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. Author manuscript; available in PMC: 2025 Dec 1.
Published in final edited form as: CNS Drugs. 2024 Sep 16;38(12):973–983. doi: 10.1007/s40263-024-01117-9

Early Disease-Modifying Treatments for Presymptomatic Multiple Sclerosis

Burcu Zeydan 1,2, Christina J Azevedo 3, Naila Makhani 4,5, Mikael Cohen 6, Melih Tutuncu 7, Eric Thouvenot 8,9, Aksel Siva 7, Darin T Okuda 10, Orhun H Kantarci 2, Christine Lebrun-Frenay 6
PMCID: PMC11560559  NIHMSID: NIHMS2031689  PMID: 39285136

Abstract

Radiologically isolated syndrome (RIS) is the earliest stage in the disease continuum of multiple sclerosis (MS). RIS is discovered incidentally in individuals who are asymptomatic but have typical lesions in the brain and/or spinal cord suggestive of demyelination. The 2009 and revised 2023 RIS criteria were developed for diagnosis. Presymptomatic individuals who fulfill the 2009 RIS criteria by having 3–4 of 4 dissemination in space McDonald 2005 MS criteria are still diagnosed with RIS using the revised 2023 RIS criteria. In presymptomatic individuals who do not fulfill the 2009 RIS criteria, the revised 2023 RIS criteria target to secure an accurate and timely diagnosis: In addition to (a) having one lesion in two of four locations (periventricular, juxtacortical/cortical, infratentorial, spinal cord), (b) two of three features (spinal cord lesion, cerebrospinal fluid (CSF)-restricted oligoclonal bands, and new T2 or gadolinium-enhancing lesion) should be fulfilled. Among laboratory biomarkers, CSF kappa-free light chain can also increase diagnostic accuracy. Once the diagnosis is confirmed, the established risk factors, including demographics, imaging, and laboratory biomarkers, should be evaluated for symptomatic MS transition and prognosis. Younger age, male sex, increased neurofilament-light chain, CSF abnormality, and the presence of infratentorial, spinal cord, or gadolinium-enhancing lesions on imaging are the main risk factors for transition to symptomatic MS. Two randomized clinical trials showed significant efficacy of disease-modifying treatments in delaying or preventing the development of the first clinical event in RIS. However, because some individuals remain as RIS, it is crucial to identify the individuals with a higher number of risk factors to optimize disease outcomes by early intervention while minimizing adverse events. Discussing each RIS case with an expert MS team is recommended because there is still a lack of clinical guidelines to improve care, counseling, and surveillance.

1. What is Radiologically Isolated Syndrome (RIS)?

Radiologically isolated syndrome (RIS) represents the earliest detectable presymptomatic stage in the disease spectrum of multiple sclerosis (MS), which has been recognized both in adults and children [1, 2]. An individual is diagnosed with RIS if the central nervous system (CNS) imaging of brain and/or spinal cord MRIs obtained for indications other than MS incidentally display lesions characteristic in size, morphology and location of demyelination while the individual does not have any typical clinical symptoms, which can be attributed to a CNS demyelinating disease [1, 3, 4].

Some individuals with RIS remain as RIS without developing any MS symptoms during their lifetime. In contrast, many individuals with RIS develop clinical symptoms associated with MS during follow-up. The latter group may transition to relapsing MS if they develop acute demyelinating clinical attacks. Once individuals with RIS evolve into RRMS, with age, some of these individuals may also enter the progressive phase and become secondary progressive MS (SPMS) throughout the years [5]. However, individuals with RIS may also directly transition to the progressive phase and become primary progressive MS (PPMS) if they show insidious and irreversible worsening of neurological symptoms in the absence of clinically definite attacks. Interestingly but not surprisingly, as progressive symptoms appear, the disease prognosis mirrors what has been described in historical progressive MS cohorts [6].

The RIS phase is a critical window of opportunity to intervene to stop or delay the development of symptomatic MS (relapsing or progressive), particularly in individuals with a higher risk of developing clinical symptoms. However, individuals being symptom-free in the RIS phase understandably complicates the management approach and whether to start treatment or not. Therefore, to improve counseling and care in persons with RIS, the first step is to secure a correct diagnosis of RIS using criteria including specific biomarkers. Once the diagnosis is confirmed, the second step should identify risk factors and predictive biomarkers of symptomatic disease development. The final step is evaluating effective treatment options to prevent or hold disease evolution along with identifying prognostic biomarkers, which can be used successfully in the clinic and standardize the follow-up [7].

