Thursday, 1 January 2015

ClinicSpeak: asymptomatic MS

When does MS begin? #ClinicSpeak #MSBlog #MSResearch

"The fact that approximately 25% of people who have evidence of MS in their brains when they die are not diagnosed in life, suggests that a large number of people who have ‘pathological MS’ have asymptomatic MS.

Did you know that about 10% of siblings of MSers have lesions on the brain MRI scans that are compatible with demyelinating lesions, when only about 1-in-40 to 1-in-80 siblings of MSers go onto develop MS?
The Canadian paediatric study discussed yesterday shows that when children present with their first clinical attack of MS, or CIS (clinically-isolated syndrome), they already have smaller brains than control subjects. This would indicate that MS has probably been present for awhile, stunting the growth of the brains of these young CISers. The childhood data is compatible with what we know about adult CISers; about 80% of adult CISers have multiple lesions on their brain, at presentation, that don’t enhance with gadolinium indicating that they are old lesions and have been present for months and possibly years. In addition, a large proportion of CISers already have brain atrophy and mild cognitive impairment indicating that they have probably had asymptomatic MS for several years. Why several years? We now know that brain atrophy is a delayed process and takes time to develop; all indicators suggest that brain atrophy in MS that is occurring now, i.e. the next 6-12 months, is probably driven by MS-related focal inflammation that was active more than 12 months ago, and possibly longer. The reason for this brain atrophy lag is that when an axon or neuron dies it takes the brain’s clean-up systems many months to clear the debris from the dying cells, only once the clean-up processes are over do you see end-result or brain shrinkage.

A recently published study from Argentina on CISers also supports MS as having a long presymptomatic phase. All school children do standardised examinations in the last 3 years of school in Argentina. If someone develops CIS after leaving school you can go back and look at their school performance and compare them to matched control subjects. What the Argentinian study shows is that cognitive performance in the last 3 years of school is poorer in subjects presenting with CIS after school compared to appropriately matched control subjects. Academic school performance was worse in subjects the closer their CIS presentation occurred to their final year of leaving school. The effect on academic school performance was noted up to 10 years after leaving school. What this study is telling us is that MS has a long asymptomatic period, that may be as long as 10 years, which affects cognitive ability years before the first clinical attack. This observation is not too dissimilar to the prodrome, called minimal cognitive impairment (MCI), that we observe in people who are destined to develop Alzheimer's disease.

Recent publications in subjects with asymptomatic MS or RIS (radiologically isolated syndromes) supports the observations above. RISers are people who have MRI scans for another reason, for example as part of a workup for chronic headaches, and are found to have lesions on the MRI that are compatible with demyelination. Please note I that I say compatible with demyelination and not MS; MS is a clinical diagnosis and not an MRI diagnosis. RISers are not dissimilar to CISers in that a significant proportion already have brain atrophy and mild cognitive impairment; albeit a slightly lower number (~25%) compared to CISers (~40%).

What all these observations are telling us is that when you present with your first clinical symptoms of MS you have probably had ‘pathological MS’ a lot longer. The advantage that MS has over other autoimmune diseases, for example type 1 diabetes, is that when it presents there is still a lot of brain and spinal cord to protect hence disease-modifying therapies can have an impact on the natural history of the disease. In comparison when someone presents with type 1 diabetes most of the end-organ (beta cells in the pancreas that produce insulin) have already been destroyed by the immune system and hence it is too late for DMTs. This is why my colleagues who are working in the type 1 diabetes field are trying to get DMT trials off the ground in the so called presymptomatic phase of the disease, i.e. before it is too late. I have a similar vision for MS; we need to be able to diagnose the disease in the ‘at-risk’ or ‘asymptomatic’ phase so that we can start treatment even earlier than we are doing now. In other words we need to prevent MS before it manifests clinically. Some of my colleagues doubt we will be able to do this; what do you think?"


27 comments:

  1. How about aggressive work to develop an MS vaccine instead? Or Subsidize the delivery of Vit D to people who live in high risk areas to see if number of incidences can be stabilized or reduced. Give treatment option to everyone, and not just people who might 'qualify' for early DMT use .... prevention requires rethinking how we might tackle this growing problem.

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    1. Re: "MS vaccine"

      I assume you are referring to an EBV vaccine? There is renewed interest on this front, but that is a 20-30 year project. 10 years to develop a safe vaccine and at least 20 years to see if it works.

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    2. Re: "Subsidize the delivery of Vit D"

      What dose of vD and what about adherence? I attended an International taskforce on vD and MS and the experts could not agree with themselves when it came to what the best study design was. We are not giving-up; it is too important not to work on this issue.

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  2. I think you're just becoming a stuck record. If these DMTs actually worked then they will positively effect all MSers in some way, which, as clinically proven, they do not.

    Prof G, how about you promote better holistic care or positive attitudes rather than advocating questionable and highly dangerous DMTs?

