OBJECTIVES: A study of cognitive, psychological and social aspects in benign MS.
METHODS: 163 benign MS’ers (defined as disease duration > or = 15 years and Expanded Disability Status Scale (EDSS) score < or = 3.0 ) underwent neuropsychological testing on the Rao’s Brief Repeatable Battery (BRB)* and the Stroop test*, evaluation of depression on the Montgomery and Asberg Depression Rating Scale (MADRS)*, of fatigue on the Fatigue Severity Scale (FSS)* and of handicap on the Environmental Status Scale (ESS)*.
Patients’ cognitive performance was compared with that of 111 demographically matched healthy controls.
Cognitive impairment was defined as the failure in at least 3 tests, using the fifth percentile of controls’ performance as the cut-off point.
* these are all standardised measurement scales.
RESULTS: Cognitive assessment led to the identification of 74 subjects (45%) with cognitive impairment. Significant fatigue was found in 80 subjects (49%) and depression in 88 patients (54%). In comparison with cognitively preserved subjects, cognitively impaired patients exhibited higher handicap scores on the ESS (p = 0.005). In the regression analysis, only EDSS scores were significantly associated with cognitive impairment (OR 1.8, 95%CI 1.2-2.6).
CONCLUSION: Current definitions of benign MS may overestimate this entity, since they are mainly weighted for the patients’ motor abilities and fail to capture relevant disease-related cognitive, psychological and social problems.
“Despite fulfilling a contemporary definition of benign MS this study shows MS’ers with so called benign MS have significant problems with cognitive impairment (45%), fatigue (49%) and depression (54%).”
Isn't the real issue here that 'benign' is simply a misnomer as it (usually wrongly) implies a version of MS without any negative effect as people have come to understand 'benign' in cancer lingo? This is why the term is so controversial. Even 'benign' MS will likely have some impact on the person; an EDSS of 2 after 15 years is 'benign' by MS definition but actually means it causes the person objective neuro signs that they are hardly likely to welcome. In fact, one interesting question – what is the prevelance of truly benign cases of MS (i.e. EDSS of 0 after 15 years but MRI findings and subjective symptoms eg tingling/mild numbness etc which don't meet EDSS criteria). They do exist (people diagnosed on autopsy, MRI findings in siblings of MS patients etc) but these truly benign cases are almost certainly very rare, I think.That said re: benign MS, it is surely undoubtedly the case that MS is an incredibly varied disease in terms of its impact ranging from really quite mild to extremely severe. Many people – up to 45% in community populations – have what could fairly be described as 'mild' MS. That's not to say it isn't a significant feature of their lives and even these people will have a spectrum of severity, of course. But, repeating the point that started this controversy yesterday, people shouldn't automatically believe their MS is going to be severe when there's, statistically, a good chance of it being mild; still something of significance, but not life destroying. That optimism is, understandably given their raison d'etre, largely missing from most websites focused on MS including the MS Society etc. A newly diagnosed person visiting that site could be forgiven for descending into despair when confronted, quite early on, with pages detailing info on carers and wheelchairs etc. The aim of DMT, absent a true cure for MS, is surely to make the MS as 'mild' as can be for everyone? Predicting the mild from the severe is very difficult, hence why some people will not want to take the chance and take aggressive treatments early. That should be their choice but that's back to another debate…
I totally agree with this viewpoint. My MRI scans suggest a mild form of MS but the physical symptoms are really present all the time. And there is no crystal ball in this disease. What I would be interested in seeing is a cost analysis of all the DMTs… both first and second line treatment… an analysis that is split into two areas:1. The actual cost to NHS at point of treatment2. The savings NHS might have from a large cohort analysis of disability progression prevention and the financial impact of the state (isn't there a study that shows £x for each increase in EDSS score?)Then the informed patient could argue that even with a mild form of the disease taking 2nd tier drugs could be cost effective. The risk issue is something that, I think, informed patients should be allowed to take. Not paternalistic doctors. I've had two endocrinologist friends of mine say that the side effects of Campath thryoidism are alot more manageable than PML, for instance. I wonder if the new NICE guidelines are going to factor in informed patient choice as well as cost implications. Probably the latter. But I imagine that will mean less access than more.
Re: "Then the informed patient could argue that even with a mild form of the disease taking 2nd tier drugs could be cost effective. The risk issue is something that, I think, informed patients should be allowed to take. Not paternalistic doctors. "I agree! This is what health economists do and what NICE tries to do; except NICE only looks at direct NHS costs and not indirect or societal costs.
