Thursday, 28 September 2017

#ClinicSpeak: how early is too early?

Cognitive impairment may begin before the first attack of MS. #ClinicSpeak #ResearchSpeak

Summary: The following post makes the case to change the MS diagnostic criteria to include asymptomatic MS. This will allow us to identify high-risk patients for treatment at an earlier stage. 

I was at a meeting early this week I voiced my disappointment that the new diagnostic criteria for MS will not extend the diagnosis of MS into the asymptomatic phase. That is the radiologically isolated syndrome or RIS, will not be defined as a disease. This has implications for people with RIS (pwRIS). Because they don't have a disease they won't be eligible for treatment. 

Is this a problem? The study below shows that over 25% of pwRIS have significant cognitive impairment. These findings underpin the observation that one of the major hidden burdens of MS is the early impact it has on cognition. Fortunately, most of you won't notice early cognitive impairment as your brain has the remarkable ability to compensate for damage. The consequences of this adaptation are increased energy consumption and the need for greater concentration and attention to complete cognitive tasks. As you know pwMS are easily distracted and find it difficult to multi-task cognitively. Compensating with cognitive impairment is associated with mental fatigue and other hidden symptoms such as depression and anxiety. 

The argument against diagnosing MS earlier is the possibility of over-diagnosis, over-medicalisation and over-treatment of pwMS. I agree that this is potentially the downside of defining asymptomatic MS as a disease. Interestingly, with the other neurodegenerative diseases, in particular, Alzheimer's disease and Parkinson's disease, the diagnostic criteria are evolving to diagnose the diseases earlier. Why? So that disease-modifying therapies can be tested at an earlier phase, before too much brain has been lost. Is MS any different? We know that a proportion of pwRIS already have significant brain atrophy and cognitive impairment, why wouldn't we want to protect their brains? 

A small number of people diagnosed with MS initially present to memory clinics with dementia and are subsequently diagnosed with MS. These people must have RIS for many years prior to developing frank dementia. The question we need to ask is do we want to protect the group of people who won't develop MS, or problems from their RIS, or do we want to identify the pwRIS who are likely to develop problems in the future, for example, dementia? 


Please note that is many areas of the country neurologists don't treat CIS. Do you think they would treat RIS? The good news is that there are two trials of DMTs in patients diagnosed with RIS. A US trial testing DMF (Tecfidera) to placebo and a European trial testing Teriflunomide (Aubagio) to placebo. The primary outcome in these trials is time to first attack, i.e. time to CIS or MS. Maybe we will have to wait for the outcome of these trials before we can challenge the diagnostic criteria for MS? Or we could be bold and do a Donald Trump; we could simply ignore the new criteria and define a new set. We could call them the Alternative MS Diagnostic Criteria?

Amato et al. Association of MRI metrics and cognitive impairment in radiologically isolated syndromes. Neurology. 2012 Jan 31;78(5):309-14.

OBJECTIVE: To evaluate cognitive changes in a cohort of radiologically isolated syndromes (RIS) suggestive of MS and to assess their relationship with quantitative MRI measures such as white matter (WM), lesion loads, and cerebral atrophy.

METHODS: We assessed the cognitive performance in a group of 29 subjects with RIS recruited from 5 Italian MS centers and in a group of 26 patients with RRMS. A subgroup of 19 subjects with RIS, 26 patients with RRMS, and 21 healthy control (HC) subjects also underwent quantitative MR assessments, which included WM T1 and T2 lesion volumes and global and cortical brain volumes.


RESULTS: Cognitive impairment of the same profile as that of RRMS was found in 27.6% of our subjects with RIS. On MR scans, we found comparable levels of lesion loads and brain atrophy in subjects with RIS and well-established RRMS. In subjects with RIS, high T1 lesion volume (ρ = 0.526, p = 0.025) and low cortical volume (ρ = -0.481, p = 0.043) were associated with worse cognitive performance.

CONCLUSIONS: These findings emphasize the importance of including accurate neuropsychological testing and quantitative MR metrics in subjects with RIS suggestive of MS. They can provide a better characterization of these asymptomatic subjects, potentially useful for diagnostic and therapeutic decisions.


CoI: multiple

13 comments:

  1. Are you advocating population screening?

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    Replies
    1. Re: "Are you advocating population screening?"

      No, just incidental RIS. Population screening is a different ball game and raises a lot of other issues.

      Delete
  2. Do patients with chronic fatigue syndrome get to have an MRI scan? and if so, do any have RIS?

    I had mono in my teens. Then in my early twenties I went through a period of time of extreme tiredness/fatigue this carried on for a few years and then I recovered. Fast forward 15 years and I had my first MS relapse. I wonder if I might of had RIS during my early twenties.

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    Replies
    1. No not all chronic fatigue patients have an MRI. However, about 3% of patients presenting with CFS turn-out to have MS. Please note it is a small number.

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  3. A RIS or CIS shouldn't be accompanied by a spinal tap by default? If possitive, no need to wait.

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    1. I would always do a LP to aid in the diagnosis of RIS/CIS. You only have one chance to get the diagnosis right and that is in the beginning of the disease. The main reason for doing a LP and CSF analysis is to exclude MS mimics and to test for OCBs. The latter helps with putting the disease into the MS spectrum.

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  4. Completely agree. The common knowledge of symptomatic ms only being the tip of the iceberg... And yet ignoring this fact is damaging and counterproductive.

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  5. May be you should do a trial of cladribine in RIS? Extend the CIS data earlier.

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    Replies
    1. Very good idea. The question is risks and benefits. Based on its current EMA license ethics committees may have a problem give us permission to do this study.

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  6. I remember a post from a couple of months ago where you said that it took an average of 8 years for most people to get a diagnosis of MS? Surely the energy and resources needs to be targeted at making sure the group of people with symptoms are getting access sooner.

    I don't think I would want treatment at RIS anyway. It Might never happen. Also I've never been particularly convinced that taking a CRAB at CIS/RIS stage would have any impact on my long term outcome anyway.

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  7. I know that I wouldn't have been sent for an MRI if it wasn't for my family history of MS. I am very lucky, I was caught before serious damage was done. Could someone explain why we couldn't try a small population screen? If a small town in northern Scotland has a history of MS, how is that different from my family history.

    As I have said before I think the focus should shift to earlier diagnosis for MS and it should be treated like an emergency- steroids and Rituxan within 24 hrs.

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  8. The MS Society UK target is to have 70% pwRRMS on dmt. Surely this should be 100%? Perhaps it should be 100% offered dmt? Anyway, don't hold your breath for treatment for CIS let alone RIS here in UK, hard enough getting confirmed MS treated.

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  9. Prof GG, since MS-related damage can go unnoticed many years prior to MS diagnosis, how can one define the point in the time when the disease got into action for the first time?

    I am asking with regards to the claim that an EBV infection PRECEDES almost all MS cases.

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