational diagnostic rule, core to understanding the diagnosis of MS, is
referred to as dissemination in time and space. All diagnostic criteria in MS (which
have seen many iterations over the years) have been based on this core rule.
However, in practice, one must see typical lesions in location, orientation, and
shape on MRI. In the absence of these typical lesions, other diagnostic
possibilities should be entertained. Also, in some patients with aggressive
presentations, sequential lesions could develop in intervals shorter than 1 month.
Activity status, as described above, is also used to further describe patients as
having active or inactive relapsing-remitting MS during a specific time period
(FIGURE 3-1).
After a first-ever or “singular” clinical event, the term clinically isolated
syndrome applies (FIGURE 3-1). When a patient experiences another clinical
relapse (clinically active disease),14 clinically isolated syndrome evolves into
clinically definite relapsing-remitting MS.15 According to the 2016 Magnetic
Resonance Imaging in Multiple Sclerosis (MAGNIMS) and the 2017 McDonald
criteria updates, MRI activity can fulfill dissemination in time and space criteria
without the need for another clinical relapse.16,17
Clinically isolated syndrome can be further subgrouped into two categories
(FIGURE 3-1). The term solitary sclerosis is used to define patients whose imaging
findings at the time of clinically isolated syndrome do not fulfill the minimum
MRI requirement for an MS diagnosis ( at least three of the four imaging
criteria),18 but the existing “multiple” additional CNS lesions are unexplained by
other pathology and are typical of MS in location, orientation, and shape. When a
patient with solitary sclerosis proceeds to fulfill the minimum MRI requirement
for an MS diagnosis (at least three of the four imaging criteria),18 the diagnosis of
single-attack MS may be used. While the ever-evolving diagnostic criteria have
included parts of clinically isolated syndrome with relapsing-remitting MS,
keeping clinically isolated syndrome separated as such into two subgroups has
three uses in real-world practice. First, all the original clinical trials in clinically
isolated syndrome were done without this division, but many patients
represented high-risk groups more like single-attack MS than solitary sclerosis by
the MRI criteria of dissemination in time and space used today. When the
single-attack MS category is categorized together with relapsing-remitting MS,
the application of these trials in current practice becomes limited to the solitary
sclerosis group for which they were not specifically designed to be enriched.
Until these subgroups are separated, it is clear from clinical practice and the
original clinically isolated syndrome trials that efficacy of preventing a second
642 JUNE 2019

KEY POINTS
● The relapsing-remitting
multiple sclerosis diagnosis
that most clinicians are
familiar with requires the
presence of multiple
clinically distinct events
affecting different parts of
the central nervous system
separated in time (arbitrarily
defined as at least 1 month
apart). This operational
diagnostic rule, core to
understanding the diagnosis
of multiple sclerosis, is
referred to as dissemination
in time and space.
● When a patient presents

with symptoms not typical
of multiple sclerosis (MS)
and an MRI is obtained that
fulfills the diagnostic
imaging criteria, a diagnosis
FIGURE 3-1 of radiologically isolated
Evolution within and between phases of multiple sclerosis (MS). syndrome is given. When
CIS = clinically isolated syndrome; PPMS = primary progressive multiple sclerosis; PSS = progressive these patients develop their
solitary sclerosis; RIS = radiologically isolated syndrome; RRMS = relapsing-remitting multiple sclerosis; first MS symptom, they
SAMS = single-attack multiple sclerosis; SAPMS = single-attack progressive multiple sclerosis; fulfill the criteria for
SPMS = secondary progressive multiple sclerosis; SS = solitary sclerosis. single-attack MS (30% in
Modified with permission from Zeydan B, Kantarci O, Neurol Clin.13 © 2017 Elsevier Inc. 5-year follow-up). This
evolution is significantly
faster in pediatric
radiologically isolated
syndrome (60% in 1-year
relapse was greatest in patients with high lesion loads. Therefore, caution should follow-up).
be exercised in discussion of disease-modifying therapy initiation with patients
with solitary sclerosis as evidence of efficacy has not been explicitly studied.
Second, each of these categories can evolve into a specific progressive phenotype
of progressive solitary sclerosis (FIGURE 3-1) that is not covered by the classic
definitions of primary progressive MS or secondary progressive MS. Third, as the
asymptomatic presentations discussed below evolve, this subcategorization
allows for a diagnosis to be established. Otherwise, the physician is left with
trying to fit the diagnosis into a category that does not really fit any diagnostic
criteria and there are gaps in the diagnostic continuum of phases of MS.
When a patient presents with symptoms not typical of MS and an MRI is
obtained that fulfills the diagnostic imaging criteria,18 a diagnosis of
radiologically isolated syndrome is given.19–21 When these patients develop their
first MS symptom, they fulfill the criteria for single-attack MS (30% in 5-year
follow-up).22–26 This evolution is significantly faster in pediatric radiologically
isolated syndrome (60% in 1-year follow-up).27
Many asymptomatic individuals present with lesions typical for MS but do not
fulfill the diagnostic imaging criteria, so, technically, a radiologically isolated
syndrome diagnosis cannot be established.18 The term pre–radiologically isolated
syndrome is used by some to define such cases. Currently, it is unclear how many
of these individuals with pre–radiologically isolated syndrome will evolve to

having radiologically isolated syndrome when they fulfill the imaging criteria or
evolve into having solitary sclerosis when they develop their first clinical event.
Progressive Phase
The progressive phase of MS is assumed to be established after 1 year of clinical
progression is documented. During this phase, patients can continue to have
active disease with symptomatic relapses or asymptomatic MRI activity because
of temporal overlap between the relapsing and progressive phases. The patient is
then further described as having active progressive or inactive progressive MS.
This is independent of the further progressive MS subgroup definition as
described below.
The progressive phase is classified into subgroups based on the presence or
absence of preceding clinical relapses before the onset of a progressive disease
course (FIGURE 3-1). Primary progressive MS refers to radiologically isolated
syndrome followed by the progressive phase (although, in most cases, this is
inferred, as discussed below when patients present with progression),23
single-attack progressive MS refers to single-attack MS followed by the
progressive phase,8,28 and secondary progressive MS refers to relapsing-
remitting MS followed by the progressive phase. If solitary sclerosis leads to a
progressive phase, it is described as progressive solitary sclerosis.29,30 Special
consideration should be given to understanding the primary progressive MS
diagnosis as, in most cases, patients have evidence of MRI activity compatible
with a previous radiologically isolated syndrome at the time of primary
progressive MS presentation, although a formal diagnosis of radiologically
isolated syndrome had not been previously established. It is, however, natural to
assume that if these patients had been imaged earlier, they would be compatible
with a radiologically isolated syndrome diagnosis.
The differences between the progressive MS subtypes do not seem to be
because of different progression mechanisms but rather because of why disease
activity remains subclinical in some individuals. This argument is specifically
supported by the following:
u The progressive phase of all subtypes of progressive MS seems to become symptomatic,

on average, in the mid-fifth decade (FIGURE 3-2)8,31,32
u Subclinical MRI activity in patients with radiologically isolated syndrome who develop primary
progressive MS cannot be reliably differentiated from subclinical MRI activity in patients
with relapsing-remitting MS who develop secondary progressive MS (FIGURE 3-333)23
u Even a single critically located lesion is enough to set up a patient for a progressive disease
course29,30
u The pathologic signatures of progressive MS, such as appearance of “smoldering plaques,”
are also age-dependent processes that are not strongly impacted by disease activity during
the preprogressive phase (FIGURE 3-4)34
Among patients with secondary progressive MS, once the progressive MS

course is set and patients reach moderate disability levels, any further disability
worsening is linear and follows a similar slope regardless of how long it took to
get to moderate disability levels in the first place (FIGURE 3-5).35 It almost seems
as if the disease has forgotten about the preprogression phase. Therefore, onset of
the progressive phase of MS seemingly is age dependent but agnostic to disease
duration and preprogressive phase.13 While the mechanisms of such an age
644 JUNE 2019

KEY POINT
● Onset of the progressive

phase of multiple sclerosis
seemingly is age dependent
but agnostic for disease
duration and preprogressive
phase.
FIGURE 3-2
Age at onset of clinically progressive multiple sclerosis (MS) is preprogression disease course
agnostic and does not differ between primary progressive MS, single-attack progressive
MS, and secondary progressive MS. The progressive phase of all subtypes of progressive MS
seems to become symptomatic, on average, in the mid-fifth decade. Therefore, age at onset
of clinically progressive MS is preprogression disease course agnostic and does not differ
between primary progressive MS, single-attack progressive MS, and secondary progressive MS.
CIS = clinically isolated syndrome; PPMS = primary progressive multiple sclerosis; RRMS = relapsing remitting
multiple sclerosis; SAPMS = single-attack progressive multiple sclerosis; SPMS = secondary progressive
multiple sclerosis.
Modified from Tutuncu M, et al, Mult Scler.8 © 2013 SAGE Publications.
dependence of progressive MS onset are yet to be fully understood, any future

(eg, regenerative) intervention to halt progressive MS should be applicable to
any progressive MS subtype regardless of what happened before the onset of the
progressive phase.
Whether a patient has none, one, or multiple clinical relapses before the onset
of progressive MS does not alter the age when clinically obvious progression
ensues.8,28,31,32,36 However, the potential imaging markers of subclinical
progression (eg, whole brain, thalamic, or spinal cord atrophy) likely starts long
before clinical progression is evident. Deep or cortical gray matter atrophy can
present as early as radiologically isolated syndrome.6 Patients with secondary
progressive MS have detectable spinal cord atrophy before or at the time
of progressive MS onset more than age- and sex-matched patients with
radiologically isolated syndrome and relapsing-remitting MS.7 Additionally,
limited recovery from the relapse(s) as early as the first relapse seems to accelerate
the progressive MS evolution regardless of later disease course (FIGURE 3-6).9
The combined conclusion from these studies is that mechanisms of the progressive
phase of MS are set in motion long before it is clinically evident. Hence, future
repair interventions targeting better recovery from relapses that are more frequent
early on may help delay the progressive MS phenotype. One caveat is that
spontaneous recovery potential from relapses is higher when patients are
younger and declines with age (FIGURE 3-7).37 Therefore, experience in a 2018
recovery trial has found a higher magnitude of effect in older patients with

FIGURE 3-3
Imaging of a patient with radiologically isolated syndrome that evolves into primary
progressive multiple sclerosis. A, At age 33, the patient is experiencing tension headaches
and the MRIs at the diagnosis of radiologically isolated syndrome reveal active and inactive
lesions: three periventricular lesions, one of which is gadolinium-enhancing; three juxtacortical
lesions; three infratentorial lesions; and one cervical spinal cord lesion at C3-C4. B, At
ages 36 through 38, MRIs at the follow-up of radiologically isolated syndrome reveal new
active and inactive juxtacortical and cortical lesions, periventricular lesions, subcortical
lesions (gadolinium-enhancing), and infratentorial lesions. C, At age 43, the patient presented
with progressive myelopathy. MRIs reveal an extensive lesion load, including T1-weighted
dark lesions; thoracic spine atrophy; and new inactive periventricular, subcortical, cervical
spinal cord, and thoracic spinal cord lesions.
Modified with permission from Kantarci OH, et al, Ann Neurol.33 © 2015 John Wiley & Sons.
limited recovery potential than in younger patients with spontaneous and

strong recovery potential.38 Also, it seems plausible to prevent even the first
relapse in the form of clinically isolated syndrome using currently available
disease-modifying therapies if one is to impact the future disease course in MS.
Such clinical trials in radiologically isolated syndrome are under way.
Several clinically useful predictors of evolution to progressive MS (other than
age) are having spinal cord lesions, being male, consuming tobacco, being obese,
and having a low serum 25-hydroxyvitamin D3 level.22–26 Even in the absence
of specific medications targeting progression alone in MS, some of these factors
are modifiable and, together with an active lifestyle and physical therapy, can
potentially help build nervous system reserve and resistance to injury.
Once the progressive phase starts, the relapse-based disability accumulation
gives secondary progressive MS and single-attack progressive MS a head start
over primary progressive MS at the time of progressive MS onset, leading to a
646 JUNE 2019

KEY POINTS
● Several clinically useful

predictors of evolution to
sclerosis (other than age) are
having spinal cord lesions,
being male, consuming
tobacco, being obese, and
having a low serum
25-hydroxyvitamin D3 level.
Even in the absence of
specific medications
targeting progression alone
in multiple sclerosis, some
of these factors are
modifiable and, together
with an active lifestyle and
physical therapy, can
potentially help build
nervous system reserve and
resistance to injury.
● Disease-modifying
therapies are efficacious
FIGURE 3-4 early in multiple sclerosis,
The pathologic phenotype of multiple sclerosis is age dependent. but the utility of continuing
Modified with permission from Frischer JM, et al, Ann Neurol.34 © 2015 John Wiley & Sons. them in patients older than
age 60 should be considered
on an individual basis.
higher starting point of disability.31,39 Also, mirroring the preprogressive phase,

patients with secondary progressive MS or single-attack progressive MS have a
higher tendency for clinically active MS than patients with primary progressive
MS.39 Clinically active progressive MS reaches severe disability milestones faster
than inactive progressive MS (FIGURE 3-840), but this clinically active phase has
an age limit, with chances of having a relapse decreasing to less than 5% in the last
part of the sixth decade and less than 1% after the sixth decade (FIGURE 3-941).31,39
The relevance of these observational data is seen in the context of currently
available disease-modifying therapies. FIGURE 3-9 shows that when considering
the overlap between onset of relapses and onset of progression, clear age periods
can be defined when available relapse prevention strategies would be the most
impactful. Interestingly, disease-modifying therapy trials have mostly included
more patients in the average impact period of 27 to 46 years of age rather than the
potentially more impactful period of earlier ages. In a 2017 meta-analysis of all
trials, disease-modifying therapy efficacy was found to be lower in older patients
compared to younger patients (FIGURE 3-10),42 likely reflecting the decrease in
relapses and increase in progressive MS with age. Disease-modifying therapies
are efficacious early in MS, but the utility of continuing them in patients older
than age 60 should be considered on an individual basis.
Pathologic Basis for Age Dependence of Phase Switches in

Multiple Sclerosis
Further research into understanding progression mechanisms and why some
patients never manifest clinical relapses in MS is needed. Pathologic studies have

FIGURE 3-5
The two-phase model of disability worsening in multiple sclerosis (MS) illustrates that while
it may take longer to reach moderate disability levels for different individuals, after that
point the disability worsening slope is linear and similar among different patients.
EDSS = Expanded Disability Status Scale.
Modified with permission from Leray E, et al, Brain.35 © 2010 The Authors.
FIGURE 3-6
Recovery from early relapses and progressive multiple sclerosis (MS) onset. Good recovery
from early relapses in MS delays the onset of progressive MS by decades.
Modified with permission from Novotna M, et al, Neurology.9 © 2015 American Academy of Neurology.
648 JUNE 2019

FIGURE 3-7
Recovery from first-ever and last-ever relapses from the same individuals. In a paired
analysis of first-ever or last-ever relapse in patients from a population-based cohort,
evidence of linear decline is seen in relapse recovery potential by age expressed as the
amount of recovery from Expanded Disability Status Scale (EDSS) score at the peak of a
relapse to maximum recovery attained. Pink dots represent the recovery from the first-ever
relapse. Green dots represent last-ever relapse in the same individuals, separated on
average by about 15 years. As recovery is measured by a drop of points from the peak deficit,
negative numbers indicate better recovery. It is clear that patients whose first-ever relapses
happen at an earlier age recover better than those whose first-ever relapses happen later in
life or whose last-ever relapses happen later in life. This is true for ages between 20 and 60,
but beyond these extremes, confidence intervals do not allow us to deduce a reliable
conclusion. Between these limits, however, an individual loses approximately a full point of
recovery potential in EDSS score and relatively linearly.
Modified from Conway BL, et al, Mult Scler.37 © 2018 SAGE Publications.
provided partial but critical understanding of some of the mechanisms involved

in phase switches in MS.
A cascade of tissue injury occurs in progressive MS that follows the general
order of demyelination, oligodendrocyte loss, thin axonal damage, astrocytic
gliosis, and absence of remyelination.43,44 Once the functional axonal threshold
(a factor of both axonal number and individual axonal function) is exceeded, the
progressive phase likely starts.45–47 When and how to interfere in this cascade
is not yet clear. The aging nervous system might simply be losing the trophic
support48 and myelin maintenance capacity to preserve the reserve that was
developed earlier in life.49,50 Oxidative stress followed by mitochondrial injury
due to higher levels of iron in the aging oligodendrocytes may contribute to
the age dependence of progressive MS onset.1 Trapped, compartmentalized
inflammation may also be a potential mechanism in the progressive phase of MS,
limiting anti-inflammatory access.1 Most recent studies also indicate a potential
role of changes in microglial activity by aging that impact the local immune
system response, leading to limited recovery and neurodegeneration.51,52

FIGURE 3-8
Impact of preprogression-onset relapses and postprogression-onset relapses on disability
accumulation in multiple sclerosis (MS).
EDSS = Expanded Disability Status Scale; PPMS = primary progressive multiple sclerosis; SAPMS = single-attack
progressive multiple sclerosis; SPMS = secondary progressive multiple sclerosis.
Modified with permission from Paz Soldán MM, et al, Neurology.40 © 2015 American Academy of Neurology.
MS pathology occurs on a continuum. Different MS plaque types (ie, active,

inactive, shadow, and smoldering)43,53 are present to different degrees at various
stages of disease. Some of this is predictable from clinical phase descriptions of
MS. Active plaques correlate with symptomatic relapses or asymptomatic MRI
activity.54 Inactive plaques with limited numbers of activated microglia are
present mainly in inactive progressive MS. Shadow plaques with full
remyelination capacity55 are present across all phases of MS.34 Smoldering
plaques are associated with both secondary progressive MS and primary
progressive MS and have a slowly expanding active rim of microglia with an
inactive center.34,43,56 Seemingly a pathologic hallmark of progressive MS, these
smoldering plaques peak in frequency at around the fifth decade, a time when
the dominant plaque type also switches from active to inactive plaques34
(FIGURE 3-4), mirroring the independent epidemiologic observation of
established mean age of progressive MS onset of 45 years (FIGURE 3-2).8 The
compact myelination in human brain terminates by the fourth decade, and white
matter integrity as measured by MRI is slowly lost in the following years.57,58
As the white matter reserve starts to decline in the fifth decade when all these
pathologic changes are happening, this likely forms the “perfect storm” for
progressive MS to manifest clinically.
CONCLUSION
The age of a patient seems to be highly relevant to the predicted phase of MS he
or she is in. While clinical milestones help define phases of MS, subclinical
disease processes have likely long been active, making imaging an integral part of
650 JUNE 2019

KEY POINT
● Seemingly a pathologic
hallmark of progressive
multiple sclerosis,
smoldering plaques peak in
frequency at around the
fifth decade, a time when
the dominant plaque type
also switches from active to
inactive plaques, mirroring
the independent
epidemiologic observation
of established mean age of
sclerosis onset of 45 years.
FIGURE 3-9
Overlapping age-dependent relapsing-remitting and progressive phases of multiple
sclerosis (MS) and their impact on potential treatment decisions. The 5% dotted line
marks the point below which there are only 5% of the patients crossing the line.
Therefore, in this superimposed image, 95% of individuals have their first relapse before
age 46, while 95% of individuals develop progressive MS after age 27. The dashed blue
line represents last-ever relapse, but this would be impacted by treatment as the others
are not. (Patients do not get treated before first-ever relapse and existing disease-
modifying treatments are not known to change progressive MS onset age as is). The
conclusion would be if one aimed to prevent the critical lesion(s) leading to progressive
MS in 95% of individuals, one needs to treat the patients at an age earlier than 27 with
disease-modifying treatments (ie, “high impact chance”). The other natural conclusion is
that after the second half of the fifth decade, continuing treatment will be nonproductive
for most patients (ie, “no impact chance”).
SD = standard deviation.
Modified with permission from Novotna M, et al, Neurology.41 © 2016 American Academy of Neurology.
understanding the disease course in MS. All patients start with a high-risk period
that is determined by genetic and environmental factors. This phase is followed
by the presymptomatic active phases of MS, followed by the relapsing-remitting
phase and, finally, in most patients, a progressive phase of MS. Therefore, MS is a
dynamic continuum of phenotypic phases. Each phase is linked to a change in
disability worsening that can result from poorly recovered relapses, progression,
and non-MS–related factors. Thus, it is evident that optimal windows of
opportunity exist for different types of interventions, such as the available
disease-modifying therapies, future reparative or regeneration therapies, or even
preventive strategies. For example, the optimal window for existing disease-
modifying treatments is earlier in life when the disease is more likely to be active.
However, our current strategy of treatment with escalation from weaker to strong
drugs may indeed be the opposite of what we should do. This author believes that
we will likely see an evolution of concepts toward more aggressive early treatment
with maintenance approaches later in life, especially in patients with relatively
active disease. As the definition of active MS is evolving, as is our understanding

FIGURE 3-10
Impact of age on disability worsening outcome in multiple sclerosis (MS) clinical trials. This
figure illustrates that, accounting for the size of individual clinical trials with disease-
modifying therapies, when placed against the age axis, their impact on reduction of disability
worsening (mainly due to active MS) declines with age. Same agents, such as the example
with ocrelizumab, utilized in different age groups for different trial constructs illustrate this
point better as an age effect that is seemingly true across the board.
Reprinted from Weideman AM, et al, Front Neurol.42 © 2017 The Authors
of the safety of disease-modifying drugs, we will be able to make better

individualized decisions in the future. Aging and the loss of ability to maintain
nervous system reserve must be kept in context when making these decisions.
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654 JUNE 2019

Management of Multiple REVIEW ARTICLE
Sclerosis Relapses

C O N T I N U UM AUDIO
ONLINE
By Pavle Repovic, MD, PhD
ABSTRACT
PURPOSE OF REVIEW: This article provides an overview of the clinical and
pathologic features of multiple sclerosis (MS) relapses and reviews
evidence-based approaches to their treatment.
RECENT FINDINGS: Despite the increasing number and potency of MS

treatments, relapses remain one of the more unpredictable and
disconcerting disease aspects for many patients with MS, making their
accurate recognition and treatment an essential component of good
clinical care. The expanding range of relapse treatments now includes oral
corticosteroids, comparable in efficacy to IV methylprednisolone at a
fraction of the cost. While this development improves access to prompt CITE AS:
treatment, it also underscores the importance of recognizing mimics of MS 2019;25(3, MULTIPLE SCLEROSIS
relapses to reduce corticosteroid overuse and its attendant risks. AND OTHER CNS INFLAMMATORY
SUMMARY: Like MS itself, MS relapse remains primarily a clinical diagnosis.

Address correspondence to Dr
The treatment options for MS relapse include corticosteroids, Pavle Repovic, MS Center,
adrenocorticotropic hormone (ACTH), plasma exchange, and rehabilitation, Swedish Neuroscience Institute,
1600 E Jefferson St, Ste A,
used singly or sequentially, with the goal of limiting the duration and impact Seattle, WA 98122,
of associated disability. Even when treated promptly and effectively, pavle.repovic@swedish.org.
clinical or subclinical sequelae of MS relapses frequently remain.
Dr Repovic has served as a
consultant for Biogen; EMD
Serono, Inc; Genentech, Inc;
INTRODUCTION Sanofi Genzyme; and Teva
F
or the majority of patients with multiple sclerosis (MS), especially those Pharmaceutical Industries Ltd
and has received personal
early in the disease course, relapse is the most apparent and compensation for speaking
unpredictable manifestation of their disease. The diagnosis (and name) engagements from Biogen; EMD
of relapsing MS is principally based on this event, the prominence of and Teva Pharmaceutical
which belies our understanding of its etiology. MS relapse can be Industries Ltd. Dr Repovic
defined as “a monophasic clinical episode with patient-reported symptoms and receives research/grant
support from Alexion, the
objective findings typical of multiple sclerosis, reflecting a focal or multifocal National Institutes of Health
inflammatory demyelinating event in the CNS, developing acutely or subacutely, (5U10NS077309), Novartis AG,
with a duration of at least 24 hours, with or without recovery, and in the absence and Genentech, Inc.
of fever or infection.”1 Symptoms of MS relapse typically evolve over hours to UNLABELED USE OF
days, reaching a nadir in a matter of days, followed by a gradual and variable PRODUCTS/INVESTIGATIONAL
USE DISCLOSURE:
recovery course over ensuing weeks to months. Both hyperacute and very
Dr Repovic reports no
gradual (eg, >12 weeks) presentations are uncommon and should prompt disclosure.
consideration of alternative etiologies.
Typical manifestations of MS relapses include optic neuritis, spinal cord © 2019 American Academy
syndromes, and brainstem syndromes (TABLE 4-12). Analysis of relapse of Neurology.

MANAGEMENT OF MS RELAPSES
phenotypes in 14,696 MS patients showed that most relapses are

monosymptomatic (71%) and involve sensory (48%), pyramidal (34%), or visual
(20%) functional systems.3 The relapse phenotype may change over the course of
MS; early in the disease course, sensory, visual, and brainstem relapses are
relatively more common than pyramidal, bowel/bladder, or cerebellar relapses,
which are more common later in the disease course. A tendency exists for
relapses to recur in a previously affected system, although the timing and the
location of a relapse remain unpredictable.3
The frequency of MS relapses decreases with both age and time from
diagnosis. Female patients, on average, experience more relapses than males
throughout the course of the disease.4 Based on the placebo arms of clinical trials,
a typical patient with MS has 0.27 to 1.66 relapses per year (ie, one relapse
approximately every 7 months to 4 years).5 This relapse rate has decreased over
the past 30 years; this appears to be more likely because of a change in study
recruitment patterns rather than a change in the nature of MS.5 MS relapses are
most frequent in early spring and least frequent in the winter of each
TABLE 4-1 Manifestations of Multiple Sclerosis Relapsesa
Common Features of Multiple Less Common Features of Multiple Atypical Features Not Expected in
Sclerosis Relapse Sclerosis Relapse Multiple Sclerosis Relapse
Optic nerve
Unilateral optic neuritis; pain on eye Uveitis (mild, posterior); no pain; no light Progressive optic neuropathy; severe
movement; partial and mainly central perception; bilateral simultaneous optic continuous orbital pain; persistent
visual blurring; normal disc or mild neuritis; moderate to severe disc complete loss of vision; neuroretinitis
disc swelling swelling with no hemorrhages (optic disc swelling with macular star);
uveitis (severe, anterior)
Brainstem/cerebellum
Bilateral internuclear Unilateral internuclear ophthalmoplegia; Complete external ophthalmoplegia,

ophthalmoplegia; ataxia and facial palsy, facial myokymia; one-and- vertical gaze palsies; vascular territory
multidirectional nystagmus; sixth a-half syndrome; trigeminal neuralgia, syndrome (eg, lateral medullary); third
nerve palsy; facial numbness deafness nerve palsy; progressive trigeminal
sensory neuropathy; focal dystonia;
torticollis
Spinal cord
Partial myelopathy; Lhermitte sign; Complete transverse myelitis; Anterior spinal artery territory lesion;
deafferented hand; numbness; paroxysmal tonic spasms; cauda equina syndrome; sharp sensory
urinary urgency, incontinence, radiculopathy, areflexia; segmental loss level to all modalities and localized
erectile dysfunction of pain and temperature sensation; spinal pain; complete Brown-Séquard
partial Brown-Séquard syndrome; fecal syndrome; acute urinary retention
incontinence
Cerebral hemispheres
Mild subcortical cognitive Epilepsy; hemianopia Encephalopathy (obtundation,

impairment; hemiparesis confusion, drowsiness); cortical
blindness
a
656 JUNE 2019

hemisphere6 and correlate with not only the seasonal variation in vitamin D KEY POINTS
levels and sunlight exposure but also latitude.7,8
● Typical manifestations of
multiple sclerosis relapses
PATHOPHYSIOLOGY OF MULTIPLE SCLEROSIS RELAPSES include optic neuritis, spinal
On a cellular level, the shared pathologic substrate of MS relapses is impaired cord syndromes, and
axonal conduction resulting from the combined effects of demyelination, brainstem syndromes.
inflammation, and a variable degree of neuronal loss.9 Loss of myelin, either
● The shared pathologic
between the nodes of Ranvier or through the widening of a nodal gap, increases substrate of multiple
the electrical capacitance of an axon, requiring higher current to depolarize the sclerosis relapses is
node. At the same time, newly demyelinated axolemma offers greater surface impaired axonal conduction
area to disperse the available current. Combined, these effects of myelin loss lead resulting from the combined
effects of demyelination,
to axonal conduction block by increasing the nodal firing threshold and reducing inflammation, and variable
the current available to do so. In addition, proinflammatory cytokines (tumor degree of neuronal loss.
necrosis factor-a, interferon gamma) contribute to axonal block either through
direct action on ion channels or indirectly by promoting local synthesis of nitric ● Viral and bacterial
infections increase the risk
oxide, a potent conduction blocker.9 of multiple sclerosis
The immunopathologic events leading to MS relapse are only partially known. relapse.
Initial triggers of MS relapse have long been sought through association studies,
ruling out exercise and epidural anesthesia.10,11 To date, evidence suggests that
systemic infections, perceived stress, the postpartum trimester, and assisted
reproductive techniques are associated with increased risk of MS relapse.4 Viral
and bacterial infections increase the risk of MS relapse, presumably by eliciting
helper T cell type 1 (TH1) immune response, whereas parasitic infections, which
elicit helper T cell type 2 (TH2) response, do not.
Given the strong and consistent relationship between viral or bacterial
infections and MS relapses, strategies to prevent infections, including
vaccination, are reasonable and recommended. Inactivated vaccines are
considered safe in MS, and for some vaccines (against seasonal influenza,
tetanus, and hepatitis B), compelling evidence exists that they do not increase
the risk of MS relapse.12 Live attenuated vaccines, on the other hand, require
caution, especially for patients with MS on immunosuppressants, as the
attenuated virus may cause the disease it was meant to prevent. In addition, some
live attenuated vaccines (eg, yellow fever vaccine) may increase the risk of MS
relapse and require careful consideration of risks and benefits.13 Current
guidelines recommend routine vaccination against seasonal influenza using
standard-dose inactivated (but not live attenuated) vaccine.14 Until more safety
data are available, the high-dose inactivated seasonal influenza vaccine is not
recommended for patients with MS.15 The recently approved nonlive herpes
zoster vaccine may be safer than the live attenuated vaccine. Vaccination within
4 to 6 weeks of a disabling MS relapse is not recommended, unless the delay
would harm the patient (eg, tetanus vaccine after open wound).14
Whatever triggers a relapse, it is followed by the inflammatory phase,
characterized by the trafficking of autoreactive immune cells into the central
nervous system (CNS). This influx is facilitated by the breakdown of the
blood-brain barrier, the macroscopic correlate of which can be seen on MRI as
extravasation of gadolinium from the circulation into the CNS parenchyma.
Serial MRI scans show that gadolinium enhancement is a temporary feature of
most (but not all) new lesions, only observable for several weeks, after which the
blood-brain barrier is repaired and the lesion ceases to take up contrast.16
Magnetic resonance spectroscopy and histopathologic studies indicate that

CASE 4-1 A 37-year-old woman with relapsing-remitting multiple sclerosis (MS)

presented with the subacute onset of bilateral blurred vision that began
3 weeks earlier and had gradually worsened. She reported no associated
temporal or retroorbital pain, change in color perception, diplopia, or any
other symptoms. The patient was concerned that her blurred vision could
be another episode of optic neuritis.
She had been diagnosed with MS 3 years earlier, based on a history of
partial transverse myelitis with supportive MRI findings of a gadolinium-
enhancing spinal cord lesion at the T5 level, along with two enhancing
and several nonenhancing T2-hyperintense brain lesions consistent with
demyelinating disease. She had been treated with dimethyl fumarate for
11 months but then had an episode of optic neuritis in her left eye. Repeat
brain MRI at that time detected several lesions, some with enhancement,
that had developed despite reported adherence to treatment. Her
disease-modifying therapy was changed to fingolimod at that time, with
good tolerability and no subsequent relapses or additional lesions on
surveillance MRIs. She was diagnosed with diabetes mellitus 6 months
before this presentation, but her medical history was otherwise
unremarkable.
On examination, her visual acuity was 20/25 in both eyes, with pinhole
correction, a change from her baseline 20/20 vision. No relative afferent
pupillary defect or color desaturation was apparent. Ophthalmoscopic
examination was unremarkable. However, on Amsler grid testing, she
reported distortion of lines in her left eye. She was referred for urgent
ophthalmologic evaluation for possible macular edema, a known, albeit
uncommon, adverse effect of fingolimod. The ophthalmologist’s report
received later that day reported normal findings. However, the patient
did not have optical coherence tomography at this visit; when she
returned for the test the following day, it demonstrated bilateral macular
thickening consistent with cystoid macular edema. Fingolimod was
discontinued, and her vision returned to normal within several weeks.
COMMENT Because this patient’s blurred vision developed over several weeks and
had no associated pain or change in color perception, it did not fit the
expected pattern of optic neuritis, prompting consideration of alternative
etiologies. Fingolimod-associated macular edema is uncommon (incidence
of 5 per 1000), but this patient’s risk may have been higher owing to her
recent diagnosis of diabetes mellitus. Discontinuation of fingolimod leads
to resolution of macular edema and associated symptoms in over 90% of
affected patients.21
658 JUNE 2019

demyelination and axonal loss occur during this inflammatory phase of the KEY POINTS
relapse.9 Four distinct histologic patterns of lesions have been described, based
● Resolution of the
on the relative prevalence of macrophages and complement/antibody deposits inflammatory phase of a
and the presence or absence of oligodendrocyte apoptosis.17 multiple sclerosis relapse is
Resolution of the inflammatory phase of a relapse is followed by a reparative followed by a reparative
phase. During this reparative phase, the blood-brain barrier is repaired, MRI phase.
enhancement resolves, and surviving axons are remyelinated. As the myelin
● Even when symptoms are
sheath is regenerated and local inflammation subsides, axonal conduction is unequivocally multiple
restored, manifesting clinically as gradual return of neurologic function. Even in sclerosis–related, a
the absence of remyelination, axonal conduction block may be reversed within distinction needs to be
weeks through redistribution of sodium channels. Remyelination is variable made between a bona fide
multiple sclerosis relapse
among individuals and, while it generally declines with age, is not restricted only and a pseudorelapse.
to young patients or to a specific phase of MS.18 Reparative processes are slower
than the inflammatory phase and may take up to 12 months.19 ● Fluctuation of symptoms
in patients with multiple
sclerosis is attributed to
PSEUDORELAPSES variable efficiency of repair
Recognition of MS relapse can sometimes be challenging for several reasons. following a relapse.
First, patients may underreport or overreport their symptoms. In one survey, as
many as 28% of patients did not report their most recent relapse.20 Second,
clinicians may misattribute reported symptoms to MS, even if that is not the case
(CASE 4-1), or dismiss reported symptoms, especially in patients who tend to
overreport them. Finally, even when the symptoms are unequivocally
MS-related, a distinction needs to be made between a bona fide MS relapse and
a pseudorelapse.
Considering that relapse frequency is a primary outcome of many therapeutic
trials in MS, attempts have been made to define a “confirmed” relapse; however,
these algorithms often rely on expert panel and complex criteria that are
impractical in routine clinical practice. To date, no simple biomarker or
algorithm is available to confirm an MS relapse, and its diagnosis ultimately relies
on clinical judgment. To aid the clinician in this task, some common and less
common features of MS relapses, organized by functional system, are listed in
TABLE 4-1. This list is neither exhaustive nor absolute. Nevertheless, if atypical
features are present, they warrant a search for an alternative cause other than
MS. Common features of typical relapses could also be used to educate patients
with MS to reduce underreporting.
Fluctuation of symptoms in patients with MS is attributed to variable
efficiency of repair following a relapse. Repaired myelin sheath is almost always
thinner (having fewer folds) and with shorter internodal distances than native
myelin. In addition, axonal segments that are not remyelinated adapt via sodium
channel redistribution, resulting in more continuous (as opposed to normal
saltatory) conduction of action potentials. This microsaltatory conduction and
incomplete remyelination lead to slower axonal conduction that can be
quantified as increased latency of visual, somatosensory, or brainstem evoked
potentials. Conduction slowing in an optic nerve is responsible for the Pulfrich
phenomenon: an object oscillating in a vertical plane is perceived instead as
following an elliptical trajectory in a horizontal plane, or, more prosaically,
oncoming traffic is seen as veering toward the driver.9
Demyelinated and remyelinated neurons exhibit other electrophysiologic
aberrations that underpin some of the clinical symptoms in MS. These include
positive phenomena (such as spontaneous or movement-induced generation of

CASE 4-2 A 58-year-old man with relapsing-remitting multiple sclerosis (MS)

presented with symptoms of worsening ambulation and falls. He had
been diagnosed with MS 12 years earlier, when he presented with
diplopia and a prior episode of right leg weakness as well as MRI
evidence of brain and spinal cord lesions. Despite treatment with
interferon beta followed by glatiramer acetate, he continued to have
relapses, so 7 years ago, he started treatment with natalizumab. Since
then, he had experienced no additional relapses or MRI lesions on
surveillance scans and had no evidence of antibodies to JC virus on
quarterly tests. For ambulatory problems, he had been treated with
dalfampridine.
In clinic, he reported more difficulty standing up from a seated position
and more difficulty ambulating for the previous 2 weeks. He had started
using a cane after his right leg had buckled and he fell at home 3 days
before. The episode reminded him of the symptoms he had 2 years
earlier, when he ran out of dalfampridine because of a change in
insurance.
On examination, his right hip flexion was measurably weaker than
previously, and his timed 25-foot walk was 6.7 seconds, worse than his
baseline of 5.4 to 5.8 seconds over the past year. He reported more
fatigue but denied any other focal symptoms. He also denied any fever,
symptoms of an infection, or change in mentation. Four weeks earlier, he
had started taking baclofen to help with leg spasticity. His most recent
natalizumab infusion was 3 weeks before this presentation.
Because of his treatment with natalizumab, an urgent MRI was
performed, which showed no new lesions or lesions suspicious for
progressive multifocal leukoencephalopathy. Laboratory tests showed
normal electrolytes and liver function; however, urinalysis was positive
for nitrites and leukocyte esterase. Urine culture grew more than 100,000
Escherichia coli colony-forming units per milliliter, resistant to
fluoroquinolones and trimethoprim-sulfamethoxazole but sensitive to
nitrofurantoin. He was treated with nitrofurantoin, with improvement in
leg weakness and ambulation over the next 2 weeks.
COMMENT This patient presented with recurrence of his prior neurologic symptom
(leg weakness) against the background of well-controlled MS relapses on
an effective disease-modifying therapy and in the setting of subclinical
infection. While potential causes of pseudorelapse were being
investigated, he underwent evaluation for progressive multifocal
leukoencephalopathy, as should any patient on natalizumab who is
experiencing new symptoms, regardless of his or her JC antibody status.
Another possible contributor to his symptoms could have been the
initiation of baclofen, as antispasticity agents may uncover existing
weakness by reducing the tone of affected muscle.
660 JUNE 2019

electrical impulse, as seen with neck flexion in the Lhermitte sign) as well as KEY POINTS
negative phenomena (intermittent filtering or conduction block that follows a
● Uhthoff phenomenon
sustained train of impulses). The most prominent of the negative phenomena, refers to reoccurrence of a
the Uhthoff phenomenon, refers to reoccurrence of a neurologic deficit from an neurologic deficit from an
earlier relapse (eg, visual blurring in a patient with a history of optic neuritis) in earlier relapse in the setting
the setting of increased core body temperature, classically observed with of increased core body
temperature, classically
exercise. The rise in core body temperature, even by a few fractions of a degree,
observed with exercise.
elicits conduction block due to temperature-related prolongation of the refractory
(eg, nonexcitable) period of demyelinated axons. Although the Uhthoff ● Several clinical trials and
phenomenon typically manifests as recapitulation of neurologic deficit from two meta-analyses provide
prior relapse, occasionally it may unmask previously unknown neuronal injury22 evidence that high-dose
corticosteroids hasten
or manifest less focally as cognitive or ambulatory decline.23,24 Drowning, neurologic recovery after
scalding, and other accidents have been attributed to this phenomenon.9 multiple sclerosis relapse.
The Uhthoff phenomenon is typically short-lasting and reverses readily with
cooling as the axonal conduction block resolves. When the recrudescent
symptoms persist for longer periods of time, mimicking MS relapse, the event
is referred to as a pseudorelapse. Pseudorelapses typically affect the same body
part and symptom constellation as a historical relapse, although symptoms may
not be as intense. Pseudorelapses can be seen in diverse settings that lead to an
increase in core body temperature, most frequently with fever, overt or occult
infection (eg, urinary tract infection), menstrual period, or stress (CASE 4-2).
A pseudorelapse should always be considered when patients report symptoms
similar to past MS relapses. In the absence of obvious triggers, laboratory testing
(eg, urinalysis with culture if indicated, complete blood cell counts, serum
electrolytes, and liver function tests) can help uncover triggers of pseudorelapse,
as can assessment of recent changes in medications. In case of infections,
however, caution is warranted since a pseudorelapse may be followed by a bona
fide MS relapse.
TREATMENT OF MULTIPLE SCLEROSIS RELAPSE

The majority of MS relapses are followed by some degree of spontaneous
recovery even without dedicated treatment. The dynamics of MS relapses
combined with their diverse phenotypes have made it challenging to distinguish
the additive effect of any given treatment to the natural course of recovery.
A number of clinical trials have attempted to address this conundrum, leading to
the current evidence that supports the use of corticosteroids, adrenocorticotropic
hormone (ACTH), and plasma exchange for MS relapse. Unfortunately, these
trials also suggest that while treatments hasten the recovery from a relapse in the
short term, they may not alter the long-term outcome in terms of our current
measures of neurologic disability. Nevertheless, the treatment of MS relapses
remains valuable in that it alleviates suffering, since the full impact of a relapse,
including emotional and financial costs to patients and their social networks, goes
well beyond the measures of neurologic function.
Corticosteroids
Corticosteroids are the principal treatment modality for MS relapses. Since their
earliest published use in MS in 1951,25 numerous studies have addressed the
effects of corticosteroids on MS. As a result, considerable variability remains
regarding the dose, type, and duration of corticosteroid regimens used for MS
relapses. Several clinical trials and two meta-analyses provide evidence that

high-dose corticosteroids hasten the neurologic recovery after MS relapse. In one

meta-analysis, compared to placebo, patients treated with high-dose steroids
improved by 0.76 points on the Expanded Disability Status Scale (EDSS) 5 to
7 days after treatment and by 0.85 points 2 to 4 weeks later.26 In another
meta-analysis, high-dose steroids reduced the odds of no improvement 5 weeks
after treatment to 0.2 compared to placebo.27 High-dose steroid treatment
was defined as at least 500 mg methylprednisolone or equivalent, given daily
for at least 3 days. One commonly used steroid regimen is 1000 mg daily IV
methylprednisolone for 3 to 5 days.28
Unless the relapse is very severe and leads to hospitalization, IV corticosteroids
can be administered at home or in an outpatient setting, with similar efficacy.29
Methylprednisolone, approved for medical use in 1951, is relatively inexpensive,
although the cost of its IV administration remains significant, about $2400 for a
3-day course on outpatient basis, according to a 2016 analysis.30
Oral steroids are less expensive, somewhat more convenient, and no less
effective than IV steroids for the treatment of MS relapses. Five clinical trials and
their meta-analysis, comprising 215 patients, provided initial evidence that oral
and IV steroids offer similar benefits.31 However, because of methodologic flaws
in some of the studies, these conclusions were regarded as tentative by some
specialists, awaiting confirmation from a larger, sufficiently powered
double-blind randomized clinical trial. The COPOUSEP (Oral Versus
Intravenous High-dose Methylprednisolone for Treatment of Relapses in
TABLE 4-2 Some Common Adverse Effects Associated With the Use of
Corticosteroids and Mitigation Strategies
Adverse Effect Mitigation Strategya

Flushing Reduce the rate of steroid infusion (if IV)
Insomnia Zolpidem 5 mg (female) or 5–10 mg (male) oral, lorazepam

0.5 mg oral, or doxepin 25 mg oral
Anxiety, agitation, or Lorazepam 0.5 mg oral

euphoria
Gastrointestinal pain/ Over-the-counter indigestion aids, omeprazole 20 mg oral

indigestion
Nausea/vomiting Metoclopramide 25 mg oral, ondansetron 4 mg oral
Elevated blood pressure Low-salt diet, adjustment of antihypertensive medication
Hyperglycemia Insulin sliding scale
Hypokalemia Potassium chloride 1000 mg oral if low potassium on basic

metabolic profile, or if patient on acetazolamide or taking
potassium-wasting diuretic
Edema Hydrochlorothiazide 12.5–25 mg oral
Metallic taste (dysgeusia) Breath mints
IV = intravenous.
a
In patients with history of prior adverse effect(s), mitigation strategies may be used prophylactically.
662 JUNE 2019

Patients With Multiple Sclerosis) trial, published in 2015, provided this KEY POINTS
evidence.32 This multicenter trial enrolled 199 patients who were randomly
● Oral steroids are less
assigned to receive 1000 mg methylprednisolone daily for 3 days, either IV or expensive, somewhat more
orally (as 10 tablets of 100 mg methylprednisolone, a tablet strength that is not convenient, and no less
available in the United States). Steroid treatment was initiated within 15 days of effective than IV steroids for
symptom onset (average 7 days). The primary objective of this study was to the treatment of multiple
sclerosis relapses.
compare the proportion of patients who improved by day 28 without additional
steroid treatment. Eighty-one percent of oral and 80% of IV subjects met this ● Given the considerable
end point, offering the strongest evidence of noninferiority between these frequency of steroid side
two routes of steroid administration. The extent of improvement, time to effects, a proactive
improvement, need for additional treatment, and proportion of patients who approach to minimize their
impact on patients is
fully recovered at 28 days or 6 months were no different between oral and IV recommended.
groups. The proportion of patients who subsequently experienced a relapse
within 6 months also did not differ between the two routes of administration.
Oral steroids were tolerated as well as IV steroids, except for insomnia, which
was more common with oral steroids (77% compared to 64%), leading to the
recommendation that steroid tablets be taken in the morning rather than in the
evening. This study did not use imaging-based outcomes, but an earlier study of
49 patients showed that oral and IV steroids have equivalent effects on MRI
outcomes in MS relapses.33 Another study of 55 patients with optic neuritis
compared bioequivalent doses of 1000 mg IV methylprednisolone and 1250 mg
oral prednisone and reached much the same conclusions with regard to recovery
of visual acuity and visual evoked potentials.34
In the United States, the convenience of oral corticosteroids is somewhat
offset by the number of tablets patients must take to reach doses comparable to
those used in the studies discussed above. With the currently available
formulations, this translates into a daily regimen of 25 tablets of 50 mg
prednisone or 32 tablets of 6 mg dexamethasone.
Following a pulse of high-dose corticosteroids, a tapering dose is not necessary in
most cases. Early trials used steroid taper after high-dose treatment to avoid acute
adrenal insufficiency or to prolong the anti-inflammatory effect. Subsequent
research has shown that this taper is not necessary after a brief (3- to 5-day) course
of high-dose steroids, since such a brief steroid pulse does not significantly suppress
the hypothalamic-pituitary-adrenal axis,35 nor does taper contribute to recovery.36
Common side effects of high-dose steroids are listed in TABLE 4-2. Almost all
patients exposed to high-dose steroids experience at least one of these side
effects. In one survey, the most common steroid-related adverse effects were
metallic taste, facial flushing, and gastrointestinal disturbance. One-third of
adverse effects were deemed severe by patients and impacted their activities of
daily living. More side effects were seen with longer (5-day) steroid courses than
with shorter (3-day) steroid courses. CNS-related adverse effects were twice as
common among patients with higher disability and higher burden of disease.37
Given the considerable frequency of steroid side effects, some trials have
taken a proactive approach to minimize the impact of side effects on patients. In
the COPOUSEP study, for example, sucralfate and omeprazole were universally
administered,32 possibly explaining fewer reports of gastrointestinal symptoms
compared to the study by Jongen and colleagues37 (44% versus 53%). These and
other mitigation strategies are outlined in TABLE 4-2. Uncommon but serious side
effects of corticosteroids include avascular bone necrosis, pancreatitis, hepatitis,
and psychosis.

Adrenocorticotropic Hormone
A preparation of purified ACTH in gelatin that provides a prolonged release after
IM injection was approved for use in MS based on the results of the United States
Cooperative Study, conducted from 1965 to 1968.38 This was a double-blind
study that randomly assigned 197 patients within 8 weeks of a relapse to either
placebo or ACTH gel for 2 weeks. Patients with advanced MS and those who were
recently treated with ACTH or corticosteroids were excluded. ACTH gel was
administered as IM injection at a tapering dose (40 U 2 times a day for 7 days,
followed by 20 U 2 times a day for 4 days and 20 U daily for 3 days). Patients were
evaluated weekly for 4 weeks. Compared to placebo, a greater proportion of
the ACTH-treated group showed improvement at weekly assessments during
weeks 1 to 3 after relapse; by week 4, however, the difference was not statistically
significant.38 The benefit seemed to be limited to patients who had no
improvement of relapse symptoms before entering the study.
ACTH gel is contraindicated in patients with osteoporosis, a history of peptic
ulcer disease, or chronic heart failure and in those allergic to porcine proteins.
The immunogenic potential of ACTH gel is also recognized, with antibodies
formed either to the ACTH itself or other proteins in the preparation.39
Compared to corticosteroids, ACTH use in MS relapses is not well defined.
Assertions that ACTH gel is better tolerated than corticosteroids have not been
substantiated by clinical trials to date.27,40 It also remains unknown whether
ACTH effects on MS relapses extend beyond corticosteroid induction via its
melanocortin receptor–mediated actions or whether ACTH may improve the
recovery of patients with incomplete response to corticosteroids. Several clinical
trials are currently under way to evaluate these uses of ACTH. ACTH is used less
frequently than methylprednisolone as an initial treatment for MS relapses
because of the unpredictable rise in serum cortisol and inconvenience of IM
injections. The staggering rise in the cost of this treatment has also limited its use.
The price of a single vial of ACTH gel in the United States increased from $40 in
2001 to $34,000 in 2014, resulting in over half a billion dollars of Medicare spending
in 2015 (or $162,371 per patient), although not all of it in patients with MS.41
SECOND-LINE THERAPY
While some degree of recovery follows most MS relapses, full recovery to
baseline is less common. Analysis of relapses from the placebo arms of several
trials showed that 2 months after a relapse, 42% patients had residual worsening
of 0.5 points or more on the EDSS scale.42 In trials of ACTH or corticosteroids
for MS relapses, about one-fourth of MS relapses did not improve by the end of
the trial.32,38,43 Severity of relapse and older age correlate with less recovery after
MS relapses treated with corticosteroids.44 Higher nonfasting blood glucose
levels during steroid treatment were recently reported as another negative
predictor of recovery, but this finding awaits validation.45 Amelioration of
neurologic deficits was seen as early as 5 to 7 days after treatment with
methylprednisolone or ACTH,27,38 and most studies to date have defined lack of
improvement by 2 weeks as indication for additional treatment.43,46
Second-line treatment options include repetition of corticosteroid treatment
(sometimes using a different dose, route, or type of steroid), ACTH, plasma
exchange, or, outside the United States, immunoadsorption. Among these
options, clinical evidence47 best supports the use of plasma exchange, based on
several retrospective studies, subgroup analysis of a randomized clinical trial,48
664 JUNE 2019

and a randomized clinical trial specifically addressing its use when relapses fail to KEY POINTS
improve with steroids.46 This trial enrolled 22 patients (12 with MS, 10 with other
● Compared to
inflammatory demyelinating diseases) who remained severely impaired, with corticosteroids,
paraplegia, hemiplegia, or quadriplegia despite high-dose corticosteroid adrenocorticotropic
treatment. Patients were randomly assigned in a crossover design to undergo hormone use in multiple
plasma exchange (seven exchanges every other day) or sham treatment. After sclerosis relapses is not
well defined.
14 days, plasma exchange led to significant improvement in 42% of the cases,
compared to only 5% with sham treatment.46 A retrospective review of ● Second-line treatment
steroid-unresponsive demyelinating episodes treated by plasma exchange options for multiple
identified predictors of response to this treatment: male gender, preserved or sclerosis relapse include
brisk deep tendon reflexes, and initiation of exchange within 60 days of repetition of corticosteroid
treatment (sometimes using
relapse.49 Analysis based on description of four histopathologic patterns of MS a different dose, route, or
lesions17 suggests that pattern II lesions (characterized by antibodies and type of steroid),
complement) showed the best response to plasma exchange, followed by pattern I adrenocorticotropic
lesions (T-cell/macrophage predominance), whereas pattern III lesions (distal hormone, and plasma
exchange.
oligodendrogliopathy) showed no improvement after plasma exchange.50 The
clinical utility of these findings, however, remains limited until these patterns ● In one study, plasma
can be reliably distinguished without invasive sampling (biopsy). Plasma exchange led to significant
exchange can be performed via peripheral access most of the time. Scheduling improvement in 42% of
patients who remained
exchanges every other day reduces, but does not eliminate, the risk of
severely impaired after
hypotension. Anemia, heparin-induced thrombocytopenia, and paresthesia relapses treated with
have been reported with plasma exchange. high-dose corticosteroids,
The benefits of plasma exchange notwithstanding, it should be noted that if a compared to only 5% with
sham treatment.
patient fails to respond to the initial course of corticosteroids, a second course of
steroids or ACTH is sometimes pursued, although clinical evidence is not yet available ● The decision whether to
to justify this strategy. This may be because of patient convenience, moderate (rather treat or monitor a multiple
than severe) relapse-related impairment, or limited access to plasma exchange.43 sclerosis relapse should be
made jointly between a
patient and a clinician,
REHABILITATION considering the impact
While rehabilitation is broadly perceived as beneficial in MS, few formal of both the relapse and
attempts have been made to determine the added benefit of this intervention in the proposed treatment
the management of MS relapses. In one randomized (but not blinded) trial, on a patient.
patients received IV steroids either with or without multidisciplinary therapy
consisting of physical therapy, occupational therapy, and other rehabilitation
modalities. Both therapists and the patients reported better neurologic recovery
up to 3 months later with multidisciplinary therapy as compared to the patients
who received steroids alone.51 Whether patients should rest while receiving
steroids or engage in rehabilitation at the same time remains unknown and is the
subject of at least one ongoing clinical trial.
ADDITIONAL CONSIDERATIONS
Because most MS relapses are followed by some degree of spontaneous recovery,
it is acceptable to monitor (rather than treat) some milder relapses. The decision
whether to treat or monitor a relapse should be made jointly between a patient
and a clinician, considering the impact of both the relapse and the proposed
treatment on a patient. Compared to controls, patients who were educated about
the role of corticosteroids in relapse treatment tended to treat fewer relapses,
preferred oral to IV steroids, and perceived higher levels of autonomy.52
Whether actively treated or not, MS relapses should always entail a discussion
of adherence to disease-modifying therapy. MRI may also be considered to

evaluate for evidence of additional subclinical disease activity. For most

disease-modifying therapies, a combination of breakthrough relapses and
MRI lesions is a poor prognostic factor and may argue for a change to a more
effective disease-modifying therapy. For some disease-modifying therapies
(eg, beta interferons, natalizumab), laboratory testing for antidrug antibodies
can inform this decision for the patient and clinician (CASE 4-3). If plasma
exchange is used, a disease-modifying therapy susceptible to removal by
CASE 4-3 A 28-year-old woman presented with new onset of double vision and
unsteadiness that she noticed upon waking. Her examination revealed
incomplete left ptosis, diagonal diplopia, impaired coordination of
her right arm and leg, and gait ataxia. Brain MRI showed an enhancing
left medullary lesion along with 12 supratentorial nonenhancing
T2-hyperintense lesions in periventricular and juxtacortical locations,
leading to the diagnosis of relapsing-remitting multiple sclerosis.
Because of gait instability, she was admitted for a course of IV
methylprednisolone (1000 mg daily for 5 days). By the fifth day of
admission, some of her deficits improved, but she developed new
dysarthria and weakness of her right arm and leg. Repeat brain MRI
showed resolution of enhancement in the medullary lesion but also new
left parasagittal midbrain and cerebral peduncle lesions. Seven cycles of
plasma exchange were performed. Her symptoms began improving after
the third exchange, and she was discharged to an acute rehabilitation
facility. Recovery from this relapse was slow, and 1 year later she still had
residual gait ataxia and trace diplopia.
Disease-modifying therapy with IV natalizumab (300 mg every 4 weeks)
was initiated. Seventeen months later, she experienced a relapse
manifesting as numbness that developed in her right hand and spread
over the next 3 days to involve her right arm up to the shoulder. Brain MRI
showed four nonenhancing lesions that were new compared to an MRI
from 7 months prior; spinal cord MRI showed an enhancing lesion at the
C4 level. Treatment with IV methylprednisolone (1000 mg daily for 3 days)
led to full resolution of her symptoms within 2 weeks. On further testing,
the patient was found to have antinatalizumab antibodies, prompting a
change of her disease-modifying therapy.
COMMENT This patient’s initial severe relapse did not respond to treatment with IV
methylprednisolone, prompting escalation of therapy to plasma exchange.
However, her subsequent relapse did respond to steroids, indicating that
steroid responsiveness may vary from relapse to relapse. When a patient
relapses while on disease-modifying therapy, the clinician should assess
adherence and, if relevant, biological resistance to the disease-modifying
therapy. In this case, the detection of antidrug antibodies allowed for a
timely change in treatment. Although most patients with antibodies to
natalizumab have infusion reactions, this patient had tolerated her
infusions without any incident.
666 JUNE 2019

plasma exchange (eg, natalizumab) may need to be administered earlier than
routinely scheduled.
Clinicians treating MS relapses during pregnancy should be familiar with the
risks of corticosteroids and avoid their use during the first trimester, as they
increase the risk of cleft palate.53
Breast-feeding mothers can minimize exposure of the infant by not
breast-feeding for 8 hours after IV methylprednisolone; this period may be
longer if high-dose oral steroids are used.54,55 Patients with a documented allergy
or intolerance to one corticosteroid may benefit from a different type of steroid
as cross-reactivity is rare56 or from the use of ACTH instead. Of note, a true
allergy to corticosteroids is less common than pseudoallergic reactions due to
rapid IV infusion (eg, flushing, hypotension, bradycardia). A history of serious
behavioral problems (eg, psychosis) or metabolic dysregulation (eg, severe
hyperglycemia) triggered by prior steroid treatment justifies inpatient admission
for monitoring and management of these anticipated adverse events.
CONCLUSION
The goal of MS relapse treatment is to reduce the impact of relapse on the patient.
Current treatment consists of corticosteroids, ACTH, plasma exchange, and
rehabilitation, used singly or sequentially. Education of patients about cardinal
features of MS relapses, treatment options, and expected outcomes is an integral
component of relapse management. Recognition of pseudorelapses is also
important to limit unnecessary treatment.
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oral prednisone in multiple sclerosis. Neurology
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doi:10.1212/NXI.0000000000000378.
WNL.0000138572.82125.F5.
46 Weinshenker BG, O’Brien PC, Petterson TM, et al.
55 Strijbos E, Coenradie S, Touw DJ, Aerden LAM.
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High-dose methylprednisolone for multiple
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6<878::AID-ANA10>3.0.CO;2-Q.
56 Baker A, Empson M, The R, Fitzharris P. Skin
47 Cortese I, Chaudhry V, So YT, et al.
testing for immediate hypersensitivity to
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Neurology. Neurology 2011;76(3):294–300.
doi:10.1212/WNL.0b013e318207b1f6.

REVIEW ARTICLE

Clinically Isolated
ONLINE
Syndrome and Early
Relapsing Multiple
Sclerosis
By Luanne M. Metz, MD, FRCPC
ABSTRACT
PURPOSE OF REVIEW: This article reviews management of clinically isolated
syndrome and early relapsing-remitting multiple sclerosis (MS). It provides
a general approach to patient management and determination of
prognosis, reviews first-line disease-modifying therapies, and provides an
approach to treatment selection.
RECENT FINDINGS: Revision of the MS diagnostic criteria allows an earlier

MS diagnosis, which reduces diagnostic uncertainty and often allows
additional treatment options. Identification of factors that influence
disease activity and progression highlights the importance of counseling
patients about behavior modifications that, along with disease-modifying
therapy, may improve long-term outcomes. Recommended lifestyle
CITE AS: modifications include smoking cessation, vitamin D supplementation,
2019;25(3, MULTIPLE SCLEROSIS a healthy diet, maintaining a healthy weight, remaining active, and
AND OTHER CNS INFLAMMATORY management of cardiovascular risk factors. Identifying individuals at
high risk for future disability allows them to make informed decisions
about the use of highly effective, higher-risk disease-modifying therapies.
Dr Luanne M. Metz, Foothills
Hospital, 1403 29th St NW, SUMMARY: Patients with clinically isolated syndrome, even those with only
Calgary, Alberta, Canada
T2N 2T9, lmetz@ucalgary.ca.
dissemination in space but not dissemination in time, and patients with
relapsing-remitting MS and disease activity within the prior 2 years, are at
RELATIONSHIP DISCLOSURE: high risk of disease activity within the next 2 years. Lifestyle modification
Dr Metz receives research/
grant support from Alberta suggestions and disease-modifying therapy should be considered.
Innovates Health Solutions Treatment decisions should be made in collaboration with patients using
(201300669) and the Multiple
the shared decision-making approach.
Sclerosis Society of Canada.
UNLABELED USE OF
USE DISCLOSURE:
Dr Metz was the principal
INTRODUCTION
T
investigator on a phase 3 study he early period after a diagnosis of multiple sclerosis (MS) or clinically
on the use of minocycline for isolated syndrome is challenging. While no cure currently is known,
the treatment of clinically
isolated syndrome. medications and lifestyle modifications can decrease inflammatory
activity and reduce symptom burden and the accumulation of
disability. With education, support, and guidance, patients with
of Neurology. clinically isolated syndrome or early relapsing MS can make healthy lifestyle
670 JUNE 2019

decisions and select a disease-modifying therapy acceptable to them. With
many treatment options available, if the initial disease-modifying therapy is
not tolerated or is ineffective, alternatives are available. The current optimism
should not, however, dissuade patients from initiating disease-modifying
therapy. Early treatment initiation appears to be most effective. Everyone with
MS and recent disease activity, or with clinically isolated syndrome and
dissemination in space but not dissemination in time, is likely to benefit from
disease-modifying therapy. Ongoing research aims to identify those who may
be better suited for highly effective disease-modifying therapy.
This article provides the information and tools to manage patients with
clinically isolated syndrome and early MS. A general approach to management
follows a short discussion of how the new MS diagnostic criteria force clinically
isolated syndrome trial outcomes to be reframed as measuring time to new
disease activity rather than time to an MS diagnosis. The use of prognostic factors
to help make treatment decisions, first-line disease-modifying therapies, the
decision-making process, and what is hoped will be future tools to guide early
management are also discussed.
DEFINITIONS AND DIAGNOSTIC CRITERIA

The first consideration in managing clinically isolated syndrome and early
MS is often making a diagnosis. An MS diagnosis removes the ambiguity of
the clinically isolated syndrome diagnosis, which is a term disliked by patients,1
and may reduce anxiety2 and increase treatment options. A diagnosis of
relapsing-remitting MS indicates that evidence of more than one inflammatory
episode exists. MS can now be confirmed in most patients with clinically isolated
syndrome if CSF oligoclonal bands are present.3 A lumbar puncture should be
considered if it will confirm MS and allow access to additional treatment options.
Previously unrecognized relapses may support an MS diagnosis when residual
signs remain on examination or on paraclinical testing, such as visual evoked
potentials. Historical relapses may, therefore, determine disease duration or
previous relapse history when a diagnosis can otherwise be confirmed, but
purely historical relapses should not be used to confirm a diagnosis.
Clinically isolated syndrome can be diagnosed after a single episode of focal
neurologic symptoms, which is presumed, after appropriate investigation, to
be due to central nervous system inflammatory demyelination.4 The episode
must last at least 24 hours and is usually accompanied by lesions on brain MRI
that are suggestive of MS. Optic neuritis and incomplete transverse myelitis may
not be accompanied by T2 lesions on brain MRI, but most other focal events
with normal or very nonspecific brain MRI would be unlikely to be considered
demyelinating. All clinically isolated syndrome phase 3 clinical trial participants
had recent onset of focal clinical events and at least two T2 hyperintensities on
brain MRI. Minimum MRI criteria were similar in most trials. Lesions generally
had to be greater than 3 mm in diameter, and one lesion had to be periventricular,
juxtacortical, or infratentorial. Less specific MRI changes were considered
unlikely to evolve to MS in the short term. Patients with suspected historical
relapses were excluded from clinically isolated syndrome trials. Clinically
isolated syndrome trials of interferon beta-1a (subcutaneous5 or IM6), interferon
beta-1b,7 glatiramer acetate,8 teriflunomide,9 oral cladribine,10 and minocycline11
all demonstrated that early treatment delayed the time to an MS diagnosis and
that the risk of further disease activity is high if untreated. Retrospective review

CLINICALLY ISOLATED SYNDROME AND EARLY RELAPSING MS
of the characteristics of clinically isolated syndrome trial participants has shown

that all clinically isolated syndrome trials included a substantial proportion of
patients who would be diagnosed with MS, not clinically isolated syndrome, if
seen today. The changing criteria do not reduce the value of clinically isolated
syndrome trials; instead, clinically isolated syndrome trial outcomes can now be
reframed as measuring time to new disease activity rather than time to an MS
diagnosis. Time to clinically definite MS approximates the time to a second
relapse, and time to MS as defined by the 2005 McDonald criteria12 approximates
the time to any new clinical or MRI activity.
GENERAL APPROACH TO MANAGEMENT

Management of patients with clinically isolated syndrome and early MS is
complex. In addition to determining the diagnosis, prognostic factors must be
identified and the initial attack and residual symptoms and disability must be
managed. Patients need education, support, and identification and management
of modifiable lifestyle factors that impact MS risk. Disease-modifying therapy
should usually be discussed, selected, and initiated. A checklist may help ensure
all these issues are covered. TABLE 5-1 lists common patient information needs
during the early stages of their disease. Education may require several
encounters. A multidisciplinary team or referral to written or online educational
material will help guide clinicians through the long list of educational topics.
Diagnostic evaluation and assessment of early prognostic factors will likely
dominate clinical activities at the initial assessment. The patient’s clinical and
demographic characteristics, health behaviors, and MRI and CSF results will
determine the risk of further disease activity and future disability and guide
disease-modifying therapy recommendations. It is important for patients to
understand the natural history of MS and their own risk of further brain injury,
even subclinical injury, so they can make better management decisions. Patients
may otherwise not appreciate the importance of early intervention, sometimes
with aggressive therapy. Providing patients with the best understanding that
they are capable of will likely help develop a good working relationship between
patient and physician; this relationship will be critical to optimize their long-term
outcome. For more information on the approach to the diagnosis of multiple
sclerosis, refer to the article “Diagnosis, Differential Diagnosis, and Misdiagnosis
of Multiple Sclerosis” by Andrew J. Solomon, MD,13 in this issue of Continuum.
Assessment of factors that predict risk in MS should be evaluated at onset and
reevaluated over time.
Management of the initial attack may also be an immediate concern.
Corticosteroids and management of symptoms and disability should be
considered, and the impact of symptoms on activities of daily living, personal
and family responsibilities, education, employment, and participation in sport
and leisure activities should be determined. Patients should be informed if risk
exists in continuing their usual activities, especially if activity exacerbates their
symptoms, but they should also be advised on which activities they can safely
continue. Remaining active is generally recommended, and exercise may improve
long-term recovery,14 but fatigue and physical disability are commonly limiting.
Driving safety, continuation of employment, and whether work accommodations
or modifications are required must be considered. For more information on
management of MS relapses, refer to the article “Management of Multiple
Sclerosis Relapses” by Pavle Repovic, MD, PhD,15 and for more information on
672 JUNE 2019

symptom management in MS, refer to the article “Management of Multiple KEY POINTS
Sclerosis Symptoms and Comorbidities” by W. Oliver Tobin, MBBCh, BAO,
● A serious diagnosis such
PhD,16 in this issue of Continuum. as multiple sclerosis may
A serious diagnosis may motivate people toward a healthy lifestyle; an MS motivate people toward a
diagnosis provides an opportunity to inform patients that smoking, low serum healthy lifestyle. Diagnosis
vitamin D levels, obesity, a sedentary lifestyle, and comorbid cardiovascular provides the opportunity to
inform patients of health
disease are associated with worse MS outcomes.14,17–19 Although randomized
behaviors that are
controlled trials have not confirmed that making lifestyle changes in any of these associated with worse
areas improves MS outcomes, managing modifiable risk factors is an appropriate multiple sclerosis
general health recommendation. outcomes.
Patients frequently ask about dietary changes. No consistent evidence
● Education and supported
supports any specific diet for people with MS, but they may consider the self-management are the
Mediterranean diet to be a reasonable and healthy dietary option as it reduces the mainstays of chronic disease
risk of cardiovascular disease, which is a poor prognostic indicator in MS.20 management.
Choosing a healthy diet that fits their own lifestyle and beliefs and makes them
feel well should be encouraged.
Considerable evidence suggests that infections can trigger relapses,21,22 so general
hygiene behaviors such as handwashing, avoidance of unnecessary infectious
exposures, and annual influenza vaccinations should also be encouraged. Infections
can also trigger pseudorelapses. The concepts of pseudorelapses, symptom
fluctuation, and symptom progression should be explained to patients. While
relapses indicate new inflammatory activity, pseudorelapses occur when fever or
another stress unmasks previous neurologic injury. Previous injury may have been
from a prior relapse, from lesions previously detected only by MRI, or from injury
undetected by MRI. Injured brain has less functional reserve, so symptoms may
appear as pseudorelapses during a time of stress. It can be difficult to tell the
difference between relapses and pseudorelapses, so patients should be
encouraged to report or record all new symptoms.
Immunization status should be discussed early. At disease onset, it is unclear
which patients will require disease-modifying therapies that reduce immunization
effectiveness, increase the severity of acquired infection, and increase the risk of
activation of latent infection. Patients’ immunization status should be confirmed,
and early screening for immunity to hepatitis A, B, and C and varicella should be
performed. Patients should be advised to update their immunizations, including
immunization for human papilloma virus, according to local public health
recommendations. Routine screening for latent tuberculosis and HIV is not
indicated unless a therapy is planned that may activate these infections. Many
people with MS incorrectly assume that their immune system is weak; patients
should be advised to avoid immune stimulants, which may be recommended by
alternative care providers, and informed that some disease-modifying therapies
suppress immune overactivity.
Education and supported self-management are the mainstays of chronic
disease management. Education requires time and repetition, generally over
several encounters. Having a variety of learning modalities available, including
group learning, written material, podcasts, internet sources, and one-to-one
interactions, can be helpful. Useful patient resources include the websites of the
US, Canadian, and UK MS Societies, and local resources may also be helpful
(refer to the Useful Websites section at the end of this article). Patients should be
informed that the perspectives, terminology used, and treatment options
discussed in these various sources may differ according to the author’s

perspective (eg, patient, nurse, physician, family), the culture, the health care
system, and the therapies that are available and locally supported. This may help
them interpret differing information. Patients should also be reminded that
anything can be posted on the internet by anyone, so it is safest to stick with
reliable noncommercial sources.
With so much information to absorb early in the disease, patients should be
helped to retain as much as possible at every encounter. They should be
encouraged to write down their questions, perhaps in order of priority, and to
bring a companion to appointments. It is best practice to provide patients with
written information about the key topics discussed and to provide them with
their individual diagnosis and treatment plan in writing.
Patients may be unprepared for the psychological impact of receiving an MS
diagnosis. It can take months to years to begin to understand their own relationship
with MS. The distress that follows diagnosis may even temporarily impact cognition
by reducing patients’ ability to focus and by affecting normal sleep. Adjustment
reactions and grieving are common,23 even in those who recover completely from
TABLE 5-1 Patient Information Needs in Clinically Isolated Syndrome and Early
Multiple Sclerosis
Diagnosis
◆ General information about clinically isolated syndrome, multiple sclerosis (MS), and disease
course (phenotypes)
◆ Reasons for each investigation and potential and expected results
◆ Alternative diagnoses being considered, if any
◆ Information about prognosis and risk factors
◆ Discuss disclosure of the diagnosis
Prognosis and Risk Factors
◆ Natural history of clinically isolated syndrome and MS
◆ Prognostic factors and individual prognosis
◆ Management of modifiable risk factors: smoking cessation, vitamin D supplementation,
diet, weight management, exercise, avoidance of immune stimulants, and infections
◆ General discussion about the benefits of disease-modifying therapy
Disease-Modifying Therapy Selection
◆ Treatment goals
◆ Categories of disease-modifying therapy: injectable, oral, infusions
◆ The difference between first-line and second-line disease-modifying therapies
◆ The common approaches to disease-modifying therapy selection: dose escalation or
starting with highly effective therapy
◆ Personal values commonly considered in selection: effectiveness, convenience, safety and
tolerability, cost, physician recommendation, familiarity with a specific disease-modifying
therapy, readiness to start disease-modifying therapy, urgency to start
674 JUNE 2019

their initial symptoms, and they can have a major influence on the early years
with MS. Concurrent depression can impact disease-modifying therapy
adherence, so it is important to be watchful and recommend management if it
appears.24,25 It can also be very challenging for patients to decide what to disclose
about their diagnosis. In these days of social media, many people keep few
secrets, but patients should be reminded very early that sharing their diagnosis
cannot be erased. They need to be sure they want others to know they have MS or
clinically isolated syndrome before they tell anyone. Counseling may be
required, but many people adapt well just knowing that what they are going
through is normal. Family members also require information and support.
Some unique patient situations may require further management, including
pregnancy, concurrent comorbidities, and social situations impacted by MS.
Patients may need to make decisions regarding interruptions in education or
employment. For more information on the management of children with MS,
refer to the article “Pediatric Central Nervous System Demyelinating Diseases”
by Tanuja Chitnis, MD, FAAN,26 and for more information on pregnancy and

