Clinically isolated syndromes suggestive of multiple sclerosis




A clinically isolated syndrome (CIS) is a single monosymptomatic attack compatible with multiple sclerosis (MS), such as optic neuritis. An episode of CIS can create a diagnostic and therapeutic dilemma. Over 80 percent of patients with a CIS and magnetic resonance imaging (MRI) lesions go on to develop MS, while approximately 20 percent have a self-limited process [1,2]. Identifying those 80 percent may have particular importance, since accumulating evidence suggests that starting disease modifying therapies early in the course of MS improves outcomes.

This topic will discuss the evaluation and treatment of clinically isolated syndromes suggestive of MS. Optic neuritis and other aspects of MS are discussed separately.



There are no clinical findings that are unique to multiple sclerosis (MS), but some are highly characteristic of the disease.
Common presenting symptoms of MS are listed in the table. Any of these may present as a clinically isolated syndrome (CIS). These symptoms are discussed in greater detail separately. They are summarized here.

The typical patient presents as a young adult with a single episode of central nervous system (CNS) dysfunction followed by at least partial resolution. The following are among the more common types of presentation with a clinically isolated syndrome (CIS):

  • Sensory symptoms are a common initial feature of MS. Symptoms are commonly described as numbness, tingling, pins-and-needles, tightness, coldness, or swel ling of the limbs or trunk. Radicular pains also can be present, particularly in the low thoracic and abdominal regions. An intense itching sensation, especially in the cervical dermatomes and usually unilateral, is suggestive of MS.
  • Optic neuritis (ON) is the most common type of involvement of the visual pathways. It usually presents as acute or subacute unilateral eye pain that is accentuated by ocular movements. This is followed by a variable degree of visual loss (scotoma) affecting mainly central vision.
  • Motor symptoms present as leg weakness more commonly than arm weakness due to the frequent occurrence of lesions in the descending motor tracts of the spinal cord. Physical findings include spasticity, usually more marked in the legs than in the arms. The deep tendon reflexes may be exaggerated, and extensor plantar responses may be observed.
  • Diplopia may result from lesions in the brainstem or in cerebellar pathways.
  • Coordination problems include gait imbalance, difficulty in performing coordinated actions with the arms, and slurred speech. These may occur as a result of impairment of cerebellar pathways. Physical examination may reveal dysmetria, decomposition of complex movements, hypotonia, or an intention tremor. Ocular findings of nystagmus, ocular dysmetria, and failure of fixation suppression (square wave jerks) suggest cerebellar or cerebello-vestibular connection dysfunction. Speech can be scanning or explosive in character.
  • Vertigo is a reported symptom in 30 to 50 percent of patients with MS. It is commonly associated with symptoms reflecting dysfunction of adjacent cranial nerves such as hyper- or hypoacusis, facial numbness, and diplopia.



Identification of those patients with clinically isolated syndromes (CIS) who are likely to progress to multiple sclerosis (MS) is a major goal of current research.

After isolated optic neuritis 

In the Optic Neuritis Treatment trial, the cumulative five-year incidence of clinically definite MS was 30 percent following a first episode of idiopathic demyelinating optic neuritis [3].
 The cumulative incidence increased to 40 percent at 12 years [4]. The presence of characteristic demyelinating lesions on magnetic resonance imaging (MRI) are a strong predictor of developing MS . 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 [4].

McDonald MRI criteria 

The original 2001 McDonald diagnostic criteria for MS incorporated MRI findings, potentially allowing for earlier diagnosis of patients with CIS, since two clinical events are not necessary [5,6]. The McDonald criteria were revised in 2005 and specify MRI findings to demonstrate dissemination of lesions in time and space.

However, it is not clear that these criteria are sufficiently sensitive or accurate in patients with CIS to make decisions regarding disease-modifying therapy. A number of studies have evaluated the ability of the original 2001 McDonald criteria [5] to predict which patients with CIS will go on to develop MS.

One study prospectively evaluated 50 patients with CIS by clinical and MRI examinations at three months, one year, and three years of follow-up; the 2001 McDonald criteria were retrospectively applied [7].

  • At three months after the CIS, fulfillment of the 2001 McDonald criteria had a sensitivity, specificity, and accuracy of 59, 93, and 80 percent, respectively, for the development of clinically definite MS at three years
  • At one year, fulfillment of the 2001 McDonald criteria had a sensitivity, specificity, and accuracy of 83 percent each for the development of clinically definite MS at three years [7].

A second similar study prospectively evaluated 139 patients with CIS and retrospectively applied the 2001 McDonald criteria, but is limited by the fact that MRI was performed at one year rather than three months and inconsistently used contrast [8]. Nevertheless, the sensitivity, specificity, and accuracy in predicting conversion to MS (74, 86, and 80 percent, respectively) were similar to the previous report.

