ClinicSpeak: wait too long and the horse may have already bolted…..treat early

How long should we wait before trying to switch off  the shredder? #ClinicSpeak #MSBlog #MSResearch

“MRI as a tool has matured and is now being used to look at the integrity of the brain and spinal cord. One method is diffusion tensor imaging, which is able to map the diffusion of water molecules in space. In the case of a white matter, or nerve fibre, tract this water diffusion should only be in one direction; the direction that the nerve fibres run in. Using DTI you can assess the anatomy of the fibre tracts and their structural integrity. If you have a disease that cuts, or shreds, fibre tracts such as MS you can assess the extent of damage using DTI.”

“This study below shows quite clearly that fibre tracts are damaged (shredded) very early in the course of MS and the damage gets worse with time. This is not a new observation. We know from numerous other studies that in most MSers, MS begins many years before the first clinical attack. Therefore to maximise brain health and brain integrity we really need to stop the shredding as soon as possible. This is why we continue to push the early effective treatment paradigm. Why wait for damage to get worse before treating this disease?”

“In the past the ABN guideline on treating MS stated that we should only treat CISers if they had 9 or more T2, or Gd-enhancing, lesions on their MRI. What is the difference between a CISer with only 2 T2 lesions on their baseline MRI study and a CISer with 17 T2 lesions on their baseline MRI scan? The latter CISer, with more lesions, is likely to have been unlucky and have had the disease longer and it is only now that his/her disease has declared itself. In comparison the person with 2 T2 lesions is lucky and in that their disease has declared itself much earlier and therefore has more to protect. This does not mean we shouldn’t treat the person with the high lesion load, it simply to make the point is why would we want to wait for the person with a low lesion load to acquire more damage (more lesions), and lose neuronal reserve, before we tried to suppress their MS disease activity? This study below supports this early treatment approach. Do you agree or disagree?”

Asaf et al. Injury to white matter tracts in relapsing-remitting multiple sclerosis: A possible therapeutic window within the first 5 years from onset using diffusion-tensor imaging tract-based spatial statistics. Neuroimage Clin. 2015 Apr 30;8:261-6.

Background: DTI (diffusion tensor imaging) studies in multiple sclerosis (MS) reveal white matter (WM) injury that occurs with disease progression. 

Aims: In the present study we aimed to elucidate the relationship of microstructural WM damage in patients with varying periods of disease duration. 

Methods: DTI scans were acquired from 90 MS patients and 25 healthy controls. Patients were grouped to short (<1 year), moderate (1 up to 6 years) and long (6-10 years) disease duration periods. Statistical analyses of the fractional anisotropy (FA) data were performed using tract-based spatial statistics (TBSS). 

Results: Whole-brain skeletal FA measurements showed a significant decrease between healthy controls and the short MS disease duration group, as well as between moderate disease duration and long disease duration groups, but failed to show a significant difference between short and moderate disease duration groups. Voxelwise analysis revealed clusters of diffuse FA reductions in 40 WM tracts when comparing healthy controls and MS short disease duration group, with the point of maximal significant difference located in the left inferior longitudinal fasciculus. Comparing short with long disease duration groups, progressive FA reduction was demonstrated across 30 WM tracts, with the point of maximal significant difference migrating to the body of the corpus callosum. 

Conclusions: A non-linear pattern of WM microstructure disruption occurs in RRMS. Alterations are seen early in the disease course within 1 year from onset, reach a plateau within the next 5 years, and only later additional WM changes are detected. An important period of a possible therapeutic window therefore exists within the early disease stage.

18 thoughts on “ClinicSpeak: wait too long and the horse may have already bolted…..treat early”

  1. When I was first diagnosed my neuro wouldn't put me on DMT because "many people don't have another attack for many years". He said he wants to "wait and see".The question there is wait and see what? Wait and see if I get more irreversible damage? Wait and see if I end up in a wheelchair, at which point it's too late to do anything about it?In the meantime, I picked up 2 more lesions and new symptoms. And even then, more "wait and see" from him as I had "mild MS" by his standards – despite going from 0 to 8 lesions in the space of a year.Rubbish.

  2. This study below supports this early treatment approach. Do you agree or disagree? Prof G – sometimes your questions leave me speechless. Do you think my answer is going to be – no, I don't agree I'd prefer to loose lots of brain tissue and start on an ineffective treatment. The problem isn't with patients, it's neuros. Recently a friend called to say that her brother in law had been dx with rrms. I sent him an email sharing my experience of Lemtrada and suggesting that he discussed highly effective treatments with his neuro. A month or so later he contacted me to say the neuro had started him on copaxone. The neuro is an ms specialist in a London hospital. Surely these neuros see what happens 10-15 years down the line!

    1. I agree Prof G often preaches to the converted, but I think his target audience may not be us but some of the neuros who occasionally read this blog.

