REVIEW ARTICLE

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
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CITE AS:
CONTINUUM (MINNEAP MINN)
2019;25(3, MULTIPLE SCLEROSIS
AND OTHER CNS INFLAMMATORY
DISEASES):670–688.
Address correspondence to
Dr Luanne M. Metz, Foothills
Hospital, 1403 29th St NW,
Calgary, Alberta, Canada
T2N 2T9, lmetz@ucalgary.ca.
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
T
investigator on a phase 3 study
on the use of minocycline for
the treatment of clinically
isolated syndrome.
© 2019 American Academy
of Neurology.
670
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
Clinically Isolated
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
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 disease-modifying therapies.
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.
INTRODUCTION
he early period after a diagnosis of multiple sclerosis (MS) or clinically
isolated syndrome is challenging. While no cure currently is known,
medications and lifestyle modifications can decrease inflammatory
activity and reduce symptom burden and the accumulation of
disability. With education, support, and guidance, patients with
clinically isolated syndrome or early relapsing MS can make healthy lifestyle
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

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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

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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

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CLINICALLY ISOLATED SYNDROME AND EARLY RELAPSING MS

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

CONTINUED ON PAGE 675

674 JUNE 2019

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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

CONTINUED FROM PAGE 674

◆ 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

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CLINICALLY ISOLATED SYNDROME AND EARLY RELAPSING MS

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.

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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

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CLINICALLY ISOLATED SYNDROME AND EARLY RELAPSING MS

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.

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 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.

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CLINICALLY ISOLATED SYNDROME AND EARLY RELAPSING MS

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

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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

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CLINICALLY ISOLATED SYNDROME AND EARLY RELAPSING MS

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.

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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
The US National Multiple Sclerosis (MS) Society
website has information about the disease and its
treatment and resources for patients.
nationalmssociety.org
MULTIPLE SCLEROSIS SOCIETY
The UK Multiple Sclerosis Society website offers
research information and care and support
resources for patients.
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

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CLINICALLY ISOLATED SYNDROME AND EARLY RELAPSING MS

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.

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