Assessment of Early Evidence of Multiple Sclerosis in a Prospective Study of Asymptomatic High-Risk Family Members

Abstract

Importance: Subclinical inflammatory demyelination and neurodegeneration often precede symptom onset in multiple sclerosis (MS).

Objective: To investigate the prevalence of brain magnetic resonance imaging (MRI) and subclinical abnormalities among asymptomatic individuals at risk for MS.

Design, setting, and participants: The Genes and Environment in Multiple Sclerosis (GEMS) project is a prospective cohort study of first-degree relatives of people with MS. Each participant's risk for MS was assessed using a weighted score (Genetic and Environmental Risk Score for Multiple Sclerosis Susceptibility [GERSMS]) comprising an individual's genetic burden and environmental exposures. The study dates were August 2012 to July 2015.

Main outcomes and measures: Participants in the top and bottom 10% of the risk distribution underwent standard and quantitative neurological examination, including disability status, visual, cognitive, motor, and sensory testing, as well as qualitative and quantitative neuroimaging with 3-T brain MRI and optical coherence tomography.

Results: This study included 100 participants at risk for MS, with 41 at higher risk (40 women [98%]) and 59 at lower risk (25 women [42%]), at a mean (SD) age of 35.1 (8.7) years. Given the unequal sex distribution between the 2 groups, the analyses were restricted to women (n = 65). When considering all measured outcomes, higher-risk women differed from lower-risk women (P = .01 by omnibus test). Detailed testing with a vibration sensitivity testing device in a subgroup of 47 women showed that higher-risk women exhibited significantly poorer vibration perception in the distal lower extremities (P = .008, adjusting for age, height, and testing date). Furthermore, 5 of 65 women (8%) (4 at higher risk and 1 at lower risk) met the primary neuroimaging outcome of having T2-weighted hyperintense brain lesions consistent with the 2010 McDonald MRI criteria for dissemination in space. A subset of participants harbor many different neuroimaging features associated with MS, including perivenous T2-weighted hyperintense lesions and focal leptomeningeal enhancement, consistent with the hypothesis that these individuals are at higher risk of developing clinical symptoms of MS than the general population.

Conclusions and relevance: Higher-risk asymptomatic family members of patients with MS are more likely to have early subclinical manifestations of MS. These findings underscore the importance of early detection in high-risk individuals.

Trial registration: clinicaltrials.gov Identifier: NCT01353547.

Figure 1. Study Design and Quantitle-quantile (qq) plot

(A) Detailed characterization of neurologically asymptomatic first-degree family members from the Genes and Environment in Multiple Sclerosis (GEMS) cohort who are at the extremes of the risk profile for multiple sclerosis susceptibility. GERS_MS, genetic and environmental risk score; MRI, magnetic resonance imaging; OCT, optic coherence tomography. (B) For a given outcome, the expected p-values (−log10 [p-value]) are shown on the x-axis, and the observed p-values (−log10 [p-value]) are shown on the y-axis. The expected p-values assume a null distribution, with no difference between higher and lower risk participants. The corresponding dark and light grey areas indicate the extreme ranges of the qq-plots as generated by chance, at a threshold of p=0.10 and at p=0.05, respectively. The 90% and 95% confidence intervals were derived empirically by randomly assigning participants to the higher or lower risk group and repeating the analysis 10,000 times. When the distribution of the observed p-values for measured outcomes was taken as a whole, the overall difference between the higher and lower risk participants was unlikely to have occurred by chance (omnibus p=0.0125). For phenotypes where we took measurements from both sides of each participant (e.g., vibratron-II), we used the measurement from the worse side to avoid inclusion of highly correlated phenotypes. For a given outcome, we expect the difference between higher and lower risk participants to be beyond chance if the observed probability is outside the confidence interval and the further to the right. This is the case for Vibratron-II measurements of vibration sensitivity from the worse side (*), which is the great toe on the side with the higher measurement or worse vibration sensitivity. (This is also the case for vibratron-II measurement in left great toe, in the right toe, and the average of the measurement in the left and right great toe; not shown in this plot.) For the vibratron-II measurement from the worse side, we also compared the observed p-value (univariate: 0.0002; multivariate: 0.0078) to the set of minimum p-values, as taken across all measured outcomes, generated from the 10,000 randomly sampled permutations (10,000 minimum p-values), and found an empirical p-value of 0.0016, suggesting that the p-value for this phenotype remains significant after adjusting for multiple testing.

Figure 2. Representative 3-tesla brain magnetic resonance imaging scans

of a neurologically asymptomatic participant from the Genes and Environment in Multiple Sclerosis cohort meeting the 2010 McDonald Criteria for dissemination in space. (A) Lesions typical of multiple sclerosis are seen in the periventricular region on the sagittal T2-weighted FLAIR sequence. (B) The lesions are hypointense on the corresponding T1-weighted sequence. (C–D) A lesion’s central blood vessel is appreciated on the T2*-weighted sequence.

Figure 3. Plots of the vibration sensitivity as quantified by Vibratron-II

comparing the higher-risk (n=20) and lower-risk (n=27) neurologically asymptomatic women from the Genes and Environment in Multiple Sclerosis cohort of first-degree family members. (A) The x-axis indicates the higher and lower risk subgroups according to the genetic and environmental risk score (GERS): women with GERS at the top 10% (High) and bottom 10% (Low) from the Genes and Environment in Multiple Sclerosis Cohort. The y-axis indicates vibration sensitivity in vibration units (vu), which are the amplitudes of vibration and are proportional to the square of applied voltage. Vibration sensitivity threshold was quantified in the right and left great toe separately, and an average measure was calculated. A higher vibration unit indicates worse vibration sensitivity. The p-value represents the univariate comparison between the higher and lower-risk group. (B) A participant with the highest GERS in the study who was diagnosed with MS after the testing is shown in the larger red bubble. The GERS is shown in the x-axis. The y-axis indicates the vibration sensitivity as the average measurement of both great toes. The z-axis indicates the vibration sensitivity as the measurement from the worse side. Of note, the two vibratron measurements do not perfectly correlate in this participant. Higher-risk (H) women are shown in the red bubbles. Lower-risk (L) women are shown in the green bubbles.