Thursday, 30 October 2014

ClinicSpeak: when does MS actually begin?

How long is the asymptomatic period of MS? #ClinicSpeak #MSBlog #MSResearch

"The data below was presented at last year's AAN meeting in San Diego and I have been presenting it in my talks ever since. It supports my MS dementia rebranding exercise. In Argentina all people do standardised examinations in the last 3 years of school. If someone develops a clinically isolated syndrome (CIS) after leaving school you can go back an look at their school performance and compare them to matched control subjects. What this study shows 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. Interestingly, cognitive performance was worse in subjects the closer their CIS presentation occurred after school. It appears as if the effect on cognition was noted up to 10 years after leaving school. What does this mean? It is telling us that MS has a long asymptomatic period that is obviously culling cognitive ability years before the first clinical attack. This is similar to the prodrome, called minimal cognitive impairment (MCI), that is seen in people who go onto develop Alzheimer's disease."


"Should you be surprised by these findings? Not really, these observations are congruent with several other observations. Firstly, most people presenting with CIS have several older lesions on their MRI indicating that the disease has been presented for sometime prior to the new lesion causing their CIS. People with both clinically-isolated and radiologically-isolated syndromes (RIS) often have pre-existing brain atrophy and cognitive impairment indicative of the disease being present for a period of time. Children presenting with CIS, or MS, have smaller brains than children presenting with acute disseminated encephalomyelitis (ADEM) indicating that MS has an asymptomatic period affecting brain development and ADEM, a monophasic disease, does not."



"How long is the asymptomatic period of MS? These data would suggest it being years and possibly loner than 10 years. This sets a challenge for us to try and diagnose MS in the presymptomatic phase so that we can try intervene earlier in the course of the disease. This was one of the drivers of our so called endophenotype project. The question is would someone start treatment before they have a clinical attack? This is happening already; I am aware of several neurologist across the globe who has patients with RIS (asymptomatic MS) on DMTs. Please note treating RIS would not be allowed in the UK and at presenting RIS is not part of the diagnostic criteria of MS. I suspect this will change in the future; MS is a biological disease before it is a clinical disease!"

Epub: Sinay et al. School performance as a marker of cognitive decline prior to diagnosis of multiple sclerosis. Mult Scler. 2014. pii: 1352458514554054.

BACKGROUND: For many years, cognitive impairment has been established as a well-known symptom of MS. Moreover, we know that it was present even at the beginning of the disease.

OBJECTIVE: In this case-control study, we decided to evaluate whether there is an impairment of cognitive functions even before onset in those people who will eventually suffer from multiple sclerosis.


METHODS: We evaluated the overall school performance, and particularly school performance in math and language in a group of people who would later develop the disease and we compared our findings with a control group.


RESULTS: We found that school performance was poorer in subjects who were to become patients. And we found that the later the start of the first symptom, the better the qualifications.


CONCLUSION: Testing a premorbid cognitive deficit by a validated indirect evaluation method allowed us to verify that there was evidence of neurological compromise even before a clinical diagnosis or the completion of the first magnetic resonance imaging in patients who would then suffer from multiple sclerosis.

43 comments:

  1. Prof G,

    Rather depressing stuff. I keep a close eye on my children. I don't really understand why you say that MS is a biological disease. Surely all diseases are? I hope some bright sparks are working on methods to test for the disease. Then children who are at higher risk could be tested at regular intervals so that the disease could be detected and then treated before any clinical symptoms are seen. If I had the money I'd be funding a research project focussed on the children who get MS. This might provide a better chance of understanding the early stages i.e. what causes it.

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    1. I agree with you that children at higher risk could provide insight into early MS pathology. Since a breach in the BBB is necessary for neuroinflammation it would be interesting to test those individuals that displayed cognitive deficiencies for BBB disruption.