2. Updates in the RIS diagnostic criteria

2.1. 2009 RIS diagnostic criteria

The initial diagnostic criteria for RIS in adults date back to 2009 [1, 3, 4] and require the presence of ovoid and well-circumscribed lesions that are >3 mm with or without corpus callosum involvement, which fulfill ≥3 of 4 of the following imaging findings based on McDonald 2005 MS criteria for dissemination in space (DIS)[8]: 1) Nine or more T2 hyperintense lesions or one gadolinium-enhancing lesion, 2) three or more periventricular lesions, 3) one juxtacortical lesion, and 4) one infratentorial or spinal cord lesion. In addition to DIS, 2009 RIS criteria require at least one of the following for dissemination in time (DIT): 1) one gadolinium-enhancing lesion three months after baseline or 2) one new T2 lesion.

The 2009 RIS diagnostic criteria have been validated and can successfully predict transition to symptomatic MS with developing an initial clinical attack in about 1/3 of individuals with RIS at five years [9] and in about half of individuals with RIS at ten years.[10] In contrast, although not validated, in 2017, the MAGNIMS recommendations [11] included McDonald 2017 criteria of DIS and DIT used for MS to be applied in RIS as well [12]. McDonald 2017 criteria for DIS include one or more lesions in at least two of the four suggestive locations: 1) periventricular, 2) juxtacortical or cortical, 3) infratentorial or 4) spinal cord.

2.2. Revised 2023 RIS diagnostic criteria and implications for MS diagnostic criteria

Despite the success of the 2009 RIS criteria, the main shortcoming was that some presymptomatic individuals present with lesions that are highly suggestive of demyelination in size, location, morphology, and distribution, but they only fulfill ≤2 of 4 McDonald 2017 DIS criteria but were excluded in the 2009 RIS diagnostic criteria. This critical observation prompted another natural history study of asymptomatic individuals with white matter lesions characteristic of MS but who do not fulfill the 2009 RIS/2005 DIS criteria. Transition rate to symptomatic MS and the role of previously confirmed risk and prognostic factors have been investigated in this cohort [9, 10, 13]. Consequently, the RIS criteria were recently updated and validated in 2023 [14]. Ultimately the 2009 RIS criteria related to 3–4/4 DIS is still sufficient for diagnosis of RIS as part of the revised 2023 criteria. However, the revised 2023 diagnostic criteria now allow additionally to diagnose those with only 1–2/4 DIS, if they have even 1 lesion and 2/3 additional risk factors. Specifically, individuals who do not fulfill the 2009 RIS criteria can still be diagnosed with RIS if they have 1) DIS: one lesion in one of four locations (periventricular, juxtacortical or cortical, infratentorial or spinal cord) and 2) Two of three additional features: spinal cord lesion, CSF-restricted oligoclonal bands, and DIT: new T2 or gadolinium-enhancing lesion on any follow-up scans. This expands the diagnosis and Figure–1 further highlights this concept graphically. Using the revised RIS criteria, the number of individuals recognized is expected to increase with the improvement in sensitivity while maintaining the specificity [14, 15]. Furthermore, since there is a lack of established guidelines for clinical work-up and follow-up, with this more applicable and relatively less conservative approach of the revised 2023 RIS criteria, it is aimed at identifying presymptomatic individuals earlier to improve care, counseling, and surveillance in RIS and timely enroll these individuals into clinical trials [14, 15]. However, as a word of caution, the authors recommend discussing each potential case with MS experts from tertiary care institutions, as the risk of misdiagnosis with MRI mimics is still high.

Figure 1. Practical diagnosis and management considerations in individuals with RIS.

Figure 1.

