Management of clinically and radiologically isolated syndromes suggestive of multiple sclerosis

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 magnetic resonance imaging (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, but some will not.

This topic will discuss the management of CIS and 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".)

DEFINITIONS

Clinically isolated syndrome (CIS) — A CIS is the first clinical episode 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 (CNS) dysfunction, such as unilateral optic neuritis, a focal brain syndrome, a focal brainstem or cerebellar syndrome, or partial myelopathy [1]. Symptoms usually develop over hours to days and then gradually remit over 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 (RIS) — RIS is defined by incidental brain or spinal cord MRI findings that are highly suggestive of MS, based upon location and morphology within the CNS, 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. (See "Evaluation and diagnosis of multiple sclerosis in adults", section on 'For a radiologically isolated syndrome'.)

INITIAL EVALUATION

Clinically isolated syndrome (CIS) evaluation — The diagnosis of MS can be made for some patients at the time they present with a first clinical attack (ie, a typical CIS) if a single MRI obtained at any time shows dissemination in space (DIS) and, as evidence for dissemination in time (DIT), by the simultaneous presence of gadolinium-enhancing and nonenhancing lesions, or by the presence of cerebrospinal fluid (CSF)-specific immunoglobulin G (IgG) oligoclonal bands (OCBs) (table 1). (See "Evaluation and diagnosis of multiple sclerosis in adults", section on 'For a clinically isolated syndrome'.)

●Imaging – All patients presenting with a CIS should have neuroimaging with a contrast-enhanced MRI of the brain, optic nerve, and spinal cord to determine if there is an explanatory acute inflammatory lesion 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'.)

●Lumbar puncture – We suggest lumbar puncture and CSF examination for patients with a CIS who have a brain MRI that shows no or few lesions (ie, findings that do not meet the McDonald criteria for DIS and/or DIT) (table 1). OCBs would not confirm an MS diagnosis if DIS is not met, but the presence of CSF-specific OCBs would signify a CIS at increased risk meeting MS criteria over time. Qualitative assessment using isoelectric focusing that detects OCBs in CSF but not in a concomitant serum specimen can:

•Provide supportive evidence that the underlying disorder is inflammatory and demyelinating

•Help to refine the risk estimation for progression to MS in equivocal cases

•Fulfill criteria for DIT and thereby confirm the diagnosis of MS in a patient with MRI evidence of DIS

A positive CSF is based upon the finding of either OCBs 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. (See 'Oligoclonal bands' below.)

●Other tests – In select cases, testing for anti-aquaporin 4 (AQP4) or anti-myelin oligodendrocyte (MOG) antibodies may be appropriate. (See "Evaluation and diagnosis of multiple sclerosis in adults", section on 'Autoantibody testing'.)

Radiologically isolated syndrome (RIS) evaluation — 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.

●For patients with an RIS, we suggest obtaining a spinal cord MRI. Spinal cord lesions are a risk factor for subclinical MS; identifying such lesions would provide additional rationale for preventive treatment. (See 'Risk with a radiologically isolated syndrome' below.)

●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 CSF-specific OCBs would suggest an increased risk of conversion to MS [3].

Differential diagnosis — The differential diagnosis of CIS and RIS is essentially the same as that of MS and includes a number of inflammatory, vascular, infectious, genetic, granulomatous, and other demyelinating disorders (table 2). 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 radiologically isolated syndrome (RIS) or clinically isolated syndrome (CIS) not meeting criteria for MS at presentation who are likely to progress to MS is a major research goal.

Risk with a clinically isolated syndrome

Overall risk — In various older studies performed from 2002 to 2012, the long-term (ie, 10- to 20-year) likelihood of developing MS for patients with CIS and MRI lesions characteristic of MS ranged from 60 to 80 percent [4-9], with most of the data suggesting that the true rate of conversion was closer to the lower end of this range.