◆ Common barriers to treatment selection, adherence, and monitoring (including insurance
and financial and geographic factors)
◆ Other considerations that influence treatment selection: plans for pregnancy, limiting
comorbidities, concomitant medications, and need for immunizations and baseline
assessments.
◆ Monitoring effectiveness of treatment
◆ Information about specific disease-modifying therapies: include information about the
route, benefits and risks, tolerance and safety, cost, safety monitoring, pregnancy risks, and
supports available for initiation
Relapses
◆ General information about relapses and pseudorelapses
◆ Relapse management options and outcomes
Symptoms and Disability
◆ Common symptoms and symptom management options
◆ Impact on driving and employment
General Topics
◆ Genetics of MS
◆ Adjustment and grieving
◆ Review of immunizations
◆ Impact of MS on pregnancy and parenting
◆ Identification of reliable sources of information
◆ Travel considerations: immunization considerations, out-of-country health insurance,
protecting disease-modifying therapy from heat or freezing

MS, refer to the article “Pregnancy and Family Planning in Multiple Sclerosis” by
Annette M. Langer-Gould, MD, PhD,27 in this issue of Continuum.
Finally, the patient’s prognosis and the benefits of treatment should be
discussed. If disease-modifying therapy is not recommended, the reasoning
should be explained. If disease-modifying therapy is indicated, treatment
selection and initiation will be required. Because so much information must
be discussed when the diagnosis of clinically isolated syndrome or MS is made,
a separate office visit is recommended for disease-modifying therapy
selection.25
Incorporating Prognostic Information Into Recommendations

Several prognostic factors influence patient outcomes and may guide treatment
decisions. Some can be identified at disease onset; others depend on a period of
follow-up. Some have a short-term influence, while others impact long-term
outcomes. Patients at low risk of disease activity over the short term are less likely
to benefit from disease-modifying therapy but may still benefit from disease
monitoring because risk assessment is not precise. Patients at high risk of disease
activity will likely benefit from disease-modifying therapy, and those at very
high risk should likely be particularly careful to avoid delay in initiating
disease-modifying therapy. These risk groups are described in TABLE 5-2.25
All patients with recent clinically isolated syndrome and at least two
T2-hyperintense lesions on brain MRI suggestive of MS are at high risk of further
disease activity, even if they do not meet criteria for dissemination in time.5–11
TABLE 5-2 Risk of New Disease Activity in Clinically Isolated Syndrome and Early
Multiple Sclerosisa
Risk Group Phenotype Disease-modifying Therapy
Low risk Clinically isolated syndrome with a normal brain MRI Not indicated
Medium risk Radiologically isolated syndrome; higher risk with spinal cord Unclear
lesions or positive oligoclonal bands
Relapsing-remitting multiple sclerosis (MS) without relapses or

new MRI activity over the previous 2 years while untreated.
High risk Clinically isolated syndrome with two or more T2 lesions ≥3 mm Indicated
in diameter on brain MRI; higher risk in smokers, those younger
than age 30, and those with low serum vitamin D levels
Very high risk Single attack but meets 2017 diagnostic criteria for MS; Indicated
highest risk if two or more enhancing lesions on brain MRI
Clinically isolated syndrome phenotype followed by

new disease activity on brain MRI
Relapsing-remitting MS with two or more inflammatory events

within the previous 2–3 years (relapses or new T2 or
enhancing lesions on brain MRI)
MRI = magnetic resonance imaging.

a
New disease activity is defined as new relapse or new T2 or enhancing lesions on brain MRI within the next 2 years.
676 JUNE 2019

The placebo groups of the pivotal clinically isolated syndrome trials had KEY POINTS
remarkably similar outcomes, so the risk of further disease activity in clinically
● Patients at low risk of
isolated syndrome is well understood. Clinically isolated syndrome trials required disease activity over the
similar participation criteria, and participants were synchronized for their stage short term are less likely to
of disease; participants typically had a focal clinical event within the previous benefit from disease-
6 months (often less) and MRI abnormalities typical of MS. Without active modifying therapy but may
still benefit from disease
treatment, the risk of a second relapse within 2 years was 45% to 50%, and the
monitoring because risk
risk of any new disease activity (clinical or MRI) was 60% to 70% within assessment is not precise.
6 months and 80% to 90% within 2 years.6–11 Baseline features that identify those
at greatest risk of future disease activity include younger age of onset, the ● In clinically isolated
presence of enhancing lesions or nine or more T2 lesions on the initial brain MRI, syndrome, the chance of
new clinical or MRI activity is
and the presence of CSF oligoclonal bands.28,29 Most of these features now help to 60% to 70% within 6 months
identify those diagnosed with MS at onset.3 Natural history studies previously and 80% to 90% within
suggested better long-term outcomes in those presenting with optic neuritis, but 2 years.
this has not appeared to be true in clinically isolated syndrome trial populations
● Factors associated with
in which all participants had MRI abnormalities at baseline. Previous natural greater risk of long-term
history studies included patients with optic neuritis and normal brain MRI.30 disability may identify those
A 2015 observational study of clinically isolated syndrome has shown that the most likely to benefit from
only patients with optic neuritis who have a very low risk of future relapses and initiation of highly effective
therapy or additional
disability are those with a normal brain MRI.31 The prognostic impact of the
vigilance in monitoring
anatomic site of the initial neurologic attack (sometimes called topology) has been disease-modifying therapy
inconsistent across studies. effectiveness.
Estimates of short-term risk prediction are less precise at later stages of
relapsing-remitting MS. While more than 90% of patients with clinically isolated
syndrome who develop a new T2 lesion on brain MRI during follow-up will have
a second attack within 3 years of the initial attack,32 considerable variability
exists in the outcomes (relapses, MRI activity, and disability) observed in the
placebo-treated groups of relapsing-remitting MS clinical trials.33 The number of
relapses over the 2 years before inclusion into a clinical trial and the number of
enhancing lesions on a baseline brain MRI did, however, predict the relapse rate
during the trial.34
Factors associated with greater risk of long-term disability may identify those
most likely to benefit from initiation of highly effective therapy or additional
vigilance in monitoring disease-modifying therapy effectiveness. Patients with
indicators of poor long-term prognosis may be more motivated to start
disease-modifying therapy or more likely to accept higher treatment risks.
Factors that indicate a relatively worse long-term prognosis include onset after
age 30, male sex, nonwhite race, motor or cerebellar onset, poor relapse recovery,
frequent early attacks, the presence of CSF oligoclonal bands, being a previous or
current smoker, comorbid cardiovascular disease, low baseline vitamin D level,
high burden of disease (T2 volume), the presence of brain atrophy, and ongoing
disease activity (enhancing or new T2 lesions).17,20,31,35–38 Identification of
modifiable risk factors can also guide individualized interventions (eg, smoking
cessation, correction of low serum vitamin D levels, and management of
comorbid cardiovascular disease). Prognostic factors that suggest a relatively
more favorable course, such as early age at onset, female sex, presentation with
optic neuritis or pure sensory symptoms, and good attack recovery, are probably
less useful in guiding management. For example, while onset before age 30
predicts slower accumulation of disability, slower disease progression, and longer
time until a cane is required, disability still appears at the same age as in those

with older age at MS onset.39 These factors do not identify patients who can
safely delay disease-modifying therapy initiation.
Classic natural history studies have shown that about half of patients with
relapsing-onset MS require a cane within 20 years.40 While this outcome has
been less frequent in contemporary studies, use of disease-modifying therapy
also reduces disease activity, the accumulation of MRI disease burden, and
long-term accumulation of disability.31,41–43 The ability of disease-modifying
therapy to prevent evolution to progressive disease is less clear. Several
research teams are developing and validating decision tools to identify patients
at very high risk.44,45 In the future, these tools will likely help guide disease-
modifying therapy decisions.
Therefore, the only patients with clinically isolated syndrome or relapsing-
remitting MS unlikely to benefit from disease-modifying therapy are patients
with clinically isolated syndrome with normal MRI scans and possibly patients
with clinically isolated syndrome or relapsing-remitting MS known to have
no disease activity over the previous 2 years despite being untreated with
disease-modifying therapy. However, while disease-modifying therapy is not
recommended for patients with clinically isolated syndrome with a normal
brain MRI, annual MRI monitoring for 5 years to confirm stability is
recommended.25 Likewise, if patients with inactive relapsing-remitting MS do
not start disease-modifying therapy (for more information, refer to the
article “Incorporating Clinical Practice Guidelines and Quality Measures Into
High-Quality Cost-Effective Care for Patients With Multiple Sclerosis” by
Alexander D. Rae-Grant, MD, FRCPC, FAAN,46 in this issue of Continuum), annual
MRI monitoring for 5 years is recommended.25 After discussing the risks and
benefits of treatment, disease-modifying therapy should therefore be offered to
patients with clinically isolated syndrome with MRI abnormalities suggestive of
MS and to untreated patients with relapsing-remitting MS who have had disease
activity within the previous 2 years.25
First-line Treatment Options

The greatest advance in managing MS has been the introduction of a wide
array of therapies to prevent MS disease activity. Disease-modifying therapies
may be classified by mode of administration or as first line or second line. This
article focuses on the approach to treatment initiation and describes first-line
disease-modifying therapies. Approved first-line disease-modifying therapies
include both injectable and oral forms. Based on their presentation and choice,
some patients may initially be treated with a second-line disease-modifying
therapy. For more information on second-line, or highly effective therapies,
refer to the article “Highly Aggressive Multiple Sclerosis” by James D. Bowen,
MD,47 and for more information on monitoring disease-modifying therapies,
refer to the article “Monitoring, Switching, and Stopping Multiple Sclerosis
Disease-Modifying Therapies” by Robert H. Gross, MD, and John R. Corboy,
MD, FAAN,48 in this issue of Continuum.
Injectable therapies have been available since 1993. They include several
formulations of interferon beta and two formulations of glatiramer acetate.
Generic options are available. The main advantages of interferon beta and
glatiramer acetate are their long-term safety profiles; serious long-term risks
have not emerged. Their main disadvantages are modest efficacy and that, being
injectable, tolerance and convenience are limited.
678 JUNE 2019

Interferon beta was the first disease-modifying therapy approved by the KEY POINTS
US Food and Drug Administration (FDA). Today several formulations are
● The main advantage of
available: low-dose interferon beta-1a (IM once weekly),49,50 high-dose the injectable therapies
interferon beta-1a (subcutaneous 3 times a week),51,52 interferon beta-1b interferon beta and
(subcutaneous alternate days),53,54 and pegylated interferon beta-1a glatiramer acetate is their
(subcutaneous alternate weeks).55 Interferon beta reduces the chance of long-term safety profile.
The main disadvantages are
further disease activity in patients with clinically isolated syndrome and
modest efficacy and limited
relapsing-remitting MS and probably reduces disability accumulation. tolerance and convenience
Common adverse events include flulike symptoms (myalgia, fatigue, because they are injectable.
headache, and chills), injection site reactions, and injection pain. Flulike
symptoms may limit adherence and continuation but may remit after weeks or ● The first-line oral
therapies dimethyl fumarate
months and can be managed by concurrent acetaminophen or nonsteroidal and teriflunomide are
anti-inflammatory drugs; chronic use of these agents, however, must be convenient, but they are
added to the treatment risk. IM interferon beta has also been associated with relatively new and cause
abscess formation. Liver toxicity, lymphopenia, and thyroid disorders are immune suppression long
term. Safety, including
uncommon but require laboratory monitoring. Preexisting spasticity may a long-term risk of
worsen. Worsening depression is also a concern. malignancy, is a concern.
Glatiramer acetate was the second disease-modifying therapy approved Teriflunomide must be used
by the FDA. Formulations include 20 mg once a day56,57 and 40 mg 3 times a with caution in women of
childbearing age because
week58 by subcutaneous injection. Glatiramer acetate reduces the chance of of the risk of fetal
further disease activity in people with clinically isolated syndrome and malformation.
relapsing-remitting MS. Common adverse events include injection site reactions
and injection pain. With long-term use, lipoatrophy and injection fatigue become
common. Systemic postinjection reactions can include symptoms of dizziness,
shortness of breath, chest pain, diaphoresis, and syncope. These reactions are
uncommon, but, if severe, they are very frightening. They can occur with any
injection, even years into treatment. Glatiramer acetate has no toxicities that
require laboratory monitoring.
The oral therapies are convenient, but, as they are relatively new and cause
immune suppression, long-term safety (including a long-term risk of malignancy)
is a concern. First-line oral therapies include dimethyl fumarate and
teriflunomide.
Dimethyl fumarate 240 mg 2 times a day reduces disease activity in
relapsing-remitting MS. Disability accumulation was reduced in one of two
trials.59,60 It has not been evaluated in clinically isolated syndrome. Common
adverse effects include flushing, abdominal pain, nausea, and diarrhea.
Immune suppression can lead to opportunistic infection, herpes zoster
activation, and disseminated viral infections. Several cases of progressive
multifocal leukoencephalopathy have been reported. Laboratory monitoring
for lymphopenia and liver function are required. All cases of progressive
multifocal leukoencephalopathy were associated with prolonged lymphopenia.61
Daily aspirin may improve flushing, but this adds the risk of gastrointestinal
hemorrhage. Administration with food may also reduce the rate and severity
of flushing and gastrointestinal intolerance.62
Teriflunomide 7 mg or 14 mg 2 times a day reduces the chance of further
disease activity in patients with clinically isolated syndrome or relapsing-
remitting MS and reduces accumulation of disability.63,64 Common adverse
events include hair thinning, headache, nausea, and diarrhea. Patients should
be monitored for hypertension and peripheral polyneuropathy. Laboratory
monitoring is required because of potential lymphopenia and liver toxicity.

Teriflunomide may cause severe fetal abnormalities so special caution, including

use of two effective birth control methods, is advised if used in women of
childbearing potential.25 Women must also be aware that urgent cholestyramine
washout is necessary for unexpected pregnancy. Because teriflunomide has a
very long half-life and can be detected in serum up to 2 years after
discontinuation, this washout is required even when teriflunomide had been
stopped months before the pregnancy. Effective contraception should also be
considered in male patients because teriflunomide is detectable in seminal
fluid.25 Tuberculosis must be excluded before treatment initiation. For more
information on teriflunomide and pregnancy, refer to the article “Pregnancy
and Family Planning in Multiple Sclerosis” by Annette M. Langer-Gould,
MD, PhD,27 in this issue of Continuum.
Sometimes approved options are unavailable to patients because of cost or
insurance limitations, and therapy initiation may be delayed for many reasons,
including patient preference, while they consider their options. Minocycline
may then be considered as a bridging therapy. A 2017 phase 3 randomized
placebo-controlled clinical trial showed that minocycline 100 mg 2 times a day
reduced the chance of reaching an MS diagnosis according to the 2005
McDonald criteria for MS at 6 months by 27.6%.11 It was effective as early
as 3 months and was still effective at 12 months; however, the benefit could
not be demonstrated at 24 months. Off-label use of minocycline is therefore
supported by evidence, and minocycline is inexpensive, widely available, safe,
and reasonably well tolerated. The most common side effects are dizziness,
nausea, diarrhea, abdominal pain, and skin rash. Photosensitivity makes
sun avoidance or sunscreen necessary. The risk of antibiotic resistance is low,
but a slightly increased risk of vaginal candidiasis exists. Minocycline is not
immune suppressing and has been used for long-term treatment of acne for
many decades. Liver toxicity is possible, so it is prudent to monitor liver function
if continued long term. After months or years of use, blue- gray discoloration
of the skin, gingiva, teeth, and sclera can occur, but it is easily detectable with
clinical monitoring; it is usually reversible.
Deciding on Treatment
With so many individual patient factors to consider and so many treatments to
choose from, decision making can be challenging. It requires knowing the natural
history of MS and which prognostic factors apply to an individual patient,
understanding the risks and benefits of the various disease-modifying therapy
options, determining patient-specific risks for each treatment, and considering
competing philosophies about the best approach to treatment initiation. The
three competing philosophies include the escalation approach; starting with
a higher risk, highly effective therapy; and the induction approach. It is
important to discuss treatment options with patients in a process of shared
decision making to incorporate their preferences into treatment
recommendations.25
The most common approach to treatment selection is the escalation
approach, in which low-risk, often less effective therapies are started first.
This approach is based on the premise that these treatments will be effective for
many individuals and the risks are lower. This approach often overlaps with a
common requirement to start less expensive therapies first and move to more
effective, higher-cost therapies, if required. Treatment escalation is generally
680 JUNE 2019

considered when intolerance or treatment failure is encountered. An alternative KEY POINT
approach is to start with a highly effective therapy based on the premise that
● A shared decision-making
the consequences of treatment failure are severe enough that the greater process should be used to
treatment risk is worth taking. This approach may be most appropriate for select a preferred disease-
those who have a worse long-term prognosis; however, this option should be modifying therapy option.
discussed with patients, so they can decide if the treatment risk is more
acceptable to them than the risk of the treatment failure. A third approach
is the classic induction approach, which begins with a risky but highly
effective therapy to settle disease activity followed by lower-risk, less efficacious
therapy.
None of these approaches have been compared in long-term head-to-head
trials, but a randomized trial comparing the usual escalation therapy with early
aggressive therapy is ongoing.65
Shared decision making is a process in which the clinician, care team, and
patient participate together in the decision to start a disease-modifying
therapy and to select a preferred option. Information about the risks and
alternatives should be provided, including the option of not starting
disease-modifying therapy. Resources for patients to choose a treatment
option that best suits their own values should also be provided.66 As only
patients will experience the adverse effects, inconvenience, costs, and risks
of a disease-modifying therapy, they need to participate in the decision.
Shared decision making has been shown to improve treatment adherence,
outpatient self-care behaviors, self-management, health outcomes, and
reported quality of life.66–69 Decision aids such as written material, video or
audio tapes, and interactive media70 may support the discussion required for
selection but do not replace it.
A common approach to shared decision making for disease-modifying therapy
selection is to start by explaining the natural history of clinically isolated
syndrome or MS and the overall expected treatment outcomes: preventing
relapses, brain injury due to inflammation, and the accumulation of residual
neurologic symptoms and disability. The patients’ prognostic indicators should
be incorporated into this discussion, so they understand if they are more or less
likely than average to experience these consequences. The main treatment
categories and differentiating features should also be explained. Common issues
that narrow treatment options include insurance limitations, pregnancy
planning, comorbidities, concomitant medications, willingness to consider
injectable therapy, and willingness to accept the uncertain long-term risks that
come with newer treatment choices. Without naming any specific therapy, the
options could be presented as injectable therapies, which have the longest safety
record; oral first-line therapies, which are more convenient but have less
long-term safety data; and second-line therapies, which are more likely to
stabilize the disease but have higher treatment risks so are often considered if
an initial therapy fails. Clear patient preference for a therapy with a longer
safety record or for an oral therapy will also quickly narrow the discussion.
Comorbidities, concomitant medications, and plans to become pregnant soon
may also limit the options to be discussed in detail. In most cases, two or three
disease-modifying therapy options will remain for further discussion (CASE 5-1).
Interferon beta and glatiramer acetate can initially be discussed as a class of
therapy without describing each brand, because too many choices are
overwhelming. Present the rationale for your recommendations in view of the

CASE 5-1 A 24-year-old woman presented with a 36-hour history of ascending

paresthesia, progressive leg weakness, and gait clumsiness. She had brisk
reflexes and mild spasticity in her legs, bilateral extensor plantar
responses, bilateral hip flexor weakness of 4+/5, and a sensory level to T8.
MRI of her spine revealed a nonenhancing focal hyperintensity at C8.
Brain MRI demonstrated two T2-hyperintense lesions, both greater than
3 mm in diameter, one subcortical and one periventricular; neither
enhanced. Demyelination was suspected, but only a clinically isolated
syndrome could be diagnosed. The spinal cord lesion and the
periventricular lesion confirm dissemination in space; the subcortical lesion
was nonspecific so was not useful. (An enhancing lesion as well as a
concurrent nonenhancing lesion would have confirmed dissemination in
time and allowed a diagnosis of multiple sclerosis [MS] to be made.)
High-dose pulse oral steroids were prescribed for relapse management.
Vitamin D3 and calcium were initiated.
Ten days later, her symptoms had resolved but hyperreflexia remained.
Disease-modifying therapy was recommended to reduce the risk of further
disease activity. She was informed that within 6 months the chance of either
another relapse or new activity on a follow-up brain MRI was more than
60%. As she was a heterosexual, sexually active woman, interferon beta and
glatiramer acetate were recommended as preferred safe therapeutic
options. She declined injectable therapy. The potential benefit of a lumbar
puncture to confirm MS and allow her to consider dimethyl fumarate was
discussed. (Dimethyl fumarate would not be covered by her insurance
unless an MS diagnosis could be confirmed.) Teriflunomide was also
discussed as an alternative, but she was informed that adequate double
contraception would be critically important because the risk of fetal
abnormalities make teriflunomide a less preferred disease-modifying
therapy for most young women.
She agreed to have the lumbar puncture; oligoclonal bands were
detected, therefore demonstrating dissemination in time and confirming a
diagnosis of MS. She started dimethyl fumarate.
COMMENT This case illustrates a common presentation of clinically isolated

syndrome/MS. Detection of CSF oligoclonal bands to confirm MS may
increase treatment options. Because this patient did not have
characteristics of a very high risk of future disability, highly effective
therapy would likely not be recommended. Off-label minocycline could
have been offered if MS could not be confirmed and she declined
teriflunomide or if she had no insurance coverage.
682 JUNE 2019

patient’s preferences. Recommendations can be adapted based on this KEY POINT
discussion, sometimes returning to a therapy that was initially set aside. Another
● Delays in disease-modifying
member of the care team, often a nurse, may discuss these treatment options in therapy should be avoided.
more detail and continue guiding the patient’s decision, including selection of a The risk of reaching an
brand. Details discussed should include safety, tolerance, route of Expanded Disability Status
administration, cost, and monitoring requirements. Treatment goals should Scale score of 4.0 is
increased by 7.4% for every
again be reviewed, making sure patients do not expect these preventive therapies
year of delay in treatment
to reverse disability or improve current symptoms.25 Patients should be advised initiation after multiple
to report new or worsening symptoms, intolerance, and challenges with sclerosis onset.
adherence to either treatment or safety monitoring.
Potential delays in treatment initiation should be discussed. Patients are often
ambivalent about starting disease-modifying therapy, may need time to adjust to
the need for treatment, may be delayed for immunizations or insurance
approval, or may have other reasons to delay therapy initiation. Recent evidence
that the risk of reaching Expanded Disability Status Scale (EDSS) score of 4.0 is
increased by 7.4% for every year of delay in treatment initiation after MS onset
highlights the importance of early treatment.71 Delays in escalating to a highly
effective (second-line) therapy should also be avoided, especially in patients at
high risk of future disability (CASE 5-2).
FUTURE CONSIDERATIONS
In the future, disease-modifying therapy selection may be guided by genetic or
epigenetic indicators to optimize and individualize treatment choices. Risk
assessment tools may stratify risk and guide therapy selection. These tools may
utilize advanced imaging techniques that include imaging measures not yet used
in standard clinical practice. Better indicators of treatment response seem near;
measurement of serum neurofilament light chain levels looks particularly
promising.72 Another strategy believed to improve long-term outcomes is to
initiate disease-modifying therapy as early as possible. This will require early
identification of MS as well as strategies to remove barriers to early treatment.
CONCLUSION
The management of clinically isolated syndrome and early MS requires
assessment of risk factors for further disease activity, patient education, and
developing a long-term collaborative management plan with patients. This
should include management of lifestyle factors that impact long-term outcomes
and working together with patients to select an acceptable disease-modifying
therapy. Delay should be minimized before disease-modifying therapy is initiated.
USEFUL WEBSITES
NATIONAL MULTIPLE SCLEROSIS SOCIETY MULTIPLE SCLEROSIS SOCIETY
The US National Multiple Sclerosis (MS) Society The UK Multiple Sclerosis Society website offers
website has information about the disease and its research information and care and support
treatment and resources for patients. resources for patients.
nationalmssociety.org mssociety.org.uk
MULTIPLE SCLEROSIS SOCIETY OF CANADA

The Multiple Sclerosis Society of Canada website
offers information about treatments and clinical
resources available in Canada.
mssociety.ca

CASE 5-2 A 34-year-old man was seen for diplopia. He reported an episode of right
eye visual blurring associated with pain on eye movement 8 months
earlier and an episode of clumsy gait with numbness and tingling in his
feet 18 months earlier. Both lasted a few weeks.
On examination, he had a right afferent pupil defect, incomplete left
internuclear ophthalmoplegia, reduced pinprick and touch perception
from his fingertips to mid forearm in his left hand, reduced vibration in his
toes bilaterally, and hyperreflexia in his right arm and both legs. MRI
demonstrated more than 50 T2-hyperintense lesions throughout the brain
and spine highly suggestive of multiple sclerosis; five lesions were
enhancing.
A diagnosis of relapsing-remitting multiple sclerosis was made. He was
prescribed oral methylprednisolone 1 g/d for 5 days. Because of the
severity of the relapse, a steroid taper was also prescribed (prednisone
60 mg/d, decreasing by 10 mg every 5 days); the dose and use of a taper is
based only on experience as evidence supporting a taper is lacking.
He was also informed that he had several worrisome prognostic
factors that increased his chance of becoming disabled, including older
age of onset (age older than 30), male sex, nonwhite race (the patient was
African American), residual disability, frequent relapses, very high MRI
burden of disease, and highly active MRI.
Disease-modifying therapy initiation was recommended with minimal
delay. His insurance required the escalation approach. High-dose
interferon, glatiramer acetate, teriflunomide, and dimethyl fumarate
were recommended options. He chose teriflunomide as he did not want
injectable therapy and thought he would forget to take a pill 2 times a
day. A follow-up MRI was scheduled for 6 months later, and he returned
within 4 to 6 weeks to discuss potential second-line therapies so that
prescreening and recommended immunizations could be completed to
avoid further delay in initiating highly effective treatment if he showed
evidence of early treatment failure.
COMMENT This case illustrates management of a patient at high risk of future severe
disability based on the features of older age of onset (age older than 30),
male sex, nonwhite race, residual disability, frequent relapses, very high
MRI burden of disease, and highly active MRI. His risk of future relapse and
disability was very high, so disease-modifying therapy was not delayed
and preparations were made to be ready to escalate therapy rapidly if he
had breakthrough disease clinically or on MRI. Choosing to start a highly
effective (second-line) disease-modifying therapy would have been
considered reasonable by many physicians if it had been an option.
684 JUNE 2019

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Pegylated interferon β-1a for relapsing- 65 ClinicalTrials.gov. Traditional Versus Early
remitting multiple sclerosis (ADVANCE): a Aggressive Therapy for Multiple Sclerosis Trial
randomised, phase 3, double-blind study. (TREAT-MS). clinicaltrials.gov/ct2/show/
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688 JUNE 2019

Highly Aggressive REVIEW ARTICLE
Multiple Sclerosis

C O N T I N U UM AUDIO
ONLINE
By James D. Bowen, MD
CITE AS:
ABSTRACT 2019;25(3, MULTIPLE SCLEROSIS
PURPOSE OF REVIEW: Newly introduced disease-modifying therapies offer
DISEASES): 689–714.
greater efficacy than previous therapies but also have serious side effects.
This article reviews factors useful in identifying those at risk of developing Address correspondence to
aggressive relapsing multiple sclerosis (MS) and therapies available Dr James D. Bowen, Multiple
Sclerosis Center, Swedish
for treatment. Neuroscience Institute,
1600 E Jefferson St, Ste A,
Seattle, WA 98122, james.
RECENT FINDINGS:Several factors predict aggressive MS, including bowen@swedish.org.
demographic factors, relapses, symptom characteristics, MRI activity, and
other biomarkers. These can be used to select patients for more aggressive RELATIONSHIP DISCLOSURE:
Dr Bowen has served as a
therapies, including natalizumab, alemtuzumab, fingolimod, and consultant for Biogen; Celgene
ocrelizumab. Additional off-label treatments are available for patients Corporation; EMD Serono, Inc;
with severe disease. The benefits and side effects of these treatments Genentech, Inc; and Novartis
AG and has received personal
must be considered when making therapeutic decisions. compensation for speaking
engagements from Biogen; EMD
SUMMARY: Selecting patients who are most appropriate for aggressive
and Novartis AG. Dr Bowen
therapy involves considering risk factors for poor outcomes, early receives research/grant
recognition of treatment failure, balancing treatment efficacy and side support from Alexion; Alkermes;
Biogen; Celgene Corporation;
effects, and sharing the decision with patients to assist them in making Genentech, Inc; the National
optimal treatment choices. Vigilance for signs of treatment failure and Institute of Allergy and
early switching to more aggressive therapy are important components in Infectious Diseases
(UM1AI110557); the National
optimal care. Institutes of Health/National
Institute on Aging
(U01AG006781); the National
Institutes of Health/National
INTRODUCTION Institute of Allergy and
T
Infectious Diseases (N01AI15416);
reatment options for multiple sclerosis (MS) have expanded the National Institute of
remarkably since the introduction of the first disease-modifying Neurological Disorders and
therapy in 1993. Newer disease-modifying therapies offer greater Stroke (U10NS077309); and
Sanofi Genzyme.
efficacy and convenience, but they also have serious side effects.
One of the great challenges of treating MS is determining which UNLABELED USE OF
patients will benefit the most from higher-efficacy, higher-risk treatments. This PRODUCTS/INVESTIGATIONAL
USE DISCLOSURE:
article discusses risk factors for aggressive MS and reviews higher-efficacy Dr Bowen discusses the
disease-modifying therapies. unlabeled/investigational use of
cyclophosphamide, high-dose
immunosuppressive therapy
RISK FACTORS FOR AGGRESSIVE MULTIPLE SCLEROSIS with stem cell transplantation,
and rituximab for the treatment
Prospectively identifying aggressive MS would allow more appropriate targeting of highly aggressive multiple
of higher-efficacy, higher-risk therapies. Unfortunately, the ability to predict sclerosis.
future courses of individual patients is imprecise. Nevertheless, several risk
factors have been recognized that identify patients at higher risk of aggressive © 2019 American Academy
disease (TABLE 6-1). of Neurology.

HIGHLY AGGRESSIVE MULTIPLE SCLEROSIS
Demographic Factors
Demographic risk factors for MS include male sex, onset after 40 years of age,
nonwhite race, and smoking.
MALE SEX. Men with MS reach disability milestones in two-thirds to three-fourths

of the time required for women with MS.1–4 Also, the number of males reaching
higher levels of disability is greater than the number of females.5,6 However,
the effects of sex on MS outcomes is modest. Ten years after starting
disease-modifying therapy, mean Expanded Disability Status Scale (EDSS)
TABLE 6-1 Risk Factors for Aggressive Multiple Sclerosis
Demographic Factors
◆ Male
◆ Onset after age 40
◆ Nonwhite race
◆ Smoking
Clinical
◆ Relapse characteristics
◇ Number of relapses
◇ Short interval between relapses
◇ Incomplete recovery from relapse
◇ Unfavorable neurologic symptoms (pyramidal, cerebellar, sphincter, cognitive)
◇ Multifocal presentation
◆ Disability
◇ Rapidly worsening disability
◆ Phenotype of multiple sclerosis
◇ Progression from onset
MRI Characteristics
◆ T2 lesion burden
◆ Gadolinium-enhancing lesions
◆ T1-hypointense lesions
◆ Brain atrophy
◆ Infratentorial lesions
◆ Spinal cord lesions
CSF
◆ Oligoclonal bands
Biomarkers
◆ Neurofilament light chain (not commercially available)
690 JUNE 2019

scores were slightly worse in males (0.26 points),7 with the proportion of males KEY POINTS
reaching disability milestones 1.17 times higher than females.8 The time from onset
● Demographic factors that
for a 30-year old to reach an EDSS score of 6.0 (needing a cane) was 9.7 years for suggest a more aggressive
females and 8.2 years for males.9 Some studies found no significant association multiple sclerosis course
between sex and disability.10 include male sex, onset
after 40 years of age,
AGE AT ONSET, ESPECIALLY IF AFTER AGE 40. Those presenting with MS after age nonwhite race, and smoking.
50 reach disability milestones at least twice as fast as those in their twenties.1,2
● Clinical characteristics
Each decade of age at onset worsens disability on the EDSS by 0.43.7 The EDSS is that predict the risk of
a 10-point scale ranging from no disability(0) to death (10).7 The mean age of aggressive multiple sclerosis
onset was 46.4 in those needing a cane by 5 years compared to 35.6 in those who include frequent relapses;
did not.6 However, a slowly progressive component of MS drives most shorter interattack intervals;
incomplete recovery from
correlations with age, whereas short-term aggressive inflammation can occur at attacks; pyramidal,
any age.11 Modest correlations between age and disability have been found in cerebellar, sphincter, or
other studies.5,8,9 The relationship between age and disability is weakened by cognitive symptoms; and
confounding variables such as baseline disability or brain atrophy.10 multifocal onset.
NONWHITE RACE. African Americans reach higher levels of disability in about

three-fourths of the time of whites.12 African Americans represented 6.6% of
those with nonbenign courses and 3.8% of those with benign courses.5 The
proportion of those with African ancestry requiring a cane was 2.2 to 2.8 times
that of whites.3,4
SMOKING. Of those not needing a cane by 5 years, 44.5% were smokers; of those
needing a cane by 5 years, 64.5% were smokers.6 A meta-analysis found that
smoking increased EDSS scores only slightly, by a mean of 0.15 points. However,
the rate at which smokers and nonsmokers reached disability milestones was
not statistically different.13
Clinical Characteristics
Clinical characteristics that predict the risk of aggressive MS include frequent
relapses; shorter interattack intervals; incomplete recovery from attacks;
pyramidal, cerebellar, sphincter, or cognitive symptoms; and multifocal onset.
FREQUENT RELAPSES. Relapses during the first year of treatment predict

worsening disability or treatment failure in the subsequent 3 years. This risk is
almost doubled for those having one attack and tripled for those with two or
more attacks.14 Attacks of MS during the first few years increase the risk of
reaching various disability milestones, such as moderate disability in a single
neurologic system, limited walking distance, or needing a cane.1–4 Each attack
during these early years further increases the risk of disability.15 The number
of attacks over time (annualized relapse rate) also correlates with poor
outcomes.10 After starting a disease-modifying therapy, continued attacks
worsen the prognosis.7
SHORTER INTERATTACK INTERVALS. The time to develop difficulty walking was

6.6 years if the interval between the first and second attacks was less than 2 years,
9.6 years if the interval was 2 to 5 years, and 16.1 years if the interval was longer
than 5 years (CASE 6-1).1 Shorter times to reach other disability milestones, such
as requiring a cane, are also seen with shorter interattack intervals.15 Compared
to people with longer intervals between attacks, those with less than 2 years

CASE 6-1 A 33-year-old woman developed optic neuritis. One year later, she had
an episode of leg weakness. A diagnosis of multiple sclerosis (MS) was
confirmed by brain MRI. She was treated with glatiramer acetate, but
within 18 months, she had an attack with recurrence of left footdrop,
which did not improve with corticosteroids. Three months later, she had
another attack, with weakness in the right leg. An MRI showed 10 new
lesions, six of which showed gadolinium enhancement (FIGURE 6-1). After a
discussion of treatment options, she was switched to natalizumab
following a negative JC virus antibody test. Additional JC virus antibody
tests were performed every 6 months. Follow-up MRIs at 6 and 18 months
were stable.
FIGURE 6-1
Axial postcontrast T1-weighted brain MRI demonstrates multiple enhancing lesions in the
right frontal (A) and right parietal (B) regions. Unrelated to multiple sclerosis, an incidental
meningioma is present in the left parasagittal parietal lobe.
COMMENT This case illustrates a patient at high risk of having aggressive MS. Although
her initial demographic factors (female with optic neuritis onset) were
benign, her subsequent course with two attacks in 2 years was a sign of an
aggressive course. Furthermore, she had many new T2 lesions and
gadolinium-enhancing lesions. She also developed disability, with the
failure of her footdrop to resolve. Her treatment was appropriately
escalated to a more aggressive medication.
692 JUNE 2019

between the first and second attacks reached moderate disability in about half KEY POINTS
the time and required a cane in less than one-third the time.3,4
● Rapidly worsening
INCOMPLETE RECOVERY FROM ATTACKS. In natural history population studies, disability and multiple
sclerosis that is progressive
disability milestones such as moderate disability or requiring a cane were reached from onset predict an
in about half the time in those with incomplete recovery.1,2 The proportion of aggressive course.
people reaching these milestones was increased about tenfold in those with
incomplete recovery.3,4 Residual disability as indicated by EDSS score after the ● MRI characteristics that
predict more aggressive
onset exacerbation was the single strongest predictor of having difficulty course include the number
walking after 10 years.8 and volume of T2 lesions;
the presence of
PYRAMIDAL, CEREBELLAR, SPHINCTER, OR COGNITIVE SYMPTOMS. The gadolinium-enhancing
proportion of people reaching disability requiring a cane is higher if pyramidal or lesions; the volume of
cerebellar systems are involved.3 The proportion of patients reaching disability T1-hypointense lesions; and
the presence of atrophy,
milestones is almost 4 times higher in those with residual pyramidal symptoms, infratentorial lesions, or
2 times higher in those with residual sphincter dysfunction, 1.5 times higher in spinal cord lesions.
those with residual cerebellar dysfunction, and 1.25 times higher in those with
brainstem dysfunction.8 Having motor or cerebellar symptoms at onset increased
the risk of disability.6 However, motor symptoms are highly correlated with age,
sex, and progressive onset, which confounds the association.9 Baseline cognitive
changes also predicted greater disability on the EDSS, although the EDSS is
primarily a scale of motor dysfunction.16 Vision symptoms have a more benign
prognosis, but this effect was modest after controlling for age, male sex, and
progressive onset.9 Similarly, sensory symptoms have a better prognosis.6 Sensory
symptoms decrease the risk of reaching disability milestones by half.8 Brainstem
symptoms have been associated with disability in some studies but not in others.1,15
MULTIFOCAL ONSET. Many studies have suggested that multifocal symptoms at

onset increase the risk of disability. However, this has not been found in
all studies.15
Rapidly Worsening Disability

Those with shorter times from onset to moderate disability have faster onset of
disability and more severe disabilities.15 Baseline EDSS and EDSS progression
during the first 24 months were strongly correlated with several measures of
disability 8 years later.10
Progression From Onset

Progression from onset more than doubles the risk of disability compared to
relapsing-onset MS.8,11 Patients with progressive onset reach disability milestones
in approximately one-third to half the time of those with relapsing-remitting
onset.1,2,9 Progressive onset strongly correlates with a nonbenign course.5
MRI Characteristics
Characteristics seen on MRI that may indicate a more aggressive MS course
include the number and volume of T2 lesions; the presence of gadolinium-
enhancing lesions; the volume of T1-hypointense lesions; and the presence
of atrophy, infratentorial lesions, or spinal cord lesions.
T2 BURDEN. The number of baseline T2 lesions and new T2 lesions developing

over time correlates with future disability.17 In a study of people with clinically

isolated syndrome, the proportion of people reaching moderate disability

at 20 years after disease onset was 36% for those with one to three T2 lesions
at baseline, 50% for those with four to nine T2 lesions at baseline, and 65% for
those with 10 T2 lesions at baseline.18 In a large European database, having
three or more new T2 lesions over 1 year best predicted future disability
compared to other MRI parameters.14 Baseline volume of T2 lesions also
predicted future disability,19 as did the growth of lesion volume over time.18
In a multivariate model, the number of new T2 lesions over time was the best
MRI predictor of future disability, followed by new enhancing lesions, baseline
enhancing lesions, baseline T2 lesion number, and baseline T2 lesion volume.17
Two measures of lesion location (spinal cord and infratentorial) and two
measures of disease activity (baseline gadolinium enhancement and new T2
lesions at 3 months) correlated best with subsequent disability.17 Other studies
suggest that baseline brain volume may be a better predictor than T2
lesion parameters.10
GADOLINIUM-ENHANCING LESIONS. Gadolinium-enhancing lesions at

baseline and newly developing over time are associated with increased
risk of future disability. 17
T1-HYPOINTENSE LESIONS. Patients with clinically isolated syndrome who

were destined to have moderate disability by 5 years had triple the baseline T1
lesion volume compared to those not reaching this level of disability. T1 lesion
volume also increased more quickly over time in those developing disability.19
However, T1 lesion volume may not be as accurate in predicting aggressive MS as
T2 lesion number.17
ATROPHY. In some studies, brain atrophy correlates poorly with disability.17

However, in other studies, brain volume strongly correlates with several markers
of poor clinical outcome.10 Patients with higher rates of atrophy were more
likely to reach moderate levels of disability at 5 years than those with less
atrophy. However, atrophy accounts for only a small portion of the risk of
developing disability.19
INFRATENTORIAL LESIONS. Infratentorial lesion location is associated with

disability, but the strength of the association is weak.17
SPINAL CORD LESIONS. The proportion of patients who develop moderate

disability is over 5 times greater in those with spinal cord lesions compared to
those without spinal cord lesions.20 Baseline spinal cord lesions and spinal cord
lesions that develop over time correlate with disability.19 Of the MRI locations
commonly used in MS diagnosis, the spinal cord correlates the best with
disability.17 However, in patients with clinically isolated syndrome, brain and
spinal cord factors were highly correlated, and adding spinal cord factors
improved the prediction of disability only slightly.19
Cerebrospinal Fluid Characteristics

Oligoclonal bands, indicating active B-cell clones within the central nervous
system (CNS), are associated with several markers for aggressive MS.21
However, the number of bands does not add additional prognostic information
694 JUNE 2019

beyond their presence. The production of IgG by CNS plasma cells, as indicated KEY POINT
by the IgG index or IgG synthesis rate, increases the risk of an aggressive course22
● Oligoclonal bands are
with an approximately 50% increase in the rate of developing disability over associated with several
time.23 IgM oligoclonal bands and CSF free kappa light chains also predict a markers for aggressive
more severe course, but these studies are not usually available from clinical multiple sclerosis.
laboratories.24,25
Neurofilament Light Chain

Many biomarkers have been proposed for MS. However, most have performed
poorly or are not available for use in the clinic. Currently, the marker with
the most promise is neurofilament light chain. This has usually been measured
in CSF, making it impractical as a longitudinal marker. However, an assay
using serum is now available. Standardized percentiles based on age (serum
neurofilament light chain increases with age) correlate with current EDSS
score and with EDSS score worsening at 1 year.26 This test is not yet
commercially available.
Integration of Risk Factors for Future Disability

Using these risk factors to determine future disability in an individual patient
remains problematic. Risk factors are often highly correlated and cannot simply
be added together. For example, later age of onset, male sex, pyramidal
involvement, and progressive onset often occur together, and each factor would
not independently contribute to risk. Furthermore, known risk factors account
for only a small part of the overall risk in an individual patient. Multivariate
analyses found an R2 of only 0.35 in an 8-year follow-up of a clinical trial cohort.10
This means that only 35% of the variability between patients could be accounted
for based on the included risk factors. Better prediction may be found in
combining both initial evaluations and ongoing monitoring. This results in an
emphasis on early disabling symptoms (motor, sphincter, increasing EDSS score)
and disease activity (clinical or MRI attacks) as the best models.27
DEFINING AGGRESSIVE MULTIPLE SCLEROSIS

Many definitions of aggressive MS have been used in clinical research settings.28
These generally emphasize three markers for aggressive disease: clinical attacks,
disability, and MRI activity. The three most common schemata for identifying
aggressive disease, the Canadian MS Working Group Assessment, the modified
Rio score, and the Multiple Sclerosis Decision Model, are outlined in TABLE 6-2,
TABLE 6-3, and TABLE 6-4.
29
The Canadian MS Working Group Assessment rates changes in relapses,

disability, and MRI as having low, medium, or high levels of concern (TABLE 6-2).
The Working Group recommends switching to more aggressive therapy if a
high level of concern is present in any one domain, a medium level of concern
is present in any two domains, or a low level of concern is present in all
three domains.30
The modified Rio score was developed in patients newly starting
disease-modifying therapies.31 Many measures were analyzed to determine
which best predicted outcomes over years 2 to 4. Because many measures were
interrelated, the final model retained only two criteria: new T2 lesions and
clinical relapses, with points assigned in each category (TABLE 6-3). A patient
with a score of 0 has a 24% probability of disability worsening by the end of year 4.

TABLE 6-2 Canadian Multiple Sclerosis Working Group Assessment for Suboptimal
Response to Disease-Modifying Therapies
Level of Concern
Criteria Low Medium High
Relapses
Rate One in second year of One in first year of treatment More than one in first year of
treatment treatment
Severity Mild: Moderate: Severe:

Steroids not required Steroids required Steroids/hospitalization
required
Minimal effect on activities Moderate effect on
of daily living activities of daily living Severe effect on activities
of daily living
One functional domain More than one functional
affected domain affected More than one functional
domain affected
No or mild motor/cerebellar Moderate motor/
involvement cerebellar involvement Severe motor/cerebellar
involvement
Recovery Prompt recovery; no Incomplete recovery at Incomplete recovery at

functional deficit 3 months; some functional 6 months; functional
impairment impairment
Disability progression
EDSS ≤3.5 ≤1 point 2 points at 6 months >2 points at 6 months

2 points at 12 months
EDSS 4.0–5.0 <1 point 1 point at 6 months >1 point at 6 months

1 point at 12 months
EDSS ≥5.5 NA 0.5 points at 6 months >0.5 points at 6 months
Clinically No motor symptoms; minor Some motor, cerebellar, or Pronounced motor,

documented sensory symptoms cognitive symptoms; multiple cerebellar, or cognitive
progression EDSS domains affected symptoms; multiple EDSS
domains affected
Timed 25-foot walk ≤20% confirmed at 6 months >20% and <100% increase ≥100% increase confirmed at
confirmed at 6 months 6 months
MRI activity
New gadolinium- 1 lesion 2 lesions ≥3 lesions

enhancing lesions
OR
Accumulation of new
T2 lesions per year
EDSS = Expanded Disability Status Scale; MRI = magnetic resonance imaging; NA = not applicable.
696 JUNE 2019

Those with scores of 1 have a 33% probability, and those with scores of 2 or higher
have a 65% probability.
The Multiple Sclerosis Decision Model (TABLE 6-4) is designed to identify
patients who do not attain “no evidence of disease activity” (NEDA). NEDA
means no relapse, disability, or MRI activity.32 This model identifies patients with
even minimal activity in these areas.29 The interpretation scores are color coded
for each domain. If all four domains are green, therapy remains unchanged. If
one domain is yellow, the patient should be reassessed in 3 months. If two
domains are yellow or one is red, an immediate change in therapy should
be considered.
TREATMENTS FOR AGGRESSIVE MULTIPLE SCLEROSIS

Currently, seven aggressive treatments for MS are approved by the US Food and
Drug Administration (FDA). Phase 3 study results are impossible to compare
between these medications because of differences in study design, comparator
arm treatments, outcome measures, inclusion criteria, and baseline patient
characteristics. The six commonly used aggressive medications are discussed
here in order of FDA approval.
Natalizumab
Natalizumab is a humanized monoclonal antibody that binds to the α4 subunit
of two integrin adhesion molecules, α4β1 and α4β7. An IgG4 subclass, it does not
fix complement or lyse cells. α4β1 and α4β7 are proteins expressed on the surface
of all leukocytes except neutrophils. They bind complementary proteins
expressed on endothelial cells: α4β1 to VCAM-1 and α4b7 to MAdCAM-1.
Leukocytes exiting the bloodstream bind their complementary molecules on
endothelial cells, allowing them to stop, go between the endothelial cells, and
enter the target tissue. Natalizumab, by binding to the α4 subunit, prevents the
Modified Rio Score TABLE 6-3
Criteria Points Assigned
MRI done at 6 months
≤5 new T2 lesions 0
>5 new T2 lesions 1
MRI done at 1 year
≤4 new T2 lesions 0
>4 new T2 lesions 1
Relapse over 1 year
0 relapses 0
1 relapse 1
≥2 relapses 2

TABLE 6-4 The Multiple Sclerosis Decision Modela
Criteria Points Assigned Interpretationb
Relapse 0 points = green
Each relapse 3 1–4 points = yellow
Characteristics ≥5 points = red
Functionally relevant 1
Residual symptoms after 3–6 months 2
Interval since start or change of therapy
>12 months 0
6–12 months 1
>3 to <6 months 2
Disability 0 points = green
MS Functional Compositec 1 point = yellow
Each test with worsening by 20% 1 ≥2 points red
Each test with worsening by 40% 2
Symbol Digit Modality Test
Worsening by ≥4 points 1
Worsening by ≥8 points 2
Neuropsychology 0 points = green
Fatigue Scale for Motor and Cognitive Functions 1 point = yellow
Worsening by 1 category 1 ≥2 points = red
Worsening by 2 categories 2
Worsening by 3 categories 3
Depression (HADS) –1
Anxiety (HADS) –1
Quality of life (MSIS-29) No points
MRI 0–2 points = green
Each gadolinium-enhancing lesion 1 ≥3 points = yellow
Each new/enlarging T2 lesion 1
HADS = Hospital Anxiety and Depression Scale; MRI = magnetic resonance imaging; MS = multiple sclerosis;
MSIS-29 = Multiple Sclerosis Impact Scale-29.
a
Modified from Stangel M, et al, Ther Adv Neurol Disord.29 © 2014 The Authors.
b
The interpretation scores are color coded for each domain. If all four domains are green, therapy remains
unchanged. If one domain is yellow, the patient should be reassessed in 3 months. If two domains are yellow
or one is red, an immediate change in therapy should be considered.
c
The MS Functional Composite includes the timed 25-foot walk, the 9-hole peg test, and the low-contrast
Sloan letter chart.
698 JUNE 2019

leukocyte from adhering to the endothelium cell, thus blocking its exit from the
bloodstream. Thus, natalizumab prevents leukocytes from entering the CNS.
Natalizumab was approved by the FDA in 2004 for relapsing forms of MS
based on the results of the AFFIRM (Natalizumab Safety and Efficacy in
Relapsing-Remitting Multiple Sclerosis) study, which compared the medication
to placebo, and the SENTINEL (Safety and Efficacy of Natalizumab in
Combination With Interferon Beta-1a in Patients with Relapsing-Remitting
Multiple Sclerosis) study, which compared the medication to weekly interferon
beta-1a.33,34 Common adverse effects of natalizumab are listed in TABLE 6-5.
The most serious adverse effect of natalizumab is progressive multifocal
leukoencephalopathy (PML). PML is an infection of oligodendrocytes by the JC
virus. The JC virus commonly infects the kidneys, where it remains latent but
intermittently becomes active. JC virus entering the bloodstream is easily
controlled by the immune system. However, in the setting of mutations making
the JC virus more likely to infect the CNS (neurotrophic) and immunosuppression,
the virus may gain access to the brain, causing PML. Symptoms of PML resemble
MS, including cognitive, motor, sensory, and visual symptoms (CASE 6-2).
However, PML slowly worsens over weeks, whereas most MS symptoms worsen
over days (for acute exacerbations) or months (for progressive forms of MS).
Suspected PML is diagnosed by MRI and confirmed by an ultrasensitive
Important Adverse Effects of Natalizumab TABLE 6-5
Allergic Reactions
◆ Hypersensitivity 1.9–4%, urticaria 2%
◆ Anaphylactic/anaphylactoid 0.8%
Liver Injury/Failure
Malignancies
◆ Melanoma
◆ Primary central nervous system lymphoma
Infection
◆ Herpes simplex virus type 1 encephalitis, meningitis
◆ Varicella-zoster meningovasculitis
◆ Acute retinal necrosis: herpes simplex virus types 1 and 2, varicella-zoster virus, Epstein-Barr
virus
◆ Mycobacterium avium intracellulare
◆ Aspergillosis
◆ Cryptococcal fungemia/meningitis
◆ Candida pneumonia
◆ Pneumocystis carinii pneumonia
◆ Burkholderia cepacia
◆ Cryptosporidial gastroenteritis
◆ Progressive multifocal leukoencephalopathy
Rebound After Stopping Medication

CASE 6-2 A 52-year-old woman with multiple sclerosis presented with several
weeks of difficulty focusing her eyes and subtle cognitive slowing.
Her initial care was at a different institution. When initially diagnosed
with multiple sclerosis 8 years ago, she was treated with interferon
beta-1a, but she had three additional attacks over 2 years and was
switched to natalizumab after 4 years. Her CD4:CD8 ratios were tracked
monthly and trended about 1400:750, or approximately 2.0 (normal).
She was positive for antibodies against the JC virus at the time that
she started the natalizumab, but a JC virus antibody index was not
performed. She had received 40 doses of natalizumab at the time of this
presentation.
MRI demonstrated changes consistent with progressive multifocal
leukoencephalopathy (PML) in the right posterior temporal white matter
(FIGURE 6-2). After recognizing that she likely had PML, she was transferred
to this institution for specialty care. An ultrasensitive polymerase chain
reaction (PCR) for JC virus was positive in her CSF with 272 copies/mL.
The natalizumab was discontinued, and five courses of plasma exchange
were given. She stabilized and remained stable 3 years later, with fixed
cognitive and visual deficits.
FIGURE 6-2
Axial fluid-attenuated inversion recovery (FLAIR) brain MRI shows a confluent lesion in the
white matter of the inferior (A), middle (B), and superior (C) temporal lobe and adjacent
regions of the right parietal lobe.
COMMENT PML presents with symptoms developing over a few weeks. It is diagnosed
by MRI and confirmed by ultrasensitive PCR for JC virus in CSF. Risk
factors include time on natalizumab, prior use of immunosuppressive
medications, and a high JC virus antibody index (>0.9). The JC virus
antibody test is reported as positive or negative, but an index may be
requested from the clinical laboratory. The index should be followed every
6 months. CD4:CD8 ratios, as had been previously followed in this patient,
do not predict PML risk with natalizumab and should not be used for that
purpose.
700 JUNE 2019

polymerase chain reaction (PCR) test on CSF for the JC virus. Typical MRI KEY POINTS
findings in PML are one or more hyperintense lesions on T2-weighted or fluid-
● The most serious side
attenuated inversion recovery (FLAIR) sequences with a sharp border at the effect of natalizumab is
gray-white junction and less distinct borders toward the white matter. Lesions progressive multifocal
from PML may affect white matter areas of the hemispheres, basal ganglia, external leukoencephalopathy.
capsule, or posterior fossa. Enhancement may or may not be present.35 Standard The risk of
progressive multifocal
sensitivity PCR testing from most laboratories is inadequate in this setting.
leukoencephalopathy is
The risk of PML for patients on natalizumab is estimated using three factors: estimated by the duration of
time on natalizumab, prior immunosuppressive medications, and JC virus natalizumab therapy, prior
antibody index. FIGURE 6-3 illustrates how to estimate PML risk.36,37 Rare cases immunosuppressive use,
and JC virus antibody index.
have occurred in patients without antibodies to the JC virus.38 Some have
advocated extending dosing intervals to 6 to 8 weeks in high-risk patients, but ● Rebound can occur
this remains controversial.39 between 3 and 6 months
Rebound may occur when discontinuing natalizumab, especially 3 to after stopping natalizumab.
6 months after the last dose.40 Up to 27.9% of patients have rebound Other disease-modifying
therapies should be started
exacerbations within 6 months, and 37% of these are severe, with the median before this time to minimize
baseline EDSS score of 3.0 (moderate disability) increasing to 6.0 (requiring a rebound risk.
cane). Rebound can be minimized by starting another disease-modifying therapy
before the 3- to 6-month rebound period.41 Many advocate starting another
disease-modifying therapy about 4 weeks after the last natalizumab dose.
Before starting natalizumab, obtain liver function tests, a JC virus antibody
index, and a brain MRI (for comparison if new PML symptoms develop). During
treatment, obtain a JC virus antibody index every 6 months. The dose of
natalizumab is 300 mg IV every 4 weeks.
Alemtuzumab
Alemtuzumab is a humanized monoclonal antibody binding CD52. CD52 is
expressed on lymphocytes, natural killer cells, monocytes, and dendritic cells.
FIGURE 6-3
Risk of progressive multifocal leukoencephalopathy (PML) in patients taking natalizumab.
Risk is determined by months on medication, prior use of immunosuppressive medications
(IS), and JC virus antibody index (JCVI).39

The function of CD52 is poorly understood. Alemtuzumab, an IgG1 subclass,

binds complement and lyses target cells. It causes a rapid depletion of all types of
lymphocytes. Different lymphocyte types recover at different rates and degrees,
causing long-term increases in regulatory and memory T cells, decreased TH1 and
TH17 cells, and changes in cytokine profiles.28
Alemtuzumab was approved by the FDA in 2014 for relapsing forms of MS
that had inadequate responses to two or more drugs indicated for the treatment
of MS. Two pivotal studies, the CARE MS-I (Comparison of Alemtuzumab and
Rebif Efficacy in Multiple Sclerosis, Study One) and CARE MS-II (Comparison
of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis, Study Two) compared
alemtuzumab with interferon beta-1a 3 times a week.42,43 The CARE MS-II
study originally had an arm receiving alemtuzumab 24 mg/d, which was
discontinued to increase recruitment into the other arms.
Common adverse effects of alemtuzumab are listed in TABLE 6-6. Infusion
reactions with flushing are usually due to a lymphocyte lysis syndrome with
cytokine release. However, true anaphylaxis with hives, airway constriction
(wheezing), or cardiovascular instability can occur. Autoimmune diseases are
TABLE 6-6 Important Adverse Effects of Alemtuzumab
Infusion Reactions: 92%,

Anaphylaxis: 3%
Autoimmunity
◆ Graves disease: 34%
◆ Immune thrombocytopenia: 2%
◆ Autoimmune glomerular nephropathies: 0.3%
◆ Others (0.2% each): autoimmune hemolytic anemia and autoimmune pancytopenia,
undifferentiated connective tissue disorders, anti-Factor VIII antibodies
◆ Others (0.2% each): rheumatoid arthritis, type 1 diabetes mellitus, vitiligo, retinal pigment
epitheliopathy
◆ Guillain-Barré syndrome, chronic inflammatory demyelinating polyradiculoneuropathy (CIDP)
Malignancies
◆ Thyroid: 0.3%
◆ Melanoma: 0.3%
◆ Lymphoproliferative disorders: lymphoma, mucosa-associated lymphoid tissue lymphoma,
Castleman disease, Burkitt lymphoma
Infections: Overall 71% Compared to 53% in Interferon Control
◆ Herpes: herpes simplex virus types 1 and 2, varicella-zoster virus, herpetic meningitis
◆ Human papilloma virus: cervical dysplasia (2%)
◆ Tuberculosis: 0.3%
◆ Vaginal candidiasis: 12% compared to 3% in interferon control
◆ Listeria monocytogenes meningitis, encephalitis, sepsis, and gastroenteritis
Acute Acalculous Cholecystitis
Hypersensitivity Pneumonitis, Pneumonitis With Fibrosis
702 JUNE 2019

presumably caused by imbalances in immune regulation as lymphocytes recover KEY POINT
to different degrees. The risk of malignancy is due to decreased immune
● The side effects of
surveillance. alemtuzumab include
Before starting alemtuzumab, obtain a complete blood cell count with immediate infusion
differential, liver function tests, blood urea nitrogen (BUN), creatinine level, reactions, autoimmune
varicella-zoster titer, urinalysis with microscopic examination, and purified diseases, infections, and
malignancies.
protein derivative or QuantiFERON Gold test. A skin examination should also be
performed to assess for baseline skin cancers, and all required vaccines should be
administered 6 or more weeks before treatment.
During treatment, patients should be premedicated with methylprednisolone
1000 mg IV before each of the first 3 days of the series, an antihistamine
(cetirizine 10 mg orally plus diphenhydramine 50 mg IV), and an antipyretic
(acetaminophen 500 mg) and given acyclovir 400 mg to 800 mg 2 times a day.
Acyclovir should be continued for 2 months or until the CD4 lymphocyte count is
200 cells/mm3 or higher, whichever is longer. After treatment, a complete blood
cell count with differential, creatinine level, and urinalysis with microscopic
examination should be conducted monthly until 48 months after the last
dose of alemtuzumab. A thyroid function test, including measurement of
thyroid-stimulating hormone (TSH), and examination for thyroid nodules,
should be performed every 3 months until 48 months after the last dose. A
dermatologic examination and testing for the human papilloma virus in women
(Papanicolaou test [pap smear]) should be conducted annually. The dose of
alemtuzumab is 12 mg/d on 5 consecutive days. One year later, 12 mg/d is given
for 3 consecutive days. Pivotal studies were halted before most people received
additional doses because of thrombocytopenia. Many patients remain stable
without additional doses. However, if relapses occur, 12 mg/d on 3 consecutive
days can be given as often as annually.
Fingolimod
Fingolimod binds the sphingosine-1-phosphate receptor, causing it to be
internalized and removed from the cell surface. It binds four of the five
sphingosine-1-phosphate receptors but not sphingosine-1-phosphate receptor 2.
These receptors are found on immune system cells, endothelial cells, neurons,
oligodendrocytes, and astrocytes.44 Fingolimod’s benefit is attributed to its
effect on lymphocytes. Naïve and central memory lymphocytes use the
sphingosine-1-phosphate receptor to exit lymph nodes. Without this receptor,
they get trapped in lymph nodes and removed from the circulation. Effector and
effector memory lymphocytes do not traffic through lymph nodes and remain in
circulation. Naïve lymphocytes comprise about 80% of circulating lymphocytes,
so fingolimod decreases absolute lymphocyte counts by 80%. The 20% remaining
are effector cells. The differential sequestration of naïve lymphocytes explains
why leukocyte and lymphocyte levels do not correlate with the degree of
immunosuppression or side effects with this medication.
Fingolimod was approved by the FDA in 2010 for relapsing forms of MS based
on the results of the FREEDOMS (FTY720 Research Evaluating Effects of Daily
Oral therapy in Multiple Sclerosis) study, which compared the medication to
placebo, and the TRANSFORMS (Trial Assessing Injectable Interferon Versus
FTY720 Oral in Relapsing-Remitting Multiple Sclerosis) study, which compared
the medication to interferon beta-1a weekly.45,46 The pivotal trials contained a
third arm dosed at 1.25 mg/d that was not commercialized (data are not included

here). The FREEDOMS II (Efficacy and Safety of Fingolimod [FTY720] in Patients

With Relapsing-Remitting Multiple Sclerosis) study, conducted to include US
patients, was used for safety but not efficacy during the FDA submission.
Common adverse effects of fingolimod are listed in TABLE 6-7. After the first
dose, the patient’s pulse slowly decreases, reaching a nadir at 4 to 5 hours before
increasing again. This occurs because fingolimod initially has an agonist effect on
cardiac sphingosine-1-phosphate receptors before their removal from the cell
surface. After sphingosine-1-phosphate receptor removal, the drug has no effect
on heart rate. Blood pressure and pulse should be monitored hourly for 6 hours
after the first dose, with an ECG before and after. Symptomatic bradycardia,
seen in 0.6%, is treated by having the patient lie recumbent since the pulse will
increase over 1 to 2 hours in most cases without treatment. If patients are
nonadherent to the medication for 14 days, receptors return in sufficient
numbers that first-dose monitoring must be repeated. Drugs that prolong the QT
interval are contraindicated before starting fingolimod. After about 2 weeks,
most of these medications can be reinstated because the sphingosine-1-phosphate
receptors are no longer present. Atrioventricular block can occur following the
first dose, usually benign first-degree or Mobitz type I blocks, but rare
third-degree blocks have occurred.
TABLE 6-7 Important Adverse Effects of Fingolimod
Cardiac
◆ Bradycardia during first dose
◆ Avoid medications that prolong the QT interval before first dose, including Class Ia and
Class III antiarrhythmic medications
Infections
◆ Herpes
◇ Herpes simplex infection: encephalitis, disseminated infections
◇ Varicella-zoster: shingles, disseminated zoster
◇ Kaposi sarcoma: (human herpesvirus 8)
◆ Cryptococcal: meningitis, disseminated
◆ Atypical mycobacteria
Macular Edema
Posterior Reversible Encephalopathy Syndrome (PRES)
Respiratory Effects
Hepatic Injury
Blood Pressure
Cutaneous Malignancies
◆ Basal cell
◆ Melanoma
◆ Merkel cell
704 JUNE 2019

Overall, infection rates are similar with fingolimod and placebo. However, KEY POINT
opportunistic infections have been seen with fingolimod. Herpetic infections
occur in 9% of patients treated with fingolimod and 7% of patients receiving fingolimod include
placebo. Cryptococcal infections are seen in 1 in 20,000. The current rate of PML is first-dose bradycardia.
approximately 1 per 12,000, increasing to 1 per 5,000 in those treated longer than Fingolimod and siponimod
2 years (Overview of Fingolimod in Adults: Efficacy & Safety and Q4 2018 PML may cause macular edema
and opportunistic
Update, November 2018, email communication April 1, 2019). Unlike with
infections, including
natalizumab, no markers are known to predict PML risk with fingolimod. Specifically, Cryptococcus and
lymphocyte counts, CD4:CD8 ratios, and JC virus index do not predict risk. progressive multifocal
Macular edema occurs in 0.5% of patients treated with fingolimod and 0.4% of leukoencephalopathy. Risk
for infection cannot be
patients on placebo but may be seen in 20% in those with diabetes mellitus or
assessed using absolute
uveitis. Most cases occur within the first 3 to 4 months of treatment. Pulmonary lymphocyte counts.
spirometry measures are approximately 2% lower than in placebo and are
usually clinically meaningful only in patients with severe baseline pulmonary
dysfunction. Transaminase elevation is usually mild, with testing recommended
only if hepatic symptoms occur. Elevations in blood pressure average 3 mm Hg
systolic, 2 mm Hg diastolic. Basal cell carcinomas are seen in 2% of those treated
with fingolimod and 1% on placebo. Periodic skin examination is recommended.
Melanoma and Merkel cell carcinomas have been reported.47
Before starting fingolimod, obtain a complete blood cell count with differential,
liver function tests, BUN and creatinine levels, and varicella-zoster titer. An eye
examination for macular edema (optical coherence tomography) should also be
performed. First-dose monitoring includes blood pressure and pulse hourly for
6 hours under medical observation and ECG immediately before and after the
6-hour first-dose monitoring. After treatment, eyes should be examined for
macular edema 3 to 4 months after starting therapy and if visual symptoms are
noted thereafter. Blood pressure should be monitored during office visits.
The dose of fingolimod is 0.5 mg/d. Fingolimod became the first disease-
modifying therapy to receive FDA approval in pediatric patients age 10 or
older.48 Patients weighing more than 40 kg (88 lb) take the adult dose of
0.5 mg/d. Those weighing 40 kg (88 lb) or less take 0.25 mg/d.
Siponimod
Similar to fingolimod, siponimod binds the sphingosine-1-phosphate receptor,
but, unlike fingolimod, it only binds to subtypes 1 and 5. It was approved by the
FDA on March 27, 2019, for relapsing forms of MS, including clinically isolated
syndrome, relapsing-remitting disease, and active secondary progressive disease.
This was based on the results of the EXPAND (Exploring the Efficacy and Safety
of Siponimod in Patients With Secondary Progressive Multiple Sclerosis) trial
of patients with secondary progressive MS.49
Common adverse events are similar to those of fingolimod (TABLE 6-7).
Variants of cytochrome P450 metabolize siponimod more slowly. This requires
CYP2C9*1/*3 or *2/*3 genotype testing before initiation of therapy because
patients with these variants should receive half of the normal dose. Patients who
are homozygous for the CYP2C9*3/*3 genotype should not receive the drug.
Unlike fingolimod, siponimod is initiated with a 4-day upward titration. As a
result, first-dose monitoring is required only for those with sinus heart rates less
than 55 beats/min, first- or second-degree atrioventricular block, or a history of
myocardial infarction or heart failure. The maintenance dose of siponimod is 2 mg/d,
except in those with CYP2C9*1/*3 or *2/*3 genotype, who should take 1 mg/d.

