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Official reprint from UpToDate®

www.uptodate.com © 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Management of clinically and radiologically isolated

syndromes suggestive of multiple sclerosis
Authors: Michael J Olek, DO, Jonathan Howard, MD
Section Editor: Francisco González-Scarano, MD
Deputy Editor: John F Dashe, MD, PhD

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Feb 2023. | This topic last updated: Feb 22, 2022.

INTRODUCTION

A clinically isolated syndrome (CIS) is a first symptomatic episode compatible with

demyelination or multiple sclerosis (MS). In a radiologically isolated syndrome (RIS) an
individual presents without overt clinical symptoms but with MRI findings highly suggestive of
MS. CIS and RIS can create diagnostic and therapeutic dilemmas, since a substantial percentage
of patients with CIS and MRI lesions go on to develop clinically definite MS.

This topic will discuss the management of CIS and of RIS suggestive of MS.

Other aspects of MS are discussed separately. (See "Clinical presentation, course, and prognosis
of multiple sclerosis in adults" and "Evaluation and diagnosis of multiple sclerosis in adults" and
"Manifestations of multiple sclerosis in adults" and "Initial disease-modifying therapy for
relapsing-remitting multiple sclerosis in adults" and "Treatment of secondary progressive
multiple sclerosis in adults" and "Symptom management of multiple sclerosis in adults" and
"Optic neuritis: Pathophysiology, clinical features, and diagnosis" and "Optic neuritis: Prognosis
and treatment".)

CLINICALLY ISOLATED SYNDROME

A CIS is the first clinical episode that is consistent with a demyelinating etiology and suggestive
of MS, as described in detail separately. (See "Clinical presentation, course, and prognosis of

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multiple sclerosis in adults", section on 'Clinically isolated syndrome'.)

The typical patient with a CIS is a young adult with a single episode of central nervous system
dysfunction, such as unilateral optic neuritis, a focal brain syndrome, a focal brainstem or
cerebellar syndrome, or partial myelopathy [1]. Symptoms usually develop over the course of
hours to days and then gradually remit over the ensuing weeks to months, though remission
may not be complete. While CIS is, by definition, isolated to a single attack in time, it is not
necessarily isolated in space, as approximately one-quarter of patients present with multifocal
abnormalities. CIS should not be considered a different disease than MS, rather it is a potential
precursor to MS. As the diagnostic criteria for MS have expanded, fewer patients meet the strict
criteria for CIS.

RADIOLOGICALLY ISOLATED SYNDROME

A RIS is defined by incidental brain or spinal cord MRI findings that are highly suggestive of MS,
based upon location and morphology within the central nervous system, in an asymptomatic
patient lacking any history, symptoms, or signs of MS [2]. Typically, the MRI has been obtained
for a completely unrelated condition such as headaches or trauma.

INITIAL EVALUATION

All patients with a CIS should have neuroimaging with a contrast-enhanced MRI of the brain
(and the spinal cord as clinically indicated) in order to determine whether there is an
explanatory acute inflammatory lesion in the brain or spinal cord and whether there are
additional lesions on MRI that are indicative of MS. The evaluation of a CIS and suspected MS is
described in detail elsewhere. (See "Evaluation and diagnosis of multiple sclerosis in adults",
section on 'Evaluation'.)

We suggest cerebrospinal fluid examination for patients with a CIS who have a brain MRI that
shows no or few lesions (ie, MRI findings that do not meet the McDonald criteria for
dissemination in space). Qualitative assessment of cerebrospinal fluid using isoelectric focusing
for oligoclonal immunoglobulin G (IgG) bands that are not present in a concomitant serum
specimen can help to refine the risk estimation for progression to MS in equivocal cases.
Elevation of the cerebrospinal fluid immunoglobulin level relative to other protein components
is also a common finding in patients with MS and suggests intrathecal synthesis. A positive
cerebrospinal fluid is based upon the finding of either oligoclonal bands different from any such
bands in serum, or by an increased IgG index. The IgG level may be expressed as a percentage

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of total protein (normal <11 percent), as a percentage of albumin (normal <27 percent), by use
of the calculated IgG index (normal value <0.66 to <0.9, depending upon the individual
laboratory), or by use of a formula for intrathecal fluid synthesis of IgG. Thus, the presence of
oligoclonal bands can provide supportive evidence that the underlying disorder is inflammatory
and demyelinating. (See 'With oligoclonal bands' below.)

The diagnosis of MS can be made for some patients at the time they present with a first clinical
attack (ie, a CIS) if a single MRI obtained at any time shows dissemination in space and, as
evidence for dissemination in time, by the simultaneous presence of gadolinium-enhancing and
nonenhancing lesions, or by the presence of cerebrospinal fluid-specific oligoclonal bands. (See
"Evaluation and diagnosis of multiple sclerosis in adults", section on 'For a clinically isolated
syndrome'.)

In select cases, testing for anti-AQP4 or anti-MOG antibodies may be appropriate. (See
"Evaluation and diagnosis of multiple sclerosis in adults", section on 'Autoantibody testing'.)

A patient with a RIS, identified by incidental findings on a brain MRI, is asymptomatic by

definition and has no history, symptoms, or signs of MS. Further investigations are not clearly
indicated at the time of the MRI presentation, but follow-up is important to monitor for the
possible onset of clinical features consistent with MS. However, some experts recommend
lumbar puncture in patients with an RIS who have high-risk MRI features, such as a large
number of demyelinating brain lesions (hyperintense lesions on T2-weighted MRI) or even a
single demyelinating spinal cord lesion, since the additional finding of oligoclonal bands would
suggest an increased risk of conversion to MS [3].

The differential diagnosis of CIS and RIS is essentially the same as the differential of MS and
includes a number of inflammatory, vascular, infectious, genetic, granulomatous, and other
demyelinating disorders ( table 1). This is discussed in detail separately. (See "Evaluation and
diagnosis of multiple sclerosis in adults", section on 'Differential diagnosis'.)

RISK OF PROGRESSION TO MULTIPLE SCLEROSIS

Identification of those patients with RIS or CIS who are likely to progress to MS is a major goal
of current research.

Overall risk with a CIS — In various studies, the long-term (ie, 10- to 20-year) likelihood of
developing MS for patients with CIS and MRI lesions characteristic of MS ranges from 60 to 80
percent [4-9], with most of the data suggesting that the true rate of conversion is closer to the

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lower end of this range. In patients with a CIS who have a normal baseline MRI, limited data
suggest that the long-term prevalence of MS is approximately 20 percent [7].