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  2. I really hope early treatment with Gilenya at CIS will pay off for me in the long term ! , I have very minimal symptoms but more then 15 lesions in my brain and 2 on my C spine :(

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  3. Interesting as it is, the abstract does not state the magnitude of the observed difference ( always a bad sign, is the difference statistically significant, but not clinically significant?) I cannot open the full text article :-(
    J

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    1. The site is down at the moment, as soon as it's back up I'll pull out the data for you.

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    2. I am not sure full text has been released yet, has anybody seen it?

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    3. Thanks for being helpful MouseDoctor2 :-), did you manage to dig the info out of the PubMed rubble?
      J

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    4. This is from the paper and a summary of the results. I can't copy the table of results so hope this will do. All the best!

      For specific school performance, the variables
      (marks obtained) were finally dichotomized with a
      cut-off of 8 out of 10, based on the distribution of the
      data in the sample (75th percentile). In this model,
      we found that all the variables were associated with
      the presence of multiple sclerosis in the unadjusted
      model, and most of them were associated with multiple
      sclerosis in the adjusted model. The highest OR
      in the adjusted model was for 4th year mathematics
      (4.68 95% CI 1.5–7.14).
      At the same time, we assessed the correlation between
      time elapsed since age 18, the end of secondary
      school, and the onset of the disease. We found that
      there was an increased risk of worse performance if
      the disease’s onset was closer in time to the end of
      high school. The dispersion curve using the Spearman
      Rho test showed a significant level of p=0.025 for 5th
      year average (Figure 1).
      On the other hand, going back in time, we found that
      the statistical significance is diluted back year by year
      in school, and no significant differences were detected
      in the third year of the high school cycle at age 16, as
      we saw in 4th and 5th years

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    5. Thanks for your help, MouseDoctor2 :-). Call me picky, but in a study like that one needs to know how many children with MS were in the study, how many controls matched for each MS patient and how the controls were matched and so on. Epidemiological studies are useless unless done meticulously well.
      J

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  4. I guess my asymptomatic period would have been before 17, as this was when I started getting sensory symptoms. The same ones I get now. It then took 18 years to get a diagnosis, despite seeing MS neurologists every few years at Queen's Square, and all dismissing me as a bit of a hypochondriac. Would it have done any good to have been diagnosed sooner? Not sure, yes it would have helped me to know I wasn't bonkers but as there were no treatments such as DMTs then, probably not!

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    1. I should add that I have a first class degree from Cambridge, and since then two masters, and numerous other post grad things, so I don't think I can retrospectively sue anyone for not diagnosing me earlier :). Interestingly a friend at school also developed MS around the same time and she did get a diagnosis. She was meant to read veterinary medicine at Edinburgh but the doctors told her and her parents that the stress would be too much and why not become a vet nurse instead. Well, she took their advice and four years later was in a wheelchair, ten years later she was dead (from MS complications). As there is no such thing as one size fits all with MS, it's likely she had a different more aggressive form to me but I could also speculate that the advice she and her parents got to not aim high, may have had something to do with this.

      Who knows, I know I would have not been happy to hear this and, as stress plays a role in the MS I have, I may also have gone down hill more rapidly had I been told this. Carpe diem!

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    2. Actually, Anonym. from Cambridge, it's very interesting question. Is stressing MS brain out really bad or actually a good thing, helping to keep the relapses at an arm lenght? Is it worth to press on a MS patient with cognotive issues when there is no hope for academic excellence or better let such a person in peace, letting the brain to creep up at it own speed?

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    3. It is a very interesting question. At the point my friend was diagnosed, she was very bright and the MS was not affecting her cognitively (in the end, if you saw her lying in bed by this time blind, unable to speak or understand you'd think she had CJD not MS). I often wonder what would have happened if her family had ignored the doctors' advice. I know it sent her into a tailspin of depression that she never recovered from, and her final years (she was 35 when she died) were absolute hell. Perhaps, (I've no idea) she had a very rapid version of PPMS because she declined so quickly and this would have occurred regardless of taking up her uni place (I can't see how it could have made things worse). Actually, thankfully things have changed since then in terms of doctor-patient interactions, as at the time these were of the extremely patriarchal, 'doctor knows best' variety, regardless of whether they did or not. So I really am quite thankful I wasn't diagnosed until much later.

