Progression occurs independent of relapse


Association of Brain Atrophy With Disease Progression Independent of Relapse Activity in Patients With Relapsing Multiple Sclerosis

Alessandro Cagol, MD1,2Sabine Schaedelin, MSc3Muhamed Barakovic, PhD1,2et al

JAMA Neurol. 2022. doi:10.1001/jamaneurol.2022.1025

Key Points

Question  Is disability progression independent of relapse activity (PIRA) in relapsing multiple sclerosis associated with increased rates and specific patterns of brain atrophy?

Findings  In this cohort study that included 516 patients with relapsing multiple sclerosis and 1904 brain magnetic resonance imaging scans, PIRA was associated with significantly increased brain volume loss. With respect to clinically stable patients, patients with PIRA presented an accelerated total brain atrophy, which was particularly evident in the cerebral cortex.

Meaning  The association between PIRA and brain atrophy points at the need to identify insidious disease progression in patients with relapsing multiple sclerosis and to further investigate therapeutic approaches to prevent irreversible brain tissue loss in these patients.

Importance  The mechanisms driving neurodegeneration and brain atrophy in relapsing multiple sclerosis (RMS) are not completely understood.

Objective  To determine whether disability progression independent of relapse activity (PIRA) in patients with RMS is associated with accelerated brain tissue loss.

Design, Setting, and Participants  In this observational, longitudinal cohort study with median (IQR) follow-up of 3.2 years (2.0-4.9), data were acquired from January 2012 to September 2019 in a consortium of tertiary university and nonuniversity referral hospitals. Patients were included if they had regular clinical follow-up and at least 2 brain magnetic resonance imaging (MRI) scans suitable for volumetric analysis. Data were analyzed between January 2020 and March 2021.

Exposures  According to the clinical evolution during the entire observation, patients were classified as those presenting (1) relapse activity only, (2) PIRA episodes only, (3) mixed activity, or (4) clinical stability.

Main Outcomes and Measures  Mean difference in annual percentage change (MD-APC) in brain volume/cortical thickness between groups, calculated after propensity score matching. Brain atrophy rates, and their association with the variables of interest, were explored with linear mixed-effect models.

Results  Included were 1904 brain MRI scans from 516 patients with RMS (67.4% female; mean [SD] age, 41.4 [11.1] years; median [IQR] Expanded Disability Status Scale score, 2.0 [1.5-3.0]). Scans with insufficient quality were excluded (n = 19). Radiological inflammatory activity was associated with increased atrophy rates in several brain compartments, while an increased annualized relapse rate was linked to accelerated deep gray matter (GM) volume loss. When compared with clinically stable patients, patients with PIRA had an increased rate of brain volume loss (MD-APC, −0.36; 95% CI, −0.60 to −0.12; P = .02), mainly driven by GM loss in the cerebral cortex. Patients who were relapsing presented increased whole brain atrophy (MD-APC, −0.18; 95% CI, −0.34 to −0.02; P = .04) with respect to clinically stable patients, with accelerated GM loss in both cerebral cortex and deep GM. No differences in brain atrophy rates were measured between patients with PIRA and those presenting relapse activity.

Conclusions and Relevance  Our study shows that patients with RMS and PIRA exhibit accelerated brain atrophy, especially in the cerebral cortex. These results point to the need to recognize the insidious manifestations of PIRA in clinical practice and to further evaluate treatment strategies for patients with PIRA in clinical trials.

So the way I read this is that people who are worsening clinically have more evidence of brain shrinkage but this appartently is not associated with relapse. I guess one could say that’s interesting but one could also say ” So what”. We have been told that you may have ten lesional events for every clinical attack. So things are going on that are not clinical attacks. I can accept this but one could also say “it’s behind you” because one could say the deterioration will develop over time and the damage may have happened before you look and we have also made the point that damage in the spinal cord may play out with damage in the cortical grey matter in the brain. If you only look in the brain you are unlikey to find the cause.

Key Points

They say “These results point to the need to promptly identify patients with PIRA in clinical practice, because they may benefit from optimized therapeutic regimens. In this context, clinical trials to assess the potential benefit of treatment escalation/induction in patients with RMS and PIRA are warranted.

So what treatment are on offer.

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  • Nice reasoning


    “deterioration will develop over time ”

    This is also true for healthy controls i suppose it makes matters worse for us pwms

  • MD,

    Thanks for this.

    It appears that over the last few years the understanding of MS has unravelled and most of the old thinking has been shown to be incorrect.

    MS was described as autoimmune, but recent research points to ebv as the trigger and perhaps driver of the disease.

    MS was four types (CIS, RRMS, SPMS, PPMS), but is now seen as one disease.

    Progression (neurodegeneration) was a consequence of focal inflammation (relapses), but it now appears that neurodegeneration is there from the start and relapses are just the external immune system’s response.

    This new understanding of the disease should be good news for MSers diagnosed in the future. Surely better treatments which target ebv and tackle the mechanisms (microglia / macrophages) causing neurodegeneration will provide much better patient outcomes. The focus on relapses (a cash cow for pharma) blinded many researchers / neuros from identifying the real MS. Hopefully better imaging techniques and better ways to test drugs which tackle ebv and the mechanisms causing neurodegeneration will come quickly.

    • I think most of the old thinking is people not thinking, not reading and not assimilating
      Howevery, I have to say EBV directed immunotherapy has not been that startling so far and blindly throwing things at it may bring disappointment eg.vaccinating against EBV antigens to prevent infection, when you they possibly do studies in MS where infection has already occurred may not be the right thinng

      Four types now one disease….This is the fault of pharma by making MS an orphan disease (lesss than 200,000 in US) allowed beta interferon to reach people with MS…but it made progression a different entity and so it bites them in the bum as they are having to do trials in relapsing MS and progressive MS. In the US most approved drugs get licence from CIS to progressive (SPMS) MS.

      Neurodegeneration there from the start….whats so surprising about this you only have to read and think. Do not dismiss the damage that relapses do, as shown in natalizumab studies.

      New hope for newly diagnosed…agree but are we going to change treatment approaches….Will Octupus (MS trial) do monotherapies (single drugs as opposed tocombinations)…Early very effective treatment will take achange in mindset

      Better treatments that target EBV….yes but willit stop MS?

      Trageting microglial…yes…but to forget about lymphocytes as an issue I woulddo that

      Relapses a cash cow…..Maye but it has given you twenty licenced treatments….copmare it to morotrneuron disease/Alzheimers….it hasgivenyoutreatmentsforprogressice MS

  • I guess I am to assume that DMT use was not considered and everything mentioned is irrespective of same? Also, what was the dividing line in time, of a relapse and non-relapse? Sometimes it’s pretty slow and masked within what is already there. Is the research, then, suggesting if we stop our relapses we will see NO benefit in atrophy? A lot of people will not like that, at all.

    • The should be benefit because relapses are damaging…so if that is the message it is not a good one

  • Anecdotal evidence but I’ve only had one attack but I feel am becoming cognitively slower. I used to be able to remember in detail if I took my daily pill or not. Nowadays I fumble a bit recalling the days

  • I thought there had been studies/ evidence (from c.2016?) which showed that some treatments (eg Alemtuzumab) normalised rates of brain atrophy? Is that right? And does that held reduce PIRA?



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