Therefore, patients with a CIS who have MRI abnormalities characteristic of MS in these MS-
typical regions (periventricular, cortical or juxtacortical, infratentorial, and spinal cord) either at
presentation or within three to six months of the event are candidates for early disease-
modifying therapy. (See 'Who should receive early DMT?' below.)

After isolated optic neuritis — In the Optic Neuritis Treatment trial (ONTT), the cumulative
five-year incidence of clinically definite MS was 30 percent following a first episode of idiopathic
demyelinating optic neuritis [10]. The cumulative incidence increased to 40 percent at 12 years
[11], and to 50 percent at 15 years [6]. The presence of characteristic demyelinating lesions on
brain MRI is a strong predictor of developing MS ( image 1). In the ONTT, the risk of MS after
10 years was 56 percent among those with one or more lesions on MRI versus 22 percent
among those with no lesions [11].

Optic neuritis is discussed in detail separately. (See "Optic neuritis: Prognosis and treatment".)

After acute transverse myelitis — Acute transverse myelitis is an inflammatory disorder that
presents with the rapid onset of weakness, sensory alterations, and bowel and bladder
dysfunction. (See "Transverse myelitis".)

Patients presenting with acute complete transverse myelitis (complete or near complete clinical
deficits below the lesion) have a generally cited risk of MS of only 5 to 10 percent [12], although
some reports suggest a higher conversion rate [13]. However, partial or incomplete myelitis
with mild or grossly asymmetric spinal cord dysfunction is a much more common clinical entity
and bears more relevance to MS. Patients who have acute partial myelitis as an initial
presentation and cranial MRI abnormalities showing lesions typical for MS have a transition rate
to MS over three to five years of 60 to 90 percent [13-15]. In contrast, patients with acute partial
myelitis who have a normal brain MRI develop MS at a rate of only 10 to 30 percent over a
similar time period [16]. Studies suggest that patients with monosymptomatic disease who
have positive oligoclonal bands have a higher risk of evolution to MS than those without
oligoclonal bands [17].

With oligoclonal bands — In patients with CIS, the presence of oligoclonal bands in the
cerebrospinal fluid may be an independent risk factor for progression to MS. Supporting
evidence comes from a prospective study of 415 patients with CIS, which found that the
presence of oligoclonal bands was associated with a significantly increased risk of developing
clinically definite MS (hazard ratio [HR] 1.7, 95% CI 1.1-2.7) [18]. This increased risk was
independent of the number of lesions on baseline MRI. Among 113 patients with a negative
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MRI (ie, no lesions), the risk of developing MS in those with and without oligoclonal bands was
23 and 4 percent, respectively. These findings suggest that progression to MS is unlikely in
patients with a CIS who have few or no MRI lesions and no oligoclonal bands in the
cerebrospinal fluid [9].

Risk with an RIS — Patients with a RIS are at risk of developing CIS and MS, but data are
limited. One of the largest studies evaluated an international cohort of over 450 retrospectively
identified subjects (approximately 78 percent female) with RIS from 22 databases [19]. With a
mean follow-up of 4.4 years, independent predictors for the development of a first clinical event
were younger age (HR 0.98, 95% CI 0.96-0.99), male sex (HR 1.93, 95% CI 1.24-2.99), and MRI
lesions in the cervical or thoracic spinal cord (HR 3.08, 95% CI 2.06-4.62). Conversion to
symptomatic MS occurred in approximately 30 percent; of those who converted to MS, criteria
for primary progressive MS were met in 12 percent [20]. Another study of 75 patients with RIS
found that the presence of oligoclonal bands in the cerebrospinal fluid was associated with an
increased risk of conversion to MS [21].

These data and expert consensus suggest that patients with an RIS have an increased risk of
subclinical MS if and one or more of following features are present [22]:

● Age <35 years

● Male sex
● Cervical or thoracic spinal cord lesions on MRI
● Dissemination in time on MRI (gadolinium-enhancing and/or new T2 lesions)
● High T2 lesion load on MRI
● Cortical and/or juxtacortical lesions on MRI
● Presence of oligoclonal bands in the cerebrospinal fluid
● Abnormal visual evoked potentials
● Deficits of specific cognitive functions (ie, information processing speed, complex
attention, episodic memory, and executive functions)

Other features are "red flags" that suggest an alternative diagnosis [22]:

● Migraine or chronic headache

● Seizures
● Paroxysmal symptoms
● Psychiatric disturbances
● Overt cognitive impairment
● Head trauma

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The presence of "red flag" features casts doubt on a diagnosis of RIS, and should prompt
consideration of other conditions that may explain the symptoms.

Larger prospective studies are needed to better define the risk of MS associated with RIS.

MANAGEMENT

An acute relapse in a patient with CIS should be managed with oral or intravenous
glucocorticoids, as is done for acute exacerbations of MS. (See "Treatment of acute
exacerbations of multiple sclerosis in adults".)

Further management of patients with a CIS or RIS includes monitoring for manifestations of MS
disease activity and deciding about early disease-modifying therapy (DMT) for select patients
with a CIS.

Monitoring — Patients with a CIS or RIS should be monitored for possible manifestations of MS
disease activity including acute clinical attacks (relapses), new lesions on MRI, and onset or
progression of sustained disability. Our preferred protocol is to assess the clinical status of
patients routinely (eg, every three to six months or as needed) with a neurologic examination
and sometimes with the full Expanded Disability Status Scale ( table 2). We obtain a repeat
brain or spine MRI whenever there are new clinical symptoms suggestive of MS.

For patients without new symptoms, the following imaging schedule and treatment strategy is
suggested:

● For patients with a CIS and a normal baseline brain MRI (ie, no demyelinating lesions), a
brain MRI should be repeated between three and six months, and, if stable, another MRI
should be obtained one year later. If these serial MRIs are stable, further scanning is
recommended if there are new symptoms. If any of the serial brain MRI scans show the
interval development of hyperintense T2 lesions that are characteristic of MS in at least
two of four MS-typical regions, treatment with a DMT is suggested. (See 'Who should
receive early DMT?' below.)

● For patients with a CIS and demyelinating lesions on baseline brain MRI who were not
started on early DMT, follow-up is similar to that for patients who are on DMT with a
repeat brain MRI every 12 months.

