Background

Multiple sclerosis (MS) is an autoimmune, neurodegenerative, inflammatory disorder that affects nerve fibers of the central nervous system.1 Myelin, the protective sheath surrounding nerve fibers, becomes damaged by immune-mediated destruction, resulting in demyelination and axonal as well as neuronal loss in the central nervous system. Demyelination and axonal as well as neuronal loss are believed to contribute to MS-related cognitive impairment. Memory disorder is one of the most frequent cognitive impairments in MS, with estimates suggesting that 40-65% of individuals are affected. Typically, long-term and working memories are affected; however, specific cognitive impairments may differ depending on the MS subtype.

There are a number of pharmacological interventions for memory disorder in MS, including disease-modifying drugs (e.g. interferon [beta]-1a and [beta]-1b, glatiramer acetate, natalizumab, mitoxantrone, fingolimod, teriflunomide, dimethyl fumarate and alemtuzumab). Other therapies specific for memory disorder include acetylcholinesterase inhibitors (e.g. donepezil and rivastigmine), psychostimulants (e.g. methylphenidate, L-amphetamine sulfate, modafinil, amantadine and pemoline), N-methyl-D-aspartate antagonist (e.g. memantine) and other pharmacological agents such as Ginkgo biloba extracts, aminopyridines and cannabinoids.

Evidence that supports the use of these pharmacological agents in the treatment of memory loss in patients with MS is unclear, with inconsistencies in study results. Therefore, it is uncertain whether these pharmacological interventions are effective in treating memory disorder in MS and whether they are well tolerated to use in this population group.

Objective(s)

The key aims of the review were:

1. to assess the efficacy, tolerability and safety of pharmacological treatments for memory disorders in patients with MS;

2. to determine which of these treatments are the most effective, most tolerated and least harmful.

Intervention/methods

Studies considered were double-blind, randomized controlled parallel trials on pharmacological treatments for memory disorders in patients with MS. Study participants were adults with a definite diagnosis of MS. All MS subtypes were considered involving patients who showed at least mild memory impairment with 0.5 standard deviation (SD) below age-based and sex-based normative data using a validated memory scale.

Interventions included pharmacological treatment for memory disorders (any dose, route of administration and frequency) administered for at least 12 weeks, compared with placebo treatment, or one or more pharmacological treatments.

Primary outcome measures were memory performance at 12 weeks at least measured with one of the following memory scales: California Verbal Learning Test - Second Edition, Spatial Recall Test (SRT), Brief Visuospatial Memory Test - Revised, Wechsler Memory Scale - Third Edition, 10/36 SRT, 7/24 SRT, Backward Digit Span, Logical Memory subset of the Wechsler Memory Scale - Revised, Rey Auditory Verbal Learning Test, Paced Auditory Serial Addition Test or Symbol Digit Modalities Test; and the number of patients with the five most frequently reported adverse events at week 12 or later.

An extensive search of the literature was conducted using a number of databases to identify studies for inclusion. Two independent authors independently evaluated studies for quality and extracted data.

Results

Seven randomized controlled trials (625 participants) were included, evaluating the efficacy of donepezil, Ginkgo biloba, memantine and rivastigmine compared with placebo in improving memory performance using differing assessment scales. Participants mostly had relapsing-remitting, secondary-progressive and primary-progressive MS. The majority of studies had methodological limitations. Two studies of moderate quality were considered to be the highest quality, and included donepezil with small sample sizes and low power of test. Subgroup analysis of these two studies showed no observed treatment effects for donepezil versus placebo on total recall on SRT [mean difference 1.68; 95% confidence interval (CI) -2.21 to 5.58], total correct scores on the 10/36 SRT (mean difference -0.93; 95% CI -3.18 to 1.32), Symbol Digit Modalities Test (mean difference -1.27; 95% CI -3.15 to 0.61) and the Paced Auditory Serial Addition Test (2 + 3 s) (mean difference 2.23; 95% CI -1.87 to 6.33). The main adverse drug events were diarrhea (risk ratio 3.88; 95% CI 1.66 to 9.05), nausea (risk ratio 1.71; 95% CI 0.93 to 3.18) and abnormal dreams (risk ratio 2.91; 95% CI 1.38 to 6.14).

Conclusion

The systematic review authors concluded that there was no convincing evidence to support the use of donepezil, Ginkgo biloba, memantine and rivastigmine as effective symptomatic treatments for memory disorder in adults with MS. There was moderate-quality evidence that donepezil at a daily dose of 10 mg was ineffective at improving memory in adults with MS with mild memory problems. Donepezil was well tolerated, with side effects of nausea, diarrhea and abnormal dreams only infrequently reported. No serious side effects were reported for Ginkgo biloba, memantine and rivastigmine and they were also well tolerated.

Implications for practice

Based on the existing, limited evidence of low methodological quality, pharmacological interventions such as donepezil, Ginkgo biloba, memantine and rivastigmine are well tolerated, but they are not effective at treating MS-associated memory disorder, and therefore should not be considered for this indication. Further research is required in this area using high-quality methodological studies with larger sample sizes to better inform nursing practice.

Reference