Brain atrophy and CIS

MRI lesion load at baseline predicts brain volume loss in the future. #MSResearch #MSBlog

“The following study in CISers shows a link between focal lesion load at baseline and brain atrophy in the future; CISers with the highest lesion count at baseline had the greatest brain volume loss over the next 4 years. This shows that brain volume changes are primed by past inflammatory lesions and indicates that we will need to adjust how we use brain volume changes in clinical trials. We have to take into account the therapeutic lag associated with brain volume changes; i.e. brain volume loss in this year and possibly next year will be primed by inflammatory lesions in the past few years. Why the lag? I suspect it relates to the delayed biological vacuum cleaner; it takes many months to clear up the debris from inflammatory lesions and hence to feed through into brain volume loss.”

“This study is a stark reminder of how much damage may have already occurred prior to the first clinical event (CIS). In the majority of CISers the pathology of MS has been present for many years and explains why so many CISers already have cognitive deficits at presentation. The latter observations are why we have to treat MS early and effectively and if possible suppress all inflammatory activity; zero tolerance with treat-2-target of NEDA (no evident disease activity).”

“On a positive note CISers are lucky in that the disease declares itself early. In comparison PPMSers only get to know about their disease many years later after they have lost their reserve capacity and present with progressive disease. We need to do something about the latter? If only we could get to PPMS in the asymptomatic phase of the disease.”

Epub: Varosanec et al. Longitudinal Mixed-Effect Model Analysis of the Association between Global and Tissue-Specific Brain Atrophy and Lesion Accumulation in Patients with Clinically Isolated Syndrome. AJNR Am J Neuroradiol. 2015.

BACKGROUND AND PURPOSE: The relationship between lesion formation and brain atrophy development in the early phase of multiple sclerosis is unclear. We investigated the association between new lesion accumulation and brain atrophy progression in patients with clinically isolated syndrome over 48 months.

MATERIALS AND METHODS: Patients with clinically isolated syndrome (n = 210) were evaluated with 1.5T MR imaging at baseline and at 6, 12, 24, 36, and 48 months as part of a multicenter observational study of early administration of intramuscular interferon β-1a. Mixed-effect model analyses, adjusted for age, sex, and treatment status, investigated the association between accumulation of contrast-enhancing and T2 lesions and brain-volume percent changes in a 48-month period.

RESULTS: In patients with clinically isolated syndrome, the average whole-brain volume decreased 2.5%, the mean lateral ventricle volume increased 16.9%, and a mean of 7.7 new/enlarging T2 lesions accumulated over the follow-up period. Patients with clinically isolated syndrome who showed greater percentages of change in whole-brain, white and gray matter, cortical, and lateral ventricle volumes over the follow-up period had more severe lesion outcomes at baseline (all P < .007). There were significant associations between decreased individual brain-volume measures at baseline and greater percentages of change during follow-up (P < .05). We found a significant association between the total cumulative number of new/enlarging T2 lesions and the evolution of whole-brain (P < .001), lateral ventricle (P = .007), gray matter and thalamic (P = .013), subcortical deep gray matter (P = .015), and cortical (P = .036) volumes over the follow-up period.

CONCLUSIONS: Lesion accumulation and brain-volume changes occur simultaneously in the early phase of clinically isolated syndrome. More severe lesion and brain-volume outcomes at baseline were associated with greater development of brain atrophy over the follow-up period in patients with clinically isolated syndrome.

About the author

Prof G

Professor of Neurology, Barts & The London. MS & Preventive Neurology thinker, blogger, runner, vegetable gardener, husband, father, cook and wine & food lover.


  • What do the ABN make of this, given their non-committal approach to NEDA/highly effective treatments in the new guidelines?

    How do they reconcile the two?

    • Echo Matt's question. Are UK neurologists blind to this and why is it treated differently in other countries? Are UK neurologists that risk averse, or do they just not have access to the latest research?

      Whatever it is, seems like we are seriously lagging behind in the UK. Why should patients have to do their own research to find out about all the treatments? It's fine for somebody young and internet savvy, but what about those who are not that way inclined? They wouldn't even dream of asking about "highly effective treatments" or NEDA? What chance have they got??