● For patients with an RIS who remain asymptomatic, a repeat brain MRI at 6 to 12 months
and then at yearly intervals for up to five years is suggested.

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Who should receive early DMT? — The results of randomized controlled trials cited below
support early DMT of suspected MS for patients with CIS who have additional clinically silent
lesions in the brain or spinal cord detected by MRI (see 'Efficacy of DMTs for CIS' below). We
suggest disease-modifying treatment for patients with a CIS who do not fulfill McDonald criteria
for a diagnosis of MS but have an abnormal brain MRI with one or more hyperintense T2
lesions that are characteristic of MS in at least two of four MS-typical regions at presentation or
within three to six months of the event.

Currently, there is no clear indication for the use of disease-modifying treatment for patients
with RIS (ie, asymptomatic but with incidental MRI findings suggestive of MS) [23]. (See
'Radiologically isolated syndrome' above.)

All patients with a CIS who meet diagnostic criteria for MS should be started on a DMT. (See
"Evaluation and diagnosis of multiple sclerosis in adults", section on 'For a clinically isolated
syndrome' and "Initial disease-modifying therapy for relapsing-remitting multiple sclerosis in
adults".)

Approved DMTs — Most DMTs approved for relapsing forms of MS are also approved in the
United States for the treatment of CIS. These are:

● Platform injection therapies: Interferons and glatiramer acetate (see "Disease-modifying

therapies for multiple sclerosis: Pharmacology, administration, and adverse effects",
section on 'Platform injection therapies')

● Oral therapies (see "Disease-modifying therapies for multiple sclerosis: Pharmacology,

administration, and adverse effects", section on 'Oral therapies'):

• Fumarates: Dimethyl fumarate, diroximel fumarate, and monomethyl fumarate

• Teriflunomide
• Sphingosine-1-phosphate receptor modulators: Fingolimod, siponimod, ozanimod, and
ponesimod

● Monoclonal antibodies: Natalizumab, ocrelizumab, and ofatumumab (see "Disease-

modifying therapies for multiple sclerosis: Pharmacology, administration, and adverse
effects", section on 'Monoclonal antibodies')

However, not all DMTs approved for CIS have been tested specifically for the treatment of CIS.
(See 'Efficacy of DMTs for CIS' below.)

Choice of DMT — The recombinant human interferon beta agents or glatiramer acetate are
options for high-risk patients with a CIS. Teriflunomide is an alternative for patients who prefer
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oral therapy, but its use is contraindicated for women of child-bearing potential because of the
risk of teratogenicity, and monthly lab testing is indicated for the first six months to screen for
potential hepatoxicity. These medications are preferred because of their benign safety profile
and from clinical trials supporting their efficacy in CIS. (See 'Efficacy of DMTs for CIS' below.)

Among the interferons, we prefer treatment with recombinant human interferon beta-1a 30
mcg/week by intramuscular injection or pegylated interferon beta-1a, which is administered by
subcutaneous injection every two weeks, beginning with 63 mcg on day one, 94 mcg on day 15,
and 125 mcg every 14 days beginning on day 29.

Interferon beta-1a is also available in formulations for subcutaneous injection, with a target
dose of either 22 mcg or 44 mcg given three times weekly. Prescribing information in the
United States recommends initial treatment starting at 8.8 mcg three times a week, gradually
increasing over four weeks to the final recommended dose of 44 mcg three times a week.
Doses of subcutaneous interferon beta-1a should be separated by at least 48 hours.

Recombinant human interferon beta-1b, given by subcutaneous administration, is started at

0.0625 mg (2 million units [0.25 mL]) every other day. The dose is gradually increased by 0.0625
mg every one to two weeks to a target dose of 0.25 mg (8 million units [1 mL]) every other day.

Injection site reactions, flu-like symptoms, and asymptomatic liver dysfunction (transaminitis)
are relatively common adverse effects of interferons. (See 'Interferons' below and "Disease-
modifying therapies for multiple sclerosis: Pharmacology, administration, and adverse effects",
section on 'Interferons'.)

Glatiramer acetate, administered by subcutaneous injection, is dosed at 20 mg daily or 40 mg

three times a week. Side effects of glatiramer acetate include local injection site reactions and,
uncommonly, transient systemic postinjection reactions such as chest pain, flushing, dyspnea,
palpitations, and/or anxiety. (See 'Glatiramer acetate' below and "Disease-modifying therapies
for multiple sclerosis: Pharmacology, administration, and adverse effects", section on
'Glatiramer'.)

Teriflunomide, an oral medication, is dosed at 7 or 14 mg daily. Risks of hepatoxicity and

teratogenicity are important limitations to its use. (See 'Teriflunomide' below and "Disease-
modifying therapies for multiple sclerosis: Pharmacology, administration, and adverse effects",
section on 'Teriflunomide'.)

Other DMTs, such as oral fumarates (eg, dimethyl fumarate), the sphingosine 1-phosphate (S1P)
receptor modulators (eg, fingolimod), have not been studied specifically in CIS, but given their
efficacy in relapsing-remitting MS, they are likely effective for CIS and they are approved for CIS.
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Several monoclonal antibody DMTs (natalizumab, ocrelizumab, and ofatumumab) are also
approved for CIS, but they are not usually considered first-line for CIS because of the increased
risk of serious adverse effect. (See "Initial disease-modifying therapy for relapsing-remitting
multiple sclerosis in adults".)

Dimethyl fumarate is a twice-daily pill. Dimethyl fumarate can lead to gastrointestinal upset and
has rarely been associated with progressive multifocal leukoencephalopathy. Diroximel
fumarate and monomethyl fumarate are similar medications that have fewer gastrointestinal
side effects compared with dimethyl fumarate.

Fingolimod is a once-daily pill that blocks the S1P receptor, which is found primarily on lymph
nodes. It may cause bradycardia with the first dose and macular edema. It has rarely been
associated with progressive multifocal leukoencephalopathy and cryptococcal meningitis. It has
also been associated with severe rebound disease on discontinuation. Siponimod, ozanimod,
and ponesimod are more selective sphingosine 1-phosphate receptors.

Follow-up — Patients on DMT should have clinical follow-up with careful attention to possible
manifestations of disease activity including acute attacks (relapses) and onset or progression of
sustained disability. Many or most experienced clinicians supplement the clinical information
with periodic MRI studies to monitor the development of new asymptomatic lesions. (See
'Monitoring' above.)