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    1. Re: "Prof G, how about you promote better holistic care or positive attitudes rather than advocating questionable and highly dangerous DMTs?"

      http://multiple-sclerosis-research.blogspot.com/2013/08/clinic-speak-holistic-approach-to-ms.html

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    2. Re: "I think you're just becoming a stuck record. If these DMTs actually worked then they will positively effect all MSers in some way, which, as clinically proven, they do not."

      This is sounds like a statement of fact; when it is not. If you are hypothesising that these therapies do not work then you need to try and disprove the hypothesis. This is how Karl Popper, one of the most influential scientific philosophers, framed the scientific process. If I can advise you; as a start I would set-up a list of criteria that define a DMT as not working and then to do a meta-analysis of all the phase 3 trials to see which DMTs tick your boxes. What you also need to remember that scientific evidence needs to be adopted by the wider community and the general public; there is no point in setting such strict criteria to define your treatment as not working that nobody accepts them. What happens then the community would simply ignore your conclusions and move on. The scientific process (evidence) is very different to religion (beliefs); what you need to do is convince us that your statement is based on scientific evidence and not a belief.

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    3. Prof G and MD; I think you have just been trolled. The post does not even mention any specific DMTs; this person clearly has an axe to grind with you and this blog. In future I would recommend not allowing such senseless comments through your filter.

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  3. Suppose a symptom-free sibling of an MSer has an MRI and it shows over 10 brain lesions and several spinal cord lesions, all non-enhancing, and the person has a normal neurological exam

    How would you treat this case if you weren't constrained by NICE guidelines, etc?

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    1. Re: "Suppose a symptom-free sibling of an MSer has an MRI and it shows over 10 brain lesions."

      I would first make sure they have 'biological MS' and do a lumbar puncture, make sure they are EBV positive and do baseline evoked potentials. I would not treat them unless their asymptomatic MS was active; i.e. Gd-enhancing lesions or new T2 lesions with follow-up MRI. If there disease was active, i.e. subclinical relapses, I would offer them a DMT. Why would I do this? SImply because active MS causes damage and all the evidence suggests that by stopping activity you prevent damage and protect reserve capacity.

      Please note we can't treat RIS or asymptomatic MS in the UK. To get around this is to do a clinical trial.

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    2. Thank you for the reply.
      What if the disease was inactive - any advice that might help to keep it in that state?

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    3. Prof G - please could you "define" what you refer to above as "subclinical relapses".
      I've never had any acute episodes that I can be certain were relapses, and am not on any DMT at the moment. My MS definitely is not asymptomatic, but seems to have been fairly stable over the last 12 months, with only a relatively small increase in the severity of some symptoms. I have another MRI coming up soon, and it will be the first one where Gadolinium will be used (Gad was not used with any of my previous MRIs). If this next MRI shows Gd-enhancing lesions does this mean that my MS is active but sub-clinical? If I have the option of taking a DMT (I'm not in the UK) should I consider doing so? I suspect that if a DMT is suggested it will be Tysabri, and I would be a bit worried about the known problems with rebound activity if I were to go on Tysabri but then had to stop for some reason - I'm not on any DMT at the moment because of bad and ongoing side effects of the one I was on (which included making all of my symptoms quite a lot worse). I would be a bit worried about my MS firing up if I had similar side effect problems with Tysabri and had to stop taking it, especially as since I stopped the DMT I was on I have been feeling heaps better and quite a few of my symptoms have improved nearly back to what they were a year ago.

      I suppose what I'm asking is what course of action would you follow in these circumstances if you were not constrained by the NHS rulebook?

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  4. If 10 per cent of sIblings have lesions it suggests that the influence of genes has been underestimated. Is the viral hypothesis still valid? Can we really be sure that treating aggressively very early on will stop MS developing?

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    1. Re: "Is the viral hypothesis still valid?"

      Absolutely. I can show many infectious diseases that are 'genetic'. Genetic factors are know to protect and increase your risk of acquiring an infection. The same could apply to MS.

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  5. Prof G, are you the kind of doctor who, let's say a patient of yours with MS says they feel depressed, will instinctively rush to prescribe antidepressants rather than tell them to take it easy? I need to know this because that way one gets a better sense of the type of doctor you are.

    I know I may seem to be criticising you but I just want to know if you think all of life's problems can be healed through medicines?

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    1. Re: Treating depression.

      Depression in MS is a symptom and may be part of a syndrome; in short there are many reasons why a person with MS may be depressed. In my experience MSers rarely complain of depression, but usually manifest with other, but related, symptoms. You often have to ask them about symptoms of depression. In my experience MS-related depression is usually associated with anxiety and/or stress; if you don't treat or manage the anxiety the depression won't lift. I have a few patients who have had a major depression (unipolar or bipolar) and I have to refer them to a psychiatrist for management of their depression. These patients have all ended-up on antidepressants and mood-stabilizers. Depression can also be a manifestation of poor sleep, or sleep deprivation, a side effect of medication, a feature of alcohol or other substance misuse, seasonal affective disorder, associated medical problems (e.g. hypothyroidism), etc. We shouldn't forget that MSers have a higher risk of suicide than the general public; depression is one of the predictors of suicide. It is important to identify those at risk of suicide so they can be proactively managed. In short, the treatment of depression is complex and depends on the associated co-morbidities, the cause, the severity and whether or not there is a risk of suicide.