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A diagnostic algorithm with a clinical follow-up recommendation, and when to consider treatment in individuals with RIS are illustrated. Both validated and updated diagnostic criteria for RIS, as well as natural history studies with prognostic determinants for RIS and the clinical trials in RIS are utilized to reflect our practical use of the knowledge in clinical practice. The following references have been utilized to construct the figure: * Lebrun-Frenay C, et al. The radiologically isolated syndrome: revised diagnostic criteria. Brain. 2023. ** Polman CH, et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald Criteria”. Ann Neurol. 2005. † Okuda DT, et al. Radiologically isolated syndrome: 5-year risk for an initial clinical event. PLoS One. 2014 and Lebrun-Frenay C, et al. Radiologically Isolated Syndrome: 10-Year Risk Estimate of a Clinical Event. Ann Neurol. 2020, †† Okuda DT, et al. Dimethyl Fumarate Delays Multiple Sclerosis in Radiologically Isolated Syndrome. Ann Neurol. 2023 and Lebrun-Frenay C, et al. Teriflunomide and Time to Clinical Multiple Sclerosis in Patients With Radiologically Isolated Syndrome: The TERIS Randomized Clinical Trial. JAMA Neurol. 2023.

DMT= Disease modifying therapies; Gd= Gadolinium; MRI= magnetic resonance image; RIS= radiologically isolated syndrome

Another important concept to note relates to diagnosis of MS. Because RIS is part of the MS disease continuum and multiple predictive biomarkers are common in RIS and MS, it would be reasonable if RIS diagnostic criteria become part of the upcoming MS diagnostic criteria. However, at its current state, the DIS requirements for McDonald 2017 criteria [12] may not accurately capture every individual with RIS because the revised 2023 RIS diagnostic criteria require minimum of one T2 lesion with additional supportive features. In contrast, the McDonald 2017 criteria require minimum of two T2 lesions with additional features. Conceptually, however, the consensus committee could logically consider incorporating this pre-symptomatic/asymptomatic phase of MS together with symptomatic MS in a harmonized manner.

2.3. Pediatric RIS

As in adults, the risk of MS is significant but also higher in children with RIS, with a 42% risk of transition to MS within two years of the index MRI. However, at this younger end of the age spectrum, children continue to have the risk for misdiagnosis of RIS and MS.[16] In an international study of children with RIS, younger (<12 years) compared to older children and boys compared to girls were less likely to have CSF obtained for diagnostic work-up. To secure the RIS diagnosis, these age and sex differences in the diagnostic work-up support the need for developing consensus guidelines for children with RIS as well [17]. Compared to 2010 MRI DIS criteria, 2005 MRI DIS criteria show higher specificity as they are more stringent, but due to high clinical transition rate in children, 2010 MRI DIS criteria were proposed to be used for RIS in children and to increase accuracy, the additional use of CSF-restricted oligoclonal bands were recommended as it increases the specificity [16].

2.4. Pre-RIS

For individuals who are presymptomatic and present with typical lesions suggestive of demyelinating disease but do not fulfill ≥3 of the 4 2009 RIS criteria, we had introduced the term “pre-RIS” in previous publications [5, 18]. Some of these individuals evolved directly to symptomatic MS and some of them transitioned to RIS forming the basis of the studies that led to the validation and development of the revised 2023 diagnostic criteria for RIS. With the current revised 2023 RIS criteria, this classification has evolved into 1) having ≤2 DIS criteria and having 2) ≤1 of the 3 features: spinal cord lesion, CSF-restricted oligoclonal bands and new T2 or gadolinium-enhancing lesion (Figure–1). We need updated studies to follow the natural history of these patients. However, it is still important to clinically identify and monitor individuals with pre-RIS (Figure–1), considering the ongoing developments in predictive biomarkers and effective treatment options in RIS.

2.4. Differential diagnosis

The 2009 and 2023 RIS diagnostic criteria aim to reliably and accurately diagnose presymptomatic individuals with RIS. However, given multiple mimics of demyelinating disease in adults and children, a careful and comprehensive investigation is always necessary [7]. Other inflammatory diseases such as sarcoidosis, rheumatologic diseases such as systemic lupus erythematosus, and vascular diseases are among the differential diagnoses [7, 19]. In children, infections, metabolic or genetic diseases, and malignancies should also be considered [20]. Moreover, with aging (specifically in adults who are older than 50 years of age), white matter hyperintensities due to ischemic or other pathologies might contribute to diagnostic challenges [19]. However, MR imaging characteristics of white matter lesions often help mitigate these challenges. For instance, white matter hyperintensities that are mostly symmetrical or bilateral subcortical or distributed in the frontal and parietal white matter or very small and punctate are not typical for demyelinating diseases [7]. Additionally, white matter hyperintensities that lack typical features of MS lesions such as being ovoid, located in the corpus callosum, posterior fossa, spinal cord or periventricular regions, having central vein sign or iron rims are most likely not demyelinating in nature [7].

