Back to school: Does one new MRI lesion matter?

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Although neurologists love to brag about their ‘fingerspitzengefühl’, pwMS will have experienced that the clinical examination is only a smokescreen for what really determines clinical management: brain imaging. Especially during the COVID-19 pandemic, MRI was our germ-free way into an MS brain. The goal of requesting an MRI is to compare the number and volume of MS lesions with the previous scan. If new lesions appear or when lesions grow over time, that’s an indication of active disease. From “once upon a time”, we know that 5-10 lesions on MRI correlated with one clinical event.

In MS, there are two “schools”: 

First, you have the school of NEDA which is the abbreviation of ‘No Evidence of Disease Activity’. NEDA is defined by having 1) no clinical relapses, 2) no new MRI lesions, and 3) no clinical worsening. The goal of treating pwMS is to achieve a radiologically and clinically stable disease. This means that if at least one convincing new MRI lesions is present, this is an indication to escalate treatment, and to move upwards on the DMT ladder towards a more immune suppressive drug or to move horizontally (if upwards is not possible for whatever reason) to a DMT with a different mode of action. The location and size of the lesion does not matter for the ultimate decision. 

Second, you have the school of MEDA which is the abbreviation of `Minimal Evidence of Disease Activity’. The goal of treating pwMS is to suppress inflammation but not to knock it down. This school will only respond to the presence of 2 or more MRI lesions on MRI. If one new lesion appears while being on treatment, you are most likely to continue with the same DMT over the next year. For many neurologists, there are some MEDA modifiers in clinical practice. Large lesions are less likely to be tolerated. Lesions in the cervical cord or cerebellum are less likely to be tolerated. On the other hand, two small new lesions are more easily tolerated. Of note, both large and spinal cord lesions are more likely to be symptomatic and thus giving rise to clinical symptoms.

When an interval scan shows two or more new lesions, it is mostly crystal-style clear that any DMT you are currently using is not controlling the inflammation and that switching DMT gear is essential.  But what if there is only one small or medium new lesion. And what if it’s located in a region of the brain that is mainly involved in information processing such as the frontal brain regions. Lesions in these regions do not give rise to weakness or numbness in arms or legs; they make you mentally and physically slower. 

Photo by Dan-Cristian Pădureț on Unsplash

How do you choose between these schools? Well, it depends on how you calibrate the available evidence. 

In a longitudinal follow-up study, researchers assessed the risk of reaching an EDSS of 6 (= needing a walking aid) after starting interferon-beta or glatiramer acetate based on the presence of MRI lesions/relapses. At follow-up, 148/1036 (14.3%) patients reached EDSS 6: 61/685 (8.9%) with low score (no relapses and <3 new T2 lesions), 57/241 (23.7%) with medium score (no relapses and ≥3 new T2 lesions) and 30/110 (27.3%) with high score (relapse and ≥3 new T2 lesions or ≥2 relapses)) after the first year of treatment. In the low score subgroup, the risk was further reduced in the absence of contrast-enhancing lesions. NEDA and low score in the absence of contrast-enhancing lesions shared the same risk (8.1 vs. 15.4%). 

The first key issue to interpret this study relies on whether you think the lesion cut-offs that are used in this study (less than three, more than three) are chosen arbitrary or are biologically relevant boundaries. In other words: Do you think the induced brain damage done by one or two focal inflammatory lesions is ‘benign’ whereas the brain damage done by three or more is not anymore? 

The second key issue to interpret this study relies on whether you consider EDSS as a useful outcome marker in MS. Do you feel that an outcome marker which is heavily biased towards ability to walk accurately covers the extent of disability among pwMS? Or do you think that a composite outcome marker such as NEDA, but also NEDA+ versions incorporating for example cognitive measures, upper limb function, neurofilament levels, brain volume data, … would allow more lesion granularity? Another recent study by the same group showed that even when people reach ordinary NEDA in the first two years after treatment (IFNB or GA), one in four pwMS still showed disability progression 12 years from now. So also NEDA is most likely insufficient as a treatment target. 

The devil’s advocate now arguments that by being too stringent and applying NEDA targets in clinical practice almost all pwMS will end up on second or third line therapy which exposes them unnecessary to the risks of immune suppression. This is a fair argument. The contradiction is, however, that first line therapies such as Tecfidera/Aubagio/Fingolimod/Ozanimod are chronically immune suppressive because there is no end date when you can officially stop them. Second line more efficacious therapies such as Mavenclad and Lemtrada are immune reconstitution therapies which you only use for two consecutive years whereafter you are still protected from recurrent disease activity and are monitored solely with clinical examination and MRI. And this is most likely also the future for Ocrevus.

