Management Approaches in Radiographically Isolated Syndrome

There is increasing evidence that the pathobiology of multiple sclerosis (MS) often begins in advance of clinical symptoms.¹ There have been documented cases of lesions consistent with MS being discovered at autopsy in individuals who had no clinical symptoms during their lifetime.^1,2 Emerging data have shown increased healthcare utilization and elevated serum neurofilament light chain levels (a biomarker of neuroaxonal injury) in people who go on to develop MS up to 5 to 6 years before the clinical onset of disease, suggesting that a prodromal state exists in some individuals as well.^1,3

Radiographically isolated syndrome (RIS) represents a subset of individuals within the preclinical/prodromal MS space; it is diagnosed when a brain MRI conducted for other reasons (like headache, cognitive deficits, or trauma) identifies white matter lesions highly suggestive of demyelination (Figure 1).^1,4,5 RIS provides a serendipitous window into early, preclinical disease and allows for prospective identification of these at-risk individuals.^1,4,5 There has been substantial debate in the field regarding how to define RIS, and its definition has undergone revision in an attempt to increase the sensitivity and specificity of this diagnosis.^4,5

Even for people with unambiguous RIS, substantial challenges exist in determining the best management approach. This mainly stems from the uncertainty surrounding which people with RIS will go on to develop clinical MS, because some of these individuals remain clinically asymptomatic throughout their lifetime.^1,2 There are no established consensus guidelines to assist clinicians in navigating the care of individuals with RIS, but 2 management strategies are often used: (1) a strategy which includes regular MRI scans and clinical surveillance, and (2) a strategy of early disease-modifying therapy (DMT) initiation.^6-8

This review focuses on RIS with the aim of evaluating the current definition, management approaches, and future considerations.

What Is RIS?

RIS was initially defined by Okuda et al⁵ in 2009. At that time, diagnostic criteria required patients to meet stringent parameters, including the presence of incidentally identified central nervous system T2 white matter anomalies that (1) fulfill Barkhof criteria (at least 3 out of 4 criteria for dissemination in space), (2) are ovoid and well-circumscribed, and (3) measure >3 mm.⁵ Such MRI anomalies could not be better accounted for by an alternate disease process, and individuals in whom they were identified could not have a history of clinical symptoms suggestive of a demyelinating attack or progression or a history of clinical symptoms causing substantial functional impairment.⁵ Individuals meeting these criteria were studied in a prospective multicenter cohort (the RIS Consortium), and longitudinal evaluation revealed that these people with RIS had a 13.8% chance of converting to clinically definite MS (CDMS) within a 2-year time period, increasing to 34% at 5 years and 51.2% at 10 years.^9-11 Younger age at the time of RIS diagnosis, presence of infratentorial or spinal cord lesions, gadolinium-enhancing lesions at baseline or follow-up imaging, male sex, and cerebrospinal fluid (CSF)–restricted oligoclonal bands (OCB) were all predictors of converting to clinically definite disease in various studies.^9-11

These risk factors were accounted for in the proposed 2023 revisions to the RIS diagnostic criteria.^4,12 The revised criteria align more closely with the 2017 McDonald criteria (which are used for MS diagnosis) and require a lower burden of radiologic disease.^4,12 In the revised RIS criteria, at least 1 lesion in a typical MS-related location (ie, juxtacortical, periventricular, infratentorial, spinal cord) is required, in association with at least 2 of the following high-risk factors: spinal cord lesions, CSF-restricted OCB, and new T2 or gadolinium-enhancing lesions during follow-up.⁴ The 5-year risk of converting to CDMS from RIS increased from 29% to 38% when baseline spinal cord lesions and CSF-restricted OCB were present.⁴ Clinical factors, such as cognitive dysfunction, have also been proposed as markers of prodromal MS, the presence of which may increase an individual’s risk of converting to CDMS.¹ These factors were not incorporated into the revised RIS criteria, however, because there is substantial ambiguity regarding how to incorporate and test for these nonspecific clinical features.^1,2,12

Management Approaches in RIS

Although many people with RIS ultimately develop clinical disease, not all do, and management decisions are therefore complex.^1,2 Two recent randomized clinical trials illustrated that the use of MS DMTs significantly reduced the likelihood that people with RIS would experience a first clinical attack.^6,7 However, this potential benefit needs to be balanced by the risk of using long-term immunosuppression in young people who lack substantial associated clinical symptoms and may never develop any symptoms.^1,4-7 Consideration of the risk factors noted previously can influence how clinicians approach management decisions.^4,8-12 People with newly identified RIS can be risk-stratified during a thorough workup, including brain and spinal cord MRI scans and CSF analysis.^4,8-12 Obtaining additional ancillary testing with visual evoked potentials and cognitive testing has also been proposed.^2,12