      My close family member got diagnosed with CIS and the neurologist (a top top neurologist) has basically said we have to wait for something else to happen before we can treat and even if we treat all the evidence is that treating CIS makes no difference – he referenced some study or the other, but am not convinced what relevance a 10 year study of old-school drugs on who knows what end-points has on what is available now? Arghh. Rant over.

    • "Are UK neurologists that risk averse, or do they just not have access to the latest research?"
      They would have access to the latest research, whether they bother to read it is another matter. I suspect a huge case of risk aversion on behalf of the majority, in contrast to the good prof G.

  • MD2, ironically by being risk averse, they are taking more risks with the patient's MS.

    Simply, there should be choice given to patients. My experience is that most neurologists will simply not lay out your options. I don't care about ABN guideliness, I would rather have all options. A neurologist should:

    1.) Explain to a patient of how bad MS can get.
    2.) Explain all of the options for treatment.
    3.) Explain the risks of each treatment strategy.
    4.) Let the patient make an informed decision.

    • I agree, it should be up to pwMS to make informed decisions on risk. As you say the risk of being too conservative with treatment can have irreversible negative consequences.

    • It's a wonder why they don't just call the four steps outlined above their guidance. They obviously don't believe patients are sensible enough to make decisions for themselves. The funny thing is that in many other developed countries that is not the case at all.

  • Is it time to stop letting neurologists off the hook as being "risk averse", and call it for what it is? i.e. Blundering incompetence?

    I'm not mud slinging, but really, you've just published a study that says 95% of patients fail on the currently most oft recommended treatments within 10 years. And the response of these luminary geniuses at the head of the field is not to say "Woah – what are we doing? We need to have a serious rethink here", but rather to crack on and release guidelines that say "Good job guys – let's carry on as we are!".

    It's hard to justify a label of "risk averse", when the consequences of their actions are a 95% certainty of failure in controlling the disease. And to quote your infographic at the bottom of this page, this puts me on a course for a life of misery, an early grave, and "a fate worse than death". Doesn't sound very risk averse to me!

    Statistically speaking, this means the ABN are actually backing gambling my ability to walk, think, swallow, have a family life, drive, earn money, avoid early death/suicide/financial destitution, etc., on a bet which has odds of 19:1 against. And that's just within 10 years (god knows how it looks after 20 years).

    To be honest, I wouldn't even stick a tenner on odds like that.

    I'd liken it to your house burning down, and the fire brigade turning up and trying to put the fire out with their breath, because they don't want to risk using the water house on the fire engine in case it gets everything wet.

    You wouldn't call that person risk averse. You'd just call them a muppet. 🙂

    • Absolutely perfectly sums up my feelings.

      It makes me worry that the neurologists don't believe that the drugs they're prescribing work. If that's the case they should say it then consider whether or not the field of MS treatment is for them.

      The brain and spinal cord are obviously pretty much the most complex organs in the body (though the immune system seems to be pretty mysterious too). Why do some treat MS as such a frivolous thing. Offering reassurance to MSers and nothing else will not make the disease go away. As I've heard others say before "there's no such thing as a brain transplant", if you do that you've transplanted the person.

      Either people believe the drugs work or they don't. If they don't believe they work then stand up and say it so that we know who you are, then go and find something that does work. But please let MSers know so that they can make their own decisions. I'm allowed to look after my own money…. I'm absolutely going to make sure I take responsibility for my own health.

    • Prof G,

      Do you think there are different phenotype a of RRMS? Just as say the pattern of a skin condition such as psoriasis differs in pattern between people?

      Are there those with mainly smaller lesions, or a differing lesion ratio between grey and white matter? Is there any evidence for differences between say fewer big lesions and more smaller lesions?

      Thanks for the blog as always

  • Let me see if I understand this…If you start with a heavier lesion load, you end up with more atrophy 4 years later. But they allowed lesions to continue to accumulate in that four-year period. An average of nearly 2/year. If they had stopped disease activity at baseline, would you have still seen the same level of atrophy?

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