However, given the broadening of MS diagnostic criteria over time, extrapolating prognostic and management data from older CIS studies may not be appropriate, since older studies included patients who would now be diagnosed immediately with MS. Patients now presenting with a CIS who do not yet fulfill MS criteria are by definition at a lower risk of fulfilling criteria for MS.

The risk of developing MS is associated with the presence of lesions on MRI at presentation, including increased lesion load, more than three periventricular or brainstem lesions, and/or spinal cord lesions [7,10-13].

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) at presentation may be candidates for early disease-modifying therapy. (See 'Candidates for early disease-modifying therapy' below.)

Risk modifiers — The presence of oligoclonal bands (OCBs) in the cerebrospinal fluid (CSF) and the type of clinical presentation are modifiers of the risk of progression to MS.

Oligoclonal bands — In patients with CIS, the presence of OCBs in the CSF 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 OCBs was associated with a significantly increased risk of developing clinically definite MS (hazard ratio [HR] 1.7, 95% CI 1.1-2.7) [14]. 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 OCBs 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 OCBs in the CSF [9].

Clinical presentation

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 [15]. The cumulative incidence increased to 40 percent at 12 years [16] and 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 without lesions [16].

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

Transverse myelitis — 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 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 [17,18], although some reports suggest a higher conversion rate [19]. This finding would be more consistent with neuromyelitis optic spectrum disorder (NMOSD) rather than MS. (See "Neuromyelitis optica spectrum disorder (NMOSD): Clinical features and diagnosis", section on 'Transverse myelitis'.)

A 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 subacute 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 [19-21]. By contrast, patients with subacute partial myelitis who have a normal brain MRI develop MS at a rate of only 10 to 30 percent over a similar time period [22]. Studies suggest that patients with monosymptomatic disease who have positive OCBs have a higher risk of evolution to MS than those without OCBs [23].

The length of the spinal cord lesion is also associated with the risk of progression to MS. 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 (CNS), 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) [24]; the latter patients likely had neuromyelitis optica spectrum disorder (NMOSD) or myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). (See "Neuromyelitis optica spectrum disorder (NMOSD): Clinical features and diagnosis" and "Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD): Clinical features and diagnosis".)

Risk with a radiologically isolated syndrome — 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 participants (approximately 78 percent female) with RIS from 22 databases [25]. 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 [26]. Another study of 75 patients with RIS found that the presence of OCBs in the CSF was associated with an increased risk of conversion to MS [27].

These data and expert consensus suggest that patients with an RIS have an increased risk of subclinical MS if one or more of the following features are present [28,29]:

●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 OCBs in the CSF

●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 [28]:

●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.

ACUTE TREATMENT FOR CLINICALLY ISOLATED SYNDROME — 

The indications for glucocorticoid therapy for an acute attack of clinically isolated syndrome (CIS) are similar to those for an acute exacerbation of MS, particularly attacks with functionally disabling symptoms. Mild sensory attacks may not require treatment. (See "Treatment of acute exacerbations of multiple sclerosis in adults", section on 'Indications'.)

ROLE OF EARLY DISEASE-MODIFYING THERAPY — 

Management of patients with a clinically isolated syndrome (CIS) or radiologically isolated syndrome (RIS) includes monitoring for manifestations of MS disease activity and deciding about early disease-modifying therapy (DMT) for select patients with a typical CIS or RIS. The use of early DMT should be considered only in consultation with neurology and preferably with an MS specialist where available.

Patients who fulfill criteria for multiple sclerosis — All patients who present with a CIS and meet diagnostic criteria for relapsing MS (table 1) should be counseled about DMT for MS. (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".)