After the initial diagnostic testing, clinicians will typically choose to implement either a strategy of close MRI and clinical surveillance (every 6 to 12 months) or a strategy of early DMT initiation (Figure 2).^6-8 In surveys directed at determining how clinicians manage RIS, 89% of those polled stated that they would not initiate DMT if spinal cord imaging was negative and 88% would opt to perform surveillance MRI scans in conjunction with clinical follow-up, often within a 12-month timeframe.⁸ However, other surveys have shown that 17.8% of individuals with RIS receive early DMT.¹²

Early DMT Use in RIS: Pros

Observational studies have shown that the risk of converting from RIS to CDMS increases over time, especially in individuals with high-risk features.^9-11 The ARISE trial (Assessment of Tecfidera in Radiologically Isolated Syndrome, NCT02739542) demonstrated that using dimethyl fumarate (Tecfidera; Biogen, Cambridge, MA) in people with RIS reduced the risk of a first clinical demyelinating event (unadjusted hazard ratio, 0.18 [95% CI, 0.05–0.63]; P=.007; 82% risk reduction) and the number of new or newly enlarging T2 lesions when adjusted for the number of enhancing lesions at baseline (rate ratio, 0.2 [95% CI, 0.04–0.94]; P=.042).⁷ Likewise, the TERIS trial (Teriflunomide in Radiologically Isolated Syndrome, NCT03122652) demonstrated that using teriflunomide in people with RIS reduced the risk of a first clinical demyelinating event (unadjusted hazard ratio, 0.37 [95% CI, 0.16–0.84]; P=.02; 63% risk reduction) but did not show significant reductions in new MRI lesions or changes in patient-reported outcomes.⁶ Overall, both studies provide prospective evidence supporting early use of DMT initiation in this population; however, there are drawbacks to this approach that limit its widespread implementation (Table).^6,7

Early DMT Use in RIS: Cons

Because individuals with RIS are by definition neurologically asymptomatic, fostering buy-in to long-term immunosuppression can be challenging.^1,2 Collectively, MS DMTs can slightly increase infection risk, and may be associated with other day-to-day side effects.^6,7 An increase in moderate adverse reactions (often infections and musculoskeletal connective tissue disorders) were noted in the dimethyl fumarate group in the ARISE trial (32% vs 21%).⁷ More frequent adverse events (eg, gastrointestinal upset, dysmenorrhea, benign respiratory infections, general disorders or conditions, transient increases in transaminase levels) were also seen in the teriflunomide group in the TERIS trial.⁶ Only 1 participant withdrew from the TERIS trial because of adverse effects, and severe adverse events were similar between the dimethyl fumarate and placebo arms in the ARISE trial, but the increased risk of even mild or moderate adverse effects can be difficult for individuals to accept, given that a proportion of those with RIS will never convert to CDMS.^1,2,4,6,7

Additionally, there can be significant psychosocial stressors associated with the diagnosis of RIS, whether or not DMT is pursued.² The lack of clinical signs and heavy reliance on ancillary testing lead to diagnostic ambiguity, and the uncertainty about whether CDMS will emerge is often a large stressor for individuals that may provoke anxiety and mood disorders.^1,2 This uncertainty also makes committing to early DMT use difficult, especially when these therapies may not be covered by insurance, can affect life decisions (such as pregnancy planning), and lack the support of established treatment guidelines.^1,2,8,12

Conclusion

Despite increasing evidence that RIS usually represents a subset of individuals with preclinical or prodromal MS, uncertainty remains about the best way to approach the diagnosis and management of this syndrome.^1,2,4-12 Future research will need to address how RIS can best be defined in a way that maximizes specificity, while allowing for high sensitivity, and how to ascertain the individuals who are at the greatest risk of converting to CDMS.¹ Innovative ways of screening for preclinical MS also are needed, because RIS is inherently a serendipitous diagnosis and represents only a subset of those who have asymptomatic demyelinating central nervous system disease.^1,2,12 Future clinical trials could explore the use of higher-efficacy DMT for a limited timeframe (an induction approach to therapy). This treatment strategy might help balance the expected benefits and risks of early DMT use in this population.