Are you in team MEDA or NEDA?

Twitter: @SmetsIde

Disclaimer: Please note that the opinions expressed here are those of dr. Ide Smets and do not necessarily reflect the position of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust.

JNNP 2020 Mar;91(3):271-277.doi: 10.1136/jnnp-2019-322348. Epub 2020 Jan 23.

Minimal evidence of disease activity (MEDA) in relapsing-remitting multiple sclerosis

Luca Prosperini 1, Chiara Mancinelli 2, Shalom Haggiag 3, Cinzia Cordioli 2, Laura De Giglio 4 5, Nicola De Rossi 2, Simonetta Galgani 3, Sarah Rasia 2, Serena Ruggieri 3 4, Carla Tortorella 3, Carlo Pozzilli 4 6, Claudio Gasperini 3

  • PMID: 31974130
  • DOI: 10.1136/jnnp-2019-322348

Abstract

Objective: This study aimed to define the minimal evidence of disease activity (MEDA) during treatment that can be tolerated without exposing patients with relapsing-remitting multiple sclerosis at risk of long-term disability. Methods: We retrospectively collected data of patients followed up to 10 years after starting interferon beta or glatiramer acetate. Survival analyses explored the association between the long-term risk of reaching an Expanded Disability Status Scale≥6.0 and early clinical and MRI activity assessed after the first and second year of treatment. Early disease activity was classified by the so-called ‘MAGNIMS score’ (low: no relapses and <3 new T2 lesions; medium: no relapses and ≥3 new T2 lesions or 1 relapse and 0-2 new T2 lesions; high: 1 relapse and ≥3 new T2 lesions or ≥2 relapses) and the absence or presence of contrast-enhancing lesions (CELs). Results: At follow-up, 148/1036 (14.3%) patients reached the outcome: 61/685 (8.9%) with lowscore (reference category), 57/241 (23.7%) with medium score (HR=1.94, p=0.002) and 30/110 (27.3%) with high score (HR=2.47, p<0.001) after the first year of treatment. In the low score subgroup, the risk was further reduced in the absence (49/607, 8.1%) than in the presence of CELs (12/78, 15.4%; HR=2.11, p=0.01). No evident disease activity and low score in the absence of CELs shared the same risk (p=0.54). Similar findings were obtained even after the second year of treatment.Conclusions: Early marginal MRI activity of one to two new T2 lesions, in the absence of both relapses and CELs, is associated with a minor risk of future disability, thus representing a simple and valuable definition for MEDA.

Neurol Neuroimmunol Neuroinflamm 2021 Aug 9;8(6):e1059.doi: 10.1212/NXI.0000000000001059.

Prognostic Accuracy of NEDA-3 in Long-term Outcomes of Multiple Sclerosis

Luca Prosperini 1, Serena Ruggieri 2, Shalom Haggiag 2, Carla Tortorella 2, Carlo Pozzilli 2, Claudio Gasperini 2

  • PMID: 34373345
  • PMCID: PMC8353667
  • DOI: 10.1212/NXI.0000000000001059

Free PMC article

Abstract

Background and objectives: To estimate the proportions of patients with relapsing-remitting multiple sclerosis who despite achieving the no evidence of disease activity-3 (NEDA-3) status in the first 2 treatment years experienced relapse-associated worsening (RAW) or progression independent from relapse activity (PIRA) in the following years. Methods: We selected patients with NEDA-3-defined as no relapse, no disability worsening, and no MRI activity-in the first 2 years of either glatiramer acetate or interferon beta as initial treatment. We estimated the long-term probability of subsequent RAW and PIRA (considered as 2 contrasting outcomes) by cumulative incidence functions. Competing risk regressions were used to identify the baseline (i.e., at treatment start) predictors of RAW and PIRA. Results: Of 687 patients, 224 (32.6%) had NEDA-3 in the first 2 treatment years. After a median follow-up time of 12 years from treatment start, 58 patients (26%) experienced disability accrual: 31 (14%) had RAW and 27 (12%) had PIRA. RAW was predicted by the presence of >9 T2 lesions (subdistribution hazard ratio [SHR] = 3.92, p = 0.012) and contrast-enhancing lesions (SHR = 2.38, p = 0.047) on baseline MRI scan and either temporary or permanent discontinuation of the initial treatment (SHR = 1.11, p = 0.015). PIRA was predicted by advancing age (SHR = 1.05, p = 0.036 for each year increase) and presence of ≥1 spinal cord lesion on baseline MRI scan (SHR = 4.08, p = 0.016). Discussion: The adoption of NEDA-3 criteria led to prognostic misclassification in 1 of 4 patients. Different risk factors were associated with RAW and PIRA, suggesting alternative mechanisms for disability accrual.