Patients with clinically isolated syndrome who do not fulfill criteria for multiple sclerosis

Candidates for early disease-modifying therapy — Patients diagnosed with CIS but not MS who have a high risk of transitioning to relapsing MS are the most likely to benefit from DMT. These are patients who present with a typical CIS (a single episode of central nervous system [CNS] dysfunction, such as unilateral optic neuritis, a focal brain syndrome, a focal brainstem or cerebellar syndrome, or partial myelopathy) and fail to meet criteria either for dissemination in space (hyperintense T2 MRI lesions in at least two of four MS-typical regions: periventricular, cortical or juxtacortical, infratentorial, and spinal cord) or criteria for dissemination in time (eg, because they lack cerebrospinal fluid [CSF]-specific oligoclonal bands [OCBs] in the CSF or because lumbar puncture is not successful). (See 'Overall risk' above.)

There is no consensus approach to treating this group of patients [30]. Options include:

●Immediate initiation of DMT. Early treatment beginning before the technical diagnosis of MS is likely to have a greater impact than later treatment on delaying further disease activity prompting reclassification to MS. However, the benefit of early treatment for reducing disability is not firmly established, and there is concern that these patients will potentially be exposed to greater harm from adverse effects of medications than in the past, when only safer, moderate-efficacy therapies were available.

●Withholding DMT for several months while awaiting repeat brain and spinal cord MRI. DMT can be started if MRI shows new lesions that fulfill criteria for dissemination in time or space. If not, periodic clinical and imaging surveillance is used to determine whether the patient progresses to a diagnosis of MS and has a clear indication for DMT. (See 'Monitoring' below.)

Patients with a CIS who have minimal or no MRI lesions are typically not offered DMT but require continued clinical and imaging follow-up. (See 'Monitoring' below.)

Shared decision-making — For patients who have a CIS but fail to meet updated criteria for MS at presentation, we employ shared decision-making regarding the use of DMT, including discussions about what is known and what is uncertain about benefits, risks, and burdens of therapy.

●Pros of starting DMT – There is likely a benefit of starting treatment to prevent further activity if the patient is at increased risk for changes that make the MS diagnosis definite.

●Cons of starting DMT – Although a CIS is a category of less diagnostic certainty, starting therapy commits you to the diagnosis of MS. If DMT is started and nothing further happens, is the lack of disease activity due to the treatment or due to misdiagnosis (ie, the underlying condition is not MS)? There is also increased risk of harm associated with DMT, especially if starting higher-efficacy DMTs that are associated with higher risks (eg, infections).

It may be perfectly appropriate to watch and wait. It may also be reasonable to seek a second opinion from an MS expert if there is diagnostic uncertainty or uncertainty about whether to start a DMT.

Potential benefits and risks — The benefit of MS DMT for patients with a CIS who do not fulfill McDonald criteria for MS at presentation is uncertain [30]. The results of randomized controlled trials performed before 2017, using older definitions of CIS, supported the early use of DMTs (including interferons, glatiramer acetate, and teriflunomide) for delaying or preventing progression to MS in patients with a monofocal CIS not meeting MS criteria who had additional clinically silent lesions in the brain or spinal cord detected by MRI [31-39]. However, most of these trials included a substantial proportion of patients who would now be diagnosed with relapsing-remitting MS (RRMS) at presentation using the 2017 McDonald criteria, which allow confirmation of MS by the detection of unique OCBs in the CSF to fulfill the requirement for dissemination in time [30]. Updated trials of patients who have typical CIS but do not yet meet RRMS criteria at presentation are needed to determine whether DMTs are beneficial for patients diagnosed with CIS but not RRMS using the existing definition.

The risks of early DMT are mainly dependent on the specific DMT chosen for treatment. (See 'Selection of disease-modifying therapy for patients who choose treatment' below.)

In general, we suggest an escalation approach for patients who chose DMT by starting with older, lower-efficacy injectable DMTs (interferon beta formulations and glatiramer acetate) that have good evidence of long-term safety. Serious adverse effects of these drugs are uncommon. Several oral DMTs, including the fumarates and teriflunomide, are also reasonable options for some patients. (See "Overview of disease-modifying therapies for multiple sclerosis", section on 'Interferons' and "Overview of disease-modifying therapies for multiple sclerosis", section on 'Glatiramer acetate' and "Clinical use of oral disease-modifying therapies for multiple sclerosis", section on 'Fumarates' and "Clinical use of oral disease-modifying therapies for multiple sclerosis", section on 'Teriflunomide'.)

