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. 2013 Dec 17;2013(12):CD008876.
doi: 10.1002/14651858.CD008876.pub3.

Pharmacological treatment for memory disorder in multiple sclerosis

Dian He  1 , Yun Zhang, Shuai Dong, Dongfeng Wang, Xiangdong Gao, Hongyu Zhou
Affiliations

Pharmacological treatment for memory disorder in multiple sclerosis

Dian He et al. Cochrane Database Syst Rev. .

Abstract

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

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

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

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

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

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

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

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Conflict of interest statement

None known.

Figures

1
1
Study flow diagram.
2
2
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
3
3
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
4
4
Efficacy on the primary outcomes reported in each study.
1.1
1.1. Analysis
Comparison 1 Subgroup analysis for donepezil versus placebo, Outcome 1 The mean change of total recall on the Selective Reminding Test (SRT) from baseline.
1.2
1.2. Analysis
Comparison 1 Subgroup analysis for donepezil versus placebo, Outcome 2 The mean total recall on the Selective Reminding Test (SRT) at exit.
1.3
1.3. Analysis
Comparison 1 Subgroup analysis for donepezil versus placebo, Outcome 3 The mean change of total correct score on the 10/36 Spatial Recall Test (10/36 SRT) from baseline.
1.4
1.4. Analysis
Comparison 1 Subgroup analysis for donepezil versus placebo, Outcome 4 The mean total correct score on the 10/36 Spatial Recall Test (10/36 SRT) at exit.
1.5
1.5. Analysis
Comparison 1 Subgroup analysis for donepezil versus placebo, Outcome 5 The mean change of total correct score on the Symbol Digit Modalities Test (SDMT) from baseline.
1.6
1.6. Analysis
Comparison 1 Subgroup analysis for donepezil versus placebo, Outcome 6 The mean total correct score on the Symbol Digit Modalities Test (SDMT) at exit.
1.7
1.7. Analysis
Comparison 1 Subgroup analysis for donepezil versus placebo, Outcome 7 The mean change of total correct score on the Paced Auditory Serial Addition Test (PASAT) (2+3 sec) from baseline.
1.8
1.8. Analysis
Comparison 1 Subgroup analysis for donepezil versus placebo, Outcome 8 The mean total correct score on the Paced Auditory Serial Addition Test (PASAT) (2+3 sec) at exit.
1.9
1.9. Analysis
Comparison 1 Subgroup analysis for donepezil versus placebo, Outcome 9 The number of patients experiencing diarrhoea.
1.10
1.10. Analysis
Comparison 1 Subgroup analysis for donepezil versus placebo, Outcome 10 The number of patients experiencing diarrhoea.
1.11
1.11. Analysis
Comparison 1 Subgroup analysis for donepezil versus placebo, Outcome 11 The number of patients experiencing nausea.
1.12
1.12. Analysis
Comparison 1 Subgroup analysis for donepezil versus placebo, Outcome 12 The number of patients experiencing nausea.
1.13
1.13. Analysis
Comparison 1 Subgroup analysis for donepezil versus placebo, Outcome 13 The number of patients experiencing abnormal dreams.
1.14
1.14. Analysis
Comparison 1 Subgroup analysis for donepezil versus placebo, Outcome 14 The number of patients experiencing abnormal dreams.
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References

References to studies included in this review

Krupp 2004 {published data only}
    1. Krupp LB, Christodoulou C, Melville P, Scherl WF, MacAllister WS, Elkins LE. Donepezil improved memory in multiple sclerosis in a randomized clinical trial. Neurology 2004;63(9):1579‐85. - PubMed
Krupp 2011 {published data only}
    1. 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. - PMC - PubMed
Lovera 2007 {published data only}
    1. 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. - PubMed
Lovera 2010 {published data only}
    1. 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. - PubMed
Lovera 2012 {published data only}
    1. 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. - PMC - PubMed
Mäurer 2013 {published data only}
    1. 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. - PubMed
Shaygannejad 2008 {published data only}
    1. 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. - PubMed

