ClinicSpeak: asymptomatic MS

When does MS begin? #ClinicSpeak #MSBlog #MSResearch

"The fact that approximately 25% of people who have evidence of MS in their brains when they die are not diagnosed in life, suggests that a large number of people who have ‘pathological MS’ have asymptomatic MS.

Did you know that about 10% of siblings of MSers have lesions on the brain MRI scans that are compatible with demyelinating lesions, when only about 1-in-40 to 1-in-80 siblings of MSers go onto develop MS?
The Canadian paediatric study discussed yesterday shows that when children present with their first clinical attack of MS, or CIS (clinically-isolated syndrome), they already have smaller brains than control subjects. This would indicate that MS has probably been present for awhile, stunting the growth of the brains of these young CISers. The childhood data is compatible with what we know about adult CISers; about 80% of adult CISers have multiple lesions on their brain, at presentation, that don’t enhance with gadolinium indicating that they are old lesions and have been present for months and possibly years. In addition, a large proportion of CISers already have brain atrophy and mild cognitive impairment indicating that they have probably had asymptomatic MS for several years. Why several years? We now know that brain atrophy is a delayed process and takes time to develop; all indicators suggest that brain atrophy in MS that is occurring now, i.e. the next 6-12 months, is probably driven by MS-related focal inflammation that was active more than 12 months ago, and possibly longer. The reason for this brain atrophy lag is that when an axon or neuron dies it takes the brain’s clean-up systems many months to clear the debris from the dying cells, only once the clean-up processes are over do you see end-result or brain shrinkage.

A recently published study from Argentina on CISers also supports MS as having a long presymptomatic phase. All school children do standardised examinations in the last 3 years of school in Argentina. If someone develops CIS after leaving school you can go back and look at their school performance and compare them to matched control subjects. What the Argentinian study shows is that cognitive performance in the last 3 years of school is poorer in subjects presenting with CIS after school compared to appropriately matched control subjects. Academic school performance was worse in subjects the closer their CIS presentation occurred to their final year of leaving school. The effect on academic school performance was noted up to 10 years after leaving school. What this study is telling us is that MS has a long asymptomatic period, that may be as long as 10 years, which affects cognitive ability years before the first clinical attack. This observation is not too dissimilar to the prodrome, called minimal cognitive impairment (MCI), that we observe in people who are destined to develop Alzheimer's disease.

Recent publications in subjects with asymptomatic MS or RIS (radiologically isolated syndromes) supports the observations above. RISers are people who have MRI scans for another reason, for example as part of a workup for chronic headaches, and are found to have lesions on the MRI that are compatible with demyelination. Please note I that I say compatible with demyelination and not MS; MS is a clinical diagnosis and not an MRI diagnosis. RISers are not dissimilar to CISers in that a significant proportion already have brain atrophy and mild cognitive impairment; albeit a slightly lower number (~25%) compared to CISers (~40%).

What all these observations are telling us is that when you present with your first clinical symptoms of MS you have probably had ‘pathological MS’ a lot longer. The advantage that MS has over other autoimmune diseases, for example type 1 diabetes, is that when it presents there is still a lot of brain and spinal cord to protect hence disease-modifying therapies can have an impact on the natural history of the disease. In comparison when someone presents with type 1 diabetes most of the end-organ (beta cells in the pancreas that produce insulin) have already been destroyed by the immune system and hence it is too late for DMTs. This is why my colleagues who are working in the type 1 diabetes field are trying to get DMT trials off the ground in the so called presymptomatic phase of the disease, i.e. before it is too late. I have a similar vision for MS; we need to be able to diagnose the disease in the ‘at-risk’ or ‘asymptomatic’ phase so that we can start treatment even earlier than we are doing now. In other words we need to prevent MS before it manifests clinically. Some of my colleagues doubt we will be able to do this; what do you think?"

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