3. Diagnostic, predictive, and prognostic biomarkers of RIS

The natural step to improve RIS management is the identification of biomarkers in RIS. Biomarkers play an essential role in RIS as they help increase diagnostic accuracy, predict MS disease evolution, and prognosticate disease outcomes in individuals with RIS.

3.1. Imaging biomarkers

Several RIS Consortium studies have evaluated risk factors for developing symptomatic disease. In a multicenter group of 451 individuals with RIS, 34% developed clinical events within five years of the first brain MRI scan. Male sex and having spinal cord lesions at baseline were identified as strong predictors of disease evolution in the first 5-year period [9]. In the 10-year follow-up, the sex effect was lost as an independent variable. This highlights the possibility of time and age impact on risk factors such as sex that may need to be better evaluated for future studies.[10]

As a follow-up study, a 10-year risk estimate of a clinical event was evaluated in 277 of 451 individuals [10]. 51% of the individuals developed a first clinical event within ten years of the index MRI. As expected, age under 37 was again identified among risk factors. However, new biomarkers were identified as well. In addition to having CSF oligoclonal band positivity, having infratentorial lesions or spinal cord lesions on MRI at baseline independently predicted the first clinical event. During follow-up, gadolinium-enhancing lesions were another risk factor for a subsequent clinical event. These retrospective data were confirmed in a large prospective RIS Consortium cohort [13].

In addition to transitioning to CIS or RRMS, about 12% of RIS individuals may directly transition to the progressive phase [6] at a similar frequency seen in general MS populations, which is mainly an age-dependent phenomenon [21]. However, in addition to older age; male sex and having spinal cord lesions (100% of all who transitioned) were again identified as predictors of developing primary progressive MS in persons with RIS.

To increase diagnostic accuracy in RIS, central vein sign (CVS) can be used as an effective MRI biomarker because a threshold of ≥6 CVS lesions differentiates RIS from non-MS lesions with a high performance (sensitivity 95%, specificity 83%), which is similar to the CVS performance observed in MS (sensitivity 98%, specificity 83%) [22]. As expected, this shows that perivenous inflammatory demyelination is present in RIS as well. More importantly, the presence of OCB in addition to CVS increases the specificity to 100% for the RIS diagnosis. In another study on CVS in RIS, 19 of 20 participants had ≥6 lesions with CVS, and a significant correlation was found between the proportion of CVS-positive white matter lesions and spinal cord lesions [23]. As the presence of spinal cord lesions is an important predictor factor for symptomatic MS transition in RIS individuals [9, 10], it is suggested that the proportion of CVS positive white matter lesions can be a candidate predictor of transition to MS but this was not confirmed so far [23].

Similarly, lesions with paramagnetic rim sign (PRLs), which display a paramagnetic rim associated with the presence of iron, were evaluated in 28 individuals with RIS using susceptibility-based imaging [24]. 17 of 28 showed at least one PRL and the number of PRLs correlated with spinal cord lesion number. This again raised the possibility of PRLs as a prognostic factor in RIS since it indicates subclinical chronic active inflammation.

Tissue loss in the brain often presents in RIS and precedes clinical transition. As a significant relay with numerous cortical and subcortical connections, the thalamus is a critical location of early neurodegeneration in MS. In a cohort of RIS and age- and sex-matched controls, while total gray and white matter volumes were similar between the groups, the thalamic volumes were lower in RIS [25]. Spinal cord, which is another essential relay of the CNS, was evaluated in a cohort of RIS, RRMS, and SPMS. The cervical spinal cord cross-sectional area was smaller in SPMS compared to RIS. In contrast, it did not differ between RRMS and RIS [26] Moreover, cervical spinal cord cross-sectional areas were similar between RIS and controls [27]. However, at the RIS stage, in addition to thalamic atrophy and lower cortical thickness [28, 29], volume loss is already seen in other regions of the CNS such as cerebellum [30] and whole brain [29].