Higher-efficacy DMTs, including some oral and monoclonal antibody DMTs, are generally associated with a higher risk of serious adverse effects, including infections. (See "Clinical use of oral disease-modifying therapies for multiple sclerosis" and "Clinical use of monoclonal antibody disease-modifying therapies for multiple sclerosis".)

Patients with radiologically isolated syndrome — There is no clear indication for the use of DMT for patients with an RIS (ie, asymptomatic but with incidental MRI findings suggestive of MS) [40]. (See 'Radiologically isolated syndrome (RIS)' above.)

Some experts favor treatment with DMT using a shared decision-making process for select patients with RIS considered to be at increased risk of progression to MS (eg, younger age, presence of spinal cord lesions or gadolinium-enhancing lesions on MRI, OCBs in the CSF, and/or identification of new lesions on MRI over time) [41-43]. However, just as for CIS, the diagnosis of RIS for people with brain lesions that do not represent early MS leads to the possibility of harm with no expected benefit from inappropriate exposure to DMTs.

Emerging data from small randomized trials suggest a potential benefit of DMT for RIS [44,45]. The ARISE trial of patients with RIS (n = 87) found that the risk of a first acute clinical event at 96 weeks was reduced with dimethyl fumarate compared with placebo (7 versus 33 percent, HR 0.18, 95% CI 0.05-0.63) [44]. While the effect size was large, confidence in the results is limited by small patient numbers, a high dropout rate, and early stopping due to slow enrollment [44].

The TERIS trial of 89 participants with an RIS found that teriflunomide reduced the risk of a first clinical event during follow-up compared with placebo (18 versus 44 percent, HR 0.37, 95% CI 0.16-0.84) [45]. Like ARISE, the effect size was large, but small patient numbers and a high dropout rate limit confidence in the results.

Selection of disease-modifying therapy for patients who choose treatment — For patients with CIS (or RIS) who lack a diagnosis of MS and choose to start DMT, we generally prefer an escalation approach to minimize the risks of serious harms, considering the less certain benefits. This approach involves initial treatment using older injectable DMTs (beta interferons and glatiramer acetate), which have modest efficacy but long-term evidence of safety. Certain oral DMTs (the fumarates and teriflunomide) are also reasonable in this setting. Among these options, glatiramer acetate may have the lowest risk of troublesome or serious adverse effects. Escalation to higher efficacy oral or infusion DMTs is then implemented only for patients who develop new MS attacks or evidence of new lesions on brain MRI. (See "Initial disease-modifying therapy for relapsing-remitting multiple sclerosis in adults", section on 'Starting with low-risk therapy (escalation approach)'.)

DMTs approved for relapsing forms of MS are also approved in the United States for the treatment of CIS. These are discussed in detail separately:

●Older 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"):

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

•Teriflunomide

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

●Monoclonal antibodies: Natalizumab, ocrelizumab, ofatumumab, and ublituximab (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, and the trials that have been done used an outdated definition of CIS that likely included many patients who would now be diagnosed with RRMS (see 'Potential benefits and risks' above). Still, it is unlikely that substantial differences in DMT effectiveness would be expected between RRMS and CIS if the CIS is truly a first manifestation of MS, rather than a monophasic event or a manifestation of another condition.

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' below.)

Patients with CIS who progress to a diagnosis of clinically definite MS despite persistent use of DMT may benefit from modification of DMT, 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. However, caution is advised when stopping certain DMTs (mainly natalizumab and sphingosine 1-phosphate receptor modulators), since paradoxical worsening of MS disease activity can occur after cessation of these DMTs. (See "Indications for switching or stopping disease-modifying therapy for multiple sclerosis", section on 'Risk of rebound of MS activity'.)