  3. There's a lot of people who find many lesions on first scans as like you say the disease has been present for many years. Rightly so you comment that the horse may already have bolted, but what about those that are seen with one lesion or no lesions but obvious signs of Ms, only to be told there's not enough 'evidence'These people have a chance to get ahead of the game but are told all to often to 'wait and see' there has to be a better approach than this surely. If inflamation could be stopped in this case then the chances you would think would be even greater for neda.How do you propose catching the horse before its bolted. And sadly I think due to be nature of Ms, those who care are those whose horse has long bolted and those who should care are blissfully unaware of it all

    1. Re: "How do you propose catching the horse before its bolted."We have a research programme called Predict-MS, which has sadly stalled when the scientist in our group leading on it had to leave suddenly. I am hoping to reactivate Predict-MS this year, but will have to start rebuilding the project from scratch as some of the work underpinning it needs to be repeated. However, I am part of an International consortium looking into this issue.

    2. Is predict Ms bio markers or based on sylptoms and clinical examsI think from reading the comments above you can see we're all in agreement, and the anon comment regarding target audience may be correct.But how do you or patients approach these neuros? Is it a demand for a higher efficacy drug or the threat to use a different neuro which slows the process anywayAnd then with PPMS it's even worse, there are no rreatmwnts no optionsI asked earlier about your sodium channel blocker theory, would you Prof G suggest anyone showing neuralgic pain try a sodium channel blocker for the 'pain' given what you believe

  4. What happens if you have clinical signs of MS with O+ bands but on a 1.5 Tesla you show no lesions? Is this the low intensity of the MRI? And if you only had a very small lesion load how can you justify high dose drugs with major side effects if it could be benign?

    1. I think it is becoming clearer, and clearer that there's really no such thing as benign MS. Even if you have no lesions, you may still experience increased brain shrinkage, and symptoms. In a 'benign' case, I'd still think folks would at least want to try something like Copaxone to try and hedge their bet.

      1. Benign Multiple Sclerosis – Recognition as a Defined Clinical Subtype
        Our objective is to determine if there is a subset of patients with multiple sclerosis who have a
        favorable long term clinically benign disease course.
        It is believed that untreated or minimally treated MS is inevitably associated with long-term
        disability. However, most aggressive therapies are associated with potentially serious adverse effects and may
        not be necessary in all patients. In this study, we followed clinically definite MS patients for at least 15 years
        following initial diagnosis to define the entity of benign MS (BMS).
        In this IRB approved study, we examined data from 1,520 consecutiive patients seen at the
        Tisch MSRCNY by a single neurologist. We selected patients as having benign disease if the following criteria
        were met: disease duration of at least 15 years or more during which neither clinical relapses or change in EDSS
        occurred and MRI findings remained stable. In addition, all patients were either untreated or treated with a single
        therapeutic agent. Furthermore, cognition evaluation was either formally or informally tested in all patients.
        Patients who had accumulated an EDSS of greater than 2.5 were excluded from the study.
        Of the total number of patients, 265 met the criteria for BMS (17.4%). Of these BMS patients, 211 were
        female (79.6%) and 54 were male (20.4%). Approximately 62.6% were treated with a single disease-modifying
        medication and while 37.4% were untreated. The average age at disease onset was 33.7, and the average
        duration of disease was 22.6 years. Moreover, 25.3% (67 of 265) of BMS patients had been followed for more
        than 25 years post diagnosis. None of the BMS patients had significant cognitive impairment, cerebellar
        dysfunction or spasticity.
        BMS is an entity that should be considered as an entity when treatments with potentially serious
        adverse events are initiated
        Aan 2019

  5. How common is it for people to have lesions in their brain? If it is uncommon then the requirement for >9 lesions seems overly conservative. If however lesions are not that rare when someone has an MRI scan then maybe the requirement is not that unreasonable.There must be some basis for this requirement and my guess is that lesions are not that rare. So the question is do you want to start someone on Lemtrada according to Team G's analysis who really suffers from headaches?

    1. My understanding is that in any of the relapsing forms of MS, lesions are the norm, and a lack of them the exception. I think they're much less common in non-relapsing forms (PPMS, SPMS). However, there's probably still 'battle scars' in most of the SPMers from their earlier, RRMS days.

    2. Team G is talking about using "highly effective" therapies for people who are not diagnosed yet with Ms (CISer). So if a person comes to G with <9 white matter lesions he is advocating starting them on Lemtrada immediately to stop further damage.Cooler heads may want to know if white matter lesions are prevalent in the general population such as the case for migraine sufferers. In essence, G wants to use the results of an MRI scan to start aggressive therapy, but the MS world that lives in reality knows that this is not that reliable hence the >9 lesion requirement.

    3. Also, Team G would like you believe that it takes the accumulation of 9 or more T2 lesion before you can start treatment. The reality is that a CISer whose first scan shows less than 9 lesion but is suspected of having ms is monitored. If on their next scan (6 months) more lesions appear (even just 1) they can then start treatment. Or if they have another relapse one month after the relapse they had that brought them to see the doctor initially, they can start treatment.I think the current criteria is not that outrageous and it seems to be developed by well respected researchers and clinicians in the field of MS.

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