In contrast, despite early damage and related atrophy in the CNS, the damage seems to be still below the individual’s clinical threshold in RIS, resulting in asymptomatic presentation. The white matter lesions with conventional MRI look identical in RIS and other MS phenotypes. Still, advanced imaging techniques may provide a closer look at the potentially milder level of microstructural tissue damage in RIS. In a study of diffusion tensor imaging (DTI) and resting functional MRI (fMRI), patients with RIS and RRMS had lower fractional anisotropy than controls on DTI. Functional connectivity was similar between RIS and controls but increased in RRMS compared to RIS on fMRI. It was hypothesized that the lack of functional reorganization in RIS may be due to the milder damage in the white matter in asymptomatic individuals [31].

Similarly, in a cohort of RIS and RRMS, the lesion volume and distribution were found to be similar between RIS and RRMS [32]. However, as a reflection of more significant damage to the myelinated fibers, patients with RRMS had lower lesional magnetic transfer (MT) ratio than RIS, especially in the memory and sensorimotor networks. Hence, while macroscopic brain pathology was similar, more subtle changes were detected by MT MRI between RIS and RRMS, showing that the extent of myelin/axonal damage was lower in RIS. This difference in MT ratios was suggested to contribute to remaining below the clinical threshold in RIS individuals. Furthermore, in the same study, the MT ratio values in normal-appearing brain tissues were similar between RIS and controls [32]. In parallel, in the spinal cord, DTI metrics were similar between individuals with RIS and controls [27].

To evaluate the damage beyond white matter lesions in RIS, in another study using DTI, no significant difference was found between RIS and controls in the normal-appearing brain tissue, which implied that the microstructural changes are mostly limited to visible MS lesions in RIS [33]. In the same study, using MR spectroscopy, in RIS and controls, the NAA and NAA/Cr concentrations were similar in the mid-parietal gray matter [33].

3.2. Laboratory biomarkers

The use of laboratory biomarkers helps enhance the risk stratification in symptomatic MS transition [34]. As an essential laboratory biomarker in RIS, abnormal CSF independently predicts the first clinical event in 10 years [10]. The CSF abnormality was defined as having ≥2 unique oligoclonal bands (OCBs) in the CSF and/or IgG index >0.7. The presence of CSF-restricted OCBs was shown as a predictive biomarker of clinical evolution to symptomatic MS both in adults and children with RIS [2, 16, 35], and associated with a shorter time of transition to symptomatic MS [35]. Furthermore, as a potential non-invasive alternative, OCBs were reliably evaluated in tears, which could be used as a potential future method to increase feasibility [36].

CSF kappa free light chain (kFLC), which reflects B-cell activity intrathecally, is an emerging MS biomarker. In a RIS study, although the numbers were small, kFLC index (CSF kFLC/serum kFLC)/(CSF albumin/serum albumin) was identified as a predictive factor for new T2 lesion development in RIS and was suggested as a potential DIT marker to be used in future MS diagnostic criteria, as it is a fully automated and quantitative biomarker performing well or even better than OCBs [37].

As a marker of axonal damage and neurodegeneration, neurofilament light chain (NfL) is another emerging biomarker used in different phenotypes of MS. CSF NfL was found higher in CIS, RRMS, and PPMS than in RIS and controls [38]. Similar to OCB positivity, CSF NfL is an independent risk factor of transition to CIS and MS, and high CSF NfL levels are associated with shorter time to CIS and MS [35]. As a less invasive and more accessible alternative, serum NfL levels are also associated with disease transition in RIS. In a study on US military personnel, serum NfL levels were increased in individuals up to 6 years before first clinical symptoms [39]. Moreover, in a cohort of 61 individuals with RIS, higher levels of NfL at diagnosis both in CSF and serum (CSF NfL >260 pg/mL, serum NfL >5.0 pg/mL) were independent predictive factors of transition to symptomatic MS [40].