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  5. Honestly, we need more education on what neurological symptoms look like. I lived for 15 adult years with classic but non-disabling ms symptoms and it never occurred to me that I might be sick or that they needed investigating. Just who I am. A little clumsy. Eye trouble, well need new glasses. Can' t walk a straight line, bump into friends walking, well just me. Intermittent photosensitivity, same thing.

    Now that you have treatments, you need outreach, both to diagnosing gp's and to the public.

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    1. I've had non-classic, non-disabling symptoms for a long time.
      Like Anonymous 2.39 "it never occurred to me that I might be sick or that they needed investigating. Just who I am": a little clumsy, more than a little absent-minded, low-energy, has problems multi-tasking, and more ...

      I never once suspected a medical cause and am thankful nobody else did either

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  6. It's more than dispiriting to know this, while NHS rules require two attacks in a year to get onto a DMT. What if you a only have occasional relapses? You have to wait until you're properly messed up before an intervention .. Seems too little too late. Added to which, consultants can be very laisser faire about new options (mine prescribed nothing for 5 years. Then when I had bad relapses, he tried very hard to dissuade me from campath. His big plan was Rebif.) Furthermore, countless people are misdiagnosed (trapped nerve, eye infection, low vitamin b are some instances.) I fell that Prof G team's efforts to secure early intervention are highly laudable. But from my experience and that of other MSers I know, the reality is a lottery depending on your GP, consultant, etc, and not helped by guidelines which prohibit early intervention on cost grounds.

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  7. Early treatment is MSers' best (only?) chance. Sadly misdiagnosis, wishful thinking and risk averse neuros, plus exorbitant costs of DMTs mean that early intervention is an impossible dream for most of us.

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    1. You hit the nail on the head. The desire to treat this disease needs to catch up a bit with the new treatments. Though I can see where the reticence is given that the long term effects of the drugs isn't absolutely clear. However, I would be interested to hear why more conservative neurologists put people on treatment at all if they have doubts about the drugs then they should probably stop treating anyone.

      It irritated me when Cameron started talking about dementia diagnosis when MS is a potentially treatable dementia of young people (or at least initially detected in young people in a pre-dementia phase) where those with the disease get mucked around for years first for diagnosis, then for treatment.

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    2. "However, I would be interested to hear why more conservative neurologists put people on treatment at all if they have doubts about the drugs then they should probably stop treating anyone."
      They should be drummed out of the field, in my opinion. Inertia and complacency are the enemies of MS.

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  8. For Anonymous at 4:45pm (and any interested others)

    Please don’t underestimate the potential impacts of a Vit B12 deficiency – it is one of the acknowledged MS mimics, and if undiagnosed and untreated it can be as devastating as MS, and the neurological damage it can cause can be every bit as bad as MS (and just as irreversible). And even worse – it is far more common in today’s affluent first world countries than it should be, but it is too simple an answer for many medicos, and is too often overlooked or not even checked. Furthermore, appropriate B12 tests are an awful lot cheaper than an MRI and a lumbar puncture, it is cheap to treat, and if it does turn out to be the problem you don’t have to put up with the heavy duty drugs used for MS, with all their side effects and huge costs.

    And I too had many irritating and worsening symptoms for many years before things got bad enough that I finally got to see a neurologist 18 months ago, as I never had any episodes which could be called a relapse – just an ongoing increase in loss of functioning. Finally 12 months ago an MS diagnosis was handed to me (based on one MRI, symptom history, and with no blood tests or lumbar puncture done). I recently found out that I had a B12 reading several years ago that was considered “normal” in my country, but I now know that it was actually on the low side of “normal” at that time, and in quite a number of countries would have triggered further investigations. Who knows – it could have been a contributing factor to my symptoms as it is also recognised that for some individuals “low normal” is actually a deficiency for that person. Anyway, it’s too late now if B12 was a factor – I’m now officially 3.5 on the useless EDSS (but more like 5 if my walking capacity is taken into account)

    Leaving aside the NICE guidelines (which don’t apply in my country and which I have read and am disappointed in), I would be very interested to know Team G’s recommendations as to what tests should be carried out in order to arrive at an MS diagnosis. Over to Team G………

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  9. Some interesting posts here. I think some people with mild symptoms will have better lives if they stay un-investigated and un-diagnosed.