Patients with CIS who progress to a diagnosis of clinically definite MS may benefit by
modification of disease-modifying treatment, as discussed separately. (See "Initial disease-
modifying therapy for relapsing-remitting multiple sclerosis in adults".)

Duration of therapy — The option of stopping treatment can be discussed for patients with a
CIS who remain stable for several years with no new symptomatic episodes or clinical
progression and no evidence of active disease by MRI.

Efficacy of DMTs for CIS — The results of randomized controlled trials cited below support
early disease-modifying therapy of suspected MS for patients with CIS who have additional
clinically silent lesions in the brain or spinal cord detected by MRI. Early treatment beginning
prior to the technical diagnosis of MS is likely to have a greater impact than later treatment on
delaying disease progression to MS. However, the benefit of early CIS treatment for reducing
disability is not firmly established. A 2017 meta-analysis found only low-quality evidence
suggesting a small and uncertain benefit of early DMT treatment compared with placebo [24],
whereas a prospective cohort study found that a longer exposure time to DMT was associated
with reduced disability [25].

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DMTs with evidence of efficacy for CIS include interferons, glatiramer acetate, and
teriflunomide.

Interferons — Early treatment with recombinant human interferon beta (IFNB) for patients
with CIS delays the occurrence of a second attack, and therefore the onset of clinically definite
MS, for up to five years [26-33]. However, early treatment in patients with CIS has not been
shown to prevent long-term disability.

The effectiveness of IFNB for patients with CIS was examined in a meta-analysis published in
2008 that identified three trials (ETOMS, CHAMPS, and BENEFIT) with a total of 1160 patients
(639 treatment and 521 placebo) [30]. The probability of converting to clinically definite MS was
significantly lower with IFNB treatment compared with placebo both at one year (pooled odds
ratio [OR] 0.53, 95% CI 0.40-0.71) and at two years of follow-up (pooled OR 0.52, 95% CI 0.38-
0.70).

At least three randomized controlled trials (CHAMPS, ETOMS, and REFLEX) have investigated
recombinant human interferon beta-1a for patients with CIS. One trial (BENEFIT) evaluated
recombinant human interferon beta-1b for patients with CIS.

● The CHAMPS trial enrolled 383 patients who had suffered a first acute clinical
demyelinating event and who also had evidence of prior subclinical demyelination on
brain MRI [26]. During three years of follow-up, patients treated with glucocorticoid
therapy followed by weekly intramuscular injections of recombinant human interferon
beta-1a 30 mcg had a significantly lower probability of developing clinically definite MS
than those treated with glucocorticoids followed by placebo injections (cumulative
probability 35 versus 50 percent).

All patients in CHAMPS were offered weekly intramuscular injections of recombinant

human interferon beta-1a (30 mcg) in an ongoing open-label extension study called the
CHAMPIONS study [31]. Patients initially assigned to recombinant human interferon beta-
1a in CHAMPS were considered the immediate treatment group and those initially
assigned to placebo were considered the delayed treatment group. At five years, the
immediate treatment group continued to have a lower risk of developing clinically definite
MS compared with the delayed treatment group (adjusted hazard ratio [HR] 0.57; 95% CI
0.38-0.86). Few patients in either the immediate or delayed treatment group developed
major disability within five years (11 versus 14 percent).

● The ETOMS trial enrolled 308 patients with a CIS and MRI findings suggestive of MS [27].
With two years of follow-up, significantly fewer patients developed clinically definite MS in
the interferon beta-1a group (22 mcg weekly by subcutaneous injection) than in the
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placebo group (34 versus 45 percent). In addition, the time at which 30 percent of patients
had converted to clinically definite MS was significantly longer in the recombinant human
interferon beta-1a group compared with placebo (569 days versus 252). The number of
new T2-weighted MRI lesions and the increase in lesion burden were also significantly
lower with active treatment. A later analysis of this study population found that
recombinant human interferon beta-1a treatment significantly reduced the rate of global
brain atrophy compared with placebo [28].

● The BENEFIT trial randomly assigned 292 patients with CIS to recombinant human
interferon beta-1b (250 mcg every other day by subcutaneous injection) and 176 patients
to placebo [29]. At two years, significantly fewer patients treated with recombinant human
interferon beta-1b had converted to clinically definite MS, a primary outcome measure,
than those receiving placebo (28 and 45 percent, HR 0.5, 95% CI 0.36-0.70). Similar results
were found for the co-primary outcome measure of MS as defined by the McDonald
criteria (69 and 85 percent, HR 0.54, 95% CI 0.43-0.67). Active treatment was also
associated with significant reductions in the cumulative number of newly active lesions
and change in T2 lesion volume on brain MRI.

In the follow-up extension studies of BENEFIT, the patients initially assigned to

recombinant human interferon beta-1b (ie, the early treatment group) were compared
with those who were initially assigned to placebo with the option of starting recombinant
human interferon beta-1b after a diagnosis of clinically definite MS or after two years (ie,
the delayed treatment group) [32-35]. Blinding to initial treatment allocation was
maintained for five years. Compared with delayed treatment, early recombinant human
interferon beta-1b treatment was associated with a statistically significant reduction in the
risk of developing clinically definite MS at three years (absolute risk reduction [ARR] 14
percent) [32], five years (ARR 11 percent) [33], and eight years (ARR 10 percent) [34].
However, the benefit of early treatment for preventing disability was small at three years
[32] and was lost by five years [32,33,36].

● The REFLEX trial evaluated 517 patients with a CIS and at least two clinically silent T2
lesions on brain MRI. At two years, the probability of MS diagnosed by the McDonald
criteria was significantly lower with subcutaneous interferon beta-1a 44 mcg dosed either
three times a week or once a week (63 and 76 percent, versus 86 percent for placebo) [37].
In the subsequent extension phase of the trial, all patients (n = 403) received interferon
beta-1a [38]. At five years, the group assigned to interferon beta-1a treatment in the
placebo-controlled phase (ie, early treatment) continued to have a reduced probability of

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conversion to MS and fewer new MRI lesions compared with the group whose treatment
was delayed for up to two years.