Glial fibrillary acidic protein (GFAP) is an intermediate astroglial cytoskeleton protein, and complementary to NfL, it is an emerging potential biomarker of progression in MS. In a study of RIS, the association of imaging metrics with plasma NfL and GFAP levels was investigated [41]. While the correlations with NfL were not significant, plasma GFAP levels were associated with white matter lesions with CVS. Still, T1 black holes and PRLs often reflect chronic inflammation and poorer clinical outcomes in MS. Therefore, plasma GFAP was suggested as a potential prognostic biomarker in RIS.

miRNA, which can be extracted from serum, plasma and CSF, is a novel candidate prognostic biomarker that has been investigated in MS. As small noncoding RNA molecules, miRNAs play an essential role in post-transcriptionally regulating gene expression and consequently in controlling various biological processes [42]. In a small group of 16 RIS individuals, using CSF and plasma samples, a signature pattern of circulating miRNAs was identified in RIS who remained as RIS compared to who transitioned to symptomatic MS [43].

4. Current treatment approach in RIS

The third step to improve RIS management is to optimize treatment decisions by choosing the right RIS individuals to treat promptly (Figure–1). Early use of disease modifying therapies (DMTs) is already recommended in established MS [44] and it successfully leads to decrease in inflammatory activity and a more benign disease course with lower disability [45]. Particularly, in clinically isolated syndrome (CIS), which is the earliest symptomatic relapsing MS phenotype, clinical trials have shown the efficacy of multiple DMTs in preventing or delaying the development of further new lesions and/or relapses [44–56]. These trials using interferon [44–54], glatiramer acetate [55, 56], teriflunomide [57], and cladribine [58] highlighted the importance of early intervention in delaying a subsequent demyelinating event and having better outcomes in individuals who experienced an initial clinical relapse. Moreover, to prevent motor disability worsening, immediate DMT initiation is specifically crucial in patients with CIS presenting without good recovery after the first relapse [45].

In contrast, some individuals with RIS may stay asymptomatic throughout their lifetime. Therefore, committing to a long-term treatment becomes more challenging in these individuals, mainly when safety profiles and potential side effects of DMTs are considered [15]. This concern was partially reflected in physician surveys conducted before any randomized clinical trials were available. A survey was conducted among MS experts from 207 MS centers in the US in 2012 [59]. In a hypothetical person who had incidental white matter lesions in the brain MRI, which were highly suggestive of demyelinating disease, the consensus was first to perform a spinal cord MRI (88%), not to initiate treatment if the spinal cord MRI was normal (89%) and to follow-up with MRI within a year (91%). In another survey with the same RIS case scenario, which was conducted on 233 MS experts in Europe in 2017, similarly, the consensus was not to treat RIS in the absence of additional evidence and to follow up with a brain MRI in 6 months but to treat individuals with spinal cord lesions [60]. Moreover, in both surveys, DMT initiation was more likely to be favored, if new lesions developed during follow-up [59, 60].

Although the initial physician preference of not to treat most individuals with RIS, some individuals with RIS was already introduced to approved DMTs before the randomized controlled trials in RIS were conducted [9]. In the RIS Consortium cohort, 16% (73/451) of individuals were exposed to DMTs such as interferons, glatiramer acetate, fingolimod and natalizumab before a mean duration of 3 years to clinical transition. The risk of having a first clinical event in 5 years was not different between treated and non-treated groups. Although treatment did not show a benefit in delaying the onset of the first clinical event, the decision-making process of the referring providers and RIS individuals was unclear and might have been biased. Therefore, a sufficiently powered randomized clinical trial on treatment in RIS was necessary to resolve the challenges in treatment decision-making.

There are two multicenter, randomized, double-blind, placebo-controlled clinical trials conducted on individuals with RIS: Assessment of Tecfidera in Radiologically Isolated Syndrome (ARISE) [61] and TERIS (Teriflunomide, in Radiologically Isolated Syndrome) [62].

