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).
Multiple sclerosis (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 people with MS 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 people with MS but the results were not consistent.
To assess the absolute and comparative efficacy, tolerability and safety of pharmacological treatments for memory disorder in adults with MS.
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.
All double-blind, randomised controlled parallel trials on pharmacological treatment versus placebo or one or more pharmacological treatments in adults with MS 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.
We included seven randomised controlled trials (RCTs) involving 625 people 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.
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 patients with MS remains inconclusive. However, there is moderate-quality evidence that donepezil 10 mg daily was not effective in improving memory in MS patients 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.