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Pharmacological treatment for memory disorder in multiple sclerosis

  1. Dian He1,
  2. Yun Zhang2,
  3. Shuai Dong3,
  4. Dongfeng Wang3,
  5. Xiangdong Gao3,
  6. Hongyu Zhou4,*

Editorial Group: Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group

Published Online: 17 DEC 2013

Assessed as up-to-date: 25 JUL 2013

DOI: 10.1002/14651858.CD008876.pub3


How to Cite

He D, Zhang Y, Dong S, Wang D, Gao X, Zhou H. Pharmacological treatment for memory disorder in multiple sclerosis. Cochrane Database of Systematic Reviews 2013, Issue 12. Art. No.: CD008876. DOI: 10.1002/14651858.CD008876.pub3.

Author Information

  1. 1

    Affiliated Hospital of Guiyang Medical College, Department of Neurology, Guiyang, Guizhou Province, China

  2. 2

    Jinan No. 6 People's Hospital, Clinical Laboratory, Jinan, Shandong Province, China

  3. 3

    Jinan No. 6 People's Hospital, Department of Neurology, Jinan, Shandong Province, China

  4. 4

    West China Hospital, Sichuan University, Department of Neurology, Chengdu, Sichuan, China

*Hongyu Zhou, Department of Neurology, West China Hospital, Sichuan University, No. 37, Guo Xue Xiang, Chengdu, Sichuan, 610041, China. Hyzhou98@yahoo.com.

Publication History

  1. Publication Status: New search for studies and content updated (no change to conclusions)
  2. Published Online: 17 DEC 2013

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Summary of findings    [Explanations]

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Differences between protocol and review
  16. Index terms

 
Summary of findings for the main comparison. Donepezil for memory disorder in multiple sclerosis

Donepezil for memory disorder in multiple sclerosis

Patient or population: Patients with memory disorder in multiple sclerosis
Settings: USA
Intervention: Donepezil

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

ControlDonepezil

The mean change of total recall on the SRT from baseline
Scale from: 0 to 72
Follow-up: median 24 weeks
The mean change of total recall on the SRT from baseline ranged across control groups from 0.7 to 1.7 The mean change of total recall on the SRT from baseline in the intervention groups was 1.68 higher (2.21 lower to 5.58 higher)-189
(2 studies)
⊕⊕⊕⊝
moderate1
-

The mean change of total correct score on the 10/36 SRT from baseline
Scale from: 0 to 40
Follow-up: median 24 weeks
The mean change of total correct score on the 10/36 SRT from baseline ranged across control groups from
1.2 to 16
The mean change of total correct score on the 10/36 SRT from baseline in the intervention groups was 0.93 lower (3.18 lower to 1.32 higher)-189
(2 studies)
⊕⊕⊕⊝
moderate1
-

The mean change of total correct score on the SDMT from baseline
Scale from: 0 to infinity
Follow-up: median 24 weeks
The mean change of total correct score on the SDMT from baseline in the control groups was 2 The mean change of total correct score on the SDMT from baseline in the intervention groups was 1.27 lower (3.15 lower to 0.61 higher)-189
(2 studies)
⊕⊕⊕⊝
moderate1
-

The mean change of total correct score on the PASAT (2+3 sec) from baseline
Scale from: 0 to 120
Follow-up: median 24 weeks
The mean change of total correct score on the PASAT (2+3 sec) from baseline ranged across control groups from 0.8 to 3.5 The mean change of total correct score on the PASAT (2+3 sec) from baseline in the intervention groups was 2.23 higher (1.87 lower to 6.33 higher)-189
(2 studies)
⊕⊕⊕⊝
moderate1
-

The number of patients experiencing diarrhoea
Follow-up: median 24 weeks
LowRR 3.88
(1.66 to 9.05)
189
(2 studies)
⊕⊕⊕⊝
moderate1
-

65 per 1000252 per 1000
(108 to 588)

The number of patients experiencing nausea
Follow-up: median 24 weeks
LowRR 1.71
(0.93 to 3.18)
189
(2 studies)
⊕⊕⊕⊝
moderate1
-

140 per 1000239 per 1000
(130 to 445)

The number of patients experiencing abnormal dreams
Follow-up: median 24 weeks
LowRR 2.91
(1.38 to 6.14)
189
(2 studies)
⊕⊕⊕⊝
moderate1
-

86 per 1000250 per 1000
(119 to 528)

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
10/36 SRT: 10/36 Spatial Recall Test;CI: confidence interval; PASAT: Paced Auditory Serial Addition Test;RR: risk ratio; SDMT: Symbol Digit Modalities Test; SRT: Selective Reminding Test;

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1 Both studies had a small sample size and a power of test lower than 80%.

 

Background

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Differences between protocol and review
  16. Index terms
 

Description of the condition

Multiple sclerosis (MS) is an autoimmune inflammatory disorder characterised by demyelination and axonal and neuronal loss in the central nervous system (CNS). Besides the evident lesions within the white matter of the CNS, extensive damage of grey matter is also involved in the pathology of MS (Geurts 2012), and both cortical demyelination and axonal loss are believed to contribute to neurological and neuropsychological disability in MS (Vercellino 2005; Calabrese 2012).

 

(1) The patterns of multiple sclerosis-related cognitive dysfunctions

The most frequently affected cognitive domains in MS include memory, processing speed, attention and executive function (Rao 1991a). Among them, memory disorder is the most consistently impaired cognitive function and is seen in 40% to 65% of patients; furthermore, MS-related memory dysfunctions most typically affect long-term and working memory (Rao 1993). It was thought that memory difficulties in MS were due to impaired retrieval from long-term storage (Thornton 2002), and inadequate acquisition of new knowledge (Chiaravalloti 2008). Cognitive changes occur in patients with all MS subtypes, even in those presenting with a first event suggestive of MS known as clinically isolated syndrome (CIS) (Feuillet 2007; Potagas 2008), and tend to decline over time (Glanz 2012). Cognitive impairment differs in different disease courses (Huijbregts 2004), and different phases of the disease (Foong 1998; Morrow 2011). Patients with primary-progressive MS (PPMS) presented with a wide range of cognitive deficits in information processing speed, attention, working memory, executive function and verbal episodic memory, whereas the impairments in patients with relapsing-remitting MS (RRMS) were limited to information processing speed and working memory. Cognitive deficits were more severe in patients with PPMS than in patients with RRMS (Ruet 2013). Depression and fatigue, as two concurrent disorders, are strongly associated with perceived cognitive functioning (Kinsinger 2010). MS-related cognitive dysfunction has a great negative impact on the quality of life (QoL) of patients with MS, concerning activities of daily living, employment and social functioning (Rao 1991b).

 

(2) The mechanism underlying cognitive impairment in multiple sclerosis

The exact mechanism underlying cognitive impairment in MS has not been fully elucidated. However, it is considered that disconnection of cognitively important processing regions by injury to the interconnecting white matter is a potential mechanism for cognitive impairment in MS. MS-related cognitive dysfunction results from a series of domain-specific disconnection phenomena. As such, disruption of critical white-matter tracts will lead to reduced functional connectivity between cortico-cortical and cortico-subcortical cognitive processing regions, resulting in impairment to specific cognitive domains (Dineen 2009; Leocani 2000; Mesaros 2012; Rossi 2012). In addition, grey matter lesions and atrophy also contribute to the development of cognitive impairment in MS (Amato 2004; Calabrese 2009; Morgen 2006; Sanfilipo 2006). Regional lobar atrophy predicts MS-associated memory disorder (Benedict 2005), particularly the deep grey matter atrophy and the mesial temporal lobe atrophy (Benedict 2009).

 

(3) Cognitive tests used in neuropsychological test batteries

Two cognitive batteries are particularly reliable and validated in MS, being widely used in clinical practice and also for research purposes: the Brief Repeatable Battery of Neuropsychological tests (BRBN) (Boringa 2001) and the Minimal Assessment of Cognitive Function in MS (MACFIMS) (Benedict 2006). The BRBN, from a previous application of a comprehensive neuropsychological battery (Rao 1990a), includes the selective reminding test (SRT) for auditory-verbal memory and the 10/36 spatial recall test (10/36 SRT) for visual-spatial memory, the paced auditory serial addition test (PASAT) and the symbol digit modality test (SDMT) for processing speed/working memory, and the controlled oral word association test (COWAT) for language. The MACFIMS includes the PASAT and the SDMT, the California Verbal Learning Test-II (CVLT-II) for auditory-verbal memory, and the Brief Visuospatial Memory Test-Revised (BVMTR) for visual-spatial memory, the D-KEFS Sorting Test for executive functions, the Judgment of Line Orientation Test for Visual perception/Spatial processing and the COWAT for language.