Twelve MS centers in the US were involved in ARISE and individuals with RIS were randomized to dimethyl fumarate (DMF) (n=44, oral, 240 mg, twice daily) or placebo (n=43) for 96 weeks [61]. Time to clinical symptom onset attributable to a demyelinating event within 96 weeks was the primary endpoint of the study. The risk of developing a first clinical demyelinating event in 96 weeks of follow-up was significantly reduced in the treatment group (7%) compared to placebo (33%) (unadjusted hazard ratio (HR)=0.18, 95% confidence interval (CI)=0.05–0.63, p=0.007), which corresponded to an 82% risk reduction in a first clinical symptom onset favoring DMF. Similarly, the number of new or newly enlarging T2 lesions was reduced in the DMF group compared to placebo (HR=0.20, 95% CI=0.04–0.94, p=0.042). The difference in time to a first clinical event remained significant after adjusting for age at diagnosis, sex, MS family history, EDSS, T2-weighted lesion volume, and the presence of gadolinium-enhancing lesions (HR=0.07, 95% CI=0.01–0.45, p=0.005). Moderate adverse events were higher in the DMF group (n=34) compared to the placebo (n=19), with infections and connective tissue disorders being the most likely reasons. In contrast, severe adverse events were similar between the groups. Consequently, ARISE was the first randomized clinical trial that showed the beneficial effect of DMT in preventing or delaying a first demyelinating clinical event and in reducing new and/or newly enlarging T2 lesions in RIS individuals in 2 years.

Twenty-one centers in Europe and Türkiye were involved in TERIS [62]. Individuals with RIS were randomized to teriflunomide (n=44, oral, 14 mg, daily) or to placebo (n=45) for 96 weeks and also were allowed to continue in the randomization arm until week 144, if no symptoms have occurred. The study’s primary endpoint was investigating the time to the first clinical demyelinating event. The risk of developing a first clinical demyelinating event in 96 weeks of follow-up was significantly reduced in the teriflunomide group (8 clinical events) compared to placebo (20 clinical events) (unadjusted HR=0.37, 95% CI=0.16–0.84, p=0.02), which corresponded to a 63% risk reduction in a first clinical symptom onset favoring teriflunomide. Results remained significant with 72% risk reduction in a first demyelinating event, after adjusting for age at diagnosis, sex, MS family history, EDSS, T2-weighted lesion volume, and the presence of baseline gadolinium-enhancing lesions (HR=0.28, 95% CI=0.11–0.71, p=0.007). The beneficial effect of immune intervention in extending the time to a clinical event in RIS, observed in ARISE, was confirmed by the sister study, TERIS, using a different DMT with a different mode of action. Additionally, while transitioning to PPMS was not observed in ARISE within two years, four individuals in TERIS developed PPMS (2 in the treatment arm and 2 in the placebo arm) during the third year. The demographic characteristics of the participants were primarily similar in ARISE and TERIS. However, the TERIS study cohort was more active at baseline compared to the ARISE study cohort, with more active brain MRIs demonstrating Gadolinium-enhancing lesions. This could be partially due to individuals being younger (37.8 years) than ARISE (44.2 years). Moreover, patient-reported outcomes, including fatigue and quality of life, were collected in TERIS but not in ARISE and were not different between the groups.

Another multicenter, randomized, double-blinded clinical trial, CELLO, was designed as a phase 4 study to investigate the effectiveness of ocrelizumab, an anti-CD20 monoclonal antibody, in modifying the disease course and improving long-term outcomes in individuals with RIS identified according to the 2017 MAGNIMS recommendations [63]. However, the slow pace in recruitment resulted in early discontinuation of the study.

RIS is part of the MS disease continuum, but existing trials in CIS and MS are not fully translatable to this unique group of individuals who are not symptomatic. However, as a previously unmet need, in two randomized RIS clinical trials discussed above, DMF and teriflunomide, with a relatively good long-term safety profile, showed efficacy in delaying or preventing a first clinical symptomatic demyelinating event in individuals with RIS. These results may translate to a potential benefit with all DMTs in RIS. Though, it is critical to investigate whether the treatment benefit would persist after two years and identify the RIS individuals who would benefit the most from DMTs. Therefore, more clinical trials are needed in individuals with RIS and potentially pre-RIS.

5. Conclusions

RIS represents the presymptomatic phenotype of MS and stands as the earliest stage in the MS disease continuum (Figure–2). RIS is discovered incidentally, and as individuals with RIS are symptom-free, they may be susceptible to misdiagnosis, considering the presence of multiple imaging mimics of RIS. However, the revised 2023 RIS criteria were introduced to identify RIS individuals more accurately and in a timely fashion.

Figure 2. Example MRI of RIS.

Figure 2.