My sense is that, for many MSers, the fear of the future is often worse than the reality of the present. That's not to minimise the difficulties of the present for many but the overwhelming sentiment I hear is "I can deal with what I have now but I'm all consumed by the fear of what 'might' happen." That is certainly my position – my current symptoms are, if I'm honest, a nuisance, nothing more. Yet all I think about, day and night, is MS. Why? Because I am terrified about what will happen in 1,5,10,15,20 and 30 years (each on different levels – in 5 years I worry my young children will not have a fully involved Dad, in 30 years I worry my wife's retirement will be scarred by having to care for a disabled husband etc etc). This fear can be as disabling in its own right as the actual real symptoms. What QoL is there for people spending their whole time paralysed by the fear of what tomorrow might bring? This is why I think posts like the above, bringing some balance to the future prospects for MSers are really important. They help people like me get some perspective amidst the worry. It is also why I think I should be allowed to choose what treatment best suits me. If Alemtuzumab makes me think I've done all I can do and takes away a little of the fear and replaces it with a dose more optimism then it will have done more than just it's clinical job… Does that make sense to people?
I absolutely understand that and that's why I took my medication in my own hands – abandoned interferons and switched to fumarate on my own accord. And I feel better just by taking control.I believe that as long as scientists/doctors are not able to predict definately what kind of MS I will be having in the future they have no right to blight my present time by horror scenarios. It's simply unethical to seed fear without any hard evidence to the contrary and then wonder why MSer are having extreme stress and depression.
There's clearly a balance to be drawn. There's plenty of evidence to justify a degree of fear. People shouldnt refuse treatment because they are wrongly lead to believe their MS will be fine. It's just sometimes the other side of the coin – allowing some optimism – isn't presented as well.
What form of Fumerate are you on and how did you access it? My understanding was only Fumaderm was similar enough to BG12 and that that is prescription only and in Germany only?
These responses should, Prof G, get you to do a questionnaire: "Do you think that your concerns about your prognosis of MS are properly addressed by your neurologist?"Or something like that… what do you think?I wonder, too, if there is an issue of gender here too. Is there something about men with MS responding worse to the diagnosis emotionally, given the societal expectations of bread-winning and all the rest? I know it is, or at least should be, an increasingly even playing field when it comes to earning in the household (and my wife earns more than I do) – but we as men often can't easily consider a future where we are the ones cared for rather than the ones in control and being strong…I am not diminishing how women react to MS prognosis here. It is hard for both sexes and I think women have often the burden of MS and childcare etc. to contend with.I am just saying that, as a man, I feel I have been told all my life to provide and protect. And now I wonder if I will be able to do either.There is some evidence that men's outcome is worse than women's too. Which doesn't help.I wonder if a London based Men with MS support group for the newly diagnosed (and others) would be of use at all? I'd be happy to suggest a place and a time if there is interest out there…It seems when women get a disease they set up a support group. When men do they set up a shed. (you get my point, no?)
The evidence re men's disease worse than women's is weak and has been contradicted in many studies. That said, you are spot on re: the burden on men as 'providers' being something that worries newly diagnosed. There is, in reality, no reason why the vast majority with MS can't carry on working; especially with proactive management with the right DMT. The fact that Iain on another post is talking (albeit not contemplating) about suicide says it all in terms of only the worst side of the condition being presented. That 45%-ish have mild (not benign!) MS and yet newly diagnosed fear the very worst says something is wrong with the public image of the disease. We need to hear more good news stories – positive studies, people doing well after many years etc. Most forums are full of people at the worse end of the spectrum as, I guess, one would expect (those barely affected aren't spending time in MS forums!). In terms if studies, for example, a 2006 British Columbia population study (before DMT's) showed 'population progression slower than previously thought' and showed 28 years average to EDSS 6 (cane) and that only 20% needed a cane after 15 years. The average age to need a cane was 58.8 – 60.1 years old. I realise EDSS has its flaws but I can live with needing a cane at 60 – and that's as an average, not best case. It's needing a cane at 40 that terrifies me. That's the kind of positive study that brings much needed hope and shouldn't be hidden away. I have MS but that doesn't mean my life is over or that I will be disabled, by any means, and there should be more of that message (albeit with a heavy dose of 'but you could be so make sure you treat!).
Re: "It's just sometimes the other side of the coin – allowing some optimism – isn't presented as well."It is important to know the facts about the disease. Reality is what its about; this is the only way you can make informed decisions about your treatment. This blog is very optimistic about the emerging DMTs and neuroprotection; so it's not all bleak!
Re: "These responses should, Prof G, get you to do a questionnaire: "Do you think that your concerns about your prognosis of MS are properly addressed by your neurologist?"Good idea; I will run this survey next!