 

Description of the intervention

Pharmacological interventions for memory disorder in MS have been based mainly on the use of disease-modifying drugs (DMDs) (such as interferon β-1a, interferonβ-1b, glatiramer acetate, natalizumab, mitoxantrone, fingolimod, teriflunomide, dimethyl fumarate, alemtuzumab). Furthermore, specific therapies for memory disorder include: acetylcholinesterase inhibitors (AChEI) (such as donepezil and rivastigmine), psychostimulants (methylphenidate, L-amphetamine sulphate, modafinil, amantadine and pemoline), N-methyl-D-aspartate (NMDA) antagonist (such as memantine) and some other pharmacological agents (such as Ginkgo biloba (GB) extracts, aminopyridines and cannabinoids).

 

How the intervention might work

The beneficial effects of DMDs 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, may derive from disruption of cholinergic pathways and impaired axonal transport of acetylcholine due to demyelination and axonal transection (Ruberg 1987). An additional mechanism of action may include increases in cerebral glucose utilisation (Amato 2006). 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, hippocampus and thalamus, could be related to cognitive impairment in MS, especially memory (Paulesu 1996).

On the basis of functional imaging studies, it is hypothesised 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.

Glutamate toxicity has been implicated in the pathogenesis of MS (Pitt 2000). What role NMDA antagonist receptors and glutamate toxicity may play in cognitive dysfunction is uncertain.

GB extracts may improve cognitive performance through their effects on acetylcholine release (Nathan 2000), glycine and gamma-aminobutyric acid (GABA) receptors (Huang 2004). GB extracts also contain compounds that have neuroprotective effects (Ahlemeyer 2003).

L-amphetamine sulphate is a psychostimulant that is used to treat attention deficit disorder. Its major mechanisms of action are stimulation of dopamine release and dopamine-reuptake inhibition; meanwhile, it produces equivalent increases in noradrenaline (norepinephrine) in the hippocampus and cortex (Kuczenski 1995).

 

Why it is important to do this review

Some existing randomised controlled trials with these oral and parenteral pharmacological agents seemed to provide promising results. However, it is uncertain whether pharmacological treatments are really effective in treating memory disorder in patients with MS and which pharmacological 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.

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).

 

Objectives

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Differences between protocol and review
  16. Index terms

To assess the absolute and comparative efficacy, tolerability and safety of pharmacological treatments for memory disorder in patients with MS.

 

Methods

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Differences between protocol and review
  16. Index terms
 

Criteria for considering studies for this review

 

Types of studies

All double-blind, randomised controlled parallel trials on pharmacological treatment for memory disorder in patients with MS. We excluded quasi-randomised, single-blind or unblinded trials.

 

Types of participants

Adults with a diagnosis of definite MS according to the Poser's (Poser 1983) and McDonald's (McDonald 2001; Polman 2005; Polman 2011) diagnostic criteria, all of MS subtypes (RRMS, secondary-progressive (SPMS), PPMS or progressive-relapsing (PRMS)), who displayed 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: pharmacological treatments for memory disorder without restrictions regarding dose, route of administration, frequency. Administration duration 12 weeks or greater.
Control intervention: placebo treatment or one or more pharmacological treatments.

 

Types of outcome measures

 

Primary outcomes

(1) Memory performance at week 12 (or later), as measured with one of the following memory scales:

  • 7/24 Spatial Recall Test (7/24 SRT) (Rao 1991c);

  • Logical Memory (LM) subset of the Wechsler Memory Scale-Revised (WMS-R) (Wechsler 1987);

  • Rey Auditory Verbal Learning Test (RAVLT) (Lezak 2004);

(2) Adverse events (AEs) at week 12 (or later): the number of patients with the five most frequent AEs reported in studies.

 

Secondary outcomes

(1) Clinical Global Impression of Change (CGIC) on memory at week 12 (or later).

(2) MS-specific health-related QoL at week 12 (or later). The following scales were accepted: the Medical Outcomes Study (MOS) 36-Item Short-Form Health Survey (SF-36) (Ware 1992) or the Multiple Sclerosis Quality of Life-54 (MSQOL-54) (Vickrey 1995) or the Multiple Sclerosis Quality of Life Inventory (MSQLI) (Fischer 1999) or the Functional Assessment of Multiple Sclerosis (FAMS) (Cella 1996).

 

Search methods for identification of studies

We applied no language restrictions to the search.

 

Electronic searches

The Review Group Trials Search Co-ordinator searched the Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group Specialised Register (24 July 2013), which, among other sources, contains trials from:

  1. the Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 3, 2013);
  2. MEDLINE (PubMed) (1966 to 24 July 2013);
  3. EMBASE (Embase.com) (1974 to 24 July 2013);
  4. CINAHL (EBSCOhost) (1981 to 24 July 2013);
  5. LILACS (Bireme) (1982 to 24 July 2013);
  6. PEDro (1990 to 24 July 2013);
  7. Clinical trials.gov (www.clinicaltrials.gov);
  8. World Health Organization (WHO) International Clinical Trials Registry Portal (apps.who.int/trialsearch/).

Information on the Cochrane Multiple Sclerosis Group's Trials Register and details of search strategies used to identify trials can be found in the 'Specialised Register' section within the Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group's module.

The keywords used to search for this review are listed in Appendix 1.

In addition to the search run by the Trials Search Co-ordinator, we searched:

1. PsycINFO (1980 to 26 June 2013);
2. CBMdisc (1978 to 24 June 2013).

The search strategies are listed in Appendix 2 and Appendix 3.

 

Searching other resources

We checked the reference lists of identified articles and manually searched the following journals: Annals of Neurology (1994); Multiple Sclerosis (2004, 2011 and 2012) and Neurology (1999, 2001 and 2012).

We handsearched the abstracts of the 25 to 28 Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), the 15th annual meeting of Americas Committees for Treatment and Research in Multiple Sclerosis (ACTRIMS) (5 June 2010), the 5th Joint Triennial Congress of the European and Americas Committees for Treatment and Research in Multiple Sclerosis (ECTRIMS/ACTRIMS)(19 to 22 October 2011) and the World Congress on Treatment and Research in Multiple Sclerosis (joint meeting of ECTRIMS, ACTRIMS and LACTRIMS) (17 to 20 September 2008). We also communicated with authors of identified studies in an effort to identify further published, unpublished and ongoing studies.

 

Data collection and analysis

 

Selection of studies

Two review authors (He and Dong) independently screened titles and abstracts of the citations retrieved by the literature search for inclusion or exclusion. We obtained the available full texts of potentially relevant studies for further assessment. We independently evaluated the eligibility (on the basis of information available in the published data) of these studies. We listed papers that did not meet the inclusion criteria in the Characteristics of excluded studies table with the reasons for omission. We resolved any disagreement regarding inclusion by discussion or by referral to a third review author (Zhou) if necessary.

 

Data extraction and management

Two review authors (He and Dong) independently extracted data from the selected trials using standardised forms. We extracted information about study design, participants, interventions and outcome measures. We contacted principal investigators of included studies in order to request additional data or confirmation of methodological aspects of the study. We discussed and resolved disagreements by consensus among the review authors.

 

Assessment of risk of bias in included studies

We based the methodological criteria on the Cochrane Handbook for Systematic Review of Interventions Version 5.1.0 (Higgins 2011). Two review authors (He and Dong) independently evaluated the methodological quality of the studies using the 'Risk of bias' tool under the domains of sequence generation, allocation concealment, blinding, incomplete outcome data, selective outcome and other biases. We discussed and resolved disagreements among the review authors on the methodological quality of the identified studies by consensus.

 

Measures of treatment effect

We treated the data on memory scales and QoL scales as continuous outcomes because both were longer ordinal rating scales and had a reasonably large number of categories, therefore a mean difference (MD) was used if trials had used the same rating scale to assess outcome, and where different rating scales had been used, the measure of the treatment difference was expressed as the standardised mean difference (SMD). CGIC on memory belonged to shorter ordinal data (binary outcomes), along with the number of patients with AEs, the treatment effect was described using risk ratio (RR).

We extracted the pre and post mean values, the mean change from baseline, standard deviation, 95% confidence interval (CI), P value, the number of patients incurring the event and the number of patients for each treatment group of individual studies. Standard deviation was calculated from the CI or t-tests when it was not reported. The standard error of the mean change was calculated from standard deviation.

