Early Evidence of Multiple Sclerosis in Asymptomatic High-Risk Family Members

Higher-risk asymptomatic family members of patients with multiple sclerosis (MS) are more likely to have early subclinical manifestations of MS.

In a study published in JAMA Neurology, investigators sought to determine if early evidence of dysfunction in family members at high-risk of MS existed. They hypothesized that neurologically, asymptomatic, higher-risk individuals were more likely to manifest subtle inflammatory demyelination or neurodegeneration.

Included in the study were 100 neurologically asymptomatic Genes and Environment in Multiple Sclerosis (GEMS) project study participants, who traveled to the National Institutes of Health between August 2010 and July 2015 for detailed neuroimaging, laboratory, and neurological examination.

The GEMS project is a prospective cohort study of first-degree relatives of MS, aged 18 to 50 years.

To assess the participants’ risk for MS, the investigators used the Genetic and Environmental Risk Score for Multiple Sclerosis Susceptibility (GERS_MS) that comprised an individual’s genetic burden and environmental exposures.

The 100 study participants at the top and bottom 10% of risk distribution—– who were neurologically asymptomatic at the time of testing––underwent standard and quantitative neurological examination, including disability status, and visual, cognitive, motor, and sensory testing; as well as qualitative and quantitative neuroimaging with 3-T brain MRI and optical coherence tomography.

There were 41 higher-risk patients (98% women) from the top 10% and 59 lower-risk participants (42% women) from the bottom 10%. Due to the unequal sex distribution between the groups, the analyses were restricted to women.

The primary outcome measure of the study was predefined as the presence of T2-weighted hyperintense lesions that met the 2010 McDonald MRI criteria for dissemination in space (DIS). Secondary outcomes were defined as additional MRI measures.

Overall, the results of the study showed differences between higher-risk women and lower-risk women. In a subgroup of 47 women, a vibration sensitivity testing device showed that higher-risk women had significantly poorer vibration perception in the distal lower extremities (P = 0.008).

The investigators also found that 5 of 65 women met the primary neuroimaging outcome of having T2-weighted hyperintense brain lesions. There was a subset of study participants who harbored multiple different neuroimaging features associated with MS, according to the authors. This included perivenous T2-weighted hyperintense lesions and focal leptomeningeal enhancement, consistent with the investigators’ hypothesis.

Some limitations to the study were the analyses were restricted to women; the cross-sectional assessment did not allow for definitive conclusions regarding the sequence of events over time; vibration sensitivity thresholds were generally within normal range for both risk groups; the cohort included slightly older participants because the investigators initially aimed to identify participants with RIS; and qualitative and quantitative clinical and neuroimaging measures used in the study were primarily based on their usefulness in studies of patients with MS and healthy controls.

“Higher-risk asymptomatic family members of people with MS are more likely to have early subclinical manifestations of MS,” the authors concluded. “Findings from this prospective cohort study underscore the importance of early detection in individuals at higher-risk for MS.”