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    1. If my "irritating but worsening" but previously mild symptoms had been investigated much earlier, resulting in an earlier diagnosis I probably would not be where I am now, as I would have had access to medication which MAY have slowed or halted my progression. Although, having said that, so far there aren't really any meds that have been confirmed to slow progression if you don't actually have relapses, but at least I now have some answers and can try and deal with it - and while the future is not particularly rosy, it's better to know what I'm dealing with rather than still facing a great unknown.

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    2. "Although, having said that, so far there aren't really any meds that have been confirmed to slow progression if you don't actually have relapses....."
      Hopefully this is going to change in the foreseable and I hope, near future. Watch this space.

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  10. Find out what causes MS, give a vaccination in infancy. Save millions.

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    1. Ha ha ha, I was wondering when we'd get a visit from an anti-vaccine conspiracy theorist. It also gives you autism as well presumably?

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    2. MD2 I think anon is stating that a vaccine will prevent the onset of MS if the causative infectious agent or antigen is found, not that vaccines themselves are causative.

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    3. Fair enough, it's a bit unclear but I've seen so many "vaccination gives you this or that" stuff that my b*****it detector goes off scale! My apologies.
      I would love to see a paediatric EBV vaccine be widely available, though it'd take 30 years or so before we knew if it was the true cause of MS or not.

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    4. Thank you Steve S, that is exactly what I meant. Actually Mousedoctor2, I had my vaccine to prevent pneumonia today.

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  11. Clearly what is needed is an inexpensive method to detect MS such as a blood test. This should be at the pinnacle of MS research instead of repurposing immunosuppressive drugs. Me thinks this would put a lot of "MSologists" out of work but it would prevent a lot of misery.

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    1. But what would you look for and why bother when MRI does the job very well.
      A blood test to measure neurofilament levels as a measure of neurodegeneration and disease progession would be useful as a routine test and also to measure potential neuroprotectants as ways of slowing progression.
      At the moment I think the prospect of MSologists being put out of work is unlikely or indeed desirable.

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    2. I left school at 17 with more good exam results than my peers. I was even accused of cheating by my maths teacher which I definitely didn't do. I was diagnosed at 21. However, I did have to leave the hall to go to the toilet in every exam and had to take a doctor's note to school. Also,during the study I took part in for the Institute of Neurology, the researcher changed the test, as she said I had a high IQ. I had a job that needed good maths and had to attend numerous courses. I just can't understand this research. Did they choose MSers already known to have Cognitive problems?

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    3. Well perhaps you're an outlier and your high IQ masks cognitive deficit so you would have an even higher IQ if you didn't have MS. That seems more likely than "they choose MSers already known to have Cognitive problems".

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    4. Or somebody wanted to publish some findings that actually were not that convincing and got away with it?

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    5. Makes me wonder. I have a very high IQ, and in the last 30 years that this has been measured, it's dropped a little bit from when first measured, which is normal as I'm much older now according to the test administrators, and I can't say I notice any difference. I think this is normal brain ageing stuff and nothing to do with the MS. I feel it is important that individuals don't get paranoid and conflate normal cognitive changes that happen, not only due to age, but also fluctuations due to stress etc with the first signs of dreaded dementia!

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    6. This is quite interesting on cognitive decline and ageing:http://onlinelibrary.wiley.com/doi/10.1111/anae.12510/abstract;jsessionid=B86F390E6CFA6921C76ED7B8E66E66A9.f04t01

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  12. It makes it difficult to know what is the 'early' in early effective treatment when you could've had asymptomatic MS for years eg alemtuzumab within 2-3 years of a CIS would seem good, but maybe you've had MS for 12-13 years.