 

Unit of analysis issues

We only included studies with a parallel group design so participants had been randomised to either intervention or control with subsequent analysis at individual allocation level. We selected a single time point (at exit) and analysed data at this time (final values), along with change score from baseline for trials in which it was presented. In future updates, if studies with multiple intervention groups are included, we will create a single pair-wise comparison by combining groups if appropriate, or we will select one pair of interventions and exclude the others.

 

Dealing with missing data

This review involved four different types of pharmacological agents (donepezil, GB, memantine and rivastigmine). There were clinical and methodological heterogeneities across the included studies. A high attrition bias existed in trials for most types of agents except for donepezil. Therefore, we did not carry out a meta-analysis to evaluate the efficacy of pharmacological treatment for memory disorder in MS and only performed a subgroup analysis for donepezil. We contacted the study investigators for missing data. We used a last-observation-carried-forward imputation strategy for data not missing at random and used an intention-to-treat principle for analyses. For the data assumed to be missing at random, we only analysed the available data. We addressed the potential impact of missing data on the findings of the review in the Discussion section.

 

Assessment of heterogeneity

We assessed clinical heterogeneity by examining the characteristics of the studies, the similarity between the types of participants, the interventions, and the outcomes as specified in the criteria for included studies. The variability in study design and the risk of bias (methodological heterogeneity) was also evaluated. We evaluated statistical heterogeneity where the clinical and methodological heterogeneities were not obvious across the included studies. When pooling trials in meta-analyses, we calculated the I2 statistic to identify heterogeneity across studies. When the I2 was greater than 30%, there was some level of heterogeneity (Higgins 2011). If tests for heterogeneity were statistically significant, but inspection of the individual results suggested that it was still logical to combine results, we calculated the overall effects using a random-effects model.

 

Assessment of reporting biases

We did not assess the reporting biases because of the limited number of studies included for data synthesis. In future updates, and if more studies are included, we will examine potential publication bias using a funnel plot. For continuous outcomes, we will use standard errors as the vertical axis and MDs as the horizontal axis in funnel plots. For dichotomous outcomes, we will plot odds ratios (OR) or RRs on a logarithmic scale as the horizontal axis and will use standard errors as the vertical axis.

 

Data synthesis

We gave a descriptive summary of the results and combined data at exit (final values), along with change score from baseline for donepezil because clinically and methodologically homogeneous RCTs with low bias were only identified with donepezil. We conducted a subgroup analysis using Review Manager 5 (Review Manager 2012). We used a fixed-effect model because each study on donepezil was estimating exactly the same quantity. For the outcome data with a statistically significant heterogeneity (I2 > 30%), but inspection of the individual results suggested that it was still logical to combine results, we used a random-effects model instead. For the outcomes treated as continuous data (memory performance as measured with memory scales and MS-specific health-related QoL as measured with QoL scales), we selected the inverse-variance fixed-effect model method and the inverse-variance random-effects model method. For the outcomes treated as dichotomous data (the number of patients with AEs and CGIC on memory), we selected the Mantel-Haenszel fixed-effect model method and the Mantel-Haenszel random-effects model method.

 

Subgroup analysis and investigation of heterogeneity

We carried out a subgroup analysis based on the different types of pharmacological agents, but the updated data only permitted us to conduct an analysis for donepezil because the clinical and methodological heterogeneities or high attrition bias existed across the studies for the other pharmacological agents. In future updates and if further data become available, we plan to carry out subgroup analyses based on duration of treatment, different administration routes, dosage, the severity of memory disorder or specific MS subtype.

 

Sensitivity analysis

We undertook sensitivity analyses to assess the influence on results of the different treatment effects by comparing RRs with ORs and on results of the same treatment effect (MD) by comparing the mean change of total score from baseline with the mean total score at exit. In future updates, where possible, we will also conduct sensitivity analyses to assess the robustness of our review results of fixed-effect model versus random-effects model assumptions and of including trials at high risk of bias as well as the effects of analysing by intention to treat and the effect size (the MD versus SMD).

 

Results

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Differences between protocol and review
  16. Index terms
 

Description of studies

See: Characteristics of included studies, Characteristics of excluded studies, Characteristics of studies awaiting classification and Characteristics of ongoing studies tables.

 

Results of the search

We found 1270 articles using the search strategies. After screening of titles and abstracts, we provisionally selected 73 articles. After obtaining the full papers of the 73 articles, we found seven studies that met the inclusion criteria (Krupp 2004; Krupp 2011; Lovera 2007; Lovera 2010; Lovera 2012; Mäurer 2013; Shaygannejad 2008). We excluded 66 studies: 18 studies were non-randomised studies (Barak 2002; Flechter 2007; Greene 2000; Huolman 2011; Iaffaldano 2012; Krause 2012; Lang 2012; Lacy 2013; Mattioli 2011a; Mattioli 2011b; Melanson 2010; Oliveri 1998; Patti 2009; Patti 2010; Portaccio 2013; Selby 1998; Zéphir 2005; Zéphir 2008); 10 studies were cross-over design (Aragona 2009; Bever 1996; Bruce 2012; Cohen 1989; Decoo 2004; Rorie 2001; Rossini 2011; Sailer 2000; Smits 1994; Villoslada 2009); two studies were open-label trials (Krupp 1999; Schwid 2007); one study was an observational study with an open-label retrospective analysis (Schröder 2011); one study was a cross-sectional study (Honarmand 2011); in nine studies, administration duration was less than 12 weeks (Benedict 2008; Geisler 1996; Harel 2009; Lange 2009; Möller 2011; Morrow 2009; Morrow 2013; Uttner 2005; Wade 2004); in three studies, no memory scales were used in the outcomes (Barak 1999; Jeffery 2011; Selmaj 2012); in 18 studies, the participants did not meet the inclusion criteria for memory impairment prespecified in the protocol (Bosca 2004; Cabrera-Gomez 2003; Cohen 2002; Cohen 2010; Comi 2012; Fischer 1994; Fischer 2000; Havrdova 2006; Kappos 2010; Miller 2011; Montalban 2009; Panitch 2004; Pliskin 1994; Pliskin 1996; Rudick 2006; Weinstein 1999; Weinstock-Guttman 2012a; Weinstock-Guttman 2012b); two papers (Christodoulou 2006; Sumowski 2011), were respectively based primarily on studies previously published (Krupp 2004; Morrow 2009); and two studies were not double-blind (Wilken 2004; Wilken 2008). See Figure 1. The trial that was previously classified in ongoing studies (NCT01074619), was completed in November 2011, but we could not find a publication. In this update, we listed it in the Characteristics of studies awaiting classification table. One double-blind, randomised, placebo-controlled, parallel group study is currently ongoing (NCT01466114), and will be assessed when it is published and the results become available.

 FigureFigure 1. Study flow diagram.

 

Included studies

We included seven studies. Krupp 2004 and Krupp 2011 evaluated the effect of donepezil in treating memory and cognitive dysfunction in MS patients (n = 69 and n = 120, respectively). Lovera 2007 and Lovera 2012 determined if GB improves the cognitive function in people with MS (n = 43 and n = 121, respectively). Lovera 2010 determined whether memantine improves cognitive performance among people with MS and cognitive impairment (n = 126). Shaygannejad 2008 and Mäurer 2013 evaluated the effect of rivastigmine in treating memory and cognitive dysfunction in MS patients (n = 60 and n = 86, respectively).

 

Characteristics of the study design

Seven studies were randomised, double-blind, placebo-controlled clinical trials with parallel design.