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Ide Smets

19 comments

  • Really interesting post Ide. I’m sure that there should be a wider consideration than just lower limb function given to pwMS. I’m probably NEDA3 but I’m much older and
    haven’t been on any DMTs. My concern is BVL.

    • Agree, and unfortunately MEDA and NEDA do not specifically take this into account (yet). Classic NEDA is actually already outdated, and would need to be expanded with OCT for example.

  • What do you mean when you say Ocrevus treatment is going the same way as the IRT? ‘This is most like the future with Ocrevus’

    Interesting article thank you. Perhaps explains the difference in neurologists management.
    EDSS rubbish- aside from being narrowly focused it is very subjective.

  • Another recent study by the same group showed that even when people reach ordinary NEDA in the first two years after treatment (IFNB or GA), one in four pwMS still showed disability progression 12 years from now. So also NEDA is most likely insufficient as a treatment target.

    Its not NEDA fault maybe its starting (IFNB or GA) thats the problem

    Nice post

    • I thought that Prof G was of the view that smouldering MS was the real MS and started first ie something is going on in the brain / CNS (?virus) which results in tissue damage. The external immune system kicks off when it realises that something is going on in the brain / CNS and this results in focal inflammation / lesions. I think Prof G argues that focal inflammation / lesions are not the real MS as:

      – despite shutting down all focal inflammation / lesions, damage continues to accumulate in the brain / CNS;

      – MS is one disease. It’s a progressive disease from the start. The key difference is that in RRMS the external immune system gets involved.

      This is my interpretation of Prof G’s theory / argument.

      If we are ever to get on top of this disease, the key question to answer is what is going on in the brain / CNS which damaged tissue. Perhaps the Sizomus trial will shine some light on this ie is it plasma cells that are causing damage in the brain / CNS?

      I would be interested in Ide’s view on what is the real MS ie what comes first.

      • I think the initial trigger is inflammation, but it immediately from the outset incites also a degenerative process. So although the trigger is inflammation, the consequence is indeed degeneration/progression/worsening/accelerated ageing or whatever you would want to label it. Therefore immunosuppressive drugs on their own will never be sufficient to treat/cure pwMS.

        • Ide,

          Thank you for your response. I think many of the leading MSologists are coming round to the view that MS in one disease and that progression / neurodegeneration is there from the start. What we desperately need are drugs to address the neurodegenerative mechanisms in the CNS.

    • The resolution of the MRI’s we use in clinical practice is overall not sufficient to demonstrate whether a lesion is smouldering. But integrating disappearance of smouldering lesions in NEDA would definitely be a good idea – once technically possible.

  • >Another recent study by the same group showed that even when people reach ordinary NEDA in the first two years after treatment (IFNB or GA), one in four pwMS still showed disability progression 12 years from now.

    I am actually surprised it’s only 25%. That’s better than I would have expected. As to NEDA vs. MEDA, obviously NEDA. How can any amount of tissue damage in the brain or spinal cord be considered benign? Would any neurologist accept MEDA as a treatment target for their own brain? I doubt it.

    • This is indeed better than suspected but these data come from an observational 2-center single city (Rome) cohort study which is a study design that is always prone to inclusion and reporting bias. Of note, only in three pwMS in this study actually reached NEDA in the first two years of treatment with IFNB.

  • Nice Post Ide, thank you!

    We talk about a toxic environment the CNS becomes after the initial onset of the disease, worsened with each new lesion/relapse.

    Is there any biomarker to quantify the quality of CNS environment? Number of lymphocytes? Inflammation markers? (Other than NfL?)

    Anything we can do to modify the enviounment?

    • Oligoclonal bands and especially disappearance or reduction in number of oligoclonal bands after treatment is definitely also a promising treatment target reflecting CNS inflammation

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