References to studies excluded from this review

Aragona 2009 {published data only}
    1. Aragona M, Onesti E, Tomassini V, Conte A, Gupta S, Gilio F, et al. Psychopathological and cognitive effects of therapeutic cannabinoids in multiple sclerosis: a double‐blind, placebo controlled, crossover study. Clinical Neuropharmacology 2009;32(1):41‐7. - PubMed
Barak 1999 {published data only}
    1. Barak Y, Gabbay U, Gilad R, Sarova‐Pinhas I, Achiron A. Neuropsychiatric assessment as a secondary outcome measure in a multiple sclerosis intravenous immunoglobulin (IVIg) trial. International Journal of Psychiatry in Clinical Practice 1999;3:31‐4. - PubMed
Barak 2002 {published data only}
    1. Barak Y, Achiron A. Effect of interferon‐beta‐1b on cognitive functions in multiple sclerosis. European Neurology 2002;47(1):11‐4. - PubMed
Benedict 2008 {published data only}
    1. Benedict RH, Munschauer F, Zarevics P, Erlanger D, Rowe V, Feaster T, et al. Effects of l‐amphetamine sulfate on cognitive function in multiple sclerosis patients. Journal of Neurology 2008;255(6):848‐52. - PubMed
Bever 1996 {published data only}
    1. Bever CT Jr, Anderson PA, Leslie J, Panitch HS, Dhib‐Jalbut S, Khan OA, et al. Treatment with oral 3,4 diaminopyridine improves leg strength in multiple sclerosis patients: results of a randomized, double‐blind, placebo‐controlled, crossover trial. Neurology 1996;47(6):1457‐62. - PubMed
Bosca 2004 {published data only}
    1. Bosca I, Bueno A, Gadea M, Casanova B, Coret F. Donepezile and cognitive impairment in multiple sclerosis: a double‐blind pilot study. Multiple Sclerosis 2004;10(Suppl 2):S150.
Bruce 2012 {published data only}
    1. Bruce J, Hancock L, Roberg B, Brown A, Henkelman E, Lynch S. Impact of armodafinil on cognition in multiple sclerosis: a randomized, double‐blind crossover pilot study. Cognitive and Behavioral Neurology 2012;25(3):107‐14. - PubMed
Cabrera‐Gomez 2003 {published data only}
    1. Cabrera‐Gomez JA, Echazabal‐Santana N, Porrero‐Martin P, Valenzuela‐Silva C, Rodriguez CA, Fuentes‐Suarez I, et al . Interferon‐alpha2b recombinant improved the cognitive dysfunction in patients with relapsing remitting multiple sclerosis. Revista de Neurologia 2003;37(3):214‐20. - PubMed
Christodoulou 2006 {published data only}
    1. Christodoulou C, Melville P, Scherl WF, Macallister WS, Elkins LE, Krupp LB. Effects of donepezil on memory and cognition in multiple sclerosis. Journal of Neurological Sciences 2006;245(1‐2):127‐36. - PubMed
Cohen 1989 {published data only}
    1. Cohen RA, Fisher M. Amantadine treatment of fatigue associated with multiple sclerosis. Archives of Neurology 1989;46(6):676‐80. - PubMed
Cohen 2002 {published data only}
    1. Cohen JA, Cutter GR, Fischer JS, Goodman AD, Heidenreich FR, Kooijmans MF, et al. Benefit of interferon beta‐1a on MSFC progression in secondary progressive MS. Neurology 2002;59(5):679‐87. - PubMed
Cohen 2010 {published data only}
    1. Cohen JA, Barkhof F, Comi G, Hartung HP, Khatri BO, Montalban X, et al. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. New England Journal of Medicine 2010;362(5):402‐15. - PubMed
Comi 2012 {published data only}
    1. Comi G, Jeffery D, Kappos L, Montalban X, Boyko A, Rocca MA, et al. Placebo‐controlled trial of oral laquinimod for multiple sclerosis. New England Journal of Medicine 2012;366(11):1000‐9. - PubMed
Decoo 2004 {published data only}
    1. Decoo D, on behalf of the MS Rehab Study Group. Effects of donepezil in multiple sclerosis: a single‐centre trial. Multiple Sclerosis 2004;10(Suppl 2):S150.
Fischer 1994 {published data only}
    1. Fischer JS, Goodkin DE, Rudick RA, Perkins KK, Barilla DY, Daughtry MM, et al. Low dose (7.5 mg) oral methotrexate improves neurophysiological function in patients with chronic progressive multiple sclerosis. Annals of Neurology 1994;36:289.
Fischer 2000 {published data only}
    1. Fischer JS, Priore RL, Jacobs LD, Cookfair DL, Rudick RA, Herndon RM, et al. Neuropsychological effects of interferon beta‐1a in relapsing multiple sclerosis. Multiple Sclerosis Collaborative Research Group. Annals of Neurology 2000;48(6):885‐92. - PubMed