Glatiramer acetate — Early treatment with glatiramer acetate delays conversion from CIS to
clinically definite MS. Supporting evidence comes from the multicenter, blinded trial, PreCISe,
that enrolled 481 adults with a CIS [39]. The trial was stopped early because of benefit with a
mean average exposure to glatiramer of 2.3 years. By intention-to-treat analysis, glatiramer
acetate therapy (20 mg subcutaneously daily) significantly reduced the risk of conversion to
clinically definite MS (HR 0.55, 95% CI 0.40-0.77), prolonged the time for 25 percent of patients
to convert to clinically definite MS (772 days, versus 336 for placebo), and reduced the
frequency of conversion to clinically definite MS (25 percent, versus 43 percent with placebo).
Adverse events, mainly injection site reactions and systemic allergic reactions, led to withdrawal
of 6 percent of subjects assigned to glatiramer acetate.

As noted earlier, it is unknown whether treatment with glatiramer acetate prevents or delays
disability in patients with CIS.

Teriflunomide — Teriflunomide also reduces the risk of progression to multiple sclerosis. In

the TOPIC trial, 618 adults with a CIS were randomly assigned in a 1:1:1 ratio to treatment with
oral teriflunomide 14 mg daily, teriflunomide 7 mg daily, or placebo for up to 108 weeks, with a
median treatment duration of over 70 weeks [40]. The trial was stopped early by the sponsor
upon publication of the 2010 revisions to the McDonald criteria, which allowed an earlier
diagnosis of MS [41]. Compared with placebo, teriflunomide reduced the risk of relapse
defining clinically definite MS at both the 14 mg dose (HR 0.57, 95% CI 0.38-0.87) and the 7 mg
dose (HR 0.63, 95% CI 0.42-0.95) [40]. The most common adverse effects of teriflunomide were
elevated alanine aminotransferase (ALT) levels, diarrhea, hair thinning, paresthesia, and upper
respiratory tract infection.

Because of the risk of hepatotoxicity, patients with known liver disease should not be treated
with teriflunomide. Baseline transaminase and bilirubin levels should be obtained before
starting treatment with teriflunomide, and ALT levels should be monitored monthly for at least
six months once treatment is started. The drug should be discontinued if drug-induced liver
injury is suspected. Patients should be brought up to date with all immunizations before
initiating therapy with teriflunomide. Live vaccines should not be given concurrently.

Due to the risk of teratogenicity, teriflunomide is also contraindicated for women who are
pregnant or trying to conceive, and women of childbearing age must have a negative
pregnancy test before starting the drug. Teriflunomide is also found in semen. While available
studies have found no pregnancy safety concerns [42,43], women who become pregnant and

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people who wish to conceive a child should discontinue teriflunomide and undergo an
accelerated drug elimination procedure, as described elsewhere. (See "Disease-modifying
therapies for multiple sclerosis: Pharmacology, administration, and adverse effects", section on
'Teriflunomide'.)

Other treatments — Intravenous immune globulin (IVIG) [44] and minocycline [45,46] have
been studied for the treatment of CIS or first demyelinating event, but are not established as
effective.

SOCIETY GUIDELINE LINKS

Links to society and government-sponsored guidelines from selected countries and regions
around the world are provided separately. (See "Society guideline links: Multiple sclerosis and
related disorders".)

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level and are best for patients who want in-depth information and are comfortable with some
medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print
or e-mail these topics to your patients. (You can also locate patient education articles on a
variety of subjects by searching on "patient info" and the keyword(s) of interest.)

● Basics topics (see "Patient education: Multiple sclerosis in adults (The Basics)" and "Patient
education: Multiple sclerosis in children (The Basics)")

SUMMARY AND RECOMMENDATIONS

● A clinically isolated syndrome (CIS) is defined as a single first clinical episode reflecting a
focal or multifocal demyelinating event in the central nervous system. The typical patient

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with a CIS is a young adult with a single episode of central nervous system dysfunction
followed by at least partial resolution. Symptoms usually develop over the course of hours
to days and then gradually remit over the ensuing weeks to months, though remission
may not be complete. In contrast, a radiologically isolated syndrome (RIS) is defined by
incidental MRI findings that are highly suggestive of multiple sclerosis (MS), based upon
location and morphology within the central nervous system, in an asymptomatic patient
lacking any history, symptoms, or signs of demyelination. (See 'Clinically isolated
syndrome' above and 'Radiologically isolated syndrome' above.)

● All patients with a CIS should have neuroimaging with a contrast-enhanced MRI in order
to determine whether there is an explanatory acute inflammatory lesion in the brain or
spinal cord and whether there are additional lesions on MRI that are suggestive of MS. In
addition, for patients with a CIS who have a brain MRI that shows no or few lesions (ie,
MRI findings that do not meet the McDonald criteria for dissemination in space), we
suggest cerebrospinal fluid examination, as the presence of oligoclonal bands can be
helpful in determining therapy. The diagnosis of MS can be made for some patients at the
time they present with a first clinical attack (ie, a CIS) if a single MRI obtained at any time
shows dissemination in space and, as evidence for dissemination in time, the
simultaneous presence of gadolinium-enhancing and nonenhancing lesions, or (as a
substitute for dissemination in time) by the presence of cerebrospinal fluid-specific
oligoclonal bands. (See 'Initial Evaluation' above and "Evaluation and diagnosis of multiple
sclerosis in adults", section on 'For a clinically isolated syndrome'.)

● The long-term likelihood of progression to clinically definite MS for patients with a CIS is
approximately 60 percent if the baseline brain MRI reveals demyelinating lesions
suggestive of MS, and approximately 20 percent if the MRI is normal. The risk may vary
according to the type of CIS (eg, optic neuritis, acute transverse myelitis) and with the
presence of oligoclonal bands in the cerebrospinal fluid. (See 'Risk of progression to
multiple sclerosis' above.)

● Patients with a CIS or RIS should be monitored for possible manifestations of MS disease
activity including acute clinical attacks (relapses), new lesions on MRI, and onset or
progression of sustained disability. (See 'Monitoring' above.)

● For patients with CIS who do not fulfill McDonald criteria for a diagnosis of MS but have an
abnormal brain MRI with hyperintense T2 lesions that are characteristic of MS in at least
two of four MS-typical regions at presentation or within three to six months of the event,
we suggest disease-modifying treatment (DMT) with one of the recombinant human
interferon beta agents or with glatiramer acetate (Grade 2A). Teriflunomide is one
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alternative for patients who prefer oral therapy, but its use is contraindicated for women
who are pregnant or couples who are trying to conceive, and monitoring is required due
to the risk of hepatotoxicity. Other alternatives include the oral fumarates and S1P
receptor modulators. (See 'Choice of DMT' above and 'Efficacy of DMTs for CIS' above.)

