Study Offers First Characterization of Patients With Nonspecific Presentations of Multiple Sclerosis

When the 2024 McDonald criteria for diagnosing multiple sclerosis (MS) were released, they allowed for MS to be diagnosed in patients without clinical symptoms typical of the condition but with biomarker evidence of underlying disease — the first time this allowance had been made. “Until the 2024 criteria, the diagnosis required a typical attack — specific neurological symptoms lasting 24 hours or more — or progressive neurological dysfunction over 12 months,” notes Daniel Ontaneda, MD, PhD, a co-author of the 2024 criteria. “The new criteria enable the diagnosis in a set of individuals who previously could not be diagnosed.”

Now, a new study has found that among a group of those individuals — i.e., patients presenting to MS referral centers with either nonspecific symptoms or incidental imaging findings — a full 19% fulfilled the 2024 McDonald criteria. The study, conducted by a group of international MS experts, was published in Neurology (2026;107[1]:e218183).

“A large number of people met the 2024 McDonald criteria for MS who would not have been diagnosed using the previous criteria,” says Dr. Ontaneda, the study’s senior and corresponding author and a neurologist with Cleveland Clinic’s Mellen Center for MS Treatment and Research. “This gives people with MS the opportunity to start therapy at the earliest time, when there is a better chance to delay and prevent disability.”

Boosting diagnostic specificity for patients in a gray zone

The 2024 McDonald criteria are particularly helpful when diagnostic certainty based on symptoms is low, Dr. Ontaneda explains. In patients with symptoms not specific for MS and those with atypical symptoms meeting dissemination in space criteria (lesions in two or more anatomical locations), dissemination in time can now be replaced by one of the following features highly specific for MS:

• The central vein sign, appearing as a thin dark line or dot running through a white matter lesion on magnetic resonance (MR) susceptibility images, signifying inflammatory demyelination around a vein. To fulfill the criteria, at least six such lesions must be present (“Select 6”).
• Presence of oligoclonal bands or increased kappa free light chains in cerebrospinal fluid, indicating evidence of intrathecal immunoglobulin synthesis.
• Development of new lesions, or presence of both active and nonactive lesions.

Prior to this study, the impact of the new criteria on the diagnostic yield of patients with nonspecific presentations had not been studied in multicenter populations. This study was also the first to characterize presentations of patients with nonspecific symptoms for MS.

Study design and findings

This cross-sectional post-hoc analysis used data from baseline visits of participants in the multicenter Central Vein Sign in MS (CAVS-MS) study (NCT04495556). All had been seen at a referral center for suspicion of MS. Eleven North American academic sites participated, including Cleveland Clinic.

Out of 420 participants in the CAVS-MS study:

• 166 (39.5%) had symptoms that were not specific for MS.
• 25 (6.0%) were asymptomatic with incidental imaging findings suggestive of demyelination (radiologically isolated syndrome).

Of these combined two groups (n = 191 patients; mean age of 42 years, 78% female), 36 (19%) fulfilled 2024 McDonald diagnostic criteria at baseline, representing 17% (n = 28) of the group with nonspecific symptoms and 32% (n = 8) of the group of asymptomatic individuals with incidental findings.

Among patients who presented with symptoms not specific for MS, the most common type of symptoms in those who met the 2024 diagnostic criteria were cognitive problems, visual disturbances and nonspecific sensory symptoms. In contrast, nausea/vomiting, pain syndromes, dizziness and bowel/bladder dysfunction were present more commonly in participants who did not meet the 2024 criteria.

“Disturbances in sensation, vision and cognition are commonly present in early MS,” Dr. Ontaneda adds. “These findings suggest that such symptoms, even in the absence of a classic MS attack presentation, reflect central nervous system demyelination.”

Should asymptomatic patients be treated?

Starting MS treatment as early as possible has been a critical strategy since the availability of highly effective disease-modifying therapies. However, now that MS can be diagnosed in a totally asymptomatic patient, some clinicians — and patients — may hesitate to start potent medications that will likely be taken for many decades.

“I counsel my patients that the optimal time to treat MS is before symptom onset,” Dr. Ontaneda says. “But I also consider their MR findings and, ultimately, their risk tolerance. Some opt for a wait-and-see approach.”

Limitations of the findings

Dr. Ontaneda cautions that the study findings are not generalizable to all patients in the community with nonspecific neurological symptoms. Participants in this study were referred to a center for evaluation for suspected MS and thus represented a select population at presentation.

Another limitation is that only baseline data were used; Dr. Ontaneda notes that longitudinal imaging and clinical assessment would help determine whether overdiagnosis is occurring using the new criteria. He says the group is continuing to study the cohort and will soon have 24-month findings.

A philosophical shift

Dr. Ontaneda underscores the importance of the change in thinking behind the 2024 McDonald criteria and how, as this study indicates, it will likely spare many patients from disability by allowing disease-modifying therapy to be started before classic symptoms of MS appear.

“The ability to fulfill the diagnosis of MS based on the presence of specific biomarkers reflects a shift in the 2024 McDonald criteria focusing more on identifying the biological onset of MS,” he concludes. “This change acknowledges that MS likely has a preclinical phase that can be detected and treated.”

Dr. Ontaneda acknowledges the contributions of the study’s first author, Alexandra Scharf, a medical student at Case Western Reserve University School of Medicine working with investigators at the Mellen Center.