 

Characteristics of the participants

All participants had the diagnosis of definite MS according to Poser's or McDonald's diagnostic criteria (McDonald 2001; Poser 1983; Polman 2005), with an age ranging of 18 to 65 years with the exception of Shaygannejad 2008 (actual age range, 16 to 54 years). All patients exhibited stable neurological functioning for at least one month prior to study entry (Krupp 2004; Lovera 2012; Shaygannejad 2008), or without a significant MS exacerbation (Lovera 2007; Lovera 2010; Mäurer 2013), or without steroid treatment within four weeks of screening (Krupp 2011). All trials reported a baseline comparability of the characteristics of participants between treatment groups, and most of characteristics of patients at baseline were similar except for gender (Krupp 2004; Lovera 2012), mean Expanded Disability Status Score (EDSS) (Krupp 2004), MS subtypes (Krupp 2004; Lovera 2010), the z-scores for the Long Delay Free Recall (LDFR) on the CVLT-II (Lovera 2010), the subtests of digit span and visual reproduction in WMS (Shaygannejad 2008), education and disease duration (Krupp 2011), the reading scores on the Wide Range Achievement Test 3 and self report on the Occupational Functioning Questionnaire (OFQ) (Krupp 2011). No information at baseline was reported on disease-modifying therapies (Lovera 2007; Lovera 2010; Mäurer 2013), depression (Shaygannejad 2008), and fatigue (Lovera 2007; Shaygannejad 2008). Krupp 2004; Krupp 2011; Lovera 2007; and Shaygannejad 2008 reported the proportion of patients using concomitant antidepressants at baseline. Most patients displayed at least mild memory impairment at least 0.5 standard deviations below age- and sex-based normative data on a validated memory scale; however, selection of targeted sample was not fully specific for memory impairment in Lovera 2012 and Mäurer 2013. Patients in Krupp 2004 and Lovera 2007 had no severe cognitive impairment. Krupp 2004; Krupp 2011; Lovera 2007; Lovera 2010; Lovera 2012; and Mäurer 2013 excluded patients with major depression. Mäurer 2013 included patients with RRMS, SPMS and CIS. Lovera 2012 included patients with all types of MS. The other studies included patients with RRMS, SPMS and PPMS.

 

Characteristics of the interventions

Krupp 2004 and Krupp 2011 compared donepezil versus placebo with a 24-week treatment duration and initial dose of 5 mg per day, increasing to 10 mg per day at week four. Lovera 2007 and Lovera 2012 compared GB (120 mg twice a day) versus placebo with a 12-week treatment duration. Lovera 2010 compared memantine (10 mg twice a day (four-week titration followed by 12 weeks on the highest tolerated dose)) versus placebo with a 16-week treatment duration. Shaygannejad 2008 compared rivastigmine (1.5 mg once daily increment over four weeks to 3 mg twice daily for a total of 12 weeks) versus placebo with a 12-week treatment duration. Mäurer 2013 compared rivastigmine patches (initially 5 cm2 (4.6 mg/day), and increased to 10 cm2 (9.5 mg/day) at week four) versus placebo with a 16-week double-blind treatment duration.

 

Characteristics of the outcome measures

Our primary outcomes were reported in all trials, memory performance on the CVLT-II (Lovera 2007; Lovera 2010; Lovera 2012); SRT (Krupp 2004; Krupp 2011; Mäurer 2013); WMS-III (Shaygannejad 2008); 10/36 SRT (Krupp 2004; Krupp 2011; Mäurer 2013); Backward Digit Span (Shaygannejad 2008); the LM subset of the WMS-R (Shaygannejad 2008); PASAT (Krupp 2004; Lovera 2007; Krupp 2011; Lovera 2010; Lovera 2012; Mäurer 2013); and SDMT (Krupp 2004; Krupp 2011; Lovera 2007; Lovera 2010; Mäurer 2013). The BVMTR, 7/24 SRT and RAVLT were not reported in the included studies. All trials reported the frequency of AEs.

Our secondary outcomes were reported in some trials: CGIC on memory (Krupp 2011); MSQLI (Lovera 2007) and SF-36 (Lovera 2010). The MSQOL-54 and FAMS were not reported in the included studies.

 

Excluded studies

All of the studies that were excluded from this review and the reasons for their exclusion are available in the Characteristics of excluded studies table.

 

Risk of bias in included studies

Further details of this assessment are available in the relevant section of the 'Characteristics of included studies' table and are also presented in the 'Risk of bias' graph (Figure 2) and 'Risk of bias' summary (Figure 3).

 FigureFigure 2. Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
 FigureFigure 3. Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

 

Allocation

Sequence generation and allocation concealment were adequate in all studies. The risks for selection bias were low. The randomisation lists were generated by an independent pharmacist or staff using a random number generator (Krupp 2004; Krupp 2011; Lovera 2007), a computer program that differed from a random number generator (Shaygannejad 2008), by an external clinical research organisation (CRO) using a validated system that automated the random assignment of the treatment arms (Mäurer 2013), or by an independent biostatistician or research pharmacist using an EXCEL random number generator (Lovera 2010; Lovera 2012). The pharmacist was informed of all randomisation assignments and was responsible for labelling the study drug and maintaining a master list linking the participants and their treatment assignments and the masking of the active and placebo treatments was preserved by creating treatments that looked identical (Krupp 2004; Krupp 2011; Shaygannejad 2008). In Lovera 2007, the staff at the Oregon Health and Science University Medical Informatics and Clinical Epidemiology Department generated the allocation sequence, and sequentially numbered the containers provided by the manufacturer accordingly. The remainder of the study personnel did not have access to the allocation sequence until the study was completed. In Lovera 2010, the independent statistician's staff received a fax with the participant's study ID, randomised the participant, and then sent a fax to the pharmacy indicating the treatment allocation. Only the independent statistician's staff and the research pharmacists had access to the allocation sequence until the analysis was completed. In Lovera 2012, the research pharmacists assigned the participants to either GB or matching placebo tablets and dispensed the tablets to them in identical containers. Only the research pharmacists had access to the allocation sequence. In Mäurer 2013, the investigator enrolled and assigned the participants to treatment according to the randomisation list.

 

Blinding

All trials were double-blinded and had low risks for performance bias and detection bias. In Krupp 2004, all clinical staff and patients were masked regarding treatment assignment. The masking of the active and placebo treatments was preserved by creating treatments that looked identical. In Lovera 2007, the blinding was implemented by using identical containers, instructions and labels. The participants, physicians and research assistants did not know the treatment allocation at any point until the data analysis was completed. In Lovera 2010, only the independent statistician's staff and the research pharmacists had access to the allocation sequence until the analysis was completed. The questionnaires administered at the end of the study indicated that blinding of the participants, evaluating physicians and evaluating research assistants was successful. In Krupp 2011, except for the pharmacists, all research staff and participants were masked regarding treatment assignment. Masking of active and placebo treatments was preserved by creating capsules that appeared identical. In Lovera 2012, only the research pharmacists had access to the allocation sequence. The research pharmacists assigned the participants to either GB or matching placebo tablets and dispensed the tablets to them in identical containers. One research assistant assessed AEs and another administered the neuropsychological tests. They were instructed not to discuss AEs between them to ensure that the cognitive test assessments would be masked. In Mäurer 2013, patients, investigator staff, people performing the assessments and data analysts remained blinded throughout the entire study period. Study drugs were identical in packaging, labelling, schedule of administration, appearance and odour. In Shaygannejad 2008, the trial was double-blinded in that both patient and physician who assessed the outcome were not aware of treatment. The masking of the active and placebo treatments was preserved by creating treatments that looked identical.

 

Incomplete outcome data

Most studies provided enough details about the number of and the reasons for drop-out except for Krupp 2011, where the reasons for drop-out were not recorded, however, the dropout rate and the amount of missing data were low, a last-observation-carried forward imputation strategy was used for missing data and the intention-to-treat principle was used for analyses. The risk for attrition bias was low. In Krupp 2004, the missing data and reasons were balanced between groups, the risk for attrition bias was low. In Lovera 2007, although the dropout rate and the amount of missing data were low, the reasons differed across groups. Moreover, an intention-to-treat principle was not used for analyses. The risk for attrition bias was high. In Lovera 2010, the dropout rate and the amount of missing data were high. Moreover, the reasons for drop-out differed across groups. The researchers excluded the patients who were lost to follow-up and did not use the intention-to-treat principle for analyses. The risk for attrition bias was high. In Lovera 2012, the reasons for drop-out were carefully recorded and differed across groups; however, the dropout rate and the amount of missing data were low, and the modified intention-to-treat principle was used for analyses. The risk for attrition bias was low. In Mäurer 2013, although the modified intention-to-treat principle was used for analyses, attrition bias was high. The high rate of drop-outs had potential impacts on the results. Generally, the potential impact of missing continuous outcomes increases with the proportion of participants with missing data. In Shaygannejad 2008, no participants were lost to follow-up, and the risk for attrition bias was low.

 

Selective reporting

All listed outcomes were adequately reported in most studies except for Lovera 2007 and Lovera 2010, in which some of outcomes were lack of data, resulting in unclear risks for reporting bias.