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A–C Brain T2 FLAIR images display multiple subcortical and periventricular hyperintense lesions. The sagittal view clearly shows several lesions oriented perpendicular to the ventricles (A, B axial, C sagittal). D Brain T1 MPRAGE image displays multiple T1 hypointense “black hole” lesions consistent with axonal loss. E, F Cervical spinal cord T2 images display a dorsal spinal cord lesion at the C2 level (E sagittal, F axial). This individual fulfilled the 2023 RIS criteria and had multiple risk factors for transition to symptomatic MS (younger age, spinal cord lesion on the index scan and CSF-restricted oligoclonal bands). Therefore, she was started on an MS disease-modifying therapy, dimethyl fumarate, and has been stable. CSF= cerebrospinal fluid, FLAIR= fluid attenuated inversion recovery, MRI= magnetic resonance image, MPRAGE= magnetization prepared rapid gradient echo, RIS= radiologically isolated syndrome

Using potential biomarkers, such as lesions with CVS and PRLs, can help avoid misdiagnosis in RIS. The CSF kFLC is another important biomarker that enhances diagnosis. Once the correct RIS diagnosis is secured, the use of established and promising imaging and laboratory biomarkers is critical in estimating the transition to symptomatic MS and predicting prognosis. Individuals with RIS can remain asymptomatic or can more likely develop clinical symptoms (relapses and/or progression) over time. Younger age (<37 years), male sex, having infratentorial or spinal cord lesions, the presence of gadolinium-enhancing lesions, and the CSF abnormality (OCB positivity and/or IgG index >0.7) are significant predictors of transition to the symptomatic MS in 5 to 10 years with increasing risk over time.

Atrophy in CNS regions such as the thalamus can start as early as during RIS, but CNS lesions are often indistinguishable between RIS and other MS phenotypes. However, advanced imaging techniques such as DTI may provide more insight into the potential milder microstructural damage in RIS, which could be linked to being asymptomatic. Among the laboratory biomarkers, in addition to CSF OCB and kFLC, although the data is limited so far, CSF and serum NfL are emerging predictive biomarkers, and serum GFAP, as well as miRNA, may be promising in the prognostication of RIS.

Two multicenter, randomized, double-blind, placebo-controlled clinical trials were completed in RIS: ARISE (from the US, DMF) and TERIS (from Europe and Türkiye, teriflunomide). The risk of developing a first clinical demyelinating event in 96 weeks, the primary endpoint in both studies, was significantly reduced in the treatment group compared to the placebo in ARISE using DMF. The same endpoint was replicated and confirmed in TERIS using teriflunomide. A phase 4 clinical trial (CELLO, ocrelizumab) on RIS was discontinued early.

The clinical trial results are encouraging because two different DMTs with different modes of action effectively delayed or prevented the first clinical event in 2 years in RIS with similar adverse event rates. Key steps to optimize management include applying the most current RIS criteria to refine diagnosis, comprehensively evaluating risk factors for symptomatic MS transition, and utilizing the established biomarkers to estimate prognosis. These require discussing the diagnosis and management strategies with an expert MS team.

Key points:

  • Radiologically isolated syndrome (RIS) is the presymptomatic stage of multiple sclerosis (MS) and in addition to the 2009 RIS criteria, the revised 2023 RIS criteria aims to secure an accurate and timely RIS diagnosis.

  • In the management of RIS, the established risk factors, including demographics and imaging and laboratory biomarkers, should be evaluated to predict symptomatic MS transition and prognosis.

  • Two randomized clinical trials showed significant efficacy of disease-modifying treatments in delaying or preventing the development of the first clinical event in RIS.

Funding:

Burcu Zeydan receives funding from National Institutes of Health [U54 AG044170 and K12 AR084222].

Conflicts of Interest:

Burcu Zeydan is the recipient of the Mayo Clinic Eugene and Marcia Applebaum Award and the Radiology Research Award. Mikael Cohen has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen, Merck, Sanofi, Roche, Celgene-BMS, Janssen, Alexion, Horizon Therapeutics and Ad Scientiam. Eric Thouvenot received consulting and lecturing fees, travel grants or unconditional research support from the following pharmaceutical companies: Actelion, Biogen, BMS, Merck, Novartis, Roche, Teva pharma. Rest of the authors did not report disclosures.

References

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