Saturday, 20 September 2014

ClinicSpeak: MS phenotypes by MRI

Brain atrophy is ready for prime time: MRIologists need to sort-out the technology. #ClinicSpeak #MSBlog #MSResearch

"The study below divides MSers into four categories based on two MRI metrics; (1) high or low T2 volumes, an integrator of focal inflammation or visible lesions and (2) high or low brain volume, an integrator of MS-related neurodegeneration. Only in the group of MSers with both a high T2 lesion volume and high brain atrophy was their a correlation with EDSS. I think the reason that there was no correlation in the other three groups is because this is a relatively small study with limited power."

"A much larger and more definitive study is Maria-Pia Sormani's meta-analysis  of 13 phase 3 trials with over 13,500 study subjects. She showed a strong correlation between both T2 volume and brain atrophy in year 2 and EDSS progression over 2 years. What is remarkable is that when you combined these two metrics together you got a R-squared value of 0.75; in statistical terms R is the correlation coefficient and R-squared the variance of the correlation. What does this mean? It means that 75% of the variance of EDSS progression can be explained by T2 lesions and brain atrophy in year two. Therefore if you can stop all new T2 lesions forming and normalise brain atrophy rates in year two you will reduce disease progression by at least 75%. This study is very important as it gets to the heart of treating MS effectively; to do so we need to used DMTs that suppress both T2 lesions (focal inflammatory events) as much as possible and also reduce brain atrophy rates to near 'normal' in year 2. In reality there are only three treatments that do this currently, natalizumab, alemtuzumab and bone marrow transplantation.  The other treatments with a significant impact on both T2-lesions and brain atrophy are fingolimod and daclizumab (yet to be licensed), but they are not as effective as the three big guns. Interestingly, interferon-beta-1a (Avonex) is the only drug in the moderate efficacy band that impacts brain atrophy. Why Avonex and not the other interferons do this is an interesting point and may have to do with the fact that Avonex is a pulsed interferon and the others interferon's continuously stimulate the interferon receptor. It will be interesting to see what happens to brain atrophy with pegylated interferon-beta-1a? I suspect it won't have an impact on brain atrophy as it is also an interferon that stimulates the receptor continuously."

"The obvious conclusion of the Maria-Pia Sormani meta-analysis is that if you want to tackle MS head on and treat-2-target of NEDA and prevent end-organ damage you need to be on very high efficacy drugs. The pressing question is can you identify MSers who don't need this aggressive approach? I suspect you can but we will need to incorporate routine brain atrophy measurements into clinical practice. At the moment due  to issues of measurement variability and factors that cause short-term fluctuations in brain volume we can't implement this routinely in clinical practice. However, as I say this I am aware of about 5 MS centres in the world that use brain atrophy in clinical practice. One of these centres is in Prague and when I visited the centre earlier this year I was impressed by the power of their technology. It also made me realise that without brain atrophy measurements some of the less effective therapies are creating a false sense of security. I saw several serial brain MRI series of patients with NEDA (no evident disease activity) that had remarkable brain volume loss over 6-8 years of follow-up. These patients must have ongoing MS activity beneath the surface and are acquiring damage that is not clinically apparent. In other words  the shredder is chewing up their reserve capacity and it is only a matter of time before they present with clinically overt SPMS. As we now have drugs that slow down brain atrophy rates these patients may be eligible for these treatments. Unfortunately, we don't have the evidence that escalating treatment based purely on brain atrophy will be effective or not.  What we need is a clinical trial to test this hypothesis."

Tauhid et al. MRI phenotypes based on cerebral lesions and atrophy in patients with multiple sclerosis. J Neurol Sci. 2014 Sep 6. pii: S0022-510X(14)00579-6

BACKGROUND: While disease categories (i.e. clinical phenotypes) of MS are established, there remains MRI heterogeneity among patients within those definitions. MRI-defined lesions and atrophy show only moderate inter-correlations, suggesting that they represent partly different processes in MS. We assessed the ability of MRI-based categorization of cerebral lesions and atrophy in individual patients to identify distinct phenotypes.