Ocrelizumab
Ocrelizumab, a humanized monoclonal antibody directed against CD20, is an
IgG1 subclass that fixes complement and lyses cells. The function of CD20 is
uncertain, but it is found predominantly on B cells. It is not expressed on stem
cells, early pro-B cells, plasmablasts, or plasma cells. Since plasma cells are
spared, antibody levels are minimally affected. It is assumed that ocrelizumab’s
mechanism of action relates to the role of B cells in presenting antigens to
T cells and producing cytokines. A small subset of T cells have CD20, but their
function is unclear.
Ocrelizumab was approved by the FDA in 2017 for relapsing MS based on
the result of the OPERA (A Study to Evaluate the Efficacy and Safety of
Ocrelizumab in Comparison to Interferon-β-1a in Patients With Relapsing
Multiple Sclerosis) I and OPERA II studies, which compared the medication to
interferon beta-1a 3 times a week.50 It is also approved by the FDA for primary
progressive MS based on the results of the ORATORIO (A Study of Ocrelizumab
in Patients With Primary Progressive Multiple Sclerosis) study, which compared
the medication to placebo.51 Common adverse effects of ocrelizumab are listed in
TABLE 6-8. Infusion reactions, seen in 34% to 40%, are primarily B-cell lysis
syndromes with flushing and throat irritation. These are most common with the
first infusion and less common with subsequent infusions because few B cells
remain. Symptoms usually respond to slowing the infusion rate so that cells do not
lyse so rapidly. Anaphylaxis with hives, airway obstruction, or cardiovascular
instability is seen in 0.3%.
Infections are higher in ocrelizumab (58%) compared to interferon (52%).
Upper and lower respiratory infections are modestly higher. Herpes infections
are more common with ocrelizumab compared to interferon, including
varicella-zoster (2.1 versus 1.0%), oral herpes (3.0 versus 2.2%), and genital
herpes (0.1 versus 0%). PML and reactivation of hepatitis B are listed as risks
with ocrelizumab, but no cases have been seen to date. They have occurred
with rituximab, another anti-CD20 agent, but in people with hematologic
TABLE 6-8 Important Adverse Effects of Ocrelizumab
Infusion Reactions
Infections
◆ Hypogammaglobulinemia
◆ Upper/lower respiratory infections
◆ Herpes
◇ Varicella-zoster
◇ Human herpesviruses 1 and 2
◇ Pasteurella
◆ Hepatitis B reactivation
Malignancies
◆ Breast (refer to article text for details)
706 JUNE 2019

malignancies or in those receiving multiple immunosuppressive medications,
both of which can contribute to the occurrence of these infections. The risk of
PML is estimated to be 1 in 30,000 with rituximab.52 It is uncertain whether
ocrelizumab increases the risk of malignancies. The risk of all malignancies was
1.3% with ocrelizumab, 0.24% with interferon, and 0.8% with placebo. Breast
cancer occurred in 6 of 781 women compared to none with placebo.50,51
However, this number is well within the expected rate for age-matched women,
and zero is lower than expected. Postmarketing breast cancer rates have
remained stable and within the expected range.
Before starting ocrelizumab, obtain hepatitis B serology. Although not
required, some obtain varicella-zoster virus titers and IgG levels. Ocrelizumab is
given intravenously. The first course is two doses of 300 mg, given 2 weeks apart;
subsequent courses are 600 mg given once every 6 months.
Cladribine
Cladribine, a purine analogue, is metabolized to its active form and concentrated
in lymphocytes and monocytes but not in other cells. Single-stranded DNA
breaks cannot be repaired, eventually resulting in cell death. The FDA
application for cladribine was withdrawn in 2011 because of malignancy
concerns. With additional data now available, cladribine was approved by the
FDA on March 29, 2019. Approval was based on the results of the CLARITY
(A Safety and Efficacy Study of Oral Cladribine in Subjects With Relapsing-
Remitting Multiple Sclerosis [RRMS]) study that compared cladribine to placebo
in patients with relapsing-remitting MS.53 The ORACLE MS (Oral Cladribine
in Early Multiple Sclerosis [MS]) study evaluated cladribine in those with
clinically isolated syndrome, but side effects precluded an FDA approval for this
indication.54 It is approved for relapsing-remitting disease and active secondary
progressive disease in those who have had an inadequate response to or are
unable to tolerate an alternate drug.
Common adverse effects are listed in TABLE 6-9. Malignancies remain a
concern, with 0.27 events per 100 person-years with cladribine and 0.13 events
per 100 person-years with placebo. A variety of cancers was seen, consistent with
Important Adverse Effects of Cladribine TABLE 6-9
Lymphopenia
Neutropenia
Infections
◆ Varicella-zoster
◆ Hepatitis B and C reactivation
◆ Tuberculosis reactivation
Malignancies
Rash
Alopecia

an effect on immunosurveillance rather than direct toxicity to a particular organ.

Because of the risk of teratogenicity, both males and females should use effective
contraception for 6 months after the last dose of treatment. Liver injury with
transaminase elevations has been seen in 0.3% of patients. Cases of acute cardiac
failure with myocarditis have been reported with cladribine.
The dose of cladribine is 1.75 mg/kg per year, taken as 10 mg/d to 20 mg/d for
4 to 5 days in week 1 and week 5. The dose is repeated 1 year later. No treatment
is given in years 3 and 4. Oral tablets are 10 mg.
Mitoxantrone
Mitoxantrone, an anthracenedione chemotherapy agent, intercalates into DNA
and blocks type II topoisomerase. This disrupts DNA replication, causes DNA
strand breaks, and inhibits DNA repair. It is rarely used now in the United States
because of toxicity, primarily cardiotoxicity and acute myelogenous leukemia,
and the availability of safer alternative medications.
Daclizumab
Daclizumab received FDA approval in 2016 but was voluntarily withdrawn
from the market in March 2018 because of inflammatory encephalitis/
meningoencephalitis, some of which was eosinophilic. It is mentioned here for
completeness.
INVESTIGATIONAL AND OFF-LABEL THERAPIES

In addition to FDA-approved therapies, several medications have been used
off-label in patients with aggressive MS. These include cyclophosphamide,
rituximab, and high-dose immunosuppressive therapy followed by hematopoietic
stem cell transplantation.
Cyclophosphamide
Cyclophosphamide, a nitrogen mustard alkylating agent, cross-links DNA,
leading to apoptosis independent of cell cycle. Aldehyde dehydrogenase, which
catabolizes the drug, is present in most cells, including bone marrow stem cells.
This allows the marrow to recover, even after large doses. It is a broad suppressor
of immune cells and their cytokines.
Studies of cyclophosphamide in MS are relatively small. Some suggest very
positive results, especially in earlier disease,55 while others suggest little
long-term effect.56,57 A high-dose protocol has also been proposed.58
Side effects include immunosuppression, myelosuppression, gonadotoxicity,
nausea, alopecia, ototoxicity, cardiac toxicity, and the syndrome of inappropriate
secretion of antidiuretic hormone (SIADH). Hemorrhagic cystitis can be
minimized with high levels of hydration and by administering mesna. Several
types of malignancies, especially hematologic and bladder, are more common
after cyclophosphamide. Malignancies and gonadotoxicity limit the lifetime
cumulative dose to 80 g to 100 g.
Cyclophosphamide is typically dosed as follows:
u Induction: 600 mg/m2 IV plus methylprednisolone 1000 mg/d IV for 5 days (or every other
day) followed by 700 mg/m2 IV every other month for 2 years
u High-dose cyclophosphamide (HiCy) induction: 50 mg/kg/d IV for 4 days, then 5 mcg/kg/d
IV granulocyte colony-stimulating factor
708 JUNE 2019

Rituximab KEY POINTS
Rituximab is a chimeric antibody against CD20, similar to ocrelizumab.59,60
It has less antibody-dependent and more complement-dependent ocrelizumab include infusion
cytotoxicity than ocrelizumab and a different binding site on the CD20 molecule. reactions, infections
It is more highly immunogenic than ocrelizumab. The mechanism of action (especially herpes
is similar. Efficacy in relapsing-remitting MS was studied in the phase 2 HERMES infections), and
possible malignancy;
(Helping to Evaluate Rituxan in Relapsing-Remitting Multiple Sclerosis) trial
progressive multifocal
in 69 patients treated with rituximab and 35 patients who received placebo.61 leukoencephalopathy and
The primary end point, the mean number of gadolinium-enhancing lesions reactivation of hepatitis B
over 24 weeks, was 5.5 in the placebo arm and 0.5 in the rituximab arm. are theoretical risks, but
thus far no cases have
Benefit was also seen in T2 lesions and exacerbations. Rituximab is substantially
been seen.
cheaper than ocrelizumab. The typical dose used in MS is 500 mg or 1000 mg
IV every 6 months. Rituximab is not approved for use in MS by the FDA. ● Cladribine is an oral
immunosuppressant that
High-dose Immunosuppressive Therapy With Stem Cell was recently approved by
Transplantation the US Food and Drug
Administration. Side effects
High-dose immunosuppressive therapy with stem cell transplantation uses include infections and
high-dose chemotherapy to ablate the immune system, then reconstitutes malignancies.
the immune system with stem cells from the patient. This leads to long-lasting
shifts in immune cell populations, cytokine profiles, and removal of dominant ● Mitoxantrone’s use has
been limited by
T-cell clones.62 The effectiveness of high-dose immunosuppressive therapy cardiotoxicity and acute
with stem cell transplantation in producing NEDA approaches 70% at 5 years, myelogenous leukemia.
about twice as effective as other highly aggressive therapies.63 Serious side effects
include 2.8% transplant-related mortality within the first 100 days.64 Steps in the ● Cyclophosphamide is
widely available and has
process include the following:
some evidence to support
its use, but definitive trials
u Stem cell mobilization with granulocyte colony-stimulating factor or immunosuppressants have not been performed.
u Collection of stem cells by leukapheresis
● Rituximab’s mechanism
u Conditioning regimen (high-dose chemotherapy); one of the following three regimens are of action and side effects
commonly used: are similar to those of
◇ Busulfan plus antithymocyte globulin, which is highly myeloablative and has risks of ocrelizumab. Rituximab is
myelosuppression and veno-occlusive liver disease not US Food and Drug
Administration approved for
◇ Carmustine, etoposide, cytarabine, and melphalan plus antithymocyte globulin multiple sclerosis, but many
(BEAM/ATG), which has intermediate myeloablation and risk of myelosuppression have used it off-label
◇ Cyclophosphamide plus antithymocyte globulin, which is nonmyeloablative and because it is less expensive
includes the same risks described in the cyclophosphamide section above than ocrelizumab.
u Infusion of stem cells and reconstitution of the bone marrow ● High-dose

immunosuppressive therapy
A Canadian study using the busulfan/antithymocyte globulin65 with stem cell
conditioning regimen showed activity-free survival at 3 years of 69.6%; one transplantation is the most
death from veno-occlusive disease occurred. The HALT-MS (High-Dose aggressive therapy available
for multiple sclerosis today.
Immunosuppression and Autologous Transplantation for Multiple Sclerosis) Outcomes are possibly
study used carmustine, etoposide, cytarabine, and melphalan /antithymocyte double the rate of “no
globulin66 as the conditioning regimen and showed event-free survival at evidence of disease
5 years of 69.2%. In another study, patients for whom traditional therapy had activity” of other therapies.
Thus far, only phase 2
failed either received another disease-modifying therapy determined by their studies have been
treating physician or received a transplant using the cyclophosphamide/ completed.
antithymocyte globulin67 conditioning regimen. The primary end point, time
to worsening of disability, was 24 months in the disease-modifying therapy
arm. Time to worsening disability could not be calculated in the high-dose

immunosuppressive therapy with stem cell transplantation arm because there

were too few events.
The more myeloablative regimens are believed to have better disease control,
but this comes at the cost of side effects. Over half of the transplants for MS
worldwide use intermediate myeloablative regimens, with 18.9% using
high-intensity and 17.4% using low-intensity regimens.64 The best results are
seen in those younger than 32 years of age with relapsing-remitting MS for whom
no more than two prior therapies have failed (CASE 6-3).64
APPROACH TO AGGRESSIVE THERAPY

Current knowledge is insufficient to predict which patients would most
benefit from early aggressive therapy. Future studies, for example,
TREAT-MS (Traditional Versus Early Aggressive Therapy for Multiple Sclerosis
Trial), comparing early aggressive therapy with traditional therapy should
CASE 6-3 A 17-year-old girl presented with diplopia in 2000. An MRI was obtained
at that time, which showed multiple periventricular and juxtacortical
lesions, one of which enhanced, leading to a diagnosis of multiple
sclerosis. She had a relapsing-remitting course of diplopia, optic neuritis,
leg weakness, paresthesia, and fatigue. Treatment with interferon
beta-1a subcutaneous and glatiramer acetate were unsuccessful because
of recurrent attacks. She was switched to mitoxantrone, receiving a
96 mg/m2 total cumulative dose between 2002 and 2004. She went back
on glatiramer acetate but continued to have attacks. She was then
switched to natalizumab in 2010, but it was discontinued after 25 doses
because she tested positive for JC virus antibodies. She continued to
have attacks despite fingolimod, dimethyl fumarate, and
cyclophosphamide. MRIs performed after these treatments showed
multiple enhancing lesions in the cortical white matter (FIGURE 6-4).
She then underwent high-dose immunosuppressive therapy followed
by autologous hematopoietic stem cell transplantation using a
carmustine, etoposide, cytarabine, and melphalan plus antithymocyte
globulin (BEAM/ATG) protocol in 2014. She had no new clinical
exacerbations and stable MRI images without enhancement 4 years after
this procedure.
COMMENT This case illustrates the potential for high-dose immunosuppressive

therapy with stem cell transplantation to control inflammatory disease
activity in some patients with aggressive disease despite prior treatment
with highly efficacious therapies. This patient had both clinical and MRI
attacks. Early use of aggressive therapies included mitoxantrone,
natalizumab, fingolimod, and cyclophosphamide. Despite these, she
continued to have exacerbations. High-dose immunosuppressive therapy
followed by autologous hematopoietic stem cell transplantation was
successful in controlling her disease.
710 JUNE 2019

provide better guidance.68 Until further data are available, the following
approach is suggested:
u Consider initial aggressive therapy (natalizumab, fingolimod, ocrelizumab, alemtuzumab)

for patients who appear to be at high risk for aggressive disease and early disability
u Consider switching patients to more aggressive therapy in the presence of breakthrough

disease (exacerbations, MRI activity, or worsening disability)
u Periodically evaluate neurologic examination and MRI to assess breakthrough disease

u Monitor patients so that side effects can be detected as early as possible
Ultimately, the patient must participate in the decision-making process. This

requires the physician to educate patients about benefits and side effects of each
treatment option so that patients can decide what level of risk they want to
assume in return for higher efficacy.
F I GURE 6-4
Axial postcontrast T1-weighted MRI demonstrates multiple enhancing lesions in the white
matter of both periventricular regions (A) and the left periventricular region (B).

CONCLUSION
A number of factors can help identify patients at risk for aggressive MS. Older
nonwhite males with motor, sphincter, and cognitive symptoms have more
aggressive disease, as do those with disease activity on MRI. These patients can
consider using early or even initial aggressive therapies. Patients for whom other
therapies fail should consider switching to more aggressive disease-modifying
therapies. However, these treatments have greater side effects that must be
balanced against their increased efficacy. It is hoped that upcoming randomized
trials will provide more answers on balancing efficacy and side effects during
early use of these treatments. Until these results are available, use of these
medications will require the participation of patients in decision making,
monitoring of disease activity, and vigilance regarding complications.
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714 JUNE 2019

Monitoring, Switching, REVIEW ARTICLE

and Stopping Multiple C O N T I N U UM A U D I O
ONLINE
Sclerosis Disease-
Modifying Therapies
By Robert H. Gross, MD; John R. Corboy, MD, FAAN
ABSTRACT CITE AS:

PURPOSE OF REVIEW: This article reviews appropriate monitoring
of the various CONTINUUM (MINNEAP MINN)
multiple sclerosis (MS) disease-modifying therapies, summarizes the 2019;25(3, MULTIPLE SCLEROSIS
reasons patients switch or stop treatment, and provides a framework for DISEASES):715–735.
making these management decisions.
Dr Robert H. Gross, Anschutz
RECENT FINDINGS:With the increasing number of highly effective Outpatient Pavilion, Mail Stop
immunotherapies available for MS, the possibility of better control of the F727, 1635 Aurora Ct, 5th Floor,
disease has increased, but with it, the potential for side effects has Aurora, CO 80045,
Robert.Gross@ucdenver.edu.
rendered treatment decisions more complicated. Starting treatment early
with more effective and better-tolerated disease-modifying therapies RELATIONSHIP DISCLOSURE:
Dr Gross reports no disclosure.
reduces the likelihood of switching because of breakthrough disease or lack Dr Corboy serves as editor of
of compliance. Clinical and radiographic surveillance, and often blood and Neurology Clinical Practice, as a
other paraclinical tests, should be performed periodically, depending on consultant for a legal matter for
Mylan NV, and on the research
the disease-modifying therapy. Helping patients navigate the uncertainty steering committee for Novartis
around switching or stopping treatment, either temporarily or permanently, AG. Dr Corboy has received
is one of the most important things we do as providers of MS care. personal compensation for
speaking engagements from
PRIME Education, LLC, and the
SUMMARY: Ongoing monitoring of drug therapy is a crucial component of Rocky Mountain Multiple
Sclerosis Center and receives
long-term MS care. Switching treatments may be necessary for a variety of research/grant support from
reasons. Permanent discontinuation of treatment may be appropriate for MedDay Pharmaceuticals, the
some patients with MS, although more study is needed in this area. National Multiple Sclerosis
Society, Novartis AG, and the
Patient-Centered Outcomes
Research Institute. Dr Corboy
has served as a consultant on
INTRODUCTION medicolegal proceedings for
T
medical malpractice.
his article discusses the appropriate monitoring of patients on
multiple sclerosis (MS) immune-based disease-modifying therapy, UNLABELED USE OF
how to approach the decision to switch treatments, and when patients PRODUCTS/INVESTIGATIONAL
USE DISCLOSURE:
may consider a trial off therapy. As the number of disease-modifying Drs Gross and Corboy discuss
therapies available for MS grows, treatment decisions have become the unlabeled/investigational
use of cyclophosphamide and
increasingly complex. While newer treatments offer the possibility of higher
rituximab for the treatment of
rates of efficacy, they may also present risks of serious side effects, underscoring multiple sclerosis.
the need for regular clinical follow-up and surveillance.
After a diagnosis of relapsing MS is confirmed, the doctor and patient typically © 2019 American Academy
discuss treatment options. A major component of this discussion should be issues of Neurology.

MONITORING, SWITCHING, AND STOPPING DISEASE-MODIFYING THERAPIES
surrounding monitoring of potential benefits; short-term adverse events and

long-term risks; and a description of contexts in which a patient may consider a
switch to an alternative disease-modifying therapy, potential short-term or
permanent discontinuation of the selected disease-modifying therapy, or
discontinuation of all disease-modifying therapies in general. Numerous studies
have reported on the various factors associated with good or poor adherence,
persistence, tolerance, switching, and discontinuing disease-modifying
therapies.1–11 These studies highlight that adherence is extremely variable and
that switching or discontinuing disease-modifying therapies is very common in
both the long and short term. This article focuses on aspects of decision making
as they relate to monitoring, switching, and discontinuing MS disease-modifying
therapies but does not discuss adherence except as it relates to switching or
permanently discontinuing disease-modifying therapies.
The decision to switch disease-modifying therapies may be driven by patients,
providers, or both and—similar to the selection of initial treatment—involves drug-
centered (cost, convenience, safety, tolerability, development of drug antibodies,
efficacy, removal from the market, end of a clinical trial), patient-centered (likelihood
of adherence, pregnancy plans, medical comorbidities, MS aggressiveness), and
provider-centered (drug availability, infusion capability, provider familiarity)
determinants. In addition, when switching treatments, clinicians have the benefit
of knowing what has not worked for a particular patient, an empirical process that
allows for an even greater degree of personalized treatment.
After starting a disease-modifying therapy, perhaps the single most important
question the patient may have is, “How long should I continue to use this, or any,
disease-modifying therapy?” As with switching, the reasons for discontinuation
may be drug-centered, patient-centered, or provider-centered, and the reasons are
quite similar to the reasons for switching. When patients discontinue a disease-
modifying therapy, it may be a temporary or permanent discontinuation, with the
caveat that it may not be clear at the time of discontinuation whether it is temporary
or permanent. If the discontinuation is temporary, the patient may resume that
treatment or switch to a different one. Discontinuation may be temporary because
of insurance interruption; a desire to become pregnant, becoming pregnant, or
lactating; lack of adherence (for many reasons); or deliberate installation of a
washout period between medications when switching disease-modifying therapies
to limit overlapping risks with two medications used in sequence. The rate of
discontinuation of, or lack of persistence with, a disease-modifying therapy among
patients who are newly diagnosed and starting their first disease-modifying therapy
may be as variable as 3% to 53% over 2 years for different medications.1–11
TREATMENT PARADIGMS
Although we now tend to think of switching disease-modifying therapies in
terms of going from one US Food and Drug Administration (FDA)–approved
MS medication to another, a patient’s treatment course could be changed in other
ways. The immunotherapy could remain the same, but specific symptoms
(eg, worsening gait, dysesthesia) could be treated with symptomatic medication,
physical therapy, or some other intervention. Adding an immunotherapy to an
existing one to intensify treatment was previously used much more frequently; it
has now largely been replaced by serial monotherapies out of theoretical concern
for over-immunosuppression or lack of added benefit. The largest combination
disease-modifying therapy trial, CombiRx (Combination Therapy in Patients
716 JUNE 2019

With Relapsing-Remitting Multiple Sclerosis), showed no clinical advantage of KEY POINTS
low-dose interferon beta-1a plus glatiramer acetate compared to glatiramer
● Studies of factors
acetate alone (although a benefit was shown on some MRI metrics) or interferon related to multiple
alone.12 Switching from an FDA-approved medication to an off-label sclerosis disease-
immunosuppressant or enrolling in a clinical trial for an experimental modifying therapies
therapy are other ways of trying to control refractory disease. If a patient highlight that adherence
is extremely variable and
experiences side effects on a disease-modifying therapy, a clinician might choose
that switching or
to lower the dose (although lower doses are not readily available for most discontinuing disease-
disease-modifying therapies other than interferons or teriflunomide) or modifying therapies is very
lengthen the interval between dosing. The latter technique has been studied with common in both the long
and short term.
fingolimod and natalizumab. With fingolimod, every other day dosing may
correct profound lymphopenia without worsening disease unless the patient has ● Discontinuation of
gadolinium-enhancing lesions on daily dosing.13 With natalizumab, disease-modifying therapy
extended-interval dosing may reduce the risk of progressive multifocal may be temporary because
leukoencephalopathy (PML) in patients who are JC virus positive without of insurance interruption; a
desire to become pregnant,
risking rebound disease activity.14,15 becoming pregnant, or
Of course, whether the patient switches and to which disease-modifying lactating; lack of
therapy depend to a great extent on what the patient uses first. Several adherence (for many
different treatment algorithms have been proposed, taking into account the reasons); or deliberate
installation of a washout
drug-, patient-, and provider-related factors already mentioned, but none is period between
universally accepted. In part reflecting the history of the development of medications when
disease-modifying therapies, one common approach is to use the older, switching disease-
injectable disease-modifying therapies (such as beta interferons and modifying therapies to
limit overlapping risks
glatiramer acetate) as first-line treatment and only escalate therapy to more
with two medications
effective disease-modifying therapies in the event of new disease activity or used in sequence.
progression (FIGURE 7-1). This method is commonly used in Canada and
Europe, where fingolimod and natalizumab are generally considered
second-line therapies.
Although Class I evidence is still lacking in many instances, and even
rejecting cross-trial comparisons as inherently biased, in head-to-head clinical
trials of MS disease-modifying therapies, a clear pattern emerges: older
injectables and oral teriflunomide are the least efficacious and infusibles
(natalizumab, ocrelizumab, and alemtuzumab) are the most efficacious, with
the oral agent fingolimod and perhaps also dimethyl fumarate somewhere in
between.16–22 While it is logical to extrapolate from this that switching to a
higher-efficacy treatment after treatment failure would provide a higher
likelihood of success, as suggested by the American Academy of Neurology
2018 MS disease-modifying therapy guideline,23,24 rigorous randomized
comparator switch studies are nonexistent. Still, nonrandomized observational
studies, including propensity score matching and open-label extensions of
clinical trials, can provide useful information about switching. After treatment
failure with interferon beta or glatiramer acetate, switching to natalizumab is
superior to switching to a different injectable.25 In open-label extension studies,
patients who switched from interferon beta-1a to ocrelizumab26,27 and
alemtuzumab28 experienced rapid reductions in disease activity. Switching from
natalizumab to injectables is not as protective as switching to fingolimod,29 but
switching from natalizumab to fingolimod appears less effective than switching
to rituximab30,31 or alemtuzumab.32
Arguing against the escalation approach is the natural history data for MS
showing that relapses and new MRI changes are greatest—and presently available

FIGURE 7-1
Escalation treatment paradigm. Initiation with lower-efficacy therapy, such as an older
injectable medication, then over time escalation to a more highly efficacious therapy
following treatment failure. This model is predicated on frequent reassessment of the
patient’s disease status to ensure optimal treatment response. (Cyclophosphamide and
hematopoietic stem cell transplantation are not US Food and Drug Administration
[FDA]–approved therapies for multiple sclerosis.)
DMT = disease-modifying therapy.
disease-modifying therapies most effective—at the onset of MS, when patients are
youngest. In addition, failure rates and intolerance of the older injectables are so
high that the majority of individuals will ultimately transition to more effective
and better-tolerated medications. Thus, requiring patients to use less effective and
less tolerable disease-modifying therapies first simply subjects patients to
greater disability and discomfort over time.
On the other end of the spectrum, potent lymphocyte-depleting agents,
such as mitoxantrone33,34 and cyclophosphamide,35 have been used in early,
active MS for a defined period of time as induction (to borrow a concept from
oncology), typically followed by safer maintenance therapies (FIGURE 7-2).
While very effective at reducing MS activity, these treatments come with
considerable risk for serious side effects, so early identification of appropriate
candidates based on perception of disease severity is crucial. Alemtuzumab has
likewise been used in this way, although whether subsequent de-escalation is
even necessary given its particularly long-lasting effect is unclear. Another
alternative is the early and persistent use of newer, highly effective disease-
modifying therapies, especially natalizumab (if the patient remains JC virus
antibody negative) and anti-CD20 disease-modifying therapies, without
de-escalation (FIGURE 7-3). None of these strategies has yet been compared
head to head, but upcoming studies will compare early intensive and escalation
approaches in MS.36,37 As of this writing, two new oral disease-modifying
718 JUNE 2019

KEY POINTS
● Requiring patients to use

less effective and less
tolerable disease-modifying
therapies first simply
subjects patients to greater
disability and discomfort
over time.
● Ultimately, best practice

likely reinforces that
individual aspects should
dictate the optimal
approach for any one
patient.
● Decisions made at the

beginning of the disease
course have potential
long-term implications for
use of other disease-
modifying therapies.
FIGURE 7-2
Induction/maintenance treatment paradigm. Initiation with potent immunosuppressant
therapy followed either by lower-efficacy but safer maintenance therapy or by watchful
waiting. In this model, an early assessment is made that the disease is severe or aggressive.
The induction medication is typically continued for a prespecified duration or targeting a
prespecified physiologic response. Subsequent maintenance therapy may not be necessary,
as with alemtuzumab or hematopoietic stem cell transplantation. (Cyclophosphamide and
hematopoietic stem cell transplantation are not US Food and Drug Administration
[FDA]–approved therapies for multiple sclerosis.)
therapies, siponimod and cladribine, were recently approved by the FDA,

both including indications for active secondary progressive MS in addition
to relapsing-remitting disease. It is too soon to say how they might be used
within these paradigms.
Ultimately, best practice likely reinforces that individual aspects should
dictate the optimal approach for any one patient. A neurologist might opt for
escalation when there does not appear to be any urgency (eg, a reproductive-
aged woman with a history of two mild sensory relapses, full recovery, several
years between attacks, and minimal disease burden on MRI) but be more
proactive in a more aggressive case (eg, an African American man with several
motor or brainstem attacks in rapid succession, poor recovery, and significant
disease burden on MRI). Given the widely variable rates of discontinuation and
switching between disease-modifying therapies and the potential downstream
effects of prior use of one drug on use of another (eg, higher risk of
natalizumab-associated PML among individuals who have prior exposure to
chemotherapies such as mitoxantrone or potential prolonged lymphopenia with
use of dimethyl fumarate affecting use of other lymphocyte-depleting approaches
subsequently), decisions made at the beginning of the disease course have
potential long-term implications for use of other disease-modifying therapies.

FIGURE 7-3
Second-generation first-line treatment paradigm. Persistent treatment with highly
efficacious treatment from the beginning. In this model, preference is given to highly
efficacious infusible medications (ie, natalizumab and B-cell depletion) as initial treatment
in the vast majority of patients. With appropriate safety monitoring (such as assessing for
JC virus antibodies with natalizumab), patients may remain on these treatments for years.
MONITORING TREATMENT
In addition to risk screening for use of the various MS medications, ongoing
laboratory and MRI monitoring is important to maintain the highest level of
safety for patients with MS.
Interferon Beta
The oldest MS immunotherapy, interferon beta, now exists in several different
formulations of interferon beta-1a and interferon beta-1b, although monitoring is
essentially the same for all of them. Patients should be warned about the high
likelihood for undesirable side effects, such as injection site reactions and flulike
symptoms, including myalgia, fevers, chills, and fatigue, and provided with
techniques to prevent or mitigate these symptoms (eg, cold compresses,
premedication with nonsteroidal anti-inflammatory drugs). Blood tests, including
complete blood cell count and testing of liver and thyroid function, should be
performed before treatment initiation and regularly thereafter (in the authors’
practice, every 3 months for 6 months, then annually). Checking for neutralizing
antibodies in the setting of breakthrough disease is controversial, especially now
that many other available treatment classes are available.
Glatiramer Acetate
Glatiramer acetate is the other first-generation injectable agent still in use for MS.
It, too, frequently causes injection site reactions and occasionally an idiosyncratic
720 JUNE 2019

postinjection reaction involving flushing, anxiety, shortness of breath, and
rapid heartbeat, which generally subsides within 30 minutes. No blood tests are
required to monitor glatiramer acetate, which comes in daily doses of 20 mg and
3 times weekly dosing of 40 mg. A randomized double-blind clinical trial found
similar efficacy, safety, and tolerability between the brand name 20 mg
formulation and the generic alternative.38
Natalizumab
Natalizumab is an infusible monoclonal antibody that targets a lymphocyte
surface protein, α4β1 integrin (very late antigen-4 [VLA-4]). Enrollment in a Risk
Evaluation and Mitigation Strategy program (TOUCH in the United States) is
required before starting treatment because of the association of natalizumab with
PML, an opportunistic infection caused by the JC virus. In accordance with the
TOUCH program, JC virus antibody testing should be performed regularly (the
frequency of testing is not specified, although it is most commonly done every
6 months). Prior immunosuppression, a high level of JC virus antibodies, and
longer treatment duration (eg, >2 years) further increases PML risk, as shown
in FIGURE 7-4.39 PML may present with cognitive or personality changes,
seizures, hemiparesis, or visual disturbance, or it may be asymptomatic at the
time of discovery. While no specific treatments are currently available once a
person is diagnosed with PML, early detection and discontinuation of
natalizumab (and perhaps also plasma exchange, although this remains
controversial) may be protective. Regular monitoring for radiographic signs of
the illness is recommended during natalizumab treatment and for at least
6 months afterward.
Natalizumab infusions are generally well tolerated and typically given without
premedication, although headaches and fatigue have been reported. Allergic
reactions from hives and chest tightness to anaphylaxis are possible, usually
occurring within 2 hours of the beginning of an infusion. About 6% of patients
treated with natalizumab develop persistent antinatalizumab antibodies,17 which
can contribute to infusion reactions and limit effectiveness.
Fingolimod
Fingolimod, a first-in-class sphingosine-1-phosphate receptor modulator, was the
first oral immunotherapy approved to treat MS. Because bradycardia is common
with the first dose, a supervised first-dose observation is required, typically
lasting for 6 hours. Macular edema occurred in roughly 0.5% of subjects who
received fingolimod in its phase 3 clinical trials21,40; as a result, examination of the
macula (eg, with optical coherence tomography) is needed before treatment and
3 to 4 months after treatment initiation. A history of diabetes mellitus or uveitis
substantially increases the risk of macular edema. With treatment cessation,
macular edema typically resolves. Although not required, some neurologists
recommend regular dermatology visits because of reports of increased risk of skin
cancers, including basal cell carcinoma and melanoma. Changes in pulmonary
function testing have been seen with fingolimod, including decreased diffusion
lung capacity for carbon monoxide (DLCO) and forced expiratory volume over
1 second (FEV1); providers considering fingolimod may refer patients with
preexisting lung disease to a pulmonologist, as fingolimod use has not been studied
in this population. Fingolimod increases the risk for certain infections, including
PML; as of this writing, more than 20 cases of fingolimod-associated PML not

FIGURE 7-4
Updated progressive multifocal leukoencephalopathy (PML) risk estimate algorithm showing
estimated risk per 1000 patients based on natalizumab exposure, prior immunosuppression
(IS) use, and anti–JC virus (JCV) antibody index. PML risk estimates in anti-JCV antibody-
positive patients were derived using a life-table method based on the pooled cohort of
21,696 patients who participated in the STRATIFY-2, TOP, TYGRIS, and STRATA clinical
studies. Anti-JCV antibody status was determined using an anti-JCV antibody test
(enzyme-linked immunosorbent assay [ELISA]) that has been analytically and clinically
validated and was configured with detection and inhibition steps to confirm the presence of
JCV-specific antibodies with an analytical false-negative rate of 3%. The calculation of PML
risk in anti-JCV antibody-negative patients has not changed from the original algorithm and
was estimated here based on postmarketing data from approximately 125,000 natalizumab-
exposed patients.
a
Data beyond 6 years of treatment are limited.
b
The majority of prior IS use from these studies included mitoxantrone, azathioprine, cyclophosphamide,
and/or mycophenolate.
c
Variability may be due to small sample size.
Reprinted with permission from Koendgen H, et al, ECTRIMS.39 © 2016 The Authors
attributable to prior natalizumab use have been reported; in addition to JC virus

seropositivity, presumably, PML risk factors in fingolimod-treated patients
appear to include older age and treatment duration.41,42 Reactivation of latent
infections, such as shingles, has also been seen. Cases of fatal herpes simplex
virus encephalitis and disseminated herpes zoster were reported among subjects
in the fingolimod clinical trials.21,40 Fungal infections, including fatal cases of
cryptococcal meningitis and disseminated cryptococcal infections, have also
been reported. Elevations of liver transaminases more than 3 times the upper
limit of normal occurred in 14% of subjects treated with fingolimod 0.5 mg in the
clinical trials. Blood tests, including complete blood cell count, liver function
tests, and varicella-zoster virus IgG, should be checked before starting
fingolimod, then complete blood cell count and liver function tests every 3 to
6 months thereafter. If the patient is not varicella-zoster virus immune,
fingolimod initiation should be delayed 1 month after vaccination to allow the
vaccination to take effect (an effective wait time of 3 months, since the new
recombinant zoster vaccine is given as separate doses 2 months apart).
722 JUNE 2019

Teriflunomide
Teriflunomide, an inhibitor of pyrimidine synthesis, became the second
FDA-approved oral medication for MS in 2012. Because of the risk for severe
hepatotoxicity, liver function tests should be performed at baseline and monthly
for the first 6 months. Asymptomatic alanine aminotransferase elevations were
common in the clinical trials of teriflunomide, with levels more than 3 times the
upper limit of normal, prompting discontinuation in 2.6%.43 Before starting
treatment, skin or blood test for latent tuberculosis should be performed.
Hypersensitivity reactions, including anaphylaxis, angioedema, and serious skin
conditions (such as Stevens-Johnson syndrome and a fatal case of toxic epidermal
necrolysis) have been reported. Other side effects include alopecia, peripheral
neuropathy, and an increase in blood pressure.43 A single case of PML has been
reported in a patient previously treated with natalizumab for more than 2 years,
with a high JC virus index.44 Because of extensive enterohepatic circulation,
complete elimination of teriflunomide upon discontinuation can take as long as
2 years, so an accelerated elimination procedure involving an 11-day course of
cholestyramine or activated charcoal is recommended in certain instances, such
as a desire to become pregnant, an unexpected pregnancy, or serious adverse
events such as those described. Teratogenicity occurred in animals administered
teriflunomide45; it should therefore be stopped in both women and men (because
of potential transfer via semen) before conception, potentially with an accelerated
elimination procedure, or ideally not used when future pregnancy is a possibility.
Patients should be counseled on the appropriate use of contraceptives.
Dimethyl Fumarate
Dimethyl fumarate was approved by the FDA to treat MS in 2013. The actual
mechanism of action of dimethyl fumarate is uncertain, perhaps involving
activation of the nuclear factor erythroid 2-related factor (Nrf-2) pathway.
One important side effect that should be monitored for is lymphopenia. The
absolute lymphocyte count remained persistently below 0.5 109/L in 2.2%
of patients treated with dimethyl fumarate in the clinical trials, typically during
the first several months of treatment.46 CD8-positive T-lymphocyte counts
are disproportionally reduced compared to CD4-positive T lymphocytes,
raising concerns for opportunistic infection, specifically viral, given the
suppression of cell-mediated immunity.47 As of this writing, six cases of dimethyl
fumarate–associated PML have been reported, which have all occurred in the
context of moderate to severe lymphopenia, suggesting that providers should
exercise greater vigilance when the absolute lymphocyte count begins to fall
and in patients who are JC virus antibody positive (although no specific
recommendations exist regarding, for example, the frequency of MRI in such
patients) (Evan Riddle, PhD, Biogen, written communication, January 2019).
After cessation, lymphocyte reconstitution may lag for up to many months.46,47
Ocrelizumab
Ocrelizumab is the first anti-CD20 monoclonal antibody FDA approved to treat
relapsing forms of MS and the first of any disease-modifying therapy to gain
approval for primary progressive MS. Monitoring of CD20+ B cells is
recommended while on ocrelizumab. Data from ocrelizumab clinical trials show
that average (median) B-cell counts stay suppressed through 96 weeks, although
in the authors’ experience, about 9% will have some degree of early (before

6 months) B-cell reconstitution. This does not necessarily correspond to new

clinical or radiographic disease activity; conversely, having no B cells does
not guarantee that no breakthrough disease activity will occur, although it is
very unlikely. Still, the unexpected presence of B cells in the blood could increase
the risk for infusion reactions or breakthrough disease, possibly through the
development of anti-ocrelizumab antibodies. Regular monitoring of white
blood cells and subsets should also be done. Rarely, clinically significant
neutropenia and neutropenic fever can occur with CD20-depleting therapy.
An immunoglobulin panel should be checked at least annually, perhaps
more frequently if the levels are declining into the subnormal range
(hypogammaglobulinemia potentially raises the risk of infection), but no
explicit cutoff for stopping treatment exists. Patients should be counseled
about the potential risk for infections, including urinary, herpetic, and skin
infections, although overall infection and serious infection rates were comparable
with interferon beta-1a in the clinical trials over a 2-year period.18
Practices vary with respect to vaccinations before starting ocrelizumab (and
other immunomodulatory medications), and guidelines are somewhat vague. It is
known that anti-CD20 therapy can impair humoral responses to vaccines.48
At this time, decisions to delay treatment before obtaining, for example, the
pneumococcal or zoster vaccine should be made following a risk-benefit
assessment with each individual patient (the recombinant zoster vaccine, in
particular, would delay treatment start by several months). Active hepatitis B
infection is a contraindication to anti-CD20 treatment; chronic hepatitis B carriers
should consult with a liver specialist before treatment and may consider the use of
antiviral therapy during and for 6 months after cessation of ocrelizumab.
It is too early to define a risk for PML, if any, with ocrelizumab. No
definitive evidence of an increased risk of malignancy has been seen with
ocrelizumab, although the possibility of an increased risk of breast cancer has
been raised. A postmarketing surveillance study found that as of February 2018,
the rate of malignancy, and specifically of female breast cancer, in patients
treated with ocrelizumab remained within the expected range based on
epidemiologic data.49
Mitoxantrone and Alemtuzumab

As mitoxantrone and alemtuzumab are immunosuppressive agents linked
to several serious adverse reactions (leukemia and cardiomyopathy for
mitoxantrone; serious infusion reactions, secondary autoimmunity, infections,
neoplasms, and cases of arterial dissection and stroke for alemtuzumab), their
use should be restricted to highly active MS under the supervision of providers
with a high degree of familiarity and expertise with these medications. For
alemtuzumab, in particular, which is given by IV infusion as an initial course of
12 mg/d for 5 consecutive days, then a second course 1 year later of 12 mg/d for
3 consecutive days, very close monitoring is required, consisting of monthly
blood and urine tests until 4 years after the last course. In addition, anti–herpes
virus prophylaxis should be given for at least 2 months after each dose or longer if
the CD4 count remains below 200 cells/mm3.
TABLE 7-1 provides a monitoring rubric for the FDA-approved MS therapies.
Of note, the use of some inactivated vaccines, such as influenza, has been shown
to be safe and effective with several of the disease-modifying therapies,
especially those that are not immunosuppressive, but no data have been
724 JUNE 2019

published on the use of the new subunit-derived shingles vaccine in patients KEY POINTS
using any of the disease-modifying therapies. The Centers for Disease Control
● One source of ambiguity
and Prevention recommends avoidance of live or live-attenuated vaccines with when considering switching
any immunosuppressive medication. disease-modifying therapy
is that no standard definition
WHEN TO SWITCH of treatment “failure”
exists, nor is there a
One source of ambiguity is that no standard definition of treatment “failure” exists,
universally accepted
nor is there a universally accepted standard as to the appropriate time to switch standard as to the
disease-modifying therapies in MS. This is complicated by the fact that some appropriate time to switch
disease-modifying therapies might take longer to become fully active than others, disease-modifying therapies
in multiple sclerosis.
prompting many clinicians to order a baseline MRI 3 to 6 months after treatment
initiation, with the understanding that new lesions do not necessarily represent ● With the recognition of
treatment failure. A Consortium of Multiple Sclerosis Centers survey of 107 MS “no evidence of disease
experts published in 2016 failed to yield a clear consensus on the question of the activity” as a treatment goal
amount of MRI activity that would prompt a disease-modifying therapy switch: and ever-higher rates of no
evidence of disease activity
66% of respondents (95% CI, 56.5% to 74.9%) would consider a disease-modifying emerging from clinical trials
therapy change in an asymptomatic patient with relapsing-remitting MS with two of multiple sclerosis
new T2 lesions after 2 years, and 52% (95% CI, 42.3% to 61.7%) would consider a disease-modifying
change in the same patient with one new gadolinium-enhancing lesion after therapies, disease activity
that previously would have
2 years.50 These practice patterns are likely different than those of neurologists been tolerated is now
who are not MS experts, who might take a more conservative approach. It is frequently no longer
undoubtedly true that willingness to change course now is generally higher than, deemed acceptable.
perhaps, 15 years ago, when switching disease-modifying therapy in the face of
● Practices vary regarding
poor tolerability or breakthrough disease entailed a lateral move from one
the use and length of
injectable to another of roughly equal tolerability and efficacy (then sometimes washout periods, and
back to the original one). With the recognition of “no evidence of disease activity” evidence from randomized
(NEDA) as a treatment goal and ever-higher rates of NEDA emerging from controlled trials to guide
clinical trials of MS disease-modifying therapies, disease activity that previously management is limited.
would have been tolerated is now frequently no longer deemed acceptable.

The Rio score51 and its modified version52 identified suboptimal disease-
modifying therapy responders by using clinical and radiographic markers from the
first year of treatment to predict worse 3-year outcomes. Prosperini and
colleagues53 found that patients with new lesions on MRI after 1 year of treatment
had a higher risk of accumulating disability over a mean follow-up of 4.8 years.
When following an escalation paradigm, these and similar strategies54–57 may be
helpful early prognostic tools to evaluate response to interferon beta, glatiramer
acetate,58 and teriflunomide,59 based on the theory that “run-of-the-mill” MS
could be effectively managed with these generally less effective disease-modifying
therapies, but treatment can be (relatively) quickly intensified to more effective
agents in nonresponders. CASE 7-1 provides an example of a patient who wants to
switch disease-monitoring therapies.
Once the decision to switch is made, the question becomes how long to wait
before starting the new disease-modifying therapy. Practices vary regarding the
use and length of washout periods, and evidence from randomized controlled
trials to guide management is limited. The aim of a washout is to avoid excessive
immunosuppression; while an increased risk of infections from using two
immunosuppressive medications close together in time remains more of a
theoretical concern at present, certain long-acting disease-modifying therapies
associated with lymphocyte depletion, such as teriflunomide, cladribine,
ocrelizumab, and alemtuzumab, would seem to present a greater risk.

TABLE 7-1 Disease-Modifying Therapies Used in Multiple Sclerosis
Common Potentially
Dosing/ Baseline On-Therapy Special Adverse Serious
Drug Route Monitoring Monitoring Considerations Effects Adverse Effects
Interferon Variable; IM/ Complete Complete blood Development Injection site Anemia, leukopenia,
beta-1a/1b subcutaneous blood cell cell count, of neutralizing reaction, thrombocytopenia,
count, liver liver function antibodies flulike depression, liver
function tests, thyroid symptoms, injury, skin necrosis
tests, thyroid function tests fatigue
function tests every 3 months
for 6 months
then annually
Glatiramer 20 mg/d; None None Postinjection Injection site Skin necrosis

acetate 40 mg systemic reaction,
3 times a reaction lipoatrophy,
week; (flushing, vasodilation,
subcutaneous tightness rash
of chest,
shortness
of breath,
anxiety)
Fingolimod 0.5 mg/d; Complete blood Macular optical First-dose Diarrhea, Progressive multifocal
oral cell count, liver coherence observation; mild blood leukoencephalopathy
function tests, tomography varicella- pressure (PML) fungal infection,
varicella-zoster (at 3 months); zoster virus increase, shingles, liver injury,
virus titer, macular complete blood immunity headache, macular edema,
optical coherence cell count, back pain, pulmonary function
tomography liver function cough test changes
tests every
3–6 months; skin
examinations
regularly
Dimethyl Initiate at Complete blood Complete blood Consider Flushing, PML, lymphopenia,
fumarate 120 mg cell count, liver cell count, liver slow titration abdominal liver injury,
2 times a function tests function tests to lessen pain, anaphylaxis
day and every 3–6 months side effects; diarrhea,
titrate up can use H2 nausea,
to 240 mg blockers or pruritus
2 times a proton pump
day; oral inhibitors for
gastrointestinal
symptoms; can
use aspirin for
flushing
Teriflunomide 14 mg once Complete blood Liver function Pregnancy Alopecia, Toxic epidermal
a day; oral cell count, liver tests monthly category X; diarrhea, necrosis/Stevens-
function tests, for 6 months; accelerated nausea, Johnson syndrome,
tuberculosis test, complete blood elimination headache, teratogenicity,
pregnancy test cell count every procedure paresthesia infection, interstitial
3–6 months (cholestyramine lung disease,
or activated peripheral neuropathy,
charcoal) hypertension
726 JUNE 2019

Common Potentially
Dosing/ Baseline On-Therapy Special Adverse Serious
Drug Route Monitoring Monitoring Considerations Effects Adverse Effects
Natalizumab 300 mg Complete JC virus antibody Risk Evaluation Infusion PML, anaphylaxis
every blood cell testing every and Mitigation reactions,
4 weeks; IV count, liver 3–6 months; Strategy; headache,
function tests, complete blood antinatalizumab urticaria,
JC virus cell count and antibodies diarrhea,
antibody liver function mild
tests every leukocytosis,
6 months eosinophilia
Alemtuzumab 12 mg/d Complete Skin examinations Risk Evaluation Infusion Autoimmune

for 5 days; blood cell and human and Mitigation reactions diseases (thyroid,
1 year later, count, serum papilloma virus Strategy; idiopathic
12 mg/d for creatinine, screening varicella-zoster thrombocytopenic
3 days; IV urinalysis, annually; virus immunity; purpura, Goodpasture
thyroid function complete blood antiherpes syndrome), anaphylaxis,
tests, varicella- cell count, serum treatment infections, malignancy,
zoster virus creatinine, and starting on arterial dissection, and
titer, hepatitis urinalysis monthly day 1 for stroke
B virus core until 48 months 2 months or
antibody and after last infusion; until CD4+
surface antigen, thyroid function count >200
hepatitis C tests every
virus, human 3 months until
immunodeficiency 48 months after
virus (HIV), infusion
tuberculosis test,
skin examination
Ocrelizumab Complete
Initial doses: Complete blood Antivirals for Infusion Neutropenia,
300 mg blood cell count, cell count, hepatitis reactions, hypogammaglobulinemia
2 (2 weeks comprehensive comprehensive B virus carrier; respiratory
apart); IV metabolic profile, metabolic profile, treatment for infections,
lymphocyte lymphocyte latent urinary tract
Subsequent subsets, hepatitis subsets every tuberculosis infections,
doses: B virus core 6 months, herpes
antibody and immunoglobulins infections
600 mg surface antigen, every
every hepatitis C virus, 6–12 months
6 months; IV HIV, tuberculosis
test, serum
immunoglobulins
IM = intramuscular; IV = intravenous.

CASE 7-1 A 50-year-old man with multiple sclerosis presented to discuss switching
his disease-modifying therapy. He had been diagnosed with relapsing-
remitting multiple sclerosis (MS) 9 years earlier after having intermittent
left upper extremity paresthesia for several years followed by an
episode of optic neuritis. His vision improved after a course of IV
methylprednisolone at that time, and a brain MRI at that time showed
eight characteristic demyelinating lesions in the periventricular and
subcortical white matter, and CSF was positive for five oligoclonal bands.
He was initially treated with interferon beta-1a but could not tolerate
the flulike symptoms, so after 6 months he switched to glatiramer
acetate. He continued to notice the left upper extremity paresthesia from
time to time, particularly when he was under stress; he also reported
moderate fatigue but otherwise developed no new symptoms and
continued to exercise 2 to 3 times a week.
Follow-up brain MRIs were stable for 7 years, then he developed a
new small nonenhancing lesion in the right centrum semiovale. Because
of that and his preference for an oral medication, he switched to
fingolimod. He tolerated the fingolimod well, although he had a painful
episode of herpes zoster (shingles) 6 months after starting it. He traveled
frequently for work for several weeks at a time and twice forgot to take
his medication with him, resulting in having to repeat first-dose
monitoring. He heard about fingolimod being associated with progressive
multifocal leukoencephalopathy (PML) and was concerned that if he
died, there would be no one to care for his children. He was JC virus
antibody positive.
COMMENT This case highlights the common side effects and concerns that MS
providers typically encounter with several of the disease-modifying
therapies. Interferon beta is the least well tolerated among the classes of
MS disease-modifying therapies,4 largely because of the frequent
occurrence of flulike symptoms. Sometimes, decisions to switch disease-
modifying therapies are made for a combination of reasons, such as
injection fatigue and a new MRI lesion, when either one individually would
not necessarily be enough to warrant a change.
The desire to give up injectables in an older patient doing well clinically
should be weighed against the higher risk of side effects with second-
generation agents such as fingolimod. The risk of PML with fingolimod
(approximately 1 in 12,000 overall and 1 in 5000 if treated for more than
2 years) is less than with natalizumab but certainly higher than with the first-
generation injectables, which do not confer additional risk of PML.
Teriflunomide or dimethyl fumarate might be reasonable options if the
patient does not want to go back to an injectable, although a very small
PML risk exists with dimethyl fumarate (approximately 1 in 50,000) and
perhaps also with teriflunomide.
728 JUNE 2019

An overly lengthy washout, on the other hand, risks disease reactivation, KEY POINTS
especially with disease-modifying therapies that impair lymphocyte migration or
● An overly lengthy
trafficking and the cessation of which can be associated with rebound activity washout risks disease
(fingolimod, siponimod, natalizumab).60–63 Studies have shown that MRI reactivation, especially with
activity starts to return 12 weeks after natalizumab discontinuation64 and that disease-modifying therapies
switching from natalizumab to fingolimod should be done with a washout period that impair lymphocyte
migration or trafficking and
of 3 months or less.65–67 In fact, evidence indicates that decreasing the wait time
the cessation of which can
for switching from natalizumab to fingolimod to less than 6 weeks,68 or even less be associated with rebound
than 1 month,69 is more protective than longer washouts without appearing to activity (fingolimod,
sacrifice safety. natalizumab).
The decision to use a washout depends on both the current and future
● In the natural history of
disease-modifying therapy as well as on the reason for the switch. One might be multiple sclerosis, the risk of
more inclined to use a washout when switching from dimethyl fumarate to what are considered new
ocrelizumab if the reason for the switch is lymphopenia than if the reason is episodes of inflammation,
disease activity. An accelerated elimination procedure with cholestyramine or relapses, and gadolinium-
enhancing lesions on MRI
activated charcoal is required when teriflunomide results in liver toxicity but is scans is highest after
not necessarily needed if a patient switches from teriflunomide to natalizumab clinical onset and generally
because of new lesions on brain MRI. In general, the authors recommend either a diminishes significantly with
limited or no washout period when switching from an injectable or oral agent to age, so that by age 50 the
annual risk of any of the
natalizumab, ocrelizumab, or alemtuzumab and, if possible, to wait no more than three is below 10%.
4 weeks to start another disease-modifying therapy after natalizumab (eg, when
switching because of JC virus antibody positivity). Ultimately, though, more
research needs to be done given the amount of uncertainty that remains about
washout timing.
WHEN TO STOP
As noted, the reasons for disease-modifying therapy discontinuation are many,
but the two most common are intolerance and perceived progression of MS
disability or lack of response. A number of personal factors also have been
associated with stopping disease-modifying therapies, including higher rates
among women; younger patients; previously treatment-naïve patients; and those
with higher education levels, longer times between diagnosis and starting a
disease-modifying therapy, lower (or higher) disability scores, and higher
relapse rates before starting a disease-modifying therapy.5–9 In addition,
disease-modifying therapy discontinuation has been associated with lack of
patient motivation, lower quality of life measures, fatigue, living without a
partner, and taking a higher number of prescription medications.10–11
However, some patients elect to discontinue disease-modifying therapies after
prolonged periods of time with no new relapses or if, despite having no relapses,
they enter a progressive phase of the illness that does not appear to respond to
their disease-modifying therapy. In the natural history of MS, the risk of what are
considered new episodes of inflammation, relapses, and gadolinium-enhancing
lesions on MRI scans is highest after clinical onset and generally diminishes
significantly with age, so that by age 50 the annual risk of any of the three is
below 10%.70,71 This risk does not go to zero, however. Conversely, the risk of
slow progression with or without relapses increases after about age 35, with a
mean onset between 40 and 45 years of age, and is typically ongoing for those
who develop progression.72 Consistent with the clinical data, pathologic studies
reveal a substantially lower number of active inflammatory white matter lesions
in older patients,73 while also noting an increased level of microglial activation74

and development of B-cell/plasma cell clusters in the meninges of older patients

with MS.75 These B-cell clusters are associated with earlier age at entering a
progressive phase of the illness, earlier death from MS, and greater cortical
pathology.76,77 What specific effect these pathologic changes have on response to
disease-modifying therapies is unknown.
The presently available disease-modifying therapies have mostly been studied
in patients age 55 and younger, with the exception of some studies in patients
with progressive MS. The research has revealed variable effects on lessening risk
of relapses, progression of disability, development of new T2 and T1 lesions,
excessive progression of brain volume loss, worsening of cognitive function, and
other outcomes. The more efficacious disease-modifying therapies may also be
associated with some actual improvements in quality of life and disability
measures. Thus, benefits of treatment with disease-modifying therapies may be
profound. As all presently available disease-modifying therapies alter, modulate,
or suppress the immune system, however, with minimal documented effects on
potential repair or regeneration of the nervous system, the benefits have been
shown to be greatest in those with active inflammatory disease (ie, younger
patients). Indeed, only one registration study including participants older than
the age of 55 has shown a benefit on the primary outcome measure studied.78
A meta-analysis of 38 clinical trials involving MS disease-modifying therapies
CASE 7-2 A 72-year-old woman with a 45-year history of multiple sclerosis (MS)
presented in follow-up to discuss discontinuing her disease-modifying
therapy. Her initial symptoms were blurry vision and lower extremity
numbness. She did well for several years without new neurologic
symptoms, but 20 years ago had an episode of vertigo, which lasted 1 to
2 days, so she was started on interferon beta-1b at that time. After
6 years, she switched to daily glatiramer acetate because of flulike
symptoms, and 12 years later switched to 3 times a week dosing.
Her Expanded Disability Status Scale (EDSS) score at the time of this
visit was 1.0 (sensory). MRIs of her brain from the past 17 years were
unchanged and showed periventricular and deep white matter T2/fluid-
attenuated inversion recovery (FLAIR) hyperintense lesions suggestive of
demyelinating disease with a mild disease burden, no brainstem
involvement, and no T1-hypointense lesions. She asked how much longer
she should stay on glatiramer acetate.
COMMENT Young age, a recent MS diagnosis, and recent disease activity (relapses or
MRI changes) are characteristic of those most likely to benefit from MS
immunotherapy. Someone diagnosed with MS more than 45 years ago and
without recent disease activity is unlikely to benefit from any currently
available disease-modifying therapy. In this case, it is not entirely clear that
the event precipitating initiation of disease-modifying therapy was, in fact,
an MS relapse. No MRI changes over the past 17 years is certainly reassuring
(although could be because of ongoing treatment). Discussing treatment
discontinuation would be a reasonable option at this point.
730 JUNE 2019

found that older age significantly decreases the likelihood that a disease-modifying KEY POINTS
therapy will slow disease progression. Based on the manner in which the study was
● As all presently available
performed using median ages from the respective clinical trials, the regression disease-modifying therapies
model predicted no further benefit for the average patient after age 53.79 alter, modulate, or suppress
Stopping disease-modifying therapies may have potential benefits, including the immune system, with
fewer side effects, long-term risks, costs, and reminders that the patient minimal documented
effects on potential repair
has MS. Continued use of disease-modifying therapies also poses ongoing, perhaps
or regeneration of the
worsening, risks (such as PML), as the risk increases with more prolonged use of nervous system, the
the immunosuppressive drugs with which it is associated and the risk of being benefits have been shown to
exposed to the causative JC virus increases with age. Similarly, risks of significant be greatest in those with
active inflammatory disease
comorbidities, such as diabetes mellitus and hypertension, that may enhance
(ie, younger patients).
risk of use of some disease-modifying therapies increase with age.
Overall, however, the major risk of discontinuing an MS disease-modifying ● Stopping disease-
therapy is fear of recurrence or worsening of disease activity. Thus, the question modifying therapies may
is raised whether it is necessary to continue to use disease-modifying therapies as have potential benefits,
including fewer side effects,
people age, especially if they have not had new relapses or MRI changes over long-term risks, costs, and
time. Asked another way, is it safe to discontinue disease-modifying therapies as reminders that the patient
people age? Studies in younger patients clearly show resumption of clinical and has MS.
MRI disease activity, especially for those younger than 50 years of age. This has
● Young age, a recent MS
been seen most graphically in those who have undergone so-called washout
diagnosis, and recent
periods after being on natalizumab. Rebound has even been seen after disease activity (relapses or
natalizumab discontinuation in those with an average age of 50.80 MRI changes) are
A number of databases have collected ongoing clinical and sometimes MRI characteristic of those most
likely to benefit from MS
data on patients with MS over many years, including disease-modifying therapy
immunotherapy.
use. In MSBase, those with an average age of 45 who stopped their injectable
disease-modifying therapy had no greater risk of relapse several years after
stopping compared to those who did not stop disease-modifying therapy, but risk
of worsened disability began to slightly increase about 2 years after stopping.
Younger age and less disability were predictors of risk of relapse recurrence, and
higher EDSS score was a predictor for risk of progression.81 An expanded analysis
with 4842 stoppers (but with no comparator) and a mean stopping age of 36 years
reaffirmed that risk of relapse was greatest in younger patients.82 In the
Innsbruck database, those who continued disease-modifying therapy after age 45
and who had no relapses in the 4 years before stopping their disease-modifying
therapy had a 94% reduction in risk of a new relapse compared to those
discontinuers younger than 45 or who had a relapse in the prior 4 years.83 In
the Rennes database, patients with secondary progressive MS with an average
age of 47 years at the time of stopping their disease-modifying therapy had
no increased risk of relapse at years 1 and 3 after discontinuation. Older age
was not a predictor of relapse or gadolinium-enhancing lesion activity after
discontinuation, but gadolinium enhancement in the 3 years before
discontinuation and an EDSS score of less than 6.0 were. Risk of disability
progression was not increased after discontinuation.10
Thus, while the natural history of MS and our understanding of who
benefits to the greatest degree with MS disease-modifying therapies is consistent
with the concept that discontinuation of disease-modifying therapies may be safe
and appropriate in older individuals, especially those who have been quiescent
clinically, with no relapses and no new activity on MRI scans for significant
periods of time, available data are inadequate to guide decision making regarding
stopping MS disease-modifying therapies (CASE 7-2). A randomized controlled

discontinuation study is presently under way, including 300 patients with

relapsing-remitting and progressive MS who have not had a relapse for a
minimum of 5 years or new MRI lesion for a minimum of 3 years, and should
have results by the middle of 2021.84 It is hoped this will answer some of these
important questions.
CONCLUSION
This article reviewed treatment strategies regarding initiation, switching, and
discontinuation of disease-modifying therapies in MS, which now number over a
dozen. While no definitive treatment algorithm is universally practiced,
convincing evidence exists that early initiation with highly effective therapy is
more beneficial in the long run than escalation strategies. Monitoring should
include clinical and radiographic signs of breakthrough disease as well as
potential side effects and long-term safety concerns; different immunotherapies
have different monitoring requirements. The long-term consequences of
immunosuppression with overlapping agents when switching disease-modifying
therapies need more study. Recommendations regarding disease-modifying
therapy discontinuation are limited by the lack of randomized controlled trials,
but existing data suggest that older patients without recent disease activity may
be able to discontinue them safely.
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REVIEW ARTICLE
Progressive Multiple
Sclerosis

ONLINE
By Daniel Ontaneda, MD
ABSTRACT
PURPOSE OF REVIEW: This article provides an update on progressive forms of
multiple sclerosis (MS), with a focus on pathogenic mechanisms, clinical
features, imaging features, and recent therapeutic advances.
RECENT FINDINGS: Progressive forms of MS are identified by a history of

progressive accrual of disability independent of relapse, but they share
many biological, clinical, and MRI features with relapsing MS. Both
relapses and new lesions can occur in the context of progressive MS, and
CITE AS:
establishing when the transition from relapsing to progressive MS occurs is
CONTINUUM (MINNEAP MINN) often difficult. Several pathogenic mechanisms coexist in progressive MS.
2019;25(3, MULTIPLE SCLEROSIS Targeting inflammation in both primary and secondary progressive MS
appears to reduce the accumulation of disability.
Address correspondence to SUMMARY: Progressive MS remains a diagnostic challenge, and the

Dr Daniel Ontaneda, Mellen
pathogenesis underlying progression is complex. Significant overlap in the
Center for Multiple Sclerosis
Treatment and Research, biology and clinical and imaging features of progressive MS exists with
Cleveland Clinic Foundation, relapsing forms of the disease. The use of disease-modifying and
9500 Euclid Ave, U-10, Cleveland,
OH, ontaned@ccf.org.
symptomatic treatments may improve the quality of life for patients with
progressive MS.
Dr Ontaneda serves as a
consultant for Biogen;
Genentech, Inc; and Sanofi
Genzyme and receives
INTRODUCTION
M
research/grant support from ultiple sclerosis (MS) affects approximately 1 million people
Genentech, Inc; the National in the United States,1 and progressive forms of the disease
Institutes of Health; the National
Multiple Sclerosis Society; account for approximately 10% to 15% of newly diagnosed
Novartis AG; the MS cases.2 Progressive MS is characterized by gradual
Patient-Centered Outcomes
accumulation of disability and may occur from disease onset
Research Institute; Race to Erase;
and Sanofi Genzyme. (primary progressive MS) or after a period of relapsing disease (secondary
progressive MS).3 Progressive forms of MS share many clinical, imaging, and
UNLABELED USE OF
pathologic features with the more common presentation of the disease
USE DISCLOSURE: (relapsing-remitting MS). Rather than a clear demarcation between relapsing
Dr Ontaneda discusses and progressive MS, the clinical and pathologic phenotype of disease course
clinical trial results for biotin,
fingolimod, ibudilast, exists along a spectrum, with focal inflammatory lesions associated with relapses
mycophenolate mofetil, at one end and neurodegeneration with progressive accumulation of disability
natalizumab, and rituximab for at the other.4 Most patients with relapsing-remitting MS develop a progressive
the treatment of progressive
multiple sclerosis. disease course 10 to 15 years after disease onset, and a period of diagnostic
uncertainty between the two phases may exist, suggesting mechanisms in
progressive and relapsing MS likely coexist.5 One notable difference is that
of Neurology. progressive forms of MS are more difficult to treat, and therapies are not as
736 JUNE 2019

effective in modifying the disease course. Over the past several decades, most
clinical trials in progressive MS have been negative; only recently have trials with
positive results emerged, leading to US Food and Drug Administration (FDA)
approval for treatment of primary progressive MS. Recent advances in
understanding of the disease pathology, novel therapeutics, and more refined
clinical trial design will likely result in expansion of treatment options and better
outcomes for patients with progressive MS.6 The availability of therapies and
positive trials have opened a window of hope into what was previously described
as an “untreatable” form of MS. This article discusses the basic pathology and
clinical and imaging features of progressive MS as well as reviews recent
advances in treatment of progressive MS and future directions for research
and therapeutics.
PATHOGENESIS OF PROGRESSIVE MULTIPLE SCLEROSIS

MS is a chronic demyelinating and degenerative condition of the central nervous
system, and progressive MS shares many pathologic features with the more
common relapsing form of the disease.7 While focal inflammatory lesions of the
white matter are the hallmark of relapsing-remitting MS, the pathologic
processes underlying progressive MS are more complex and include a variety
of different mechanisms and pathways (FIGURE 8-1).8 Several of these
mechanisms are present in both relapsing and progressive MS, and differences
between relapsing and progressive MS are more relative than absolute.
Pathology varies between patients and even in a single patient over time. In
progressive MS, clinical disability is not well explained by lesions, and other
processes (such as diffuse tissue injury in normal-appearing white and gray
matter, progressive volume loss of the brain, cortical lesions, and degeneration in
FIGURE 8-1
Pathologic mechanisms in progressive multiple sclerosis.
DNA = deoxyribonucleic acid.
© 2018 Cleveland Clinic.

the spinal cord) may play a more important role.9 Several mechanisms may
explain these pathologic findings, and all are current or future targets
for therapeutics.
Inflammation
In relapsing MS, inflammatory infiltrates with focal breakdown of the
blood-brain barrier are drivers of immune-mediated demyelination and axonal
transection through formation of new lesions.10 While active lesions are common
in relapsing MS, in progressive disease, both chronic active and chronic inactive
lesions are predominant.11 In progressive MS, inflammation likely continues to
drive injury, but this inflammation typically occurs in the setting of an intact
blood-brain barrier.12 Inflammation in progressive MS is documented by the
presence of CSF-specific oligoclonal bands and identification of inflammatory
infiltrates in the brains of patients with primary progressive MS.13 Inflammation
likely decreases over disease duration and is likely qualitatively different in
progressive MS as compared to relapsing MS. It is hypothesized that B cells may
play an important role in progressive MS.14 Meningeal lymphoid aggregates,
densely populated by B cells and resembling follicles, have been detected
adjacent to an intact blood-brain barrier, suggesting that a compartmentalized
inflammatory mechanism occurs in progressive MS.15 Meningeal aggregates may
partially explain the presence of cortical lesions and loss of gray matter volume.16,17
Microglial activation is a prominent pathologic feature in progressive MS that
may drive degenerative changes.
Axonal Degeneration
Axon loss is a prominent feature on postmortem examination of patients with
progressive MS.18 Mechanisms for ongoing axonal loss include anterograde and
retrograde injury as well as transsynaptic degeneration distant to an area of
axonal transection. Axon injury occurs in an intact axon as an energetic/
metabolic failure caused by compensatory mechanisms aimed at preserving
impulse conduction. Demyelination results in an impairment in saltatory
conduction, with a compensatory increase in sodium channels leading to an
increased demand on the sodium/potassium ATPase. The limited energy supplies
with subsequent sodium accumulation in the axon result in activation of the
sodium/calcium exchanger. The influx of calcium into the axons results in
secondary neurodegeneration and axonal loss.19
Microglial Activation/Oxidative Injury

Microglial activation occurs as a result of demyelination and oligodendrocyte
turnover. In progressive MS, microglia are found surrounding focal lesions (most
prominently chronic active lesions) in the cortex and in normal-appearing white
matter.20 The role of microglia as beneficial or harmful cells in neurodegeneration
is debated.21 Microglial activation results in increased production of reactive
oxygen species and nitric oxide, which may provide a toxic environment for the
axon.22 In addition, microglia may play a role favoring immune activation
through presentation of antigen and inflammation. Microglial cells also associate
with regions of axonal degeneration and may favor either degeneration or
protection.23 Oxidative injury is amplified by accumulation of iron that is
released by oligodendrocytes and picked up by microglia, typically at the edge
of lesions and in deep gray matter structures.24
738 JUNE 2019

Mitochondrial Injury KEY POINTS
Demyelination causes both dysfunction of the mitochondria and nuclear/
● Progressive multiple
mitochondrial DNA mutations.25 Mitochondrial dysfunction makes axons more sclerosis was previously
susceptible to oxidative injury, and the resultant increase in oxidation products considered an untreatable
causes further mitochondrial DNA injury with subsequent amplification.26 from of the disease, but
Aberrant mitochondrial displacement within demyelinated axons results in current and future
disease-modifying agents
further energy failure and, ultimately, axonal degeneration.
will change our approach to
this form of the disease.
Glutamate Excitotoxicity
Increased glutamate production in macrophages and microglia occurs as a ● Several mechanisms are
consequence of accumulation of reactive oxygen species. Excess glutamate present in both relapsing
and progressive multiple
may result in further injury through direct toxic effects on myelin as well as sclerosis, and differences
dysregulation of calcium homeostasis inside axons and oligodendrocytes.27 between relapsing and
This causes a vicious cycle of glutamate overload and further production of progressive multiple
oxidative products. sclerosis are more relative
than absolute.
CLINICAL FEATURES ● Inflammation plays a

