Asymptomatic first-degree relatives of multiple sclerosis patients at high risk for developing the disease were significantly more likely to show subclinical signs of MS than were family members at lower risk, in the Genes and Environment in Multiple Sclerosis prospective cohort study. The findings were published online on Jan. 17 in JAMA Neurology.

The Genes and Environment in Multiple Sclerosis (GEMS) project is the first prospective study of populations at risk for MS and is the first detailed cross-sectional examination of higher-risk and lower-risk family members to date, according to investigators led by Zongqi Xia, MD, PhD , of Brigham and Women’s Hospital, Boston. Although the totality of evidence put together through neuroimaging and numerous clinical tests in the study indicate that individuals with the highest risk for MS have higher risk for the disease than do those with the lowest risk, simple vibration threshold testing gave the best results, Dr. Xia and his colleagues reported.

“Our results further point to a possible sequence of events leading to MS, in which changes in vibration sensitivity may precede the appearance of demyelinating lesions in the brain,” they wrote.

The study involved 100 neurologically asymptomatic adults aged 18-50 years who were first-degree relatives of people with MS who participated in the GEMS project during August 2012 to July 2015. These 100 comprised 41 high-risk participants from the top 10% of a Genetic and Environmental Risk Score (GERS) and 59 low-risk participants from the bottom 10% on the GERS. The GERS included genetic risk factors (HLA alleles and several MS-associated non-HLA genetic variants) and environmental factors, such as smoking status, body mass index, history of infectious mononucleosis and migraine, and vitamin D levels.

However, because 40 of the 41 high-risk individuals were female and 25 of the 59 low-risk individuals were female, the investigators limited the study to the 65 female participants to avoid “attributing any potential difference primarily to the role of sex.”

To help in identifying early signs of MS, the researchers used brain MRI and optical coherence tomography and other measures of neurological function, including the Expanded Disability Status Scale, timed 25-foot walk, Nine-Hole Peg Test, Paced Auditory Serial Addition Test, Symbol Digit Modalities Test, Timed Up and Go, and high-contrast and low-contrast visual acuity (JAMA Neurol. 2017 Jan 17. doi: 10.1001/jamaneurol.2016.5056).

Overall, high-risk women showed more subclinical signs of MS than did low-risk women based on an omnibus test that globally assessed the burden of neurological dysfunction by comparing the overall differences between the two groups when considering all of the measured outcomes (P = .01). However, impaired vibration perception yielded a stronger result; of 47 women (27 high-risk and 20 low-risk) tested in this manner, high-risk women showed significantly reduced vibration perception in the distal lower extremities (P = .008).

One individual in the high-risk group converted to clinically definite MS during the study. Four of the high-risk women had T2-weighted hyperintense lesions that met the 2010 McDonald MRI criteria for dissemination in space, compared with one low-risk woman. The 2016 proposed consensus MRI criteria for MS diagnosis were met by two high-risk women and one low-risk woman. Radiological isolated syndrome occurred in one woman of each group, and there was a single foci of leptominengeal enhancement in three high-risk women and one low-risk woman.

The findings were limited by several factors including the small size, lack of male participants, cross-sectional nature of the study, and the fact that vibration sensitivity thresholds were in the normal range for high-risk and low-risk individuals. However, the researchers wrote that they “plan to confirm the finding of change in vibration sensitivity with a follow-up study,” and they noted that the “study highlights the important need to develop and test more sensitive measures, particularly with biometric devices, to detect subtle subclinical changes early in the disease process.”

The National Institutes of Health and the National Multiple Sclerosis Society supported the study. Some of the authors reported receiving awards from the National Multiple Sclerosis Society, the American Academy of Neurology, and the National Institute of Neurological Disorders and Stroke.


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