Saturday, 19 March 2016

ResearchSpeak: the changing natural history of MS

Are we changing the natural history of MS? #MENACTRIMS2016 #MSBlog #ResearchSpeak #MSResearch

"The following is my first talk from MENACTRIMS 2016 that is being held in Amman, Jordan. Rather than bore my audience into the usual torpor that goes with conferences I decided to change my title and focus my talk on the 'changing natural history', rather than 'the natural history', of MS. I think my tactic worked and it looked as if most of the audience stayed awake to listen. Another explanation is that it may have nothing to do with me; there is no collective hangover at this congress, it refreshingly alcohol free, which leaves you feeling wide-eyed and very attentive."




"As you know the Middle East is seeing a surge in new cases of MS. Why? One reason is simple demographics; these countries have very young populations with the majority of people in the 'at risk' age group. In slide 4, I use Egypt as an example; it is clear that some of the increased MS prevalence is being driven by this young demographic profile. However, this can't explain it all. It is clear that the sex ratio of incident MS cases can't be explained by demographics; many more women are developing MS in this region than men, e.g. the F:M ratio in Iran is ~5:1. Therefore there must be some other environmental factor explaining this surge in incidence. I suspect it is vD; we know for cultural factors that women in this area have much lower blood vD levels than men."

"In my talk I go onto explain how the changing definition of MS is altering the natural history; this is occurring due to the Will Rogers' phenomenon. As soon as you change, or move, the dividing line between those who have MS and those who have pre-MS (CIS) you improve the prognosis in both groups. Interestingly, this also applies to PPMS. When the McDonald Criteria Committee dropped the need for a positive CSF analysis from being essential (2001) to make the diagnosis of PPMS, to being non-essential (2005), they inadvertently changed the natural history of PPMS making it more benign."

"I go onto looking at the validity of the MS Diagnostic criteria and explain sensitivity and specificity. As usual people are surprised when they discover the criteria are not 100% specific. In other words people are misdiagnosed as having MS when they have some other disease. Based on the published data about 1 in 20 people who are diagnosed with MS don't have MS. With regard to sensitivity of the MS diagnostic criteria it is difficult to be certain, but based on post-mortem data and modelling we estimate that about 25% of people who have MS at post-mortem, as defined using the conventional, or pathological, defintion of the disease are not diagnosed as having MS in life. We have to assume that these people were either asymptomatic, or had very mild or atypical symptoms that never required a diagnostic work-up when they were alive for MS."

"I then focus on the secondary progressive MS and show that how we define this disease is essentially a thumb-suck. The time to diagnosis of SPMS has also changed. In the London, Ontario, database George Ebers and George Rice used to diagnose SPMS based on history and an abnormal neurological examination. For example, if someone described a dragging leg after 30 minutes walking and year later this worsened and now occurred after 10 minutes of walking, they were diagnosed as being secondary progressive provided they had an abnormal neurological examination (e.g. upgoing plantar response). This is why people with MS were being diagnosed with SPMS with a median EDSS of 2.0-2.5, long before they were overtly disabled. In my opinion the Georges' were clearly right and I now refer to this as clinically apparent SPMS. However, this has changed. In the modern era people are only being given the diagnosis of SPMS well after EDSS 4.0 (overt walking problems). I have seen a patient for a second opinion with an EDSS of 6.5 (bilateral support), who had clearly had non-relapsing progression, still being referred to as having relapsing MS. Why? This simply relates to access to DMTs. In most countries you have to stop DMTs once somebody enters the SPMS phase of the disease. To prevent this from happening you simply never label your patients as having SPMS. In other words cultural, or non-biological factors, are dictating how we define SPMS. I personally think this is 'bullshit' and we need to move away from clinical, and cultural definitions, of progressive MS and focus on a biological definition. The scary thing is if we do this we will realise that that the progressive phase of the disease is there from the outset; SPMS doesn't magically appear at some time point in the disease. If you are interested in my musing on this topic you need to read my previous posts on the topic and my hypothesis on MS being a length-dependent axonopathy."

"I then provide arguments that effective DMTs are clearly changing the natural history of the disease. Some sceptics still argue to the contrary, but I suspect if they really analyse the data they would have a difficult time disproving the hypothesis."

"I closed my talk making a strong argument to include RIS (radiologically isolated syndrome) and people at 'high-risk of developing MS' in the diagnostic spectrum of MS; i.e. the so called MS endophenotype. It is clear from my talk and comments above that I am not a big supporter of the philosophy used, or non-philosophy used, that underpins the current diagnostic criteria for MS. I personally think we need a biological definition of MS that frames the disease differently that then allows one to make the clinical criteria work better."