Flechter 2007 {published data only}
    1. 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. - PubMed
Geisler 1996 {published data only}
    1. Geisler MW, Sliwinski M, Coyle PK, Masur DM, Doscher C, Krupp LB. The effects of amantadine and pemoline on cognitive functioning in multiple sclerosis. Archives of Neurology 1996;53(2):185‐8. - PubMed
Greene 2000 {published data only}
    1. 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. - PubMed
Harel 2009 {published data only}
    1. 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. - PubMed
Havrdova 2006 {published data only}
    1. 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}
    1. 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. - PMC - PubMed
Huolman 2011 {published data only}
    1. 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. - PubMed
Iaffaldano 2012 {published data only}
    1. 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. - PMC - PubMed
Jeffery 2011 {published data only}
    1. Jeffery D, Comi G, Kappos L, Montalban X, Boyko A, Filippi M. Laquinimod's impact on patient‐reported fatigue and functional status: results from Allegro, a placebo‐controlled phase III trial for relapsing‐remitting multiple sclerosis. Multiple Sclerosis 2011;17:S313‐4.
Kappos 2010 {published data only}
    1. Kappos L, Radue EW, O'Connor P, Polman C, Hohlfeld R, Calabresi P, et al. A placebo‐controlled trial of oral fingolimod in relapsing multiple sclerosis. New England Journal of Medicine 2010;362(5):387‐401. - PubMed
Krause 2012 {published data only}
    1. 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}
    1. 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}
    1. 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. - PubMed
Lang 2012 {published data only}
    1. Lang C, Reiss C, Mäurer M. Natalizumab may improve cognition and mood in multiple sclerosis. European Neurology 2012;67(3):162‐6. - PubMed
Lange 2009 {published data only}
    1. Lange R, Volkmer M, Heesen C, Liepert J. Modafinil effects in multiple sclerosis patients with fatigue. Journal of Neurology 2009;256(4):645‐50. - PubMed
Mattioli 2011a {published data only}
    1. 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. - PubMed
Mattioli 2011b {published data only}
    1. Mattioli F, Stampatori C, Bellomi F, Capra R. Natalizumab efficacy on cognitive impairment in MS. Neurological Sciences 2011;31(Suppl 3):321‐3. - PubMed
Melanson 2010 {published data only}
    1. 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. - PubMed
Miller 2011 {published data only}
    1. 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}
    1. 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. - PubMed
Montalban 2009 {published data only}
    1. 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. - PubMed
Morrow 2009 {published data only}
    1. 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. - PubMed
Morrow 2013 {published data only}
    1. 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. - PubMed
Oliveri 1998 {published data only}
    1. Oliveri RL, Sibilia G, Valentino P, Russo C, Romeo N, Quattrone A. Pulsed methylprednisolone induces a reversible impairment of memory in patients with relapsing‐remitting multiple sclerosis. Acta Neurologica Scandinavica 1998;97(6):366‐9. - PubMed
Panitch 2004 {published data only}
    1. 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. - PubMed
Patti 2009 {published data only}
    1. Patti F, Amato MP, Bastianello S, Caniatti L, 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. - PMC - PubMed
Patti 2010 {published data only}
    1. Patti F, Amato MP, Bastianello S, Caniatti L, 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. - PubMed
Pliskin 1994 {published data only}
    1. 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}
    1. 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. - PubMed
Portaccio 2013 {published data only}