METHODS: We studied 175 MSers [age (mean±SD) 42.7±9.1years, 124 (71%) women, Expanded Disability Status (EDSS) score 2.5±2.3, n=18 (10%) clinically isolated demyelinating syndrome (CIS), n=115 (66%) relapsing-remitting (RR), and n=42 (24%) secondary progressive (SP)]. Brain MRI measures included T2 hyperintense lesion volume (T2LV) and brain parenchymal fraction (to assess whole brain atrophy). Medians were used to create bins for each parameter, with MSers assigned a low or high severity score.

RESULTS: Four MRI phenotype categories emerged: Type I=low T2LV/mild atrophy [n=67 (38%); CIS=14, RR=47, SP=6]; Type II=high T2LV/mild atrophy [n=21 (12%); RR=19, SP=2]; Type III=low T2LV/high atrophy [n=21 (12%); CIS=4, RR=16, SP=1]; and Type IV=high T2LV/high atrophy [n=66 (38%); RR=33, SP=33]. Type IV was the most disabled and was the only group showing a correlation between T2LV vs. BPF and MRI vs. EDSS score (all p<0.05).

CONCLUSIONS: We described MRI-categorization based on the relationship between lesions and atrophy in individual patients to identify four phenotypes in MS. Most patients have congruent extremes related to the degree of lesions and atrophy. However, many have a dissociation. Longitudinal studies will help define the stability of these patterns and their role in risk stratification.


Sormani et al. Treatment effect on brain atrophy correlates with treatment effect on disability in multiple sclerosis. Ann Neurol. 2014 Jan;75(1):43-9. doi: 10.1002/ana.24018. Epub 2014 Jan 2.

OBJECTIVE: To evaluate the extent to which treatment effect on brain atrophy is able to mediate, at the trial level, the treatment effect on disability progression in relapsing-remitting multiple sclerosis (RRMS).

METHODS: We collected all published randomized clinical trials in RRMS lasting at least 2 years and including as endpoints disability progression (defined as 6 or 3 months confirmed 1-point increase on the Expanded Disability Status Scale), active magnetic resonance imaging (MRI) lesions (defined as new/enlarging T2 lesions), and brain atrophy (defined as change in brain volume between month 24 and month 6-12). Treatment effects were expressed as relative reductions. A linear regression, weighted for trial size and duration, was used to assess the relationship between the treatment effects on MRI markers and on disability progression.

RESULTS: Thirteen trials including >13,500 RRMS patients were included in the meta-analysis. Treatment effects on disability progression were correlated with treatment effects both on brain atrophy (R(2)  = 0.48, p = 0.001) and on active MRI lesions (R(2)  = 0.61, p < 0.001). When the effects on both MRI endpoints were included in a multivariate model, the correlation was higher (R(2)  = 0.75, p < 0.001), and both variables were retained as independently related to the treatment effect on disability progression.

INTERPRETATION: In RRMS, the treatment effect on brain atrophy is correlated with the effect on disability progression over 2 years. This effect is independent of the effect of active MRI lesions on disability; the 2 MRI measures predict the treatment effect on disability more closely when used in combination.


  1. Thanks for your post. You mention the three highly effective treatments. Is any work being done to develop even more effective treatments e.g. next generation Alemtuzumab? Will the B cell depleting therapies in the pipeline have similar efficacy?

  2. myprediction is that alemtuzumab is living on borrowed time and other agents will knock it off its perch may anti CD20 will do this.

    1. There is an opinion that anti-cd20 would not be an induction therapy. They see that activity comes back in 6-18 months.

    2. My experience: infusions have been every 6 to 9 months, because fatigue and some symptoms come back. I don't know if this is typical
      How much longer this can continue is a grey area.

    Interesting interview regarding MRI techniques to quantify myelination in MS using water fraction MRI and PET to measure microglial activation. There is also a second part. They discuss phenotypic variation of remyelination, measured by water fraction, to explain the discrepancies between EDSS and MRI. Could be another MRI technique to measure effectiveness of highly effective therapies.

  4. "I am aware of about 5 MS centres in the world that use brain atrophy in clinical practice."

    Would you please list these centers?


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