Vitamin D — It may be reasonable to consider vitamin D supplementation for patients with CIS or early MS but benefit is uncertain.

The evidence from randomized trials evaluating vitamin D treatment for CIS and RRMS is inconsistent; most trials [46-50] and meta-analyses [51,52] have found no benefit for clinical outcomes. In contrast, the D-Lay MS trial reported that high dose vitamin D reduced disease activity in patients with CIS and early RRMS [53].

From 2013 to 2020, D-Lay MS enrolled 316 adults with CIS duration <90 days and serum vitamin D level <40 ng/mL (100 nmol/L); most patients (89 percent) fulfilled 2017 McDonald criteria for RRMS [53]. The patients were randomly assigned in a 1:1 ratio to treatment with oral vitamin D3 (cholecalciferol) 100,000 IU or placebo every two weeks for 24 months. Over 24 months, the number of patients with disease activity (a composite outcome defined by the occurrence of a clinical relapse and/or a new or contrast-enhancing MRI lesion) was lower in the vitamin D group compared with the placebo group (60.3 versus 74.1 percent; hazard ratio [HR] 0.66, 95% CI 0.50-0.87). The number of patients with a relapse was also lower in the vitamin D group compared with the placebo group, but the difference was not statistically significant (17.9 versus 21.8 percent; HR 0.69, 95% CI 0.42-1.16). Outcomes for measures of disability, quality of life, fatigue, and anxiety were similar between the vitamin D and placebo groups. In contrast, outcomes for measures of MRI activity were lower in the vitamin D group. Adverse events were similar for the two groups; none were attributed to cholecalciferol.  

D-Lay MS used a higher dose of vitamin D per administration than most earlier trials. However, the average daily dose was not dissimilar to some prior trials that did not show a benefit of vitamin D [53]. Participants in D-Lay MS were untreated with DMT at trial entry. Thus, it is possible that the benefit of vitamin D was masked by the benefit of DMTs in the trials of add-on vitamin D. However, there was no benefit of vitamin D monotherapy in the Australian CIS trial, in which patients refrained from DMT use [46]. Thus, the apparent benefit of high-dose vitamin D for CIS and early RRMS shown by D-Lay MS requires confirmation in further clinical trials.

Other treatments — Intravenous immune globulin (IVIG) [54] and minocycline [55,56] have been studied for the treatment of CIS or first demyelinating event, but they are not established as effective.

MONITORING — 

Patients with a clinically isolated syndrome (CIS) or radiologically isolated syndrome (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 3).

We obtain a repeat brain or spine MRI if we cannot determine clinically whether new symptoms represent a true MS relapse or pseudorelapse. MRI may not be required for patients with a definite MS relapse or similar repetitive pseudorelapses.

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

●For patients with a CIS and no demyelinating lesions on baseline brain or spine MRI, a brain MRI should be repeated at 6 months, 12 months, and, if stable, annually for a few years. If these serial MRIs are stable, further scanning is recommended only if there are new symptoms.

●For patients with a CIS and demyelinating lesions on baseline brain or spine MRI who were not started on early disease-modifying therapy (DMT), follow-up brain MRI every 6 to 12 months is suggested [57].

●For patients with a CIS, if any of the serial brain MRI scans show the interval development of hyperintense T2 lesions that lead to fulfillment of MS criteria, treatment with a DMT is suggested. (See 'Patients who fulfill criteria for multiple sclerosis' above and "Initial disease-modifying therapy for relapsing-remitting multiple sclerosis in adults".)

●For patients started on a DMT who remain stable, a brain MRI is warranted approximately three to six months after starting treatment, and annually thereafter [57]. Some experts include cervical and thoracic spinal cord imaging every other year. However, clear recommendations are lacking given that spinal cord MRI is technically challenging and disproportionally increases scanning time [57].

●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.