Progressive MS is clinically characterized by accrual of disability independent of significant role in the
relapses. Key clinical differences between the relapsing and progressive course pathogenesis of progressive
multiple sclerosis.
types are presented in TABLE 8-1. Clinical progression can occur in any neurologic
sphere, but the most common phenotypic presentation is a progressive ● Because of the insidious
myelopathy.28 Previously, the type of progressive MS was defined solely by how onset of symptoms, the
it evolved as either primary progressive (progression from onset) or secondary diagnosis of progressive
progressive (progression after an initial relapsing course).29 Updated definitions multiple sclerosis is typically
delayed, both as the initial
provide qualifiers for describing the recent course of the disease. Progressive presentation in primary
disease can occur with or without activity (clinical relapses or MRI evidence of progressive multiple
new, enlarging, or enhancing lesions) and with or without clinical progression sclerosis and when
(worsening of neurologic examination deficits). Determination of progression reclassifying a patient with
relapsing-remitting multiple
can be made by worsening reported by patients, changes on the neurologic sclerosis as having
examination, or worsening on neurologic performance tests.3 It is important to secondary progressive
note that these qualifications are made retrospectively over a given time course multiple sclerosis.
of the disease.
Evidence indicates that primary progressive MS occurs more equally between
males and females and occurs with a later age of onset (typically after age 40)
than relapsing-remitting MS and secondary progressive MS.30 Progressive forms
of MS are more commonly associated with motor presentation,31 and the
prognosis of primary progressive MS is worse, with more rapid accrual of
disability and earlier time to require ambulatory assistance.32 Primary
progressive MS represents approximately 10% of subjects diagnosed with MS,
and this proportion holds true also in patients who initially presented with
asymptomatic brain lesions compatible with MS (radiologically isolated
syndrome).33
Because of the insidious onset of symptoms, the diagnosis of progressive MS is
typically delayed, both as the initial presentation in primary progressive MS34
and when reclassifying a patient with relapsing-remitting MS as having
secondary progressive MS.35 Common mimickers of primary progressive MS
include compressive myelopathy, neurosarcoidosis, central nervous system
infections, systemic inflammatory disorders, anterior horn cell disease, subacute
combined degeneration, adrenomyeloneuropathy, and mitochondrial disease.36
These differentials should be carefully considered in patients suspected of having

progressive MS. The 2017 revised McDonald diagnostic criteria for MS include
specific criteria for primary progressive MS, including 1 year of disability
progression (retrospectively or prospectively determined) independent of
relapses plus at least two of the following: one or more T2 lesions in characteristic
regions on brain MRI, two or more spinal cord MRI lesions, or the presence of
CSF oligoclonal bands.37 The only revisions from the 2010 McDonald criteria
were the removal of the distinction between symptomatic and asymptomatic
MRI lesions and the addition of cortical lesions as a characteristic brain lesion
type, joining periventricular, juxtacortical, and infratentorial patterns.
Progressive and relapsing MS should be considered to occur on a spectrum
rather than as different diseases, and the understanding that these two forms
share several common features in biology, clinical evolution, and imaging
findings is growing.
TABLE 8-1 Differences Between Progressive and Relapsing Multiple Sclerosis
Relapsing-Remitting Primary Progressive Multiple Secondary Progressive Multiple

Multiple Sclerosis Sclerosis Sclerosis
Clinicala
Overall clinical Predominance of relapses Progressive accrual of disability Progressive accrual of disability after
course without relapses an initial relapsing course; may or may
not have concomitant relapses
Typical clinical Optic neuritis, acute partial Progressive myelopathy, Progressive myelopathy, progressive
syndromes transverse myelitis, progressive brainstem brainstem dysfunction, progressive
brainstem syndromes dysfunction, progressive cerebellar syndrome
cerebellar syndrome
Female to male 3:2–3:1 1:1 3:2–3:1

ratio
Age at onset 20–40 40+ 10–15 years after initial disease

presentation
MRIa
Brain lesion Low initial lesion volume that Lower brain lesion volume as High lesion volume as compared to
burden increases over time. compared to relapsing-remitting relapsing-remitting MS
multiple sclerosis (MS)
Spinal cord Low initial lesion volume that Greater spinal cord lesion volume High lesion volume as compared to
lesion burden increases over time as compared to relapsing- relapsing-remitting MS
remitting MS
Cortical lesions Low initial lesion volume that Higher cortical lesion volume as High lesion volume as compared to
increases over time compared to relapsing-remitting relapsing-remitting MS
MS
Gadolinium Frequent Rare Rare

enhancement
New lesion High Low Low

development

a
Differences are more relative than absolute.
740 JUNE 2019

Large natural history studies indicate that median time to reach secondary KEY POINTS
progressive MS is approximately 10 to 20 years, with male gender, motor
● The 2017 McDonald
presentation, and older age at onset all associated with more rapid development diagnostic criteria for
of secondary progressive MS.38 It should be noted that although younger age of multiple sclerosis include
MS onset is associated with longer time to reach secondary progressive MS, specific criteria for primary
patients diagnosed at a younger age reach secondary progressive MS at a younger progressive multiple
sclerosis, including 1 year of
age as well. This likely reflects the fact that advancing age (typically above 40)
disability progression
and disease duration are likely both predictors of secondary progressive MS (retrospectively or
onset. A large multicenter cohort study identified the following definition for prospectively determined)
secondary progressive MS: worsening of Expanded Disability Status Scale independent of relapses
plus at least two of the
(EDSS) score occurring in the absence of a relapse, confirmed after 3 months and
following: one or more T2
in the context of an overall EDSS score of 4.0 or more and a pyramidal (motor) lesions in characteristic
score of 2.0 or more.39 This definition, although providing high accuracy (87%), regions on brain MRI, two or
may be a relatively late definition of progressive disease. The possibility that a more spinal cord MRI
progressive component exists in earlier stages of the disease has long been lesions, or the presence of
CSF oligoclonal bands.
considered, and recruiting younger, less disabled patients for trials may improve
the likelihood of success. ● Progressive and relapsing
The overall prognosis of progressive MS remains highly variable. Initial studies multiple sclerosis should be
showed that variability in reaching disability milestones in secondary progressive considered to occur on a
spectrum rather than as
MS was related to the time to reach an EDSS score of 3.0 (significant impairment different diseases, and the
in at least one functional system), with subsequent trajectories to EDSS score understanding that these
of 6.0 (unilateral assistance required to ambulate 100 meters) being unaffected two forms share several
by the time to reach the early milestone.40 A large observational study showed common features in biology,
clinical evolution, and
highly variable rates of accumulation of disability in primary progressive MS,
imaging findings is growing.
identifying three disability trajectory subgroups (mild, moderate, severe) for
reaching an EDSS score of 6.0.41 ● Measurement of
progressive accrual of
Measurement of Disease Progression disability is inherently
difficult and remains a
One of the most significant challenges in progressive MS has been the ability to significant obstacle in
reliably and accurately measure clinical progression of the disease. This is an progressive multiple
inherently difficult task because progression occurs slowly, varies significantly sclerosis.
between patients, changes in rate over time, and spans several different types
of neurologic function. The instrument most used to measure progression
has been the EDSS score, which is derived using a combination of the neurologic
examination, gait performance, and patient report of disability.42 The EDSS
score ranges from 0 (normal neurologic examination) to 10 (death due to MS),
with major milestones at 6.0 (unilateral gait assistance), 6.5 (bilateral gait
assistance), and 8.0 (restricted to bed or chair). Its advantages include
familiarity, expression of disability by a single discrete numeric value, and a
long track record of use in clinical trials. However, the EDSS has several
disadvantages. The scale is ordinal, with unequal functional differences
between EDSS steps, making interpretation and analysis of EDSS score change
difficult.43 The EDSS also suffers from poor interrater and intrarater
variability44 and relies heavily on lower extremity function with little
contribution of cognitive function. Electronic scoring of the EDSS is available
and has been used in clinical trials, showing improvement in inconsistencies
and interrater reliability.45
For assessment of disability progression, worsening in the EDSS score by a
given change must be confirmed as sustained over a given period of time.
Although several definitions exist, the most commonly used are 3-month and

6-month sustained worsening of at least 1 point. The magnitude of EDSS

sustained worsening many times is defined on the baseline level of disability.
Definitions have included a 1 point sustained change for those with a baseline
EDSS score of less than 6.0, 1.5 points for baseline EDSS score of 0, and 0.5 point
for baseline EDSS score greater than 6.0.46 A 2015 study showed that requiring
demonstration of sustained worsening for longer periods (12 to 24 months)
improved accuracy and that 3- to 6-month sustained worsening likely
overestimates accumulation of lasting disability.47 These definitions are
commonly used in clinical trials but are not commonly used in clinical practice.
In clinical practice, progression often is defined by objective worsening on
neurologic examination or simply by patient report of sustained worsening over
time assessed retrospectively.
To overcome the limitations of the EDSS, the Multiple Sclerosis Functional
Composite (MSFC) was designed as a quantitative composite of neurologic
performance across several spheres. The early iteration of the MSFC included
measures of lower extremity function (timed 25-foot walk), upper extremity
function (9-hole peg test [a test of manual dexterity in which the time to place
nine pegs into a 3 3 array is recorded]), and cognitive function (Paced Auditory
Serial Addition Test).48 Analysis of the MSFC includes calculation of z score for
each domain and then an overall composite from addition of the z scores. Some
limitations of the MSFC include a learning effect as well as ceiling and floor
effects with some of the measures. Regulatory agencies, including the FDA,
originally were unwilling to use the MSFC as a clinical outcome given the lack of
obvious face validity. The MSFC has undergone several refinements, including
replacement of the Paced Auditory Serial Addition Test by the Symbol Digit
Modalities Test (a timed processing speed test involving matching figures and
numbers) and addition of low-contrast letter acuity as a measurement of visual
function.49 In addition to these changes, thresholds of clinical change have been
established for each of the measures and include a 20% change in the timed
25-foot walk,50 a 20% change in the 9-hole peg test,51 a 4-point (10%) change in
the Symbol Digit Modalities Test,52 and a 7-point change in low-contrast
letter acuity.53
Clinical trials have attempted to apply a combination of EDSS measures and
components of the MSFC to create more robust outcome measures for clinical
trials. A measure known as the EDSS-Plus uses EDSS progression plus 20%
confirmed worsening on the timed 25-foot walk and 9-hole peg test, which, when
applied to a secondary progressive MS clinical trial, was able to clearly separate
progressors from nonprogressors.54 Different combinations of composite
outcomes have been analyzed in clinical trial data and demonstrate that the
combination of MSFC measures with the EDSS could be superior to the EDSS
alone and may reduce sample sizes.55
Patient-reported outcomes are receiving increased attention as a way of
directly accessing patient perspective on disease worsening. Patient-reported
outcomes can be used to validate neurologic performance measures or even as
primary outcomes. The Multiple Sclerosis Impact Scale covers both physical and
psychological quality of life; it has been used for several years and has been
proposed as an end point in progressive MS trials.56 Novel technology-based
measures incorporating both patient-reported outcomes and neurologic
performance tests are being developed and may hold promise as outcome
measures in the future.
742 JUNE 2019

IMAGING FEATURES KEY POINTS
Imaging features differentiating progressive from relapsing MS relate to the
● Brain lesions in
location and number of lesions present in the brain and spinal cord. Brain lesions progressive multiple
in progressive MS are indistinguishable from those seen in relapsing MS; sclerosis are
however, on average, patients with primary progressive MS tend to have fewer indistinguishable from those
brain T2 lesions and fewer lesions with gadolinium enhancement.57 In secondary seen in relapsing multiple
sclerosis; however, on
progressive MS, lesions have accumulated mostly during the relapsing-remitting
average, patients with
phase of the disease, with some ongoing accrual over time; as a result, patients primary progressive multiple
with secondary progressive MS typically have higher lesion volumes. Several sclerosis tend to have fewer
studies describe a larger number of lesions and more diffuse changes in the spinal brain T2 lesions and fewer
lesions with gadolinium
cord in progressive MS.58 Advanced MRI in both lesional and normal-appearing
enhancement.
tissue demonstrates greater levels of tissue impairment in progressive forms of
MS as documented by magnetization transfer ratio imaging,59 diffusivity ● Conventional and
measures,60 and spectroscopy.61 This highlights the fact that progressive MS may advanced spinal cord MRI
be associated with more diffuse, nonlesional injury. Estimates of brain volume measures hold promise as
potential biomarkers for
show greater loss of volume in progressive MS. Volume loss is greater not only in progressive multiple
the brain overall but also in specific deep gray matter structures, including the sclerosis.
thalamus, hippocampus, and caudate nucleus.62 It appears that the contribution
of volume loss related to age likely varies over time, which is of particular
importance when interpreting volume changes in older patients with secondary
progressive MS.63 Patterns of brain volume loss suggest that while patients with
relapsing-remitting MS lose most volume close to the cerebral ventricles, patients
with progressive MS lose most volume in the cortex.59 Evidence also shows that
in progressive forms of the disease, a greater load of cortical lesions is seen.
Although current MRI techniques only identify a small proportion of these
lesions, ultra-high-field imaging studies have demonstrated that cortical lesions
are more frequent in primary progressive MS and secondary progressive MS than
in relapsing-remitting MS.64 Techniques that target more specific pathologic
processes, such as myelin, microglia, iron, and axons, may provide further
insights into the disease process, serve as trial outcome measures, and improve
the ability to predict clinical evolution.
The clinical picture of progressive MS is often one of progressive myelopathy;
therefore, considerable research has been conducted examining imaging measures
of the spinal cord. Spinal cord lesions are more common in progressive MS,65 and it
is not uncommon to find diffuse changes in the spinal cord of patients with
progressive MS. Technical difficulties, including physiologic noise, the relatively
small size of the spinal cord, and field distortions, make imaging of this area a
challenge. Despite these challenges, a large body of MRI evidence suggests that
spinal cord abnormalities are strongly associated with disability in progressive
MS.66 Progressive MS is also marked by greater loss of cross-sectional area of the
upper cervical cord, with strong correlations to clinical disability and performance
measures.66,67 Advanced MRI measurements of the spinal cord, including
diffusion tensor imaging and spectroscopy, demonstrate strong correlations with
neurologic function and may also refine our ability to predict clinical change.68
TREATMENT APPROACH
The treatment of progressive MS encompasses both use of disease-modifying
therapies and symptomatic management. This article focuses on the use of
disease-modifying therapies for progressive MS. For more information on
symptomatic treatment, refer to the article “Management of Multiple Sclerosis

Symptoms and Comorbidities” by W. Oliver Tobin, MBBCh, BAO, PhD,69 in this

issue of Continuum.
Immune Modulation
The recognition of an ongoing inflammatory component in progressive MS
has led to trials examining the effects of immunosuppressive and
immunomodulating compounds as disease-modifying agents. Although initial
results were negative, recent trials have demonstrated positive effects. The
discrepancy in results is likely explained by improvement in trial design, with
refinements in selection of participants and outcome measures, as well as the
TABLE 8-2 Recent Progressive Multiple Sclerosis Trials
Study Sample
Medication Comparator Size Key Inclusion
Primary progressive multiple
sclerosis study name
PROMISE70 Glatiramer Placebo 943 Age: 30–65

acetate
EDSS: 3.0–6.5
Oligoclonal bands/IgG index: not required
71
OLYMPUS Rituximab Placebo 439 Age: 18–65
EDSS:2.0–6.5
Oligoclonal bands/IgG index: required
INFORMS72 Fingolimod Placebo 970 Age:25–65

EDSS:3.5–6.0
Oligoclonal bands/IgG index: not required if
positive MRI
ORATORIO73 Ocrelizumab Placebo 732 Age: 18–55

EDSS: 3.0–6.5
Oligoclonal bands/IgG index: required
Secondary progressive multiple

sclerosis study name
ASCEND74 Natalizumab Placebo 889 Age: 18–58

EDSS: 3.0–6.5
Relapse: none in the past 3 months
EXPAND75 Siponimod Placebo 1651 Age: 18–60

EDSS:3.0–6.5
Relapse: none in the past 3 months
9HPT = nine-hole peg test; CI = confidence interval; EDSS = Expanded Disability Status Scale; HR = hazard ratio; IgG = immunoglobulin G; MRI =
magnetic resonance imaging; OR = odds ratio; T25FW = timed 25-foot walk.
a
Duration refers to disease duration for primary progressive multiple sclerosis and to duration of progressive multiple sclerosis for secondary
progressive multiple sclerosis.
744 JUNE 2019

use of relatively more potent anti-inflammatory medications. TABLE 8-270-75
presents a comparison of progressive MS studies, highlighting differences in
baseline characteristics. Early trials focused on older immunosuppressant
medications, including azathioprine, cyclosporine, mycophenolate mofetil,
and cyclophosphamide.6 These studies showed generally negative results, and
many studied a combination of secondary and primary progressive MS, coined
chronic progressive MS. Encouraging results in relapsing-remitting MS then
led to a wave of studies examining the effect of relapsing-remitting MS
disease-modifying therapies in progressive disease. A placebo-controlled study
in primary progressive MS using glatiramer acetate was negative; the study
Proportion With
Mean Age Contrast Enhancing Duration Primary Outcome
(Years) Lesions (Years)a Primary Outcome Results
50.4 14.1% 10.1 Time to sustained one-step disability HR: 0.87 (95% CI:
progression 0.71–1.71, P=.18)
49.9 24.5% 9.1 Time to sustained disability HR: 0.77 (95% CI:
progression (two strata) 0.55–1.09, P=.14)
48.5 13% 5.8 Confirmed disability progression (two HR: 0.95 (95% CI
strata) or 20% increase in T25FW or 20% 0.80–1.12, P=.54)
increase in 9HPT
Placebo: 44.4 Placebo:24.7% Placebo: 6.1 Confirmed disability progression HR: 0.76 (95% CI:
Ocrelizumab: Ocrelizumab: 27.5% Ocrelizumab: (two strata) time to event 0.59–0.98, P=.04)
44.7 6.7
Placebo: 47.2 Placebo: 22% Placebo:4.9 Confirmed disability progression (two OR: 0.86 (95% CI:
strata) or 20% increase in T25FW or 20%
Natalizumab:47.3 Natalizumab: 26% Natalizumab:4.7 0.66–1.13, P=.29)
increase in 9HPT
Placebo: 48.1 Placebo: 21% Placebo: 3.6 Confirmed disability progression (two HR 0·79 (95% CI:
strata)
Siponimod: 48.0 Siponimod: 21% Siponimod:3.9 0.65–0.95, P=.013)

was notable for a relatively low proportion of subjects who entered the trial
with enhancing lesions at baseline.70 Fingolimod, a sphingosine-1-phosphate
receptor analogue with putative anti-inflammatory and neuroprotective effects,
failed to show an effect on disability progression in primary progressive MS.72
Separate European and North American studies that examined the effect
of interferon beta in secondary progressive MS did not find a convincing
effect on progression.76 Natalizumab, a monoclonal antibody directed at α1β4
integrin, did not show an effect on the primary outcome (EDSS progression)
in a placebo-controlled secondary progressive MS trial.74 An effect was seen,
however, on upper extremity function as measured by the 9-hole peg test,
suggesting performance measures may be more sensitive than EDSS for
sustained worsening in progressive MS. Siponimod, a more selective
sphingosine-1-phosphate receptor modulator than fingolimod, was studied
in a placebo-controlled study of 1651 individuals with secondary progressive
MS and showed a 21% reduction (P=.013) in 3-month confirmed disability
progression.75 It remains to be determined if the effect of siponimod seen in
this study was mediated by an effect on inflammation in a secondary
CASE 8-1 A 72-year-old woman with a 34-year history of primary progressive

multiple sclerosis (MS) presented for follow-up. She had been using a
wheelchair for 12 years and reported no relapses. MRI of her brain from
10 years earlier showed a small number of T2 lesions, while MRI of her
spinal cord showed multiple focal areas of T2 prolongation spanning less
than two vertebral segments each in the cervical and upper thoracic
regions. Serial MRI studies had been unchanged over the past 10 years,
with no new or enhancing lesions. She had an indwelling catheter and
experienced recurrent urinary tract infections. She was hospitalized
3 months earlier with pneumonia and had developed a sacral decubitus
ulcer. Her past medical history was notable for uncontrolled hypertension
and diabetes mellitus, and she smoked two packs of cigarettes a day. She
asked about the use of ocrelizumab to treat her progressive MS.
Current neurologic examination showed partial bilateral internuclear
ophthalmoplegia, spastic paraplegia, diffuse hyperreflexia with
extensor plantar responses, sensory loss in the lower extremities to all
modalities, and moderate limb ataxia.
COMMENT Although this patient has primary progressive MS and ocrelizumab is

approved by the US Food and Drug Administration (FDA) to treat primary
progressive MS, she is probably a poor candidate for this medication. She
is older than the patients with primary progressive MS who participated in
the ocrelizumab study and has no clinical or MRI evidence of inflammatory
activity; thus, the magnitude of potential benefit of ocrelizumab is unclear.
In addition, she has experienced several types of infection, and
ocrelizumab would further increase her infection risk. Treatment of
hypertension and diabetes mellitus and smoking cessation should be
important components of her treatment plan.
746 JUNE 2019

progressive MS population or if a true neuroprotective effect exists. Siponimod KEY POINTS
received FDA approval for active (presence of clinical relapses or new MRI
● Siponimod was studied in
lesions) secondary progressive MS in March 2019. a phase 3 trial in secondary
B-Cell Therapies sclerosis and is now
Rituximab, a chimeric anti-CD20 monoclonal antibody, was the first B-cell approved by the US Food
and Drug Administration for
therapy studied in progressive MS; a placebo-controlled study in primary
the treatment of active
progressive MS showed no benefit on the primary outcome of EDSS secondary progressive
progression.71 However, subsequent subgroup analysis demonstrated possible multiple sclerosis.
benefit for younger patients (≤51 years) with gadolinium-enhancing MRI lesions.
This knowledge was applied when designing the primary progressive MS study ● Ocrelizumab is now an
approved medication for
that compared ocrelizumab, a humanized anti-CD20 monoclonal antibody, with primary progressive multiple
placebo.73 A total of 732 patients were enrolled in an event-driven trial, with sclerosis and will be helpful
confirmed disability progression as the primary end point. Key inclusion criteria in treating the inflammatory
were age younger than 55, EDSS score of 3.0 to 6.5 at screening, and the presence components in patients with
the disease, especially in
of CSF-specific oligoclonal bands or positive IgG index. The study met its younger patients with
primary end point, with a 24% reduction in disability progression (P=.03), inflammatory disease on MRI.
and was the first major trial to do so in primary progressive MS. The results
led to FDA approval of ocrelizumab for primary progressive MS. It is important
to note that 27% of patients in the ocrelizumab arm had enhancing lesions at
baseline, leading to speculation that the use of a powerful anti-inflammatory in
an enriched patient population explains the positive results. Safety data were
encouraging, although a small signal of increased malignancy was found
in ocrelizumab users. Ocrelizumab is now an approved medication for primary
progressive MS and will be helpful in treating the inflammatory components
in patients with primary progressive MS. However, when selecting patients to
start this medication, the trial inclusion criteria should also be considered
(CASE 8-1 and CASE 8-2).
Continuation or Discontinuation of Disease-Modifying Therapy

Continuation of immunomodulating treatments in subjects who have transitioned
from relapsing-remitting MS to secondary progressive MS and older patients with
primary progressive MS is a topic of significant debate. No evidence of efficacy of
the currently available licensed medications for relapsing-remitting MS has been
shown in secondary progressive MS, but many clinicians continue treatment well
into the progressive disease state given the potential risk of disease reactivation with
discontinuing disease-modifying therapy. A large multicenter randomized trial will
examine the effect of disease-modifying therapy discontinuation in subjects with
progressive MS who are older than 55 years of age and have had no evidence of
inflammatory disease activity in the 5 years before enrollment.77
Neuroprotection
Several studies have been conducted examining the effects of putative
neuroprotectant medications in progressive MS, but no medications have yet
been approved. Simvastatin 80 mg showed a 43% reduction in brain volume loss
(P=.003) compared with placebo in patients with secondary progressive MS.78
These encouraging phase 2 results have led to an ongoing phase 3 trial of
simvastatin for secondary progressive MS.79 Ibudilast, a phosphodiesterase 2
inhibitor, was studied in 255 participants with primary progressive MS and
secondary progressive MS followed over 2 years.80 The study met its primary

end point of brain volume loss, and plans for a phase 3 trial are under way.
High-dose biotin modestly improved EDSS scores in a placebo-controlled phase
3 study.81 The MS-SMART (Multiple Sclerosis-Secondary Progressive Multi-Arm
Randomisation Trial) study compared the effects of riluzole, amiloride, and
fluoxetine against placebo in patients with secondary progressive MS in a large
phase 2 clinical trial, and results were negative for all therapies.82 Several trials
using remyelinating agents and cell-based therapies are under development.
Finally, the management of progressive MS should also include control of
medical comorbidities, including hypertension, hyperlipidemia, diabetes
mellitus, and vascular disease, and address issues such as weight control and
tobacco use.83 Supplementation of vitamin D, although not demonstrated to have
an effect in progressive MS clinical trials to date, should be considered with
suspected or demonstrated low vitamin D levels.
CONCLUSION
Progressive MS is a heterogeneous disease both pathologically and clinically.
Although distinguished as a separate entity, progressive MS likely occurs on a
spectrum with relapsing disease. Clinical and imaging features vary between
progressive and relapsing MS and may be used to classify the disease based on the
occurrence of progression and presence of clinical and MRI activity. The first
approved disease-modifying therapy for primary progressive MS, ocrelizumab, is
now available; a medication for active secondary progressive MS (siponimod) has
also been approved. However, the use of disease-modifying therapies will need to
be individualized considering the expected benefits and risks of each medication.
Treatment of comorbidities and symptomatic therapy should be emphasized.
CASE 8-2 A 38-year-old man presented for a second neurologic opinion with a
2-year history of progressive left lower extremity weakness and difficulty
controlling his right hand. Worsening over the past 12 months was
confirmed by his prior neurologist.
Examination revealed left lower extremity weakness, with long tract
signs, spasticity, and moderate right arm dysmetria. MRI of his brain
showed several T2 lesions, and two of the lesions demonstrated contrast
enhancement. MRI of his cervical spine showed nonenhancing discrete
lesions at C4 and T1. CSF studies showed positive oligoclonal bands with
normal glucose, protein, and cell count. He was diagnosed with primary
progressive multiple sclerosis, and he wished to start treatment.
COMMENT This patient meets diagnostic criteria for primary progressive multiple
sclerosis and would be an ideal candidate for ocrelizumab. His disease
characteristics are similar to the phase 3 study population. In addition, he is
male and young and has enhancing lesions and positive oligoclonal bands,
all suggesting that he may respond favorably to treatment. Infectious
complications, although possible, are relatively less likely than in older
patients with more advanced disability given that he is otherwise healthy.
748 JUNE 2019

ACKNOWLEDGMENT
The author wishes to thank Amanda Mendelsohn for providing medical art for
FIGURE 8-1.
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752 JUNE 2019

Management of Multiple REVIEW ARTICLE

Sclerosis Symptoms C O N T I N U UM A U D I O
ONLINE
and Comorbidities
By W. Oliver Tobin, MBBCh, BAO, PhD
ABSTRACT
PURPOSE OF REVIEW: This article discusses the prevalence, identification, and
management of multiple sclerosis (MS)–related symptoms and associated
comorbidities, including complications that can present at all stages of the
disease course.
RECENT FINDINGS: Theimpact of comorbidities on the outcome of MS is

increasingly recognized. This presents an opportunity to impact the course
and outcome of MS by identifying and treating associated comorbidities
that may be more amenable to treatment than the underlying inflammatory
and neurodegenerative disease. The identification of MS-related
symptoms and comorbidities is facilitated by brief screening tools, ideally
CITE AS:
completed by the patient and automatically entered into the patient CONTINUUM (MINNEAP MINN)
record, with therapeutic suggestions for the provider. The development of 2019;25(3, MULTIPLE SCLEROSIS
free, open-source screening tools that can be integrated with electronic DISEASES):753–772.
health records provides opportunities to identify and treat MS-related
symptoms and comorbidities at an early stage. Address correspondence to
Dr W. Oliver Tobin, Mayo Clinic,
Department of Neurology, 200
SUMMARY: Identification and management of MS-related symptoms and First St SW, Rochester, MN
comorbidities can lead to improved outcomes, improved quality of life, 55905, tobin.oliver@mayo.edu.
and reduced disease activity. The use of brief patient-reported screening
tools at or before the point of care can facilitate identification of Dr Tobin receives research/
symptoms and comorbidities that may be amenable to intervention. grant support from Mallinckrodt
Pharmaceuticals.
UNLABELED USE OF
USE DISCLOSURE:
INTRODUCTION Dr Tobin discusses the
M
ultiple sclerosis (MS) is associated in the popular consciousness unlabeled/investigational use of
amantadine, armodafinil, and
with motor disability and gait dysfunction, which were modafinil for fatigue;
initially described by Charcot and his contemporaries over lacosamide, lamotrigine, and
150 years ago. Over the course of the past century, increased oxcarbazepine for paroxysmal
symptoms; gabapentin for
recognition of disabling and treatable complications of MS has restless legs syndrome and
led to several large controlled trials of medications aimed at reducing symptoms. spasticity; and nabiximols, oral
cannabis extract, and synthetic
More recently, it has become apparent that some comorbidities not only occur tetrahydrocannabinol for the
with increased prevalence in patients with MS but also increase the risks of treatment of spasticity.
developing the disease,1–3 delayed diagnosis,4,5 relapse,6 and disability progression
(TABLE 9-1).7,8 Thus, the reasons to identify and intervene early in MS-associated © 2019 American Academy
comorbidities are to reduce MS disease activity and the risk of progression and to of Neurology.

MANAGEMENT OF MS SYMPTOMS AND COMORBIDITIES
improve quality of life and functional independence. A multidisciplinary team is

essential, as neurologists may not always be the best-equipped providers to
intervene on comorbidities. However, they are typically the main providers who
assess patients and, as such, are well placed to identify comorbidities. It is also
important to note that patient needs and comorbidities change over time, and
regular reassessment and proactive intervention are needed, particularly on
symptoms such as depression, spasticity, and obesity.
It is useful to separate the presence of symptoms directly related to MS
itself, such as spasticity, and the presence of comorbidities that are prevalent
in the MS population at higher rates than in the general population, such as
obesity. Sometimes the distinction between these two entities is less than clear. For
example, sexual dysfunction in MS is commonly present due to spinal cord
disease, but psychosocial factors unrelated to the underlying MS may also
contribute to sexual dysfunction. The American Academy of Neurology has issued
a quality measurement set to facilitate quality improvement by providers.9 This
document serves as a good foundation for evaluating the quality of clinic-based
assessments for the presence of MS complications and comorbidities, although
standardized tools to aid in this assessment are sometimes focused on research and
not always practical to use in routine clinical practice. Along with requiring
adequate documentation of the MS diagnosis and performing a comparison MRI
within 24 months of the diagnosis, this measurement set recommends recording
an MS disability scale score at each visit; evaluating for fall risk, urinary tract
infections, fatigue, cognitive impairment, depression, and physical activity; and
monitoring quality of life. TABLE 9-2 provides a summary of common symptoms
associated with MS and suggested treatments.
TABLE 9-1 Common Comorbidities and Their Impact on the Diagnosis and Disease
Course of Multiple Sclerosis
Increases the Risk of Developing Increases the Risk of

Clinically Isolated Syndrome/ Increases the Risk Multiple Sclerosis Increases the
Comorbidity Multiple Sclerosis of Diagnostic Delay Relapse Risk of Disability
Depression X X
Anxiety X X
Hypertension X X
Migraine X
Hyperlipidemia X
Ischemic heart X X
disease
Cerebrovascular X X
disease
Obesity X X X
Multimorbidity (≥3 X X X
comorbidities)
754 JUNE 2019

FATIGUE KEY POINTS
Fatigue is the most common symptom in patients with MS,10 present in almost
● Fatigue is the most
half of patients with clinically isolated syndrome11 and over 80% of patients over common symptom in
the course of the disease.10,12 The majority of patients report fatigue as their patients with multiple
worst symptom.5 Fatigue present at the onset of clinically isolated syndrome is sclerosis, present in almost
associated with a higher risk of future conversion to clinically definite MS.11 half of patients with
clinically isolated syndrome
Fatigue is multifactorial and requires a multifaceted approach to evaluation
and over 80% of patients
and management. A suggested algorithm for the evaluation and management over the course of the
of fatigue in the clinical setting is outlined in FIGURE 9-1.13 Polypharmacy is disease.
common in MS and is associated with fatigue.14 Medications for the treatment
of other symptoms associated with MS, including interferon beta and ● Restless legs syndrome
has been reported in 13% to
anticholinergic, antispasticity, and pain medications, can all contribute to fatigue 65% of patients with multiple
and cognitive symptoms. Use of complementary and alternative medicines can sclerosis and appears to be
further complicate the picture, as these are not commonly inquired about related to spinal cord
by physicians nor reported by patients.15 Prioritizing a patient’s symptom list and disease.
rationalizing medications is the first suggested step in evaluation and ● Limited evidence exists
management of fatigue. for commonly used but
Screening for depression is the next step in fatigue evaluation. It can be unapproved medications,
performed using freely available screening tools, such as the Patient Health such as amantadine,
modafinil, armodafinil,
Questionnaire-9 (PHQ-9)16,17 or its shorter derivative, the Patient Health
methylphenidate, and
Questionnaire-2 (PHQ-2),18,19 or using a combination screening instrument for amphetamine compounds
depression and anxiety such as the Patient Health Questionnaire-4 (PHQ-4).20 for management of fatigue in
Depression is strongly correlated with fatigue.21 Sedation may be minimized multiple sclerosis.
by the use of cognitive-behavioral therapy for mild depression or, if
pharmacotherapy is required, by using nonsedating selective serotonin reuptake
inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs).
When contributing medications and depressive symptoms have been
eliminated as a cause for fatigue, screening for other reversible causes is
recommended. Narcolepsy, rapid eye movement (REM) sleep behavior disorder,
sleep-disordered breathing, and insomnia are associated with MS.22 Initial
screening can identify coexisting treatable sleep disorders such as obstructive
sleep apnea and RLS, which can impact both fatigue and health-related quality
of life.23 RLS has been reported in 13% to 65% of patients with MS24–28 and
appears to be related to spinal cord disease.29,30 It is unclear whether
MS-associated RLS responds to treatments for idiopathic RLS, such as iron
supplementation, pramipexole, or gabapentin; however, these are reasonable
strategies to employ.
When secondary causes of fatigue have been ruled out, a tailored program to
reduce fatigue should be discussed with the patient. This involves components of
a regular exercise program,31 energy conservation strategies (education about
balancing, modifying, and prioritizing activities; rest; self-care; effective
communication; biomechanics; ergonomics; and environmental modification),32
mindfulness-based interventions,32 and environmental modifications such as
gait aids or using a cooling vest when walking or exercising in the heat.
Pharmacologic management for fatigue may be considered when secondary
causes for fatigue have been addressed and nonpharmacologic strategies have
been unsuccessful. Limited evidence exists for commonly used but unapproved
medications, such as amantadine, modafinil, armodafinil, methylphenidate,
and amphetamine compounds for management of fatigue in MS. Although
these medications are commonly used in general practice and in some MS

TABLE 9-2 Symptomatic Management of Multiple Sclerosis
Symptom Description Treatments
Fatigue Multifactorial Limit sedating medications

Most common symptom in patients with multiple Screen for and treat depression, obesity, obstructive
sclerosis (MS) sleep apnea
80% lifetime prevalence Energy conservation measures
Prescribe a regular exercise regimen
Depression 30% point prevalence Evaluate all patients with a positive screen for
depression
Associated with higher Expanded Disability Status
Scale (EDSS) score and anxiety Treat with cognitive-behavioral therapy, selective
serotonin reuptake inhibitor (SSRI), or serotonin
Screen with Beck Depression Inventory, Patient
norepinephrine reuptake inhibitor (SNRI)
Health Questionnaire-2, or Patient Health
Questionnaire-4 Choose treatment strategy depending on
depression severity and side effect profile
Pseudobulbar Involuntary crying or laughing that is often Dextromethorphan/quinidine 1 tablet 2 times a day
affect disproportionate or inappropriate to the social
Tricyclic antidepressant, SSRI, or SNRI
context
Cognitive Can occur at any stage in the disease, including Evaluate for and manage tobacco use, polypharmacy,
impairment clinically isolated syndrome depression, fatigue, and sleep disruption
Prevalence and severity are higher in patients Use of diaries, calendars, regular physical exercise,
with progressive MS and regular social contact
Can occur in the absence of accumulating T2 No evidence for efficacy of acetylcholinesterase
brain lesions inhibitors unless the patient has coexistent
Alzheimer-type dementia
Best screened for using serial assessments with
Symbol Digit Modalities Test or similarly validated
test
Paroxysmal Trigeminal neuralgia, Lhermitte sign, tonic spasms Typically exquisitely sensitive to sodium channel
symptoms (commonly mistaken for spasticity) blockade: carbamazepine 200 mg 2 times a day
Typically sensory with variable motor Oxcarbazepine, gabapentin, or lacosamide can be
involvement; duration 1–90 seconds considered for second-line treatment
Temperature Most common in patients with a high EDSS score; Counsel regarding maintaining an adequate ambient
dysregulation symptoms include recurrent increase in prior MS temperature and wearing adequate clothing
symptoms, encephalopathy, pupillary dilation,
and thrombocytopenia
756 JUNE 2019

Symptom Description Treatments

Spasticity Primarily driven by brainstem and spinal cord Stretching exercises twice daily; hold stretches for
disease; patients report pain and leg spasms, 30–60 seconds
particularly at night and after periods of immobility
Baclofen, tizanidine, or gabapentin; use limited by
fatigue and worsening weakness; elevated liver
enzymes with tizanidine
Oral cannabis extract, synthetic
tetrahydrocannabinol, or oral nabiximols spray
where available
Diazepam or dantrolene can be considered as a
third-line treatment, but use is limited by toxicities
For nonambulatory patients with severe spasticity,
intrathecal baclofen pump
Gait dysfunction Commonly associated with other comorbidities, Ankle-foot orthosis, gait aids, dalfampridine; monitor
including spasticity, weakness, fatigue, and renal function before commencing dalfampridine;
sensory dysfunction monitor response with a timed 25-foot walk test
Bladder Common in MS, although typically does not cause Perform urinalysis and postvoid residual ultrasound
dysfunction a nephropathy of bladder in patients with urinary symptoms
Can present as urinary frequency, urinary urgency, Fluid restriction at night; scheduled voiding; and
or mixed urinary dysfunction avoidance of bladder irritants such as caffeine,
tobacco, alcohol, carbonated beverages (including
May be exacerbated by constipation and obesity
sparkling water), chili peppers, citrus fruits, and
vitamin C supplements
If postvoid residual volume is >100 mL, consider
intermittent self-catheterization
If postvoid residual volume is <100 mL, treat with
anticholinergic medications such as oxybutynin,
trospium, or darifenacin
Third-line treatment includes intravesical botulinum
toxin injection, tibial nerve stimulation, and
consideration of surgical interventions in carefully
selected patients
Sexual Affects up to 90% of patients Broaden the definition of sexual activity

dysfunction
Erectile dysfunction is common in men with spinal Adaptive modifications for positioning
disease
Consider lubricants, moisturizers, and vibrators
Anorgasmia, reduced vaginal lubrication, and
Erectile dysfunction can be treated with
reduced libido are common in women and
phosphodiesterase inhibitors
associated with fatigue

FIGURE 9-1
Suggested algorithm for evaluation and management of fatigue in patients with multiple
sclerosis.
OSA = obstructive sleep apnea.
Reprinted from Khan, et al, Front Neurol.13 © 2014 The Authors.
specialty practices for treatment of MS-associated fatigue, the paucity of

evidence and side effect profile make it difficult to recommend their routine
use. Amantadine at a dose of 100 mg 2 times a day may have modest efficacy.33
Four randomized controlled trials of modafinil and one small crossover study
of armodafinil have failed to demonstrate efficacy for management of
MS-related fatigue, but some patients report benefit during off-label use.34–37
No trials of methylphenidate or amphetamine compounds have been
completed for treatment of MS-related fatigue, although an adequately
powered Patient-Centered Outcomes Research Institute–funded study to
address these questions is currently under way.38
DEPRESSION
The point prevalence of depressive symptoms in patients with MS is approximately
30%.8,39,40 Depression prevalence in MS is approximately double that of the
general population41; despite this, limited evidence exists regarding both
screening and treatment of MS-related depression.42 Depression is associated
with lower quality-of-life scores,43 higher Expanded Disability Status Scale
(EDSS) scores in women, and anxiety.8 Identification of depression and anxiety
can be challenging because some MS symptoms can mimic those of depression,
including psychomotor retardation, diminished ability to think or concentrate,
sleep disruption, and fatigue.
It is recommended that all patients with MS be screened for depression at
annual visits. Several brief screening tools are available, including the Beck
Depression Inventory44 and the patient health questionnaire screener tools
(PHQ-9,17 PHQ-218). More evidence supports the use of the Beck Depression
Inventory in MS,42 although the PHQ family of screeners is in the public domain
and free to use (refer to the Useful Website section). It is important to note that
758 JUNE 2019

although these tools provide suggested cutoff points, a score above the cutoff KEY POINTS
point is not diagnostic of depression. Rather, a suggestive score warrants further
● It is recommended that all
evaluation to see if the patient truly has depression. Sequentially following patients with multiple
patient responses over time can give the provider valuable insight regarding sclerosis be screened for
response to treatment. depression at annual visits.
Because of the common coexistence of anxiety and depression, screening
● Screening for depression
with a concurrent anxiety screening tool can be useful. The Hospital Anxiety
and anxiety can be
and Depression Scale45 and PHQ-420 are brief tools that are useful in the completely automated, with
primary care setting. One of the barriers to screening for depression is the patient responding
uncertainty about immediate management in patients who report suicidal electronically to brief
intent. In patients who express suicidal intent, the P4 screener may be helpful screening questionnaires
and the responses
to prioritize patients for urgent evaluation.46 This brief tool asks about the automatically recorded in
“four Ps”: past suicide attempts, suicide plan, probability of completing the patient's electronic
suicide, and preventive factors. Very few patients who express thoughts of health record.
self-harm are classified as high risk using this tool; the patients who are high
● Patients may develop
risk require an urgent psychiatry evaluation. cognitive dysfunction in the
The use of electronic health records greatly simplifies this screening process. absence of a significant
Screening for depression and anxiety can be completely automated, with patients burden of white matter
responding electronically to brief screening questionnaires and the responses disease and in the absence
of accumulating T2-
automatically recorded in the patients’ electronic health records. Provider
hyperintense brain lesions.
intervention is only required in a very small subset of patients.
Unless the patient is acutely unwell and requires hospitalization, the timing
and type of treatment for depression is typically a collaborative decision
between the provider and the patient. The treating neurologist may wish to
involve a psychiatrist in the patient’s care, depending on the neurologist’s level of
expertise in treating patients with depression. For mild to moderate depression
of recent onset, psychoeducation and subsequent follow-up may be sufficient.
With more severe or prolonged depression, evidence-based psychotherapies
or pharmacotherapy can be considered. The choice of pharmacotherapy
depends on patient response, tolerance, and other conditions that a particular
antidepressant might benefit (eg, anxiety, pain, smoking cessation, insomnia)
or aggravate (eg, weight gain, sexual dysfunction).
It is important to distinguish pseudobulbar affect, which affects 6.5% to 46.2%
of patients with MS,42 from depression. Pseudobulbar affect is characterized by
involuntary crying or laughing that is often disproportionate or inappropriate to
the social context. The only approved medication for treatment of pseudobulbar
affect is dextromethorphan/quinidine, although other medications, such as SSRIs
and tricyclic antidepressants, are commonly used in clinical practice.42
COGNITIVE IMPAIRMENT
Cognitive impairment affects 45% to 65% of patients with MS,47 with the exact
prevalence depending on the classification.48 It can occur at any stage during the
disease, including in patients with clinically isolated syndrome,49 although the
prevalence and severity of cognitive impairment tends to be worse in patients
with progressive MS.50,51 True cognitive dysfunction can be challenging to
distinguish from cognitive inefficiencies secondary to depression, fatigue, and
sleep disruption. The cognitive domains most frequently affected in MS are
recent memory, attention, information-processing speed, executive function,
and visuospatial perception,47 indicating a mixture of cortical and subcortical
dysfunction. Patients may develop cognitive dysfunction in the absence of a

significant burden of white matter disease and in the absence of accumulating

T2-hyperintense brain lesions.52 The effects on processing speed and attentional
domains can result in variable performance on individual neuropsychometric
tests over time.53 Interpretation of a cognitive assessment at a single point in time
may not provide an adequate assessment of an individual’s overall performance
(FIGURE 9-2). In addition, it is common for patients with MS to report difficulties
with multitasking and processing speed.51,54,55 This impairment is not well
evaluated by using brief clinic-based cognitive assessment tools such as the
Mini–Mental State Examination (MMSE).56
FIGURE 9-2
Neuropsychometric results for a patient with multiple sclerosis (A) and a typical patient with
Alzheimer-type dementia (B). Note the variability in scores over time and the inconsistent
pattern of scores in the patient with multiple sclerosis.
AVLT % Ret = Auditory Verbal Learning Test, percent retained; AVLT Recog = Auditory Verbal Learning Test,
recognition; BNT = Boston Naming Test; Cat Flu = Category Fluency Test; Letter Flu = Letter Fluency Test; LM
% Ret = Logical Memory subtest of the Wechsler Memory Scale, percent retained; SD = standard deviation;
TMT A = Trail Making Test Part A; TMT B = Trail Making Test Part B; VR % Ret = Visual Recognition subtest of
the Wechsler Memory Scale, percent retained.
Reprinted from Tobin WO, et al, Mult Scler.52 © 2016 SAGE Publications
760 JUNE 2019

The Consortium of Multiple Sclerosis Centers and the International Multiple KEY POINTS
Sclerosis Cognition Society have recently endorsed a recommendation for early
● Interpretation of a
baseline screening with the Symbol Digit Modalities Test or similarly validated cognitive assessment at a
test when the patient is clinically stable, with annual reassessment with the single point in time may not
same instrument.57 provide an adequate
Although these batteries are typically brief, they can take up to 15 minutes assessment of an
individual’s overall
to complete.58 In addition, the Symbol Digit Modalities Test is a proprietary
performance.
test with associated fees, which may present a barrier to widespread use
outside of a research setting.57 The Perceived Deficits Questionnaire is a ● Paroxysmal symptoms in
patient-reported cognitive dysfunction screen but has a low correlation with multiple sclerosis are
objective neuropsychological testing, suggesting that the Perceived Deficits typically sensory with
variable motor involvement.
Questionnaire does not measure cognitive dysfunction but other factors They usually last between 1
related to how patients perceive their functioning.59 Other patient-reported and 90 seconds and are
computer-based and tablet-based screening tools are in development. exquisitely sensitive to
When evaluating cognitive impairment in patients with MS, it is important sodium channel blockade.
to remember that the frequency of Alzheimer disease pathology in patients
65 years and older with MS is similar to that of the general population.60
CSF tau, phosphorylated tau, and amyloid-β1-42 are normal in patients with
clinically isolated syndrome and relapsing-remitting MS.61 In patients for
whom it is unclear whether MS is significantly contributing to cognitive
impairment, the use of both amyloid-β and neurodegeneration biomarkers
should allow accurate discrimination of MS from Alzheimer disease as the
etiology of cognitive impairment.62 Medications that are modestly effective
in neurodegenerative conditions, such as donepezil, have been studied for
the treatment of cognitive impairment in MS, but results have been
disappointing.63 Although a phase 2 trial indicated that simvastatin may
have beneficial effects on frontal lobe function and brain atrophy,64 this has yet
to be confirmed in a phase 3 trial. No pharmacologic therapy is currently
recommended for cognitive impairment in MS.
Strategies to improve cognition that can be recommended to patients include
conservative measures, such as using diaries and calendars, regular physical
exercise, and regular social contact. Comorbid conditions that may impact
cognition and may be amenable to intervention include tobacco use, depression,
fatigue, sleep disruption, and polypharmacy.
PAROXYSMAL SYMPTOMS
The classic paroxysmal symptoms of MS are trigeminal neuralgia and Lhermitte
sign, but paroxysmal symptoms can include a wide variety of transient,
stereotyped symptoms. The symptoms are thought to be secondary to ephaptic
transmission across adjacent demyelinated axons. Paroxysmal symptoms in MS
are typically sensory with variable motor involvement. They usually last
between 1 and 90 seconds and are exquisitely sensitive to sodium channel
blockade.
Tonic spasms refer to painful flexion of the arm and leg, sometimes with
contraction of ipsilateral facial muscles.65 These tend to be activation dependent
and recur multiple times during the day, as illustrated in CASE 9-1. Localization is
typically within the ipsilateral spinal cord, the posterior limb of the contralateral
internal capsule, or the cerebral peduncle.66 The presence of tonic spasms should
alert the provider to the possibility of neuromyelitis optica (NMO),67 and it
should be noted that even the original descriptions of tonic spasms included

patients with “Devic’s syndrome.”65 Tonic spasms usually remit within several
weeks but can be distressing. If treatment is needed, first-line therapy is
carbamazepine,68 which typically is effective in eliminating symptoms at low
doses (approximately 200 mg 2 times a day). Other options include
oxcarbazepine,68 gabapentin,68 or lacosamide.69
Trigeminal neuralgia is a recurrent unilateral brief electric shock–like pain
that is abrupt in onset and termination; it occurs in 2% to 5% of patients with
MS.70 The pain is restricted to one or more of the trigeminal divisions and is
triggered by innocuous sensory stimuli. Trigeminal neuralgia is often a
heralding feature of MS71 but can exist independent of the diagnosis. The
diagnosis of trigeminal neuralgia attributed to MS requires demonstration of a
trigeminal root entry zone or pontine plaque affecting the intrapontine primary
afferents either on MRI or suggested by the presence of abnormal routine
electrophysiologic studies showing impairment of the trigeminal pathways.
Approximately three-fourths of patients respond to treatment with
carbamazepine, although patients with MS are less likely to benefit from
pharmacologic and surgical interventions than patients with idiopathic
trigeminal neuralgia.72
CASE 9-1 A 52-year-old woman with a history of multiple sclerosis (MS) diagnosed
5 years earlier presented for evaluation of arm pain. She had a history of
multiple spinal attacks and had a normal MRI brain 1 year previously.
Six weeks before presentation, she had developed right shoulder
numbness that progressed over 1 week to involve her right hand. The
symptoms were maximal for 3 weeks and were associated with painful
flexion contractions of the right hand and neck every time she moved her
right arm. She had been treated with gabapentin with no effect on
symptoms.
On examination, she had a painful flexion contraction of the right hand
when she got up to walk. She had brisk reflexes in the right arm and leg, a
right extensor plantar response, and pyramidal weakness in the right arm.
Cervical spine MRI demonstrated a dorsally located T2 hyperintensity
at C2-C3 that enhanced following gadolinium administration.
She was diagnosed with tonic spasms and treated with
carbamazepine, which completely relieved her symptoms over the
course of 1 week. Subsequent testing for neuromyelitis optica (NMO)
IgG was positive, and her diagnosis was changed to NMO spectrum
disorder.
COMMENT Tonic spasms are commonly mistaken for spasticity or other forms of
neuropathic pain. They typically occur in patients with brainstem or spinal
lesions and are short-lived painful contractions of the arm and face,
typically precipitated by activation of an ipsilateral limb. The symptom is
exquisitely responsive to carbamazepine. The presence of tonic spasms
should alert clinicians to the possibility of an underlying diagnosis of NMO
spectrum disorder, as tonic spasms are more common in this disorder.
762 JUNE 2019

THERMOREGULATION DISORDERS
Temperature dysregulation in MS is a poorly recognized phenomenon of uncertain
prevalence. Patients typically present with an increase in prior MS symptoms
associated with other signs of hypothermia, including encephalopathy, pupillary
dilation, and thrombocytopenia, as illustrated in CASE 9-2. Commonly used
aural thermometers are often inaccurate in the setting of hypothermia, and
identification of hypothermia requires the use of a low-reading rectal
thermometer.73 Although a low-reading rectal thermometer is usually the
most convenient, rectal temperature can lag behind core temperature
during rewarming.74
The etiology of hypothermia is likely to be multifactorial, with thalamic,
hypothalamic, and spinal disease being implicated.75–78 Patients most commonly
have secondary progressive MS at the time of onset of hypothermia, with a
high degree of disability, suggesting at least a contribution by involvement of
the autonomic tracts within the brainstem and spinal cord. As sepsis can be
associated with hypothermia, particularly in patients who are elderly, infection
should be ruled out before making a diagnosis of primary hypothermia. Some
patients have been demonstrated to start sweating at a normal or subnormal
body temperature, suggesting that these patients have an altered thermoregulatory
sweat test balance point, compatible with a central autonomic network lesion.79
Consequently, following rewarming, patients should be counseled regarding
maintaining adequate ambient temperature and wearing adequate clothing, as a
A 62-year-old woman with a 37-year history of secondary progressive CASE 9-2

multiple sclerosis, with an Expanded Disability Status Scale (EDSS) score
of 8.0 (mobilizes in a wheelchair only), presented to her local emergency
department with recurrent encephalopathy. She had previously been
diagnosed with urinary tract infections as the cause of her encephalopathy,
although a causative organism was not identified. On each of her previous
admissions, she typically recovered within 24 to 48 hours in the absence
of any specific treatment. On this admission, she was noted to have a mild
elevation in liver enzymes and thrombocytopenia. Examination revealed
a bilateral internuclear ophthalmoplegia, a left relative afferent pupillary
defect, severe pyramidal weakness and spasticity in all four limbs, with
bilateral extensor plantar responses.
EEG demonstrated nonspecific background slowing. Lumbar puncture
was performed to assess for meningitis or encephalitis; CSF analysis was
normal, except for elevated oligoclonal bands. A low-reading rectal
thermometer recorded a temperature of 33°C (91.4°F). She returned to
her baseline over 24 hours with gentle rewarming.
Recurrent encephalopathy in patients with multiple sclerosis can be COMMENT

associated with hypothermia. This typically occurs in patients with high
motor impairment and can often be underrecognized. Prevention includes
education regarding wearing warm clothes and maintaining a high ambient
temperature within the living environment.

temperature that is comfortable for another member of the household may be

sufficient to cause hypothermia in patients with an altered thermoregulatory
sweat test balance point.
SPASTICITY AND WEAKNESS

Spasticity and weakness in MS are predominantly driven by brainstem and spinal
cord disease. Loss of γ-aminobutyric acid–mediated (GABA-ergic) inhibition of
spinal reflex arcs results in reduced inhibition of postural muscles, causing
exaggerated flexion of the arms and extension of the legs that may be associated
with weakness, stiffness, cramps, pain, and clonus. In patients who have
significant weakness and spasticity, overtreatment of spasticity may lead to loss
of function, as the presence of spasticity may facilitate transfers or walking by
providing postural support . Initial treatment of spasticity should primarily focus
on stretching exercises. Stretches should be held for at least 30 to 60 seconds, and
patients should be counseled to stretch twice daily. If this strategy is insufficient
to control spasticity, treatment with baclofen, tizanidine, or gabapentin can be
considered.80 These medications are limited by the side effects of sedation and
exacerbation of weakness. In addition, tizanidine can cause elevation in liver
enzymes in 3% to 5% of patients. Baclofen is typically used in doses of 10 mg
2 times a day, increasing in 10 mg increments every 2 to 3 days to a maximum
total daily dose of 80 mg. Some patients may require a slower titration or lower
doses to avoid drowsiness and cognitive side effects.
Tizanidine is a useful alternative to baclofen, primarily in patients who
develop significant weakness when treated with baclofen. The sedating effects of
tizanidine tend to be greater than those of baclofen; therefore, titration is
performed at 1 mg to 2 mg per day starting at 2 mg each night, increasing to a
maximum total daily dose of 12 mg in three divided doses. Gabapentin is
typically used at a total daily dose of 300 mg to 3600 mg in three divided doses,
and titration is typically limited by the side effects of sedation toward the upper
end of the therapeutic range.
Patients with severe spasticity that is not responsive to first-line antispasticity
medications may benefit from treatment with diazepam or dantrolene.
Diazepam at total daily doses of up to 30 mg reduces spasticity to a similar degree
when compared to baclofen and tizanidine. The safety profile is similar to
baclofen, despite a greater degree of sedation in patients treated with diazepam.
Long-term safety is typically not assessed in clinical trials, and benzodiazepine
dependence is a concern in patients treated with diazepam. The average total
daily dose of diazepam required to treat spasticity is 15 mg.
Dantrolene decreases the release of calcium in skeletal muscle, reducing
spasticity and causing significant weakness. Dosing starts at 25 mg once a day,
increasing to a maximum total daily dose of 400 mg in four divided doses.
Treatment is limited by weakness and by side effects of gastrointestinal
symptoms, fatigue, sedation, and dizziness. The risk of hepatotoxicity requires
monitoring of liver function before and during therapy.80
In patients with severe spasticity that is not responsive to stretching or
medications, or in patients with focal spasticity, botulinum toxin injections can
be used for both upper limb and lower limb spasticity.81 Evidence has not shown
that any formulation of botulinum toxin is superior to another. Although
botulinum toxin has been demonstrated to be effective for reducing spasticity,
the impact of botulinum toxin injections on functional outcomes is mixed,
764 JUNE 2019

suggesting that patient selection is crucial. In patients with generalized or KEY POINTS
bilateral lower limb spasticity, treatment with botulinum toxin injections may
● Commonly used aural
lead to functional loss due to weakness. In contrast, for patients with focal thermometers are often
spasticity, botulinum toxin injection may be a good first-line choice, as it allows inaccurate in the setting
them to avoid the side effects associated with baclofen, tizanidine, or gabapentin. of hypothermia, and
Despite considerable interest in the use of medical marijuana for the treatment identification of
hypothermia requires the
of MS, no cannabinoid is US Food and Drug Administration (FDA) approved for
use of a low-reading rectal
the treatment of MS-related spasticity. Two recent meta-analyses have thermometer.
concluded that oral cannabis extract, synthetic tetrahydrocannabinol (THC),
and nabiximols are probably effective at reducing patient-reported symptoms of ● Initial treatment of
spasticity in people with MS, but oral cannabis extract and synthetic THC were spasticity should primarily
focus on stretching exercises.
not found to be effective for reducing physician-administered measures of Stretches should be held
spasticity.82 Cannabinoids are generally well tolerated but are associated with an for 30 to 60 seconds, and
increased risk of psychosis and schizophrenia and so should be avoided in at-risk patients should be counseled
individuals.83–85 Additionally, cannabis use is associated with increased risk for to stretch twice daily.
myocardial infarction, hypertension, heart failure, and stroke.86,87 Variability in ● For patients who are
production and extraction procedures means that clinically significant nonambulatory with severe
batch-to-batch variability may occur when using oral cannabis extract. In spasticity that is not
addition, although oral cannabis extract is legal in some states, health insurance responsive to or intolerant
of other treatment
typically does not cover use of federally prohibited substances.
strategies, intrathecal
For patients who are nonambulatory with severe spasticity that is not baclofen is a useful strategy,
responsive to or intolerant of the above treatment strategies, intrathecal baclofen particularly for facilitating
is a useful strategy, particularly for facilitating toileting and cleaning. Greater toileting and cleaning.
intrathecal concentrations of baclofen can be achieved than when using systemic
therapy, without significant systemic side effects. The main side effects are
related to the implantation of the intrathecal catheter and pump mechanism.
Because of this, an intrathecal baclofen test should be performed before the
pump implantation to determine response and functional loss.74
Gait impairment in MS is typically multifactorial and contributed to by
spasticity, weakness, fatigue, and sensory dysfunction. The management of gait
impairment and associated weakness consists mainly of nonpharmacologic
interventions such as physical therapy; ankle-foot orthosis to reduce the impact
of footdrop; and other mobility aids such as canes, walkers, wheelchairs, and
scooters, along with addressing other comorbidities that can impact gait and
weakness. The main pharmacologic therapy to treat weakness in MS is
dalfampridine sustained release, which can improve walking ability in
approximately one-third of patients. Side effects include seizures and anxiety,
with seizures being more common in patients with renal impairment.88 Some
evidence from uncontrolled trials indicates that dalfampridine may also improve
upper limb function.89,90 A clinical response to dalfampridine can be evaluated
by performing a timed 25-foot walk test before and several weeks after starting
the medication. If the patient does not have a clinical response, it is reasonable to
discontinue the medication at that time.
BLADDER DYSFUNCTION
Neurogenic bladder dysfunction is common in patients with MS and is associated
with pontine and spinal cord lesions. Urinary symptoms are broadly categorized
into failure to store (urinary frequency), failure to empty (urinary retention), or a
combination of both. In contrast to other neurologic disorders affecting the spinal
cord, such as spina bifida, upper urinary tract disorders in MS are rare, possibly

because of the slowly progressive nature of the disease. Consequently, a more

symptom-based approach may be employed than that used in other causes of
neurogenic bladder dysfunction due to spinal injury. Features that should
prompt early referral to urology services are outlined in TABLE 9-3.91 A suggested
algorithm for the evaluation and management of neurogenic bladder
dysfunction is outlined in FIGURE 9-3.
In patients presenting with urinary symptoms, a urinalysis and postvoid
residual ultrasound of the bladder should be performed. Patients should be
counseled regarding conservative strategies, including fluid restriction at night;
scheduled voiding; and avoidance of bladder irritants such as caffeine, tobacco,
alcohol, carbonated beverages (including sparkling water), chili peppers, citrus
fruits, and vitamin C supplements. Treatment of comorbid conditions that can
exacerbate bladder dysfunction, including obesity and constipation, may also
be beneficial. If this is ineffective, patients with a postvoid residual volume of
less than 100 mL may be treated with anticholinergic medications such as
oxybutynin, trospium, or darifenacin.
Intravesical Botulinum Toxin

Patients with neurogenic detrusor overactivity who do not respond to first-line
treatment with anticholinergic medications can be considered for a variety of
second-line options, including intravesical botulinum toxin injection. This is
generally well tolerated and reduces urinary incontinence while increasing
quality of life. The main side effect of this treatment is urinary retention, which
can occur in approximately 50% of patients. Despite the efficacy of treatment and
persistence of effect with repeated doses, patients with MS tend not to continue
with long-term therapy, possibly because of progression of the disease.92
Catheterization
Patients with a postvoid residual volume of more than 100 mL should be
offered intermittent self-catheterization. Indwelling catheters are associated
with a greater risk of urinary tract infections, genital erosions, and bladder
stone formation than intermittent catheterization. Indwelling catheters are
typically considered in patients who are unable to perform intermittent
TABLE 9-3 Red Flags That Should Initiate an Early Referral to Urology Servicesa
◆ Presence of hydronephrosis
◆ Renal impairment
◆ Recurrent urinary tract infections
◆ Hematuria
◆ Suspicion of concomitant urologic pathology (eg, prostate enlargement)
◆ Stress urinary incontinence
◆ Loin and/or pelvic pain
◆ Symptoms refractory to first-line treatment
a
Reprinted from Tornic J, Panicker JN, Curr Neurol Neurosci Rep.91 © 2018 The Authors.
766 JUNE 2019

self-catheterization because of KEY POINTS
upper limb dysfunction, for
● In contrast to other
example, or in patients for neurologic disorders
whom spasticity makes affecting the spinal cord,
intermittent self-catheterization such as spina bifida, upper
challenging to perform. The urinary tract disorders in
multiple sclerosis are rare,
suprapubic route is preferable
possibly because of the
for ease of care, comfort, and slowly progressive nature of
fewer complications. Silicone the disease.
catheters are associated with less
susceptibility for encrustation ● In patients with multiple
sclerosis presenting with
and allergy than latex catheters. urinary symptoms, a
urinalysis and postvoid
residual ultrasound of the
Neuromodulation bladder should be
Percutaneous93 and performed.
transcutaneous94 tibial nerve
stimulation have been shown ● Indwelling catheters are
associated with a greater
to have short-term benefits on risk of urinary tract
urinary symptoms for patients infections, genital erosions,
with an overactive bladder and bladder stone formation
secondary to MS and may also than intermittent
catheterization.
have a positive effect on fecal
incontinence.95 Several ● Percutaneous and
treatment paradigms have been transcutaneous tibial nerve
studied, with a typical paradigm stimulation have been
for percutaneous tibial nerve shown to have short-term
benefits on urinary
stimulation consisting of symptoms for patients with
stimulating the nerve through a overactive bladder
fine gauge needle using a fixed secondary to multiple
frequency electrical signal once sclerosis and may also have
FIGURE 9-3 a positive effect on fecal
weekly for 30 minutes over an incontinence.
Suggested algorithm for evaluation and
management of urinary symptoms in a patient with 8- to 12-week period. Tibial
multiple sclerosis. nerve stimulation does not
KUB = kidney ureter bladder; UTI = urinary tract infection. increase bladder volume and,
a
Additional assessment and quantification with quality of
life and symptom questionnaires.
therefore, does not lead to an
b
By ultrasound scan or in-out catheterization. increased rate of requiring
c
Alpha1-blockers in selected cases. intermittent self-catheterization.
Reprinted from Tornic J, Panicker JN, Curr Neurol
Transcutaneous stimulation has
Neurosci Rep.91 © 2018 The Authors.
the additional benefit that it can
be performed by the patient or
caregiver at home. Both techniques are minimally invasive, and the absence of a
permanently implanted device means that no safety concerns exist regarding
future MRI scans.
Surgical Options
Surgical interventions can be considered in patients for whom conservative
treatments have failed, although this is becoming increasingly uncommon
because of the availability of less-invasive options. Procedures such as
continent/incontinent urinary diversion for debilitating urgency and frequency

KEY POINT and external sphincter/bladder neck incision for urinary retention could be
considered in carefully selected patients who have exhausted other options.
● Sexual dysfunction
affects up to 90% of patients
with multiple sclerosis
SEXUAL DYSFUNCTION
during the course of Sexual dysfunction affects up to 90% of patients with MS during the course of
the disease. the disease. Men primarily report erectile dysfunction and ejaculatory
disorders; medications and other medical issues can also contribute to these
symptoms. Sexual dysfunction in men is associated with other indicators of
spinal cord dysfunction, such as leg weakness, bladder dysfunction, and
higher EDSS scores. In women, the most common symptoms are anorgasmia,
reduced vaginal lubrication, and reduced libido. In contrast to men, sexual
dysfunction in women is not associated with higher EDSS scores and is
primarily associated with fatigue. Conservative measures to improve sexual
function in both men and women include defining sexual activity more
broadly than penile-vaginal intercourse (eg, massage, petting, kissing,
flirting, mutual sensual pleasuring). Patients should be encouraged to pursue
sexual activity when energy levels are highest. If physical disability is
contributing to sexual dysfunction, the use of cushions (eg, wedge or pillow)
for positioning may be helpful. Additional time and communication may be
required to prepare for sexual activity, and patients should take breaks during
sexual activity as needed. The use of lubricants, moisturizers, and vibrators
should be encouraged as appropriate.
After offending medications have been removed, phosphodiesterase
inhibitors are the first-line medical treatment of erectile dysfunction. Erectile
dysfunction that is resistant to treatment with phosphodiesterase inhibitors may
respond to use of a constriction band or ring placed at the base of the penis. Other
options that can be tried include a vacuum erection device used in combination
with a constriction band or ring, intraurethral alprostadil suppositories, or penile
injection of vasoactive medications.
Identification of sexual dysfunction may be facilitated by a screening tool. For
men, this can be as simple as a single question about erectile dysfunction.96 For
both men and women, a single screening question, “Do you have any sexual
problems or concerns?” can be used.97
CONCLUSION
The symptoms of MS are myriad, and comorbidities are common. Identification
and management of MS-related symptoms and comorbidities can lead to
improved outcomes, improved quality of life, and reduced disease activity. The
use of brief patient-reported screening tools at or before the point of care can
facilitate identification of symptoms and comorbidities that may be amenable
to intervention.
USEFUL WEBSITE
PATIENT HEALTH QUESTIONNAIRE (PHQ) SCREENERS
The PHQ screeners website offers free, public
domain access to the PHQ family of screening tools
(PHQ, PHQ-4, PHQ-7, PHQ-9, PHQ-15, Brief PHQ, and
PHQ-SADS) and the Generalized Anxiety Disorder
7-Item Scale (GAD-7).
phqscreeners.com
768 JUNE 2019

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80 Otero-Romero S, Sastre-Garriga J, Comi G, et al. 91 Tornic J, Panicker JN. The management of lower
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772 JUNE 2019

Pregnancy and Family REVIEW ARTICLE

Planning in Multiple C O N T I N U UM A U D I O
ONLINE
Sclerosis
By Annette M. Langer-Gould, MD, PhD
ABSTRACT
PURPOSE OF REVIEW: This article provides practical guidance on successful
management of women with multiple sclerosis (MS) through pregnancy
and the postpartum period.
RECENT FINDINGS: Recent studies indicate that most women diagnosed with
MS today can have children, breast-feed, and resume beta interferons
or glatiramer acetate per their preferences without incurring an increased
risk of relapses during the postpartum period. More than 40% of women
with mild MS do not require any treatment before conception or in the
postpartum period. Women with highly active MS can now become CITE AS:
well-controlled before, throughout, and after pregnancy via highly
effective treatments. Unfortunately, pregnancy does not protect against AND OTHER CNS INFLAMMATORY
relapses following the cessation of fingolimod or natalizumab, and some DISEASES):773–792.
women experience severe rebound relapses during pregnancy. Accidental

first-trimester exposure to teriflunomide or fingolimod increases the risk Dr Annette M. Langer-Gould,
of fetal harm. Kaiser Permanente Southern
California Permanente Medical
Group, 100 S Los Robles Ave,
SUMMARY: Most women with MS can have normal pregnancies and Pasadena, CA 91101, Annette.M.
breast-feed without incurring harm. Clinicians should avoid prescribing Langer-Gould@kp.org.
medications with known teratogenic potential (teriflunomide, fingolimod),
known risk of severe rebound relapses (fingolimod, natalizumab), or Dr Langer-Gould receives
unclear but plausible risks (dimethyl fumarate, alemtuzumab) to women of research/grant support from
the National Multiple Sclerosis
childbearing age who desire pregnancy or are not on reliable birth control. Society and the Patient-
If a treatment needs to be resumed during breast-feeding, clinicians Centered Outcomes Research
should opt for glatiramer acetate, interferon beta, natalizumab, or Institute.
rituximab/ocrelizumab, as biologically plausible risks to the infant are UNLABELED USE OF

exceedingly low. PRODUCTS/INVESTIGATIONAL
USE DISCLOSURE:
Dr Langer-Gould discusses the
use of corticosteroids and
INTRODUCTION plasma exchange to treat
multiple sclerosis relapse during
T
he majority of patients with multiple sclerosis (MS) no longer need to pregnancy, gabapentin to treat
alter pregnancy or breast-feeding plans because of their underlying neuropathic pain, natalizumab
to treat multiple sclerosis during
disease. More than 40% of women are not on treatment in the
pregnancy, and rituximab to
12 months before conception and do not incur increased risk of treat multiple sclerosis.
disability.1,2 Accidental pregnancy exposure to some of the most
commonly prescribed MS treatments in the United States, glatiramer acetate and © 2019 American Academy
various interferon beta preparations, appears safe. Breast-feeding at least briefly, of Neurology.

