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Finding what appear to be multiple sclerosis (MS) lesions on an MRI, often incidentally, sets up a conundrum for neurologists in the absence of clinical symptoms.

Radiologically isolated syndrome (RIS), as it is known, could represent the earliest detectable pre-clinical phase of MS, but these lesions could also just be the result of trauma or other processes that would never develop into inflammatory demyelination.

Even when applying radiological dissemination criteria and thoroughly excluding typically vascular explanations, only about half of people with RIS develop symptoms indicative of an MS flare within 10 years, according to one .

"The reality is, we just don't know where the beginning is," John Corboy, MD, of the University of Colorado in Aurora, told MedPage Today.

MS diagnosis requires fulfillment of clinical, radiological, and laboratory criteria without a better explanation by other medical conditions. Only once there are symptoms can an MS label be applied, often initially as clinically isolated syndrome.

Treating clinically isolated syndrome with disease-modifying therapies (DMTs) can delay progression to relapsing-remitting, secondary progressive, or primary progressive MS. "However, even treatment at this early symptomatic phase may not be soon enough given the risk for incomplete recovery and permanent disability," noted Darin Okuda, MD, of the University of Texas Southwestern Medical Center in Dallas, and colleagues writing in the .

They were the first to report on success with DMT for RIS in prevention of clinical MS at a conference in 2022.

Their now-published ARISE trial included 87 patients without clinical symptoms typical of MS but with incidental brain MRI anomalies consistent with central nervous system demyelination who were randomized to double-blind treatment with dimethyl fumarate (Tecfidera, 240 mg twice daily) or placebo.

The drug delayed risk of a first clinical demyelinating event during the 96-week study period by at least 82% (HR 0.18 in unadjusted analysis, 95% CI 0.05-0.63, P=0.007).

ARISE was followed by the 89-patient TERIS trial in which teriflunomide (Aubagio, 14 mg daily) cut risk of a first clinical demyelinating event over 96 weeks by at least 63% compared with placebo (unadjusted HR 0.37, 95% CI 0.16-0.84, P=0.018).

However, an argument against treating RIS by Ide Smets, PhD, of Erasmus Medical Center in Rotterdam, the Netherlands, in the journal , noted that even if DMTs can prevent progression, there are "large uncertainties regarding prognosis both with and without treatment" of RIS.

Perhaps half of people would be treated needlessly for "eternally, at least in a clinically meaningful way, asymptomatic" lesions, she noted. But there are consequences for them.

"At an individual level, treating RIS converts otherwise healthy individuals into patients, the emotional burden of which should not be taken lightly," she wrote. "Most certainly, this contributes to the omnipresence of depression and anxiety among recently diagnosed individuals."

Furthermore, Smets added, "real-world cohorts still need to demonstrate how durable perceived benefit of treatment will be in [people with] RIS choosing to be treated and how it will be weighed against the reality of DMT side effects and DMT-imposed restrictions on family planning or international travel."

She called for finding a better compromise between specificity and sensitivity in labeling "presymptomatic MS."

Rather than a blanket answer, "I think it's, like many things, a little bit more nuanced," agreed Corboy. And the answer "revolves around who is the patient."

He pointed to the highest risk of MS developing in people with RIS is in individuals who are younger, who are male, who not only have brain changes consistent with MS but also have spine abnormalities, and perhaps also those who have abnormal spinal fluid showing the typical findings of MS.

For a typical 50-year-old woman who fulfills the RIS criteria after an incidental MRI finding due to migraine, an examination would be warranted to ensure no prior clinical symptoms and probably imaging her spine. Spinal fluid examination is often done as well, Corboy noted. With a negative spinal fluid result, her likelihood of a clinical attack over 5 or more years is probably around 20%, he said.

"Whereas if they're a male under [age] 37, with spinal cord lesions and spinal fluid abnormalities, their likelihood of going on to have clinical events and then fulfill criteria for MS in the first 5 to 10 years is markedly higher, it's in the probably 80 [percent]-plus range," said Corboy. "And so they're not all the same."

His group is conducting the to identify risk factors for the very early signs of MS to potentially enable intervention before symptoms develop, including MRI scans of first-degree relatives of MS patients along with a look at genetics, immunological markers, and markers of nerve damage.

"Is there an algorithm that we can come up with that would define the very earliest signs on MRI scan consistent with MS and then come up with a screening strategy, just as we screen people with breast cancer for breast cancer starting at age 40?" he posited.

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