#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

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