I agree re: realism – please just try and keep some positivity aside from just DMT related hope! Remember, people are coming to terms with a difficult diagnosis and they should know they have an almost equal chance of not being badly affected as being moderately/badly combined.
I have a question. What determines why some people have mild MS symptoms and others really severe? I know lesion location impacts type of symptom but do we know why some people have very mild tingling where others are completely paralysed from a lesion in the same spot, for example? Is it the strength of immune response therefore degree of demyelination? Is it amount of inflammation? I'm not thinking here of degree of activity (ie frequency of relapse) but severity of symptoms during a relapse. Are some people's immune system 'more' wrong? And can we measure any of this? Or is the answer we simply don't know? Although somewhat unpredictable, my neuro told me that the immune response in terms of severity tends to be relatively consistent for each person ie whilst you can't be totally assured of mild MS based on severity/mildness of early symptoms, it is reasonably predictive of how mild/severe future attacks may be. In other words, MS is massively heterogenous between different people but reasonably homogenous in each individual (albeit with no guarantees). I.e people whose first attack is very mild tend to do much better longer term than people whose first attack is really severe. Do you agree with this?
If MS was that predictable we would be able to prognosticate accurately we can't. In other words a history of mild attacks in the past does not mean that future attacks will be mild. Why one lesion causes less damage than others is complex. It may relate to the type of inflammation, size and location of the lesion and the state of the pathway being affected. For example larger lesions in strategic locations are more likely to cause damage that small lesions in areas that are not eloquent, i.e. an area that results in symptoms. If a pathway has many lesions affecting it and has managed to compensate the next lesion in this pathway may be sufficient to cause permanent damage. This is why we think the legs are affected more than the arms in MS. The length of the nerve fibres to the legs are longer than those to the arms, therefore they are more likely to accumulate damage over time. This is a complicated area and I am not sure this answer addresses your question that well.
Is one type of benign MS where there are no/few attacks beyond the earliest one or two? We know that only 80%-ish of CIS with abnormal MRI becomes MS even on a radiological only basis, meaning no more attacks; can you have a second attack and then no more ever? Or is it the case that once you have a second attack and convert from CIS to RRMS you will always have further attacks then? A related question – do multiple lesions mean multiple attacks or can one attack cause multiple lesions? Eg does 5 lesions equal 5 attacks/relapses meaning more are almost certain or could one attack cause 5 lesions and then there never be another attack (albeit odds on that there will be as above)?
For every clinical relapse there may be ten of more seperate lesional events in the brain. This is because many of them are not clinically eloquent.
Hi Mouse. Not quite what I meant – sorry! Does 5 lesions mean there have been five separate events over time or could all five have occurred as part of one single temporal event of 'immune malfunction'? In the former case, if the clinical event is the fifth actual 'event' then a sixth etc would seem overwhelmingly likely (on the basis it's happened so many times before, why wouldn't it continue). In the latter case, a second event (which may also cause multiple lesions) is slightly less so as it seems possible to have a one off incident of demyelination. Does that make sense? I guess the question is, can multiple lesions all occur at the same time and then none occur for a period of time thereafter? A related question is in MS, are lesions occurring all the time but we just can't see all of them even on MRI or does the immune system 'behave' for a period of time and the misfire causing another lesion?
Re: "Does 5 lesions mean there have been five separate events over time or could all five have occurred as part of one single temporal event of 'immune malfunction'?"Both, lesions can come in clusters, but they can also come one at a time. Typically one lesion in an eloquent area causes a relapse and the other lesions don't cause symptoms. We believe it is the accumulation of lesions over time that causes the damage and they are related to the number of attacks on average. However, we see MSers with few attacks and a large lesion load; these MSers are either lucky to not have had relapses or lesions in eloquent areas or unlucky because if they had had more attacks, i.e. lesions in eloquent areas, they would have been on DMTs earlier or escalated to more active treatments. This is why we can't rely on clinical attacks to monitor this disease and need to do serial MRI scans.
So how would you treat CIS based on your early/aggressive theory?
I am not sure. There quite a lot of factors to consider and it all depends on your life stage and world view. When are risks acceptable to you and when are they not?
What's the choice between? No treatment and IFN etc or IFN and 'second line' more risky therapies? Would not treating CIS at all equate to the treatment nihilism to which you often refer? If one has a reasonably high risk attitude – what would you propose (leaving aside NICE etc for the purpose of this) a newly diagnosed CIS to do?