PREGNANCY AND FAMILY PLANNING IN MS
KEY POINT even if combined with formula feedings, neither increases or decreases the risk
of postpartum relapse,1 and breast-feeding exclusively for at least 2 months
● Multiple sclerosis does
not increase the risk of
postpartum appears to decrease the risk of postpartum relapses.3,4 Even when
infertility, adverse relapses occur during pregnancy or the postpartum period, they do not appear to
pregnancy outcomes, or affect long-term prognosis in most women.5 If treatment is needed during
adverse neonatal outcomes, lactation, several medications are available that pose no biologically plausible
but some multiple sclerosis
risk to the infant if exposure occurs only via breast milk.
treatments may increase
these risks. Thus, the good news is there are only a few pitfalls to be avoided when
managing and counseling women of childbearing potential; those with the
highest impact are pregnancies that occur while a woman is still taking
medications that are known to or potentially increase the risk of adverse
pregnancy outcome risks and pregnancies that occur shortly after cessation
of or while a woman is still taking fingolimod or natalizumab. Luckily, the
large number of treatment options available now make these issues easy
to avoid.
This article focuses on how to avoid these potentially high-impact errors
through proper counseling and treatment selection. Practical management
guidance is also provided for when a woman does get pregnant while on a risky
MS medication, including when high-risk obstetrics care and additional neonatal
care may be wise. This article also covers less common scenarios, including
fertility treatment and drugs to avoid in men who desire children.
BACKGROUND
The uncertainties and controversies in the counseling and management of
women with MS during pregnancy and the postpartum period have shifted
significantly over the past 30 years. Evidence generated in a landmark study6 laid
to rest concerns that pregnancy was not safe for women with MS. This study also
raised awareness that the risk of relapses is increased in the first 3 to 4 months
postpartum, particularly in women with very active MS before pregnancy. After
the introduction of MS disease-modifying therapies that have allowed women
to achieve improved disease control before pregnancy, the debate shifted to
whether women with MS should breast-feed or forego breast-feeding to
resume disease-modifying therapy in the hopes of preventing these early
postpartum relapses.
Simultaneously, researchers demonstrated a multitude of infant and
maternal health benefits of breast-feeding, and public health efforts have led to
significant rises in rates of prolonged breast-feeding in the general population.7
This is causing increasing concern that recommending foregoing breast-feeding
in women with MS could have long-lasting detrimental effects for the mother
and infant. This issue is particularly concerning as multiple revisions in the MS
diagnostic criteria have allowed for earlier diagnosis in patients with milder
disease. This means that today many women with MS who get pregnant may
have much milder disease than those included in the historical studies from
which the concerns of postpartum relapses arose (CASE 10-1).
In the past 5 years, evidence has been increasing in MS and other autoimmune
diseases that recommending foregoing breast-feeding is unnecessary8 and that
exclusive breast-feeding may reduce the risk of postpartum MS relapses,4
particularly in women with milder forms of MS. But a new issue has arisen:
severe relapses occurring during pregnancy following cessation of natalizumab9
or fingolimod,10,11 which were virtually unheard of before.
774 JUNE 2019

Other studies have been published confirming that MS itself does not increase
the risk of infertility, adverse pregnancy outcomes, or adverse neonatal
outcomes.12,13 However, with the introduction of oral disease-modifying
therapies, particularly teriflunomide, clinicians should ensure that women are on
effective birth control to prevent fetal toxicity and that they plan their
pregnancies.14 In addition, if alemtuzumab was used before pregnancy,
neurologists should monitor the mother closely for development of autoimmune
thyroiditis, as this can result in neonatal thyroid disease and its numerous risks.
DEVELOPMENT OF BEST PRACTICE RECOMMENDATIONS

The recommendations presented herein were developed for use by neurologists
and pharmacists practicing in Kaiser Permanente Southern California by the
author and the MS specialists group. They balance the mother’s risk of disability
A 24-year-old woman with multiple sclerosis (MS) presented to discuss CASE 10-1
pregnancy and breast-feeding. She had been diagnosed with MS at age
20 when she presented with optic neuritis and met McDonald criteria for
MS by brain MRI. She was started on a modestly effective disease-
modifying therapy but stopped after 6 months. She had not had any
further relapses.
Her neurologic examination was normal. Her brain MRI showed a
single new nonenhancing periventricular lesion since diagnosis.
She was worried about the risk of postpartum relapse and her ability
to care for a baby. She was reassured that her disease was quite mild and
that if a postpartum relapse occurred, it would also likely be mild and
treatable like her past relapses; exclusive breast-feeding was also
recommended.
In the next 3 years, she had two children and remained relapse-free
and untreated. Both pregnancies were uncomplicated, both infants were
breast-fed exclusively until 6 months of age, and she planned to
continue to breast-feed her 1-year-old child. She was not sure whether
she wanted more children and was not on birth control.
This case illustrates an increasingly common scenario as the MS diagnostic COMMENT

criteria undergo revisions allowing women to be diagnosed earlier and with
milder disease. Recommending this patient resume a disease-modifying
therapy before or shortly after pregnancy, particularly if it meant she
could not breast-feed, was not necessary as she did not have frequent
relapses, significant accumulation of new lesions on MRI, or disability
from previous relapses. Supporting her in her desire to breast-feed was
appropriate. Now that she may be done having children, it would be
appropriate to check another noncontrast brain MRI to assess for lesion
progression. If she has new or enlarging lesions, starting glatiramer acetate
or interferon beta would be compatible with breast-feeding and the
possibility that she may become pregnant accidentally before
discontinuation of treatment.

KEY POINTS with risks to the infant and practical considerations, including the mother’s
preferences and simplicity. Where clear evidence in humans is available, it
● Potential risks not
captured by US Food and
takes precedence over animal data. When solid data in humans are lacking,
Drug Administration which is usually the case with newer drugs, we rely on biological plausibility
pregnancy categories obtained by considering the combination of animal data, pharmacologic
include neonatal properties, mechanism of action, and case series in humans. Both risks captured
immunosuppression,
by the US Food and Drug Administration (FDA) risk categories (fertility,
impaired early-life
neurocognitive fetotoxicity, major malformations) and those not captured by those categories
development, delayed are considered. These additional risks include the impact on the infant’s
toxicities in the child (eg, developing immune system and vaccine responses, potential neurologic sequelae
cancer), and risks incurred
that can result directly from drugs or from increased risk of preterm labor or
from severe rebound
relapses in pregnancy. low birth weight, later-life cancers or other delayed offspring toxicities, and
risks incurred from severe rebound relapses during pregnancy. When the
● It is important to assess evidence is mixed, the author recommends caution and counseling women
whether the patient’s regarding the uncertainties. In areas where the risks are high and the evidence
disease activity is
adequately controlled
is rapidly evolving, the author recommends consulting a neurologist who is an
before counseling about expert in MS and pregnancy for the most up-to-date guidance.
pregnancy. First decide Women have strong preferences regarding family planning, breast-feeding
whether patients with choices, and use of drugs during pregnancy and lactation. Thus, only in rare
multiple sclerosis need to
be on highly effective or
circumstances would the author strongly recommend treating with disease-
modestly effective modifying therapy until conception or during pregnancy or resuming disease-
disease-modifying therapy modifying therapy shortly after delivery. In most scenarios, we openly
to control their disease discuss the pros and cons with the mother and support her decision,
activity, then consider the
while monitoring for disease activity should she choose a very risk-averse
possibility of pregnancy
when choosing a disease- approach.
modifying therapy.
Incorporating Family Planning in Starting, Stopping, or Switching Multiple
Sclerosis Treatments
FIGURE 10-1 describes best practice recommendations for how to incorporate
family planning when starting, stopping, or switching MS treatment plans. The
first decision for any patient with MS to make is whether to start a highly or
modestly effective disease-modifying therapy. If patients are already on a
disease-modifying therapy, the question is whether their MS is well controlled
and, if not, whether they should be switched to another disease-modifying
therapy to reduce risk of long-term disability.
The author recommends a risk-stratified treatment approach for all patients
with MS that considers their underlying risk of long-term disability when
deciding whether to start or switch to a highly effective disease-modifying
therapy. The strongest risk factors for long-term disability are progressive disease
course and, in patients with relapsing-remitting MS, sphincter involvement with
or without motor involvement (ie, spinal cord), incomplete recovery from
relapses, and frequent relapses early in the disease course.15 In these patients, the
author recommends starting or switching to a highly effective disease-modifying
therapy. For patients who have continued disease activity on modestly effective
disease-modifying therapies (defined as relapses or unequivocally new lesions on
MRI scans after ≥6 months on disease-modifying therapy), the author also
recommends escalating to a highly effective disease-modifying therapy rather
than switching to another modestly effective agent.
Highly effective disease-modifying therapies are defined as those that have
demonstrated superiority to a modestly effective disease-modifying therapy in
776 JUNE 2019

FIGURE 10-1
Starting, stopping, or switching multiple sclerosis disease-modifying therapies in women of
childbearing potential. This figure depicts best practice recommendations to balance
optimal disease control while minimizing risks to the offspring in women who want to get
pregnant or are of childbearing age and not on reliable contraception. Teriflunomide is
highly teratogenic (US Food and Drug Administration [FDA] pregnancy Category X) and should
be rapidly eliminated in women who desire pregnancy before stopping contraception.
Fingolimod and natalizumab cessation can cause rebound relapses; thus, the author
recommends switching women to rituximab before stopping contraception. Rituximab
infusions before conception appear safe, but data on risk of spontaneous abortions are
lacking. Dimethyl fumarate exposure in animal models is not safe and human data are
lacking, thus the author recommends stopping before conception. Alemtuzumab frequently
causes autoimmune thyroiditis and subclinical antithyroid antibody formation, which, in
turn, could result in adverse pregnancy/infant outcomes, although human data are scarce.
© 2018 Kaiser Permanente.
head-to-head randomized controlled trials or have demonstrated potency in

randomized controlled trials via testing only high-risk patients (alemtuzumab,
fingolimod, natalizumab, rituximab/ocrelizumab). Modestly effective agents are
defined as those that failed to demonstrate superiority in efficacy in head-to-head
randomized controlled trials (glatiramer acetate, interferon beta, dimethyl fumarate,
teriflunomide). The author does not use mitoxantrone because of cardiac toxicity
and secondary malignancies, although this would be classified as highly effective
for potency as it demonstrated efficacy in patients with very aggressive disease.

Once a patient has been assessed and it is determined whether a highly

effective treatment should be started or continued to reduce her risk of long-term
disability, it is time to inquire about her plans to start a family and birth control.
I ask my patients of childbearing age, “Are you planning on having children in
the next 2 years?” If the answer is no, I ask, “What kind of birth control are you
using?” If they are not on reliable birth control, I explain that this influences
which medication I would recommend for them. Reliable birth control is defined
as hormonal contraceptives, an intrauterine device, surgical sterilization, or
same-sex partnership. The withdrawal method, spermicide gel, and statements
such as “I don’t have a boyfriend” and “I can’t get pregnant” (unless infertility
is documented by an obstetrician) are not reliable forms of birth control.
Discussing how contraception choice impacts disease-modifying therapy
selection is important in helping patients make an informed decision. In some
instances, women will opt to start reliable birth control so they can take an oral
disease-modifying therapy or natalizumab.
It is important to ask patients about changes in pregnancy plans and
contraceptive use regularly, particularly women on oral disease-modifying
therapies or natalizumab. For women using oral contraceptives, the author
recommends checking to make sure they are refilling their contraceptive
prescriptions at the same time they request refills on their oral disease-modifying
therapies, in addition to inquiring at clinic visits. Unplanned pregnancies in
women with MS are common, even in randomized controlled trials, most of
which require that patients use at least two forms of birth control. In the author’s
practice, teriflunomide is almost never prescribed to women of childbearing
potential for three reasons: (1) the relatively high risk of teratogenicity with
accidental pregnancy exposure (FDA pregnancy Category X), (2) the availability
of safer alternatives, and (3) the acknowledgment that continuously assuring use
of reliable birth control is laborious and not fail-proof.16 The author also avoids
use of teriflunomide in men who could potentially father a child because the drug
is secreted in the semen, thereby potentially exposing the fetus.
Multiple Sclerosis Treatment for Women Trying to Conceive or Not on

Reliable Birth Control
Contemporary population-based studies show that more than 40% of women
with MS who became pregnant were not on any MS disease-modifying therapy
in the 12 months before conception (K. Fink, MD, written communication,
August 2018).2,16 Being untreated increased neither their risk of relapses during
pregnancy nor postpartum relapses.4 This is consistent with the preference of
many women to avoid even the slightest risk of adverse outcomes for their
babies. Being untreated before and during pregnancy and during the postpartum
period is seen most often in women with a history of mild MS disease activity,
which is defined as having little to no disability, infrequent relapses, and low
lesion burden load on MRI, or those who required only modestly effective
disease-modifying therapies to control their disease activity in the past. Thus, if
a woman with mild MS informs her neurologist that she wishes to get pregnant
and avoid all fetal risks, the author reasons that the most prudent approach is
to stop her modestly effective disease-modifying therapy at the time she stops
contraception. The one exception is if the patient is taking teriflunomide; if so,
the patient should continue her contraception until a rapid elimination procedure
has been undertaken and the drug is no longer detectable.17 In the author’s
778 JUNE 2019

experience, many of the women who stopped disease-modifying therapies with KEY POINTS
prior pregnancies and want to have subsequent children opt to remain untreated
● It is important to ask
and may not even seek neurologic care between pregnancies. patients with multiple
In practice, glatiramer acetate and interferon beta are the author’s preferred sclerosis about pregnancy
modestly effective disease-modifying therapies for women who are planning a plans and contraception
pregnancy within the next 2 years or not on reliable birth control. This is because regularly.
accidental first-trimester exposure with glatiramer acetate or interferon beta
● Many patients with
appears safe and both disease-modifying therapy types are easy to use in general multiple sclerosis have
practice settings, as interferon beta requires only minimal additional safety adequately controlled
monitoring and glatiramer acetate requires none. For glatiramer acetate, disease without any
accidental first-trimester pregnancy exposure has now been firmly established as treatment or only modestly
effective disease-modifying
safe, with more than 4000 exposed human pregnancies.18 Accidental interferon therapies. If these patients
beta exposure is similarly safe, with more than 1200 exposed human pregnancies, start trying to conceive,
although a slight risk of decreased infant birth weight has not been fully excluded.19,20 discontinuing treatment, if
Thus, if a woman is very risk averse, stopping glatiramer acetate or interferon any, is prudent.
beta at the time of stopping contraception can be recommended, but she should ● Glatiramer acetate and
be reassured that if she does get pregnant accidentally on either of these drugs, interferon beta are the
there is no reason for alarm. In women who are not so risk averse, glatiramer preferred modestly
acetate and interferon beta can be safely continued until they find out they are effective disease-modifying
therapies for women who
pregnant. No additional obstetric or neonatal care is required (FIGURE 10-2).
are not on reliable birth
Rarely, a clinician may continue glatiramer acetate (or interferon beta) control.
throughout a patient’s pregnancy. The author does not recommend this for two
reasons. First, no disease-modifying therapy has been shown to be safe for use ● Consider a B-cell–
throughout pregnancy. Second, it seems illogical, because the protective effect depleting drug if a highly
effective disease-modifying
of pregnancy on MS disease activity far outweighs the effect of glatiramer acetate therapy is needed for a
or interferon beta in both historical6 and contemporary cohorts.1,4 woman who is trying to get
The author recommends stopping dimethyl fumarate at the time of stopping pregnant or not on reliable
contraception because of the uncertain but plausible risks. Human data are too birth control. Assess for
pregnancy before each
sparse to draw conclusions (known pregnancy outcomes in 58 of 104 exposed infusion and do not infuse
pregnancies).21 Animal studies show that first-trimester exposure caused delayed the medication if the patient
development, including small birth size, spontaneous abortions, and delayed is currently pregnant.
ossification, and exposure during the third trimester and lactation caused
decreased fetal viability, decreased fetal growth, and impaired learning and
memory, albeit at twice the recommended human dose.22
In women who require a highly effective disease-modifying therapy to control
their disease while trying to get pregnant or not on reliable birth control,
rituximab is the author’s preferred choice because (1) it is not associated with
rebound disease activity, (2) it has prolonged protective effects even after the
medication has been eliminated, (3) it is easy to avoid accidental pregnancy
exposure by asking about last menstrual period and, if necessary, performing
a urine pregnancy test shortly before each infusion, and (4) it does not appear to
be teratogenic or otherwise adversely affect pregnancy outcomes, although
data here are from less than 400 exposed pregnancies (K. Fink, MD, AM
Langer-Gould, MD, PhD, unpublished data, August 2018).23,24
The typical rituximab dose used in Sweden and in Kaiser Permanente
Southern California (through a collaborative Patient-Centered Outcomes
Research Institute [PCORI] observational study) is 500 mg or 1000 mg for the
first infusion and 500 mg every 6 months thereafter, because clinical experience
in Sweden showed that a 500 mg maintenance dose was equally effective and
safer than 1000 mg every 6 months.25 The author recommends checking a urine

FIGURE 10-2
Recommendations for additional maternal, fetal, and neonatal monitoring if first-trimester
exposure to multiple sclerosis (MS) disease-modifying therapy has occurred. This figure
depicts how to monitor for potential pregnancy and neonatal complications in the event a
woman finds out she is pregnant after first-trimester exposure to MS disease-modifying
therapy has already occurred. Teriflunomide should be stopped and a rapid elimination
procedure initiated immediately; the mother should be counseled about the increased risk of
teratogenicity. A high-risk obstetrics specialist should follow the patient. Fingolimod should
be stopped immediately and pregnancy monitored for maternal rebound disease activity and
malformations in the infant. If a steroid-refractory rebound relapse occurs, the author
recommends contacting a neurologist who is an expert in MS and pregnancy to aid in
treatment decisions. The author also strongly recommends contacting a neurologist who is an
expert in MS and pregnancy if a woman gets pregnant on natalizumab to aid in the decision of
stopping treatment or continuing at prolonged dosing intervals through the second trimester
of pregnancy. If natalizumab is continued, a neonatologist should be present at delivery to
monitor for hematologic abnormalities and their complications (eg, thrombocytopenia and
bleeding). Little is known about the risks of accidental first-trimester rituximab exposure, but
it is plausible that it could result in infant B-cell depletion. Thus, the author recommends
neonatal screening for B-cell depletion and pancytopenia; if present the Centers for Disease
Control and Prevention (CDC) should be contacted to determine whether the infant
vaccination series should be adjusted.
780 JUNE 2019

pregnancy test in women of childbearing potential before rituximab infusion and
holding infusions during pregnancy. As with other monoclonal antibody drugs,
active transport across the placenta of rituximab will begin in the second
trimester and increase rapidly through the remainder of pregnancy. With an
estimated half-life of 18 to 22 days, rituximab should be cleared by 90 to 110 days
after the last dose. Thus, the author recommends waiting 1 month after each
infusion to ensure that the drug is cleared before placental transfer begins in the
second trimester, although should a woman become pregnant even within 1 week
after the last infusion, there is no cause for alarm. The author does not use
rituximab during pregnancy unless absolutely necessary (ie, a severe relapse), as it
causes infant B-cell depletion,23,24 which could theoretically increase the risk of
neonatal infections and inadequate vaccine responses. It should be noted that the
FDA label recommends stopping rituximab 1 year before conception but provides
no rationale for this.26 The author does not recommend such a long washout, as
it may increase the risk of return of MS disease activity in the postpartum year.
Some insurance carriers do not cover rituximab; in these instances, the author
recommends using the lowest effective dose of ocrelizumab or other similar
anti-CD20 B-cell–depleting agent. Human experience with ocrelizumab and
pregnancy is scant,27 and animal data raise concern that infusion during
pregnancy at currently recommended ocrelizumab doses may result in more fetal
harm than reported with rituximab in humans. The FDA package insert states,
“Following administration of ocrelizumab to pregnant monkeys at doses similar
to or greater than those used clinically, increased perinatal mortality, depletion
of B-cell populations, renal, bone marrow, and testicular toxicity were observed
in the offspring in the absence of maternal toxicity.”28
The author does not recommend fingolimod in women who are not on reliable
birth control, primarily because of increased risk of adverse fetal outcomes
with accidental exposure. During the clinical development program, major
malformations/fetal toxicities were detected in 6 of 41 women (14.6%) who
attempted to carry their pregnancies to term, which far exceeds the expected
rate of 3% to 4%. The fetal toxicities observed resulted in four pregnancy
terminations and were consistent with animal model studies, including tetralogy
of Fallot, failure of fetal development, and intrauterine death, including a baby
with acrania, a severe neural tube defect.29 The manufacturer has an ongoing
pregnancy registry with more than 800 pregnancies, but outcomes are known for
less than 400. The manufacturer concludes that there is no increased risk of
major malformations but reports outcomes only on live births, not those that
were terminated because of major malformations or intrauterine death.30
Thus, until high-quality, reassuring data are available, the author continues to
recommend continuing effective contraception until 2 months after cessation
of fingolimod.
In the rare instance in which a woman continues to have uncontrolled central
nervous system inflammation while treated with natalizumab and again when
switched to rituximab/ocrelizumab, the author would consider using
alemtuzumab before pregnancy. Alemtuzumab is also a monoclonal antibody;
negative pregnancy tests are required before each infusion, thereby minimizing
risk of fetal exposure. The main concern with prepregnancy exposure to
alemtuzumab is the relatively common risk of autoimmune thyroiditis
(approximately 40%). Maternal thyroiditis can result in increased fetal risks,
including low birth weight, preterm birth, preeclampsia, and neurocognitive

impairment. Even in euthyroid women, antithyroid antibodies are frequently

detected, which could result in neonatal Graves disease via transplacental
transport of maternal autoantibodies. Severity of neonatal Graves disease can
range from mild self-limited illness to neurocognitive impairment and even
death. The onset of autoimmune thyroiditis following alemtuzumab varies
widely, usually starting at 6 months and peaking 36 months after the first
infusion.31 Thus, the author recommends thyroid hormone and autoantibody
screening before pregnancy and frequent monitoring during pregnancy and the
early postpartum period. The author recommends that patients treated with
alemtuzumab should delay conception until at least 12 months after the last dose,
because the development of other autoimmune diseases that may require
treatments incompatible with pregnancy peak around this time.32
CASE 10-2 A 26-year-old woman with relapsing-remitting multiple sclerosis (MS)

presented in follow-up. She had been diagnosed with MS at the age of 18;
multiple modestly effective disease-modifying therapies were
prescribed but failed to control her MS, and she had frequent relapses
and new lesions on MRI. At age 20, she was started on natalizumab. After
2 years of being relapse-free and having no new lesions on MRI
(FIGURE 10-3A), she accidentally became pregnant. Natalizumab was
stopped, with her last dose at approximately 8 to 10 weeks of gestation.
During the late second trimester (4.5 months after her last dose of
natalizumab), she had a relapse with significant unilateral leg weakness
requiring her to use a cane. She was treated with IV methylprednisolone
with some improvement; this was the most severe relapse she had ever
had. In her early third trimester (1 month later), she had a second
pregnancy relapse (optic neuritis) that was treated with IV
methylprednisolone with complete resolution. She had a normal labor
and delivery. Her baby had normal Apgar scores but was small for
gestational age. She resumed natalizumab within 2 weeks following
delivery and remained relapse-free. She breast-fed for only 3 weeks. An
MRI obtained 1 month postpartum showed a dramatic increase in lesions
(FIGURE 10-3B).
At 4 years of age, her child had met all normal neurocognitive
milestones. The mother’s Expanded Disability Status Scale (EDSS) score
was 2.5, and she was limited by fatiguing weakness in her leg.
782 JUNE 2019

Risk of Rebound Relapse After Cessation of Fingolimod or Natalizumab
It has recently become clear that pregnancy does not protect against the risk of
return of disease activity or rebound relapses after cessation of fingolimod or
natalizumab, although the magnitude of this risk is uncertain. Return of disease
activity in the year following cessation of fingolimod or natalizumab is common,
occurring in more than 40% of patients; in some instances, it can be very severe,
even life-threatening.9,33 Severe rebound relapses during pregnancy have been
reported as early as 1 month after stopping fingolimod10,11 and 3 to 4 months after
stopping natalizumab.9 In nonpregnant patients, disease activity usually returns
4 to 7 months after natalizumab cessation.34
Cases of severe rebound disease activity, particularly during pregnancy, are
frightening (CASE 10-2), yet it remains unclear how many women are at risk.
FIGURE 10-3
Sagittal fluid-attenuated inversion recovery (FLAIR) MRIs of the patient in CASE 10-2 showing
natalizumab rebound disease activity during pregnancy. A, Prepregnancy; MRI shows minimal
signs and the patient had no disability and an Expanded Disability Status Scale (EDSS) score of
1.5. B, 1 Month postpartum; the patient had unilateral leg weakness and an EDSS score of
4.0. C, 10 Months postpartum; the patient had fatiguing leg weakness and an EDSS score of 2.5.
This case illustrates that pregnancy does not protect against natalizumab COMMENT
rebound relapses and that multiple relapses can occur. The severity of
relapses in this patient was not catastrophic, and they responded to
corticosteroid treatment. But exposing a baby to multiple courses of
corticosteroids has been associated with low birth weight, which, in turn,
has been associated with multiple complications. Had her relapses not
responded to corticosteroids, resuming natalizumab during pregnancy may
have been necessary. Resuming natalizumab as soon as possible after
delivery restored her excellent disease control. A brain MRI obtained
10 months postpartum showed lasting damage (FIGURE 10-3C), and some leg
weakness persisted. The optimal approach would have been to switch her
to rituximab before conception to prevent return of disease activity
following cessation of natalizumab.

Recent studies from the German Multiple Sclerosis and Pregnancy Registry
and the Italian multicenter cohort suggest that following cessation of natalizumab,
pregnancy relapses that require treatment with steroids are common (42% in the
German Multiple Sclerosis and Pregnancy Registry35 and 36.5% in the Italian
multicenter cohort33), and severe relapses with resulting permanent disability
occur in less than 15% (K. Hellwig, MD, written and oral communication, August
2018). These are likely overestimations of the true risk in community-based
settings, as both studies recruited women with more severe disease activity.
For women treated with fingolimod, much less is known about the incidence of
pregnancy-related relapses aside from case series affirming that they can be
catastrophic.10,11 Recent findings from the German Multiple Sclerosis and
Pregnancy Registry suggest that the risk of relapses occurring during pregnancy
following cessation is 27%.36 In Kaiser Permanente Southern California and Sweden,
we have too few women who were on fingolimod around the time of conception to
draw conclusions. Rare use of fingolimod in women of childbearing potential seems
to reflect widespread awareness among neurologists of its teratogenic potential.17
In a case series of 12 women who developed severe steroid-refractory
natalizumab rebound relapses that required resuming natalizumab infusions
during pregnancy, 10 of the 13 infants had self-limited hematologic abnormalities
or hyperbilirubinemia, or both, including one case of thrombocytopenia with an
asymptomatic intracranial hemorrhage. Most of these women had stopped
natalizumab when they found out they were pregnant.9 These hematologic
abnormalities are consistent with the mechanism of action of natalizumab and
high likelihood of fetal exposure with second- and third-trimester infusions.
Preventing Rebound Relapses

For women who are currently well-controlled on fingolimod or natalizumab and
want to get pregnant, the author recommends switching them to rituximab
before stopping their birth control to prevent rebound disease activity37 and
minimize risk to the child. Although the magnitude of risk of incurring a severe
relapse during pregnancy is uncertain (currently estimated at 10%),38 treating
relapses during pregnancy with high-dose corticosteroid infusions, resuming
natalizumab, or starting rituximab all appear to carry higher risks than prepregnancy
exposure to rituximab. With this approach, fewer than 1% of pregnancies occur
annually while a woman is still treated with fingolimod or natalizumab.16
For women who accidently become pregnant on natalizumab, the author
recommends consulting with a neurologist who is an expert in MS and pregnancy
as the evidence of balancing maternal and fetal risk is rapidly evolving
(FIGURE 10-2). Natalizumab exposure during early pregnancy does not appear to
be fetotoxic and should not be a cause for alarm. A natalizumab exposure
pregnancy registry tracked outcomes in 96.2% of 369 pregnancies and found
that accidental first-trimester natalizumab exposure is associated with a slightly
higher risk of major and minor malformations (5.05%) but without a clear
pattern.39 This is consistent with the lack of fetotoxicity in animals as well.
The expert may recommend continuing natalizumab at 6- to 8-week extended
intervals, with the last dose occurring at less than 30 weeks, or stopping it,
considering a woman’s prenatalizumab disease severity, prior attempts to
stop natalizumab, and her preferences. For women who accidentally become
pregnant on fingolimod, the author recommends immediate cessation of the
drug because of potential teratogenic effects.
784 JUNE 2019

It is important to remember that steroid-refractory rebound relapses KEY POINTS
during pregnancy or the postpartum period are treatable. The author has
● Pregnancy does not
seen two cases, and is aware of other reports, in which the treating neurologists protect against the risk of
were unaware of this and the patients died.40,41 Treatment options for severe return of disease activity or
steroid-refractory rebound relapses occurring during pregnancy include rebound relapses after
plasma exchange and, if necessary, resuming natalizumab or starting rituximab. cessation of fingolimod or
natalizumab.
The author strongly recommends consulting a neurologist who is an expert
in MS and pregnancy to provide the most up-to-date treatment options. ● To prevent return of
For women who are very risk averse and do not want to incur the low but disease activity or rebound
uncertain risks of prepregnancy rituximab treatment, the author recommends relapses during pregnancy
stopping natalizumab or fingolimod and continuing contraception until the risk after cessation of
fingolimod or natalizumab,
of rebound relapse has passed (6 to 12 months) before trying to conceive. Rituximab consider switching women
could be started if a rebound relapse occurs during this washout period. It is to a B-cell–depleting
important to note that other treatments, including glatiramer acetate, interferon therapy before conception.
beta,42 and dimethyl fumarate,43,44 do not appear to reduce the risk of
● Fingolimod and
rebound relapses. natalizumab rebound
relapses are treatable, even
Breast-Feeding, Postpartum Relapses, and Multiple Sclerosis if they occur during
Disease-Modifying Therapies pregnancy.
The plethora of short- and long-term infant health benefits, particularly with
● Encourage and support
prolonged and exclusive breast-feeding, include reduced risk of infections, breast-feeding for optimal
asthma, obesity, and type 1 and type 2 diabetes mellitus.7 Maternal health benefits infant and maternal health.
of breast-feeding include reduced risk of obesity, type 2 diabetes mellitus,
breast and ovarian cancer, and metabolic syndrome.7 These benefits have become ● Glatiramer acetate and
interferon beta pose
clear over the past 20 years, during which women with MS had been actively exceedingly low risk to
discouraged to breast-feed by many clinicians in order to resume infants via breast milk
disease-modifying therapies,1 causing the rates of breast-feeding to drop in exposure and can be
women with MS compared with their contemporaries.1,3,4 This overly resumed when desired.
conservative approach was adopted by most clinicians because of the FDA’s
official position that breast-feeding is not recommended while the patient is on
any disease-modifying therapy because of the lack of human data, in many
instances without any biologically plausible reason. Some clinicians also believed
that resuming disease-modifying therapies would reduce the risk of relapses in the
early postpartum period.1 Over the past decade, it has become increasingly clear
that this approach is flawed for several reasons:
u No evidence has shown that breast-feeding increases the risk of postpartum relapses,
even when compared to women who resume medications1,4,45
u Exclusive breast-feeding appears to reduce the risk of postpartum MS activity, even when
compared to women who do not breast-feed or resume disease-modifying therapies4
u Resuming glatiramer acetate or interferon beta early in the postpartum period does not
reduce the risk of relapses within the first 6 months4,45,46
u Exceedingly low biological plausibility exists that glatiramer acetate and interferon beta
exposure through breast milk would adversely affect the infant47,48
u Low biological plausibility exists that natalizumab,49,50 rituximab,51 or ocrelizumab
exposure through breast milk would adversely affect the infant52
In addition, it is not clear whether the risk of early postpartum relapses

described in a group of women who were diagnosed with highly active disease
before pregnancy6 in the 1980s and early 1990s remains in today’s women, who,

TABLE 10-1 Factors That Determine Compatibility of Multiple Sclerosis Disease-

Modifying Therapies With Breast-Feeding and Summary Recommendation
Disease- Compatible
Modifying Detectable in Transluminal Expected Effects With
Therapy Description Breast Milk? Transfer?a With Infant Exposureb Lactation?
Large molecules
Glatiramer Large molecule Not done, unlikely Yes, as with any None Yes
acetate (4.7–13 kDa) amino acid
heterogeneous
strings of amino acids
Interferon beta Large molecule, 0.0006% relative Exceedingly low Flulike symptoms Yes
protein infant dose
Monoclonal
antibodies
Natalizumab IgG4 <1:200 of maternal Exceedingly low Infections,c impaired Yes, if

serum level; 2–5% vaccine responses or needed
relative infant dose disseminated disease
from live vaccines,c
hepatitis,c anemiac
Rituximab IgG1 Approximately Exceedingly low B-cell depletion, Yes, if

1:240 of maternal infections,c impaired needed
serum level vaccine responses or
disseminated disease
from live vaccinesc
Small molecules
Dimethyl Immediately Animals yes/ High Neurocognitive No

fumarate metabolized to humans not done impairment,
monomethyl fumarate but highly likely in lymphopenia,
(129 Da), low protein high amounts gastrointestinal upset,
binding infections,c vaccine
responsesc
Fingolimod Highly protein bound, Animals yes/ Moderate Infections,c vaccine No

long half-life humans not done responses,c
but highly likely in cardiovascular
low amounts effects,c pulmonary
toxicity,c hepatitisc
Teriflunomide Inhibits pyrimidine Animals yes/ High Pancytopenia, No

synthesis, highly humans not done infections, vaccine
protein bound, very but highly likely responses,c
long half life hepatotoxicity, later-
life neoplasmsc
IgG = immunoglobulin G.
a
Likelihood of transfer of disease-modifying therapy from infant’s gut into its circulation assuming a large amount of disease-modifying therapy is
present in breast milk.
b
Assumes large amounts of the disease-modifying therapy have entered the infant’s circulation.
c
Plausible but unknown risk.
786 JUNE 2019

in general, are diagnosed earlier and have milder disease. Other than rebound KEY POINT
relapses, most postpartum relapses, if they occur, do not appear to affect
● Natalizumab and
long-term prognosis.5 rituximab have very low
TABLE 10-1 summarizes the biological plausibility of excretion of disease- theoretical risks to infants
modifying therapies into human breast milk, transluminal transfer from the with breast milk exposure
infant’s gut into its bloodstream, and the potential effects on the infant if a only and may be resumed
during lactation if
significant amount were to enter the infant’s circulation and provides a
necessary.
recommendation based on this information. Several factors influence a drug’s
potentially harmful effects on the infant if exposure occurs through breast milk
only (ie, no pregnancy exposure):
u The possibility of excretion in significant amounts into the breast milk, as is likely
for small-molecule disease-modifying therapies (eg, fingolimod, dimethyl fumarate,
teriflunomide), particularly those with low protein binding (eg, dimethyl fumarate).48
u The possibility of transport from the infant’s gut into its bloodstream. This is common
for oral agents (fingolimod, dimethyl fumarate, teriflunomide), whereas transluminal
transport is exceedingly unlikely for IgG drugs (rituximab, ocrelizumab, natalizumab),
particularly in full-term infants.52
u The potentially harmful effects on the developing systems of the infant in addition to
the known toxicities in adults. Given the highly plausible effects of the oral agents on
the infant’s developing neurocognitive, immune, cardiovascular, or pulmonary systems
and safer alternative disease-modifying therapies, the author never recommends
the use of oral disease-modifying therapies during breast-feeding.
The author’s recommendations to continue breast-feeding when resuming

natalizumab or rituximab in women with active disease, rather than discouraging
breast-feeding when resuming treatment, are consistent with those of many
gastroenterologists50,53 and rheumatologists.8 Large molecules, including
monoclonal antibodies, are unlikely to be excreted in breast milk in significant
amounts and, even when low levels are detectable, are exceedingly unlikely to
make it into the baby’s circulation. This is supported by limited human data
for MS disease-modifying therapies.47,50,51 In addition, a 2018 study of women
with inflammatory bowel disease treated during lactation with monoclonal
antibodies (primarily tumor necrosis factor-a antagonists) showed that low drug
levels were detectable in breast milk in some women, but no increased risk of
infections or developmental delay was seen in their babies.50 This is consistent
with the exceedingly low biological plausibility of adverse infant outcomes with
monoclonal antibody exposure during lactation.
In practice, most of the author’s patients prefer to breast-feed initially
without resuming medications. At 6 to 12 months postpartum, when breast milk is
no longer the baby’s primary source of nutrition, these women can be encouraged
to resume glatiramer acetate or interferon beta while lactating, as disease activity
usually returns by 2 years postpartum45,46 and these disease-modifying therapies
have a delayed onset of action. For women who had highly active disease in the
year before pregnancy or had a relapse during pregnancy and prefer to
breast-feed, more frequent noncontrast MRI monitoring should be considered as
they are at higher risk of postpartum relapses.1,6
Treating Relapses During Pregnancy or Breast-Feeding

Short courses of high-dose methylprednisolone are the preferred first-line
treatment option for relapses occurring during pregnancy or breast-feeding.
Because a slight increased risk of adverse fetal outcomes, including cleft palate

and low birth weight from corticosteroid exposure, cannot be excluded,8 the
author recommends their use only for clinically significant relapses and first-
trimester exposure should be avoided, if possible.
Very small amounts of methylprednisolone are detectable in breast milk,
declining rapidly within 12 hours after infusion54; thus, it is not necessary to stop
breast-feeding. The author advises women to wait 3 to 4 hours after completion
of the infusion before nursing or, for the very risk averse, to “pump and dump”
for 24 hours after infusions.
For disabling steroid-refractory relapses, the author recommends plasma
exchange. Risks associated with plasma exchange are low (eg, thromboembolic
events) and not affected by pregnancy or lactation.55
MRI and Gadolinium Use During Pregnancy and Lactation

The author does not recommend routine MRIs during pregnancy because the
treatment plan during pregnancy would not be altered based on the MRI
results alone and gadolinium should never be given during pregnancy because
it is not safe. A study of more than 1.4 million pregnancies has shown that
MRI is safe, even in the first trimester, but gadolinium at any time during
pregnancy is not. Gadolinium increases the risk of stillbirth; neonatal death;
and a wide array of inflammatory, rheumatologic, and infiltrative skin
conditions.56
During lactation, MRI disease activity should be monitored periodically in
women with relapses during pregnancy or highly active disease before
pregnancy, but gadolinium should be avoided as it is not necessary to assess
disease activity. Small amounts of gadolinium are detectable in breast milk.
Whether infant exposure to these small amounts is safe has not been established,
although the theoretical risk is low. This has led most professional societies to
conservatively recommend pumping and dumping for 24 hours after infusion57
when gadolinium administration is required.
Symptomatic Multiple Sclerosis Treatments, Pregnancy, and Lactation

Migraines, fatigue, and neuropathic pain are quite common in young women
with MS. The fetal risks of some commonly used symptomatic medications
outweigh the fetal risks of many MS disease-modifying therapies. The use of
valproate, topiramate, methylphenidate, and amphetamines should be avoided
in women who are trying to conceive or not on reliable birth control unless
absolutely necessary. Modafinil should also be avoided as it poses an unknown
risk. When necessary, tricyclic antidepressants and selective serotonin reuptake
inhibitors (SSRIs) are generally considered safe, although infants can have
withdrawal symptoms with later pregnancy exposure. Gabapentin is a safer
alternative than carbamazepine or baclofen for neuropathic pain, and modest
caffeine intake is a safer alternative for fatigue than stimulants or modafinil.
Good clinical practice recommendations include monotherapy with the lowest
possible dose, discontinuing treatment if risk of relapse of the condition is low,
and consulting obstetrics and other specialists for other treatment options.
Multiple Sclerosis Treatments and Effectiveness of Hormonal

Contraceptives
Modafinil, but not disease-modifying therapies, may decrease the effectiveness
of hormonal contraceptives.58
788 JUNE 2019

Fertility Treatments and Multiple Sclerosis
Women with MS who need fertility treatment should be treated according to the
recommendations of their reproductive specialists. Small case series had raised
concerns that gonadotropin-releasing hormone agonists (as opposed to antagonists)
may increase risk of relapse; these concerns have not been substantiated and were
most likely due to confounding, as the effect was seen only in women with higher
prepregnancy relapse rates in whom the fertility treatment was unsuccessful.59
For women who require treatment with MS disease-modifying therapies
during prolonged periods of fertility treatments, the author usually recommends
glatiramer acetate or, if a highly effective treatment is needed, rituximab.
Rituximab has been used successfully to achieve pregnancies in women with
recurrent miscarriages due to antiphospholipid antibody syndrome.60,61
Fatherhood, Multiple Sclerosis, and Multiple Sclerosis Disease-Modifying

Therapies
Teriflunomide is detectable in human semen, although it is unclear whether this
impacts fertility or fetal development. Until more is known, the FDA recommends
that males taking teriflunomide should use effective contraception.17 In
animal studies of other MS disease-modifying therapies, male fertility was not
affected. Risk factors for low sperm counts that may occur more frequently in
males with MS include marijuana use and, rarely, low testosterone from
hypothalamic involvement.
CONCLUSION
It is now possible to successfully control disease activity in the majority of
women with MS throughout pregnancy and the postpartum period while
simultaneously minimizing harm to the infant by promoting breast-feeding
and avoiding exposure to certain disease-modifying therapies. This has become
possible because of the availability of numerous disease-modifying therapies
and the efforts of many research communities. The optimal timing to resume
disease-modifying therapies in the postpartum period and how best to avoid
and treat severe relapses during pregnancy and the postpartum period is still
undetermined, particularly in women who become pregnant accidently while on
natalizumab or fingolimod. More research is needed to understand how often
this occurs and how to identify those women at highest risk. Pregnancy registries
and large health care databases should be leveraged to address these questions, as
well as to assess the safety of drugs during lactation, and to track long-term
infant and maternal health outcomes.
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792 JUNE 2019

Pediatric Central Nervous REVIEW ARTICLE

System Demyelinating CONTINUUM AUDIO
INTERVIEW AVAILABLE
ONLINE
Diseases
By Tanuja Chitnis, MD, FAAN
CITE AS:
ABSTRACT
PURPOSE OF REVIEW: This article provides an up-to-date summary of the 2 0 1 9 ; 2 5 (3, MULTIPLE SCLEROSIS
categories, diagnosis, and management of pediatric demyelinating AND OTHER CNS INFLAMMATORY
disorders.
RECENT FINDINGS: Understanding of the diverse spectrum of pediatric Dr Tanuja Chitnis, 55 Fruit St,
demyelinating disorders, including monophasic and multiphasic forms, ACC708, Massachusetts
General Hospital, Boston, MA
has improved. Pediatric multiple sclerosis (MS) is the most common 02114, tchitnis@rics.bwh.
demyelinating disorder in children, and recent genetic and environmental harvard.edu.
risk research has clarified that pediatric MS is on the same continuum of
disease as adult MS. Recent advances in the treatment of pediatric MS Dr Chitnis serves on scientific
include clinical trials leading to regulatory agency–approved treatments. advisory boards for Biogen,
Celgene Corporation,
The identification of myelin oligodendrocyte glycoprotein and F. Hoffmann-La Roche Ltd,
aquaporin-4 antibodies in children has been a major advance, allowing Novartis AG, and Sanofi
for appropriate treatment and management of these syndromes. Genzyme and as a consultant
for Biogen. Dr Chitnis receives
SUMMARY: Antibody testing is now helping to define subtypes of the Consortium of Multiple
pediatric demyelinating disorders, including myelin oligodendrocyte Sclerosis Centers; the
Department of Defense; EMD
glycoprotein–seropositive and aquaporin-4–seropositive cases that are Serono, Inc; the Guthy-Jackson
distinct from pediatric MS. Treatments for pediatric MS are being Charitable Foundation;
Mallinckrodt Pharmaceuticals;
evaluated in clinical trials.
the National Institutes of Health
(R01AG057505); the National
Multiple Sclerosis Society;
Novartis AG; Octave Bioscience;
INTRODUCTION and Verily Life Sciences LLC.
S
ignificant progress has been made in the field of pediatric central
UNLABELED USE OF
nervous system (CNS) demyelinating disorders over the past 5 years. PRODUCTS/INVESTIGATIONAL
These disorders include acute disseminated encephalomyelitis USE DISCLOSURE:
(ADEM), multiple sclerosis (MS), neuromyelitis optica spectrum Dr Chitnis discusses the
unlabeled/investigational use of
disorder (NMOSD), and clinically isolated syndromes. Major glatiramer acetate, interferon
advances in the past 5 years include improved diagnostic criteria, antibody-based beta, natalizumab, and rituximab
for pediatric multiple sclerosis
biomarkers, predictors of a multiphasic course, and treatment advances for these
and mycophenolate mofetil for
disorders, which are summarized in this article. Recent work on the genetic and myelin oligodendrocyte
environmental risk factors for pediatric MS points to similarities with adult glycoprotein antibody–
associated disorders and
disease. Immunobiological studies for MS suggest a continuum of disease with neuromyelitis optica spectrum
adult disease; however, both clinical and immunobiological features point to a disorder in children.
more inflammatory profile in children.1,2 Characterizations of the pediatric
phenotypes associated with aquaporin-4 (AQP4) antibody–seropositive NMO © 2019 American Academy
and myelin oligodendrocyte glycoprotein (MOG) antibody–associated disease of Neurology.

PEDIATRIC CNS DEMYELINATING DISEASES
KEY POINTS have demonstrated diverse phenotypes that differ from adult presentations,
which has relevance for both diagnostic and treatment considerations. Recent
● Major advances in
pediatric demyelinating
clinical trials and therapeutic cohort studies in pediatric MS have shed
disease in the past 5 years considerable light on the treatment response in this highly inflammatory disease
include improved diagnostic and established new paradigms for clinical trial design and conduct in children
criteria, antibody-based with neuroinflammatory disorders.
biomarkers, predictors of a
multiphasic course, and
treatment advances for CLASSIFICATION OF PEDIATRIC CNS DEMYELINATING DISEASES
these disorders. Recent Pediatric CNS demyelinating diseases are generally classified as either
work on the genetic and monophasic or multiphasic disorders. However, it is entirely possible that what
environmental risk factors
appears to be a monophasic episode can represent the first attack of a multiphasic
for pediatric multiple
sclerosis points to disorder. Initial attacks have been termed acute demyelinating syndromes or
similarities with adult clinically isolated syndromes and include optic neuritis, transverse myelitis, and
disease. other initial attack demyelinating syndromes. ADEM is another acute
demyelinating syndrome; it appears to have a pathophysiology that is distinct
● An important advance in
pediatric demyelinating
from clinically isolated syndromes. In contrast to clinically isolated syndromes,
disorders is the recognition ADEM rarely represents a first attack of MS in children. An important advance is
that an acute demyelinating the recognition that an acute demyelinating syndrome can represent the first
syndrome can represent the attack of not only MS but also NMOSD, MOG antibody–associated disease, and
first attack of not only
multiple sclerosis but also
other multiphasic disorders in children.3
neuromyelitis optica We now have a better understanding of predictors for a multiphasic disease
spectrum disorder course that can be seen at initial presentation. Identifying the location and
(NMOSD), myelin symptomatology of the presenting syndrome, as well as the presence of brain
oligodendrocyte
lesions, is an important key step both for managing the current attack and for
glycoprotein (MOG)
antibody–associated prognostication. Focal lesions in the optic nerve(s) may be unilateral or bilateral
demyelinating disease, and and may involve the optic chiasm. Myelitis may be focal or diffuse. The absence
other multiphasic disorders of brain lesions in the setting of optic neuritis or myelitis tends to favor a
in children.
monophasic course. A diffuse or longitudinally extensive transverse myelitis may
be seen in monophasic disorders (such as ADEM) and in MS and NMO in
children (R. Ameli, MD, and the US Network of Pediatric MS Centers,
unpublished data, 2019). The presence of encephalopathy is the hallmark of
ADEM. Common presentations of pediatric demyelinating disorders, symptoms,
and diagnostic considerations are presented in TABLE 11-1.
ACUTE DISSEMINATED ENCEPHALOMYELITIS

The incidence of ADEM was estimated to be 0.3 to 0.6 per 100,000 per year in
two population-based studies.4,5 The neurologic symptoms of ADEM generally
accrue rapidly over a period of a few days.6 Symptoms include motor or sensory
symptoms, ataxia, weakness, optic neuritis or other cranial nerve involvement,
seizures, spinal cord syndrome, and impairment of speech. Encephalopathy is a
critical component of the ADEM diagnosis.7 Acute evaluation of ADEM should
include a neurologic examination; gadolinium-enhanced MRI of the brain, spinal
cord, and orbits; evaluation for urinary retention; and CSF examination to rule
out infection, including cell count, protein, lactate, IgG index, and oligoclonal
bands (in CSF and serum) in addition to screening for infectious agents,
especially herpes simplex virus, Enterovirus, Epstein-Barr virus (EBV), and
Mycoplasma. Blood work should include white blood cell count, erythrocyte
sedimentation rate, C-reactive protein, and AQP4 and MOG antibodies.
The author’s practice is to start an infectious workup immediately; once initial
tests, including polymerase chain reaction (PCR) for herpes simplex virus,
794 JUNE 2019

return as negative, treatment with a 5-day course of IV steroids is started and
immediate transition to IV immunoglobulin (IVIg) or plasma exchange is
considered in refractory cases. A prednisone taper is generally instituted for
4 weeks, starting at 1 mg/kg/d and halving the dose every 5 days. Typically,
neurologic improvement occurs within days following initiation of steroid
treatment, and recovery to baseline is generally reached within a few weeks.8
Longer-term cognitive deficits have been observed involving executive function,
Common Presentations and Diagnostic Considerations of Pediatric TABLE 11-1

Demyelinating Disorders
Diagnostic Testing Differential Diagnosis Beyond

Presentation Key Symptoms Considerations Demyelinating Syndromes
Optic neuritis Blurred vision, loss of vision, Ophthalmoscopic examination, Sarcoidosis, Leber hereditary
pain on eye movement, MRI orbits and brain and optic neuropathy, vitamin B12
change in color vision cervical-thoracic spine with deficiency
gadolinium, visual evoked
potentials, MOG and
aquaporin-4 (AQP4) antibody
testing; consider CSF evaluation
especially if brain lesions;
optical coherence tomography
provides measures of retinal
damage
Transverse myelitis Subacute-onset arm or leg CSF evaluation; MRI cervical- Spinal cord infarction,
weakness, sensory changes, thoracic spinal cord, arteriovenous malformation,
sensory level, bowel/bladder urodynamic studies, MOG and acute flaccid myelitis, human
retention or incontinence, pain AQP4 antibody testing lymphotropic virus type I
(HTLV-I) myelopathy, systemic
lupus erythematosus, Sjögren
syndrome, vitamin B12
deficiency
Brainstem syndromes Cranial nerve involvement, CSF evaluation; MRI brain, Systemic lupus erythematosus,
ophthalmoplegia, ataxia, cervical-thoracic spine, and antiphospholipid antibody
nausea/vomiting orbits; serum and CSF antibody syndrome, brainstem glioma,
testing for autoimmune CLIPPERS, Miller Fisher
encephalitis, including NMDA syndrome
receptor antibody; serum and
CSF AQP4 antibody; serum
MOG antibody; GQ1b serum
antibody
Acute disseminated Encephalopathy, polyfocal CSF evaluation; MRI brain, Herpes simplex virus
encephalomyelitis neurologic symptoms, diffuse cervical-thoracic spine, and encephalitis, regional
(ADEM) central nervous system lesions orbits; serum and CSF antibody encephalitis/meningitis, central
testing for autoimmune nervous system vasculitis,
encephalitis, including NMDA autoimmune encephalitis,
receptor antibody; serum and leukodystrophies, lymphoma,
CSF AQP4 antibody; serum glioma, mitochondrial disorders
MOG antibody; magnetic
resonance spectroscopy
CLIPPERS = chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids; CSF = cerebrospinal fluid;
MOG = myelin oligodendrocyte glycoprotein; MRI = magnetic resonance imaging; NMDA = N-methyl-D-aspartate.

attention, verbal processing, lowered IQ scores, and behavioral changes,

especially in children younger than 5 years of age.9,10 Rarely, some children
will go on to have multiphasic disease, such as MS, NMOSD, or MOG
antibody–associated disease; prognostic factors are listed in TABLE 11-2.11–14
CLINICALLY ISOLATED SYNDROMES

Clinically isolated syndrome is a general term used for isolated demyelinating
syndromes. Clinically isolated syndrome events are heterogeneous; however,
several dominant clinical phenotypes exist.
Optic Neuritis
Optic neuritis is one of the most common presentations of acquired
demyelinating syndromes in childhood, with an estimated incidence of 0.2 per
100,000 (95% CI, 0.16–0.3) in Canada.15 In optic neuritis, inflammation of one or
both optic nerves leads to visual dysfunction. Unilateral presentation at onset
may be followed rapidly by bilateral involvement within a few weeks, or bilateral
involvement may occur at onset.16 Approximately two-thirds of children with
optic neuritis who are younger than 10 years of age present with bilateral optic
neuritis, whereas most children older than 10 years of age present with unilateral
optic neuritis.11 Pain with eye movement is reported in approximately 50%
of pediatric cases and thus does not consistently differentiate inflammatory
TABLE 11-2 Predictors of Multiphasic Demyelinating Disease in Children
Predictors of Multiphasic
Predictors of Myelin Oligodendrocyte
Neuromyelitis Optica Glycoprotein–Seropositive
Initial Presentation Predictors of Multiple Sclerosis Spectrum Disorder Disease
Optic neuritis Oligoclonal bands in CSF,4 presence Aquaporin-4 (AQP4) Persistent serum MOG
of MRI brain ovoid lesions,4,11 age >1011 antibody in serum or antibody
CSF
Persistently elevated titers of
MOG antibody
Transverse myelitis Female gender,5 presence of MRI AQP4 antibody in Persistent serum MOG
brain ovoid lesions,5 acute partial serum or CSF antibody
transverse myelitis12
Clinically isolated Female gender,13 age >10 years,6 AQP4 antibody in Persistent serum MOG
syndrome (all clinical postpubertal status in females,14 serum or CSF antibody
phenotypes) Epstein-Barr virus seropositivity,6 low
vitamin D levels,6 multifocal/
polyfocal symptoms at onset,13
fulfillment of 2010 McDonald MRI
criteria, presence of brain lesions
Acute disseminated Fulfillment of 2010 McDonald criteria, AQP4 antibody in Persistent serum MOG
encephalomyelitis Epstein-Barr virus seropositivity, low serum or CSF antibody
(ADEM) vitamin D levels, age >11 years,
postpubertal status
CSF = cerebrospinal fluid; MOG = myelin oligodendrocyte glycoprotein; MRI = magnetic resonance imaging.
796 JUNE 2019

from noninflammatory optic neuropathies in children. Other symptoms
include loss of or decreased visual acuity, decreased color vision, and visual
field deficits. Evaluation should include an ophthalmologic examination and an
MRI of the orbits and brain. Spine MRI should be included if the patient has any
myelopathic symptoms. Visual evoked potential testing and optical coherence
tomography may provide additional quantitative measures of optic nerve and
retinal damage, respectively. Testing should include serum MOG and AQP4
antibodies.
Acute management includes a course of IV steroids and, in refractory cases,
IVIg or plasma exchange. Ophthalmologic monitoring and institution of
visual aids are important in the management of children with optic neuritis.
Recovery, as measured by visual acuity, is generally good in children with
optic neuritis.17 Optic neuritis may occur in isolation or as an attack (or first
attack) of MS, NMOSD, ADEM, or MOG antibody–associated disease. Up to
one-third of children with optic neuritis will have a second attack, signifying
the onset of MS or NMOSD. Some children will have a relapsing MOG
antibody–associated disease. Prognostic factors for multiphasic disease are
listed in TABLE 11-2.
Transverse Myelitis
The incidence of acute transverse myelitis in children younger than 16 years of
age is 2 per 106 children per year, and acute transverse myelitis accounts for
one-fifth of children experiencing a first demyelinating attack.15,18 Pediatric
transverse myelitis accounts for 20% of all cases of demyelinating disease in
children and has a bimodal age distribution, with toddlers and adolescents
most affected.19 Although a slight predominance of males exists with acute
transverse myelitis, a female preponderance is seen in adolescents and is
associated with relapsing diseases, including MS and NMOSD. Symptoms can
include weakness, numbness, urinary incontinence or retention, and myelopathic
pain. Occasionally, respiratory symptoms and autonomic dysfunction may occur.
Myelopathic symptoms are a neurologic emergency, and prompt diagnosis and
treatment may lessen the severity of neurologic sequelae. Emergent spinal
imaging with contrast-enhanced pan-spine MRI rapidly discerns alternative
etiologies requiring surgical intervention. Testing should include serum MOG
and AQP4 antibodies. CSF evaluation will aid in excluding infectious etiologies.
CSF protein and white blood cell counts may be normal in up to 50% of children
with transverse myelitis.
Acute treatment includes IV steroids urgently and plasma exchange or IVIg
in refractory cases. Bladder ultrasound and catheterization should be considered
for urinary retention. Children with acute transverse myelitis have a better
outcome than adults, with 50% making a complete recovery by two years.19,20
Mortality is associated with respiratory failure and high cervical cord lesions.19,21
Sensory issues and bladder dysfunction (15% to 50%) are the most common
sequelae. Approximately one-third of patients require walking aids, and 10% to
20% of children lose mobility or bladder function.22
Other Clinically Isolated Syndromes

Clinically isolated syndromes may affect any one area or multiple areas of the
CNS. A multifocal or polyfocal onset generally is more predictive for MS.

Brainstem syndromes may occur as monophasic disorders or part of

multiphasic syndromes.
Predictors of a Multiphasic Disease Course

Several studies have identified risk factors for MS in children presenting with
a clinically isolated syndrome, including CSF profiles with pleocytosis,
EBV-positive serostatus, obesity, low vitamin D levels, and the presence of
T2 lesions on brain MRI. Age older than 11 and postpubertal status at the time
of a clinically isolated syndrome also increase the risk for MS. At present,
investigations into NMOSD and MOG-seropositive disease beyond antibody
presence are limited. The presence of AQP4 antibodies predicts multiphasic
NMOSD regardless of clinical presentation, and patients with AQP4
seropositivity should be treated with preventive immunotherapy because of the
significant disability associated with attacks. The presence of MOG antibodies at
initial attack does not necessarily predict multiphasic disease. Several studies
have suggested that persistent MOG antibodies at follow-up time points are
associated with multiphasic disease, but definitive studies to determine the
specific timeline and retesting parameters are needed.23,24
MULTIPLE SCLEROSIS
Multiple sclerosis is an immune-mediated demyelinating disorder of the CNS
with typical onset in young adulthood. Over the past 15 years, there has been a
growing recognition that MS occurs in children and adolescents.
Epidemiology and Demographics

Pediatric MS is defined as MS with an onset before age 18. The cutoff age varies,
with some studies using age 16; however, for practical purposes, most studies
(including treatment trials) use age 18 as the cutoff.25 Case reports of MS in
children as young as 2.5 to 3 years of age exist, but the vast majority of patients are
age 11 or older, with a mean age at onset of 15 at first symptom in the US Network
of Pediatric MS Centers.25
Studies in large MS cohorts have consistently found that approximately 3%
to 5% of all patients with MS are pediatric at the time of first symptoms.26
Pediatric MS cases are increasingly being diagnosed in many world regions,
particularly in countries distal to the equator. A study from California estimated
the incidence of pediatric MS as approximately 0.51 per 100,000 insured persons
younger than 18 years of age,5 while a German study estimated the incidence
as 0.64 per 100,000 between 2009 and 2011.15,18 Children with MS have a
more diverse ethnic background than adult patients with MS,26 and one study
in a large US cohort found that 40% of patients were first-generation
Americans.25
Risk Factors
The risk factors for pediatric MS are largely similar to the risk factors for adult
MS and include the environmental risk factors of low vitamin D status,13
exposure to cigarette smoking,17 obesity,6,27 and remote EBV infection. Puberty
is an important transition period for the clinical onset of pediatric MS, with 80%
to 85% of children being peripubertal or postpubertal at the time of first
symptoms in a large US cohort.27
The genetic susceptibility factors largely replicate those observed in
adult MS, with the major histocompatibility complex locus HLA-DRB1*1501
798 JUNE 2019

being the major contributor, as demonstrated in several studies of KEY POINTS
pediatric MS.2,16,28
● Several studies have
identified risk factors for
Pathophysiology
multiple sclerosis in
MS is an autoimmune disease that is mediated by a variety of immune cells, likely children, including CSF
in response to a CNS antigen.29 T lymphocytes and B lymphocytes play a key role profiles with pleocytosis,
in MS immunopathogenesis, recruiting macrophages and dendritic cells in the Epstein-Barr virus–positive
serostatus, obesity, low
peripheral immune system to participate in antigen presentation and
vitamin D levels, and the
amplification of a proinflammatory milieu. CNS immune cells, including presence of T2 lesions on
microglia and astrocytes, are activated early and increasingly in the progressive brain MRI. Age older than 11
stages of disease.30 Pediatric MS likely represents MS disease in its earliest stages. and postpubertal status at
Two studies have demonstrated increased activation of CD4+ T memory cells in the time of a clinically
isolated syndrome also
pediatric patients with MS.1,28 Increased CD4+ T-cell responses to myelin increase the risk for multiple
peptides and increased proportions of TH17 central memory T cells were found in sclerosis.
untreated pediatric patients with MS compared to healthy children and adults
with MS.1 Another group found increased proportions of memory cells and ● Puberty is an important
transition period for the
fewer recent immature T cells or thymic emigrants in children with MS in clinical onset of pediatric
comparison to healthy children.28 This study also found that the suppressive multiple sclerosis, with
function of FOXP3 regulatory cells was impaired in pediatric patients with MS. 80% to 85% of children
Increased levels of proinflammatory B cells and fewer regulatory B cells are being peripubertal or
postpubertal at the time
found in pediatric MS.2
of first symptoms in a large
The pathology of MS in adults demonstrates activated T cells and US cohort.
macrophages/microglia. Few studies of the pathology of pediatric MS have been
conducted. A systematic analysis of 19 pediatric patients with MS showed a 50% ● In general, children with
increase in acute axonal damage in pediatric patients compared to adult patients multiple sclerosis
experience 2 to 3 times as
with MS. This study found an inverse relationship of age at biopsy and acute many relapses as adult
axonal damage as well as an increase in activated macrophages and microglia in patients with multiple
pediatric patients with MS.31 sclerosis, reflecting a
continuum in the inverse
Clinical Presentation relationship of age and
relapse rate.
Pediatric-onset MS has clinical features similar to adult MS overall; however, the
pediatric disease is characterized by a more inflammatory disease course as well ● Types of relapses or
as important age-associated symptoms. attacks in pediatric multiple
sclerosis include optic
ACUTE ATTACKS. More than 95% of pediatric patients with MS present with neuritis, transverse myelitis,
the relapsing-remitting form of MS. In general, children with MS experience 2 brainstem attacks, and
cerebral attacks.
to 3 times as many relapses as adult patients with MS,32,33 reflecting a
continuum in the inverse relationship of age and relapse rate.32 Types of
relapses or attacks in pediatric MS include optic neuritis, myelitis, brainstem
attacks, and cerebral attacks. These can affect vision, cognition, motor
function, sensation, and bladder/bowel function and cause pain and
spasticity.34 The clinical course and attack types vary from patient to patient.34
In general, children tend to recover better from attacks than adults17;
however, given the higher attack rate, pediatric patients with MS can still
accrue significant disability in later life. Children with MS may also experience
subacute or chronic symptoms of fatigue, depression,35 and anxiety, which
may appear or worsen with attacks or appear independently. Cognitive
deficits may occur in the context of attacks or chronically.
DISABILITY ACCRUAL. In general, with equal disease durations, disability accrual

as measured by the Expanded Disability Status Scale (EDSS), which focuses on

locomotor disability, is slower in a child or adolescent with MS compared to an

adult patient with MS.36,37 Poor prognostic features in pediatric MS include
a short interval (less than 1 year) between the first two demyelinating
episodes, incomplete recovery after the first attack, and a progressive disease
course.37
COGNITIVE DEFICITS. Between one-third and two-thirds of pediatric patients

with MS may have significant cognitive deficits, including issues with
information processing and processing speed, memory deficits, executive
dysfunction, and lowered IQs, as well as deficits in social cognition.38,39
Evaluation and monitoring by a neuropsychologist shortly after diagnosis is
important to evaluate for the presence of cognitive dysfunction. A 504 plan or
individualized education program (IEP) should be instituted to address cognitive
deficits and ensure appropriate programming at school.
Diagnostic Criteria
The current diagnostic criteria for pediatric MS from the 2012 International
Pediatric MS Study Group7 are based on the 2010 McDonald criteria for adult MS
and were validated in children older than 11 years of age. However, these
diagnostic criteria may be nonspecific, and further work is required to
differentiate pediatric MS from the emerging entities NMOSD and MOG
antibody–associated disease.
Treatment and Management

The management of pediatric MS is subcategorized into acute attack
management, attack prevention, symptomatic therapy, and rehabilitation.
GENERAL APPROACH. Immunotherapy is generally used for acute attacks to

mitigate attack severity and duration. Disease-modifying therapies are
TABLE 11-3 Options for Disease-Modifying Treatments in Pediatric Multiple Sclerosis
Disease-Modifying Treatment Level of Evidence Potential Side Effects

Fingolimod (oral) US Food and Drug Administration (FDA) approved Bradycardia, macular edema,
for pediatric multiple sclerosis (2018) based on lymphopenia, infections, seizures
phase 2 randomized controlled trial40 (rare)
Interferon beta-1a and interferon European Medicines Agency approval for Injection site reactions, flulike
beta-1b (IM or subcutaneous children >12 years of age; prospective and symptoms, depression
injections) retrospective observational studies44,45
Glatiramer acetate Retrospective observational studies8 Injection site reactions, postinjection

(subcutaneous injections) tachycardia
Natalizumab (IV infusion) Prospective observational studies9,10 Progressive multifocal

leukoencephalopathy, infusion
reactions
Rituximab (IV infusion) Retrospective observational studies46–48 Infusion reactions, infections,

hypogammaglobulinemia
IM = intramuscular; IV = intravenous.
800 JUNE 2019

KEY POINTS
strongly recommended once a diagnosis of pediatric MS has been established.
The primary effect of disease-modifying therapies is to reduce relapse ● Between one-third and
frequency. two-thirds of pediatric
patients with multiple
ACUTE ATTACKS. Treatment of an acute attack with immunotherapy reduces the sclerosis may have
significant cognitive deficits,
degree and impact of inflammation on the CNS. Methylprednisolone, IVIg,
including issues with
and plasma exchange have been used for acute attacks in pediatric MS. IV information processing and
methylprednisolone is generally used as first-line relapse treatment at a dose of processing speed, memory
30 mg/kg/d, with a maximum of 1000 mg daily for 5 to 7 days. If response to IV deficits, executive
methylprednisolone is minimal or if the patient has severe symptoms upon dysfunction, and lowered
IQs, as well as deficits in
presentation, IVIg administered at 2 g/kg divided over 2 to 5 days or plasma social cognition.
exchange is appropriate. Upon completion of IV methylprednisolone in a first
attack, the author uses an oral steroid taper starting at 1 mg/kg/d up to 60 mg/d ● In 2018, fingolimod was
maximum dosing. The author then tapers the prednisone by reducing the dose approved by the US Food
and Drug Administration for
by half every 5 days for a total of 4 weeks starting on the first day after use as first-line treatment in
completion of IV steroids. The author generally does not use prednisone tapers children with multiple
for subsequent attacks in pediatric patients with MS to reduce the exposure to sclerosis aged 10 to 17; it has
long-term steroids. received preliminary
approval by the European
Medicines Agency as
DISEASE-MODIFYING THERAPIES. Over the past 20 years, significant advances second-line treatment
have been made in MS therapeutics, with regulatory approval by the European based on the results of the
Medicines Agency (EMA) and US Food and Drug Administration (FDA) for PARADIGMS clinical trial.
more than 15 therapies for adult MS. In 2018, fingolimod was approved by
the FDA for use as first-line treatment in children with MS aged 10 to 17; it
has received preliminary approval by the EMA as second-line treatment based
on the results of the PARADIGMS (Safety and Efficacy of Fingolimod in
Pediatric Patients With Multiple Sclerosis) clinical trial.40 Interferon beta and
glatiramer acetate have received limited approval from the EMA for use in
children 12 years of age or older based on open-label or retrospective studies.41
Safety data for interferon beta-1a subcutaneously 3 times a week for children
older than 2 years of age are included in the European label. Other treatments
studied in open-label or retrospective studies in pediatric MS include
natalizumab and rituximab. Prospective clinical trials of dimethyl fumarate,
teriflunomide, and alemtuzumab for pediatric MS are ongoing, with results
anticipated in 2019–2020.42,43 A summary of studies of disease-modifying
therapies used in pediatric MS and their potential side effects is found in
TABLE 11-3.
44–48
FINGOLIMOD. Fingolimod is an oral sphingosine-1-phosphate immunomodulator

that primarily inhibits the egress of central memory T cells from lymph
nodes. It is approved by the FDA and EMA for use in adult MS and received
FDA approval for pediatric MS in 2018 based on the result of the PARADIGMS
clinical trial.40 This study demonstrated an 82% reduction in annualized relapse
rate in patients treated with fingolimod compared to those treated with
interferon beta-1a. Fingolimod is dosed at 0.5 mg orally daily in pediatric
patients with MS who weigh more than 40 kg (88 lb) and at 0.25 mg in
patients who weigh 40 kg (88 lb) or less. First-dose observation for 6 hours is
required to monitor for bradycardia. Monitoring and pretesting for macular
edema, varicella titers, hepatic enzymes, and lymphocyte counts are
recommended.