    1. Portaccio E, Stromillo ML, Goretti B, Hakiki B, Giorgio A, Rossi F, et al. Natalizumab may reduce cognitive changes and brain atrophy rate in relapsing‐remitting multiple sclerosis: a prospective, non‐randomized pilot study. European Journal of Neurology 2013;20(6):986‐90. - PubMed
Rorie 2001 {published data only}
    1. 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}
    1. 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. - PubMed
Rudick 2006 {published data only}
    1. 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. - PubMed
Sailer 2000 {published data only}
    1. Sailer M, Heinze HJ, Schoenfeld MA, Hauser U, Smid HG. Amantadine influences cognitive processing in patients with multiple sclerosis. Pharmacopsychiatry 2000;33(1):28‐37. - PubMed
Schröder 2011 {published data only}
    1. 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. - PubMed
Schwid 2007 {published data only}
    1. 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. - PubMed
Selby 1998 {published data only}
    1. 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. - PubMed
Selmaj 2012 {published data only}
    1. 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}
    1. Smits RC, Emmen HH, Bertelsmann FW, Kulig BM, Loenen AC, Polman CH. The effects of 4‐aminopyridine on cognitive function in patients with multiple sclerosis: a pilot study. Neurology 1994;44(9):1701‐5. - PubMed
Sumowski 2011 {published data only}
    1. Sumowski JF, Chiaravalloti N, Erlanger D, Kaushik T, Benedict RH, DeLuca J. L‐amphetamine improves memory in MS patients with objective memory impairment. Multiple Sclerosis 2011;17(9):1141‐5. - PubMed
Uttner 2005 {published data only}
    1. Uttner I, Müller S, Zinser C, Maier M, Süssmuth S, Claus A, et al. Reversible impaired memory induced by pulsed methylprednisolone in patients with MS. Neurology 2005;64(11):1971‐3. - PubMed
Villoslada 2009 {published data only}
    1. Villoslada P, Arrondo G, Sepulcre J, Alegre M, Artieda J. Memantine induces reversible neurologic impairment in patients with MS. Neurology 2009;72(19):1630‐3. - PubMed
Wade 2004 {published data only}
    1. Wade DT, Makela P, Robson P, House H, Bateman C. Do cannabis‐based medicinal extracts have general or specific effects on symptoms in multiple sclerosis? A double‐blind, randomized, placebo‐controlled study on 160 patients. Multiple Sclerosis 2004;10(4):434‐41. - PubMed
Weinstein 1999 {published data only}
    1. Weinstein A, Schwid SR, Schiffer RB, McDermott MP, Giang DW, Goodman AD. Neuropsychologic status in multiple sclerosis after treatment with glatiramer. Archives of Neurology 1999;56(3):319‐24. - PubMed
Weinstock‐Guttman 2012a {published data only}
    1. 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. - PubMed
Weinstock‐Guttman 2012b {published data only}
    1. Weinstock‐Guttman B, Cree B, Seze J, Fox R, Gold R, Hartung H, et al. Effects of a 24‐week natalizumab treatment interruption on quality of life, fatigue, and cognition: results from the RESTORE Study. Neurology 2012; Vol. 78:P06.171.
Wilken 2004 {published data only}
    1. Wilken J, Kane R, Sullivan C, Kane H, Rossman S, Lawson J, et al. Combination therapy (Provigil + Avonex) in the treatment of cognitive problems in MS [abstract]. International Journal of MS Care 2004;6:68‐9.
Wilken 2008 {published data only}
    1. Wilken JA, Sullivan C, Wallin M, Rogers C, Kane RL, Rossman H, et al. Treatment of multiple sclerosis‐related cognitive problems with adjunctive modafinil: rationale and preliminary supportive data. International Journal of MS Care 2008;10:1‐10.
Zéphir 2005 {published data only}
    1. Zéphir H, Seze J, Dujardin K, Dubois G, Cabaret M, Bouillaguet S, et al. One‐year cyclophosphamide treatment combined with methylprednisolone improves cognitive dysfunction in progressive forms of multiple sclerosis. Multiple Sclerosis 2005;11(3):360‐3. - PubMed
Zéphir 2008 {published data only}
    1. Zéphir H, Sèze J, Dujardin K, Dubois G, Cabaret M, Bouillaguet S, et al. Cognitive impact of mitoxantrone and methylprednisolone in multiple sclerosis: an open label study. Revue Neurologique (Paris) 2008;164(1):47‐52. - PubMed