Modified MRI criteria 

Modified MRI criteria were proposed in 2006 as an effort to improve upon the relatively low sensitivity (at three months after CIS) of the original 2001 McDonald criteria [9]. The suboptimal sensitivity of the 2001 criteria is related to the stipulation that dissemination in time requires a gadolinium-enhancing lesion on a three-month follow-up MRI scan [5]. Of note, the revised 2005 McDonald criteria accept a new T2 lesion at any time as evidence of dissemination in time when compared with an initial scan performed 30 days from CIS onset [6].

The modified MRI criteria used simpler and less stringent definitions than the original (2001) or revised (2005) McDonald criteria [9]:

  • Dissemination in space requires at least one baseline T2 lesion in at least two of four anatomic regions included in the McDonald criteria: periventricular, juxtacortical, infratentorial, and spinal cord
  • Dissemination in time is satisfied by a new T2 lesion on follow-up MRI at any time after CIS onset, irrespective of the time of the initial scan

When retrospectively applied to 90 patients with CIS and first MRI examination within three months (median 5.5 weeks) of CIS followed by repeat MRI approximately three months after the first, the modified MRI criteria were more sensitive than the 2001 McDonald criteria (77 versus 46 percent), and had a similar specificity (>90 percent for both) for the development of clinically definite MS [9].

In a later study of 208 European patients with CIS who had two MRI scans within one year of CIS onset (the first at a median of 6.2 weeks of onset), the sensitivity for the development of clinically definite MS was higher for the modified MRI criteria than for the 2005 and 2001 McDonald criteria (72 versus 60 versus 48 percent, respectively) [10]. Specificity was similar for all three (87 versus 88 versus 91 percent).


Applying the MRI criteria 

While the specificity of the McDonald criteria is relatively high in patients with CIS, application of the criteria in this setting still leads to a significant number of false positives, which can result in patients needlessly being placed on expensive and potentially toxic life-long therapies. On the other hand, as mentioned, it is now recognized that early treatment of patients ‘at risk’ for MS may decrease disease progression.

The original 2001 McDonald criteria are also often impractical for use in clinical practice, as too few patients have sufficient data to allow precise categorization. As a result, it would be useful to have additional prospective studies demonstrating greater accuracy in patients with CIS.

A European review of evidence regarding strengths and weaknesses of the 2001 McDonald criteria was published in 2004 [11]. This report listed suggestions to improve the practical implementation of the McDonald criteria for using MRI data in patients with ON and other CIS. These observations may assist clinicians and patients in understanding the implications of clinical and MRI data.

  • At the time of diagnosis with ON or other CIS, the likelihood of MS is approximately 50 to 60 percent. At this point, brain MRI can provide a more accurate prediction of the likelihood of MS. An abnormal scan predicts a 60 to 80 percent likelihood, whereas a normal scan predicts a 20 percent likelihood of MS.
  • A T2 and gadolinium-enhanced MRI scan should be performed for patients who opt to have a scan.
  • MS is diagnosed if MRI is performed more than three months after the attack and fulfills the McDonald criteria for dissemination in time and space. (Note that revisions to the McDonald criteria published in 2005 allow for evidence of dissemination in time when a new T2 lesion is detected at least 30 days after the onset of the initial clinical event [6] ).
  • When the criteria for MS are not fulfilled by MRI (whether performed before or after three months since the attack), a repeat T2 MRI between three and six months after the original study has a significant prospect of providing MRI evidence for dissemination in space and time, provided that a new T2 lesion is allowed as evidence of dissemination in time [12].
  • Cerebrospinal fluid examination for oligoclonal bands and evoked potentials may be helpful if the diagnosis is not established by the two initial MRI studies.
  • Repeat MRI scanning beyond the two initial studies is not routinely recommended.
  • In patients with atypical syndromes, appropriate investigations should be performed to seek alternative diagnoses or to find other features of MS. Multifocal or ring enhancing white matter lesions on MRI are particularly suggestive of MS. Identification of spinal cord lesions on MRI adds specificity in differentiating MS from other inflammatory or vascular central nervous system diseases. Evoked potentials and CSF examination for oligoclonal bands should be performed.


Oligoclonal bands 

In patients with CIS, the presence of oligoclonal bands in cerebrospinal fluid may be an independent risk factor for progression to MS. Supporting evidence comes from a study of 415 patients with CIS, that found that the presence of oligoclonal bands was associated with a significantly increased risk of developing clinically definite MS (hazard ratio 1.7, 95% CI 1.1-2.7) [13]. This increased risk was independent of the number of lesions on baseline MRI.

Antimyelin antibodies 

Serum antimyelin antibodies have been studied as potential markers of disease activity and predictors of progression to MS. Although data are conflicting, most of the available studies have found that these antibodies are not associated with an increased risk of progression from a CIS to MS.



