No treatment for MS-related memory problems

Is rebranding MS a dementia stigmatizing? #MSBlog #MSResearch #ClinicSpeak

"The following meta-analysis shows that we have not found a treatment to for MS-related cognitive impairment. Are you surprised? I am not. The assumptions that drugs that work in Alzheimer's disease will work in MS is simply wrong. The substrate of cognitive impairment in MS is likely  to be very different to Alzheimer's disease. Alzheimer's cause a selective loss of neurones in specific areas of the brain and the type of cognitive impairment in Alzheimer's is different to that what we see in MS. 

"I have been lobbying Pharma, who are best at drug discovery, to focus on the issue of MS-related cognitive impairment; the unmet need is massive and having something that improves cognitive impairment in MSers will have a big impact on the quality of life of MSers. Fatigue, in particular mental fatigue, is driven by cognitive impairment. MSers adapt  to cognitive impairment by using their reserve to complete cognitive tasks. The mental effort in doing this is exhausting and leaves MSers very tired. I am sure that this is the main driver of early unemployment in MS. In Europe 50% of MSers are unemployed within 10 years of diagnosis when they are unlikely to be physically disabled (EDSS <= 3.5); why? Cognitive impairment, fatigue and mood all play a part in early unemployment rates, not to mention social stigma. This is why a treatment for MS-related cognitive impairment is so important. The other issue is premature ageing; we all rely on cognitive reserve to fight off the ravages of ageing. MSers who have lost their cognitive reserve will be less able to adapt to ageing. This is why I am actively promoting early effective treatment to protect and save as much brain as possible so MSers can age well. Prevention is better than cure hence early effective treatment with DMTs that delay or slow brain atrophy are a "no brainer" to me. What do you think?"

"I did launch a campaign earlier this year to rebrand MS a dementia, but got slapped down by MSers and my peers. They think term dementia is too stigmatizing. What do yo think? The issue is if we don't focus on this issue we won't get regulators and payers to shift the paradigm to early highly-effective treatments."

"For those of you with cognitive impairment you may be interested in the MS Trust's staying smart programme. A few MSers I look after who tried the programme have said that it helps them."

Epub: He et al. Pharmacological treatment for memory disorder in multiple sclerosis. Cochrane Database Syst Rev. 2013 Dec 17;12:CD008876.

BACKGROUND: This is an update of the Cochrane review "Pharmacologic treatment for memory disorder in multiple sclerosis" (first published in The Cochrane Library 2011, Issue 10). MS is a chronic immune-mediated, inflammatory, demyelinating, neurodegenerative disorder of the central nervous system (CNS) and can cause both neurological and neuropsychological disability. Both demyelination and axonal and neuronal loss are believed to contribute to MS-related cognitive impairment. Memory disorder is one of the most frequent cognitive dysfunctions and presents a considerable burden to MSers and to society due to the negative impact on function. A number of pharmacological agents have been evaluated in many existing randomised controlled trials for their efficacy on memory disorder in MSers but the results were not consistent.

OBJECTIVES: To assess the absolute and comparative efficacy, tolerability and safety of pharmacological treatments for memory disorder in adults MSers.

SEARCH METHODS: We searched the Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group Trials Register (24 July 2013), PsycINFO (January 1980 to 26 June 2013) and CBMdisc (1978 to 24 June 2013), and checked reference lists of identified articles, searched some relevant journals manually, registers of clinical trials and published abstracts of conference proceedings.

SELECTION CRITERIA: All double-blind, randomised controlled parallel trials on pharmacological treatment versus placebo or one or more pharmacological treatments in adults MSers who had at least mild memory impairment (at 0.5 standard deviations below age- and sex-based normative data on a validated memory scale). We placed no restrictions regarding dose, route of administration and frequency; however, we only included trials with an administration duration of 12 weeks or greater.

DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data. We discussed disagreements and resolved them by consensus among review authors. We contacted principal investigators of included studies for additional data or confirmation.

MAIN RESULTS: We included seven randomised controlled trials (RCTs) involving 625 MSers mostly with relapsing-remitting, secondary-progressive and primary-progressive MS, evaluating the absolute efficacy of donepezil, ginkgo biloba, memantine and rivastigmine versus placebo in improving memory performance with diverse assessment scales. Overall, clinical and methodological heterogeneities existed across these studies. Moreover, most of them had methodological limitations on non-specific selections of targeted sample, non-matched variables at baseline or incomplete outcome data (high attrition bias). Only the two studies on donepezil had clinical and methodological homogeneity and relatively low risks for bias. One RCT evaluating estriol versus placebo is currently ongoing.We could not carry out a meta-analysis due to the heterogeneities across studies and the high attrition bias. A subgroup analysis for donepezil versus placebo showed no treatment effects on total recall on the Selective Reminding Test (mean difference (MD) 1.68; 95% confidence interval (CI) -2.21 to 5.58), total correct scores on the 10/36 Spatial Recall Test (MD -0.93; 95% CI -3.18 to 1.32), the Symbol Digit Modalities Test (MD -1.27; 95% CI -3.15 to 0.61) and the Paced Auditory Serial Addition Test (2+3 sec) (MD 2.23; 95% CI -1.87 to 6.33). Concerning safety, the main adverse events were: diarrhoea (risk ratio (RR) 3.88; 95% CI 1.66 to 9.05), nausea (RR 1.71; 95% CI 0.93 to 3.18) and abnormal dreams (RR 2.91; 95% CI 1.38 to 6.14). However, the results in both studies were subjected to a serious imprecision resulting from the small sample sizes and the low power of test (lower than 80%), which contributed to a moderate quality of the evidence. No serious adverse events were attributed to the treatments in all experimental groups.

AUTHORS' CONCLUSIONS: We found no convincing evidence to support the efficacy of pharmacological symptomatic treatment for MS-associated memory disorder because most of available RCTs had a limited quality. Whether pharmacological treatment is effective for memory disorder in MSers remains inconclusive. However, there is moderate-quality evidence that donepezil 10 mg daily was not effective in improving memory in MSers with mild memory impairment, but had a good tolerability. Adverse events such as nausea, diarrhoea and abnormal dreams were not frequent but were associated with treatment. Ginkgo biloba, memantine and rivastigmine were safe and well tolerated and no serious adverse effects were reported. Future large-scale RCTs with higher methodological quality are needed.

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