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Management of clinically and radiologically isolated syndromes suggestive of multiple sclerosis

Management of clinically and radiologically isolated syndromes suggestive of multiple sclerosis
Literature review current through: Jan 2024.
This topic last updated: Oct 20, 2023.

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 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 — An 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 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 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 an RIS, identified by incidental findings on a brain MRI, is asymptomatic by definition and has no history, symptoms, or signs of MS, 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 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: Etiology, clinical features, and diagnosis".)

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 [12,13], although some reports suggest a higher conversion rate [14]. 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 [14-16]. By 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 [17]. 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 [18].

The length of the spinal cord lesion is also associated with the risk of progression to multiple sclerosis. In a retrospective report of 100 patients evaluated at a tertiary center between 2010 and 2018 with isolated idiopathic myelitis and no evidence of inflammation or demyelination elsewhere in the central nervous system, progression to MS with short-segment myelitis (fewer than three vertebral segments) occurred in 25 of 77 patients (32 percent), while progression to MS with longitudinally extensive myelitis occurred in none of 23 patients (0 percent) [19].

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) [20]. This increased risk was independent of the number of lesions on baseline MRI. Among 113 patients with a negative 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 an 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 [21]. 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 asymptomatic 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 [22]. 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 [23].

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 [24]:

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 [24]:

Migraine or chronic headache

Seizures

Paroxysmal symptoms

Psychiatric disturbances

Overt cognitive impairment

Head trauma

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 only 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 or spine MRI who were not started on early DMT, follow-up brain MRI every 6 to 12 months is suggested [25].

For patients started on a DMT, a brain MRI is warranted approximately three to six months after starting treatment, and annually thereafter [25]. (See 'Follow-up' below.)

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.

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' 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) [26]. (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 "Overview of disease-modifying therapies for multiple sclerosis", section on 'Injection therapies')

Oral therapies (see "Clinical use of oral disease-modifying therapies for multiple sclerosis", section on 'Introduction'):

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 "Clinical use of monoclonal antibody disease-modifying therapies for multiple sclerosis")

However, not all DMTs approved for CIS have been tested specifically for the treatment of CIS. (See 'Efficacy of DMTs' 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 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 were often used because of their benign safety profile and clinical trial data supporting their efficacy in CIS. (See 'Efficacy of DMTs' 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. "Needle-fatigue" is common as well after prolonged use. (See 'Interferons' below and "Overview of disease-modifying therapies for multiple sclerosis", 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 "Overview of disease-modifying therapies for multiple sclerosis", section on 'Glatiramer acetate'.)

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 "Clinical use of oral disease-modifying therapies for multiple sclerosis", 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. Many patients prefer oral over injectable medications, and it is reasonable to start one of these medications in patients with CIS.

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 — 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 [27], whereas a prospective cohort study found that a longer exposure time to DMT was associated with reduced disability [28].

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

A trial of patients with RIS (n = 44) found that dimethyl fumarate reduced the risk of a first acute clinical event compared with placebo, but confidence in the results is limited by small patient numbers, a high dropout rate, and early stopping [29].

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 [30-37]. 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) [34]. 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 [30]. 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 [35]. 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 [31]. 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 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 [32].

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 [33]. 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) [36-39]. 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) [36], five years (ARR 11 percent) [37], and eight years (ARR 10 percent) [38]. However, the benefit of early treatment for preventing disability was small at three years [36] and was lost by five years [36,37,40].

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) [41]. In the subsequent extension phase of the trial, all patients (n = 403) received interferon beta-1a [42]. 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 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 [43]. 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 [44]. 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 [45]. 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) [44]. 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 [46,47], women who become pregnant and people who wish to conceive a child should discontinue teriflunomide and undergo an accelerated drug elimination procedure, as described elsewhere. (See "Clinical use of oral disease-modifying therapies for multiple sclerosis", section on 'Teriflunomide'.)

Other treatments — Intravenous immune globulin (IVIG) [48] and minocycline [49,50] 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".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading 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

CIS – 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 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. (See 'Clinically isolated syndrome' above.)

RIS – 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.)

Evaluation – 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'.)

Progression to MS – 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.)

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. (See 'Monitoring' above.)

Use of DMT – 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 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' above.)

Follow-up on DMT – 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.)

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Topic 1691 Version 34.0

References

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