Monday, 30 January 2017

#ResearchSpeak: asymptomatic MS in siblings of MSers

How common is asymptomatic MS in siblings of MSers? #ResearchSpeak #MSBlog

The study below confirms that siblings of people with MS have a high incidence of sub-clinical, or asymptomatic, MS. Almost 1 in 10 siblings of pwMS have MRI features of MS. This confirms the findings of an earlier Sardinian study and other studies demonstrating that siblings of pwMS have early markers of MS. The NIH study only looked women, which will slightly bias the results as MS is commoner on women. 

We did a pilot study similar to this but had too few study subjects to pick-up a definite signal. What do we do with this information? We could use the information to power a prevention study in people at high-risk of MS. But what intervention would we use? Vitamin D? Anti-EBV drugs, for example rituximab or an small molecule antiviral? Should we be screening all siblings of people with MS and diagnosing them in the asymptomatic phase of the disease so we can intervene early with treatments? The latter is problematic as we don't have any evidence that intervening at the asymptomatic phase of the disease alters the long-term prognosis, but I suspect it will based on scientific principles underpinning treat-early and effectively. In addition, the current diagnostic criteria for MS don't allow neurologists to diagnose MS in the asymptomatic phase of the disease. This is important as payers, such as the NHS and health insurance companies, can't pay for treatments for a non-disease. I suspect it is only a matter of time until we extend the diagnostic criteria of MS into the asymptomatic phase. Once we do this we could then start clinical trials in the hope of preventing symptomatic disease later on (1st attack) and further damage.

Please note that if you are a sibling of someone with MS, or you have siblings, who are at high risk of MS you should probably be encouraging them to do what they can to lower  their risk of developing MS. At the moment this advice includes telling them not to smoke and to keep themselves vD replete.

Xia et al. Assessment of Early Evidence of Multiple Sclerosis in a Prospective Study of Asymptomatic High-Risk Family Members. JAMA Neurol. 2017 Jan 17.

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.


  1. "The latter is problematic as we don't have any evidence that intervening at the asymptomatic phase of the disease alters the long-term prognosis."

    Surely if treating early in clinically apparent RRMS improves long term prognosis, treating earlier than this (in the asymptomatic phase) would also improve the prognosis, if not more so?

    1. Yes, I agree with. Based on data in CIS and early RRMS early intervention improves prognosis. But as always we need hard data to assess risk-benefit and cost-effectiveness. How much will the NHS be prepared to spend on saving brain in the asymptomatic phase of the disease. How much risk will individuals take to save brain in the asymptomatic phase of the disease.

      This is an interesting debate to have and will not only play out in the MS space, but with other neurodegenerative diseases such as Alzheimer's disease. Watch this space.

    2. isn't the other side of the coin the prospect of over-treatment?

      i mean it's not all about the NHS is it?

  2. The other problem is if it turns out the sibling has MS mimic markers (and not MS) then to start them on an MS treatment could make things worse.
    Autoimmune diseases run in my family and extended family but I'm the only one with MS.

  3. This study really requires a sex/age control group. The status of the 'normal' population re MRI lesions within this group needs to be examined as there is significant autopsy evidence of MS plaques in as many as 20% of routine autopsies, in the absence of any clinical history.
    (see brief review by CWM Adams in 'Complications and Causes of death in MS' Ch 10 in A colour Atlas of MS, Wolfe Medical 1989.
    It may well be that the pathogenic processes in MS (entirely unknown) are common in geographical susceptible locations, but represent the famous iceberg, chiefly below the surface.

  4. For the moments the doctors should recommend to the siblings vD3 10.000 ui /day

  5. I get very worried because I have 3 sisters, women. In my family autoimmune diseases are not common (parents, uncles, cousins), but between me and my sisters I developed MS after an IM and one of my sisters has hypothyroidism. Since my diagnosis I make them take vi vitamin D3 every day, and at least every 6 months check how the vitamin D rate is in them.

    Now what if the main problem is EBV? How to prevent if not through vaccines?

  6. I was the third in my family diagnosed with MS, I had an MRI after a bout of vertigo and there was demyelination. The vertigo was cured by the physio treating for atypical positional.

    I often wonder what would have happened if I had stayed in London and had not relocated to NYC.

    I started natalizumab 27 months ago then I had no stomach reflexes, last year I had partial reflexes now they are fully returned. I think that I was very lucky.

    I have tried to get my other siblings in an MRI but the NHS doctor wouldn't prescribe, told them higher risk of cancer than MS. Which I think is stupid. I would pay for them to do an MRI privately but they think it not necessary because the neuro said so.

  7. My brother had a brain scan as he collapsed once. The doctors told him he had a lesion on his brain. He has no other symptoms and is fine since this one off collapse which was following a very stressful period. What would you advise re follow up? I have ms as his sister. However I have also read that a lot of the population have lesions which are not a problem.
    I would like to know if he should follow this up. At the time in the hospital they didn't take any action. He lives on continental Europe.

    1. I wish I could get my siblings to get an MRI, however am an Engineer not a doctor. I would recommend annual MRIs to compare against the first baseline MRI scan.

  8. The MS Trust have good information on risk to family members:

    I think worry is very detrimental to health and genes are not the whole story with MS. So, as long as they're well-informed, I'm careful not to give family members the "MS shadow". Besides - I always say - it's never what you worry about that gets you in the end.

  9. I wonder if this trend is solely related to siblings or if it is true for all first-degree relatives -- namely children of MSers.


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