If CI almost always = RRMS eventually then surely the arguments for treating CIS are the same as for treatming RRMS: nihilism or early & aggressive?In respect of the latter, isn't the answer always: the patient should be given the most effective drug with a side-effect/safety profile they are willing to accept? The problem is, even leaving side effects aside, it is so hard to judge which is the most effective as (a) the studies are not like-for-like and rarely compare DMTS and (b) what measure best evidences effectiveness (relapse rate, MRI measures, disability progression, 'chance' of possibly preventing SMPS in the future, potential neuroproective qualities etc) and (c) issue such a relapse on discontinuation eg Tysabri and Fingolimod aren't accounted for in trials. If one was to look solely at effectiveness (i.e. ignore risk which should be for the patient to judge on a fully informed basis) can we have a rough and ready attempt at putting DMTs into some sort of hierarchy of effectiveness?Here's my go at a DMD Top 10 – perhaps others can share their 'ranking' table?! I doubt Prof G or Mouse can play (too many conflicts) but it'd be fascinating if they would.1. Alemtuzumab (and not because of its social media profile!) A ARR of 0.11 can't be sniffed at; proven better efficacy vs IFN; stable MTR – might this be the induction therapy to prevent SPMS if given early enough??2. RituximabIncredible MRI results (virtually stopped sub-clinical activity at 96 weeks); missed out on top spot due to lack of phase 3 trials.3. BG12 Oral. Better than IFN and GA. Possibly neuroprotective – what's not to like?!4. IV CladribineScandalous that it is effectively parked in the UK (NB it is licensed in Oz and Russia if anyone fancies a trip and can be prescribed off-label in the UK if you have a good neuro).5. FingolimodVery effective. Possilby aids remyelination (trials underway). Some issues re: discontinuation (I think it was MouseDoc that used an analogy – it doesn't get rid of the bad guys, it puts them in prison; but when the prison is opened up…).6. TsyabriMaybe should be higher. Not down here because of PML – rather same issue as Fingolimod (discontinuation and large 'rebound' effect) and this is very likely for most people at some point in treatment. Is this drug just storing up trouble for the future?=7. Teriflunomide and LaquinimodCan't pick here. Not brilliant at relapses but might just be neuroprotective. Trouble is, it'll take years to find out….9. GAJust pips the IFNS because it doesn't make you feel like you have the flu all the time…10. IFNSSolid choice. Bad press hides the fact they work very well for 20% of people who take them… Anyone else want to play? Perhaps Prof G could do us a top 10 of 'coming soon' drugs to keep us all optimistic about the future?!
Can anyone answer the original question above – if 10-20% of CIS doesn't become RRMS, that presumably means, by definition, no further attacks. Once a second attack occurs enabling diagnosis are third and subsequent then inevitable (ie once MS 'gets going' it doesn't stop) or will some people be diagnosed and then be lucky enough never have another attack?
Yes, very rarely you can have a second attack and not a third attack. Some of these MSers then present 10 to 15 years later with SPMS. I assume others may remain benign, but we don't see these as they drop out of long-term hospital follow-up.
I'm actually interested in the timing question. Is MS an ongoing process – never stopping – or, like relapses, does it come and go? Ie is damage permanently being occasioned or is it just during periods of activity that, for most people, come and go?
In the majority of MSers, without starting a DMT, MS is an ongoing process, i.e. you can show an increase in lesion load and disease activity on annual basis. The minority, destined to have benign disease, may have long periods without disease activity. The questions we have is if we switch off disease activity with DMTs, no relapses, no MRI activity, no progression have we actually stopped MS? I suspect not as a lot of MS disease activity may occur at a microscopic level, too small, to be picked-up by MRI. I am attending a meeting at the Cleveland Clinic in a few weeks time, that is dedicated to the concept of disease activity free; how we define it and how do we achieve it!
Dear Gavin GiovannoniFirst time on site here. Are you able to share your profession & any findings (publications etc.) On the outcomes of the Cleveland Meeting you mentioned in your posting dated August 25Th 2012. I would be most interested.
Hello againI do believe I have located your presentation. Here in Australia, MRI'S are readily available if you hold insurance. I like your concept of MS being biological. Do you ever include non uk residents in clinical trials? Grazie
Yes, we do. Most large studies are involve many countries including Australia.
How does one find out more?
Clinical trials.gov and maybe MS Socieities
I'd love to see Professor G and MouseDoc's top 10 of efficacy! That's something of huge, tangible interest to us facing difficult decisions every day re: DMTS? Take safety out of the equation and just tell us which works best and let us decide on the safety-side of things… For me, the criteria should be 'which most reduces my chance of disability between now and when I die' (i.e. least relapses during RRMS phase plus best chance of stopping SPMS).