To treat or not to treat? Asymptomatic demyelination

Prof Christopher McGuigan, Consultant Neurologist at St Vincent’s University Hospital, Dublin, delivered an insightful overview of radiologically isolated syndrome (RIS) and multiple sclerosis (MS) during Irish Neurological Association and the Association of British Neurologists Joint Meeting 2023.

He described RIS as one of the many “controversies in MS we like to debate” and began with a clinical scenario. He described a young, healthy male with no history or symptoms suggestive of neuroinflammation, with normal bloods and an unremarkable clinical examination, who was found to have unexpected demyelination on MRI. The patient was diagnosed with RIS when lumbar puncture was positive for oligoclonal bands (OCBs). 

Prof McGuigan went on to say the patient “had the same questions we all have when we see these people” and acknowledged that RIS is both “difficult to define” and raises questions about primary prevention, preclinical MS treatment, and whether preclinical MS is completely asymptomatic or not. “I think we need to be a little bit cautious when we call things like that purely radiologically isolated,” he said, and referenced data suggesting that many people with clinically definite MS attended healthcare professionals more frequently, exhibited changed medication regimes, and experienced increases in anxiety and other issues in the five-to-six-year period leading up to diagnosis. Prof McGuigan went on to discuss the current diagnostic criteria for RIS, and how he anticipated new criteria in future, particularly in view of the recently updated MS criteria and emerging research in the area. 

Sharing findings from a range of datasets, including post mortems, Prof McGuigan described how not all RIS develops into a clinical event. He then examined the major risks for conversion to a demyelinating event, which include being male, aged below 37, and having spinal cord involvement, before noting findings of a 90 per cent risk of developing a clinically significant symptom within two-to-three years if all three risk factors were present. Positive OCBs, gadolinium enhancing lesions, and other risks of conversion were also highlighted. Attendees then received data from an ongoing prospective cohort indicating a 19 per cent probability of conversion within two years; 34 per cent probability at five years; and a 51 per cent probability at 10 years from the index scan at RIS diagnosis.

“That raises the obvious question, if the conversion rates are significant, should we be treating at the RIS stage, at the preclinical, asymptomatic stage to try to improve outcomes? Prof McGuigan asked as he addressed the controversy. “There isn’t much evidence for this,” he noted, but went on to examine the positive data that emerged from the recently published ARISE clinical trial investigating the efficacy of dimethyl fumarate in delaying conversion. “Given the small numbers, I think we have to be very careful interpreting this,” he said, but went on to describe that at 96 weeks, 33 per cent of the people in the placebo group had a clinical event, as opposed to 7 per cent in the treatment group. He also added that results showed no significant impact on MRI activity and there was a high dropout rate in the study. “I do consider treating [confirmed RIS] if I think they are at high risk,” he concluded, before moving on to best practice in the treatment of early, established MS. 

“In MS, there has been an explosion of treatment…. We have up to 19 licenced products we can use and that’s not including the biosimilars… and in the future we have a few clinical trials ongoing on with rituximab… there are new agents coming all the time.” 

Comparing the traditional approach of escalating treatment according to disease progression to commencing a high-efficacy therapy early, and asking “why wait?”. Prof McGuigan discussed the deficiency in available evidence, before referencing recent and emerging data from Scandinavia and other sources, that support the protection of nervous tissue from an earlier stage instead of waiting for a deterioration in function. Advocating an individualised approach, he concluded by saying, “like with RIS, I think we need to tailor our decisions more. One size doesn’t fit all… we as clinicians have to think about the subtleties of what course this patient might be on.”