INTERFERON BETA. Interferon beta is a type I interferon with diverse effects on

lymphocytes and innate immune cells approved for use in adult MS, with several
different forms and dosing schedules. Interferon beta use in pediatric MS was
compared with a control group in two randomized unblinded studies.49,50 Both
studies demonstrated a reduction of relapses and new MRI T2 lesions and delayed
disability accumulation in comparison to the untreated group.49,50 The
retrospective REPLAY (Retrospective Cohort Study of Rebif Use in Pediatric
Multiple Sclerosis Subjects) phase 4 study is the largest cohort study to be
conducted in pediatric MS; it evaluated the safety profile of interferon beta-1a in
307 pediatric patients with MS treated with 22 mcg or 44 mcg interferon beta-1a.44
This study reported adverse events (less than 2%) including allergic reactions
(1.6%), epilepsy and convulsive disorders (1.6%), thyroid dysfunction (1.0%),
autoimmune disorders (0.7%), osteogenic disorders (0.7%), and serious
infections (0.7%).
No pharmacodynamic/pharmacokinetic studies of interferon beta and
glatiramer acetate have been conducted in pediatric MS. In general, it is
recommended to initiate interferon beta therapy at 25% to 50% of the adult dose
and then titrate up to the full adult dose as tolerated, especially for children older
than 12 years of age with a body weight greater than 30 kg (66 lb).
GLATIRAMER ACETATE. Glatiramer acetate is a copolymer of peptides

administered by subcutaneous injection and is approved for use in adult MS.
Glatiramer acetate was evaluated in a retrospective cohort of seven pediatric
patients with MS with favorable clinical outcomes and safety profile.8 A case of
acute hepatotoxicity in an adolescent treated with glatiramer acetate was
reported in 2013.51 The author generally initiates and uses full adult dosing in
pediatric patients with MS.
NATALIZUMAB. Natalizumab is a humanized monoclonal antibody that targets

the α4 subunit of α4β1 integrin and is approved for the treatment of adult MS.
Several prospective observational studies have described the effect of
natalizumab in pediatric MS.9,10 The largest study to date is the Italian study
cohort of 101 patients (69 females) with a mean age of MS onset of 12.9 ±
2.7 years and mean age at natalizumab initiation of 14.7 ± 2.4 years.10 Mean
treatment duration was 34.2 ± 18.3 months. The annualized relapse rate
decreased from 2.3 ± 1.0 in the year prior to 0.1 ± 0.3 (P=.001) after natalizumab
initiation. Disability scores stabilized or improved, and MRI lesion accrual
was reduced. No relevant adverse events were reported in this study.10 The
frequency of JC virus antibodies was reported in these studies as 38% to 39%,10,52
which is lower than that reported in adults (57%) but higher than the rate in
non-MS pediatric populations. Mild to moderate side effects can include
infections and hypersensitivity. The author generally doses at 6 mg/kg IV
infusions monthly to a maximum adult dose of 300 mg per dose. JC virus
antibodies should be monitored every 6 months at minimum, and, if
seroconversion to a positive test, then consider switching to an alternate
therapy. Extensive studies in adult patients have demonstrated an increased
risk of progressive multifocal leukoencephalopathy (PML) in patients who are
JC virus positive compared to patients who are JC virus negative. Risk factors
of prolonged duration on natalizumab as well as prior immunosuppression are
associated with increased risk of PML in the setting of seropositive JC virus
802 JUNE 2019

testing. For more information on risk factors for PML, refer to the article KEY POINT
“Monitoring, Switching, and Stopping Disease-Modifying Therapies” by Robert
● Adherence to disease-
H. Gross, MD, and John R. Corboy, MD, FAAN,53 in this issue of Continuum. modifying therapy may be
challenging, particularly
RITUXIMAB. Rituximab is a monoclonal antibody that targets CD20+ B in adolescents, in the
lymphocytes and reduces clinical and magnetic resonance activity in adult setting of miseducation
patients with MS54 and in patients with NMO. A small retrospective case series about the expectations for
of 11 patients, including three pediatric patients with MS, reported stabilization disease-modifying
therapies, unaddressed
of disease.55 A detailed discussion of rituximab dosing is included in the NMO side effects, busy family
treatment section later in this article. schedules, and travel/
college.
CHEMOTHERAPEUTICS. Other treatments historically used in pediatric MS include
the chemotherapeutic agents cyclophosphamide and mitoxantrone. However,
because of their significant toxicity, these agents are now rarely used. A
retrospective study of cyclophosphamide use in 17 pediatric patients with MS
found a decreased relapse rate and stabilization of disability scores.56 However,
side effects included nausea and vomiting in 15 of 17 patients, alopecia in
10 of 17 patients, menstrual irregularities in five patients, anemia in 10 patients,
and thrombocytopenia in five patients. A case series of four pediatric
patients with MS who received mitoxantrone for highly active
relapsing-remitting MS followed for 3.8 to 18 years reported laboratory
abnormalities in all patients.57
MANAGEMENT CONSIDERATIONS. The author monitors disease-modifying

therapy response clinically and with annual MRIs.58 Annual MRIs may be
conducted with gadolinium if a new relapse is suspected. Noncontrast MRIs
may be conducted for routine monitoring to reduce the long-term exposure to
gadolinium, especially since linear forms of gadolinium have been noted to
accumulate in brain regions, although the clinical effects of this accumulation
are unclear.59 Adherence to medications may be challenging, particularly in
adolescents, in the setting of miseducation about the expectations for
disease-modifying therapies, unaddressed side effects, busy family schedules,
and travel/college.60
If evidence of intractable nonadherence, intolerance, or treatment failure
is present, switching treatments should be considered.61 Treatment failure may
be defined as one to two new lesions or attacks occurring within a 12-month
period. The tolerance for new lesions or attacks versus switching and the risks
and benefits of both should be discussed between the neurologist and family.
Contraceptives should be considered in sexually active teenagers. This is an
important conversation to have before treatment initiation, since many disease-
modifying therapies may have adverse effects on a pregnancy and some are
teratogens. For more information on the use of disease-modifying therapies in
pregnancy, refer to the article “Pregnancy and Family Planning in Multiple
Sclerosis” by Annette M. Langer-Gould, MD, PhD,62 in this issue of Continuum.
Symptomatic treatments should be considered as needed and may include
antidepressants, fatigue medications, and bladder management medications.63
NEUROMYELITIS OPTICA SPECTRUM DISORDER

NMOSDs are distinct from MS and are characterized by predominant optic
neuritis and transverse myelitis attacks. The majority of patients with NMOSDs
have AQP4 antibodies.64,65


Up to 3% to 5% of cases of NMOSD have pediatric onset.66 The overall incidence
of NMOSD in children and adults ranges from 0.05 to 4 per 100,000 per year,
and prevalence ranges from 0.52 to 4.4 per 100,000.67 In Japan, the incidence
of pediatric NMOSD was reported as 0.06 per 100,000 children.68 Patients as
young as 16 months of age have been reported; however, the typical age of
onset is 10 to 12 years.3 Females are more likely to be affected than males at a ratio
of 3:1 in the pediatric population but up to 9:1 in adults.69
Clinical Features
Pediatric NMO is a relapsing disease. A mean of 1.8 attacks per year during the first
2 years of disease was noted in a US study of 38 children with NMO.3 As described
in case series from the United States and United Kingdom, the most common
presenting symptoms are unilateral or bilateral optic neuritis, transverse myelitis,
and brainstem/cerebellar syndromes.3,70 Vomiting and intractable hiccups are
observed in area postrema syndrome and can be initial symptoms of NMOSD.71
ADEM and seizures have also been described as presenting attacks of NMO.72 As
compared to MS or ADEM, pediatric patients with NMOSD have a higher EDSS
score within 2 years of disease onset (2.25 versus 1.28 and 0.5, respectively).3
Laboratory Testing
Approximately 65% of pediatric patients with NMOSD are AQP4 antibody
seropositive; however, seropositivity may not occur at the time of the initial
attack but up to 4 years later. Therefore, serial testing is recommended for highly
suspicious cases.3 Although rare cases of AQP4 antibody in the CSF with negative
serum testing have been reported in adults, this was not observed in a large
pediatric NMOSD case series.3
TABLE 11-4 Diagnostic Criteria for Neuromyelitis Optica Spectrum Disorder From the
2015 International Panel for Neuromyelitis Optica Diagnosisa
Aquaporin-4 (AQP4) Antibody Positive

◆ One core clinical characteristic, positive AQP4 antibodies, and exclusion of alternative
diagnoses
◇ Core clinical characteristics include optic neuritis, acute myelitis, area postrema
syndrome of hiccups or nausea, symptomatic narcolepsy or acute diencephalic
clinical syndrome with MRI diencephalic lesions typical of neuromyelitis optica (NMO)
spectrum disorder, acute brainstem syndrome, and symptomatic cerebral syndrome
with NMO spectrum disorder–typical brain lesions
AQP4 Antibody Negative or Unknown AQP4 Status
◆ Two core clinical characteristics that meet all the following requirements:
◇ One core clinical characteristic must include optic neuritis, acute myelitis with
longitudinally extensive transverse myelitis, or area postrema syndrome
◇ Dissemination in space of two or more core clinical characteristics
◇ Fulfillment of additional MRI requirements

a
Data from Wingerchuk, DM, et al, Neurology.65
804 JUNE 2019

Approximately 10% to 15% of cases of pediatric NMOSD are MOG antibody KEY POINTS
seropositive, which has implications for both prognosis and treatment, and they
● Up to 3% to 5% of cases of
may be considered separately from AQP4 antibody–seropositive cases. Dual NMOSD have pediatric
seropositivity has not been reported in children. Approximately 15% of pediatric onset. The overall incidence
NMOSD cases are both AQP4 and MOG antibody seronegative. Coexisting of NMOSD in children and
autoimmune diseases, including systemic lupus erythematosus, Sjögren adults ranges from 0.05 to 4
per 100,000 per year, and
syndrome, and autoimmune thyroid disease, are observed with NMOSD and
prevalence ranges from 0.52
were reported in 16% in a multicenter US study,3 9% of patients in a Brazilian to 4.4 per 100,000. In Japan,
study,73 and 42% in a study from Mayo Clinic in children who were AQP4 the incidence of pediatric
seropositive.72 Testing for these comorbid diseases should be considered on a NMOSD was reported as
0.06 per 100,000 children.
case-by-case basis.
CSF testing in pediatric NMOSD typically shows pleocytosis with a lymphocyte ● Approximately 65% of
predominance. CSF leukocyte counts vary between 100 cells/mm3 and 200 pediatric patients with
cells/mm3 and are typically higher than in pediatric MS or ADEM.3 Among the CSF NMOSD are aquaporin-4
leukocytes, the lymphocyte percentage is approximately 75%, while pediatric MS antibody seropositive;
however, seropositivity may
typically has 90% lymphocytes. Elevated IgG index and positive oligoclonal band not occur at the time of the
testing was observed in 30% of pediatric patients with NMO.3 initial attack but up to
4 years later. Therefore,
Pathophysiology serial testing is
recommended for highly
AQP4-seropositive patients with NMO have pathologic features that are distinct suspicious cases.
from those of MS. The immune attack is focused on the astrocytes, with
secondary damage to myelin and axons; a variety of immune cells, including
T cells, B cells, plasma cells, and neutrophils, are found in NMO lesions.74,75
Complement and antibody deposition is also found in lesions.
Diagnostic Criteria
The most recent diagnostic criteria for NMOSD were published by the International
Panel for NMO Diagnosis in 2015.65 These diagnostic criteria classify patients as
AQP4 antibody positive and AQP4 antibody negative (TABLE 11-4) and were
found to detect pediatric NMO cases with a 97% sensitivity compared to earlier
diagnostic criteria.3
Treatment Options
Management of NMOSD includes treatment of acute attacks, preventive
therapy, and symptomatic management. Limited Class I evidence is available for
treatments for both pediatric and adult NMOSD.
ACUTE ATTACKS. Treatment for an acute attack with immunotherapy reduces

the degree and impact of inflammation on the CNS in patients with NMO.
Aggressive management of relapses is recommended in pediatric NMO since
these patients accrue disability with attacks and have higher disability rates
than pediatric patients with MS.3 The author’s practice is to initiate IV
methylprednisolone at a dose of 20 mg/kg to 30 mg/kg (up to 1 g/d) for 5 days.
If no evidence of improvement is seen or symptoms worsen, then five cycles
of plasma exchange should be started immediately.
PREVENTIVE THERAPY. Preventive or disease-modifying therapy is used to

decrease the risk of relapses and associated disability. Disease-modifying
treatment options used in adult and pediatric NMOSD include mycophenolate
mofetil, rituximab, and azathioprine.

MYCOPHENOLATE MOFETIL. Mycophenolate mofetil has been shown to reduce

relapse rate and stabilize disability scores in adults with NMOSD.76–78 A
retrospective study also demonstrated the efficacy of mycophenolate mofetil in
children with NMOSD.77 Mycophenolate mofetil is generally dosed based on
body surface area at 600 mg/m2 2 times a day to a maximum dose of 1000 mg
2 times a day (2000 mg maximum per day). To improve tolerability, an initial
dose titration schedule should be followed: one-fourth of 600 mg/m2 2 times a
day for 1 week; then one-half of 600 mg/m2 2 times a day for 1 week, then
three-fourths of 600 mg/m2 2 times a day for 1 week, then 600 mg/m2 2 times a
day. Side effects of this drug include gastrointestinal symptoms (nausea,
diarrhea, abdominal pain), dizziness, rash, increased risk of infection, and
fatigue.76,79 Rarely, cases of PML have been associated with mycophenolate
mofetil.80
RITUXIMAB. Rituximab is a chimeric monoclonal anti-CD20 antibody that depletes B

cells. It has been used for both adults81,82 and children with NMOSD83 as well as for
other autoimmune diseases. One retrospective study in 16 pediatric patients found a
reduction in relapse rate with rituximab.46 B-cell repopulation was associated with
recurrence of relapse; however, a wide range of time to B-cell repopulation was
noted, with a mean of 6.8 months.46 Therefore, B-cell repopulation times should be
initially monitored monthly starting at 3 months, and redosing times should be
individualized to pediatric patients. The dosing protocol for children is 375 mg/m2
every week (maximum total loading dose of 2 g) for 4 weeks and then 750 mg/m2
(maximum total dose of 1 g) at approximately 6 months or earlier upon B-cell
return.48 Side effects of rituximab include nausea, vomiting, infusion reactions, and
risk for infections, including hepatitis B virus reactivation.84 PML has been rarely
associated with rituximab in the treatment for lymphoma.85
AZATHIOPRINE. Azathioprine, a purine analogue, interferes with DNA synthesis

in proliferating B cells and T cells. Azathioprine at a dose of 2 mg/kg/d to
3 mg/kg/d decreases relapse rates in adults and children with NMOSD.86,87
However, tolerability issues were noted in children. Side effects include nausea,
elevated liver function tests, diarrhea, severe leukopenia, rash, and
hypersensitivity reactions. Lymphoma is a rare side effect.86
MEDICATIONS TO AVOID IN NEUROMYELITIS OPTICA SPECTRUM DISORDER. Some

of the disease-modifying therapies used in MS are either ineffective for or
exacerbate NMOSD, demonstrating the need for accurate diagnosis. Increased
relapses have been associated with the use of interferon,88,89 glatiramer acetate,90
dimethyl fumarate,91 alemtuzumab,92 and natalizumab.93–95
MYELIN OLIGODENDROCYTE GLYCOPROTEIN

ANTIBODY–ASSOCIATED DEMYELINATING SYNDROMES
MOG antibody–associated demyelinating syndromes are a recently recognized
group of syndromes that predominantly occur in children.

Since cell-based assays became available, anti-MOG antibodies have been reported
in the serum of 18% to 35% of children with an acute demyelinating syndrome.96,97
806 JUNE 2019

More females are affected than males at a ratio of approximately 3:1. The disease KEY POINTS
occurs throughout the age spectrum but is more common in children.
● Since cell-based assays
became available, anti–
Clinical Features MOG antibodies have been
Children with MOG antibodies in the serum present with a variety of clinical reported in the serum of 18%
syndromes that include, but are not limited to, ADEM, multiphasic ADEM, to 35% of children with an
optic neuritis, ADEM followed by optic neuritis, recurrent optic neuritis, acute demyelinating
syndrome.
encephalitis or meningitis (often associated with seizures), transverse myelitis,
and NMOSD.96–98 The phenotype seems to follow an age-related spectrum, ● MOG antibody testing has
with ADEM and optic neuritis being the most common presentations in children, now been optimized,
while NMO and transverse myelitis are the most common in adults (CASE 11-1). offering increased
sensitivity and specificity
Rarely, cases of typical MS have been associated with MOG antibodies. Other compared to other
features of MOG-seropositive disease are elevated CSF lymphocyte counts methods. The MOG
and elevated neutrophil counts.97 Brain lesions from MOG-seropositive antibody is most often
syndromes have been associated with acute inflammation with demyelination detected in the serum and
rarely in the CSF. The
and relative preservation of astrocytes.99 Occasionally MOG seropositivity
current consensus is that
has been observed in association with other CNS autoimmune syndromes, serum testing has the
including N-methyl-D-aspartate (NMDA) receptor antibody–associated highest yield.
encephalitis.100
Approximately 50% of cases follow a relapsing course.101 Of note, relapses
may occur within a few weeks or more than 10 years after the initial attack. At
present, data on which patients are at highest risk of relapse are limited.
MOG-seropositive ADEM in children seems to follow a monophasic course in
the majority of patients. Generally, demonstration of new MRI lesions or a new
relapse indicates a relapsing course and warrants longer-term immunomodulatory
treatment.
Laboratory Testing
MOG antibody testing has now been optimized with a cell-based assay
expressing a short-length MOG intracellular chain, offering increased sensitivity
and specificity compared to other methods.102 The MOG antibody is most
often detected in the serum and rarely in the CSF. The current consensus is
that serum testing has the highest yield. The presence of antibody is usually
detected at the time of acute inflammation and may decrease with time or
with immunomodulatory therapy.103 In some cases, the antibody is transient,
while in other cases, the antibody persists. The transient detection of anti-MOG
antibodies is more frequent in children at the onset of ADEM, optic neuritis,
and relapsing optic neuritis, and anti-MOG positivity predicts a non-MS disease
course.23,104 The persistence of anti-MOG antibodies has been associated with a
relapsing course, although fewer than 10% of pediatric patients with classic
features of MS have detectable anti-MOG antibodies.104
Diagnostic Criteria
Diagnostic criteria for MOG antibody–associated demyelinating syndrome have
been suggested by several groups but have not been fully validated.104
Ultimately, MOG antibody–associated demyelinating syndrome needs to be
reconciled with existing MS and NMOSD criteria, and efforts to
comprehensively evaluate clinical presentations, MRI features, and treatment
response of MOG antibody–associated demyelinating syndrome and the
similarities to and differences from MS and NMOSD are under way.

Treatment Options
The management of MOG antibody–associated demyelinating syndrome can be
divided into treatment of acute attacks and attack prevention.
ACUTE ATTACKS. Acute attacks generally respond to a 3- to 7-day course of

methylprednisolone or other high-dose IV steroids. Rebound attacks or
worsening symptoms have been described with prednisone tapers, and debate
exists regarding the duration of prednisone taper. Rebound attacks in this
setting may indicate a relapsing disease course, warranting longer-term
treatment. The author has used periodic IVIg in the case of prednisone-
dependent worsening, 1 g/kg for one to two doses (if two doses, then give
2 days apart) every 4 to 8 weeks if symptoms return. Plasma exchange has
been used in some cases with severe attacks that do not respond to steroids
or IVIg.
CASE 11-1 A 15-year-old girl presented to the emergency department with 1 week of
worsening eye pain and, over the past 2 hours, complete loss of vision in
her left eye. Her past medical history was notable for headaches with
onset in the past 2 months.
Neurologic examination showed complete blindness in the left eye,
left optic disc edema, a left afferent pupillary defect, and limited upgaze
in both eyes. Vision in her right eye was 20/20. The neurologic
examination was otherwise normal. MRI demonstrated left optic nerve
enhancement but no brain lesions. Her CSF showed a leukocyte count of
84 cells/mm3 with 80% lymphocytes and negative oligoclonal bands. She
received 3 days
of IV methylprednisolone (1 g/d) followed by 14 days of oral prednisone.
She had immediate improvement of ocular pain and slow improvement
of vision.
One week after her final dose of prednisone, she developed loss of
vision in her right eye along with pain. She again presented to the
emergency department, where she was able to count fingers in both
eyes. Examination demonstrated right optic disc edema and left optic
atrophy.
Repeat MRI 1 month later demonstrated diffuse enhancement of
the optic nerves bilaterally (FIGURE 11-1A). Full-spine MRI showed no
lesions. She received a 5-day course of IV methylprednisolone.
Six months later, she presented with an attack of right facial weakness,
dysarthria, clumsiness and weakness of her right hand, gait ataxia, and
bilateral pallor of the optic discs. MRI showed multiple new enhancing
foci in both the white and gray matter of the brain (FIGURE 11-1B). Serologic
testing demonstrated myelin oligodendrocyte glycoprotein (MOG)
antibodies. Aquaporin-4 antibody testing was negative. She was treated
with 5 days of IV steroids followed by a 4-week prednisone taper and was
started on mycophenolate mofetil 750 mg 2 times a day. She had no
further episodes over 1.5 years of follow-up.
808 JUNE 2019

PREVENTIVE THERAPY. For relapsing cases of MOG antibody–associated
demyelinating syndrome, mycophenolate mofetil and rituximab are the most
commonly used immunomodulatory treatments, with approximately 50%
efficacy.96,105 Azathioprine has also been used in MOG-seropositive patients who
meet diagnostic criteria for NMOSD.106
CONCLUSION
Much progress has been made over the past 10 years in pediatric
demyelinating diseases. The diverse spectrum of pediatric demyelinating
disorders, including monophasic and multiphasic forms, is now better
understood (FIGURE 11-2). The identification of MOG and AQP4
antibodies in children has been a major advance, which now allows for
appropriate treatment and management of these disorders. In the past 5 years,
FIGURE 11-1
Imaging of the patient in CASE 11-1. A, Axial postcontrast T1-weighted MRI showing bilateral
optic neuritis. B, Axial postcontrast T1-weighted MRIs showing multiple juxtacortical
lesions demonstrating gadolinium enhancement. C, Axial fluid-attenuated inversion
recovery (FLAIR) MRIs showing increased T2-signal lesions in the bilateral corpus callosum
and juxtacortical white matter.
This case exemplifies a diagnosis of MOG antibody–associated disease, COMMENT

which has unique features on MRI and requires management strategies that
differ from pediatric MS.

FIGURE 11-2
Spectrum of monophasic and multiphasic demyelinating disorders in children.
ADEM = acute disseminated encephalomyelitis; AQP4 = aquaporin-4; CIS = clinically isolated
syndrome; MOG = myelin oligodendrocyte glycoprotein; MS = multiple sclerosis; ON = optic neuritis;
NMO = neuromyelitis optica; NMOSD = neuromyelitis optica spectrum disorder; TM = transverse myelitis.
enormous strides have been made in the treatment of pediatric MS with

the introduction of regulatory agency–approved treatments and new clinical
trials. The establishment of refined diagnostic criteria for these disorders and
the continued development and evaluation of treatments are important
future directions. Biomarkers that aid in the prognostication of a relapsing
course or relapse may further enhance patient management. Studies focused
on long-term outcomes of all these pediatric-onset disorders are needed.
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814 JUNE 2019

Neuromyelitis Optica REVIEW ARTICLE

Spectrum Disorder and C O N T I N U UM A U D I O
ONLINE
Other Non–Multiple
Sclerosis Central Nervous
System Inflammatory
Diseases
By Eoin P. Flanagan, MBBCh
ABSTRACT
PURPOSE OF REVIEW: This article reviews the clinical features, diagnostic
approach, treatment, and prognosis of central nervous system
inflammatory diseases that mimic multiple sclerosis (MS), including those CITE AS:
defined by recently discovered autoantibody biomarkers. CONTINUUM (MINNEAP MINN)
RECENT FINDINGS: The discovery of autoantibody biomarkers of inflammatory DISEASES):815–844.
demyelinating diseases of the central nervous system (aquaporin-4 IgG
and myelin oligodendrocyte glycoprotein IgG) and the recognition that, Address correspondence to
Dr Eoin P. Flanagan, Mayo Clinic,
despite some overlap, their clinical phenotypes are distinct from MS have
Department of Neurology,
revolutionized this field of neurology. These autoantibody biomarkers 200 First St SW, Rochester,
assist in diagnosis and have improved our understanding of the underlying MN 55905,
flanagan.eoin@mayo.edu.
disease pathogenesis. This has allowed targeted treatments to be translated
into clinical trials, three of which are now under way in aquaporin-4 RELATIONSHIP DISCLOSURE:
IgG–seropositive neuromyelitis optica (NMO) spectrum disorder. Dr Flanagan receives
MedImmune/Viela Bio.
SUMMARY: Knowledge of the clinical attributes, MRI findings, CSF
parameters, and accompanying autoantibody biomarkers can help UNLABELED USE OF
neurologists distinguish MS from its inflammatory mimics. These antibody PRODUCTS/INVESTIGATIONAL
USE DISCLOSURE:
biomarkers provide critical diagnostic and prognostic information and Dr Flanagan discusses the
guide treatment decisions. Better recognition of the clinical, radiologic, unlabeled/investigational
use of azathioprine, cetirizine,
and laboratory features of other inflammatory MS mimics that lack
corticosteroids, eculizumab,
autoantibody biomarkers has allowed us to diagnose these disorders faster inebilizumab, IV immunoglobulin,
and initiate disease-specific treatments more expeditiously. methotrexate, mycophenolate
mofetil, plasma exchange,
rituximab, SA237, sivelestat, and
tocilizumab for the treatment of
INTRODUCTION neuromyelitis optica spectrum
D
disorder and other non–multiple
istinguishing multiple sclerosis (MS) from its central nervous
sclerosis central nervous system
system (CNS) inflammatory disease mimics has important inflammatory diseases.
therapeutic and prognostic implications. During the past
2 decades, advances in biomarker discovery and MRI © 2019 American Academy
characterization of CNS inflammatory disorders have aided our of Neurology.

NMOSD AND OTHER NON-MS INFLAMMATORY DISEASES
ability to distinguish MS from its mimics. This article reviews the clinical,
laboratory, and radiologic clues that help distinguish MS from other
inflammatory CNS disorders and highlights the differences in the treatment
approach. The first section focuses on CNS inflammatory demyelinating
disease mimics of MS that are accompanied by specific serum biomarkers:
aquaporin-4 (AQP4)–IgG and myelin oligodendrocyte glycoprotein
(MOG)–IgG. These disorders are summarized and compared to MS in
TABLE 12-1. The second section reviews a variety of other nondemyelinating
TABLE 12-1 Comparison of Inflammatory Demyelinating Diseases of the Central

Nervous System
Attribute Multiple Sclerosis AQP4-IgG MOG-IgG

Antecedent Rare Rare Common
infection/
immunization
Ages affected Any (median age at onset in third Any (median age at onset in fourth Any (children and young adults
decade) decade) more predisposed)
Sex (female: 2:1 9:1 1.5:1

male)
Epidemiology Prevalence: common Prevalence: rare Prevalence: unknown
Ethnicity: whites more Ethnicity: African-Americans, Ethnicity: unknown

predisposed Afro-Caribbeans more
predisposed
Geographic: regions farthest Geographic: higher proportion of Geographic: unknown

from equator total demyelinating disease is
AQP4-IgG–positive neuromyelitis
optica spectrum disorder
(NMOSD) in regions where
multiple sclerosis prevalence is low
Most common Myelitis, optic neuritis, brainstem, NMOSD (any combination of Initial episode: optic neuritis,
manifestations cerebral episodes; myelopathy single/recurrent myelitis, optic acute disseminated
for progressive multiple sclerosis neuritis, area postrema syndrome) encephalomyelitis (ADEM),
NMOSD, myelitis
Relapse: optic neuritis
Course Relapsing-remitting from onset in Typically relapsing; usually no Monophasic or relapsing; no

85% (most later develop secondary progression reports of secondary progression
secondary progression); 10–15%
progressive from onset
Attack severity Usually mild to moderate Usually moderate to severe Usually moderate to severe
Recovery from Good Often incomplete Good

attacks
816 JUNE 2019

inflammatory CNS diseases that can mimic MS and outlines how to
recognize them.
NEUROMYELITIS OPTICA SPECTRUM DISORDERS

Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory
demyelinating disease of the CNS associated with episodes of optic neuritis,
transverse myelitis, and other neurologic manifestations that can mimic MS.
AQP4-IgG is a serum biomarker found in approximately 80% of patients with
Attribute Multiple Sclerosis AQP4-IgG MOG-IgG

CSF White blood cell count White blood cell count variable White blood cell count variable
<50/mm3 (lymphocytic) (usually lymphocytic but can be (lymphocytic); oligoclonal bands
or can be normal; neutrophilic or eosinophilic); in <15%
oligoclonal bands in 85% oligoclonal bands in 30%
Blood NA AQP4-IgG MOG-IgG

biomarker
Brain MRI Ovoid periventricular, Dawson Often normal/nonspecific; if ADEM-like fluffy white matter,
fingers, juxtacortical, cortical, present, area postrema, peri- deep gray matter, diffuse/
infratentorial peripheral, ring-/ third/fourth ventricle, splenium, confluent brainstem including
open ring-enhancing diffuse corpus callosum, pencil- cerebellar peduncles
thin ependymal or cloud
enhancement
Optic nerve Unilateral; enhancement of <50% Bilateral; enhancement of >50% of Bilateral; enhancement of >50% of
MRI of nerve affected; middle of optic nerve; posterior optic optic nerve; anterior optic
optic nerve pathway involving chiasm pathway (hence optic disc edema
common)
Spine MRI Multiple lesions; Single lesion (longitudinally Multiple lesions;

short lesions; periphery of cord extensive transverse myelitis 85%; (75% longitudinally extensive
(dorsal/lateral column); ring or short 15%); central on axial; ring or transverse myelitis; 25% short);
variable enhancement variable enhancement conus involved; central on axial;
enhancement variable
Acute IV steroids; plasma exchange IV steroids; plasma exchange IV steroids; plasma exchange
treatment (rarely required) (often required) (often required); IVIg (used in
children)
Maintenance Variety of approved None approved; steroid sparing None approved; none needed if
treatment immunomodulatory medications recommended: azathioprine, monophasic; steroid sparing for
mycophenolate mofetil, rituximab, relapsing disease (azathioprine,
eculizumab, tocilizumab, IVIg, mycophenolate mofetil,
methotrexate methotrexate, rituximab)
Prognosis Majority ambulatory after Attack-related accumulation of Most disability with first attack;
20 years; most disability occurs in disability; secondary progression transient seropositivity predicts
secondary progressive phase rarely if ever occurs monophasic course; persistent
seropositivity and high titer
predict relapsing disease
AQP4 = aquaporin-4; CSF = cerebrospinal fluid; IgG = immunoglobulin G; IV = intravenous; IVIg = intravenous immunoglobulin; MOG = myelin
oligodendrocyte glycoprotein; MRI = magnetic resonance imaging; NA = not applicable.

this syndrome, and a proportion of the remaining 20% may be accounted for by
another serum antibody biomarker, MOG-IgG.
History and Terminology

The eponym Devic disease arose from a 19th century report by Devic and his
student Gault describing the autopsy findings of a patient who died from an
episode of concurrent transverse myelitis and optic neuritis.1 Subsequently, the
term neuromyelitis optica (NMO) superseded Devic disease to account for its
most common clinical manifestations, namely optic neuritis and transverse
myelitis.2 In 2004, the discovery of AQP4-IgG as a specific biomarker of NMO
allowed its distinction from MS.3,4 This discovery led to the recognition that
patients can have more limited forms of the disease (eg, recurrent transverse
myelitis without optic neuritis) or symptoms beyond the optic nerve and spinal
cord (eg, area postrema syndrome), resulting in the current nosology of
NMOSDs.5 In Asia, it has long been recognized that a CNS demyelinating disease
existed that was different than the MS that occurred in whites; it was termed
opticospinal MS or Asian MS. It is now widely accepted that these diseases fall
under the category of NMOSD. Approximately 20% of patients with NMOSD are
seronegative for AQP4-IgG.6 A proportion of these patients are MOG-IgG
seropositive, which can lead to confusion as, in contrast to AQP4-IgG NMOSD
TABLE 12-2 Clinical Features of Neuromyelitis Optica Spectrum Disordera
Cardinal Clinical Features

◆ Transverse myelitis, typically longitudinally extensive (≥3 vertebral segments; often
followed by tonic spasms and occasionally accompanied by pain or pruritus)
◆ Optic neuritis (often severe; may be bilateral)
◆ Episodes of intractable nausea and vomiting or hiccups from area postrema involvement
Other Clinical Features
◆ Narcolepsy
◆ Syndrome of inappropriate secretion of antidiuretic hormone (SIADH)
◆ Other hypothalamic presentations (eg, anorexia)
◆ Acute myopathy with hyperCKemia
◆ Brainstem syndromes (eg, ophthalmoplegia,b hearing loss [possibly related to inner ear
damage] opsoclonus/myoclonus)
◆ Myeloradiculitis
◆ Encephalopathyc (PRES-like; ADEM-like)
◆ Cognitive dysfunction (subcortical pattern [inattention, executive dysfunction, reduced
speed of processing])
◆ Hydrocephalus
ADEM = acute disseminated encephalomyelitis; CK = creatine kinase; PRES = posterior reversible

encephalopathy syndrome.
a
Reprinted with permission from Flanagan EP, Weinshenker BG, Curr Neurol Neurosci Rep.12
© 2014 Springer Science+Business Media.
b
Need to exclude coexisting myasthenia gravis as a cause.
c
Need to exclude coexisting N-methyl-D-aspartate (NMDA) receptor encephalitis as a cause.
818 JUNE 2019

(which is a disease of astrocytes), MOG-IgG NMOSD is a disease of KEY POINTS
oligodendrocytes. This has led to some debate and controversy in the field about
● Distinguishing multiple
whether to use syndrome-based (NMOSD) or biomarker-based (AQP4-IgG, sclerosis from its central
MOG-IgG) diagnostic criteria, although the syndrome-based NMOSD criteria nervous system
are currently used.5,7 inflammatory disease
mimics has important
therapeutic and prognostic
Epidemiology implications.
The prevalence of NMOSD in the United States (Olmsted County, Minnesota)
is 3.9 per 100,000, and similar results have been reported in Europe (Denmark) ● In 2004, the discovery of
at 4.4 per 100,000 and Asia (Japan) at 4.1 per 100,000.8–10 In contrast, the aquaporin-4 (AQP4)–IgG as a
specific biomarker of
prevalence is higher in populations of African descent (Afro-Caribbeans/African
neuromyelitis optica (NMO)
Americans), with a prevalence of 10 per 100,000.8 It is important to recognize allowed its distinction from
that in regions where MS prevalence is lower (eg, Asia and regions closer to the multiple sclerosis.
equator), NMOSD represents a larger proportion of CNS demyelinating diseases
and thus should be particularly considered in the differential in those regions. ● The discovery of
AQP4-IgG as a biomarker of
NMOSD is fivefold to tenfold more common in females than males.8,11 The NMO led to a recognition
disease can occur at any age, including in children and older adults. that patients can have
more limited forms of the
disease (eg, recurrent
Clinical Manifestations
transverse myelitis without
NMOSD has three cardinal manifestations: transverse myelitis, optic neuritis, optic neuritis) or symptoms
and area postrema syndrome (TABLE 12-212). The vast majority of patients follow beyond the optic nerve and
a relapsing course, and patients can have severe attacks resulting in permanent spinal cord (eg, area
deficits even after long periods of remission. A secondary progressive course is postrema syndrome),
resulting in the current
extremely rare with NMOSD, further highlighting its distinction from MS.13 The nosology of NMO spectrum
transverse myelitis episodes may present with typical findings of myelitis, with disorders (NMOSDs).
numbness, weakness, bowel/bladder impairment, and Lhermitte phenomenon,
typically reaching the nadir within days to a few weeks (progression beyond ● It is important to
recognize that in regions
1 month should raise concern for an alternative cause). In contrast to MS where multiple sclerosis
(TABLE 12-1), NMOSD myelitis attacks are often quite disabling (CASE 12-1). prevalence is lower (eg, Asia
Tonic spasms (involuntary painful episodes of flexion usually lasting less than and regions closer to the
1 minute and triggered by movement) may follow myelitis episodes and respond equator), NMOSD
represents a larger
well to low-dose carbamazepine (CASE 12-2). They are frequent in NMOSD
proportion of central
myelitis (up to 50%)14 and occur more frequently with NMOSD than with MS.15 nervous system
Optic neuritis episodes in NMOSD tend to be more severe, are associated with demyelinating diseases and
less recovery, and are more frequently bilateral than in MS.5 thus should be particularly
considered in the
The third cardinal manifestation in NMOSD is area postrema syndrome,
differential in those regions.
which results in intractable nausea and vomiting with or without hiccups.5,16
These may occur as the first manifestation and lead to initial evaluation by a ● NMOSD has three
gastroenterologist (CASE 12-2). The episodes may occur in isolation, have other cardinal manifestations:
accompanying brainstem features, or evolve into a myelitis episode.17 transverse myelitis, optic
neuritis, and area postrema
Occasionally, NMOSD is reported in a paraneoplastic context.18 A wide variety of syndrome.
other less common clinical manifestations of NMOSD are outlined in TABLE 12-2.
● Systemic autoimmune
Coexisting Autoimmunity disorders or their
Systemic autoimmune disorders or their autoantibody biomarkers frequently autoantibody biomarkers
frequently coexist with
coexist with NMOSD, including systemic lupus erythematosus, Sjögren NMOSD, including systemic
syndrome, and antiphospholipid antibody syndrome.19 The presence of optic lupus erythematosus,
neuritis, transverse myelitis, or intractable vomiting in a patient with one of Sjögren syndrome, and
these disorders should prompt AQP4-IgG testing; a positive result (given its antiphospholipid antibody
syndrome.
specificity of >99%) confirms a coexisting autoimmune neurologic disorder

rather than a neurologic manifestation of a rheumatologic disorder.19 Patients

with NMOSD with antiphospholipid antibodies or its syndrome may have an
increased risk of clotting disorders, including deep vein thrombosis and
miscarriage.20 Myasthenia gravis also coexists more frequently than expected,
with NMOSD usually occurring years to decades after myasthenia diagnosis.21
MRI Abnormalities
The MRI lesions in the optic nerve, brain, and spinal cord accompanying
AQP4-IgG–seropositive NMOSD have some notable differences from MS that
can help guide clinicians on when to order AQP4-IgG testing.
OPTIC NERVE. Optic nerve involvement is often bilateral and typically involves the
posterior optic pathway, including the optic chiasm (FIGURES 12-3A and 12-3B),
with enhancement usually extending more than half the length of the nerve.22
CASE 12-1 A 60-year-old man presented with subacute weakness and numbness in
his lower extremities and neurogenic bladder requiring intermittent
catheterization. At nadir, 2 weeks after onset, he was wheelchair
dependent.
His neurologic examination revealed severe upper motor neuron–
pattern weakness in the lower extremities and a T4 sensory level. Spine
MRI revealed a longitudinally extensive T2-hyperintense lesion
(FIGURE 12-1), and brain MRI showed no lesions suggestive of multiple
sclerosis (MS). A CSF study revealed a white blood cell count of
1727 cells/mm3 (64% lymphocytes; 16% eosinophils; 13% neutrophils),
protein of 322 mg/dL (normal, 0 to 35 mg/dL), and negative oligoclonal
bands. Serum aquaporin-4 (AQP4)–IgG was positive, and a diagnosis of
AQP4-IgG–seropositive neuromyelitis optica spectrum disorder
(NMOSD) was made.
Acute treatment with high-dose IV steroids was initiated. Because of a
lack of response, seven plasma exchanges were given, with resolution of
neurogenic bladder and a return to ambulating independently. Rituximab
was then prescribed as maintenance attack-prevention immunotherapy
along with transitional oral steroids for 1 month while rituximab took
effect.
COMMENT Longitudinally extensive transverse myelitis is a hallmark feature of NMOSD

and should prompt AQP4-IgG testing. In addition to the severity of the
episode and length of the spinal cord lesion, the presence of an elevated
CSF white blood cell count (>50 cells/mm3), absence of typical MS brain
lesions, and negative oligoclonal bands were red flags indicating a
diagnosis other than MS. This patient was African American and African
Americans are particularly predisposed to NMOSD. Clinicians should have a
low threshold to initiate plasma exchange in those with prominent residual
deficits after IV steroids. Long-term attack-prevention immunotherapy is
strongly recommended, as patients have a high risk of potentially disabling
relapses.
820 JUNE 2019

BRAIN. Most patients with NMOSD will not have typical MS lesions, and
only 10% to 20% will satisfy Barkhof MS criteria.23 Typical brain involvement
in NMOSD occurs around circumventricular organs where AQP4 expression
is highest, with lesions adjacent to the third and fourth ventricles
(dorsal medulla/area postrema) most typical (FIGURES 12-3C and 12-3D).23
Other lesions can be similar to acute disseminated encephalomyelitis (ADEM),
have a posterior reversible encephalopathy syndrome (PRES)–like appearance,
or involve the internal capsule (FIGURE 12-3E) or corpus callosum diffusely or
focally in the splenium in a “bridge-arch” pattern.23 Pencil-thin linear ependymal
enhancement (FIGURE 12-3F), leptomeningeal enhancement, and cloudlike
poorly marginated enhancement are also described.23
SPINAL CORD LESION LENGTH. Longitudinally extensive transverse myelitis

(LETM), with a T2-hyperintense lesion spanning three or more contiguous
FIGURE 12-1
Imaging of the patient in CASE 12-1. Sagittal T2-weighted cervical and thoracic spine MRIs
show a longitudinally extensive T2-hyperintense lesion extending from C3 to the conus
(A–C), with some scoliosis not allowing the lesion to be visible on a single thoracic sagittal
sequence.

vertebral segments on MRI, is characteristic of NMOSD (FIGURE 12-1) and

found in approximately 85% of patients.24 LETM is a useful discriminator
from MS myelitis, which is very rarely longitudinally extensive in adults;
however, up to 14% of MS myelitis events in children can be longitudinally
extensive.25 The timing of imaging can impact the lesion length; imaging
early can reveal a short lesion that later evolves into LETM, while imaging
late can reveal a discontinuous lesion that is no longer longitudinally
extensive.
Myelitis accompanied by short lesions (less than three vertebral segments)
occurs in 14% to 15% of AQP4-IgG myelitis attacks, and many of these patients
are initially diagnosed as having MS.24,26 Features that can help suggest those
at highest risk in whom AQP4-IgG should be tested include nonwhite race,
coexisting autoimmunity (eg, lupus), tonic spasms, central cord lesion location
on axial MRI, absence of typical MS brain lesions, and lack of CSF oligoclonal
bands.24 Despite an initial short myelitis, 90% of subsequent myelitis attacks are
associated with an LETM lesion in NMOSD.24
OTHER SPINAL CORD MRI FEATURES. Other reported spinal cord lesion features
include bright spotty (syrinxlike) regions within the T2 lesion, central
lesion T1 hypointensity, and a long segment of cord atrophy. Lesion
CASE 12-2 A 63-year-old right-handed woman developed an episode of intractable

nausea, vomiting, and hiccups lasting weeks. She was evaluated by a
gastroenterologist, but extensive investigations were unrevealing. A brain
MRI was performed and revealed an enhancing lesion in the dorsal
medulla (FIGURE 12-2A). CSF at that time revealed a white blood cell count
of 55 cells/mm3 (95% lymphocytes), protein of 50 mg/dL, and negative
oligoclonal bands. The patient was treated with IV steroids. She
subsequently developed subacute myelitis, and a second MRI showed
two short lesions extending less than three vertebral segments
(FIGURES 12-2B through 12-2E). The myelitis was followed by short-lived
episodic painful spasms in her right upper extremity, which responded
well to low-dose carbamazepine. Serum aquaporin-4 (AQP4)–IgG was
positive by cell-based assay and AQP4-IgG–seropositive neuromyelitis
optica spectrum disorder (NMOSD) was diagnosed.
COMMENT Intractable nausea and vomiting from an area postrema syndrome are
recognized as a cardinal manifestation of AQP4-IgG–seropositive
NMOSD. Patients with this syndrome are often evaluated first by
gastroenterologists. Tonic spasms commonly follow NMOSD myelitis and
respond to carbamazepine. Approximately 15% of patients will have a
myelitis accompanied by a short MRI lesion (<3 vertebral segments); thus,
its presence does not exclude NMOSD, despite being less typical than the
hallmark longitudinally extensive transverse myelitis episodes (CASE 12-1).
822 JUNE 2019

enhancement after gadolinium administration is usually patchy, but ringlike
or lens-shaped enhancement occurs in one-third of patients (FIGURES 12-2D
and 12-2E).23,27 Extension of cervical lesions to the dorsal medulla/area
postrema is suggestive of 28 but not specific for NMOSD and can be seen with
other myelopathies.29
Cerebrospinal Fluid Findings

The typical CSF findings in NMOSD are summarized in TABLE 12-1.
Aquaporin-4–IgG Testing
AQP4-IgG antibody testing is available commercially and is best tested in
blood, as CSF testing is less sensitive.30 Assay techniques have improved
over time, and cell-based assays are now recommended (using
fluorescence-activated cell sorting or direct immunofluorescence); they
yield a sensitivity of 75% to 80% and specificity of greater than 99%.5,6 The
older-generation enzyme-linked immunosorbent assay (ELISA) technique is
less sensitive and has a fivefold higher risk of false positives, particularly
when low titer, and additional diagnostic scrutiny is needed in such patients,
especially if NMOSD-atypical clinical manifestations or MRI findings
are detected.31,32
FIGURE 12-2
Imaging of the patient in CASE 12-2. A, Sagittal postcontrast T1-weighted MRI shows an
enhancing lesion in the area postrema (arrow) during an episode of intractable nausea
and vomiting. B, Sagittal T2-weighted MRI sequence taken during a subsequent myelitis
episode shows a short T2-hyperintense lesion in the cervical cord (arrows). The lesion is
central on axial T2-weighted sequences (C, arrow) and exhibits ring enhancement on
sagittal (D, arrow) and axial (E, arrow) postcontrast T1-weighted images.

FIGURE 12-3
Typical brain and optic nerve lesions in patients with aquaporin-4 IgG–seropositive
neuromyelitis optica spectrum disorder (NMOSD). Axial (A) and coronal (B) postcontrast
T1-weighted images with fat suppression show bilateral posterior optic nerve enhancement
extending to the optic chiasm (arrows). Axial fluid-attenuated inversion recovery (FLAIR) MRI
shows a T2-hyperintense lesion in the region of the area postrema (C, arrow). Coronal
T2-weighted MRI shows a characteristic lesion adjacent to the third ventricle (D, arrow). Axial
FLAIR MRI shows a left internal capsule NMOSD lesion (E, arrow). Coronal postcontrast
T1-weighted MRI with fat suppression shows pencil-thin linear ependymal enhancement
(F, arrows).
Diagnostic Criteria
Updated diagnostic criteria for NMOSD were published by the International
Panel for NMO Diagnosis in 2015 (TABLE 12-3).5 The criteria stratify the diagnosis
by those with AQP4-IgG and those without AQP4-IgG (including those for
whom testing is unavailable). The criteria use core clinical characteristics
focusing on the three cardinal manifestations of optic neuritis, myelitis, and
an area postrema syndrome, in addition to less common manifestations of
other brainstem attacks, diencephalic episodes, and cerebral episodes. The
presence of one of these core clinical characteristics in addition to AQP4-IgG
seropositivity and exclusion of other etiologies allows the diagnosis of NMOSD
with AQP4-IgG to be made. The criteria for patients who areAQP4-IgG
seronegative are more stringent, requiring additional characteristic radiologic
features be present to help avoid misdiagnosis.
824 JUNE 2019

Neuromyelitis Optica Spectrum Disorder Diagnostic Criteriaa TABLE 12-3
Diagnostic criteria for neuromyelitis optica (NMOSD) with aquaporin-4 (AQP4) IgG
1 At least one core clinical characteristic
2 Positive test for AQP4-IgG using best available detection method (cell-based assay
strongly recommended)
3 Exclusion of alternative diagnoses
Diagnostic criteria for NMO without AQP4-IgG or NMOSD with unknown AQP4-IgG status
1 At least two core clinical characteristics occurring as a result of one or more clinical attacks
and meeting all of the following requirements:
a At least one core clinical characteristic must be optic neuritis, acute myelitis with
longitudinally extensive transverse myelitis, or area postrema syndrome
b Dissemination in space (two or more different core clinical characteristics)
c Fulfillment of additional MRI requirements, as applicable
2 Negative tests for AQP4-IgG using best available detection method, or testing unavailable
3 Exclusion of alternative diagnoses
Core clinical characteristics
1 Optic neuritis
2 Acute myelitis
3 Area postrema syndrome: episode of otherwise unexplained hiccups or nausea and vomiting
4 Acute brainstem syndrome
5 Symptomatic narcolepsy or acute diencephalic clinical syndrome with NMOSD-typical
diencephalic MRI lesions
6 Symptomatic cerebral syndrome with NMOSD-typical brain lesions
Additional MRI requirements for NMOSD without AQP4-IgG and NMOSD with unknown
AQP4-IgG status
1 Acute optic neuritis: requires brain MRI showing (a) normal findings or only nonspecific
white matter lesions, OR (b) optic nerve MRI with T2-hyperintense lesion or T1-weighted
gadolinium-enhancing lesion extending over more than half optic nerve length or involving
optic chiasm
2 Acute myelitis: requires associated intramedullary MRI lesion extending over ≥3 contiguous
segments (longitudinally extensive transverse myelitis) OR ≥3 contiguous segments of
focal spinal cord atrophy in patients with history compatible with acute myelitis
3 Area postrema syndrome: requires associated dorsal medulla/area postrema lesions
4 Acute brainstem syndrome: requires associated periependymal brainstem lesions
IgG = immunoglobulin G; MRI = magnetic resonance imaging.

a
Reprinted with permission from Wingerchuk DM, et al, Neurology.5 © 2015 American Academy of Neurology

Aquaporin-4 IgG–Seronegative Neuromyelitis Optica Spectrum Disorder

Approximately 20% to 25% of patients with NMOSD are AQP4-IgG
seronegative. Up to 25% of patients with seronegative NMOSD will have
antibodies to MOG-IgG, as discussed below. The treatment approach to
AQP4-IgG–seronegative NMOSD is similar to AQP4-IgG–seropositive NMOSD.
Pathogenesis and Pathology

AQP4-IgG binds to AQP4, which is located on the end-feet of astrocytes,
initiating a cascade of immune-mediated inflammation resulting in secondary
demyelination.
A full discussion of the pathogenesis of NMOSD is beyond the scope of
this article but has been reviewed previously.33,34 Biopsy and autopsy studies
of patients with NMOSD show that lesions are associated with loss of
myelin, infiltration of inflammatory cells (macrophages, T cells and B cells,
neutrophils, eosinophils), and axonal and astrocyte loss.35 A rim-and-rosette
pattern of immunoglobulin deposition colocalized with complement is also
seen.35 AQP4 immunostaining is lost within NMOSD lesions, and cortical lesions
are not found, helping distinguish it from MS, in which AQP4 immunostaining is
preserved or increased and cortical lesions are common.36
Treatment
Treatment of NMOSD is divided into acute attack treatment and maintenance
(attack-prevention) treatment.
ATTACK TREATMENT. High-dose corticosteroids (1000 mg IV methylprednisolone

daily for 5 days) are used initially. The use of plasma exchange for five to
seven exchanges for severe, corticosteroid-refractory CNS inflammatory
demyelinating attacks is supported by data from a prospective randomized
sham-controlled crossover trial.37 The author recommends a low threshold to use
plasma exchange in those not improved or with incomplete recovery after
steroids (CASE 12-1), and a 2016 evaluation of more than 800 NMOSD attacks
highlighted its benefit.38
MAINTENANCE THERAPY. The importance of maintenance attack-prevention

immunotherapy in NMOSD is evidenced by the increasing recognition of this
disease as a relapsing disorder, compared to initial descriptions as a monophasic
disease. Despite the lack of completed randomized controlled trials in NMOSD,
preventive treatment is strongly recommended in all patients. This approach is
supported by the severity of attacks and incomplete recovery, leading to a risk of
accumulating disability with each attack, which differs from MS attacks
(TABLE 12-1). The goals of treatment are to prevent relapses while limiting side
effects. The three most commonly used medications are azathioprine,
mycophenolate mofetil, and rituximab; some observational data have suggested
that azathioprine may not be as effective as rituximab and mycophenolate
mofetil.33 Choice of treatment may depend on local availability, cost, patient
preference, and duration of concomitant oral steroids needed while the
immunosuppressant takes effect. The dosage recommendations for these
medications are outlined in TABLE 12-4. Because of its lower cost and more
widespread availability, methotrexate has also been used. Consideration for
switching maintenance immunotherapy arises if disease breakthrough occurs or
if intolerable severe side effects occur.
826 JUNE 2019

TREATMENT TRENDS IN NEUROMYELITIS OPTICA SPECTRUM DISORDER. AQP4-IgG KEY POINTS
is an IgG1 and thus can activate complement, which appears to play a role in
● In NMOSD, optic nerve
promoting the cascade of immune-mediated inflammation that follows involvement is often
AQP4-IgG binding; it is also notable that complement deposition is evident bilateral and typically
pathologically.33,35 The C5 complement inhibitor eculizumab showed possible involves the posterior optic
efficacy for attack prevention in a phase 2 open-label pilot study39 and is pathway, including the optic
chiasm, with enhancement
currently undergoing a phase 3 randomized clinical trial. After B-cell activation
usually extending more than
in lymph nodes, B cells (CD20+, CD19+) differentiate into plasmablasts half the length of the nerve.
(CD19+, CD20–) and plasma cells (CD19–, CD20–); the latter two B-cell subsets
account for the majority of antibody production. IL-6 is necessary for ● Typical brain involvement
plasmablast survival and appeared to be important in experimental studies of in NMOSD occurs around
circumventricular organs
NMOSD pathogenesis.12 Thus, there has been interest in treatments targeting where AQP4 expression is
CD19+ plasmablasts and IL-6. A randomized placebo-controlled study of highest, with lesions
inebilizumab (previously known as MEDI-551), a monoclonal antibody adjacent to the third and
targeting CD19 in attack prevention, is currently under way. Tocilizumab is an fourth ventricles (dorsal
medulla/area postrema)
antibody targeting IL-6 that has been repurposed from its use in rheumatoid most typical.
arthritis; retrospective studies suggest it may be a useful treatment in NMOSD,
with reductions in neuropathic pain a novel added benefit.40 Another IL-6 ● Longitudinally extensive
receptor monoclonal antibody, SA237, is currently being studied in a transverse myelitis, with a
T2-hyperintense lesion
randomized controlled clinical trial. Other approaches currently in
spanning three or more
development include AQP4 blocking antibodies in animal models, inhibitors contiguous vertebral
of neutrophils (sivelestat) or eosinophils (cetirizine), and studies of segments on MRI, is
immune tolerance.33 characteristic of NMOSD
and found in approximately
TREATMENT RISKS. Long-term immunosuppression is currently recommended 85% in patients.
in all patients with NMOSD, but the long-term risks have yet to be established.
● Assay techniques for
A single case of progressive multifocal leukoencephalopathy in NMOSD treated AQP4-IgG have improved
with azathioprine has thus far been reported.41 Opportunistic retinal infections over time, and cell-based
(toxoplasmosis, cytomegalovirus) from immunosuppression in NMOSD can assays are now
mimic optic neuritis attacks.42 Further studies are needed to determine whether, recommended (using
fluorescence-activated
in some patients, maintenance immunotherapy could be discontinued safely and
cell sorting or direct
thus reduce the risks associated with long-term immunosuppression. immunofluorescence); they
yield a sensitivity of 75% to
MYELIN OLIGODENDROCYTE GLYCOPROTEIN ANTIBODY DISEASE 80% and specificity of
MOG has been of interest to researchers for decades given its location on the greater than 99%.
surface of oligodendrocytes, making it a potential target for pathogenic
● Approximately 20% to
antibodies. Initial studies suggested that MOG-IgG was a biomarker of MS, 25% of patients with NMOSD
but these studies were hampered by older-generation techniques (ELISA, are AQP4-IgG seronegative.
Western blot) and failure to use MOG in its human conformational form.43
With the use of cell-based assays transfected with MOG in its conformational ● AQP4-IgG binds to AQP4,
which is located on the
form, the antibody has been shown to be a specific biomarker of a spectrum end-feet of astrocytes,
of CNS inflammatory demyelinating disease distinct from MS and initiating a cascade of
AQP4-IgG–seropositive NMOSD.43 The three disorders are compared in immune-mediated
TABLE 12-1. inflammation resulting in
secondary demyelination.
Nomenclature
No single term is widely accepted to describe this disease. Most recently, the term
MOG-antibody (MOG-IgG) disease has been suggested44; this term is used in
this article, although other terms used include MOG/MOG-IgG paired with the
relevant syndrome (encephalomyelitis, myelitis, NMOSD, optic neuritis, and
demyelinating disease).43,45

Demographics
In contrast to AQP4-IgG–seropositive NMOSD and MS, which have a female
predominance, the sex distribution with MOG-IgG disease appears to be more
equal, although a slight female predominance was reported in the largest clinical
series to date.44 MOG-IgG disease appears to have a particular predilection for
children and young adults, but any age can be impacted.44,46 The incidence and
prevalence of this disease have not yet been well elucidated, and population-
based epidemiologic studies are lacking. In the only population-based study of
autoimmune encephalitis including ADEM, MOG-IgG was the most frequent
antibody detected.47
Clinical Features
Preceding prodromal symptoms are commonly encountered and can include fever,
rhinorrhea, malaise, and cough, which can sometimes lead to the suspicion of an
infectious rather than immune-mediated disorder. The major clinical manifestations
include optic neuritis, ADEM, NMOSD (seronegative for AQP4-IgG), transverse
myelitis, and brainstem demyelinating episodes.43 The clinical presentation is in the
form of attacks that are subacute in onset similar to other CNS inflammatory
demyelinating diseases, with optic neuritis being the most common and accounting
TABLE 12-4 Common Maintenance Immunotherapy Regimens for Neuromyelitis Optica

Spectrum Disordera
Medication/Dose/Regimen (Adults) Precautions/Monitoring/Prophylaxis Common/Important Side Effects

Corticosteroids: prednisone/
methylprednisolone
1 mg/kg prednisone orally once daily Precautions/monitoring: assess for Infection, osteoporosis,
initially hyperglycemia if diabetic/at risk, baseline avascular necrosis of the hip,
bone density scan in those at risk cushingoid appearance, skin
If adding rituximab, use prednisone
thinning and easy bruising,
concurrently for 1 month and then taper Prophylaxis: calcium 1500 mg/d
insomnia, psychosis, depression,
and vitamin D 800 IU/d, trimethoprim-
If adding azathioprine or mycophenolate cataracts, hypertension, weight
sulfamethoxazole one double-strength
mofetil, use prednisone concurrently for gain and edema; addisonian crisis
tablet (800 mg/160 mg) 3 times per
6 months and taper over next 6 months; with abrupt discontinuation
week, proton pump inhibitor/histamine-2
consider low doses (10–20 mg) in
receptor blocker in those at high risk for
addition to azathioprine or
gastrointestinal ulceration
mycophenolate mofetil to maintain
remission if necessary
Induction therapy of 1 g IV
methylprednisolone daily for 5 days may
be used before starting oral prednisone
Azathioprine
Target dose: 2.5–3 mg/kg/d orally in Precautions/monitoringb: measure Infection, malignancy (lymphoma,
divided doses thiopurine S-methyltransferase enzyme skin cancers and others), nausea,
activity before startingc; complete blood macrocytic anemia, skin rash,
cell count,d renal function, and liver hypersensitivity reaction, drug
function at baseline, then weekly for fever, pancreatitis, elevated liver
1 month, every other week for 2 months function tests
and monthly thereafter
828 JUNE 2019

for the majority of relapses. The clinical presentation and radiologic appearance of
MOG-IgG myelitis may mimic that of the acute flaccid myelitis associated with
enterovirus infections.45 The episodes tend to be more severe than with MS
(CASE 12-3) but have better recovery than AQP4-IgG–seropositive NMOSD.43
MOG-IgG–related optic neuritis is associated with optic disc edema in
approximately 86% of patients, and 30% to 50% may be bilateral, distinguishing
it from MS optic neuritis in which both of these features are rare.48 MOG-IgG is
found in 15% of patients with recurrent optic neuritis without other nervous
system involvement, similar to the 13% frequency of AQP4-IgG in these patients.49
In contrast, MOG-IgG is rarely encountered (2%) with recurrent LETM, in which
AQP4-IgG accounts for up to 90% of cases.50 Bowel and bladder disturbance and
erectile dysfunction in men are common with MOG-IgG myelitis, likely due to the
frequent conus involvement.44 Episodes of intractable nausea and vomiting have
been reported, although much less frequently than with AQP4-IgG.44 Rare cases of
hemi-encephalitis and seizures have been reported with MOG-IgG.51,52
Clinical Course and Prognosis

Some patients have a monophasic course, while others go on to develop relapsing
disease. Higher titers and persistent MOG-IgG positivity over time predict a higher
Medication/Dose/Regimen (Adults) Precautions/Monitoring/Prophylaxis Common/Important Side Effects

Mycophenolate mofetil
Target dose: 1000 mg 2 times a day Monitoringb: complete blood cell count, Infection, increased risk of
orally (start at 500 mg 2 times a day renal function, and liver function at malignancy (lymphoma, skin
for 1–2 weeks, then increase to baseline, then weekly for 1 month, every cancers, and others), diarrhea,
maintenance dose of 1000 mg other week for 2 months, and monthly hypertension, hepatitis,
2 times a day) thereafter myelosuppression, renal failure
Rituximab
Initial dosee: two doses of 1000 mg Monitoringb: complete blood cell count Infusion reactions, infection
IV, 2 weeks apart monthly; CD 19+ and CD27+ counts are (opportunistic infections
monitored by somef including progressive multifocal
Redosingf every 6 months: two doses
leukoencephalopathy [risk 1/
of 1000 mg IV, 2 weeks apart
20,000]), myelosuppression,
human antichimeric antibodies,
hepatitis B reactivation,
tuberculosis reactivation
IV = intravenous.
a
Modified with permission from Flanagan EP, Weinshenker BG, Curr Neurol Neurosci Rep.12 © 2014 Springer Science+Business Media.
b
Trimethoprim-sulfamethoxazole one double-strength tablet (800 mg/160 mg) 3 times a week may be considered for Pneumocystis jiroveci
prophylaxis, but evidence for its use in this context is limited and guidelines are lacking.
c
Low activity (heterozygote for TPMT gene) increases risk for drug toxicity and may require slower titration and increased monitoring/use of
alternative agent. If no activity (homozygote for TPMT gene), use alternative agent.
d
Consider monitoring mean corpuscular volume; increases of >5 femtoliters may be associated with improved efficacy.
e
Some use an alternative dosing strategy of four weekly doses of 375 mg/m2.
f
Monitoring of CD19+ counts is done by some with redosing when CD19+ cells begin to return, although many prefer to redose every 6 months
(1000 mg repeated in 2 weeks) regardless of B-cell counts because rapid B-cell repopulation may occur that may be missed by monthly
monitoring and patients are vulnerable to relapse during repopulation periods.

risk of relapse in children and adults, as illustrated by CASE 12-3.46,53 Those with
transient seropositivity are likely to follow a monophasic course.46,53 Some may have
corticosteroid-dependent optic nerve involvement, termed chronic relapsing
inflammatory optic neuropathy.48 Relapses are dominated by optic neuritis, and
most permanent disability appears to arise from the initial episode. In contrast to
MS, a secondary progressive course has not been reported.
Radiologic Accompaniments
The MRI features of MOG-IgG disease have notable differences from AQP4-
IgG–seropositive NMOSD and MS that can help suggest those at highest risk in
whom MOG-IgG should be tested.
CASE 12-3 A 47-year-old man was admitted to the hospital with a rapidly progressive
quadriparesis and encephalopathy following a viral prodrome. At his nadir
2 weeks from onset, he required mechanical ventilation, and his examination
revealed quadriplegia, hyperreflexia, spasticity, and extensor plantar
responses bilaterally. MRI of the brain and cervical spine were abnormal,
showing multifocal white matter lesions and a myelitis lesion (FIGURE 12-4). CSF
analysis revealed a white blood cell count of 139/mm3 (75% lymphocytes),
protein of 74 mg/dL, and negative oligoclonal bands. Serum aquaporin-4
(AQP4)–IgG was negative. He underwent a brain biopsy after having no
response to high-dose IV corticosteroids, which showed myelin loss,
perivascular macrophage infiltrate, and relatively preserved axons consistent
with acute disseminated encephalomyelitis (ADEM). Myelin oligodendrocyte
glycoprotein (MOG) IgG was tested and returned positive by live cell-based
assay at high titer, confirming a MOG-IgG disease diagnosis. He completed
seven plasma exchange treatments and received oral prednisone with a
slow taper.
Three months later, his neurologic examination was normal and his MRI
lesions had resolved. During prednisone tapering, he developed right
optic neuritis, which was treated with IV methylprednisolone, a slower
taper of oral prednisone, and azathioprine as maintenance steroid-
sparing immunotherapy. Serum MOG-IgG remained persistently positive
2.5 years after onset.
COMMENT ADEM is a hallmark episode of MOG-IgG–related disease. The preceding

viral prodrome, severity of the episode, longitudinally extensive spinal cord
lesion, CSF white cell count of greater than 50/mm3, and absence of
oligoclonal bands were all atypical for multiple sclerosis. Despite severe
attacks, patients often have excellent recovery after acute treatment, as
was seen in this patient. High titers of MOG-IgG at onset and persistent
seropositivity over time predict relapsing disease. Relapses in MOG-IgG
disease are dominated by optic neuritis. Steroid-sparing immunosuppressants
are often used for attack prevention, particularly in relapsing disease,
although randomized controlled trials have not yet been undertaken.
830 JUNE 2019

OPTIC NERVE. Enhancement involves more than half of the length of the optic
nerve in 80% of patients and may involve the optic nerve sheath (FIGURE 12-5A)
or extend into the orbital fat.48 Bilateral anterior pathway optic nerve
enhancement without extension to the optic chiasm (FIGURE 12-5B) is more
typical of MOG-IgG than AQP4-IgG.54
BRAIN. Multifocal white matter T2 hyperintensities (FIGURE 12-4A) with

involvement of the deep gray matter (FIGURE 12-5C) are typical of MOG-IgG
disease, particularly with ADEM-like presentations. Infratentorial lesions tend
to be more diffuse than with MS (TABLE 12-1). However, in contrast to MS, ovoid
periventricular, inferior temporal pole, and Dawson finger lesions are typically not
FIGURE 12-4
Imaging of the patient in CASE 12-3. A, Axial fluid-attenuated inversion recovery (FLAIR) MRI
shows multifocal fluffy T2 hyperintensities that are typical of acute disseminated
encephalomyelitis (ADEM) and that did not have accompanying enhancement (not shown).
B, Sagittal T2-weighted cervical spine MRI shows an accompanying slightly discontinuous
longitudinally extensive T2-hyperintense spinal cord lesion (arrow) that also lacked
enhancement (not shown).

