Pharmacologic treatment for memory disorder in multiple sclerosis
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To assess the absolute and comparative efficacy, tolerability and safety of pharmacologic treatments for memory disorder in patients with MS.
Background
Description of the condition
Memory disorder is the most frequent cognitive impairment in patients with multiple sclerosis (MS), affecting an estimated 40% to 60% of patients (Rao 1993). As the most frequent domain of cognitive dysfunction in patients with MS, memory disorder can be detected at the early stages of MS, occurs in all disease subtypes and tends to progress over time (Amato 2001). Along with other impaired cognitive domains (such as attention and information processing speed), memory disorder has a great negative impact on the quality of life of patients with MS, concerning activities of daily living, employment and social functioning (Rao 1991a). Despite its high prevalence and the profound functional impact, very little is known about effective strategies for managing memory disorder in multiple sclerosis.
Description of the intervention
Pharmacologic intervention for memory disorder in multiple sclerosis have been based mainly on the use of disease‐modifying drugs (such as beta‐interferons and glatiramer acetate), symptomatic agents for the treatment of fatigue (such as amantadine, pemoline, 4‐aminopyridine), acetylcholinesterase inhibitors (AchEI) (such as donepezil, rivastigmine) and other pharmacologic agents (such as Ginkgo biloba (GB), Memantine, l‐amphetamine sulfate and methylphenidate).
How the intervention might work
The beneficial effects of disease‐modifying drugs may occur in the short term due to the anti‐inflammatory effects of the therapy, and in the long‐term due to the protective effects on tissue damage in the brain. They may prevent or reduce the progression of cognitive dysfunction by containing the development of new cerebral lesions or by reducing the progression of brain atrophy (Amato 2006).
Cholinergic deficits, which can underlie the cognitive deficits seen in patients with MS, might derive from disruption of cholinergic pathways and impaired axonal transport of acetylcholine due to demyelination and axonal transection. Additional mechanisms of action may include increases in cerebral glucose utilization. Further reasons to favour AChEI in the treatment of MS patients lie in the hypothesis that several structures associated with the cholinergic system, such as the temporal lobe, the hippocampus and the thalamus, could be related to cognitive impairment in MS, especially memory (Paulesu 1996).
On the basis of functional imaging studies, it is hypothesized that fatigue and cognitive dysfunction may share a common physiopathological substrate, due to the reduction of glucose metabolism in the brain (Bakshi 2003), but the mechanism of the potential action of symptomatic agents for cognition remains unclear.
GB extracts may improve cognitive performance through their effects on acetylcholine release (Nathan 2000), glycine and GABA receptors, and platelet‐activating factor. GB extracts also contain compounds that have neuroprotective effects (Ahlemeyer 2003).
l‐amphetamine sulfate is a psychostimulant that is currently used as an appetite suppressant and to treat attention deficit disorder. Its major mechanism of action is stimulation of dopamine release and dopamine‐reuptake inhibition,meanwhile, it produce equivalent increase in norepinephrine (NE) in the hippocampus and cortex (Kuczenski 1995).
Glutamate toxicity has been implicated in the pathogenesis of MS (Pitt 2000). Memantine is a N‐methyl‐D‐aspartate (NMDA) antagonist. What role NMDA receptors and glutamate toxicity may play in cognitive dysfunction is uncertain.
Why it is important to do this review
Some existing randomised controlled trials with these oral and parenteral pharmacologic agents have provided promising results. However, it is uncertain whether pharmacologic treatments are really effective to memory disorder in patients with MS and which pharmacologic treatment is the most efficient and least harmful. A systematic review of all relevant randomised controlled trials is the best way to resolve this uncertainty.
Objectives
To assess the absolute and comparative efficacy, tolerability and safety of pharmacologic treatments for memory disorder in patients with MS.
Methods
Criteria for considering studies for this review
Types of studies
All double‐blind, randomized controlled parallel trials on pharmacologic treatment for memory disorder in patients with MS. Adequately randomized or quasi‐randomized trials will be included. Single‐blind or unblinded trials will be excluded. If the required information is not available from the publication, the authors will be contacted to obtain this information.
Types of participants
Adults with a diagnosis of definite MS according to the Poser (Poser 1983) or McDonald (McDonald 2001) or 2005 Revisions to the "McDonald Criteria" (Polman 2005) diagnostic criteria, regardless of MS subtypes (relapsing‐remitting(RR), secondary progressive (SP) or primary progressive (PP)), who display at least mild memory impairment at 0.5 standard deviations below age ‐and‐sex‐based normative data on a validated memory scale.
Types of interventions
Experimental intervention: pharmacologic treatments for memory disorder without restrictions regarding dose, route of administration, frequency. Administration duration ≥12 weeks.
Control intervention: placebo treatment or no treatment or one or more pharmacologic treatments.
Types of outcome measures
Primary outcomes
(1) Improvement of memory, as measured with one of the following memory scales:
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The California Verbal Learning Test ‐ Second Edition (CVLT‐II) (Delis 2000)
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The Selective Reminding Test (SRT) (Buschke 1974)
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The Brief Visuospatial Memory Test‐Revised(BVMTR) (Benedict 1997)
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Wechsler Memory Scale ‐Third Edition (WMS‐III) (Wechsler 1997a)
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The 10/36 Spatial Recall Test (Rao 1990)
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7/24 Spatial Recall Test (Rao 1991b)
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Backward digit span (Wechsler 1997b)
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The Logical Memory (LM) subset of the Wechsler Memory Scale‐R (Wechsler 1987)
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The Rey Auditory Verbal Learning Test (Lezak 2004)
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Paced Auditory Serial Addition Test (PASAT) (Gronwall 1977)
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Symbol Digit Modalities Test (SDMT)(Smith 1982)
(2) Adverse events:The number of patients with the five most frequent adverse effects.