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  13. Article about the work and beliefs of Ella Langer, a professor of psychology at Harvard

    http://www.nytimes.com/2014/10/26/magazine/what-if-age-is-nothing-but-a-mind-set.html


    " ... just as the mind can make things better, it can also make things worse. The nocebo effect is the flip side of the more positive placebo effect, and she says that one of the most pernicious nocebo effects can occur when a patient is informed by her doctor that she is ill. The diagnosis itself, Langer says, primes the symptoms the patient expects to feel."

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  14. Interesting reading the comments above, without seeing the Method section cannot really comment on the crucial aspect of the participants - selection, schooling etc. Possibly MD2 can wave her magic wand and procure them.

    Like other well educated individuals who commented, symptoms in my past, with the benefit of hindsight probably indicated earlier MS. But, nothing at all debilitating. For me, physical trauma and stress have correlated with diagnosis. I would have put a very brief episode of what may have been considered as optical neuritis and a tingling arm 15 years prior to diagnosis as something I now recognise. Since, diagnosis, at age 49 I have completed an honours degree in Science ( was in final year Honours Psychology for a career change as a Forensic Psychologist when diagnosed) then to a Master's Degree in Social Change and Development, to currently undertaking Master of Public Health majoring in Clinical Epidemiology. In total I have spent 19 years in tertiary study - I have an obsessive love of learning. My neurologist stated, and I believe the evidence tends to point to this, that higher education is indeed "protective" for the brain.

    To have been diagnosed in my 30's, quite frankly would have distressed me terribly, and at that point in time there were no DMD's available. I was very well for 15 years, had the odd day of fatigue which I put down to working too hard. Being diagnosed would have done nothing for my mental health and would have probably fed into anxiety about wondering what was going to happen. A minor operation seems to have been the trigger for my first MS attack. To Anon, who quoted Ellen Langer on the "nocebo"effect, there are numerous cases in medical literature that would support her view. Her studies into the human mind have extended over 40 years and she is an expert in the field. She understands placebo/nocebo very well. The medical model poorly trains doctors in the field of the psychology of the mind of their patients and of the effects that a hopeful versus doomsaying doctor, might have on the outcome.

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    1. Helen: So you were diagnosed at 49, completed 2 degrees after that, and are now studying for a 3rd - did I understand that right?
      If so, it's a most inspiring story and gives me a lot of hope

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    2. Hi Helen, I believe that my MS flare that led to dx was brought on by hormone therapy for possible conception as well as fibroid removal surgery atop a stressful week at work. I yearned to get a degree in hard science but always felt it was a "not in this lifetime" pursuit-inattentive, "lazy," and not very good at maths. I did have a great love of literature and art, and was awarded a full, four year scholarship to a highly-selective college. However, I always felt like a fraud because my maths board score was so low. In HS I had fine motor tremor and erratic behaviors. I would have liked to have known it was biologically based (as opposed to a character defect or chemical imbalance), but on the other had it would have been very depressing to me and I think I may have well given up. I am sure the person I would have been if I wasn't sick would have a degree in biology. :( I definitely have worsening cognitive problems right now with short attention span, memory problems, executive functioning issues, and ability to filter out background noise and dread what the future will bring.

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  15. Prof G and MouseDoctor...why is it so difficult to get hospitals to approve using HSCT to halt MS? It's the only treatment proven to do so, completely halting the disease in 93% of patients worldwide, RRMS, PPMS and SPMS. The procedure is already approved for cancer treatment, insurance companies here are paying for the clinical trials because it's much less expensive than paying for expensive DMD's, even less then Lemtrada! What will it take to get this to be a standard treatment? People are predicting 2022, I've just been diagnosed at 55, I do not have that kind of time and certainly most of us cannot afford to go outside the country for treatment.

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  16. Re "I would have liked to have known it was biologically based (as opposed to a character defect or chemical imbalance)":

    Perhaps all character defects are biologically based too? So let's be more sympathetic to them

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