Sodium channel blockade and progression

S
Should we let bad science win? #MSBlog #MSResearch

“The following study suggests treating MSers with carbamazepine (CBZ), a sodium channel blocker, does not alter the course of MS. Should we abandon our strategy to use this approach? Not at all. This study is bad science. Why? 

1. It is retropsective, therefore it can not control for confounders.
3. The dose and duration of exposure to CBZ is variable. 
4. CBZ is typically used to treat seizures, neuralgia and pain in MSer. These are late manifestations of the disease and it may have therefore been given too late in the course of the disease to modify it. There is a window of opportunity to prevent and treat progressive MS. 
5. I have been promoting a pyramidal approach to treating MS. CBZ will need to be given on top of an anti-inflammatory drug. This was not done here in a systematic way. 
6. The study is underpowered; too small to show an effect using the multiple sclerosis severity scale MSSS or EDSS.
7. The study uses the multiple sclerosis severity scale (MSSS), a derivative of the EDSS, the EDSS is a poor outcome measure for progressive MS and in my opinion is not fit for purpose. The MSSS has also not been validated as an outcome measure therefore I am not sure how to interpret this paper.
8. The EDSS seems to be have done as part of routine clinical practice. I wonder how robustly it was measured? I personally don’t trust EDSS studies outside of well-controlled trials. 
9. I note that this study has not been published in specialist journal (neurology or MS). Why? Could it be that the science is poor? For all we know this may have been rejected by peer reviewers’ of the specialty journals. 

Therefore we are not going to abandon our strategy to further assess sodium channel blockers in progressive MS as potential neuroportective drugs. We need to test CBZ, in well controlled, double-blind, placebo controlled trials using better outcomes and using studies that are adequately published. Bad or poor science has the potential to muddy the waters and seriously impact on a field. I am therefore urging you not to take the findings of this study as an argument against testing sodium channel blocker in progressive MS. Data from our animal studies are very promising.”



BACKGROUND: There is accumulating evidence that long-term disability and disease progression in multiple sclerosis (MS) are due to prolonged sodium channel opening along demyelinated axons. Despite good evidence in animal models of MS that partial voltage-gated sodium channel (VGSC) blockade reduces disease progression, little is known about its effects in patients, despite widespread use of such agents in the symptomatic management of MS. 


OBJECTIVE: To determine if long-term exposure to the VGSC-blocking drug carbamazepine (CBZ) alters disease progression in MS.

METHODS: Using a retrospective chart review of patients diagnosed with MS, we compared progression of disability between patients exposed the VGSC blocker CBZ with those who were not exposed to the drug. Both whole-group and matched case-control analyses were performed after correcting for the influence of age, gender, MS subtype, expanded disability status score at diagnosis, use of disease-modifying therapy, and year of initial therapy. The multiple sclerosis severity scale (MSSS) was used as a measure of disease severity. The primary outcome measure was MSSS score difference between groups.

RESULTS: Four hundred patients were included; 51 received CBZ symptomatic therapy (average duration of therapy 27 months). There was no significant difference in mean MSSS between the two groups in either the whole group comparison (p = 0.63) or the matched analysis (p = 0.12).


CONCLUSIONS: Despite preclinical evidence suggesting a neuroprotective role of VGSC blockers in animal models of MS, this retrospective study suggests that long-term exposure to the VGSC-blocking drug CBZ fails to alter long-term disability and disease progression in MS patients.

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.

16 comments

  • Prof G- why are impact factors your judge for quality? I'm not sure how many of Team G's papers are in a 'decent' impact factor journal? I am sure you won't post this comment, but you are attacking these scientists. A leading MS physician has told me Team G have not contributed anything of meaning to MS research- I wonder which papers of yours will be remembered in years to come?

    • The paper posted today from our group has an impact factor of 9.9 not too shabby. Your leading MS physician might not be keeping up to date with our work but I reckon we've made a contribution, cannabis as symptom relief for MS springs immediately to mind (the number of citations suggests that this might be remembered for quite some time).
      You're right about impact factor though, many of what I consider to be our best work appeared in lower impact factor journals, they tend to be cited often though which may be a better measure of quality.
      Prof G I'm sure can speak for his own contribution, I'm sure.

    • Forget impact factors and focus on the quality of the science. This paper is a poor quality retrospective study based on a chart review. There are simply too many confounders that have not been taken into account to allow any conclusion to made from the data. Unfortunately, there are too many examples of bad science tainting a field to let this one slip by.

    • I have edited the post; I don't want this to be a debate about impact factors. We need to debate the science; good or bad.

    • Impact factors..don't get me started….Looking forward to New Years Eve.
      MS physicians now there another story

    • Re: "Prof. G would you ever sanction retrospective studies of this nature?"

      Yes of course I would. Retrospective studies are often away of testing new ideas and generating data for grant applications. They also allow juniors to get a feel for research quickly. They are what they are and should not be used to dismiss a hypothesis if they are negative. Some retrospective studies use prospective methods and these can be very high quality studies. For example DNA and sera banked many years ago can be interrogated to test new hypotheses. This is what the Harvard group have done using the Veterans Administration database to explore the links between vD and EBV and MS.

      I have been hypercritical of this study as we are about to embark on testing a carbamazepine derivative, oxcarbazepine, in early progressive MS. I wanted to make the point that the results of this study are not going to change our study plans. The PROXIMUS study will still go ahead.

  • Anonymous 3:57:00 pm; "A leading MS physician has told me Team G have not contributed anything of meaning to MS research."

    Have Team G claimed to have made a meaningful contribution to MS research? I am not sure they have (excluding MouseDoctor2's comment above).

    • What does the MS physician mean by meaningful to MS research?

      Given that there there is nothing for people with progressive MS and there are only a handful of approved MS drugs and many of them have limited efficacy and most were championed by Pharma rather than physicians, few people can have too much to bleat about.

      There are plenty of Telfon men and women out there, but if you shout too loud there are plenty of people to help you fall.

      There are a number of things that I am happy to have contributed to and I am sure ProfG will feel the same, History can do the talking as it will be the only form of talking that is worth listening too.

  • Someone commented that "All our papers go in Crap Journals". Well take today…paper in Brain, which is not that shabby..Perhaps this is an insult to all the journals we publish in!.

    However, in the day and age of "Moderation on the Blog" caused in response to the mindless few , only a fool who does not want their voice to be heard or likes to waste their time writing posts for the bin…makes very insulting and offensive comments.

  • EDSS is a poor outcome measure for progression as stated in point 7. What would be an appropriate measure for efficacy in Na channel blockade, brain volume loss using MRI?

    • I don't think people really know what the best outcome is, However a mobility scale that was more responsive that can change in time rather than changing in a stepwise fashion and a MRI outcome. Brain volume has killed off two drugs due to potential pseudo atrophy making it look like the drug is causing brain shrink. In our trials one outcome is retinal thickness in another it is the production of neurofilaments

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