Q&A 85: RIS or RRMS? What about PPMS?

Please tell her that both tolebrutinib and fenebrutinib, two new-generation BTK inhibitors, that are in trial to treat primary progressive MS.

Case

Dear Professor,

Life has a way of throwing unfortunate coincidences at us. I am writing to discuss the recent case of a close friend. She is a 40-year-old female currently under observation for suspected demyelinating disease, with a differential diagnosis between Radiologically Isolated Syndrome (RIS) and early Relapsing-Remitting Multiple Sclerosis (RRMS). She is asymptomatic. The lesions were detected incidentally in the context of a fall, which led to a cranial CT scan revealing nonspecific changes. This prompted a subsequent MRI of the brain and spinal cord, during which lesions suggestive of demyelinating disease were identified.

Clinically, she now reports cognitive complaints, and her EDSS is currently estimated at 2. Initial MRI of the neuroaxis (September 2024) revealed lesions suggestive of demyelinating pathology, both cranially and in the spinal cord, including black holes but without contrast enhancement or signs of atrophy. A follow-up brain MRI performed in March 2025 confirmed stability in lesion load, with no new lesions, no enhancement, and persistence of at least ten hyperintense T2/FLAIR lesions with topography consistent with an inflammatory demyelinating process. The T1 hypointensity of several lesions supports axonal injury.

Although oligoclonal bands were absent in the CSF, the kappa free light chain index was significantly elevated (29.03; threshold >7.25), and this result was confirmed by repeat testing in the same sample. Visual evoked potentials (VEPs) were normal, and there are no other clinical or paraclinical findings suggestive of current disease activity. Other serological tests were unremarkable.

Given the radiological findings, axonal damage on imaging, elevated kappa index, and the presence of spinal cord lesions on the initial MRI, the case raises concern for early conversion to clinically definite MS. She recently had a basal cell carcinoma removed, and her father was treated for melanoma.

We would be grateful for your opinion regarding initiating disease-modifying treatment at this stage, considering the patient’s risk profile and the growing evidence supporting early intervention in such cases. I look forward to your opinion regarding the most appropriate management strategy.

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Answers

A differential diagnosis between Radiologically Isolated Syndrome (RIS) and early Relapsing-Remitting Multiple Sclerosis (RRMS) is, in my opinion, flawed. MS is one disease, and RIS refers to the presymptomatic stage of MS….