FIGURE 12-5
Typical optic nerve and brain lesions in patients with myelin oligodendrocyte glycoprotein
antibody (MOG-IgG) disease. A, Coronal postcontrast T1-weighted orbital MRI shows
enhancement of the optic nerve and its surrounding sheath (arrow). B, Axial postcontrast
T1-weighted orbital MRI shows bilateral anterior optic nerve enhancement (arrows). C, Axial
fluid-attenuated inversion recovery (FLAIR) MRI shows a T2-hyperintense lesion in the right
thalamus (arrow), typical of the deep gray matter involvement of MOG-IgG.
FIGURE 12-6
Typical spinal cord lesions in patients with myelin oligodendrocyte glycoprotein antibody
(MOG-IgG) disease. A, Sagittal thoracic T2-weighted sequence shows a longitudinally
extensive hyperintense lesion extending for four and a half vertebral segments (arrows).
B, Sagittal T2-weighted cervical spine MRI shows a short T2-hyperintense lesion extending
two vertebral segments and forming a sagittal line (arrow). C, Sagittal T2-weighted thoracic
MRI shows a short hyperintense lesion extending one vertebral segment and involving the
conus (arrow). D, The T2 hyperintensity is central on axial sequences and highly confined
to the gray matter, forming an H pattern (arrow). E, The lesion is again confined to the gray
matter, forming an H pattern on axial view (arrow).
832 JUNE 2019

present.55 The brain MRI is more difficult to distinguish from NMOSD than MS.55
Cortical lesions and leptomeningeal enhancement have also been reported.52
SPINAL CORD. Longitudinally extensive lesions (FIGURE 12-6A) occur in the
majority (60% to 80%), while the remainder may be short (FIGURE 12-6B), although
both may be present simultaneously. In contrast to AQP4-IgG (in which a
solitary LETM is typical), with MOG-IgG, it is not uncommon to have two
separate lesions with the conus often involved (FIGURE 12-6C).45 Lesions are
usually central on axial sequences, which differs from MS (TABLE 12-1).56 The
T2-signal abnormality can be restricted to gray matter, forming a sagittal line
(FIGURE 12-6B) and axial H sign (FIGURES 12-6D and 12-6E) in approximately
one-third of patients, differing from central lesions of AQP4-IgG, which
typically involve both gray and white matter.45
Cerebrospinal Fluid Findings in Myelin Oligodendrocyte Glycoprotein IgG

Positive oligoclonal bands are found in less than 15% of patients with
MOG-IgG.44,52 The other CSF findings are reviewed and compared to
AQP4-IgG and MS in TABLE 12-1.
Myelin Oligodendrocyte Glycoprotein–IgG Testing

A 2018 consensus article outlined patients in whom MOG-IgG should be tested
and recommended against testing MOG-IgG in all patients with MS, given the
risk of false positives when testing in low-probability situations.57 In general,
testing should be reserved for those with one of the classic phenotypes of
MOG-IgG disease (TABLE 12-1) that lacks characteristic features of MS.
Testing with a cell-based assay (with direct visual immunofluorescence or
fluorescence-activated cell sorting) is strongly recommended.57 Blood testing is
recommended for MOG-IgG, and the role of CSF MOG-IgG is uncertain.57
Detection with ELISA, Western blot, or assays using the nonconformational
MOG epitope should be avoided.57
Some patients with MOG-IgG, particularly children with an ADEM phenotype,
appear to have a monophasic course. In these patients, MOG-IgG elevation is often
transient, and follow-up testing after 6 to 12 months is often negative. Some
studies have shown that higher MOG-IgG titers at onset are associated with an
increased risk of relapse, but this requires further study.46 In addition, persistent
seropositivity may predict relapse.46,53 The author generally recommends repeat
testing 6 months after the initial episode to assist prognostication.
Pathogenesis and Pathology

Pathology case reports have shown overlap with pattern II MS (demyelinating
lesions with an inflammatory infiltrate of T cells and macrophages with
accompanying complement deposition).58 A full discussion of the potential
pathogenesis of MOG-IgG is beyond the scope of this article but has been
reviewed elsewhere.59
Treatment
No randomized clinical trial data are available to guide clinicians in treating
MOG-IgG disease. Acute treatments for MOG-IgG are very similar to those for
NMOSD. A major area of study is determining which patients may have a
monophasic disorder and not require treatment. For patients with relapsing disease,
the maintenance treatment approach is almost identical to that of acute and

maintenance therapy for NMOSD (outlined above), although IV

immunoglobulin (IVIg) appears to be useful in children acutely and as a
maintenance treatment.60
ACUTE DISSEMINATED ENCEPHALOMYELITIS AND OTHER CNS

INFLAMMATORY DEMYELINATING DISEASES
Despite the discovery of neural antibody biomarkers of CNS inflammatory
demyelinating diseases, many diseases in this category lack antibody biomarkers.
At the author’s facility, testing AQP4-IgG and MOG-IgG is recommended in
all patients with ADEM, but more than 50% will be seronegative for both. ADEM
is most common in children, and the presentation often follows vaccination or an
infectious prodrome. The MRI findings include multifocal white matter T2
hyperintensities, deep gray matter lesions, and longitudinally extensive spinal cord
lesions. Acute treatment is similar to the approach outlined with NMOSD above.
Many patients with ADEM have a monophasic course, but some can go on to
develop typical MS or further non-MS relapsing course (eg, multiphasic ADEM),
and, although many of this latter group will be MOG-IgG seropositive, some are
seronegative. Other patients can have recurrent attacks of CNS demyelination
restricted to one site (eg, recurrent optic neuritis or recurrent transverse myelitis)
that do not meet criteria for MS and are seronegative for AQP4-IgG and
MOG-IgG.49,50 This subset of patients represents an important focus for research
to determine if antibody biomarkers that define those diseases exist. Treatment
for these disorders is similar to the approach for NMOSD.
OTHER INFLAMMATORY CNS DISORDERS

A wide variety of other inflammatory CNS diseases can mimic MS, which practicing
neurologists should be aware of; these are
discussed in the following sections.
Autoimmune Glial Fibrillary Acidic

Protein Astrocytopathy
In 2016, an antibody to glial fibrillary acidic
protein (GFAP-IgG) was reported
that, when detected in CSF, appeared to be
specific for an inflammatory
meningoencephalomyelitis, termed
autoimmune GFAP astrocytopathy.61 Patients
of any age can be impacted (median age of
44 years), and the frequency is similar in
males and females.62 Clinical manifestations
include subacute to chronic meningitis
(headache, neck stiffness, photophobia),
encephalitis (memory loss, tremor, ataxia),
and myelitis (urinary retention, numbness,
weakness), and thus some of its features
can mimic MS.62,63 Bilateral optic disc FIGURE 12-7
edema is a helpful clue, but intracranial Axial postcontrast T1-weighted MRI
reveals the typical radial enhancement
pressure is typically normal and thus does
accompanying antibodies to
not reflect papilledema.64 The myelitis autoimmune glial fibrillary acidic
features tend to be mild and occur in protein (GFAP) astrocytopathy.
834 JUNE 2019

conjunction with encephalitis; an isolated myelitis generally does not occur.65 KEY POINTS
Coexisting neoplasms, particularly teratoma, may be seen.62 N-Methyl-D-aspartate
● The use of plasma
(NMDA) receptor autoantibodies and AQP4-IgG may coexist.62 Samples are best exchange for five to seven
tested in CSF for optimal sensitivity and specificity; dual testing is recommended exchanges for severe,
using tissue immunofluorescence and cell-based assay confirmation of GFAP corticosteroid-refractory
central nervous system
(GFAPα appears to be the most sensitive isoform).62 Care is needed with serum
inflammatory demyelinating
positivity alone because of a high attacks is supported by data
risk of false positives. Brain MRI from a prospective
may reveal a characteristic radial randomized sham-controlled
crossover trial.
perivascular enhancement
perpendicular to the ventricles ● Despite the lack of
(FIGURE 12-7),62 although a similar completed randomized
pattern can be seen with controlled trials in NMOSD,
preventive treatment is
intravascular lymphoma, strongly recommended in
neurosarcoid, and CNS vasculitis. all patients.
Leptomeningeal enhancement is
also common. In the spinal cord, a ● With the use of
cell-based assays
longitudinally extensive faint T2 transfected with myelin
hyperintensity may be seen with oligodendrocyte
central canal or punctate glycoprotein (MOG) in its
parenchymal enhancement.65 The conformational form, the
antibody has been shown to
vast majority (>85%) of patients be a specific biomarker of a
with autoimmune GFAP spectrum of central nervous
astrocytopathy will have an system inflammatory
demyelinating disease
elevated CSF white cell count,
distinct from multiple
and oligoclonal bands are sclerosis and AQP4-
detected in half.62 Response to IgG–seropositive NMOSD.
steroids is generally brisk,
● The major clinical
although a less corticosteroid-
manifestations of MOG-IgG
responsive phenotype was noted disease include optic
in an Asian cohort.66 Prolonged neuritis, acute disseminated
oral corticosteroids are the most encephalomyelitis, NMOSD
(seronegative for AQP4-IgG),
frequent treatment used, and transverse myelitis, and
relapse is frequent during steroid brainstem demyelinating
tapering.62 Corticosteroid-sparing episodes.
agents are often prescribed to try
● Some patients with
to maintain remission, although MOG-IgG disease have a
randomized controlled trials monophasic course, while
are lacking.62 others go on to develop
relapsing disease.
Diagnostic Pearls With FIGURE 12-8

● Radiologic findings in
Inflammatory/Autoimmune Imaging of a patient with paraneoplastic myelitis.
MOG-IgG disease include
Sagittal T2-weighted cervical spine MRI shows a
Disorders Associated With longitudinally extensive hyperintensity (A,
enhancement that involves
Other Autoantibody Biomarkers more than half of the length
arrows). Sagittal (B) and axial (C) postcontrast
of the optic nerve in 80% of
Neurologic syndromes associated T1-weighted images of the same patient show
patients and may involve the
with collapsin response mediator enhancement in a characteristic tract-specific
optic nerve sheath or extend
pattern extending along both lateral columns
protein-5 (CRMP-5) autoantibody on axial sequences (C, arrows).
into the orbital fat.
(CRMP-5-IgG/anti-CV2) include Reprinted with permission from Flanagan EP et al,
optic neuropathy, retinitis, and Neurology.67 © 2016 American Academy of Neurology.

FIGURE 12-9
Axial postcontrast T1-weighted MRI shows
punctate foci of enhancement that are pontine
predominant (arrow) but also involve the
cerebellum (arrowhead) in a patient with chronic
lymphocytic inflammation with pontine
perivascular enhancement responsive to
steroids (CLIPPERS).
FIGURE 12-11
Sagittal T2-weighted cervical spine MRI of a
patient with spinal cord sarcoidosis shows a
longitudinally extensive T2-hyperintense lesion
(A, arrow) accompanied, on postcontrast
T1-weighted sagittal image, by hallmark dorsal
subpial enhancement (B, arrows) and central canal
enhancement (B, arrowheads), which on axial
postcontrast T1-weighted images form a trident
appearance (C, arrow).
Reprinted with permission from Zalewski NL, et al,
Neurology.71 © 2016 American Academy of Neurology
FIGURE 12-10
Axial T2-weighted MRI shows a hyperintense left
midbrain lesion in a patient with Behçet syndrome.
836 JUNE 2019

myelitis and thus can mimic MS KEY POINTS
or NMOSD.67 Spinal cord
● Multifocal white matter
T2-hyperintense lesions tend to T2 hyperintensities with
be longitudinally extensive and involvement of the deep
involve lateral or dorsal columns, gray matter are typical in
with a characteristic symmetric MOG-IgG disease,
particularly with acute
tract-specific enhancement
disseminated
sometimes seen (FIGURE 12-8).67 encephalomyelitis–like
The myelopathy may mimic presentations.
primary progressive MS.67 The
oncologic associations include ● Positive oligoclonal bands
are found in less than 15%
small cell lung cancer and of patients with MOG-IgG.
thymoma. γ-Aminobutyric acid
(GABA)A receptor autoantibodies ● A 2018 consensus article
can mimic MS on MRI with outlined patients in whom
MOG-IgG should be tested
multifocal white matter and and recommended against
cortical lesions.68 The disease testing MOG-IgG in all
has a particular predilection for patients with multiple
children and can occur as a sclerosis, given the risk of
FIGURE 12-12 false positives when testing
Sagittal fluid-attenuated inversion recovery postinfectious phenomenon
in low-probability situations.
(FLAIR) MRI of a patient with Susac syndrome after viral encephalitis or In general, testing for
shows snowball-like T2-hyperintense lesions may be paraneoplastic MOG-IgG should be
predominating in the corpus callosum (arrows).
(eg, thymoma).68 reserved for those with one
of the classic phenotypes
that lacks characteristic
Chronic Lymphocytic Inflammation With Pontine Perivascular features of multiple
Enhancement Responsive to Steroids sclerosis.
Chronic lymphocytic inflammation with pontine perivascular enhancement
responsive to steroids (CLIPPERS) is an inflammatory disorder of uncertain ● A major area of study in
MOG-IgG disease is
cause that may mimic MS. The presentation is that of a progressive brainstem determining which patients
syndrome with accompanying ataxia. The hallmark MRI finding is a may have a monophasic
disorder and not require
treatment.
● For patients with

relapsing MOG-IgG disease,
the treatment approach is
almost identical to that of
acute and maintenance
therapy for NMOSD,
although IV immunoglobulin
appears to be useful in
children acutely and as a
maintenance treatment.
● In 2016, an antibody to
glial fibrillary acidic protein
(GFAP) was reported that,
when detected in CSF,
appeared to be specific
for an inflammatory
FIGURE 12-13
meningoencephalomyelitis,
Imaging of a patient with primary angiitis of the central nervous system. Axial
termed autoimmune GFAP
susceptibility-weighted imaging (SWI) shows parenchymal microhemorrhages (A, arrowhead)
astrocytopathy.
and sulcal superficial siderosis, noted as dark regions with accompanying leptomeningeal
enhancement (B, arrows).

multifocal bilateral punctate (<3 mm) enhancement pattern that is centered on

the pons and often extends to the cerebellum (FIGURE 12-9).69 The absence of
mass effect is an important feature.70 CSF shows an elevated white cell count in
one-third of patients, but oligoclonal bands are infrequent (<10%). Pathology
shows dense perivascular inflammation with a T-cell predominance.70
Diagnostic criteria have been proposed and should be stringently adhered to as,
in addition to MS, lymphoma and neurosarcoid can mimic this disorder.70
Biopsy to exclude lymphoma is important if atypical features are present.70 Oral
corticosteroids and corticosteroid-sparing immunosuppressants are the mainstay
of treatment.
Neuro-Behçet Disease
Neuro-Behçet disease characteristically involves the brainstem (FIGURE 12-10),
although myelitis and cerebral venous sinus thrombosis are also reported.
Individuals from the old Silk Road (Middle East and Asia) are predisposed.
The presence of oral and genital ulcers, pathergy (exaggerated skin injury to
TABLE 12-5 Noninflammatory Diseases With Features That Mimic Central Nervous
System Inflammation
Mimic of Central Clinical MRI Discriminators

Nervous System Discriminators From From Multiple Other Helpful
Category/Disease Inflammation Multiple Sclerosis Sclerosis Investigations
Neoplastic
Primary central Increased CSF cells, Older age, Deep gray matter CSF cytology/
nervous system multifocal enhancing risk factors involvement; flow abnormal
lymphoma lesions, steroid- (immunosuppression persistent
responsive [HIV, transplant]) enhancement
(>3 months)
Erdheim-Chester Brainstem/ Bone pain, Persistent X-ray/bone scan

disease cerebellar older age enhancement for showing
enhancing lesions; more than 3 months osteosclerosis of long
inflammatory CSF bones; BRAF genetic
may occur testing or staining on
pathology
Genetic
Alexander disease Enhancing brainstem Family history Tadpole sign GFAP mutation
lesions and (autosomal (normal-sized pons,
multifocal brainstem dominant); with atrophic
signal abnormality progressive medulla), spinal
course cord atrophy
Adrenoleukodystrophy/ Enhancement at Family history Diffuse cord atrophy Long chain fatty
Adrenomyeloneuropathy edge of diffuse (X-linked); male; without spinal cord acids; ABCD1 gene
white matter T2 adrenal failure lesions
hyperintensity
838 JUNE 2019

minor trauma), and uveitis are useful clinical clues. The CSF is often
neutrophilic, helping to distinguish Behçet disease from MS, and HLA-B51
may be positive.
Neurosarcoidosis
Neurosarcoidosis should be included among the differential diagnosis of MS as
it can manifest with multifocal involvement of the CNS, including the optic
nerve, brain, or spinal cord. An elevated CSF white cell count and enhancing
lesions overlap with MS, but oligoclonal bands are usually absent; basilar
leptomeningeal enhancement and spinal cord linear dorsal subpial enhancement
extending two or more vertebral segments are suggestive.14 Occasionally, dorsal
subpial enhancement is accompanied by central canal enhancement, forming a
hallmark trident appearance on axial images (FIGURE 12-11).71 Clinical and
radiologic recurrence is frequent when IV steroids are discontinued, and
persistence of enhancement beyond 3 months helps distinguish from MS, where
enhancement is typically transient, resolving within 2 months. Prolonged
Mimic of Central Clinical MRI Discriminators

Nervous System Discriminators From From Multiple Other Helpful
Category/Disease Inflammation Multiple Sclerosis Sclerosis Investigations
Vascular
Spinal cord infarct May have Acute onset (time to Restricted diffusion; Lacks confirmatory
enhancement, nadir <12 hours), axial anterior horn tests
occasional mild severe deficit, cell T2 signal (owl
CSF pleocytosis vascular risk factors eye, snake eye);
vertebral body
infarct; adjacent
dissection
Dural arteriovenous 50–60% have Stepwise worsening Thoracic cord with Formal spinal
fistula parenchymal with exercise/ conus involved; angiogram
enhancement Valsalva; worse with flow voids; missing necessary for
steroids piece sign with diagnosis
section lacking
enhancement
Structural
Cervical spondylotic Enhancement (7%); Progressive course, Pancakelike Flexion/extension

myelopathy occasional CSF neck pain, coexisting enhancement MRI can help
inflammation radiculopathies (FIGURES 12-14A, highlight;
12-14B, and 12-14C), improvement after
axial circumferential surgery
pattern sparing gray
matter, persistent
enhancement for
more than 3 months
CSF = cerebrospinal fluid; HIV = human immunodeficiency virus; MRI = magnetic resonance imaging.

high-dose oral corticosteroid

treatment is usually required for
neurosarcoid with or without
corticosteroid-sparing
medications.
Central Nervous System

Inflammatory Vascular
Mimics of Multiple
Sclerosis
Some of the inflammatory
vascular diseases of the brain
can mimic MS. Susac syndrome
is an inflammatory
endotheliopathy that is
characterized by a triad of
branched retinal artery
occlusions, hearing loss, and
dementia/encephalopathy.
Ophthalmologic examination
can show branched retinal
artery occlusions, Gass plaques
(yellow plaques within
mid-arterioles on funduscopy),
or arterial wall hyperfluorescence
on fluorescein angiogram.72
Low-frequency hearing loss is
typical on audiogram. MRI can
mimic MS with corpus callosum
lesions, but these tend to
predominate in the center of the
corpus callosum and may have a
FIGURE 12-14 snowball-type appearance
Imaging of a patient with spondylotic myelopathy
(FIGURE 12-12), rather than the
mimicking multiple sclerosis. A, Sagittal
T2-weighted cervical spine MRI shows a short Dawson finger appearance seen
T2-hyperintense lesion (arrow) adjacent to a with MS. A “string of pearls”
region of moderate to severe stenosis appearance of beaded
(arrowheads). Sagittal (B) and axial (C) microinfarcts along the internal
postcontrast T1-weighted sequences show a
“pancakelike” transverse band of enhancement capsule is suggestive.73 Primary
(B, arrow) in a circumferential pattern sparing gray angiitis of the CNS can mimic
matter (C, arrows) characteristic of cervical MS with inflammatory-
spondylotic myelopathy with enhancement. appearing lesions, but the
presence of diffusion restriction
in defined arterial territories, microhemorrhages, and leptomeningeal
enhancement is an important discriminating feature (FIGURE 12-13).
PARACLINICAL FINDINGS MIMICKING INFLAMMATION IN

NONINFLAMMATORY CENTRAL NERVOUS SYSTEM DISORDERS
A variety of noninflammatory CNS diseases are accompanied by findings that
mimic a primary inflammatory cause; a list of common examples with clues to
840 JUNE 2019

discriminate them from MS are outlined in TABLE 12-5, with an example of KEY POINTS
spondylotic myelopathy with enhancement mimicking MS shown in
● In autoimmune GFAP
FIGURE 12-14.
74
astrocyopathy, brain MRI
may reveal a characteristic
radial perivascular
CONCLUSION enhancement perpendicular
The field of inflammatory demyelinating diseases of the CNS is evolving rapidly. to the ventricles, although
a similar pattern can be
Assays for the novel antibody biomarkers AQP4-IgG and MOG-IgG are seen with intravascular
commercially available and useful in diagnosis and distinction from MS. lymphoma, neurosarcoidosis,
Furthermore, these biomarkers have given insight into the pathogenesis of these and central nervous
diseases, allowing specific targeted treatments to be developed and translated to system vasculitis.
clinical practice, as evidenced by the three clinical trials currently under way in ● Susac syndrome is an
AQP4-IgG–seropositive NMOSD. Improved recognition of the clinical, inflammatory endotheliopathy
radiologic, and laboratory features of other CNS inflammatory mimics of MS has that is characterized by a triad
allowed clinicians to better distinguish these disorders from MS despite the of branched retinal artery
occlusions, hearing loss, and
absence of a serum biomarker in many. All these developments are leading to
dementia/encephalopathy.
improvements in diagnosis and treatment. Indeed, the future for patients
afflicted by these disorders has never been brighter.
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844 JUNE 2019

Incorporating Clinical PRACTICE ISSUES

Practice Guidelines C O N T I N U UM A U D I O
ONLINE
and Quality Measures

Into High-Quality
Cost-Effective Care
for Patients With
Multiple Sclerosis
By Alexander D. Rae-Grant, MD, FRCPC, FAAN
ABSTRACT
This article presents a hypothetical case of a patient with multiple sclerosis
(MS), reviewing the use of clinical practice guidelines and incorporation
of quality measures into practice. Appropriate diagnosis of MS is important
to avoid the cost and consequences of a misdiagnosis. Ensuring that
treatment discussion occurs when a patient with MS is receptive is good
clinical practice and a guideline recommendation from the American
Academy of Neurology. Continuing dialogue about disease-modifying
therapy and ongoing monitoring are important for patient care and
improved outcomes. Ultimately, cost-effective care in MS relates to using
appropriate medicines in patients with active MS, ensuring adherence,
and careful monitoring. CITE AS:
CASE DISEASES):845–849.
A 34-year-old left-handed woman presented to the office with tingling
paresthesia that began 1 month ago in the toes of both feet and spread Address correspondence to
Dr Alexander D. Rae-Grant, 2723
over 5 days to involve both legs, her abdomen, and her trunk up to the Cranlyn Rd, Shaker Heights, Ohio
bra line. In addition, she noted mild unsteadiness of gait and an electrical 44122, raegranta@gmail.com.
sensation down her neck with flexion of the neck. Her medical history RELATIONSHIP DISCLOSURE:
was significant for a prior major depressive event, needle phobia, and Dr Rae-Grant serves as deputy
diabetes mellitus. She worked as a nurse practitioner in a busy orthopedics editor for DynamedPlus.
practice. UNLABELED USE OF

MRI of the brain showed two paraventricular nonenhancing lesions and a PRODUCTS/INVESTIGATIONAL
single-segment enhancing lesion in the posterior spinal cord at C7.1 Lumbar USE DISCLOSURE:
Dr Rae-Grant reports no
puncture showed 12 white blood cells/mm3 (100% lymphocytes) and six disclosure.
oligoclonal bands not seen in a paired serum sample.
Three days of IV methylprednisolone was prescribed, and her symptoms
completely resolved. She was diagnosed with multiple sclerosis (MS), of Neurology.

INCORPORATING PRACTICE GUIDELINES INTO COST-EFFECTIVE MS CARE
provisional classification relapsing, active. This was based on

demonstration of dissemination in space by paraventricular lesions and a
spinal cord lesion and dissemination in time by the presence of both
enhancing and nonenhancing lesions.1 She was provided with initial
information about MS, and a follow-up appointment to discuss treatment
options, including disease-modifying therapies, was arranged.2
At the follow-up appointment, initiation of a disease-modifying therapy
was recommended based on data from multiple clinical trials in patients
with a single demyelinating event and multiple brain lesions. The goals for
therapy were discussed, including reducing the likelihood of subsequent
clinical demyelinating events, reducing new lesion formation on MRI, and
potentially reducing the risk of subsequent disability.2,3 The patient was
informed of the risks associated with the particular disease-modifying
therapy being recommended as well as other options for treatment
available to her.
The patient declined therapy, saying that she planned to “go holistic”
and work with a naturopathic physician. The risks and benefits of therapy
were reiterated, but she continued to decline disease-modifying therapy at
this point. She did agree to close monitoring of clinical and MRI measures
and agreed that if she experienced new clinical events or new lesions on
MRI, she would reconsider disease-modifying therapy. The benefits of a
healthy lifestyle were also discussed with her, particularly the benefits of a
regular exercise program.
One year later, she returned for another follow-up appointment. A brain
MRI with and without gadolinium did not show any new lesion formation,
and she had not had new clinical events. She had begun to exercise, and a
validated measure of depression was improved compared with her initial
visit. The role of disease-modifying therapies was discussed again, and she
continued to decline their use. A follow-up appointment and repeat MRI
scan was scheduled in 1 year.
Seven years later, she returned to the clinic. She had remained
asymptomatic since the initial evaluation. An MRI was obtained, which
showed one new periventricular T2 lesion compared with the imaging from
7 years earlier. Her clinical examination remained unchanged. She
continued to decline disease-modifying therapy but promised to be more
vigilant in following up clinically. She said she was maintaining her exercise
program and doing all the health maintenance activities needed for her
age. She asked if disease-modifying therapy was still recommended given
the course of her disease over the past 8 years.
DISCUSSION
C
aring for people with multiple sclerosis (MS) is becoming a
complex mix of shared decision making, personalized medicine,
and recognition of the limits of clinical knowledge in an
ever-growing field. In the United States, no medications for MS
disease management were approved by the US Food and Drug
Administration (FDA) before 1993; in 2017, more than 14 agents had been
approved.4 Integrating appropriate discussion of treatment into a busy clinical
schedule is difficult but critical for high-quality, cost-effective care. Optimizing
846 JUNE 2019

the selection of disease-modifying therapy is even more challenging, given the
variety of side effect profiles and efficacy outcomes and variation in long-term
data on the profusion of agents available. Cost is also an issue, as most of the agents
available are costly and absorb an increasing percentage of health care dollars;
analyzing costs in terms of cost-benefit analysis is more complex than just
assessment of the “sticker price” of the medicines.5 The ethical priority for a
clinician is care for the patient, but systems of care will increasingly need to
consider the cost of treatment in weighing priorities for population-based care.6
For the patient in this case, a pivotal element in both high-quality and
cost-effective care was ensured by making an accurate diagnosis of MS using
updated consensus-based criteria.1 Recent clinical studies have highlighted the
frequent problem of misdiagnosis of MS.7 Many patients coming to an MS clinic
do not have MS. Common alternative diagnoses include migraine and other
neurologic conditions and possible psychiatric disease, or the diagnosis may be
unclear.8 Many patients misdiagnosed with MS undergo treatment with
disease-modifying therapy for MS.7 Treating a person who does not have MS
with disease-modifying therapy is costly and ineffective and may lead to
potential side effects. In addition, undoing the diagnosis of MS is difficult and
potentially traumatic to the patient.9 An accurate diagnosis is the first and
possibly most critical step in quality MS care.10 Quality measures published by
the American Academy of Neurology (AAN) in 2015 include measures of
“patients who received a new diagnosis of multiple sclerosis in the past 12 months
who fulfilled international criteria.”10
In the case presented, a second visit to discuss therapy was also scheduled. A
2018 AAN guideline recommends discussing therapy at a second clinical visit
based on data showing that receiving the diagnosis of MS is stressful and
information is not well processed soon after the diagnosis of MS is made.2,11,12 A
second visit allows the patient with MS to have considered the diagnosis and its
implications before embarking on complex discussions of risks and benefits of
disease-modifying therapies.
This patient declined the recommended treatment. The clinician’s role is to
guide and advise patients but also to respect patients’ autonomy for informed
decision making.13 In a sample of the NARCOMS registry, patients favored
patient-centered decision making followed by shared decision making over other
decision-making approaches.12 The NARCOMS registry is a global self-reported
patient registry for MS research, treatment, and education. It is also important
for the clinician to adequately assess the risk for disease activity in each patient
based on known epidemiologic factors. Factors with a worse prognosis
include male gender, later onset, more early relapses, rapid early accumulation
of fixed deficits, and initial involvement of nonsensory systems.14 In this case,
the patient was in a lower risk group based on her age, sex, initial symptoms
being sensory, and a low frequency of early relapses.14 If risks were higher for
disability accrual, other methods to engage the patient in decision making to
encourage use of disease-modifying therapies might be considered.15 In this case,
sequential imaging and clinical follow-up documented that, despite not being on
a disease-modifying therapy, her course had not been marked by relapses or
clinical progression and her new lesion burden was low. Despite her refusal to
comply with the recommended treatment, the patient was monitored,
supported, and provided appropriate guidance and care to assist her in her
long-term illness. If a disease-modifying therapy had been initiated, she would

INCORPORATING PRACTICE GUIDELINES INTO COST-EFFECTIVE MS CARE
have been monitored using appropriate laboratory and clinical parameters to

assess for side effects of the particular disease-modifying therapy used.
Unfortunately, limited data are available to tell clinicians which patients,
if any, do not require disease-modifying therapy. Clearly, if a subset of patients
not requiring disease-modifying therapy could be identified, monitoring these
patients without treatment with disease-modifying therapy would be prudent
and cost-effective. At present, all patients with a single clinical demyelinating
event and two or more brain lesions characteristic of MS who decide they want
disease-modifying therapy should have it prescribed.2,3
Analysis of cost-effectiveness in the use of disease-modifying therapy for MS
is still in an early stage.16 Many factors complicate this analysis.16 When
developing some of its recommendations, the AAN guideline panel considered
cost to the patient as a factor in assigning class of evidence and strength of
recommendation.17 However, costs to patients may vary based on several factors,
including insurance, out-of-pocket expenses, and ancillary costs (eg, morbidity
of complications and medical costs for monitoring).18 Cost to patients may also
vary based on the severity of disease; in one analysis, medications were key cost
drivers for patients with less severe MS, and informal care (eg, from a family
member) and production losses (from loss of work) were more important in
patients with the most severe MS.19 Costs may include difficult-to-define
measures, such as cost of disability/disability avoided and work time lost.
Moreover, most cost analyses have included the early available disease-
modifying therapies and not more recently approved medications, which may
have different outcomes for cost-effectiveness.20,21 A 2012 systematic review of
cost-effectiveness of MS disease-modifying therapies concluded that room for
improvement remained in analysis of many areas; improved use of long-term
time horizons, societal perspectives, and quality-of-life adjusted years were
recommended for future studies.21
CONCLUSION
At present, the best approach to cost-effectiveness in the use of disease-
modifying therapy is using a disease-modifying therapy that meets patient
preference and avoids issues with known patient-specific comorbidities.
Disease-modifying therapies should be prescribed for patients with active MS (or
in the case of primary progressive MS, patients who are most likely to benefit
from treatment), in whom measures are taken to ensure safe adherence to
treatment with appropriate ongoing monitoring and discussion of efficacy and
safety over time. In other words, the best practice is to use the right medicine for
the right patient at the right time.
REFERENCES
1 Thompson AJ, Banwell BL, Barkhof F, et al. 2 Rae-Grant A, Day GS, Marrie RA, et al. Practice
Diagnosis of multiple sclerosis: 2017 revisions guideline recommendations summary: disease-
of the McDonald criteria. Lancet Neurol modifying therapies for adults with multiple sclerosis:
2017;17(2):162–173. doi:10.1016/S1474-4422(17) report of the Guideline Development, Dissemination,
30470-2. and Implementation Subcommittee of the American
777–789. doi:10.1212/WNL.0000000000005347.
848 JUNE 2019

3 Rae-Grant A, Day GS, Marrie RA, et al. 12 Cofield SS, Thomas N, Tyry T, et al. Shared
Comprehensive systematic review summary: decision making and autonomy among US
disease-modifying therapies for adults with participants with multiple sclerosis in the
multiple sclerosis: report of the Guideline NARCOMS registry. Int J MS Care 2017;19(6):
Development, Dissemination, and 303–312. doi:10.7224/1537-2073.2016-091.
Implementation Subcommittee of the American
13 Heesen C, Kasper J, Köpke S, et al. Informed
shared decision making in multiple sclerosis—
789–800. doi:10.1212/WNL.0000000000005345.
inevitable or impossible? J Neurol Sci 2007;
4 Wingerchuk DM, Weinshenker BG. Disease 259(1–2):109–117. doi:10.1016/j.jns.2006.05.074.
modifying therapies for relapsing multiple
14 Swanton S, Fernando K, Miller D. Early prognosis
sclerosis. BMJ 2016;354:i3518. doi:10.1136/
of multiple sclerosis. In: Aminoff M, Boller F,
bmj.i3518.
Swaab DF, editors. Handbook of clinical
5 Muenning P. Cost-effectiveness analysis in neurology. Amsterdam, The Netherlands:
health: a practical approach. San Francisco, CA: Elsevier, 2014:371–391.
Wiley, 2016.
15 Shay LA, Lafata JE. Where is the evidence? A
6 Chiu C, Bishop M, Pionke JJ, et al. Barriers to systematic review of shared decision making and
the accessibility and continuity of health-care patient outcomes. Med Decis Making 2014;35(1):
services in people with multiple sclerosis. Int J 114–131. doi:10.1177/0272989X14551638.
MS Care 2017;19(3):313–21. doi:10.7224/1537-
16 Palace J, Duddy M, Bregenzer T, et al.
2073.2016-016.
Effectiveness and cost-effectiveness of
7 Solomon AJ, Bourdette DN, Cross AH, et al. interferon beta and glatiramer acetate in the
The contemporary spectrum of multiple UK Multiple Sclerosis Risk Sharing Scheme at
sclerosis misdiagnosis: a multicenter study. 6 years: a clinical cohort study with natural
Neurology 2016;87(13):1393–1399. doi:10.1212/ history comparator. Lancet Neurol 2015;14(5):
WNL.0000000000003152. 497–505. doi:10.1016/S1474-4422(15)00018-6.
8 Carmosino MJ, Brousseau KM, Arciniegas DB, 17 Gronseth G, Cox J, Gloss D, et al. 2017 AAN clinical
Corboy JR. Initial evaluations for multiple practice guideline process manual. Minneapolis,
sclerosis in a university multiple sclerosis center: MN: American Academy of Neurology, 2017.
outcomes and role of magnetic resonance
18 Kobelt G, Eriksson J, Phillips G, Berg J. The burden
imaging in referral. JAMA Neurol 2005;62(4):
of multiple sclerosis 2015: methods of data
585–560. doi:10.1001/archneur.62.4.585.
collection, assessment and analysis of costs,
9 Solomon AJ, Klein EP, Bourdette D. quality of life and symptoms. Multi Scler 2017;
“Undiagnosing” multiple sclerosis: the challenge 23(2 suppl):4–16. doi:10.1177/1352458517708097.
of misdiagnosis in MS. Neurology 2012;78(24):
19 Ernstsson O, Gyllensten H, Alexanderson K, et al.
1986–1991. doi:10.1212/WNL.0b013e318259e1b2.
Cost of illness of multiple sclerosis—a systematic
10 Rae-Grant A, Bennett A, Sanders AE, et al. Quality review. PLoS One 2016;11(7):e0159129. doi:10.1371/
improvement in neurology: multiple sclerosis journal.pone.0159129.
quality measures: executive summary [published
20 Melendez-Torres G, Auguste P, Armoiry X, et al.
correction appears in Neurology 2016;86(15):
Clinical effectiveness and cost-effectiveness of
1465]. Neurology 2015;85(21):1904–1908.
beta-interferon and glatiramer acetate for
doi:10.1212/WNL.0000000000001965.
treating multiple sclerosis: systematic review
11 Heesen C, Köpke S, Solari A, et al. Patient and economic evaluation. Southampton, UK:
autonomy in multiple sclerosis—possible goals NIHR Journals Library, 2017.
and assessment strategies. J Neurol Sci 2013;
21 Yamamoto D, Campbell JD. Cost-effectiveness
331(1–2):2–9. doi:10.1016/j.jns.2013.02.018.
of multiple sclerosis disease-modifying
therapies: a systematic review of the literature.
Autoimmune Dis 2012;2012:784364.
doi:10.1155/2012/784364.

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SELF-ASSESSMENT
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MULTIPLE SCLEROSIS AND OTHER CNS INFLAMMATORY DISEASES

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POSTREADING TEST
ARTICLE 1: MULTIPLE SCLEROSIS RISK FACTORS AND PATHOGENESIS
1 Which of the following lifestyle changes has the most compelling

support to be recommended for prevention of multiple sclerosis?
A B vitamin supplementation
B gluten-free diet
C lipoic acid supplementation
D smoking avoidance/cessation
E ultraviolet radiation exposure
2 Which of the following viral infections has the strongest evidence of

a causal relationship for development of multiple sclerosis?
A cytomegalovirus
B Epstein-Barr virus (EBV)
C herpes simplex virus
D measles virus
E varicella-zoster virus
3 For which of the following environmental factors is there evidence to

suggest a reduction in risk for the development of multiple sclerosis?
A coffee
B obesity
C passive tobacco smoke exposure
D shift work
E smoking
ARTICLE 2: DIAGNOSIS, DIFFERENTIAL DIAGNOSIS, AND MISDIAGNOSIS

OF MULTIPLE SCLEROSIS
4 The 2017 McDonald criteria include which of the following revisions

for demonstration of dissemination in space that was not present in
previous versions?
A inclusion of the anterior visual system

B inclusion of symptomatic lesions
C presence of at least three periventricular lesions
D removal of cortical lesions
E there were no revisions to the dissemination in space criteria
854 JUNE 2019

5 The 2017 McDonald criteria include which of the following revisions
for demonstration of dissemination in time that was not present in
previous versions?
A CSF-specific oligoclonal bands may substitute for clinical or MRI

dissemination in time
B inclusion of the anterior visual system
C MRI dissemination in time can be demonstrated on a single
MRI scan
D there were no revisions to the dissemination in time criteria
E timing of the follow-up MRI is changed from 1 month to 1 week
6 The purpose of the 2017 McDonald criteria can best be described by

which of the following statements?
A confirm the diagnosis of multiple sclerosis in patients presenting

with concerning neurologic symptoms
B confirm the diagnosis of multiple sclerosis in patients presenting
with typical demyelinating syndromes
C confirm the diagnosis of multiple sclerosis in patients with a
long-standing diagnosis of demyelinating disease
D differentiate the diagnosis of demyelinating disease from
nondemyelinating conditions
E differentiate the diagnosis of multiple sclerosis from other
demyelinating diseases
ARTICLE 3: PHASES AND PHENOTYPES OF MULTIPLE SCLEROSIS
7 A 58-year-old woman with multiple sclerosis had 10 years of stability

without changes in her neurologic examination. However, over the past
6 months, she has developed significant pain in her right hip, especially
with weight bearing. Hip plain films show moderately severe
osteoarthritis of the hip joint. Her pain is severe enough that she has
stopped exercising and has started to use a cane, and her ambulation is
limited. She has had a gradual worsening in hip flexor strength and gait.
Brain and spine MRIs show no new lesions compared with a study
obtained 3 years ago. Which of the following terms best describes her
multiple sclerosis course?
A progressive, active
B progressive, inactive
C pseudoprogression
D pseudorelapse
E relapsing, active

POSTREADING TEST
8 A 26-year-old man presents with numbness, incoordination, and

hyperreflexia of the right leg. MRI shows two periventricular T2 white
matter lesions and one T2 lesion in the cervical spinal cord, with no
juxtacortical or enhancing lesions. These lesions are unexplained by
other pathology and are typical of multiple sclerosis in location,
orientation, and shape. He has no past history of neurologic symptoms.
Which of the following terms best describes this patient’s status?
A clinically definite relapsing-remitting multiple sclerosis

B clinically isolated syndrome, single-attack multiple sclerosis
C clinically isolated syndrome, solitary sclerosis
D pre–radiologically isolated syndrome
E radiologically isolated syndrome
9 A 26-year-old woman with no past neurologic history other than

migraines that have recently worsened in severity and frequency
undergoes a head MRI to rule out other causes of headache. The MRI is
remarkable for two periventricular white matter lesions that are
enhancing, three other periventricular lesions, one juxtacortical lesion,
and two brainstem lesions that are typical of multiple sclerosis lesions
in shape and orientation. Which of the following terms would be
most appropriate for her condition?
A clinically isolated syndrome, solitary sclerosis

B pre–radiologically isolated syndrome
C radiologically isolated syndrome, active
D radiologically isolated syndrome, inactive
E relapsing-remitting multiple sclerosis
ARTICLE 4: MANAGEMENT OF MULTIPLE SCLEROSIS RELAPSES
10 Patients in which of the following occupations will likely be most

adversely impacted by the development of the Pulfrich phenomenon?
A high school track coach

B line cook
C spin instructor
D truck driver
E welder
856 JUNE 2019

11 Oral steroids have been found to be tolerated as well as IV steroids for
the treatment of multiple sclerosis relapses with the exception of
increased incidence of which of the following adverse effects?
A avascular necrosis
B headache
C insomnia
D mania
E nausea
12 Which of the following patient characteristics is correlated with a

diminished degree of recovery after multiple sclerosis relapse treated
with corticosteroids?
A baseline cortisol levels

B male gender
C older age
D pretreatment blood glucose
E use of disease-modifying therapy
13 A 29-year-old woman with a 20-year history of type 1 diabetes mellitus

and a 5-year history of relapsing-remitting multiple sclerosis presents
to the emergency department with 3-day history of right leg numbness
that has worsened over the initial 48 hours but has since remained
unchanged. On examination, she has mild decrease to pinprick
throughout the right leg. Her gait is steady. She has not had similar
symptoms with past relapses and is afebrile without signs of infection.
She has responded well to treatment with corticosteroids for previous
exacerbations, with full resolution of prior symptoms; however, she
required significant adjustment of her daily insulin regimen, with
spiking of her blood glucose to the high 300s. She is not particularly
bothered by her symptoms but was encouraged to come in by her
husband, who is anxious about her overall health. Which of the
following is the most appropriate management plan for this patient?
A admission for treatment with adrenocorticotropic hormone

(ACTH)
B admission for treatment with IV immunoglobulin (IVIg)
C discharge home with an appointment with her outpatient
neurologist within 1 week
D discharge home with a next-day appointment in the outpatient
infusion center for IV methylprednisolone
E discharge home with a prescription for prednisone 1250 mg/d for
5 days

POSTREADING TEST
ARTICLE 5: CLINICALLY ISOLATED SYNDROME AND EARLY RELAPSING

MULTIPLE SCLEROSIS
14 For patients who present with isolated optic neuritis, which of the
following characteristics is associated with a very low risk of future
relapses and disability?
A male gender
B normal brain MRI
C poor recovery of vision
D presence of CSF oligoclonal bands
E younger age at onset
15 Which of the following multiple sclerosis disease phenotypes are at

lowest risk for new disease activity (new relapse or new T2 or
enhancing lesions on brain MRI) within the next 2 years?
A clinically isolated syndrome with three T2 lesions larger than 3 mm

in diameter on brain MRI
B radiologic isolated disease with positive oligoclonal bands
C relapsing-remitting multiple sclerosis with one new enhancing
lesion on MRI 1 year ago and one relapse 2 years ago
D relapsing-remitting multiple sclerosis without relapses or new MRI
activity over the previous 2 years and who are not taking a
disease-modifying therapy
E single clinical attack with two enhancing lesions on brain MRI
16 Which of the following disease-modifying therapies for multiple

sclerosis is associated with the common adverse effect of flushing?
A dimethyl fumarate
B fingolimod
C glatiramer acetate
D interferon beta
E teriflunomide
858 JUNE 2019

ARTICLE 6: HIGHLY AGGRESSIVE MULTIPLE SCLEROSIS
17 Which of the following MRI characteristics is the best predictor of

future disability in patients with multiple sclerosis?
A baseline enhancing lesion number

B baseline T2 lesion number
C baseline T2 lesion volume
D number of new enhancing lesions
E number of new T2 lesions
18 Which of the following biomarkers has been shown to correlate with

Expanded Disability Status Scale (EDSS) score worsening at 1 year?
A aberrantly methylated NDRG4 promoter

B cytokine interleukin β
C real-time quaking-induced conversion
D serum neurofilament light chain
E tumor necrosis factor-α
19 What is the mechanism of action of natalizumab?
A cell lysis
B complement fixation
C DNA crosslinking
D prevention of leukocyte adherence
E sequestration of lymphocytes
20 A 32-year-old woman has been on natalizumab for 37 months after

experiencing frequent relapses while on interferon beta-1a. On routine
surveillance, her JC virus antibody index is found to be strongly
positive. Which of the following treatment options is most
appropriate at this time?
A continue current treatment regimen without changes

B continue natalizumab and add another disease-modifying therapy
C discontinue natalizumab and start a different disease-modifying
therapy 4 weeks after the last natalizumab dose
D discontinue natalizumab and start a different disease-modifying
therapy 6 months after the last natalizumab dose
E initiate treatment with another disease-modifying therapy
immediately and continue natalizumab for one more treatment

POSTREADING TEST
ARTICLE 7: MONITORING, SWITCHING, AND STOPPING MULTIPLE

SCLEROSIS DISEASE-MODIFYING THERAPIES
21 Baseline and follow-up assessment for macular edema (eg, with optical
coherence tomography) is required monitoring for which multiple
sclerosis disease-modifying therapy?
A dimethyl fumarate
B fingolimod
C glatiramer acetate
D ocrelizumab
E teriflunomide
22 A skin or blood test for latent tuberculosis should be performed

before initiation of which of the following multiple sclerosis
disease-modifying therapies?
A dimethyl fumarate
B fingolimod
C interferon beta
D natalizumab
E teriflunomide
23 A 68-year-old woman with relapsing multiple sclerosis has been

treated with interferon beta-1b since it was first released in 1993. She is
wondering if she still needs to take this medication or, for that matter,
any disease-modifying therapy at all. Which of the following patient
characteristics would most strongly support continued treatment?
A age older than 65

B Expanded Disability Status Scale (EDSS) score of 6.5
C MRI showing active disease 2 years ago
D no clinical relapses for 5 years
E secondary progressive course
860 JUNE 2019

ARTICLE 8: PROGRESSIVE MULTIPLE SCLEROSIS
24 A 53-year-old woman with relapsing-remitting multiple sclerosis

(MS) who first presented with right leg numbness 5 years ago and
subsequently has had approximately one severe exacerbation per
year is concerned about developing secondary progressive MS. Which
of the following characteristics of her presentation and disease
course is associated with a more rapid development of secondary
progressive MS?
A female sex
B low frequency of exacerbations
C older age at onset
D sensory presentation
E short time since diagnosis
25 Which of the following is a limitation of the Expanded Disability

Status Scale (EDSS)?
A cognitive function is too heavily weighted

B it is an interval scale
C lack of ability to score electronically
D poor interrater and intrarater variability
E upper extremity function is too heavily weighted
ARTICLE 9: MANAGEMENT OF MULTIPLE SCLEROSIS SYMPTOMS AND

COMORBIDITIES
26 What is the most common symptom in patients with multiple

sclerosis?
A fatigue
B numbness
C urinary frequency
D visual complaints
E weakness

POSTREADING TEST
27 A 29-year-old man with multiple sclerosis is distressed by his frequent

involuntary crying spells. He reports that these spells of crying can
come on when he is not feeling particularly sad, and he tends to avoid
social situations because of fear and embarrassment that he will have
one of these spells. Which of the following is the most appropriate
medication for this patient’s symptoms?
A amantadine
B baclofen/gabapentin
C dextromethorphan/quinidine
D lorazepam
E tizanidine
28 Which of the following cognitive domains is most frequently affected

in multiple sclerosis?
A cued recall
B grammar
C information-processing speed
D long-term memory
E recognition of emotions
29 Which of the following medications has a US Food and Drug

Administration (FDA) indication to improve walking speed in
multiple sclerosis?
A amantadine
B armodafinil
C dalfampridine
D dantrolene
E lacosamide
30 Tonic spasms associated with multiple sclerosis respond well to

medications with what mechanism of action?
A activation of opioid Mu receptor

B facilitation of noradrenalin mediated descending inhibition
C interference with calcium channel function
D potassium channel blockade
E sodium channel blockade
862 JUNE 2019

ARTICLE 10: PREGNANCY AND FAMILY PLANNING IN MULTIPLE SCLEROSIS
31 Which multiple sclerosis disease-modifying therapy requires

monitoring for drug level before cessation of birth control?
A dimethyl fumarate
B interferon beta
C ocrelizumab
D rituximab
E teriflunomide
32 A 30-year-old woman has aggressive multiple sclerosis, manifested by

five or more relapses a year for the past 6 years with incomplete
recovery from her relapses. Treatment with rituximab and
natalizumab failed to control her relapses, so she was started on
alemtuzumab 23 months ago. She now wishes to get pregnant and
would like to start trying to conceive as soon as possible. Which of
the following laboratory studies should be obtained routinely during
her pregnancy?
A CD4:CD8 ratio
B factor V Leiden mutation analysis
C JC virus index
D liver function tests
E thyroid function tests
33 Multiple courses of corticosteroids during pregnancy have been most

associated with which of the following fetal complications?
A decreased vaccine responsiveness

B hepatotoxicity
C low birth weight
D lymphopenia
E pancytopenia

POSTREADING TEST
ARTICLE 11: PEDIATRIC CENTRAL NERVOUS SYSTEM DEMYELINATING

DISEASES
34 Which of the following immunologic therapies may be associated

with an increase in relapse rate in patients with pediatric
neuromyelitis optica (NMO) spectrum disorder?
A azathioprine
B cyclophosphamide
C mycophenolate mofetil
D natalizumab
E rituximab
35 In the setting of pediatric acute demyelinating disease, which of the

following symptoms is strongly suggestive of a diagnosis of acute
disseminated encephalomyelitis (ADEM)?
A ataxia
B dysarthria
C encephalopathy
D optic neuritis
E pyramidal signs
36 A pediatric presentation of an area postrema syndrome with vomiting

and intractable hiccups is most suggestive of which of the following?
A acute disseminated encephalomyelitis (ADEM)

B central nervous system vasculitis
C multiple sclerosis
D myelin oligodendrocyte glycoprotein antibody–associated
demyelinating syndrome
E neuromyelitis optica (NMO) spectrum disorder
864 JUNE 2019

ARTICLE 12: NEUROMYELITIS OPTICA SPECTRUM DISORDER AND OTHER
NON–MULTIPLE SCLEROSIS CENTRAL NERVOUS SYSTEM
INFLAMMATORY DISEASES
37 Neuromyelitis optica (NMO) spectrum disorders occur decades after

which of the following other neurologic disorders at higher rates
than would be expected?
A Bickerstaff encephalitis
B febrile seizures
C myasthenia gravis
D neurosarcoidosis
E viral meningitis
38 Myelin oligodendrocyte glycoprotein antibody (MOG-IgG) disease

typically involves which anatomic location?
A cerebellum
B conus medullaris
C corpus callosum
D inferior temporal pole
E optic chiasm
39 A 55-year-old man presents with 2 months of progressive speech

difficulty, facial tingling, and gait unsteadiness. Over the past week,
he has begun falling and now has diplopia. On examination, he
has dysconjugate gaze and nystagmus, dysarthria, mild facial
weakness, and an ataxic gait. Brain MRI reveals a multifocal bilateral
punctate enhancement pattern centered in the pons and extending
into the cerebellum. There is no mass effect. CSF shows a mild
lymphocyte-predominant pleocytosis, normal protein and glucose,
and no oligoclonal bands. Cytology and flow cytometry are negative.
Repeat lumbar puncture 4 days later also demonstrated negative
cytology and flow cytometry. What is the most appropriate next step
in the management of this patient?
A brain biopsy
B corticosteroids
C cyclophosphamide
D leptomeningeal biopsy
E plasma exchange

POSTREADING TEST
40 A 42-year-old woman presents with a 5-month history of a

constellation of progressive neurologic symptoms, including
headache, neck stiffness, photophobia, memory loss, tremor,
unsteady gait, weakness and numbness of her right side, and urinary
retention. Brain MRI reveals radial perivascular enhancement
perpendicular to the ventricles and leptomeningeal enhancement.
MRI of the spine reveals faint T2 hyperintensity from C4 to T2 with
mild central canal enhancement. Which of the following diagnostic
tests should be obtained in this patient?
A carotid ultrasound
B fluorescein angiogram
C lupus anticoagulant panel
D ovarian ultrasound
E positron emission tomography (PET) scan
866 JUNE 2019

Postreading
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CME Test—Preferred
Responses
By D. Joanne Lynn, MD, FAAN; Allison L. Weathers, MD, FAAN
MULTIPLE SCLEROSIS AND OTHER CNS INFLAMMATORY DISEASES

Following are the preferred responses to the questions in the Postreading
Self-Assessment and CME Test in this Continuum issue. The preferred
response is followed by an explanation and a reference with which you
may seek more specific information. You are encouraged to review the
responses and explanations carefully to evaluate your general
understanding of the article topic. The comments and references included
with each question are intended to encourage independent study.
US PARTICIPANTS: Upon completion of the Postreading Self-Assessment and

CME Test and issue evaluation online at continpub.com/CME, participants
may earn up to 20 AMA PRA Category 1 Credits™ toward SA-CME. US
participants have up to 3 years from the date of publication online to earn
SA-CME credits.
CANADIAN PARTICIPANTS: This program is an Accredited Self-Assessment

Program (Section 3) as defined by the Maintenance of Certification
Program of the Royal College of Physicians and Surgeons of Canada and
approved by the Office of Continuing Medical Education and Professional
Development, University of Calgary, on April 1, 2017. Refer to the CME
tab on ContinuumJournal.com for dates of accreditation. Canadian
participants should visit MAINPORT (mainport.org) to record learning
and outcomes. Canadian participants can claim a maximum of 20 hours
(credits are automatically calculated).
ARTICLE 1: MULTIPLE SCLEROSIS RISK FACTORS AND PATHOGENESIS
1 The preferred response is D (smoking avoidance/cessation). Several lifestyle

changes are reasonable approaches to reduce the risk of development of
multiple sclerosis despite the lack of robust interventional data. These include
smoking avoidance/cessation, prevention or treatment of obesity, and
treatment of vitamin D deficiency. Ultraviolet radiation exposure cannot be
recommended given the risk for cancer. There is insufficient evidence to

POSTREADING TEST—PREFERRED RESPONSES
recommend specific diets or other dietary supplements. For more information,

refer to page 601 of the Continuum article “Multiple Sclerosis Risk Factors
and Pathogenesis.”
2 The preferred response is B (Epstein-Barr virus [EBV]). The evidence for a causal
relationship between a viral infection and the development of multiple sclerosis
(MS) is strongest for EBV. The risk of MS for individuals with a history of infectious
mononucleosis is twice that of the general population. Most people with MS
have serologic evidence for prior infection with EBV. For more information, refer
to pages 600, 602 of the Continuum article “Multiple Sclerosis Risk Factors and
Pathogenesis.”
3 The preferred response is A (coffee). High consumption of coffee, which is

has been shown to have neuroprotective and anti-inflammatory effects, has
been associated with a reduction in multiple sclerosis risk. Conversely,
obesity, active and passive smoking, and shift work have all been reported to
be associated with a higher risk of multiple sclerosis. For more information,
refer to pages 603, 606 of the Continuum article “Multiple Sclerosis Risk
Factors and Pathogenesis.”
ARTICLE 2: DIAGNOSIS, DIFFERENTIAL DIAGNOSIS, AND MISDIAGNOSIS

OF MULTIPLE SCLEROSIS
4 The preferred response is B (inclusion of symptomatic lesions). The 2017

McDonald criteria now include the use of symptomatic lesions for demonstration
of dissemination in space. In patients presenting with objective evidence of a
symptomatic MRI lesion located in one of the four regions required for
dissemination in space (periventricular, cortical or juxtacortical, infratentorial,
or spinal cord), only a single additional T2-hyperintense MRI lesion in a
different region is needed to fulfill MRI dissemination in space. The anterior
visual system is not one of the regions included for MRI dissemination in space
in the 2017 criteria. Only the presence of at least one T2-hyperintense
periventricular MRI lesion is required for this region to be considered for
dissemination in space. Cortical lesions were included in the 2017 McDonald
criteria for the first time, not removed. For more information, refer to page 613
of the Continuum article, “Diagnosis, Differential Diagnosis, and Misdiagnosis
of Multiple Sclerosis.”
5 The preferred response is A (CSF-specific oligoclonal bands may substitute for

clinical or MRI dissemination in time). The 2017 McDonald criteria allow the
demonstration of two or more oligoclonal bands to substitute for demonstration
of clinical or MRI dissemination in time. This allows for earlier diagnosis of
multiple sclerosis in a patient who has objective evidence of a single clinical
attack typical for multiple sclerosis but with demonstration of only MRI
dissemination in space. While MRI dissemination in time can be demonstrated on
868 JUNE 2019

a single scan, this was not new to the 2017 criteria. Dissemination in time can be
demonstrated by the presence of a new T2-hyperintense or gadolinium-
enhancing lesion on a follow-up MRI scan compared to the baseline scan
regardless of the timing of either scan. The anterior visual system is not included
for MRI dissemination in time in the 2017 criteria. For more information, refer to
page 615 of the Continuum article, “Diagnosis, Differential Diagnosis, and
Misdiagnosis of Multiple Sclerosis.”
6 The preferred response is B (confirm the diagnosis of multiple sclerosis in

patients presenting with typical demyelinating syndromes). The 2017 McDonald
criteria are intended to confirm the diagnosis of multiple sclerosis (MS) in
patients presenting with typical demyelinating syndromes. The criteria have not
been validated in patients presenting with atypical syndromes or in patients with
typical syndromes with associated red flags. They have also not been validated
in patients with a prior long-standing diagnosis of MS. While a thoughtful
evaluation of the differential diagnosis of MS should be undertaken, the criteria
do not help differentiate the diagnosis of MS from other demyelinating diseases
or from nondemyelinating conditions that are in the differential. For more
information, refer to pages 620–621 of the Continuum article, “Diagnosis,
Differential Diagnosis, and Misdiagnosis of Multiple Sclerosis.”
ARTICLE 3: PHASES AND PHENOTYPES OF MULTIPLE SCLEROSIS
7 The preferred response is C (pseudoprogression). In this case, the patient’s

worsening seems most likely due to deconditioning secondary to her
osteoarthritic pain rather than worsening of her multiple sclerosis. The term
pseudoprogression is used to describe the gradual accumulation of disability
due to factors not directly related to multiple sclerosis, such as other
concomitant illnesses. For more information, refer to page 639 of the
Continuum article “Phases and Phenotypes of Multiple Sclerosis.”
8 The preferred response is C (clinically isolated syndrome, solitary sclerosis).

This patient has a clinically isolated syndrome, but his imaging findings do not
fulfill the minimum MRI requirement for a multiple sclerosis diagnosis. If the MRI
requirements had been fulfilled, this presentation would qualify as a clinically
isolated syndrome, single-attack multiple sclerosis. For more information, refer
to page 642 of the Continuum article “Phases and Phenotypes of Multiple
Sclerosis.”
9 The preferred response is C (radiologically isolated syndrome, active). This

woman undergoes a brain MRI for evaluation of headaches and is found to have
lesions that fulfill the diagnostic imaging criteria for a radiologically isolated
syndrome. The presence of gadolinium-positive lesions demonstrates that this
is an active process. Since she has not experienced any neurologic symptoms

related to inflammatory demyelinative processes, this is not a clinically isolated

syndrome or relapsing-remitting multiple sclerosis. For more information, refer
to pages 643–644 of the Continuum article “Phases and Phenotypes of
Multiple Sclerosis.”
ARTICLE 4: MANAGEMENT OF MULTIPLE SCLEROSIS RELAPSES
10 The preferred response is D (truck driver). The Pulfrich phenomenon is the

perception of an object oscillating in a vertical plane as following an elliptical
trajectory in a horizontal plane. It is a result of conduction slowing in an optic
nerve, usually as a result of optic neuritis. Although patients may report difficulty
with playing ball sports and pouring liquids, it is often manifested as a sense that
oncoming traffic is swerving toward the driver. Therefore, an occupation that
requires extensive driving is likely to be the most adversely impacted by the
development of this phenomenon. The other occupations listed would likely be
more adversely impacted by the development of Uhthoff phenomenon, in which
patients experience recurrence of a neurologic deficit from an earlier relapse in
the setting of increased core body temperature. For more information, refer
to page 659 of the Continuum article “Management of Multiple Sclerosis
Relapses.”
11 The preferred response is C (insomnia). The 2015 multicenter COPOUSEP (Oral

Versus Intravenous High-dose Methylprednisolone for Treatment of Relapses in
Patients With Multiple Sclerosis) trial has offered the strongest evidence of
noninferiority between oral and IV steroids, with no difference shown in a
number of outcome measures. In this trial, oral steroids were tolerated as well as
IV steroids with the exception that insomnia was more common in the oral
steroid group. For more information, refer to page 663 of the Continuum article
“Management of Multiple Sclerosis Relapses.”
12 The preferred response is C (older age). Older age and severity of the relapse
have been shown to correlate with a lesser degree of recovery after a multiple
sclerosis relapse treated with corticosteroids. Higher nonfasting blood glucose
levels during treatment may also be correlated with less recovery. Male gender
may predict positive response to plasma exchange. For more information, refer
to page 664 of the Continuum article “Management of Multiple Sclerosis
Relapses.”
13 The preferred response is C (discharge home with an appointment with her

outpatient neurologist within 1 week). Some degree of spontaneous
improvement generally occurs following multiple sclerosis relapses. Treatment
will speed up recovery but has not been found to definitively alter the long-term
outcome in patients with relapsing-remitting multiple sclerosis. In this patient
with a mild relapse without clear indication for admission (no significant safety
870 JUNE 2019

risk such as falls) and with a history of a potentially dangerous adverse reaction
to steroids, it is reasonable to discharge home with close monitoring. If
admission and treatment was felt to be indicated, admission for IV
methylprednisolone with close monitoring of her blood glucose and
management with an insulin sliding scale would be appropriate. For more
information, refer to page 665 of the Continuum article “Management of
Multiple Sclerosis Relapses.”
ARTICLE 5: CLINICALLY ISOLATED SYNDROME AND EARLY RELAPSING

MULTIPLE SCLEROSIS
14 The preferred response is B (normal brain MRI). Observational studies of

patients who present with an episode of optic neuritis have demonstrated that
only patients with a normal brain MRI have a very low risk of future relapses of
demyelinating disease and accrual of disability. Patients with CSF oligoclonal
bands and younger age of onset are at higher risk for subsequent disease activity.
For more information, refer to page 677 of the Continuum article “Clinically
Isolated Syndrome and Early Relapsing Multiple Sclerosis.”
15 The preferred response is D (relapsing-remitting multiple sclerosis without

relapses or new MRI activity over the previous 2 years and who are not taking a
disease-modifying therapy). Risk of new disease activity within the next 2 years
can be stratified by reviewing the history of inflammatory events (clinical
relapses or new T2 or enhancing lesions on brain MRI) within the prior 2 to 3 years.
Lower-risk presentations include clinically isolated syndrome with a normal
brain MRI and relapsing-remitting multiple sclerosis without any relapses or new
MRI activity over the past 2 years. Such patients are less likely to benefit from
disease-modifying therapy but should still be monitored closely for evidence of
disease activity. For more information, refer to pages 676, 678 of the Continuum
article “Clinically Isolated Syndrome and Early Relapsing Multiple Sclerosis.”
16 The preferred response is A (dimethyl fumarate). Treatment with dimethyl

fumarate is associated with the adverse effect of flushing, which can be quite
uncomfortable. Administration of the medication with food and ingestion of a
daily dose of aspirin may improve this side effect. For more information, refer
to pages 679–680 of the Continuum article “Clinically Isolated Syndrome and
Early Relapsing Multiple Sclerosis.”
ARTICLE 6: HIGHLY AGGRESSIVE MULTIPLE SCLEROSIS
17 The preferred response is E (number of new T2 lesions). While all the MRI
characteristics listed have been found to predict future disability, the number of

new T2 lesions over time has been identified as the best predictor. For more
information, refer to page 694 of the Continuum article, “Highly Aggressive
18 The preferred response is D (serum neurofilament light chain). This test is not
yet commercially available. However, as an assay using serum (as opposed to
requiring CSF) exists that has shown a correlation with current Expanded
Disability Status Scale (EDSS) score and with EDSS score worsening at 1 year,
serum neurofilament light chain currently has the most promise as a biomarker
for multiple sclerosis. For more information, refer to page 695 of the Continuum
article, “Highly Aggressive Multiple Sclerosis.”
19 The preferred response is D (prevention of leukocyte adherence). Natalizumab

binds to the α4 subunit of two integrin adhesion molecules, preventing
leukocytes from adhering to the endothelium cell. Leukocytes leaving the
bloodstream bind complementary molecules on endothelial cells. The
prevention of leukocyte adherence blocks the leukocytes from exiting the
bloodstream and entering the target tissue (the central nervous system).
Alemtuzumab binds complement and lyses target cells. Fingolimod binds the
sphingosine-1-phosphate receptor and prevents lymphocytes from exiting
lymph nodes. Cyclophosphamide crosslinks DNA, which results in apoptosis. For
more information, refer to pages 697, 699 of the Continuum article, “Highly
Aggressive Multiple Sclerosis.”
20 The preferred response is C (discontinue natalizumab and start a different

disease-modifying therapy 4 weeks after the last natalizumab dose). This
patient is at increased risk of progressive multifocal leukoencephalopathy
because of her elevated JC virus antibody index and number of months on
natalizumab. Natalizumab should be discontinued at this time. Rebound may
occur after discontinuation, with the greatest risk being 3 to 6 months following
the last dose. This risk can be minimized by starting a disease-modifying therapy
before this rebound period, with 4 weeks after the last dose felt to be the
optimal time for initiation. For more information, refer to page 701 of the
Continuum article, “Highly Aggressive Multiple Sclerosis.”
ARTICLE 7: MONITORING, SWITCHING, AND STOPPING MULTIPLE

SCLEROSIS DISEASE-MODIFYING THERAPIES
21 The preferred response is B (fingolimod). Fingolimod has been associated with

the development of macular edema in approximately 0.6% of patients within the
first few months of initiation of treatment. For this reason, monitoring with
optical coherence tomography at pretreatment baseline and 3 to 4 months after
treatment initiation is required. For more information, refer to page 722 of the
872 JUNE 2019

Continuum article “Monitoring, Switching, and Stopping Multiple Sclerosis
Disease-Modifying Therapies.”
22 The preferred response is E (teriflunomide). Cases of tuberculosis have

been observed during clinical studies of teriflunomide. Therefore, testing for
latent tuberculosis (TB) infection is recommended. The safety of treatment
of patients with latent TB is not known, but treatment of latent TB is
recommended before initiation of teriflunomide therapy. Testing for latent
TB should also be performed before initiating treatment with alemtuzumab and
ocrelizumab. For more information, refer to pages 722–723 of the Continuum
article “Monitoring, Switching, and Stopping Multiple Sclerosis Disease-
Modifying Therapies.”
23 The preferred response is C (MRI showing active disease 2 years ago). The
data available on discontinuation of multiple sclerosis (MS) disease-modifying
therapies in older patients are very limited, and no robust randomized trials
have been conducted in older patients to give definitive information to guide
decisions about treatment. In general, greater patient age in MS is associated
with less frequent relapses. Analysis of some databases shows that
discontinuation of disease-modifying therapies for older patients did not lead
to an increase in relapses. In the Rennes database, patients with secondary
progressive MS, the presence of gadolinium-enhancing lesion activity in the
3 years before discontinuation and Expanded Disability Status Scale (EDSS)
score of less than 6.0 were predictors of relapse or active MRIs after
disease-modifying therapy discontinuation. A randomized study is under way
to study discontinuation of disease-modifying therapies in patients without
evidence of new disease activity for a minimum of 5 years. For more
information, refer to page 731 of the Continuum article “Monitoring, Switching,
and Stopping Multiple Sclerosis Disease-Modifying Therapies.”
ARTICLE 8: PROGRESSIVE MULTIPLE SCLEROSIS
24 The preferred response is C (older age at onset). In addition to older age at

onset, male gender and motor presentation have been associated with a more
rapid development of secondary progressive multiple sclerosis (MS). Based on
large natural history studies, the median time to development of secondary
progressive MS is 10 to 20 years. Patients with a younger age of MS onset take
longer to reach secondary progressive MS, although they do reach it at a
younger age than those with older age at disease onset. For more information,
refer to page 741 of the Continuum article, “Progressive Multiple Sclerosis.”

25 The preferred answer is D (poor interrater and intrarater variability). The

Expanded Disability Status Scale (EDSS) is the most used instrument to measure
disease progression in multiple sclerosis, with the neurologic examination, gait
performance, and patient report of disability all contributing factors. It has
several known limitations, including poor interrater and intrarater variability and
overreliance on lower extremity function with inadequate inclusion of cognitive
function. The EDSS is an ordinal scale with unequal functional differences
between the values. It can be scored electronically. For more information, refer
to page 741 of the Continuum article, “Progressive Multiple Sclerosis.”
ARTICLE 9: MANAGEMENT OF MULTIPLE SCLEROSIS SYMPTOMS

AND COMORBIDITIES
26 The preferred response is A (fatigue). Fatigue is the most common symptom

reported by patients with multiple sclerosis and is rated by most as their most
disabling symptom. The etiology of pathologic fatigue in multiple sclerosis is
multifactorial, and it is often exacerbated by medication side effects,
deconditioning, associated sleep disorders, and depression. For more
Multiple Sclerosis Symptoms and Comorbidities.”
27 The preferred response is C (dextromethorphan/quinidine). Pseudobulbar

affect or pathologic involuntary crying or laughing is a common symptom of
many neurodegenerative diseases, such as multiple sclerosis, as well as
traumatic brain injury. The combination medication dextromethorphan/
quinidine is the only medication approved for the treatment of pseudobulbar
affect. For more information, refer to page 759 of the Continuum article
“Management of Multiple Sclerosis Symptoms and Comorbidities.”
28 The preferred response is C (information-processing speed). Multiple

sclerosis is associated with a high prevalence of mixed cortical and subcortical
cognitive dysfunction. The cognitive domains most frequently affected in
multiple sclerosis include recent memory, information-processing speed,
attention, executive function, and visuospatial perception. For more
information, refer to pages 759–760 of the Continuum article “Management of
29 The preferred response is C (dalfampridine). Dalfampridine sustained release

is indicated for the improvement of walking ability in patients with multiple
sclerosis. The clinical effect is thought to be mediated via selective reversible
inhibition of Kv1 potassium channels, causing prolonged action potentials in
spinal cord axons. Approximately one-third of patients will show
improvements in walking speed for the timed 25-foot walk test. For more
874 JUNE 2019

30 The preferred response is E (sodium channel blockade). The paroxysmal

symptoms of multiple sclerosis, such as trigeminal neuralgia, Lhermitte sign,
and tonic spasms, respond best to medications that act as sodium channel
blockers, such as carbamazepine. For more information, refer to pages 761–762
of the Continuum article “Management of Multiple Sclerosis Symptoms and
Comorbidities.”
ARTICLE 10: PREGNANCY AND FAMILY PLANNING IN MULTIPLE SCLEROSIS
31 The preferred response is E (teriflunomide). Teriflunomide is highly

teratogenic. Rapid elimination and measurements of drug levels to ensure it is
nondetectable are required in women who want to become pregnant before
they stop birth control. In women who want to avoid all fetal risks, dimethyl
fumarate and interferon beta should be stopped at the time patients stop
contraception. The US Food and Drug Administration (FDA) label for rituximab
recommends stopping it 1 year before conception, but no clear evidence is
available for this recommendation and it may increase the risk of multiple
sclerosis disease activity in the postpartum period. Rituximab will be cleared 3
to 4 months after the last dose. Animal data for ocrelizumab has shown
increased perinatal mortality and other fetal toxicities when administered
during pregnancy, and, ideally, it should be stopped before pregnancy;
however, levels are not measured before cessation of birth control. As
pregnancy tests are required before each infusion of rituximab and
ocrelizumab, the risk of fetal exposure is minimized. For more information, refer
to page 778 of the Continuum article “Pregnancy and Family Planning in
32 The preferred response is E (thyroid function tests). Autoimmune thyroiditis is

the most significant risk of prepregnancy exposure to alemtuzumab. Maternal
thyroiditis may cause low birth weight, preterm birth, preeclampsia, and
neurocognitive impairment. Neonatal Graves disease may occur, which may
result in fetal death. The peak of alemtuzumab-induced autoimmune thyroiditis
occurs 36 months after initial infusion. Thyroid hormone and autoantibody
screening is indicated before pregnancy, at routine intervals during pregnancy,
and in the early postpartum period. For more information, refer to page 781 of
the Continuum article “Pregnancy and Family Planning in Multiple Sclerosis.”
33 The preferred response is C (low birth weight). Fetal exposure to multiple

courses of corticosteroids has been associated with low birth weight. The
other complications listed have been associated with infant exposure to
various disease-modifying therapies through breast-feeding. For more

information, refer to page 783 of the Continuum article “Pregnancy and Family
Planning in Multiple Sclerosis.”
ARTICLE 11: PEDIATRIC CENTRAL NERVOUS SYSTEM DEMYELINATING

DISEASES
34 The preferred response is D (natalizumab). Disease-modifying treatment

options for neuromyelitis optica (NMO) spectrum disorder for both pediatric
and adult patients include azathioprine, mycophenolate mofetil, and rituximab.
Treatment with natalizumab has been associated with an increase in relapse
rate and florid active demyelination. Cyclophosphamide has been used with
variable efficacy. Other agents that have been reported to exacerbate NMO
include interferon beta, glatiramer acetate, dimethyl fumarate, fingolimod, and
alemtuzumab. For more information, refer to pages 805–806 of the Continuum
article “Pediatric Central Nervous System Demyelinating Diseases.”
35 The preferred response is C (encephalopathy). Encephalopathy is a hallmark of

acute disseminated encephalomyelitis (ADEM); other symptoms include
pyramidal signs, ataxia, dysarthria, optic neuritis, seizures, and spinal cord
syndrome. For more information, refer to page 794 of the Continuum article
“Pediatric Central Nervous System Demyelinating Diseases.”
36 The preferred response is E (neuromyelitis optica [NMO] spectrum disorder).