"I predict this post will generate more questions and answers, but that is why I love science and I am agnostic when it comes to religion. Science allows you to ask questions, propose hypotheses, test them, reject or accept them and move on to the next set of questions. Religion on the other hand simply requires you to believe and have faith. Unfortunately, too many people in the field of MS believe the current dogma."

15 comments:

  1. Prof G,

    I don't think belief in God is just about faith. We can see God's work if we look up to the sky at night (many astronauts have a religious experience). You must marvel at the creation which is the brain. You guys are experts, but don't really have a clue how it works.

    I digress. My main issue concerns SPMS. I took a highly effective drug (Alemtuzumab) to reduce the risk of converting to SPMS. The drug has done wonders for me - 8 years and no relapses (I had aggressive RRMS). My EDSS improved a bit and is now stable at 3. How would you classify me? What's my prognosis (woman aged 45)?

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    1. Re: "I don't think belief in God is just about faith."

      Apologies, I am knocking religion as such. I am the first to acknowledge that religion plays a vital role in society. Religion is society's glue and gets us to work together in harmony etc. I was using religion as an analogy; a belief system tends to be fixed and unquestioning. In comparison science is different.

      Yes, I do marvel at the universe and the human brain. But given sufficient time, i.e. Darwin's deep time, it is amazing what nature/evolution can do. It is all documented in our genes. The history of human brain development, and how it works, is all written down for us in our DNA. We now have to decode it and infer the selection pressures that help sculpt its evolution.

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    2. Re: "My main issue concerns SPMS. I took a highly effective drug (Alemtuzumab) to reduce the risk of converting to SPMS. The drug has done wonders for me - 8 years and no relapses (I had aggressive RRMS). My EDSS improved a bit and is now stable at 3. How would you classify me? What's my prognosis (woman aged 45)?"

      A million dollar question. If I had the money and time I would take 20 people like you and deep phenotype you to see if there was any evidence of ongoing neurodegeneration. I would be particularly interested to know if your oligoclonal bands were still there or not. I sincerely hope they have disappeared. The other option is to wait and see what happens; it will take another 10 years for us to know if long-term remission means a cure or not.

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    3. "Religion is society's glue and gets us to work together in harmony etc."

      Rubbish. Absolute bull. The kindest, most honest, sincere and helpful people I know are not this way because they believe in some personal god or religious dogma, but purely because they care about others, are not selfish, caught up in their own egos and needs.

      Religion clouds thinking, produces illogical, baseless arguments and wars. On this issue, Richard Dawkins has the intellect.

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    4. Really enjoyed the talk summary and the (non religious) answer to the person 8 yrs post lemtrada above. Plus I want the answers, now please. Yesterday would be even better :D. Bojana

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  2. Re "... strong argument to include ... people at 'high-risk of developing MS' in the diagnostic spectrum of MS; i.e. the so called MS endophenotype"

    Suppose they were included, what next for them? According to you, what would be the ideal follow-up or treatment?

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    1. Re: "Suppose they were included, what next for them? According to you, what would be the ideal follow-up or treatment?"

      We would need to a clinical trial to see if we could prevent disease onset (RIS/CIS); I would test high-dose vD vs. low-dose vD (RDA).

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  3. In a diagnosis of MS, how important is an "abnormal neurological examination"?

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  4. These slides are absolutely brilliant! I imagine the talk won't be available online :(

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  5. If spms starts earlier (edss 2-2.5) the highly effective drugs are effective in relation of these disease course. If it real, the treatment response are more dependent from the severity of the disability. But finally there was a study which shows Fingolimod may an effective treatment for severe progressive/relapsing and purley secondary progressive disease with high disability.
    https://actrims.confex.com/actrims/2016/meetingapp.cgi/Paper/1484

    We have more questions than answers, and new answers bring more new questions. May highly effective drugs the key?

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  6. Well done Professor G. Really excellent.

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  7. Where do the figures come from for the untreated patients becoming SPMS?

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  8. My friend was DX 8 years ago with aggressive RRMS, she is registered visually impaired and came off tysabri November last year. She started Gilenya on January, her mobility, speech, swallowing in her opinion has deteriorated, and I agree with her. I have told her to discuss this with her MS nurse, but she thinks its a waste of time.

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    1. How old is she?
      Her sympthoms increasing from the last three months? (started Gilenya or before?)
      Why did she change treatment? (from Ty to G) Did She use tysabri from the begining?
      What is her current EDSS score?

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    2. She is 32, overall symptoms have deteriorated, she thinks since starting G.
      Was on Ty over 2yrsrs came off as tested positive PML,not sure on EDSS, she is full-time wheelchair user 60% vision, she has 22hr live in care every day.

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