      So there is no black-and-white answer; some rare patients need to be sectioned and admitted into a psychiatric unit, some need urgent outpatient or community psychiatric input (suicidal patients), other need to improve their sleep hygiene, some need anxiety or stress provoking triggers addressed, some need medications changed, some need to be referred to an addiction service, some may need light therapy or medication, others may be choose exercise or CBT therapy. What I don't do is to tell them 'to take it easy'; I am not aware of any evidence that this approach works. You may find these two previous ClinicSpeak posts on the management of depression of use:

      http://multiple-sclerosis-research.blogspot.com/2014/10/clinicspeak-exercise-and-depression.html

      http://multiple-sclerosis-research.blogspot.com/2014/01/clinic-speak-cbt-for-depression.html

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    2. My increasingly severe depression appears to have been 95% caused by the DMT (Interferon Beta-1A) I was on - stopped the DMT and two weeks later no depression. It has stayed away for several months now, and I'm only getting the minor mood swings that tend to accompany the occasional not so good day. Has anyone else had this happen to them?

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  6. I think this should be the main goal now we have DMTs to reduced MS activity. Given that there are three people in my family with MS, I want to protect my kids from this horrific life destroying disease. Find a way if diagnosing it early and develop protective treatments and advice for those at higher risk. I am concerned that in reality there is no such thing as asymptomatic MS as it is impossible to say what a person would have been like without the demylination. Any brain damage is bad.

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    1. Re ' it is impossible to say what a person would have been like without the demylination':
      I was already a MS caregiver and recently got to know i may be an 'asymptomatic MSer' myself.
      Never had any neurological symptoms, had an excellent education with a good academic track record. But I fit the MSer profile in other ways. For example, I haven't worked for years and never had a good explanation for it. Others with much more on their plates do manage to keep working

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  7. Prof G, I see you mention trying to predict MS several times, but not survive you understand the statistics behind it. Have you read the work of Stephen Sawcer? I would appreciate a post on your statistical rationale as to why you think MS can ever be predicted, given the incidence rate and number of people who would have all risk factors?

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    1. Re: "Predicting MS"

      We are not there yet. In type 1 diabetes if you have two or three autoantibodies you have over an 85% chance of getting the disease. In the field of MS we need to do more research. That fact that we are not good at predicting who will develop MS at present doesn't mean we won't in the future. Yes, I am aware of Stephen Sawcer's position on this and I agree with him.

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  8. Yeah, that would be great. A simple blood test that could be administered by support staff (because doctors are always too busy) would be helpful. I suppose you would have to look for a combination of virus and genetic markers--because asymptomatics aren't likely to let you poke around their spinal cords "just in case."

    At the same time, even when we present with clinical signs of MS, it's usually years before we get diagnosed. Our front-line medical pros (nurses, clinic doctors, etc.) could use a little more help knowing the difference between, say, pinched nerves and demylinating disease or even BPPV and INO.

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    1. Yes. This. If treating early is important than neurological referrals need to be offered timely. Almost every diagnosis story I have heard or read includes doctors dismissing symptoms as unimportant. I was told that buzzing sensations in my chin were depression. That ear pain was nothing because no physical findings. That tremor was anxiety. It should not take years to decades of interaction with doctors before neuro symptoms are taken seriously.

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  9. "what we know about adult CISers; about 80% of adult CISers have multiple lesions on their brain, at presentation, that don’t enhance with gadolinium indicating that they are old lesions and have been present for months and possibly years. In addition, a large proportion of CISers already have brain atrophy and mild cognitive impairment indicating that they have probably had asymptomatic MS for several years"

    80% of CISers presenting with multiple lesions is much higher than I had thought. Can I ask where this figure came from? This figure seems at odds with the much lower percentage of CISers on a DMT who I presume don't meet the "Neurologists may, in certain other circumstances where the evidence for efficacy is less secure, also consider advising treatment after discussion with the patient concerning the risks and benefits. For example; (i) Patients within 12 months of a clinically significant Clinically Isolated Syndrome when MRI evidence predicts a high likelihood of a recurrent episode (i.e. development of MS) criteria in the commissioning paper.

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    1. Re: "80% of CISers presenting with multiple lesions is much higher than I had thought."

      We have just completed an International CIS study of over 1000 CISers and only 14% had no T2 lesions on MRI. This is similar to most of the other CIS studies. I agree with it being at odds with treatment rates and suggests that a lot of CISers with 2 or more T2 lesions are not getting treated. Why? Possibly because they don't want treatment or their neurologist does not think they should be on treatment or has adopted a wait and see strategy. In the UK the latter is probably the most likely explanation.

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  10. What is the definition of a lesion anyway? Is it punctate foci, or only those greater than 3mm in size?

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    1. Good question, I would be interested too in hearing a response.

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