Vomiting and intractable hiccups as symptoms of an area postrema syndrome
can be the presenting symptoms of an NMO spectrum disorder. Other
presentations may include optic neuritis, transverse myelitis, and other
brainstem/cerebellar disorders. For more information, refer to page 804 of the
Continuum article “Pediatric Central Nervous System Demyelinating Diseases.”
ARTICLE 12: NEUROMYELITIS OPTICA SPECTRUM DISORDER AND

OTHER NON–MULTIPLE SCLEROSIS CENTRAL NERVOUS SYSTEM
INFLAMMATORY DISEASES
37 The preferred response is C (myasthenia gravis). An association exists between

neuromyelitis optica (NMO) spectrum disorders and systemic autoimmune
disorders (such as systemic lupus erythematosus and Sjögren syndrome) and
their antibody biomarkers. NMO spectrum disorder has also been found to
occur years to decades after a diagnosis of myasthenia gravis at higher rates
than would be expected. It has not been associated with the other diagnoses
listed. For more information, refer to page 820 of the Continuum article
“Neuromyelitis Optica Spectrum Disorder and Other Non–Multiple Sclerosis
Central Nervous System Inflammatory Diseases.”
876 JUNE 2019

38 The preferred response is B (conus medullaris). Bowel and bladder
dysfunction and erectile dysfunction in male patients are common in myelin
oligodendrocyte glycoprotein antibody (MOG-IgG) myelitis because of the
frequent involvement of the conus medullaris. While single longitudinally
extensive transverse myelitis lesions may occur, two separate lesions are not
uncommon. Dawson finger lesions are not seen, and the cerebellum and
inferior temporal pole are not common areas of involvement. The optic neuritis
associated with MOG-IgG disease may be bilateral, and, on imaging,
enhancement is often seen to involve more than half of the length of the nerve
and may involve the optic nerve sheath and the orbital fat. Extension into the
chiasm is less typical. For more information, refer to page 833 of the
Continuum article “Neuromyelitis Optica Spectrum Disorder and Other
Non–Multiple Sclerosis Central Nervous System Inflammatory Diseases.”
39 The preferred response is B (corticosteroids). The patient’s presentation and

MRI findings are supportive of a diagnosis of chronic lymphocytic inflammation
with pontine perivascular enhancement responsive to steroids (CLIPPERS), and
his CSF studies do not suggest an alternate diagnosis. The enhancement
pattern described on MRI is a hallmark of this disease. This disorder is highly
responsive to corticosteroids and, without the presence of atypical features,
corticosteroids should be tried prior to biopsy. Lymphoma and neurosarcoidosis
are in the differential. For more information, refer to pages 837–838 of the
Continuum article “Neuromyelitis Optica Spectrum Disorder and Other
Non–Multiple Sclerosis Central Nervous System Inflammatory Diseases.”
40 The preferred response is D (ovarian ultrasound). The patient’s clinical

presentation of a subacute meningitis, encephalitis, and myelitis in association
with MRI findings of radial perivascular enhancement perpendicular to the
ventricles and leptomeningeal enhancement is supportive of a diagnosis of
autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy. This disorder
may be paraneoplastic, with teratoma being a commonly found neoplasm.
Ovarian ultrasound should be obtained in female patients with suspected GFAP
astrocytopathy. For more information, refer to page 835 of the Continuum
article “Neuromyelitis Optica Spectrum Disorder and Other Non–Multiple
Sclerosis Central Nervous System Inflammatory Diseases.”

ERRATUM
In the April 2019 issue of Continuum (Epilepsy, Vol. 25,

No. 2), the following error occurred:
In question 21 of “Postreading Self-Assessment and

CME Test–Preferred Responses” by James W. M.
Owens Jr, MD, PhD, and Allyson R. Zazulia, MD
(Continuum: Lifelong Learning in Neurology
2019;25:570), the preferred response was incorrectly
labeled by the publisher as “B (carbamazepine)”
when it should have been listed as
“A (carbamazepine).”
See the corrected question below.
Owens JWM, Zazulia AR. Postreading

self-assessment and CME test–preferred responses.
Continuum (Minneap Minn) 2019;25(2, Epilepsy):
565–575.
The publisher regrets this error.
21 Which of the following antiseizure

medications is associated with the greatest risk
of sexual dysfunction and decreased libido in
women?
A carbamazepine
B clobazam
C lamotrigine
D levetiracetam
E topiramate
The preferred response is A (carbamazepine).

Sexual dysfunction and decreased libido are
important problems in women with epilepsy that
may reflect effects of both seizures and
antiseizure medications. Sexual side effects are
most commonly reported in women taking hepatic
enzyme–inducing antiseizure medications, such as
carbamazepine, phenytoin, and phenobarbital.
For more information, refer to pages 413–415 of the
Continuum article “Treatment of Women
With Epilepsy.”
878 JUNE 2019

LEARNING OBJECTIVES AND CORE COMPETENCIES
Learning Objectives ◆ Discuss which multiple sclerosis disease-modifying

therapies should be avoided in women of childbearing
Upon completion of this Continuum: Lifelong age who are trying to get pregnant, not on reliable
Learning in Neurology Multiple Sclerosis birth control, or breast-feeding and how to minimize
and Other CNS Inflammatory Diseases issue, the risk of rebound relapses occurring during
participants will be able to: pregnancy following the cessation of natalizumab
or fingolimod
◆ Describe recent advances in the recognition of genetic ◆ Discuss the categories, diagnosis, and management
and environmental risk factors of multiple sclerosis of pediatric demyelinating disorders
and the pathogenic mechanisms involved in the
initiation and progression of the disease
◆ Recognize, diagnose, and treat inflammatory
central nervous system disorders that mimic
◆ Discuss approaches to the clinical assessment multiple sclerosis
for multiple sclerosis that may improve
diagnostic accuracy ◆ Discuss strategies to incorporate clinical practice
guidelines and quality measures into high-quality
◆ Describe the dynamic evolution of multiple sclerosis care for patients with multiple sclerosis
through different clinical and subclinical phases
and its impact on treatment decisions
◆ Describe the cardinal features of multiple sclerosis Core Competencies

relapses and their mimics and utilize evidence-based
treatment modalities for the treatment of multiple This Continuum: Lifelong Learning in Neurology
sclerosis relapses Multiple Sclerosis and Other CNS Inflammatory
Diseases issue covers the following
◆ Describe a general approach to the management
of patients with clinically isolated syndrome and early
core competencies:
relapsing multiple sclerosis, including determination
of prognosis, an understanding of first-line ◆ Patient Care
disease-modifying therapies, and treatment selection
◆ Medical Knowledge
◆ Recognize risk factors for aggressive multiple
sclerosis and the benefits and side effects ◆ Practice-Based Learning and Improvement
of therapies used to treat it
◆ Interpersonal and Communication Skills
◆ Discuss the relevant circumstances of switching
or discontinuing disease-modifying therapies ◆ Professionalism
in patients with multiple sclerosis
◆ Systems-Based Practice
◆ Differentiate key pathologic, clinical, and imaging
features of progressive multiple sclerosis and identify
disease-modifying agents shown to have beneficial
effects in its treatment
◆ Identify and manage symptomatic complications

and comorbidities, with the goal of improving
patient quality of life and clinical outcomes
in multiple sclerosis
586 JUNE 2019

LIST OF ABBREVIATIONS
Multiple Sclerosis and Other CNS IgG Immunoglobulin G

Inflammatory Diseases IgM Immunoglobulin M
IM Intramuscular
IQ Intelligence quotient
AAN American Academy of Neurology IV Intravenous
ACTH Adrenocorticotropic hormone IVIg Intravenous immunoglobulin
ADEM Acute disseminated encephalomyelitis
LETM Longitudinally extensive transverse myelitis
AQP4 Aquaporin-4
MMSE Mini-Mental State Examination
ATPase Adenosine triphosphatase
MOG Myelin oligodendrocyte glycoprotein
BUN Blood urea nitrogen
MRI Magnetic resonance imaging
CI Confidence interval
CLIPPERS Chronic lymphocytic inflammation with pontine MS Multiple sclerosis
perivascular enhancement responsive to steroids MSFC Multiple Sclerosis Functional Composite
CMV Cytomegalovirus
NEDA No evidence of disease activity
CNS Central nervous system
NMDA -methyl-D-aspartate
N-methyl-
CRMP-5 Collapsin response mediator protein-5
NMO Neuromyelitis optica
CSF Cerebrospinal fluid
DNA Deoxyribonucleic acid NMOSD Neuromyelitis optica spectrum disorder
EBNA1 Epstein-Barr nuclear antigen 1 PCR Polymerase chain reaction

EBV Epstein-Barr virus PHQ Patient Health Questionnaire
ECG Electrocardiogram PML Progressive multifocal leukoencephalopathy
EDSS Expanded Disability Status Scale PRES Posterior reversible encephalopathy syndrome
EEG Electroencephalography
REM Rapid eye movement
ELISA Enzyme-linked immunosorbent assay
RLS Restless legs syndrome
EMA European Medicines Agency
FDA US Food and Drug Administration SIADH Syndrome of inappropriate secretion
of antidiuretic hormone
FLAIR Fluid-attenuated inversion recovery
GABA γ-Aminobutyric
-Aminobutyric acid SNRI Serotonin norepinephrine reuptake inhibitor
GABA-ergic γ-Aminobutyric
-Aminobutyric acid–mediated SSRI Selective serotonin reuptake inhibitor
GFAP Glial fibrillary acidic protein THC Tetrahydrocannabinol
HIV Human immunodeficiency virus TSH Thyroid-stimulating hormone
© 2019 American Academy of Neurology.

Multiple Sclerosis and Other CNS
Inflammatory Diseases
Article 1: Multiple Sclerosis Risk Factors
and Pathogenesis
Bardia Nourbakhsh, MD, MAS; Ellen M. Mowry, MD, MCR, FAAN, FANA. Continuum
(Minneap Minn). June 2019; 25 (3 Multiple Sclerosis and Other CNS Inflammatory
Diseases):596–610.
ABSTRACT
PURPOSE OF REVIEW:
This article summarizes recent advances in the identification of genetic and environmental
factors that affect the risk of developing multiple sclerosis (MS) and the pathogenic processes
involved in acute relapses and relapse-independent disability progression.
RECENT FINDINGS:
The number of single-nucleotide polymorphisms associated with increased risk of MS has
increased to more than 200 variants. The evidence for the association of Epstein-Barr virus
infection, vitamin D deficiency, obesity, and smoking with increased risk of MS has further
accumulated, and, in cases of obesity and vitamin D deficiency, the evidence for causal
association has strengthened. Interactions between genetic and environmental factors have
been studied more extensively. Dietary factors and changes in the gut microbiota are emerging
as possible modulators of the disease risk. Several processes important to MS pathogenesis
have been newly investigated or investigated more comprehensively, including the role of B
cells, innate immune cells, meningeal inflammation, cortical and gray matter demyelination, and
early axonal and neuronal loss.
SUMMARY:
MS is a complex disease in which the interaction between genetic and environmental factors
causes a cascade of events, including activation of the adaptive and innate immune system,
blood-brain barrier breakdown, central nervous system demyelination, and axonal and neuronal
damage with variable degrees of repair. These events manifest as potentially reversible focal
neurologic symptoms or progressive nonremitting physical and cognitive disability, or both.
Advances in the understanding of the risk factors and pathogenic mechanisms of MS have
resulted in improved therapeutic strategies. The results of ongoing or future studies are needed
to successfully and fully translate these advances into clinical practice.

KEY POINTS
• Unlike several other common neurologic diseases (such as Alzheimer disease, Parkinson disease, and
amyotrophic lateral sclerosis), no mendelian form of multiple sclerosis has thus far been reported.
• No single autoantigen, autoantibody, or infectious agent has thus far been unequivocally associated with
multiple sclerosis.
• Autoreactive lymphocytes that gain access to the central nervous system start a pathogenic cascade that
culminates in demyelination, neuroaxonal degeneration, synaptic loss, dying-back oligodendrogliopathy,
and, eventually, tissue loss and astrogliosis.
• Demyelination in multiple sclerosis is not confined to the white matter, and cortical and deep gray matter
demyelination can be detected pathologically and is present even in early stages of the disease.
• Both T lymphocytes and B lymphocytes, as well as innate immune mechanisms, participate in multiple
sclerosis pathogenesis.
• Although demyelination in the central nervous system is the hallmark of multiple sclerosis, axonal injury is
present from the earliest stages of the disease and is a major contributor to physical and cognitive disability.
• More than 200 genetic variants have been discovered to be associated with modifying the risk of multiple
sclerosis.
• Low sunlight exposure, vitamin D deficiency, obesity, and smoking are factors with strong evidence for
association with multiple sclerosis risk.
• Many infectious agents have been reported to be associated with multiple sclerosis risk; however, only
Epstein-Barr virus infection has been consistently shown to be a risk factor.
• Exposure to several risk factors for developing multiple sclerosis (including Epstein-Barr virus infection and
obesity) during adolescence appears to be more detrimental than exposure in adulthood.
• Statistical interactions between risk factors and mendelian randomization studies have provided evidence
for the causal association of several environmental factors and the risk of multiple sclerosis.
• Lung irritation from inhalation of cigarette smoke is likely the mediator of association between smoking and
multiple sclerosis risk.
Article 2: Diagnosis, Differential Diagnosis,

and Misdiagnosis of Multiple Sclerosis
Andrew J. Solomon, MD. Continuum (Minneap Minn). June 2019; 25 (3 Multiple
Sclerosis and Other CNS Inflammatory Diseases):611–635.
ABSTRACT
PURPOSE OF REVIEW:
The diagnosis of multiple sclerosis (MS) is often challenging. This article discusses approaches to
the clinical assessment for MS that may improve diagnostic accuracy.
RECENT FINDINGS:
Contemporary diagnostic criteria for MS continue to evolve, while knowledge about diseases
that form the differential diagnosis of MS continues to expand. Recent data concerning causes
of MS misdiagnosis (the incorrect assignment of a diagnosis of MS) have further informed
approaches to syndromes that may mimic MS and the accurate diagnosis of MS.
SUMMARY:
This article provides a practical update on MS diagnosis through a discussion of recently revised
MS diagnostic criteria, a renewed consideration of MS differential diagnosis, and contemporary
data concerning MS misdiagnosis.

KEY POINTS
• Diagnosis of relapsing-remitting multiple sclerosis begins with confirmation of objective evidence of a
syndrome typical for multiple sclerosis.
• Knowledge of the recent revisions to the 2017 McDonald criteria is essential for the proper use of paraclinical
(ie, visual evoked potentials, CSF examination) and radiographic data to substitute for a second clinical
attack for the demonstration of dissemination in space and dissemination in time for the diagnosis of multiple
sclerosis.
• Objective evidence of a demyelinating syndrome typical for multiple sclerosis demonstrating both
dissemination in space and dissemination in time must be accompanied by a search for “no better
explanation” to confirm a diagnosis of multiple sclerosis.
• A syndrome typical for multiple sclerosis may also exhibit characteristics atypical for multiple sclerosis,
suggesting a specific alternative diagnosis.
• The demographic profile of patients presenting with syndromes typical for multiple sclerosis may provide an
important red flag prompting evaluation for alternative diagnoses.
• Noninflammatory conditions may also be mistaken for a typical presentation of multiple sclerosis.
Knowledge of broad red flags suggesting a structural, functional, metabolic, infectious, neoplastic, or other
disease may lead to a specific alternative diagnosis.
• The McDonald criteria have not been evaluated in patients presenting with atypical syndromes or typical
syndromes with red flags, and additional clinical, paraclinical, or radiographic evaluation and monitoring is
necessary to confirm a diagnosis of multiple sclerosis.
• In patients presenting to establish care with a preexisting diagnosis of multiple sclerosis, reassessment of the
accuracy of multiple sclerosis diagnosis is prudent.
• The diagnosis of primary progressive multiple sclerosis and its mimics differs from that of relapsing-remitting
multiple sclerosis and requires a thorough understanding of the assessment of clinical progression.
• Misdiagnosis of multiple sclerosis is often caused by misapplication of the McDonald criteria in patients with
atypical syndromes, overreliance on or misunderstanding of MRI dissemination in space, or consideration
of historical episodes of symptoms without objective evidence of a central nervous system lesion for
demonstration of dissemination in time.
Article 3: Phases and Phenotypes of

Multiple Sclerosis
Orhun H. Kantarci, MD. Continuum (Minneap Minn). June 2019; 25 (3 Multiple Sclerosis
and Other CNS Inflammatory Diseases):636–654.
ABSTRACT
PURPOSE OF REVIEW:
This article describes the dynamic evolution of multiple sclerosis (MS) through its phases and the
impact of this understanding on treatment decisions.
RECENT FINDINGS:
MS consists of three phases: (1) the high-risk phase, (2) the relapsing-remitting phase, and (3) the
progressive phase. Increasingly, subclinical disease activity is becoming an integral part of our
definition of disease course in MS. In many patients, the relapsing-remitting phase starts as
subclinical activity, likely long before they present with a clinically isolated syndrome.
Differentiating progressive MS subgroups is also becoming less relevant. This is illustrated by
comparing progressive MS that evolves from an asymptomatic state in individuals with

radiologically isolated syndrome (primary progressive MS) and symptomatic individuals with
relapsing-remitting MS (secondary progressive MS). In each case, the background disease
activity and pathology can be indistinguishable. These phases evolve on a continuum and largely
follow the aging process with little influence by the preceding clinical activity level. Recently, it
also became evident that one or a few poorly recovered relapses at the beginning of clinical
manifestations of MS predict much earlier progressive MS onset.
SUMMARY:
These findings suggest that interventions to prevent progressive MS, when they become
available for clinical practice, may need to be considered as early as when the asymptomatic
radiologically isolated syndrome is detected. This early treatment approach is being evaluated
with ongoing trials with available disease-modifying therapies. In contrast, continuing the use of
disease-modifying therapy beyond a certain age may have little benefit. However, being in the
progressive phase of MS is not, in itself, an argument against disease-modifying therapy use in
active disease in younger patients.
KEY POINTS
• Current disease course classification in multiple sclerosis consists of three phases: the multiple sclerosis
high-risk phase, the relapsing-remitting phase, and the progressive phase.
• Progression is the insidious and irreversible worsening of neurologic function due to multiple sclerosis over
years.
• Active disease in multiple sclerosis is defined as new symptomatic relapses or asymptomatic MRI activity
(contrast-enhancing T1-hyperintense lesions, new T2-hyperintense lesions, or enlarging T2-hyperintense
lesions).
• Worsening disability can be due to the stepwise accumulation of neurologic deficit from partially recovered
relapses, the insidious accumulation of neurologic deficit from a progressive disease course, a combination
of both, or other multiple sclerosis or non–multiple sclerosis-related factors.
• The relapsing-remitting multiple sclerosis diagnosis that most clinicians are familiar with requires the
presence of multiple clinically distinct events affecting different parts of the central nervous system
separated in time (arbitrarily defined as at least 1 month apart). This operational diagnostic rule, core to
understanding the diagnosis of multiple sclerosis, is referred to as dissemination in time and space.
• When a patient presents with symptoms not typical of multiple sclerosis (MS) and an MRI is obtained that
fulfills the diagnostic imaging criteria, a diagnosis of radiologically isolated syndrome is given. When these
patients develop their first MS symptom, they fulfill the criteria for single-attack MS (30% in 5-year follow-up).
This evolution is significantly faster in pediatric radiologically isolated syndrome (60% in 1-year follow-up).
• Onset of the progressive phase of multiple sclerosis seemingly is age dependent but agnostic for disease
duration and preprogressive phase.
• Several clinically useful predictors of evolution to progressive multiple sclerosis (other than age) are having
spinal cord lesions, being male, consuming tobacco, being obese, and having a low serum 25-hydroxyvitamin D3
level. Even in the absence of specific medications targeting progression alone in multiple sclerosis, some of
these factors are modifiable and, together with an active lifestyle and physical therapy, can potentially help
build nervous system reserve and resistance to injury.
• Disease-modifying therapies are efficacious early in multiple sclerosis, but the utility of continuing them in
patients older than age 60 should be considered on an individual basis.
• Seemingly a pathologic hallmark of progressive multiple sclerosis, smoldering plaques peak in frequency at
around the fifth decade, a time when the dominant plaque type also switches from active to inactive plaques,
mirroring the independent epidemiologic observation of established mean age of progressive multiple
sclerosis onset of 45 years.

Article 4: Management of Multiple
Sclerosis Relapses
Pavle Repovic, MD, PhD. Continuum (Minneap Minn). June 2019; 25 (3 Multiple
ABSTRACT
PURPOSE OF REVIEW:
This article provides an overview of the clinical and pathologic features of multiple sclerosis
(MS) relapses and reviews evidence-based approaches to their treatment.
RECENT FINDINGS:
Despite the increasing number and potency of MS treatments, relapses remain one of the more
unpredictable and disconcerting disease aspects for many patients with MS, making their
accurate recognition and treatment an essential component of good clinical care. The expanding
range of relapse treatments now includes oral corticosteroids, comparable in efficacy to IV
methylprednisolone at a fraction of the cost. While this development improves access to prompt
treatment, it also underscores the importance of recognizing mimics of MS relapses to reduce
corticosteroid overuse and its attendant risks.
SUMMARY:
Like MS itself, MS relapse remains primarily a clinical diagnosis. The treatment options for MS
relapse include corticosteroids, adrenocorticotropic hormone (ACTH), plasma exchange, and
rehabilitation, used singly or sequentially, with the goal of limiting the duration and impact of
associated disability. Even when treated promptly and effectively, clinical or subclinical
sequelae of MS relapses frequently remain.
KEY POINTS
• Typical manifestations of multiple sclerosis relapses include optic neuritis, spinal cord syndromes, and
brainstem syndromes.
• The shared pathologic substrate of multiple sclerosis relapses is impaired axonal conduction resulting from
the combined effects of demyelination, inflammation, and variable degree of neuronal loss.
• Viral and bacterial infections increase the risk of multiple sclerosis relapse.
• Resolution of the inflammatory phase of a multiple sclerosis relapse is followed by a reparative phase.
• Even when symptoms are unequivocally multiple sclerosis–related, a distinction needs to be made between
a bona fide multiple sclerosis relapse and a pseudorelapse.
• Fluctuation of symptoms in patients with multiple sclerosis is attributed to variable efficiency of repair
following a relapse.
• Uhthoff phenomenon refers to reoccurrence of a neurologic deficit from an earlier relapse in the setting of
increased core body temperature, classically observed with exercise.
• Several clinical trials and two meta-analyses provide evidence that high-dose corticosteroids hasten
neurologic recovery after multiple sclerosis relapse.
• Oral steroids are less expensive, somewhat more convenient, and no less effective than IV steroids for the
treatment of multiple sclerosis relapses.
• Given the considerable frequency of steroid side effects, a proactive approach to minimize their impact on
patients is recommended.
• Compared to corticosteroids, adrenocorticotropic hormone use in multiple sclerosis relapses is not well
defined.

• Second-line treatment options for multiple sclerosis relapse include repetition of corticosteroid treatment
(sometimes using a different dose, route, or type of steroid), adrenocorticotropic hormone, and plasma
exchange.
• In one study, plasma exchange led to significant improvement in 42% of patients who remained severely
impaired after relapses treated with high-dose corticosteroids, compared to only 5% with sham treatment.
• The decision whether to treat or monitor a multiple sclerosis relapse should be made jointly between a
patient and a clinician, considering the impact of both the relapse and the proposed treatment on a patient.
Article 5: Clinically Isolated Syndrome

and Early Relapsing Multiple Sclerosis
Luanne M. Metz, MD, FRCPC. Continuum (Minneap Minn). June 2019; 25 (3 Multiple
ABSTRACT
PURPOSE OF REVIEW:
This article reviews management of clinically isolated syndrome and early relapsing-remitting
multiple sclerosis (MS). It provides a general approach to patient management and
determination of prognosis, reviews first-line disease-modifying therapies, and provides an
approach to treatment selection.
RECENT FINDINGS:
Revision of the MS diagnostic criteria allows an earlier MS diagnosis, which reduces diagnostic
uncertainty and often allows additional treatment options. Identification of factors that
influence disease activity and progression highlights the importance of counseling patients
about behavior modifications that, along with disease-modifying therapy, may improve
long-term outcomes. Recommended lifestyle modifications include smoking cessation,
vitamin D supplementation, a healthy diet, maintaining a healthy weight, remaining active, and
management of cardiovascular risk factors. Identifying individuals at high risk for future disability
allows them to make informed decisions about the use of highly effective, higher-risk
SUMMARY:
Patients with clinically isolated syndrome, even those with only dissemination in space but not
dissemination in time, and patients with relapsing-remitting MS and disease activity within the
prior 2 years, are at high risk of disease activity within the next 2 years. Lifestyle modification
suggestions and disease-modifying therapy should be considered. Treatment decisions should
be made in collaboration with patients using the shared decision-making approach.
KEY POINTS
• A serious diagnosis such as multiple sclerosis may motivate people toward a healthy lifestyle. Diagnosis
provides the opportunity to inform patients of health behaviors that are associated with worse multiple
sclerosis outcomes.
• Education and supported self-management are the mainstays of chronic disease management.
• Patients at low risk of disease activity over the short term are less likely to benefit from disease-modifying
therapy but may still benefit from disease monitoring because risk assessment is not precise.
• In clinically isolated syndrome, the chance of new clinical or MRI activity is 60% to 70% within 6 months and
80% to 90% within 2 years.

• Factors associated with greater risk of long-term disability may identify those most likely to benefit from
initiation of highly effective therapy or additional vigilance in monitoring disease-modifying therapy
effectiveness.
• The main advantage of the injectable therapies interferon beta and glatiramer acetate is their long-term
safety profile. The main disadvantages are modest efficacy and limited tolerance and convenience because
they are injectable.
• The first-line oral therapies dimethyl fumarate and teriflunomide are convenient, but they are relatively new
and cause immune suppression long term. Safety, including a long-term risk of malignancy, is a concern.
Teriflunomide must be used with caution in women of childbearing age because of the risk of fetal
malformation.
• A shared decision-making process should be used to select a preferred disease-modifying therapy option.
• Delays in disease-modifying therapy should be avoided. The risk of reaching an Expanded Disability Status
Scale score of 4.0 is increased by 7.4% for every year of delay in treatment initiation after multiple sclerosis
onset.
Article 6: Highly Aggressive Multiple

Sclerosis
James D. Bowen, MD. Continuum (Minneap Minn). June 2019; 25 (3 Multiple Sclerosis
ABSTRACT
PURPOSE OF REVIEW:
Newly introduced disease-modifying therapies offer greater efficacy than previous therapies
but also have serious side effects. This article reviews factors useful in identifying those at risk of
developing aggressive relapsing multiple sclerosis (MS) and therapies available for treatment.
RECENT FINDINGS:
Several factors predict aggressive MS, including demographic factors, relapses, symptom
characteristics, MRI activity, and other biomarkers. These can be used to select patients for
more aggressive therapies, including natalizumab, alemtuzumab, fingolimod, and ocrelizumab.
Additional off-label treatments are available for patients with severe disease. The benefits and
side effects of these treatments must be considered when making therapeutic decisions.
SUMMARY:
Selecting patients who are most appropriate for aggressive therapy involves considering risk
factors for poor outcomes, early recognition of treatment failure, balancing treatment efficacy
and side effects, and sharing the decision with patients to assist them in making optimal
treatment choices. Vigilance for signs of treatment failure and early switching to more
aggressive therapy are important components in optimal care.
KEY POINTS
• Demographic factors that suggest a more aggressive multiple sclerosis course include male sex, onset after
40 years of age, nonwhite race, and smoking.
• Clinical characteristics that predict the risk of aggressive multiple sclerosis include frequent relapses;
shorter interattack intervals; incomplete recovery from attacks; pyramidal, cerebellar, sphincter, or
cognitive symptoms; and multifocal onset.
• Rapidly worsening disability and multiple sclerosis that is progressive from onset predict an aggressive course.

• MRI characteristics that predict more aggressive course include the number and volume of T2 lesions; the
presence of gadolinium-enhancing lesions; the volume of T1-hypointense lesions; and the presence of
atrophy, infratentorial lesions, or spinal cord lesions.
• Oligoclonal bands are associated with several markers for aggressive multiple sclerosis.
• The most serious side effect of natalizumab is progressive multifocal leukoencephalopathy. The risk of
progressive multifocal leukoencephalopathy is estimated by the duration of natalizumab therapy, prior
immunosuppressive use, and JC virus antibody index.
• Rebound can occur between 3 and 6 months after stopping natalizumab. Other disease-modifying therapies
should be started before this time to minimize rebound risk.
• The side effects of alemtuzumab include immediate infusion reactions, autoimmune diseases, infections, and
malignancies.
• The side effects of fingolimod include first-dose bradycardia. Fingolimod and siponimod may cause macular
edema and opportunistic infections, including Cryptococcus and progressive multifocal
leukoencephalopathy. Risk for infection cannot be assessed using absolute lymphocyte counts.
• The side effects of ocrelizumab include infusion reactions, infections (especially herpes infections), and
possible malignancy; progressive multifocal leukoencephalopathy and reactivation of hepatitis B are
theoretical risks, but thus far no cases have been seen.
• Cladribine is an oral immunosuppressant that was recently approved by the US Food and Drug
Administration. Side effects include infections and malignancies.
• Mitoxantrone’s use has been limited by cardiotoxicity and acute myelogenous leukemia.
• Cyclophosphamide is widely available and has some evidence to support its use, but definitive trials have not
been performed.
• Rituximab’s mechanism of action and side effects are similar to those of ocrelizumab. Rituximab is not US
Food and Drug Administration approved for multiple sclerosis, but many have used it off-label because it is
less expensive than ocrelizumab.
• High-dose immunosuppressive therapy with stem cell transplantation is the most aggressive therapy
available for multiple sclerosis today. Outcomes are possibly double the rate of “no evidence of disease
activity” of other therapies. Thus far, only phase 2 studies have been completed.
Article 7: Monitoring, Switching, and

Stopping Multiple Sclerosis
Disease-Modifying Therapies
Robert H. Gross, MD; John R. Corboy, MD, FAAN. Continuum (Minneap Minn). June
2019; 25 (3 Multiple Sclerosis and Other CNS Inflammatory Diseases):715–735.
ABSTRACT
PURPOSE OF REVIEW:
This article reviews appropriate monitoring of the various multiple sclerosis (MS)
disease-modifying therapies, summarizes the reasons patients switch or stop treatment, and
provides a framework for making these management decisions.
RECENT FINDINGS:
With the increasing number of highly effective immunotherapies available for MS, the possibility
of better control of the disease has increased, but with it, the potential for side effects has
rendered treatment decisions more complicated. Starting treatment early with more effective

and better-tolerated disease-modifying therapies reduces the likelihood of switching because
of breakthrough disease or lack of compliance. Clinical and radiographic surveillance, and
often blood and other paraclinical tests, should be performed periodically, depending on the
disease-modifying therapy. Helping patients navigate the uncertainty around switching or
stopping treatment, either temporarily or permanently, is one of the most important things we
do as providers of MS care.
SUMMARY:
Ongoing monitoring of drug therapy is a crucial component of long-term MS care. Switching
treatments may be necessary for a variety of reasons. Permanent discontinuation of treatment
may be appropriate for some patients with MS, although more study is needed in this area.
KEY POINTS
• Studies of factors related to multiple sclerosis disease-modifying therapies highlight that adherence is
extremely variable and that switching or discontinuing disease-modifying therapies is very common in both
the long and short term.
• Discontinuation of disease-modifying therapy may be temporary because of insurance interruption; a desire
to become pregnant, becoming pregnant, or lactating; lack of adherence (for many reasons); or deliberate
installation of a washout period between medications when switching disease-modifying therapies to limit
overlapping risks with two medications used in sequence.
• Requiring patients to use less effective and less tolerable disease-modifying therapies first simply subjects
patients to greater disability and discomfort over time.
• Ultimately, best practice likely reinforces that individual aspects should dictate the optimal approach for any
one patient.
• Decisions made at the beginning of the disease course have potential long-term implications for use of other
• One source of ambiguity when considering switching disease-modifying therapy is that no standard definition
of treatment “failure” exists, nor is there a universally accepted standard as to the appropriate time to switch
disease-modifying therapies in multiple sclerosis.
• With the recognition of “no evidence of disease activity” as a treatment goal and ever-higher rates of no
evidence of disease activity emerging from clinical trials of multiple sclerosis disease-modifying therapies,
disease activity that previously would have been tolerated is now frequently no longer deemed acceptable.
• Practices vary regarding the use and length of washout periods, and evidence from randomized controlled
trials to guide management is limited.
• An overly lengthy washout risks disease reactivation, especially with disease-modifying therapies that impair
lymphocyte migration or trafficking and the cessation of which can be associated with rebound activity
(fingolimod, natalizumab).
• In the natural history of multiple sclerosis, the risk of what are considered new episodes of inflammation,
relapses, and gadolinium-enhancing lesions on MRI scans is highest after clinical onset and generally
diminishes significantly with age, so that by age 50 the annual risk of any of the three is below 10%.
• As all presently available disease-modifying therapies alter, modulate, or suppress the immune system, with
minimal documented effects on potential repair or regeneration of the nervous system, the benefits have
been shown to be greatest in those with active inflammatory disease (ie, younger patients).
• Stopping disease-modifying therapies may have potential benefits, including fewer side effects, long-term
risks, costs, and reminders that the patient has MS.
• Young age, a recent MS diagnosis, and recent disease activity (relapses or MRI changes) are characteristic of
those most likely to benefit from MS immunotherapy.

Article 8: Progressive Multiple Sclerosis
Daniel Ontaneda, MD. Continuum (Minneap Minn). June 2019; 25 (3 Multiple Sclerosis
ABSTRACT
PURPOSE OF REVIEW:
This article provides an update on progressive forms of multiple sclerosis (MS), with a focus on
pathogenic mechanisms, clinical features, imaging features, and recent therapeutic advances.
RECENT FINDINGS:
Progressive forms of MS are identified by a history of progressive accrual of disability independent
of relapse, but they share many biological, clinical, and MRI features with relapsing MS. Both
relapses and new lesions can occur in the context of progressive MS, and establishing when the
transition from relapsing to progressive MS occurs is often difficult. Several pathogenic
mechanisms coexist in progressive MS. Targeting inflammation in both primary and secondary
progressive MS appears to reduce the accumulation of disability.
SUMMARY:
Progressive MS remains a diagnostic challenge, and the pathogenesis underlying progression is
complex. Significant overlap in the biology and clinical and imaging features of progressive MS
exists with relapsing forms of the disease. The use of disease-modifying and symptomatic
treatments may improve the quality of life for patients with progressive MS.
KEY POINTS
• Progressive multiple sclerosis was previously considered an untreatable from of the disease, but current and
future disease-modifying agents will change our approach to this form of the disease.
• Several mechanisms are present in both relapsing and progressive multiple sclerosis, and differences
between relapsing and progressive multiple sclerosis are more relative than absolute.
• Inflammation plays a significant role in the pathogenesis of progressive multiple sclerosis.
• Because of the insidious onset of symptoms, the diagnosis of progressive multiple sclerosis is typically
delayed, both as the initial presentation in primary progressive multiple sclerosis and when reclassifying a
patient with relapsing-remitting multiple sclerosis as having secondary progressive multiple sclerosis.
• The 2017 McDonald diagnostic criteria for multiple sclerosis include specific criteria for primary progressive
multiple sclerosis, including 1 year of disability progression (retrospectively or prospectively determined)
independent of relapses plus at least two of the following: one or more T2 lesions in characteristic regions on
brain MRI, two or more spinal cord MRI lesions, or the presence of CSF oligoclonal bands.
• Progressive and relapsing multiple sclerosis should be considered to occur on a spectrum rather than as
different diseases, and the understanding that these two forms share several common features in biology,
clinical evolution, and imaging findings is growing.
• Measurement of progressive accrual of disability is inherently difficult and remains a significant obstacle in
progressive multiple sclerosis.
• Brain lesions in progressive multiple sclerosis are indistinguishable from those seen in relapsing multiple
sclerosis; however, on average, patients with primary progressive multiple sclerosis tend to have fewer brain
T2 lesions and fewer lesions with gadolinium enhancement.
• Conventional and advanced spinal cord MRI measures hold promise as potential biomarkers for progressive
multiple sclerosis.
• Siponimod was studied in a phase 3 trial in secondary progressive multiple sclerosis and is now approved by
the US Food and Drug Administration for the treatment of active secondary progressive multiple sclerosis.

• Ocrelizumab is now an approved medication for primary progressive multiple sclerosis and will be helpful in
treating the inflammatory components in patients with the disease, especially in younger patients with
inflammatory disease on MRI.
Article 9: Management of Multiple

Sclerosis Symptoms and Comorbidities
W. Oliver Tobin, MBBCh, BAO, PhD. Continuum (Minneap Minn). June 2019; 25 (3
Multiple Sclerosis and Other CNS Inflammatory Diseases):753–772.
ABSTRACT
PURPOSE OF REVIEW:
This article discusses the prevalence, identification, and management of multiple sclerosis
(MS)–related symptoms and associated comorbidities, including complications that can present
at all stages of the disease course.
RECENT FINDINGS:
The impact of comorbidities on the outcome of MS is increasingly recognized. This presents an
opportunity to impact the course and outcome of MS by identifying and treating associated
comorbidities that may be more amenable to treatment than the underlying inflammatory and
neurodegenerative disease. The identification of MS-related symptoms and comorbidities is
facilitated by brief screening tools, ideally completed by the patient and automatically entered
into the patient record, with therapeutic suggestions for the provider. The development of free,
open-source screening tools that can be integrated with electronic health records provides
opportunities to identify and treat MS-related symptoms and comorbidities at an early stage.
SUMMARY:
Identification and management of MS-related symptoms and comorbidities can lead to
improved outcomes, improved quality of life, and reduced disease activity. The use of brief
patient-reported screening tools at or before the point of care can facilitate identification of
symptoms and comorbidities that may be amenable to intervention.
KEY POINTS
• Fatigue is the most common symptom in patients with multiple sclerosis, present in almost half of patients
with clinically isolated syndrome and over 80% of patients over the course of the disease.
• Restless legs syndrome has been reported in 13% to 65% of patients with multiple sclerosis and appears to be
related to spinal cord disease.
• Limited evidence exists for commonly used but unapproved medications, such as amantadine, modafinil,
armodafinil, methylphenidate, and amphetamine compounds for management of fatigue in multiple
sclerosis.
• It is recommended that all patients with multiple sclerosis be screened for depression at annual visits.
• Screening for depression and anxiety can be completely automated, with the patient responding
electronically to brief screening questionnaires and the responses automatically recorded in the patient's
electronic health record.
• Patients may develop cognitive dysfunction in the absence of a significant burden of white matter disease
and in the absence of accumulating T2-hyperintense brain lesions.
• Interpretation of a cognitive assessment at a single point in time may not provide an adequate assessment of
an individual’s overall performance.

• Paroxysmal symptoms in multiple sclerosis are typically sensory with variable motor involvement. They
usually last between 1 and 90 seconds and are exquisitely sensitive to sodium channel blockade.
• Commonly used aural thermometers are often inaccurate in the setting of hypothermia, and identification of
hypothermia requires the use of a low-reading rectal thermometer.
• Initial treatment of spasticity should primarily focus on stretching exercises. Stretches should be held for
30 to 60 seconds, and patients should be counseled to stretch twice daily.
• For patients who are nonambulatory with severe spasticity that is not responsive to or intolerant of other
treatment strategies, intrathecal baclofen is a useful strategy, particularly for facilitating toileting and
cleaning.
• In contrast to other neurologic disorders affecting the spinal cord, such as spina bifida, upper urinary tract
disorders in multiple sclerosis are rare, possibly because of the slowly progressive nature of the disease.
• In patients with multiple sclerosis presenting with urinary symptoms, a urinalysis and postvoid residual
ultrasound of the bladder should be performed.
• Indwelling catheters are associated with a greater risk of urinary tract infections, genital erosions, and
bladder stone formation than intermittent catheterization.
• Percutaneous and transcutaneous tibial nerve stimulation have been shown to have short-term benefits on
urinary symptoms for patients with overactive bladder secondary to multiple sclerosis and may also have a
positive effect on fecal incontinence.
• Sexual dysfunction affects up to 90% of patients with multiple sclerosis during the course of the disease.
Article 10: Pregnancy and Family Planning

in Multiple Sclerosis
Annette M. Langer-Gould, MD, PhD. Continuum (Minneap Minn). June 2019; 25 (3
Multiple Sclerosis and Other CNS Inflammatory Diseases):773–792.
ABSTRACT
PURPOSE OF REVIEW:
This article provides practical guidance on successful management of women with multiple
sclerosis (MS) through pregnancy and the postpartum period.
RECENT FINDINGS:
Recent studies indicate that most women diagnosed with MS today can have children,
breast-feed, and resume beta interferons or glatiramer acetate per their preferences without
incurring an increased risk of relapses during the postpartum period. More than 40% of women
with mild MS do not require any treatment before conception or in the postpartum period.
Women with highly active MS can now become well-controlled before, throughout, and after
pregnancy via highly effective treatments. Unfortunately, pregnancy does not protect against
relapses following the cessation of fingolimod or natalizumab, and some women experience
severe rebound relapses during pregnancy. Accidental first-trimester exposure to teriflunomide
or fingolimod increases the risk of fetal harm.
SUMMARY:
Most women with MS can have normal pregnancies and breast-feed without incurring harm.
Clinicians should avoid prescribing medications with known teratogenic potential
(teriflunomide, fingolimod), known risk of severe rebound relapses (fingolimod, natalizumab), or
unclear but plausible risks (dimethyl fumarate, alemtuzumab) to women of childbearing age
who desire pregnancy or are not on reliable birth control. If a treatment needs to be resumed

during breast-feeding, clinicians should opt for glatiramer acetate, interferon beta, natalizumab,
or rituximab/ocrelizumab, as biologically plausible risks to the infant are exceedingly low.
KEY POINTS
• Multiple sclerosis does not increase the risk of infertility, adverse pregnancy outcomes, or adverse neonatal
outcomes, but some multiple sclerosis treatments may increase these risks.
• Potential risks not captured by US Food and Drug Administration pregnancy categories include neonatal
immunosuppression, impaired early-life neurocognitive development, delayed toxicities in the child (eg,
cancer), and risks incurred from severe rebound relapses in pregnancy.
• It is important to assess whether the patient’s disease activity is adequately controlled before counseling
about pregnancy. First decide whether patients with multiple sclerosis need to be on highly effective or
modestly effective disease-modifying therapy to control their disease activity, then consider the possibility
of pregnancy when choosing a disease-modifying therapy.
• It is important to ask patients with multiple sclerosis about pregnancy plans and contraception regularly.
• Many patients with multiple sclerosis have adequately controlled disease without any treatment or only
modestly effective disease-modifying therapies. If these patients start trying to conceive, discontinuing
treatment, if any, is prudent.
• Glatiramer acetate and interferon beta are the preferred modestly effective disease-modifying therapies for
women who are not on reliable birth control.
• Consider a B-cell–depleting drug if a highly effective disease-modifying therapy is needed for a woman who
is trying to get pregnant or not on reliable birth control. Assess for pregnancy before each infusion and do
not infuse the medication if the patient is currently pregnant.
• Pregnancy does not protect against the risk of return of disease activity or rebound relapses after cessation
of fingolimod or natalizumab.
• To prevent return of disease activity or rebound relapses during pregnancy after cessation of fingolimod or
natalizumab, consider switching women to a B-cell–depleting therapy before conception.
• Fingolimod and natalizumab rebound relapses are treatable, even if they occur during pregnancy.
• Encourage and support breast-feeding for optimal infant and maternal health.
• Glatiramer acetate and interferon beta pose exceedingly low risk to infants via breast milk exposure and can
be resumed when desired.
• Natalizumab and rituximab have very low theoretical risks to infants with breast milk exposure only and may
be resumed during lactation if necessary.
Article 11: Pediatric Central Nervous

System Demyelinating Diseases
Tanuja Chitnis, MD, FAAN. Continuum (Minneap Minn). June 2019; 25 (3 Multiple
ABSTRACT
PURPOSE OF REVIEW:
This article provides an up-to-date summary of the categories, diagnosis, and management of
pediatric demyelinating disorders.
RECENT FINDINGS:
Understanding of the diverse spectrum of pediatric demyelinating disorders, including
monophasic and multiphasic forms, has improved. Pediatric multiple sclerosis (MS) is the most
common demyelinating disorder in children, and recent genetic and environmental risk research

has clarified that pediatric MS is on the same continuum of disease as adult MS. Recent
advances in the treatment of pediatric MS include clinical trials leading to regulatory
agency–approved treatments. The identification of myelin oligodendrocyte glycoprotein and
aquaporin-4 antibodies in children has been a major advance, allowing for appropriate treatment
and management of these syndromes.
SUMMARY:
Antibody testing is now helping to define subtypes of pediatric demyelinating disorders, including
myelin oligodendrocyte glycoprotein–seropositive and aquaporin-4–seropositive cases that are
distinct from pediatric MS. Treatments for pediatric MS are being evaluated in clinical trials.
KEY POINTS
• Major advances in pediatric demyelinating disease in the past 5 years include improved diagnostic criteria,
antibody-based biomarkers, predictors of a multiphasic course, and treatment advances for these disorders.
Recent work on the genetic and environmental risk factors for pediatric multiple sclerosis points to
similarities with adult disease.
• An important advance in pediatric demyelinating disorders is the recognition that an acute demyelinating
syndrome can represent the first attack of not only multiple sclerosis but also neuromyelitis optica spectrum
disorder (NMOSD), myelin oligodendrocyte glycoprotein (MOG) antibody–associated demyelinating disease,
and other multiphasic disorders in children.
• Several studies have identified risk factors for multiple sclerosis in children, including CSF profiles with
pleocytosis, Epstein-Barr virus–positive serostatus, obesity, low vitamin D levels, and the presence of T2
lesions on brain MRI. Age older than 11 and postpubertal status at the time of a clinically isolated syndrome
also increase the risk for multiple sclerosis.
• Puberty is an important transition period for the clinical onset of pediatric multiple sclerosis, with 80% to 85%
of children being peripubertal or postpubertal at the time of first symptoms in a large US cohort.
• In general, children with multiple sclerosis experience 2 to 3 times as many relapses as adult patients with
multiple sclerosis, reflecting a continuum in the inverse relationship of age and relapse rate.
• Types of relapses or attacks in pediatric multiple sclerosis include optic neuritis, transverse myelitis,
brainstem attacks, and cerebral attacks.
• Between one-third and two-thirds of pediatric patients with multiple sclerosis may have significant cognitive
deficits, including issues with information processing and processing speed, memory deficits, executive
dysfunction, and lowered IQs, as well as deficits in social cognition.
• In 2018, fingolimod was approved by the US Food and Drug Administration for use as first-line treatment in
children with multiple sclerosis aged 10 to 17; it has received preliminary approval by the European Medicines
Agency as second-line treatment based on the results of the PARADIGMS clinical trial.
• Adherence to disease-modifying therapy may be challenging, particularly in adolescents, in the setting of
miseducation about the expectations for disease-modifying therapies, unaddressed side effects, busy family
schedules, and travel/college.
• Up to 3% to 5% of cases of NMOSD have pediatric onset. The overall incidence of NMOSD in children and
adults ranges from 0.05 to 4 per 100,000 per year, and prevalence ranges from 0.52 to 4.4 per 100,000. In
Japan, the incidence of pediatric NMOSD was reported as 0.06 per 100,000 children.
• Approximately 65% of pediatric patients with NMOSD are aquaporin-4 antibody seropositive; however,
seropositivity may not occur at the time of the initial attack but up to 4 years later. Therefore, serial testing is
recommended for highly suspicious cases.
• Since cell-based assays became available, anti– MOG antibodies have been reported in the serum of 18% to
35% of children with an acute demyelinating syndrome.
• MOG antibody testing has now been optimized, offering increased sensitivity and specificity compared to
other methods. The MOG antibody is most often detected in the serum and rarely in the CSF. The current
consensus is that serum testing has the highest yield.

Article 12: Neuromyelitis Optica
Spectrum Disorder and Other
Non–Multiple Sclerosis Central Nervous
System Inflammatory Diseases
Eoin P. Flanagan, MBBCh. Continuum (Minneap Minn). June 2019; 25 (3 Multiple
ABSTRACT
PURPOSE OF REVIEW:
This article reviews the clinical features, diagnostic approach, treatment, and prognosis of
central nervous system inflammatory diseases that mimic multiple sclerosis (MS), including
those defined by recently discovered autoantibody biomarkers.
RECENT FINDINGS:
The discovery of autoantibody biomarkers of inflammatory demyelinating diseases of the central
nervous system (aquaporin-4 IgG and myelin oligodendrocyte glycoprotein IgG) and the
recognition that, despite some overlap, their clinical phenotypes are distinct from MS have
revolutionized this field of neurology. These autoantibody biomarkers assist in diagnosis and
have improved our understanding of the underlying disease pathogenesis. This has allowed
targeted treatments to be translated into clinical trials, three of which are now under way in
aquaporin-4 IgG–seropositive neuromyelitis optica (NMO) spectrum disorder.
SUMMARY:
Knowledge of the clinical attributes, MRI findings, CSF parameters, and accompanying
autoantibody biomarkers can help neurologists distinguish MS from its inflammatory mimics.
These antibody biomarkers provide critical diagnostic and prognostic information and guide
treatment decisions. Better recognition of the clinical, radiologic, and laboratory features of
other inflammatory MS mimics that lack autoantibody biomarkers has allowed us to diagnose
these disorders faster and initiate disease-specific treatments more expeditiously.
KEY POINTS
• Distinguishing multiple sclerosis from its central nervous system inflammatory disease mimics has important
therapeutic and prognostic implications.
• In 2004, the discovery of aquaporin-4 (AQP4)–IgG as a specific biomarker of neuromyelitis optica (NMO)
allowed its distinction from multiple sclerosis.
• The discovery of AQP4-IgG as a biomarker of NMO led to a recognition that patients can have more limited
forms of the disease (eg, recurrent transverse myelitis without optic neuritis) or symptoms beyond the optic
nerve and spinal cord (eg, area postrema syndrome), resulting in the current nosology of NMO spectrum
disorders (NMOSDs).
• It is important to recognize that in regions where multiple sclerosis prevalence is lower (eg, Asia and regions
closer to the equator), NMOSD represents a larger proportion of central nervous system demyelinating
diseases and thus should be particularly considered in the differential in those regions.
• NMOSD has three cardinal manifestations: transverse myelitis, optic neuritis, and area postrema syndrome.
• Systemic autoimmune disorders or their autoantibody biomarkers frequently coexist with NMOSD, including
systemic lupus erythematosus, Sjögren syndrome, and antiphospholipid antibody syndrome.

• In NMOSD, optic nerve involvement is often bilateral and typically involves the posterior optic pathway,
including the optic chiasm, with enhancement usually extending more than half the length of the nerve.
• Typical brain involvement in NMOSD occurs around circumventricular organs where AQP4 expression is
highest, with lesions adjacent to the third and fourth ventricles (dorsal medulla/area postrema) most typical.
• Longitudinally extensive transverse myelitis, with a T2-hyperintense lesion spanning three or more contiguous
vertebral segments on MRI, is characteristic of NMOSD and found in approximately 85% in patients.
• Assay techniques for AQP4-IgG have improved over time, and cell-based assays are now recommended
(using fluorescence-activated cell sorting or direct immunofluorescence); they yield a sensitivity of 75% to
80% and specificity of greater than 99%.
• Approximately 20% to 25% of patients with NMOSD are AQP4-IgG seronegative.
• AQP4-IgG binds to AQP4, which is located on the end-feet of astrocytes, initiating a cascade of
immune-mediated inflammation resulting in secondary demyelination.
• The use of plasma exchange for five to seven exchanges for severe, corticosteroid-refractory central
nervous system inflammatory demyelinating attacks is supported by data from a prospective randomized
sham-controlled crossover trial.
• Despite the lack of completed randomized controlled trials in NMOSD, preventive treatment is strongly
recommended in all patients.
• With the use of cell-based assays transfected with myelin oligodendrocyte glycoprotein (MOG) in its
conformational form, the antibody has been shown to be a specific biomarker of a spectrum of central
nervous system inflammatory demyelinating disease distinct from multiple sclerosis and AQP4-
IgG–seropositive NMOSD.
• The major clinical manifestations of MOG-IgG disease include optic neuritis, acute disseminated encephalomyelitis,
NMOSD (seronegative for AQP4-IgG), transverse myelitis, and brainstem demyelinating episodes.
• Some patients with MOG-IgG disease have a monophasic course, while others go on to develop relapsing
disease.
• Radiologic findings in MOG-IgG disease include enhancement that involves more than half of the length of
the optic nerve in 80% of patients and may involve the optic nerve sheath or extend into the orbital fat.
• Multifocal white matter T2 hyperintensities with involvement of the deep gray matter are typical in MOG-IgG
disease, particularly with acute disseminated encephalomyelitis–like presentations.
• Positive oligoclonal bands are found in less than 15% of patients with MOG-IgG.
• A 2018 consensus article outlined patients in whom MOG-IgG should be tested and recommended against
testing MOG-IgG in all patients with multiple sclerosis, given the risk of false positives when testing in
low-probability situations. In general, testing for MOG-IgG should be reserved for those with one of the
classic phenotypes that lacks characteristic features of multiple sclerosis.
• A major area of study in MOG-IgG disease is determining which patients may have a monophasic disorder and
not require treatment.
• For patients with relapsing MOG-IgG disease, the treatment approach is almost identical to that of acute and
maintenance therapy for NMOSD, although IV immunoglobulin appears to be useful in children acutely and
as a maintenance treatment.
• In 2016, an antibody to glial fibrillary acidic protein (GFAP) was reported that, when detected in CSF,
appeared to be specific for an inflammatory meningoencephalomyelitis, termed autoimmune GFAP
astrocytopathy.
• In autoimmune GFAP astrocyopathy, brain MRI may reveal a characteristic radial perivascular enhancement
perpendicular to the ventricles, although a similar pattern can be seen with intravascular lymphoma,
neurosarcoidosis, and central nervous system vasculitis.
• Susac syndrome is an inflammatory endotheliopathy that is characterized by a triad of branched retinal artery
occlusions, hearing loss, and dementia/encephalopathy.

Issue Overview
Multiple Sclerosis and Other CNS Inflammatory Diseases, Volume 25, Issue 3, June 2019
Continuum: Lifelong Learning in Neurology® is designed to help practicing neurologists stay
abreast of advances in the field while simultaneously developing lifelong self-directed learning
skills.
Learning Objectives
Upon completion of this Continuum: Lifelong Learning in Neurology Multiple Sclerosis and
Other CNS Inflammatory Diseases issue, participants will be able to:
 Describe recent advances in the recognition of genetic and environmental risk factors of
multiple sclerosis and the pathogenic mechanisms involved in the initiation and progression
of the disease
 Discuss approaches to the clinical assessment for multiple sclerosis that may improve
diagnostic accuracy
 Describe the dynamic evolution of multiple sclerosis through different clinical and
subclinical phases and its impact on treatment decisions
 Describe the cardinal features of multiple sclerosis relapses and their mimics and utilize
evidence-based treatment modalities for the treatment of multiple sclerosis relapses
 Describe a general approach to the management of patients with clinically isolated syndrome
and early relapsing multiple sclerosis, including determination of prognosis, an
understanding of first-line disease-modifying therapies, and treatment selection
 Recognize risk factors for aggressive multiple sclerosis and the benefits and side effects of
therapies used to treat it
 Discuss the relevant circumstances of switching or discontinuing disease-modifying therapies
in patients with multiple sclerosis

 Differentiate key pathologic, clinical, and imaging features of progressive multiple sclerosis
and identify disease-modifying agents shown to have beneficial effects in its treatment
 Identify and manage symptomatic complications and comorbidities, with the goal of
improving patient quality of life and clinical outcomes in multiple sclerosis
 Discuss which multiple sclerosis disease-modifying therapies should be avoided in women of
childbearing age who are trying to get pregnant, not on reliable birth control, or breast-
feeding and how to minimize the risk of rebound relapses occurring during pregnancy
following the cessation of natalizumab or fingolimod
 Discuss the categories, diagnosis, and management of pediatric demyelinating disorders
 Recognize, diagnose, and treat inflammatory central nervous system disorders that mimic
multiple sclerosis
 Discuss strategies to incorporate clinical practice guidelines and quality measures into high-
quality care for patients with multiple sclerosis
Core Competencies
This Continuum: Lifelong Learning in Neurology Multiple Sclerosis and Other CNS
Inflammatory Diseases issue covers the following core competencies:
 Patient Care
 Medical Knowledge
 Practice-Based Learning and Improvement
 Interpersonal and Communication Skills
 Professionalism
 Systems-Based Practice

Contributors
Dean M. Wingerchuk, MD, MSc, FRCPC, FAAN, Guest Editor

Professor and Chair, Department of Neurology, Mayo Clinic, Phoenix/Scottsdale, Arizona
Relationship Disclosure: Dr Wingerchuk serves as co–editor-in-chief of The Neurologist; as a consultant for

Alexion, Celgene Corporation, and Novartis AG; and as an adjudication committee member for MedImmune. Dr
Wingerchuk receives research/grant support from Alexion and Terumo BCT, Inc.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Wingerchuk reports no disclosure.
James D. Bowen, MD
Medical Director, Multiple Sclerosis Center, Swedish Neuroscience Institute; Clinical Associate
Professor, Neurology, University of Washington, Seattle, Washington
Relationship Disclosure: Dr Bowen has served as a consultant for Biogen; Celgene Corporation; EMD Serono, Inc;
Genentech, Inc; and Novartis AG and has received personal compensation for speaking engagements from Biogen;
EMD Serono, Inc; Genentech, Inc; and Novartis AG. Dr Bowen receives research/grant support from Alexion;
Alkermes; Biogen; Celgene Corporation; Genentech, Inc; the National Institute of Allergy and Infectious Diseases
(UM1AI110557); the National Institutes of Health /National Institute on Aging (U01AG006781); the National
Institutes of Health/National Institute of Allergy and Infectious Diseases (N01AI15416); the National Institute of
Neurological Disorders and Stroke (U10NS077309); and Sanofi Genzyme.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Bowen discusses the unlabeled/investigational use of
cyclophosphamide, high-dose immunosuppressive therapy with stem cell transplantation, and rituximab for the
treatment of highly aggressive multiple sclerosis.
Tanuja Chitnis, MD, FAAN

Professor of Neurology, Harvard Medical School; Senior Neurologist, Brigham and Women’s
Hospital and Massachusetts General Hospital; Director, Partners Pediatric Multiple Sclerosis
Center, MassGeneral Hospital for Children; Director, Translational Neuroimmunology Research
Center, Brigham and Women’s Hospital, Boston, Massachusetts
Relationship Disclosure: Dr Chitnis serves on scientific advisory boards for Biogen, Celgene Corporation, F.
Hoffmann-La Roche Ltd, Novartis AG, and Sanofi Genzyme and as a consultant for Biogen. Dr Chitnis receives
research/grant support from the Consortium of Multiple Sclerosis Centers; the Department of Defense; EMD
Serono, Inc; the Guthy-Jackson Charitable Foundation; Mallinckrodt Pharmaceuticals; the National Institutes of
Health; the National Multiple Sclerosis Society; Novartis AG; Octave Bioscience; and Verily Life Sciences LLC.
Unlabeled Use of Products/Investigation Use Disclosure: Dr Chitnis discusses the unlabeled/investigational use of
glatiramer acetate, interferon beta, natalizumab, and rituximab for pediatric multiple sclerosis and mycophenolate
mofetil for myelin oligodendrocyte glycoprotein antibody-associated disorders and neuromyelitis optica spectrum
disorder in children.

John R. Corboy, MD, FAAN
Professor, Neurology Codirector, Rocky Mountain Multiple Sclerosis Center at University of
Colorado, University of Colorado School of Medicine, Aurora, Colorado
Relationship Disclosure: Dr Corboy serves as editor of Neurology Clinical Practice, as a consultant for a legal
matter for Mylan NV, and on the research steering committee for Novartis AG. Dr Corboy has received personal
compensation for speaking engagements from PRIME Education, LLC, and the Rocky Mountain Multiple Sclerosis
Center and receives research/grant support from MedDay Pharmaceuticals, the National Multiple Sclerosis Society,
Novartis AG, and the Patient-Centered Outcomes Research Institute. Dr Corboy has served as a consultant on
medicolegal proceedings for medical malpractice.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Corboy discusses the unlabeled/investigational use of
cyclophosphamide and rituximab for the treatment of multiple sclerosis.

Consultant in Neurology and Laboratory Medicine and Pathology; Associate Professor of
Neurology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota
Relationship Disclosure: Dr Flanagan receives research/grant support from MedImmune/Viela Bio.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Flanagan discusses the unlabeled/investigational use
of azathioprine, cetirizine, corticosteroids, eculizumab, inebilizumab, IV immunoglobulin, methotrexate,
mycophenolate mofetil, plasma exchange, rituximab, SA237, sivelestat, and tocilizumab for the treatment of
neuromyelitis optica spectrum disorder and other non–multiple sclerosis central nervous system inflammatory
diseases.
Robert H. Gross, MD
Assistant Professor of Neurology, University of Colorado Anschutz Medical Campus, Aurora,
Colorado
Relationship Disclosure: Dr Gross reports no disclosure.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Gross discusses the unlabeled/investigational use of
cyclophosphamide and rituximab for the treatment of multiple sclerosis.
Associate Professor of Neurology, Mayo Clinic College of Medicine and Science, Rochester,
Minnesota
Relationship Disclosure: Dr Kantarci serves as a reviewer for Neurology and receives research/grant support from
Biogen.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Kantarci reports no disclosure.
Annette M. Langer-Gould, MD, PhD

Regional Lead for Clinical and Translational Neuroscience, Kaiser Permanente/Southern
California Permanente Medical Group, Pasadena, California
Relationship Disclosure: Dr Langer-Gould receives research/grant support from the National Multiple Sclerosis
Society and the Patient-Centered Outcomes Research Institute and has provided expert legal testimony regarding
vaccination.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Langer-Gould discusses the unlabeled/investigational

use of corticosteroids and plasma exchange to treat multiple sclerosis relapse during pregnancy, gabapentin to treat
neuropathic pain, natalizumab to treat multiple sclerosis during pregnancy, and rituximab to treat multiple sclerosis.

Luanne M. Metz, MD, FRCPC
Professor, Department of Clinical Neurosciences, Cumming School of Medicine, University of
Calgary; Coleader, Multiple Sclerosis Program, Hotchkiss Brain Institute, Calgary Alberta,
Canada
Relationship Disclosure: Dr Metz receives research/grant support from Alberta Innovates Health Solutions
(201300669) and the Multiple Sclerosis Society of Canada.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Metz was the principal investigator on a phase 3
study on the use of minocycline for the treatment of clinically isolated syndrome.
Ellen M. Mowry, MD, MCR, FAAN, FANA

Associate Professor of Neurology and Epidemiology, Johns Hopkins University, Baltimore,
Maryland
Relationship Disclosure: Dr Mowry serves as an editor for Frontiers in Neuroepidemiology, ISRN Neuroscience,
and Neuroscience Journal. Dr Mowry receives research/grant support from Biogen, the Department of Defense, the
National Multiple Sclerosis Society, Sanofi Genzyme, and Sun Pharmaceuticals Industries Ltd and publishing
royalties from UpToDate, Inc.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Mowry reports no disclosure.
Bardia Nourbakhsh, MD, MAS

Assistant Professor of Neurology, Johns Hopkins University, Baltimore, Maryland
Relationship Disclosure: Dr Nourbakhsh has served on a scientific advisory board for Jazz Pharmaceuticals Inc and
has received research/grant support from the National Multiple Sclerosis Society and the Patient-Centered Outcomes
Research Institute.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Nourbakhsh reports no disclosure.
Daniel Ontaneda, MD
Assistant Professor of Medicine/Neurology, Cleveland Clinic Lerner College of Medicine of
Case Western Reserve University; Staff Neurologist, Cleveland Clinic, Mellen Center for
Multiple Sclerosis Treatment and Research, Cleveland, Ohio
Relationship Disclosure: Dr Ontaneda serves as a consultant for Biogen; Genentech, Inc; and Sanofi Genzyme and
receives research/grant support from Genentech, Inc; the National Institutes of Health; the National Multiple
Sclerosis Society; Novartis AG; the Patient-Centered Outcomes Research Institute; Race to Erase; and Sanofi
Genzyme.
Unlabeled Use of Products/Investigational Use Disclosure: Dr. Ontaneda discusses clinical trial results for biotin,
fingolimod, ibudilast, mycophenolate mofetil, natalizumab, and rituximab for the treatment of progressive multiple
sclerosis.
Alexander D. Rae-Grant, MD, FRCPC, FAAN

Professor of Neurology, Cleveland Clinic Lerner College of Medicine of Case Western Reserve
University; Staff Neurologist, Cleveland Clinic, Cleveland, Ohio
Relationship Disclosure: Dr Rae-Grant serves as deputy editor for DynamedPlus.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Rae-Grant reports no disclosure.

Pavle Repovic, MD, PhD
Medical Director for Neurology Research, Multiple Sclerosis Center, Swedish Neuroscience
Institute, Seattle, Washington
Relationship Disclosure: Dr Repovic has served as a consultant for Biogen; EMD Serono, Inc; Genentech, Inc;
Sanofi Genzyme; and Teva Pharmaceutical Industries Ltd and has received personal compensation for speaking
engagements from Biogen; EMD Serono, Inc; Genentech, Inc; and Teva Pharmaceutical Industries Ltd. Dr Repovic
receives research/grant support from Alexion, the National Institutes of Health (5U10NS077309), Novartis AG, and
Genentech, Inc.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Repovic reports no disclosure.
Andrew J. Solomon, MD
Associate Professor of Neurological Sciences; Division Chief, Multiple Sclerosis, Larner College
of Medicine at The University of Vermont, Burlington, Vermont
Relationship Disclosure: Dr Solomon has served as a consultant for Biogen and EMD Serono, Inc, and has received
research/grant support from Biogen and personal compensation for speaking engagements from Med Learning
Group, the National Multiple Sclerosis Society, and RMEI Medical Education.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Solomon reports no disclosure.
W. Oliver Tobin, MBBCh, BAO, PhD

Consultant, Division of Multiple Sclerosis; Assistant Professor of Neurology, Mayo Clinic
College of Medicine and Science, Rochester, Minnesota
Relationship Disclosure: Dr Tobin receives research/grant support from Mallinckrodt Pharmaceuticals.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Tobin discusses the unlabeled/investigational use of
amantadine, armodafinil, and modafinil for fatigue; lacosamide, lamotrigine, and oxcarbazepine for paroxysmal
symptoms; gabapentin for restless legs syndrome and spasticity; and nabiximols, oral cannabis extract, and synthetic
tetrahydrocannabinol for the treatment of spasticity.
Self-Assessment and CME Test Writers
D. Joanne Lynn, MD, FAAN

Associate Dean for Student Life, Clinical Professor of Neurology, The Ohio State University
College of Medicine, Columbus, Ohio
Relationship Disclosure: Dr Lynn receives book royalties from Lippincott Williams & Wilkins and holds stock in
Abbott Laboratories; AbbVie Inc; Amgen Inc; Bristol-Myers Squibb Company; CVS Health Corporation; Express
Scripts Holding Company; General Electric; Merck & Co, Inc; and Zimmer Biomet.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Lynn reports no disclosure.
Allison L. Weathers, MD, FAAN

Associate Chief Medical Information Officer, Cleveland Clinic; Assistant Professor, Cleveland
Clinic Lerner College of Medicine, Cleveland, Ohio
Relationship Disclosure: Dr Weathers serves on the editorial board of Continuum and as chair of the adult
neurosciences specialty steering board for Epic.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Weathers reports no disclosure.

Methods of Participation and Instructions for Use
Continuum: Lifelong Learning in Neurology® is designed to help practicing neurologists stay
abreast of advances in the field while simultaneously developing lifelong self-directed learning
skills. In Continuum, the process of absorbing, integrating, and applying the material presented is
as important as, if not more important than, the material itself.
The goals of Continuum include disseminating up-to-date information to the practicing
neurologist in a lively, interactive format; fostering self-assessment and lifelong study skills;
encouraging critical thinking; and, in the final analysis, strengthening and improving patient
care.
Each Continuum issue is prepared by distinguished authors who are acknowledged leaders in
their respective fields. Six issues are published annually and are composed of review articles,
case-based discussions on ethical and practice issues related to the issue topic, coding
information, and comprehensive continuing medical education (CME) and self-assessment
offerings. For detailed instructions regarding Continuum CME and self-assessment activities,
visit continpub.com/CME.
The review articles emphasize clinical issues emerging in the field in recent years. Case reports
and vignettes are used liberally, as are tables and illustrations. Audio interviews with the authors
of Continuum articles are published alongside each article, and video material relating to the
issue topic accompanies issues when applicable.
The text can be reviewed and digested most effectively by establishing a regular schedule of
study in the office or at home, either alone or in an interactive group. If subscribers use such
regular and perhaps new study habits, Continuum’s goal of establishing lifelong learning patterns
can be met.

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JUNE 2019

VOL. 25 NO. 3 Multiple Sclerosis and

594 Editor’s Preface

596 Multiple Sclerosis Risk Factors and Pathogenesis

611 Diagnosis, Differential Diagnosis, and Misdiagnosis

636 Phases and Phenotypes of Multiple Sclerosis

655 Management of Multiple Sclerosis Relapses

670 Clinically Isolated Syndrome and Early Relapsing

689 Highly Aggressive Multiple Sclerosis

736 Progressive Multiple Sclerosis

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

773 Pregnancy and Family Planning in Multiple Sclerosis

793 Pediatric Central Nervous System Demyelinating Diseases

815 Neuromyelitis Optica Spectrum Disorder and Other Non–Multiple

845 Incorporating Clinical Practice Guidelines and Quality Measures

SELF-ASSESSMENT AND CME

586 Learning Objectives and Core Competencies

851 Instructions for Completing Postreading Self-Assessment and CME

853 Postreading Self-Assessment and CME Test

867 Postreading Self-Assessment and CME Test—Preferred Responses

List of Abbreviations (Back Cover)

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Dean M. Wingerchuk, MD, MSc, Tanuja Chitnis, MD, FAAN

Seattle, Washington Unlabeled Use of Products/Investigation

Unlabeled Use of Products/Investigational

588 JUNE 2019

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

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Eoin P. Flanagan, MBBCh

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● Both T lymphocytes and B

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ENVIRONMENTAL RISK FACTORS