The amount of ongoing MRI activity, as determined by the appearance of new or enlarging lesions and/or gadolinium-enhancing lesions, exceeds the observed clinical activity in MS by a factor of 5 to 10 [58]. This may be due in part to underreporting of minor symptoms and under-recognition of minor signs in patients with MS. It does, however, suggest that MS is a much more dynamic and active disease than is clinically apparent.

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 5^th to 6^th 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 10^th to 12^th 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

●Clinically isolated syndrome (CIS) – A typical CIS is defined as a single first clinical episode reflecting a focal or multifocal demyelinating event in the central nervous system (CNS). The typical patient with a CIS is a young adult with a single episode of CNS dysfunction followed by at least partial resolution. Symptoms usually develop over hours to days and then gradually remit over weeks to months, though remission may not be complete. (See 'Clinically isolated syndrome (CIS)' above.)

●Radiologically isolated syndrome (RIS) – An RIS is defined by incidental MRI findings that are highly suggestive of multiple sclerosis (MS) based upon location and morphology within the CNS, in an asymptomatic patient lacking any history, symptoms, or signs of demyelination. (See 'Clinically isolated syndrome (CIS)' above and 'Radiologically isolated syndrome (RIS)' above.)

●Evaluation – All patients with a CIS should have neuroimaging with a contrast-enhanced MRI to determine whether there is an explanatory acute inflammatory lesion in the brain, optic nerve, or spinal cord and whether there are additional lesions on MRI that allow for diagnosis of MS. For patients with a CIS who have a brain MRI that shows no or few lesions (ie, findings that do not meet the McDonald criteria for dissemination in space or time), we suggest cerebrospinal fluid (CSF) examination. The presence of oligoclonal bands (OCBs) does not confirm an MS diagnosis if the requirement for dissemination in space is not met, but the presence of CSF-specific OCBs does signify an increased risk of meeting MS criteria over time. (See 'Clinically isolated syndrome (CIS) evaluation' above.)

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) the presence of CSF-specific OCBs. (See 'Initial evaluation' above and "Evaluation and diagnosis of multiple sclerosis in adults", section on 'For a clinically isolated syndrome'.)

The differential diagnosis of CIS and RIS includes a number of inflammatory, vascular, infectious, genetic, granulomatous, and other demyelinating disorders (table 2). (See "Evaluation and diagnosis of multiple sclerosis in adults", section on 'Differential diagnosis'.)

●Progression to multiple sclerosis – Updated studies are needed to refine the risk estimates for typical CIS. In available studies, which used an outdated definition of CIS that likely included many patients who would now be diagnosed with relapsing-remitting MS (RRMS), the long-term likelihood of progression to clinically definite MS for patients with a CIS was approximately 60 percent if the baseline brain MRI revealed demyelinating lesions suggestive of MS, and approximately 20 percent if the MRI was normal. The risk may vary according to the type of CIS (eg, optic neuritis, acute transverse myelitis) and the presence of OCBs in the CSF. (See 'Risk of progression to multiple sclerosis' above.)

●Use of disease-modifying therapy (DMT) – Patients with typical CIS who fulfill criteria for MS should be offered treatment with DMT. (See "Initial disease-modifying therapy for relapsing-remitting multiple sclerosis in adults".)

For patients with a typical 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, we use shared decision-making to weigh pros and cons of DMT.

For patients who choose DMT in the context of shared decision-making, we generally prefer an escalation approach to minimize the risks of serious harms considering the less certain benefits. This involves initial treatment using older injectable DMTs (beta interferons and glatiramer acetate), which have modest efficacy but long-term evidence of safety, or certain oral DMTs (the fumarates and teriflunomide) that are generally well tolerated. Escalation to higher-efficacy oral or infusion DMTs can be employed for patients who develop new MS attacks or evidence of new lesions on brain MRI. (See 'Role of early disease-modifying therapy' above.)

●Monitoring – Patients with a CIS or RIS should have routine clinical follow-up with careful attention to possible manifestations of MS disease activity and periodic MRI to monitor for new demyelinating lesions. (See 'Monitoring' above.)