 

Other potential sources of bias

All studies had unclear risks for other bias. In Krupp 2004, the possibility of detection bias may have existed because the evaluating physician was the same as the treating physician, and biased results may have been induced due to different baseline on sex, mean EDSS and MS subtypes, even a higher percentage of donepezil patients correctly guessed their medication status. In Lovera 2007, biased results may have been induced because of a lower percentage of GB patients guessed their treatment allocation correctly and no information reported on disease-modifying therapies. In Lovera 2010, the imbalances on type of MS and the z-scores for the LDFR on the CVLT-II between two groups at baseline may have resulted in biased results. In Krupp 2011, biased results may have been induced because the donepezil group at baseline had more years of education, higher reading scores on the Wide Range Achievement Test 3 and longer self reported disease duration, and a higher percentage of donepezil patients correctly guessed their medication status. In Lovera 2012, biased results may have resulted from the difference in gender between two groups and the unspecific election of targeted sample for memory impairment due to the use of the COWAT, which is used to measure language. In Mäurer 2013, biased results may have been induced because the study was supported by Novartis Pharma GmbH, and the selection of targeted sample is not specific for memory impairment due to the use of a Multiple Sclerosis Inventarium Cognition (MUSIC). In Shaygannejad 2008, biased results may have been induced due to imbalances on the subtests of digit span and visual reproduction in WMS between two groups at baseline and no information reported on depression.

 

Effects of interventions

See:  Summary of findings for the main comparison Donepezil for memory disorder in multiple sclerosis

 

Primary outcomes

Overall, clinical and methodological heterogeneities existed across the included studies. Moreover, some of studies had a high attrition bias. Such a condition did not permit us to conduct a meta-analysis to evaluate the efficacy of pharmacological treatments for memory disorder in MS. However, we performed a subgroup analysis focusing on donepezil versus placebo from Krupp 2004 and Krupp 2011. The results showed no treatment effects on total recall on the SRT (MD 1.68, 95% CI -2.21 to 5.58 ( Analysis 1.1) and MD 1.23, 95% CI -3.07 to 5.53 ( Analysis 1.2)), total correct scores on the 10/36 SRT (MD -0.93, 95% CI -3.18 to 1.32 ( Analysis 1.3) and MD 0.29, 95% CI -2.64 to 3.23 ( Analysis 1.4)), the SDMT (MD -1.27, 95% CI -3.15 to 0.61 ( Analysis 1.5) and MD 1.15, 95% CI -2.71 to 5.01 ( Analysis 1.6 )), and the PASAT (2+3 sec) (MD 2.23, 95% CI -1.87 to 6.33 ( Analysis 1.7) and MD 5.41, -1.42 to 12.23 ( Analysis 1.8)). Concerning the safety, the treatment was associated with AEs such as diarrhoea (RR 3.88, 95% CI 1.66 to 9.05 ( Analysis 1.9 ) and OR 4.84, 95% CI 1.87 to 12.51 ( Analysis 1.10)), nausea (RR 1.71, 95% CI 0.93 to 3.18 ( Analysis 1.11) and OR 1.94, 95% CI 0.92 to 4.12 ( Analysis 1.12)), abnormal dreams (RR 2.91, 95% CI 1.38 to 6.14 ( Analysis 1.13) and OR 3.55, 95% CI 1.50 to 8.37 ( Analysis 1.14)). Sensitivity analyses by comparing RR with OR and by comparing the mean change of total score from baseline with the mean total score at exit did not show significant influence on results of the treatment effects. We graded the quality of evidence for the trials on donepezil using the GRADE approach (Schünemann 2009). Both studies had a desirable directness regarding comparison and the target population, intervention, comparator and outcomes. No serious limitations in design and implementation existed in either studies. A statistical heterogeneity of results on the primary outcome existed between the two studies, but to a large degree, it could be explained by the minor differences of the population on age, gender, education, MS subtype, disability or severity of memory impairment. Therefore, the inconsistency was negligible. However, the results in both studies were subjected to a serious imprecision resulted from the small sample sizes and the power of test (lower than 80%), which contributed to a moderate quality of the evidence ( Summary of findings for the main comparison).

Lovera 2007 reported there were no any significant differences among patients receiving GB versus placebo on the LDFR from the CVLT-II, PASAT and SDMT (exit group difference: -1.2, 95% CI -3.2 to 0.8 with CVLT-II, 1.1, 95% CI -3.1 to 4.2 with PASAT, -0.8, 95% CI -3.0 to 4.6 with SDMT), and only one person in the GB group had an AE (constipation) classified as remotely related to treatment.

Lovera 2010 reported the differences between the placebo group and memantine group in change on the LDFR from the CVLT-II and PASAT were not statistically significant (exit-baseline) (MD -0.6, 95% CI -2.0 to 0.8, P value = 0.4 with CVLT-II, MD -0.0, 95% CI -3.3 to 3.4, P value = 0.9 with PASAT), and there were no statistically significant differences between the groups on the frequency of individual AEs (bladder infection, fatigue, cough, somnolence, ataxia, spasticity, constipation and rash).

Shaygannejad 2008 reported the mean general memory score on the WMS, the LM and digit span at the end of trial did not change between rivastigmine and placebo group (exit group difference: 0.4, 95% CI -2.0 to 2.8 with general memory; 1.2, 95% CI -0.7 to 1.7 with LM, -1.3, 95% CI -1.7 to -0.9 with digit span), and reported the most common AEs associated with rivastigmine were nausea (six people), dyspepsia (five people), anorexia (five people), dizziness (two people), headache (two people), tremor (one person), anxiety (three people) and confusion (one person), appeared at the starting dose and at every increase of the dosage, but disappeared after the first month of treatment.

Lovera 2012 reported the differences (GB-placebo) at exit in the z-scores for PASAT and LDFR on the CVLT-II were not statistically significant (exit group difference: -0.2, 95% CI -0.5 to 0.1 with PASAT, 0.0, 95% CI -0.3 to 0.3 with CVLT-II). There were no significant differences in AEs. Two serious AEs occurred in the GB group (myocardial infarction and hospitalisation for depression), which were not considered to be related to treatment.

Mäurer 2013 reported patients who received rivastigmine showed a non-significant increase in total recall score on the SRT over placebo (exit-baseline) (95% CI -5.8 to 1.6; P value = 0.2576). The most frequent AE was erythema, occurring equally in both groups (15.6% in rivastigmine group and 14.6% in placebo group); the other frequent AEs included rash, nausea, nasopharyngitis, MS relapse and depression. The percentages of AEs requiring dose adjustment (3.2% and 12.1%, respectively), temporal or permanent interruption of treatment (14.9% and 19.7%, respectively) and concomitant therapy (29.8% and 40.9%, respectively) were lower in the rivastigmine group than in the placebo group. The percentage of serious adverse events was higher in the placebo group (9.1%) than in the rivastigmine group (3.2%).

See:  Table 1 and Figure 4.

 FigureFigure 4. Efficacy on the primary outcomes reported in each study.

 

Secondary outcomes

Lovera 2007 reported no statistically significant difference between the groups on the total score of the Perceived Deficits Questionnaire (PDQ) (MD 0, 95% CI -3.8 to 3.7) in the MSQLI and in the other QoL scales from the MSQLI, except for a significant difference between the groups of 1.5 points (95% CI 2.6 to 0.3, P value = 0.015) in the Retrospective Memory Scale of the PDQ, favouring the GB group.

Lovera 2010reported there was no significant difference between the two groups on any of the scales of the SF-36.

Krupp 2011 reported a trend was noted for the clinician's impression of memory change in favour of donepezil (37.7%) versus placebo (23.7%) (P value = 0.097).

 

Discussion

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Differences between protocol and review
  16. Index terms
 

Summary of main results

We excluded most retrieved studies due to cross-over design or lack of randomisation or double-blinding. We excluded many RCTs meeting the pre-specification of criteria for types of studies in this review due to inadequate selection of the target population or short administration duration and follow-up. Studies regarding disease-modifying therapy (DMT) and MS-related memory disorder were not designed to assess detailed cognitive outcomes. In addition, most cognitive investigations were secondary analyses or post hoc analyses of RCTs in which the primary purpose was to reduce relapse rate and preserve overall neurological function. We included seven studies in this review, which evaluated donepezil (two studies, n = 189), GB (two studies, n = 164), memantine (one study, n = 126) and rivastigmine (two studies, n = 146) on memory disorder in MS. One trial previously classified as an ongoing study was completed in November 2011, but had not been published by June 2013; we have listed this in the studies awaiting classification. There is one ongoing study that is likely to be of relevance to this review and may ultimately provide valuable evidence in future updates.