● Patients on disease-modifying therapy should have clinical follow-up with careful attention
to possible manifestations of MS disease activity and periodic MRI to monitor for new
demyelinating lesions. (See 'Follow-up' above.)

Use of UpToDate is subject to the Terms of Use.

REFERENCES

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sclerosis in radiologically isolated syndrome and magnetic resonance imaging,
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66:841.

4. Brex PA, Ciccarelli O, O'Riordan JI, et al. A longitudinal study of abnormalities on MRI and
disability from multiple sclerosis. N Engl J Med 2002; 346:158.
5. Frohman EM, Goodin DS, Calabresi PA, et al. The utility of MRI in suspected MS: report of
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6. Optic Neuritis Study Group. Multiple sclerosis risk after optic neuritis: final optic neuritis
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7. Fisniku LK, Brex PA, Altmann DR, et al. Disability and T2 MRI lesions: a 20-year follow-up of
patients with relapse onset of multiple sclerosis. Brain 2008; 131:808.
8. Tintoré M, Rovira A, Río J, et al. Baseline MRI predicts future attacks and disability in
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9. Miller DH, Chard DT, Ciccarelli O. Clinically isolated syndromes. Lancet Neurol 2012; 11:157.
10. Optic Neuritis Study Group. The 5-year risk of MS after optic neuritis. Experience of the
optic neuritis treatment trial. Neurology 1997; 49:1404.

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11. Beck RW, Trobe JD, Moke PS, et al. High- and low-risk profiles for the development of
multiple sclerosis within 10 years after optic neuritis: experience of the optic neuritis
treatment trial. Arch Ophthalmol 2003; 121:944.
12. Bruna J, Martínez-Yélamos S, Martínez-Yélamos A, et al. Idiopathic acute transverse
myelitis: a clinical study and prognostic markers in 45 cases. Mult Scler 2006; 12:169.
13. Gajofatto A, Monaco S, Fiorini M, et al. Assessment of outcome predictors in first-episode
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14. Morrissey SP, Miller DH, Kendall BE, et al. The significance of brain magnetic resonance
imaging abnormalities at presentation with clinically isolated syndromes suggestive of
multiple sclerosis. A 5-year follow-up study. Brain 1993; 116 ( Pt 1):135.
15. Ford B, Tampieri D, Francis G. Long-term follow-up of acute partial transverse myelopathy.
Neurology 1992; 42:250.
16. Scott TF, Kassab SL, Singh S. Acute partial transverse myelitis with normal cerebral
magnetic resonance imaging: transition rate to clinically definite multiple sclerosis. Mult
Scler 2005; 11:373.
17. Bashir K, Whitaker JN. Importance of paraclinical and CSF studies in the diagnosis of MS in
patients presenting with partial cervical transverse myelopathy and negative cranial MRI.
Mult Scler 2000; 6:312.
18. Tintoré M, Rovira A, Río J, et al. Do oligoclonal bands add information to MRI in first attacks
of multiple sclerosis? Neurology 2008; 70:1079.

19. Okuda DT, Siva A, Kantarci O, et al. Radiologically isolated syndrome: 5-year risk for an
initial clinical event. PLoS One 2014; 9:e90509.

20. Kantarci OH, Lebrun C, Siva A, et al. Primary Progressive Multiple Sclerosis Evolving From
Radiologically Isolated Syndrome. Ann Neurol 2016; 79:288.
21. Matute-Blanch C, Villar LM, Álvarez-Cermeño JC, et al. Neurofilament light chain and
oligoclonal bands are prognostic biomarkers in radiologically isolated syndrome. Brain
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22. De Stefano N, Giorgio A, Tintoré M, et al. Radiologically isolated syndrome or subclinical
multiple sclerosis: MAGNIMS consensus recommendations. Mult Scler 2018; 24:214.
23. Bourdette D, Simon J. The radiologically isolated syndrome: is it very early multiple
sclerosis? Neurology 2009; 72:780.
24. Filippini G, Del Giovane C, Clerico M, et al. Treatment with disease-modifying drugs for
people with a first clinical attack suggestive of multiple sclerosis. Cochrane Database Syst
Rev 2017; 4:CD012200.

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25. Jokubaitis VG, Spelman T, Kalincik T, et al. Predictors of disability worsening in clinically
isolated syndrome. Ann Clin Transl Neurol 2015; 2:479.
26. Jacobs LD, Beck RW, Simon JH, et al. Intramuscular interferon beta-1a therapy initiated
during a first demyelinating event in multiple sclerosis. CHAMPS Study Group. N Engl J Med
2000; 343:898.
27. Comi G, Filippi M, Barkhof F, et al. Effect of early interferon treatment on conversion to
definite multiple sclerosis: a randomised study. Lancet 2001; 357:1576.

28. Filippi M, Rovaris M, Inglese M, et al. Interferon beta-1a for brain tissue loss in patients at
presentation with syndromes suggestive of multiple sclerosis: a randomised, double-blind,
placebo-controlled trial. Lancet 2004; 364:1489.
29. Kappos L, Polman CH, Freedman MS, et al. Treatment with interferon beta-1b delays
conversion to clinically definite and McDonald MS in patients with clinically isolated
syndromes. Neurology 2006; 67:1242.
30. Clerico M, Faggiano F, Palace J, et al. Recombinant interferon beta or glatiramer acetate for
delaying conversion of the first demyelinating event to multiple sclerosis. Cochrane
Database Syst Rev 2008; :CD005278.
31. Kinkel RP, Kollman C, O'Connor P, et al. IM interferon beta-1a delays definite multiple
sclerosis 5 years after a first demyelinating event. Neurology 2006; 66:678.

32. Kappos L, Freedman MS, Polman CH, et al. Effect of early versus delayed interferon beta-1b
treatment on disability after a first clinical event suggestive of multiple sclerosis: a 3-year
follow-up analysis of the BENEFIT study. Lancet 2007; 370:389.
33. Kappos L, Freedman MS, Polman CH, et al. Long-term effect of early treatment with
interferon beta-1b after a first clinical event suggestive of multiple sclerosis: 5-year active
treatment extension of the phase 3 BENEFIT trial. Lancet Neurol 2009; 8:987.
34. Edan G, Kappos L, Montalbán X, et al. Long-term impact of interferon beta-1b in patients
with CIS: 8-year follow-up of BENEFIT. J Neurol Neurosurg Psychiatry 2014; 85:1183.
35. Kappos L, Edan G, Freedman MS, et al. The 11-year long-term follow-up study from the
randomized BENEFIT CIS trial. Neurology 2016; 87:978.
36. Pittock SJ. Uncertain BENEFIT of early interferon beta-1b treatment. Lancet Neurol 2009;
8:970.