Secondary outcomes
(1) Clinical Global Impression of Change (CGIC) on memory.
(2) MS‐specific health‐related quality of life.
Search methods for identification of studies
No language restriction will be applied to the search.
Electronic searches
The Trials Search Co‐ordinator will search the Cochrane Multiple Sclerosis Group's Trials Register using the keywords listed in Appendix 1.
Details of the Group's search strategies can be found in the 'Specialized Register' section within the Cochrane Multiple Sclerosis Group's module.
Supplementary to the search by the Trials Search Co‐ordinator, we will search:
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PsycINFO (1980‐)
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CBMdisc (1978‐)
The MS Group search strategy will also be adapted as appropriate for PsycINFO and CBMdisc.
Searching other resources
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Checking reference lists of identified articles.
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Manual searches of relevant journals (Annals Of Neurology, Archives Of Neurology, Chinese Journal Of Neurology, European Neurology, Journal Of Clinical Neurology, Journal Of Neurology, Neurology),registers of clinical trials and published abstracts of conference proceedings.
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Personal communication with authors of identified studies, other researchers in the field in an effort to identify further published, unpublished and ongoing studies.
Data collection and analysis
Selection of studies
Titles and abstracts of the identified references will be assessed independently for inclusion by two review authors (He and Guo). Irrelevant trials will be excluded. The full text will be selected for further assessment if the abstract suggests relevance. Papers that do not meet the inclusion criteria will be listed in the "Characteristic of excluded studies" table with the reason for omission. Any disagreement regarding inclusion/exclusion will be resolved by discussion, or by referral to a third assessor (Hongyu Zhou) if necessary.
Data extraction and management
Two review authors (He and Guo) will independently extract data from the selected trials using a pre‐agreed data extraction form. Information about study population, type of intervention, outcome measures, and study design will be extracted. Principal investigators of included studies will be contacted, if necessary, to provide additional data or confirmation of methodological aspects of the study. Any disagreements will be discussed and resolved by consensus among review authors.
Assessment of risk of bias in included studies
The methodological criteria is based on the Cochrane Handbook for Systematic Reviews of Interventions, version 5.0.2 (Higgins 2009).Two review authors (He and Guo) will evaluate independently the methodological quality of the studies regarding method of randomization, allocation concealment, blinding, information on loss to follow‐up, blinding of outcome assessment, selective outcome reporting and other sources of bias. If descriptions of allocation concealment and/or blinding strategies are not clear, the primary author of the study in question will be contacted in an attempt to retrieve the required information. Studies with a high risk of bias will be excluded. Disagreements among the review authors on the methodological quality of the identified studies will be discussed and resolved by consensus.
Measures of treatment effect
The outcomes measured in clinical trials of cognitive impairment often arise from ordinal rating scales. Where the rating scales used in the trials have a reasonably large number of categories, the data will be treated as continuous outcomes arising from a normal distribution.
For continuous variables, pre and post mean values, the mean change from baseline, standard deviation, the number of patients for each treatment group of individual studies will be extracted. Standard deviation will be calculated from confidence Interval or t‐tests when it is not reported. The standard error of the mean change will be calculated from standard deviation. For binary outcomes, the number of patients incurring the event will be extracted.
For trials that have used the same rating scale to assess outcome, the mean difference (historically termed weighted mean difference) will be calculated, with 95% confidence intervals (CI). Where different rating scales or tests have been used, the measure of the treatment difference is the standardised mean difference. For binary outcomes, such as clinical improvement or no clinical improvement, individual and pooled statistics will be calculated as relative ratios (RR) or odds ratio (OR) with 95% CIs, determined by the character of data.
Unit of analysis issues
For numeric values from scales, the unit should be scores.
Dealing with missing data
If sufficient data are not available from published reports, trial authors will be contacted. For binary outcomes, the missing data will be analysed using an intention‐to‐treat analysis. For continuous outcomes, a sensitivity analyses will be performed to assess the sensitivity of the results to the assumptions that are made. We will indicate the potential impact of missing data.
Assessment of heterogeneity
When pooling trials in meta‐analyses, I2 will be calculated to identify heterogeneity across studies. When I2 > 30%, there is some level of heterogeneity (Higgins 2009). If tests for heterogeneity were statistically significant and inspection of the individual results suggested that it still seemed logical to combine results, a random effects model will be used.
Assessment of reporting biases
Funnel plots will be performed to test for publication bias. For outcomes measured on a continuous (numerical) scale, the standard error will be used as the vertical axis and the mean differences will be used as the horizontal axis in funnel plots.
Data synthesis
Data will be combined using the Review Manager software (Review Manager 2008).
Subgroup analysis and investigation of heterogeneity
Subgroup analysis, where data are available, will be investigated based on different class of drugs, duration of treatment, different administration routes, dosage, the severity of memory disorder, specific MS subtype (RR, SP, PP).
Sensitivity analysis
Where possible, sensitivity analysis will be conducted to explore the influence of including certain trials or not, as well as the effects of analysing by intention to treat, on the effect size and to assess the sensitivity of the results to the assumptions that are made.