The updated data did not permit us to carry out a meta-analysis to evaluate the efficacy of pharmacological treatments for memory disorder in MS because of the clinical and methodological heterogeneities across studies and the high attrition bias. We only conducted a subgroup analysis for donepezil versus placebo. The results showed no treatment effects on total recall on the SRT (MD 1.68, 95% CI -2.21 to 5.58), total correct scores on the 10/36 SRT (MD -0.93, 95% CI -3.18 to 1.32), SDMT (MD -1.27, 95% CI -3.15 to 0.61), PASAT (2+3 sec) (MD 2.23, 95% CI -1.87 to 6.33) and the number of patients experiencing diarrhoea (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). The quality of evidence was moderate. Sensitivity analyses by comparing RR with OR and by comparing the mean change of total score from baseline with the mean total score at exit did not show significant influence on results of the treatment effects.

 

Overall completeness and applicability of evidence

In this review, it was difficult to reach valid conclusions that pharmacological treatment was effective for memory disorder in MS. We are unable to give any recommendations for clinical practice of any pharmacological agent by means of DMT or symptomatic treatment for MS-associated memory disorder. Moreover, not all primary outcomes, secondary outcomes, subgroup analysis or sensitivity analyses could be performed as planned because most included RCTs had relatively poor methodological quality and had clinical and methodological heterogeneities. The results based on a subgroup analysis for donepezil versus placebo were not in favour of donepezil as a symptomatic treatment for mild memory disorder in MS. Generally, the treatment for cognitive impairment needs an adequate administration duration and follow-up. A minimum duration of administration of 12 weeks, pre-defined in the criteria of types of interventions, was a reasonable treatment length that partly avoided the inclusion of misleading evidence.

 

Quality of the evidence

We included seven RCTs in this review, involving 625 people and four different types of pharmacological agents to mainly evaluate the absolute efficacy in improving memory performance with diverse assessment scales by direct comparison with placebo. Overall, clinical and methodological heterogeneities existed across these studies. Furthermore, most studies had methodological limitations on non-specific selections of targeted sample, non-matched variables or incomplete outcome data (high attrition bias). Therefore, we did not carry out a meta-analysis to evaluate the efficacy of pharmacological treatments for memory disorder in MS. Whether pharmacological treatment is effective in memory disorder in patients with MS remains inconclusive. However, we performed a subgroup analysis focusing on the two studies on donepezil and graded the quality of evidence by the GRADE approach. 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.

 

Potential biases in the review process

An extensive and comprehensive search was undertaken to limit bias in the review process; however, we retrieved a low number of RCTs with parallel design. The two review authors' independent assessments of eligibility of studies for inclusion in this review and the extraction of data minimised the potential for additional bias beyond that detailed in the 'Risk of bias' tables. The low rate of drop-outs and amount of missing data on the primary outcome did not have a large impact on the primary analysis. Moreover, a last-observation-carried-forward imputation strategy was used for missing data and an intention-to-treat analysis principle was used for analyses in this meta-analysis. No conflict of interests were found in relation to the review authors of this review.

 

Agreements and disagreements with other studies or reviews

We have found no other systematic review on pharmacological treatment for memory disorder in MS.

 

Authors' conclusions

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Differences between protocol and review
  16. Index terms

 

Implications for practice

We found no convincing evidence from this review to support the efficacy of pharmacological symptomatic treatments for multiple sclerosis (MS)-associated memory disorder. Whether pharmacological treatment is effective in memory disorder in patients with MS remains inconclusive. 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 and safety as adverse events such as nausea, diarrhoea and abnormal dreams were not frequent. Ginkgo biloba, memantine and rivastigmine were safe and well tolerated and no serious adverse effects were reported.

 
Implications for research

The quality of the included studies was overall low, some important variables were not matched between groups, the samples of patients were relatively small and the follow-up was short. Future RCTs with larger size are required, adequate selection of the target population and better matching on important variable (such as age, gender, education level, MS subtypes, disease duration, depression, fatigue, anxiety, concomitant medications) between groups are key to studies. MS-specific health-related quality of life should be addressed in future research.

 

Acknowledgements

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Differences between protocol and review
  16. Index terms

We wish to thank Andrea Fittipaldo, Trials Search Co-ordinator and Liliana Coco, Managing Editor of the Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group for their help and support in developing this review. We thank all peer reviewers, and Loredana La Mantia, the quality advisor of the Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group, for their constructive comments and suggestions in this review. We also would like to thank Ms Sarah Dawson (Trials Search Co-ordinator) at the Cochrane Depression, Anxiety and Neurosis Group for assistance with the search strategy for PsycINFO. In addition, we thank Dr. Guo Duan, Dr. Hao Zilong and Dr. Wu Bo, the previous authors of this review.

 

Data and analyses

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Differences between protocol and review
  16. Index terms
Download statistical data

 
Comparison 1. Subgroup analysis for donepezil versus placebo

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 The mean change of total recall on the Selective Reminding Test (SRT) from baseline2189Mean Difference (IV, Random, 95% CI)1.68 [-2.21, 5.58]

 2 The mean total recall on the Selective Reminding Test (SRT) at exit2189Mean Difference (IV, Random, 95% CI)1.23 [-3.07, 5.53]

 3 The mean change of total correct score on the 10/36 Spatial Recall Test (10/36 SRT) from baseline2189Mean Difference (IV, Random, 95% CI)-0.93 [-3.18, 1.32]

 4 The mean total correct score on the 10/36 Spatial Recall Test (10/36 SRT) at exit2189Mean Difference (IV, Random, 95% CI)0.29 [-2.64, 3.23]

 5 The mean change of total correct score on the Symbol Digit Modalities Test (SDMT) from baseline2189Mean Difference (IV, Fixed, 95% CI)-1.27 [-3.15, 0.61]

 6 The mean total correct score on the Symbol Digit Modalities Test (SDMT) at exit2189Mean Difference (IV, Fixed, 95% CI)1.15 [-2.71, 5.01]

 7 The mean change of total correct score on the Paced Auditory Serial Addition Test (PASAT) (2+3 sec) from baseline2189Mean Difference (IV, Random, 95% CI)2.23 [-1.87, 6.33]

 8 The mean total correct score on the Paced Auditory Serial Addition Test (PASAT) (2+3 sec) at exit2189Mean Difference (IV, Fixed, 95% CI)5.41 [-1.42, 12.23]

 9 The number of patients experiencing diarrhoea2189Risk Ratio (M-H, Fixed, 95% CI)3.88 [1.66, 9.05]

 10 The number of patients experiencing diarrhoea2189Odds Ratio (M-H, Fixed, 95% CI)4.84 [1.87, 12.51]

 11 The number of patients experiencing nausea2189Risk Ratio (M-H, Fixed, 95% CI)1.71 [0.93, 3.18]

 12 The number of patients experiencing nausea2189Odds Ratio (M-H, Fixed, 95% CI)1.94 [0.92, 4.12]

 13 The number of patients experiencing abnormal dreams2189Risk Ratio (M-H, Fixed, 95% CI)2.91 [1.38, 6.14]

 14 The number of patients experiencing abnormal dreams2189Odds Ratio (M-H, Fixed, 95% CI)3.55 [1.50, 8.37]

 

Appendices

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Differences between protocol and review
  16. Index terms
 

Appendix 1. Keywords for searching the Cochrane MS Group Specialised Register

{memory disorder} OR {memory loss\*} OR {memory deficit} OR {memory impairment\*} OR {memory decline} OR {memory} OR {dysmnesia} OR {amnesia} OR {cognitive deficit\*} OR {cognitive disorder\*} OR {cognitive impairment\*} OR {cognitive dysfunction\*} OR {cognitive} OR {cognition} OR {cognitive decline} OR {dementia}

 

Appendix 2. PsycINFO (1980 to 26 June 2013)

#1 Multiple Sclerosis.sh.

#2 exp Myelitis.sh.

#3 Demyelinating Diseases*.tw.

#4 Encephalomyelitis.sh.

#5 Optic Neuritis.tw.

#6 Neuromyelitis Optica.tw.

#7 Transverse myelitis.tw.

#8 Devic.tw.

#9 Demyelinating disease*.tw.

#10 Acute disseminated encephalomyelitis.tw.

#11 1 OR 2 OR 3 OR 4 OR 5 OR 6 OR 7 OR 8 OR 9 OR 10 OR 11

#12 exp Memory Disorders

#13 memor*.mp.

#14 Dymnesi*.tw.  

#15 exp Amnesia.sh.

#16 (cogniti* adj3 (disorder* OR dysfunction* OR declin* OR deficit*)).tw.