37. Comi G, De Stefano N, Freedman MS, et al. Comparison of two dosing frequencies of
subcutaneous interferon beta-1a in patients with a first clinical demyelinating event
suggestive of multiple sclerosis (REFLEX): a phase 3 randomised controlled trial. Lancet
Neurol 2012; 11:33.

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38. Comi G, De Stefano N, Freedman MS, et al. Subcutaneous interferon β-1a in the treatment
of clinically isolated syndromes: 3-year and 5-year results of the phase III dosing
frequency-blind multicentre REFLEXION study. J Neurol Neurosurg Psychiatry 2017; 88:285.
39. Comi G, Martinelli V, Rodegher M, et al. Effect of glatiramer acetate on conversion to
clinically definite multiple sclerosis in patients with clinically isolated syndrome (PreCISe
study): a randomised, double-blind, placebo-controlled trial. Lancet 2009; 374:1503.
40. Miller AE, Wolinsky JS, Kappos L, et al. Oral teriflunomide for patients with a first clinical
episode suggestive of multiple sclerosis (TOPIC): a randomised, double-blind, placebo-
controlled, phase 3 trial. Lancet Neurol 2014; 13:977.
41. Polman CH, Reingold SC, Banwell B, et al. Diagnostic criteria for multiple sclerosis: 2010
revisions to the McDonald criteria. Ann Neurol 2011; 69:292.
42. Kieseier BC, Benamor M. Pregnancy outcomes following maternal and paternal exposure
to teriflunomide during treatment for relapsing-remitting multiple sclerosis. Neurol Ther
2014; 3:133.
43. Andersen JB, Moberg JY, Spelman T, Magyari M. Pregnancy Outcomes in Men and Women
Treated With Teriflunomide. A Population-Based Nationwide Danish Register Study. Front
Immunol 2018; 9:2706.
44. Fazekas F, Lublin FD, Li D, et al. Intravenous immunoglobulin in relapsing-remitting
multiple sclerosis: a dose-finding trial. Neurology 2008; 71:265.
45. Sørensen PS, Sellebjerg F, Lycke J, et al. Minocycline added to subcutaneous interferon β-1a
in multiple sclerosis: randomized RECYCLINE study. Eur J Neurol 2016; 23:861.
46. Metz LM, Li DKB, Traboulsee AL, et al. Trial of Minocycline in a Clinically Isolated Syndrome
of Multiple Sclerosis. N Engl J Med 2017; 376:2122.
Topic 1691 Version 32.0

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GRAPHICS

Differential diagnosis of multiple sclerosis

Inflammatory disease

Acute disseminated encephalomyelitis

Behçet disease

Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids

Clinically isolated syndromes suggestive of multiple sclerosis

Myelin oligodendrocyte glycoprotein IgG-associated encephalomyelitis

Neuromyelitis optica spectrum disorder

Paraneoplastic encephalomyelopathies

Polyarteritis nodosa

Primary angiitis of the central nervous system

Sjögren syndrome

Systemic lupus erythematosus

Infectious disease
Human immunodeficiency virus

Lyme neuroborreliosis

Neurosyphilis

Progressive multifocal leukoencephalopathy

HTLV-1-associated myelopathy/Tropical spastic paraparesis

Genetic disease
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy

Granulomatous disease
Lymphomatoid granulomatosis

Sarcoidosis

Granulomatosis with polyangiitis (Wegener's)

Disease of myelin
Adrenoleukodystrophy

Adult metachromatic leukodystrophy

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Other
Arnold-Chiari malformation

Compressive spinal cord lesions

Vascular malformations

Vitamin B12 deficiency

Spinocerebellar disorders

Human T-lymphotropic virus, type I; IgG: Immunoglobulin G.

Graphic 76753 Version 9.0

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Brain MRI of a clinically isolated syndrome

suggestive of multiple sclerosis presenting as optic
neuritis

Brain MRI of a 30-year-old patient presenting with optic neuritis.

(A) Fat-saturated T2-weighted coronal image shows hyperintensity in

the right optic nerve (arrow).

(B) Post-gadolinium fat-saturated T1-weighted coronal image shows

abnormal enhancement in the right optic nerve (arrow).

(C) Four years later, sagittal FLAIR shows two plaques radiating
outward from the corpus callosum (arrowheads), suggestive of
multiple sclerosis.

MRI: magnetic resonance imaging; FLAIR: fluid-attenuated inversion

recovery.

Graphic 81188 Version 8.0

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Expanded Disability Status Scale (EDSS) and functional systems

Functional systems (FS)

Pyramidal functions

0. Normal

1. Abnormal signs without disability

2. Minimal disability

3. Mild or moderate paraparesis or hemiparesis; severe monoparesis

4. Marked paraparesis or hemiparesis; moderate quadriparesis; or monoplegia

5. Paraplegia, hemiplegia, or marked quadriparesis

6. Quadriplegia

V. Unknown

Cerebellar functions

0. Normal

1. Abnormal signs without disability

2. Mild ataxia

3. Moderate truncal or limb ataxia

4. Severe ataxia, all limbs

5. Unable to perform coordinated movements due to ataxia

V. Unknown

X. Is used throughout after each number when weakness (grade 3 or more on pyramidal)
interferes with testing

Brain stem functions

0. Normal

1. Signs only

2. Moderate nystagmus or other mild disability

3. Severe nystagmus, marked extraocular weakness, or moderate disability of other cranial nerves

4. Marked dysarthria or other marked disability

5. Inability to swallow or speak

V. Unknown

Sensory functions

0. Normal
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1. Vibration or figure-writing decrease only, in one or two limbs

2. Mild decrease in touch or pain or position sense, and/or moderate decrease in vibration in one
or two limbs; or vibratory (c/s figure writing) decrease alone in three or four limbs

3. Moderate decrease in touch or pain or position sense, and/or essentially lost vibration in one or
two limbs; or mild decrease in touch or pain and/or moderate decrease in all proprioceptive tests
in three or four limbs

4. Marked decrease in touch or pain or loss of proprioception, alone or combined, in one or two
limbs; or moderate decrease in touch or pain and/or severe proprioceptive decrease in more than
two limbs