Most of the evidence regarding treatment of CIS comes from randomized clinical trials testing beta interferons. In addition, there is limited evidence regarding the use of intravenous immune globulin for this condition.



Accumulating evidence from clinical trials suggests that early treatment with recombinant human interferon beta (IFNB) is beneficial for patients with CIS because it delays the occurrence of a second attack, and therefore the onset of clinically definite MS, for up to two years [14-18]. However, it is unknown whether treatment with interferons prevents or delays disability in patients with CIS.



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) [18]. 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).

Clinical trials 

At least two randomized controlled trials (CHAMPS and ETOMS) have investigated recombinant human interferon beta 1a (Avonex and Rebif) for patients with CIS. One trial (BENEFIT) evaluated recombinant human interferon beta 1b (IFNB-1b; Betaferon/Betaseron) for patients with CIS.
  • The CHAMPS trial enrolled 383 patients who suffered a first acute clinical demyelinating event and who also had evidence of prior subclinical demyelination on brain MRI [14]. During three years of follow-up, patients treated with corticosteroid therapy followed by weekly intramuscular injections of IFNB-1a (Avonex) 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 IFNB-1a (Avonex) 30 mcg in an ongoing open-label extension study called the CHAMPIONS study [19]. Patients initially assigned to IFNB-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 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 and followed them for two years [15]. Significantly fewer patients developed clinically definite multiple sclerosis in the interferon beta 1a group (weekly subcutaneous Rebif 22 mcg) than in the placebo group (34 versus 45 percent) [15]. In addition, the time at which 30 percent of patients had converted to clinically definite MS was significantly longer in the IFNB-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 IFNB-1a treatment significantly reduced the rate of global brain atrophy compared with placebo [16].
  • The BENEFIT trial enrolled patients with CIS (a first demyelinating event and two or more clinically silent brain MRI lesions) from Europe, Israel, and Canada and randomly assigned 292 patients to IFNB-1b (subcutaneous Betaferon 250 mcg every other day) and 176 patients to placebo [17].

At two years in the randomized placebo-controlled trial, significantly fewer patients treated with IFNB-1b had converted to clinically definite MS, a primary outcome measure, than those receiving placebo (28 and 45 percent, hazard ratio [HR] 0.5, 95% CI 0.36-0.70) [17]. 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 a follow-up extension study of BENEFIT that enrolled 89 percent of the 468 patients from the randomized controlled study and maintained blinding to initial treatment allocation, the patients initially assigned to IFNB-1b (ie, the early treatment group) were compared with those who were initially assigned to placebo with the option of starting IFNB-1b after a diagnosis of clinically definite MS or after two years (ie, the delayed treatment group) [20].

Compared with delayed treatment, early IFNB-1b treatment was associated with a statistically significant reduction in the risk of developing clinically definite MS at three years (absolute risk reduction 14 percent). However, the clinical magnitude of benefit in terms of disability progression was small [21]; there was very little change in mean expanded disability status scale (EDSS) scores between first event and last follow-up for both the early (1.52 versus 1.41) and delayed (1.43 versus 1.58) treatment groups [20]. Furthermore, to prevent one patient from developing disability progression of 1.0 on the EDSS, the number needed to treat (NNT) early was 12; to prevent one patient from converting to clinically definite MS, the NNT was 7.


Intravenous immune globulin 

Intravenous immune globulin (IVIG) may also improve outcomes after a first demyelinating event. This was illustrated in a randomized, placebo-controlled study of 91 patients ages 15 to 50 years who had a first well-defined neurologic event consistent with demyelination within 90 days prior to randomization that was confirmed by neurologic examination and brain MRI [22]. The dose of IVIG was 2 g/kg loading dose with boosters (0.4 g/kg) given once every six weeks for one year. The cumulative probability of developing clinically definite MS at one year was significantly lower in the IVIG group compared with placebo (26 versus 50 percent).



The results of these trials support early treatment of suspected MS in 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 may have a greater impact on delaying or preventing disease progression than later treatment, since it now appears that brain atrophy is occurring at the earliest phases of clinical disease. Until the advent of these studies, patients with CIS were typically not offered disease modifying therapy until they progressed to clinically definite MS.



The understanding of clinically isolated syndromes (CIS) suggestive of multiple sclerosis (MS) is rapidly evolving, and treatment options continue to expand. The recommendations given here reflect those made by the American Academy of Neurology (AAN) on disease modifying therapies in MS published in 2002 [23], the European review of the role of MRI in the diagnosis of MS published in 2004 [11], and subsequent developments in therapeutics.