#17 exp Dementia.sh.

#18 13 OR 14 OR 15 OR 16 OR 17 OR 18 OR 19 OR 20 OR 21 OR 22 OR 23 OR 24

#19 11 AND 18

#20 (198* OR 199* OR 200* OR 201*).yr, up.

#21 treatment effectiveness evaluation.sh.

#22 clinical trials.sh.

#23 mental health program evaluation.sh.

#24 placebo.sh.

#25 placebo$.ti,ab.

#26 randomly.ab.

#27 randomi#ed.ti,ab.

#28 trial.ti,ab.

#29 ((singl$ or doubl$ or trebl$ or tripl$) adj3 (blind$ or mask$ or dummy)).mp.

#30 (control$ adj3 (trial$ or study or studies or group$)).ti,ab.

#31 factorial$.ti,ab.

#32 allocat$.ti,ab.

#33 assign$.ti,ab.

#34 volunteer$.ti,ab.

#35 (crossover$ or cross over$).ti,ab.

#36 (quasi adj (experimental OR random$)).mp.

#37 "2000".md.

#38 22 OR 23 OR 24 OR 25 OR 26 OR 27 OR 28 OR 29 OR 30 OR 31 OR 32 OR 33 OR 34 OR 35 OR 36 OR 37 OR 38

#39 19 AND 20 AND 38

 

Appendix 3. CBMdisc (1978 - 25 June 2013)

#1 多发性硬化(MeSH)

#2 多发性硬化(TI/TW/AB/CT)

#3 视神经脊髓炎 (MeSH)

#4 视神经脊髓炎(TI/TW/AB/CT)

#5 脱髓鞘疾病(MeSH)

#6 脱髓鞘疾病(TI/TW/AB/CT)

#7 认知障碍(MeSH)

#8 认知(MeSH)

#9 认知?(TI/TW/AB/CT)

#10 记忆障碍(MeSH)

#11 记忆(MeSH)

#12 记忆?(TI/TW/AB/CT)

#13 遗忘(MeSH)

#14 遗忘(TI/TW/AB/CT)

#15 痴呆(MeSH)

#16 痴呆(TI/TW/AB/CT)

#17 #1 OR #2 OR #3 OR #4 OR #5 OR #6

#18 #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16

#19 #17 AND #18

 

What's new

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Differences between protocol and review
  16. Index terms

Last assessed as up-to-date: 25 July 2013.


DateEventDescription

24 July 2013New search has been performedUpdated search run 24 July 2013.

24 July 2013AmendedThe review author team was reformed.

24 July 2013New citation required but conclusions have not changedThree new trials have been included in this review.



 

Contributions of authors

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Differences between protocol and review
  16. Index terms

All correspondence: Dian He and Hongyu Zhou.
Drafting of review versions: Dian He, Shuai Dong.
Search for trials: Dian He and Yun Zhang.
Obtaining copies of trial reports: Dongfeng Wang and Xiangdong Gao.
Selection of trials for inclusion/exclusion: Dian He, Shuai Dong.
Extraction of data: Dian He, Shuai Dong.
Entry of data: Dian He, Hongyu Zhou.
Interpretation of data analyses: Dian He, Hongyu Zhou.

 

Declarations of interest

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Differences between protocol and review
  16. Index terms

None known.

 

Differences between protocol and review

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Differences between protocol and review
  16. Index terms

In the current review, types of participants were expanded by adding the new McDonald's criteria (Polman 2011). We excluded quasi-randomised trials in types of studies to avoid potential biases on results. We replaced the word "pharmacologic" with "pharmacological" in title and rephrased the primary outcome on efficacy (memory performance at week 12 (or later)) because they are more reasonable. The time of assessment (at week 12 (or later)) was specified to each outcome. All these changes from protocol to review have no effect on the review's conclusions.

* Indicates the major publication for the study

References

References to studies included in this review

  1. Top of page
  2. Abstract
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. What's new
  14. Contributions of authors
  15. Declarations of interest
  16. Differences between protocol and review
  17. Characteristics of studies
  18. References to studies included in this review
  19. References to studies excluded from this review
  20. References to studies awaiting assessment
  21. References to ongoing studies
  22. Additional references
  23. References to other published versions of this review
Krupp 2004 {published data only}
Krupp 2011 {published data only}
  • Krupp LB, Christodoulou C, Melville P, Scherl WF, Pai LY, Muenz LR, et al. Multicenter randomized clinical trial of donepezil for memory impairment in multiple sclerosis. Neurology 2011;76(17):1500-7.
Lovera 2007 {published data only}
  • Lovera J, Bagert B, Smoot K, Morris CD, Frank R, Bogardus K, et al. Ginkgo biloba for the improvement of cognitive performance in multiple sclerosis: a randomized, placebo-controlled trial. Multiple Sclerosis 2007;13(3):376-85.
Lovera 2010 {published data only}
  • Lovera JF, Frohman E, Brown TR, Bandari D, Nguyen L, Yadav V, et al. Memantine for cognitive impairment in multiple sclerosis: a randomized placebo-controlled trial. Multiple Sclerosis 2010;16(6):715-23.
Lovera 2012 {published data only}
  • Lovera JF, Kim E, Heriza E, Fitzpatrick M, Hunziker J, Turner AP, et al. Ginkgo biloba does not improve cognitive function in MS: a randomized placebo-controlled trial. Neurology 2012;79(12):1278-84.
Mäurer 2013 {published data only}
  • Mäurer M, Ortler S, Baier M, Meergans M, Scherer P, Hofmann W, et al. Randomised multicentre trial on safety and efficacy of rivastigmine in cognitively impaired multiple sclerosis patients. Multiple Sclerosis 2013;19(5):631-8.
Shaygannejad 2008 {published data only}
  • Shaygannejad V, Janghorbani M, Ashtari F, Zanjani HA, Zakizade N. Effects of rivastigmine on memory and cognition in multiple sclerosis. Canadian Journal of Neurological Sciences 2008;35(4):476-81.