5. Loss (essentially) of sensation in one or two limbs; or moderate decrease in touch or pain and/or
loss of proprioception for most of the body below the head

6. Sensation essentially lost below the head

V. Unknown

Bowel and bladder functions

0. Normal

1. Mild urinary hesitancy, urgency, or retention

2. Moderate hesitancy, urgency, retention of bowel or bladder, or rare urinary incontinence

3. Frequent urinary incontinence

4. In need of almost constant catheterization

5. Loss of bladder function

6. Loss of bowel and bladder function

V. Unknown

Visual (or optic) functions

0. Normal

1. Scotoma with visual acuity (corrected) better than 20/30

2. Worse eye with scotoma with maximal visual acuity (corrected) of 20/30 to 20/59

3. Worse eye with large scotoma, or moderate decrease in fields, but with maximal visual acuity
(corrected) of 20/60 to 20/99

4. Worse eye with marked decrease of fields and maximal visual acuity (corrected) of 20/100 to
20/200; grade 3 plus maximal acuity of better eye of 20/60 or less

5. Worse eye with maximal visual acuity (corrected) less than 20/200; grade 4 plus maximal acuity
of better eye of 20/60 or less

6. Grade 5 plus maximal visual acuity of better eye of 20/60 or less

V. Unknown

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X. Is added to grades 0 to 6 for presence of temporal pallor

Cerebral (or mental) functions

0. Normal

1. Mood alteration only (Does not affect Disability Status Scale score)

2. Mild decrease in mentation

3. Moderate decrease in mentation

4. Marked decrease in mentation (chronic brain syndrome-moderate)

5. Dementia or chronic brain syndrome-severe or incompetent

V. Unknown

Other functions

0. None

1. Any other neurologic findings attributed to MS (specify)

V. Unknown

Expanded Disability Status Scale (EDSS)

0 = Normal neurologic exam (all grade 0 in Functional Systems [FS]; Cerebral grade 1 acceptable)

1.0 = No disability, minimal signs in one FS (ie, grade 1 excluding Cerebral grade 1)

1.5 = No disability minimal signs in more than one FS (more than one grade 1 excluding Cerebral
grade 1)

2.0 = Minimal disability in one FS (one FS grade 2, others 0 or 1)

2.5 = Minimal disability in two FS (two FS grade 2, others 0 or 1)

3.0 = Moderate disability in one FS (one FS grade 3, others 0 or 1), or mild disability in three or four
FS (three/four FS grade 2, others 0 or 1) though fully ambulatory

3.5 = Fully ambulatory but with moderate disability in one FS (one grade 3) and one or two FS
grade 2; or two FS grade 3; or five FS grade 2 (others 0 or 1)

4.0 = Fully ambulatory without aid, self-sufficient, up and about some 12 hours a day despite
relatively severe disability consisting of one FS grade 4 (others 0 or 1, or combinations of lesser
grades exceeding limits of previous steps. Able to walk without aid or rest some 500 meters.

4.5 = Fully ambulatory without aid, up and about much of the day, able to work a full day, may
otherwise have some limitation of full activity or require minimal assistance; characterized by
relatively severe disability, usually consisting of one FS grade 4 (others 0 or 1) or combinations of
lesser grades exceeding limits of previous steps. Able to walk without aid or rest for some 300
meters.

5.0 = Ambulatory without aid or rest for about 200 meters; disability severe enough to impair full
daily activities (eg, to work full day without special provisions). (Usual FS equivalents are one grade

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5 alone, others 0 or 1; or combinations of lesser grades usually exceeding specifications for step
4.0.)

5.5 = Ambulatory without aid or rest for about 100 meters; disability severe enough to preclude full
daily activities. (Usual FS equivalents are one grade 5 alone, others 0 or 1; or combinations of
lesser grades usually exceeding those for step 4.0.)

6.0 = Intermittent or unilateral constant assistance (cane, crutch, or brace) required to walk about
100 meters with or without resting. (Usual FS equivalents are combinations with more than two FS
grade 3+.)

6.5 = Constant bilateral assistance (canes, crutches, or braces) required to walk about 20 meters
without resting. (Usual FS equivalents are combinations with more than two FS grade 3+.)

7.0 = Unable to walk beyond about 5 meters even with aid, essentially restricted to wheelchair;
wheels self in standard wheelchair and transfers alone; up and about in wheelchair 12 hours a day.
(Usual FS equivalents are combinations with more than one FS grade 4+; very rarely, pyramidal
grade 5 alone.)

7.5 = Unable to take more than a few steps; restricted to wheelchair; may need aid in transfer;
wheels self but cannot carry on in standard wheelchair a full day; may require motorized
wheelchair. (Usual FS equivalents are combinations with more than one FS grade 4+.)

8.0 = Essentially restricted to bed or chair or perambulated in wheelchair, but may be out of bed
itself much of the day; retains many self-care functions; generally has effective use of arms. (Usual
FS equivalents are combinations, generally grade 4+ in several systems.)

8.5 = Essentially restricted to bed much of the day; has some effective use of arm(s); retains some
self-care functions. (Usual FS equivalents are combinations, generally 4+ in several systems.)

9.0 = Helpless bed patient; can communicate and eat. (Usual FS equivalents are combinations,
mostly grade 4+.)

9.5 = Totally helpless bed patient; unable to communicate effectively or eat/swallow. (Usual FS
equivalents are combinations, almost all grade 4+.)

10 = Death due to MS

MS: multiple sclerosis.

Reproduced with permission from: Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability
status scale (EDSS). Neurology 1983; 33:1444. Copyright © 1983 Lippincott Williams & Wilkins.

Graphic 57639 Version 7.0

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Contributor Disclosures
Michael J Olek, DO No relevant financial relationship(s) with ineligible companies to disclose. Jonathan
Howard, MD Speaker's Bureau: MCE Conferences [Multiple sclerosis]. Other Financial Interest: Kopa.com
[Multiple sclerosis]. All of the relevant financial relationships listed have been mitigated. Francisco
González-Scarano, MD Patent Holder: La Crosse [Monoclonal antibodies]. All of the relevant financial
relationships listed have been mitigated. John F Dashe, MD, PhD No relevant financial relationship(s) with
ineligible companies to disclose.

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
provided to support the content. Appropriately referenced content is required of all authors and must
conform to UpToDate standards of evidence.

Conflict of interest policy

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