All patients who present with a CIS should have T2 and gadolinium-enhanced brain MRI studies as part of the initial evaluation.
  • If the initial brain MRI is abnormal (with a demyelinating lesion), the likelihood of developing MS is 60 percent, and treatment with a disease modifying agent should be started
  • If the initial brain MRI is normal (no demyelinating lesion), the likelihood of developing MS is 20 percent, and a repeat brain MRI should be obtained between three and six months.
  • If the three to six-month brain MRI is abnormal, treatment with a disease modifying agent should be started.
  • If the repeat MRI is normal, further scanning is not recommended in the absence of new symptoms.



  • For patients with CIS who have an abnormal brain MRI at presentation or within three to six months of the event, we suggest disease-modifying treatment with one of the recombinant human interferon beta (IFNB) agents. This recommendation is in keeping with the AAN guidelines, which state that interferons have been convincingly demonstrated to reduce the attack rate in patients with CIS, whether measured clinically or by MRI [23].

      - Among the interferons, we prefer treatment with recombinant human interferon beta 1a (IFNB-1a) using injections of intramuscular Avonex 30 mcg/week. An alternative is recombinant human interferon beta 1a using subcutaneous Rebif 22 mcg once a week as in the ETOMS trial. Clinicians should be aware that prescribing information for Rebif in the United States recommends initial treatment with subcutaneous injection of 8.8 mcg three times a week, gradually increasing over four weeks to the final recommended dose of 44 mcg subcutaneous injection three times a week. Doses of subcutaneous Rebif should be separated by at least 48 hours.

      - For patients with CIS who are not treated with IFNB-1a, an alternative is treatment with recombinant human interferon beta 1b (IFNB-1b) using 250 mcg subcutaneous Betaferon or Betaseron every other day as in the BENEFIT trial. 


1.                       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.

2.                       Frohman, EM, Goodin, DS, Calabresi, PA, et al. The utility of MRI in suspected MS: Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 2003; 61:602.

3.                       The 5-year risk of MS after optic neuritis. Experience of the optic neuritis treatment trial. Optic Neuritis Study Group. Neurology 1997; 49:1404.

4.                       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.

5.                       McDonald, WI, Compston, A, Edan, G, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol 2001; 50:121.

6.                       Polman, CH, Reingold, SC, Edan, G, et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald Criteria”. Ann Neurol 2005; 58:840.

7.                       Dalton, CM, Brex, PA, Miszkiel, KA, et al. Application of the new McDonald criteria to patients with clinically isolated syndromes suggestive of multiple sclerosis. Ann Neurol 2002; 52:47.

8.                       Tintore, M, Rovira, A, Rio, J, et al. New diagnostic criteria for multiple sclerosis: application in first demyelinating episode. Neurology 2003; 60:27.

9.                       Swanton, JK, Fernando, K, Dalton, CM, et al. Modification of MRI criteria for multiple sclerosis in patients with clinically isolated syndromes. J Neurol Neurosurg Psychiatry 2006; 77:830.

10.                  Swanton, JK, Rovira, A, Tintore, M, et al. MRI criteria for multiple sclerosis in patients presenting with clinically isolated syndromes: a multicentre retrospective study. Lancet Neurol 2007; 6:677.

11.                  Miller, DH, Filippi, M, Fazekas, F, et al. Role of magnetic resonance imaging within diagnostic criteria for multiple sclerosis. Ann Neurol 2004; 56:273.

12.                  Dalton, CM, Brex, PA, Miszkiel, KA, et al. New T2 lesions enable an earlier diagnosis of multiple sclerosis in clinically isolated syndromes. Ann Neurol 2003; 53:673.

13.                  Tintore, M, Rovira, A, Rio, J, et al. Do oligoclonal bands add information to MRI in first attacks of multiple sclerosis?. Neurology 2008; 70:1079.

14.                  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.

15.                  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.

16.                  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.

17.                  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.

18.                  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.

19.                  Kinkel, RP, Kollman, C, O’Connor, P, et al. IM interferon beta-1a delays definitemultiple sclerosis 5 years after a first demyelinating event. Neurology 2006; 66:678.

20.                  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.

21.                  Pittock, SJ. Interferon beta in multiple sclerosis: how much BENEFIT?. Lancet 2007; 370:363.

22.                  Achiron, A, Kishner, I, Sarova-Pinhas, I, et al. Intravenous immunoglobulin treatment following the first demyelinating event suggestive of multiple sclerosis: a randomized, double-blind, placebo-controlled trial. Arch Neurol 2004; 61:1515.

23.                  Goodin, DS, Frohman, EM, Garmany, GP Jr, et al. Disease modifying therapies in multiple sclerosis: Subcommittee of the American Academy of Neurology and the MS Council for Clinical Practice Guidelines. Neurology 2002; 58:169.


Get every new post delivered to your Inbox.

Join 26 other followers