References to studies excluded from this review

  1. Top of page
  2. Abstract
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. What's new
  14. Contributions of authors
  15. Declarations of interest
  16. Differences between protocol and review
  17. Characteristics of studies
  18. References to studies included in this review
  19. References to studies excluded from this review
  20. References to studies awaiting assessment
  21. References to ongoing studies
  22. Additional references
  23. References to other published versions of this review
Aragona 2009 {published data only}
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Barak 2002 {published data only}
Benedict 2008 {published data only}
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Bever 1996 {published data only}
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Bosca 2004 {published data only}
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Bruce 2012 {published data only}
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Cabrera-Gomez 2003 {published data only}
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Christodoulou 2006 {published data only}
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Cohen 1989 {published data only}
Cohen 2002 {published data only}
Cohen 2010 {published data only}
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Comi 2012 {published data only}
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Decoo 2004 {published data only}
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Fischer 1994 {published data only}
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Fischer 2000 {published data only}
Flechter 2007 {published data only}
  • Flechter S, Vardi J, Finkelstein Y, Pollak L. Cognitive dysfunction evaluation in multiple sclerosis patients treated with interferon beta-1b: an open-label prospective 1 year study. The Israel Medical Association Journal 2007;9(6):457-9.
Geisler 1996 {published data only}
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Greene 2000 {published data only}
  • Greene YM, Tariot PN, Wishart H, Cox C, Holt CJ, Schwid S, et al. A 12-week, open trial of donepezil hydrochloride in patients with multiple sclerosis and associated cognitive impairments. Journal of Clinical Psychopharmacology 2000;20(3):350-6.
Harel 2009 {published data only}
  • Harel Y, Appleboim N, Lavie M, Achiron A. Single dose of methylphenidate improves cognitive performance in multiple sclerosis patients with impaired attention process. Journal of Neurological Sciences 2009;276(1-2):38-40.
Havrdova 2006 {published data only}
  • Havrdova E. The effects of natalizumab on a test of cognitive function in patients with relapsing multiple sclerosis (MS) [abstract]. European Journal of Neurology 2006;13(Suppl 2):307.
Honarmand 2011 {published data only}
  • Honarmand K, Tierney MC, O'Connor P, Feinstein A. Effects of cannabis on cognitive function in patients with multiple sclerosis. Neurology 2011;76(13):1153-60.
Huolman 2011 {published data only}
  • Huolman S, Hämäläinen P, Vorobyev V, Ruutiainen J, Parkkola R, Laine T, et al. The effects of rivastigmine on processing speed and brain activation in patients with multiple sclerosis and subjective cognitive fatigue. Multiple Sclerosis 2011;17(11):1351-61.
Iaffaldano 2012 {published data only}
  • Iaffaldano P, Viterbo RG, Paolicelli D, Lucchese G, Portaccio E, Goretti B, et al. Impact of natalizumab on cognitive performances and fatigue in relapsing multiple sclerosis: a prospective, open-label, two years observational study. PLoS One 2012;7(4):e35843.
Jeffery 2011 {published data only}
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Kappos 2010 {published data only}
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Krause 2012 {published data only}
  • Krause I, Kern S, Schultheiss T, Horntrich A, Hanso H, Thomas K, et al. Cognitive dysfunction in relapsing-remitting multiple sclerosis: relation to quality of life and longitudinal changes under treatment with natalizumab. Multiple Sclerosis 2012;18:S46.
Krupp 1999 {published data only}
  • Krupp LB, Elkins LE, Scheffer S, Smiroldo J, Coyle PK. Donepezil for the treatment of memory impairments in multiple sclerosis. Neurology 1999;52(Suppl 2):A137.
Lacy 2013 {published data only}
  • Lacy M, Hauser M, Pliskin N, Assuras S, Valentine MO, Reder A. The effects of long-term interferon-beta-1b treatment on cognitive functioning in multiple sclerosis: a 16-year longitudinal study. Multiple Sclerosis 2013;19(13):1765-72.
Lang 2012 {published data only}
Lange 2009 {published data only}
Mattioli 2011a {published data only}
  • Mattioli F, Stampatori C, Capra R. The effect of natalizumab on cognitive function in patients with relapsing-remitting multiple sclerosis: preliminary results of a 1-year follow-up study. Neurological Sciences 2011;32(1):83-8.
Mattioli 2011b {published data only}
Melanson 2010 {published data only}
  • Melanson M, Grossberndt A, Klowak M, Leong C, Frost EE, Prout M, et al. Fatigue and cognition in patients with relapsing multiple sclerosis treated with interferon beta. International Journal of Neuroscience 2010;120:631-40.
Miller 2011 {published data only}
  • Miller A, O'Connor P, Wolinsky J, Confavreux C, Comi G, Kappos L, et al. Efficacy of oral teriflunomide in multiple sclerosis with relapses: cognitive outcomes from a phase III trial (TEMSO). Multiple Sclerosis 2011;17:S182.
Möller 2011 {published data only}
  • Möller F, Poettgen J, Broemel F, Neuhaus A, Daumer M, Heesen C.  HAGIL (Hamburg Vigil Study): a randomized placebo-controlled double-blind study with modafinil for treatment of fatigue in patients with multiple sclerosis. Multiple Sclerosis 2011;17(8):1002-9.
Montalban 2009 {published data only}
  • Montalban X, Sastre-Garriga J, Tintoré M, Brieva L, Aymerich FX, Río J, et al. A single-center, randomized, double-blind, placebo-controlled study of interferon beta-1b on primary progressive and transitional multiple sclerosis. Multiple Sclerosis 2009;15(10):1195-205.
Morrow 2009 {published data only}
  • Morrow SA, Kaushik T, Zarevics P, Erlanger D, Bear MF, Munschauer FE, et al. The effects of L-amphetamine sulfate on cognition in MS patients: results of a randomized controlled trial. Journal of Neurology 2009;256(7):1095-102.
Morrow 2013 {published data only}
  • Morrow SA, Smerbeck A, Patrick K, Cookfair D, Weinstock-Guttman B, Benedict RH. Lisdexamfetamine dimesylate improves processing speed and memory in cognitively impaired MS patients: a phase II study. Journal of Neurology 2013;260(2):489-97.
Oliveri 1998 {published data only}
Panitch 2004 {published data only}
  • Panitch H, Miller A, Paty D, Weinshenker B, North American Study Group on Interferon beta-1b in Secondary Progressive MS. Interferon beta-1b in secondary progressive MS: results from a 3-year controlled study. Neurology 2004;63(10):1788-95.
Patti 2009 {published data only}
  • Patti F, Amato MP, Bastianello S, Caniatti L, Di Monte E, Lijoi F, et al. Subcutaneous interferon beta-1a has a positive effect on cognitive performance in mildly disabled patients with relapsing-remitting multiple sclerosis: 2-year results from the COGIMUS study. Therapeutic Advances in Neurological Disorders 2009;2(2):67-77.
Patti 2010 {published data only}
  • Patti F, Amato MP, Bastianello S, Caniatti L, Di Monte E, Ferrazza P, et al. Effects of immunomodulatory treatment with subcutaneous interferon beta-1a on cognitive decline in mildly disabled patients with relapsing-remitting multiple sclerosis. Multiple Sclerosis 2010;16(1):68-77.
Pliskin 1994 {published data only}
  • Pliskin NH, Towle VL, Hamer DP, Reder AT, Noronha A, Pietre S, et al. The effects of interferon-beta on cognitive function in multiple sclerosis. Annals of Neurology 1994;36:326.
Pliskin 1996 {published data only}
  • Pliskin NH, Hamer DP, Goldstein DS, Towle VL, Reder AT, Noronha A, et al. Improved delayed visual reproduction test performance in multiple sclerosis patients receiving interferon beta-1b. Neurology 1996;47(6):1463-8.
Portaccio 2013 {published data only}
Rorie 2001 {published data only}
  • Rorie KD, Stump DA, Jeffery DR, Winston Salem NC. Effects of donepezil on cognitive function in patients with multiple sclerosis. Neurology 2001;56(Suppl 3):A99.
Rossini 2011 {published data only}
  • Rossini PM, Pasqualetti P, Pozzilli C, Grasso MG, Millefiorini E, Graceffa A, et al. Fatigue in progressive multiple sclerosis: results of a randomized, double-blind, placebo-controlled, crossover trial of oral 4-aminopyridine. Multiple Sclerosis 2001;7(6):354-8.
Rudick 2006 {published data only}
  • Rudick RA, Stuart WH, Calabresi PA, Confavreux C, Galetta SL, Radue EW, et al. Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. New England Journal of Medicine 2006;354(9):911-23.
Sailer 2000 {published data only}
Schröder 2011 {published data only}
  • Schröder A, Klotz P, Lee DH, Gold R, Linker RA. Stability of cognitive functions under mitoxantrone therapy in patients with progressive multiple sclerosis: a pilot analysis. Clinical Neurology and Neurosurgery 2011;113(7):527-30.
Schwid 2007 {published data only}
  • Schwid SR, Goodman AD, Weinstein A, McDermott MP, Johnson KP for the Copaxone Study Group. Cognitive function in relapsing multiple sclerosis: minimal changes in a 10-year clinical trial. Journal of Neurological Sciences 2007;255(1-2):57-63.
Selby 1998 {published data only}
  • Selby MJ, Ling N, Williams JM, Dawson A. Interferon beta 1-b in verbal memory functioning of patients with relapsing-remitting multiple sclerosis. Perceptual and Motor Skills 1998;86(3 Pt 1):1099-106.
Selmaj 2012 {published data only}
  • Selmaj K, Havrdova E, Gold R, Greenberg S, Umans K, Elkins J. Daclizumab Hyp monotherapy improved health-related quality of life parameters in relapsing-remitting multiple sclerosis: findings of the SELECT trial. Neurology 2012; Vol. 78.
Smits 1994 {published data only}
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Sumowski 2011 {published data only}
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Uttner 2005 {published data only}
Villoslada 2009 {published data only}
Wade 2004 {published data only}
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Weinstein 1999 {published data only}
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Weinstock-Guttman 2012a {published data only}
  • Weinstock-Guttman B, Galetta SL, Giovannoni G, Havrdova E, Hutchinson M, Kappos L, et al. Additional efficacy endpoints from pivotal natalizumab trials in relapsing-remitting MS. Journal of Neurology 2012;259(5):898-905.
Weinstock-Guttman 2012b {published data only}
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Wilken 2004 {published data only}
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Wilken 2008 {published data only}
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Zéphir 2005 {published data only}
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Zéphir 2008 {published data only}
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Additional references

  1. Top of page
  2. Abstract
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. What's new
  14. Contributions of authors
  15. Declarations of interest
  16. Differences between protocol and review
  17. Characteristics of studies
  18. References to studies included in this review
  19. References to studies excluded from this review
  20. References to studies awaiting assessment
  21. References to ongoing studies
  22. Additional references
  23. References to other published versions of this review
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