References to studies awaiting assessment

NCT01074619 {unpublished data only}
    1. NCT01074619. Study on cognitive disorders of multiple sclerosis. clinicaltrials.gov/ct2/show/NCT01074619 (accessed 10 December 201).

References to ongoing studies

NCT01466114 {unpublished data only}
    1. NCT01466114. Estriol treatment in multiple sclerosis (MS): effect on cognition. clinicaltrials.gov/ct2/show/NCT01466114 (accessed 10 December 2013).

Additional references

Ahlemeyer 2003
    1. Ahlemeyer B, Krieglstein J. Neuroprotective effects of Ginkgo biloba extract. Cellular Molecular Life Sciences 2003;60:1779‐92. - PMC - PubMed
Amato 2004
    1. Amato MP, Bartolozzi ML, Zipoli V, Portaccio E, Mortilla M, Guidi L, et al. Neocortical volume decrease in relapsing‐remitting MS patients with mild cognitive impairment. Neurology 2004;63(1):89‐93. - PubMed
Amato 2006
    1. Amato MP, Portaccio E, Zipoli V. Are there protective treatments for cognitive decline in MS?. Journal of the Neurological Sciences 2006;245(1‐2):183‐6. - PubMed
Bakshi 2003
    1. Bakshi R. Fatigue associated with multiple sclerosis: diagnosis, impact and management. Multiple Sclerosis 2003;9(3):219‐27. - PubMed
Benedict 1997
    1. Benedict R. Brief Visuospatial Memory Test‐Revised: Professional Manual. Odessa, Florida: Psychological Assessment Resources, 1997.
Benedict 2005
    1. Benedict RH, Zivadinov R, Carone DA, Weinstock‐Guttman B, Gaines J, Maggiore C, et al. Regional lobar atrophy predicts memory impairment in multiple sclerosis. American Journal of Neuroradiology 2005;26(7):1824‐31. - PMC - PubMed
Benedict 2006
    1. Benedict RH, Cookfair D, Gavett R, Gunther M, Munschauer F, Garg N, et al. Validity of the minimal assessment of cognitive function in multiple sclerosis (MACFIMS). Journal of the International Neuropsychological Society 2006;12(4):549‐58. - PubMed
Benedict 2009
    1. Benedict RH, Ramasamy D, Munschauer F, Weinstock‐Guttman B, Zivadinov R. Memory impairment in multiple sclerosis: correlation with deep grey matter and mesial temporal atrophy. Journal of Neurology Neurosurgery and Psychiatry 2009;80(2):201‐6. - PubMed
Boringa 2001
    1. Boringa JB, Lazeron RH, Reuling IE, Adèr HJ, Pfennings L, Lindeboom J, et al. The brief repeatable battery of neuropsychological tests: normative values allow application in multiple sclerosis clinical practice. Multiple Sclerosis 2001;7(4):263‐7. - PubMed
Buschke 1974
    1. Buschke H, Fuld PA. Evaluating storage, retention and retrieval in disordered memory and learning. Neurology 1974;24:1019‐25. - PubMed
Calabrese 2009
    1. Calabrese M, Agosta F, Rinaldi F, Mattisi I, Grossi P, Favaretto A, et al. Cortical lesions and atrophy associated with cognitive impairment in relapsing‐remitting multiple sclerosis. Archives of Neurology 2009;66(9):1144‐50. - PubMed
Calabrese 2012
    1. Calabrese M, Poretto V, Favaretto A, Alessio S, Bernardi V, Romualdi C, et al. Cortical lesion load associates with progression of disability in multiple sclerosis. Brain 2012;135(Pt 10):2952‐61. - PubMed
Cella 1996
    1. Cella DF, Dineen K, Arnason B, Reder A, Webster KA, Karabatsos G, et al. Validation of the functional assessment of multiple sclerosis quality of life instrument. Neurology 1996;47(1):129‐39. - PubMed
Chiaravalloti 2008
    1. Chiaravalloti ND, DeLuca J. Cognitive impairment in multiple sclerosis. Lancet Neurology 2008;7(12):1139‐51. - PubMed
Delis 2000
    1. Delis DC, Kramer JH, Kaplan E, Ober BA. California Verbal Learning Test. 2nd Edition. San Antonio: Psychological Corporation, 2000.
Dineen 2009
    1. DineenRA, Vilisaar J, Hlinka J, Bradshaw CM, Morgan PS, Constantinescu CS, et al. Disconnection as a mechanism for cognitive dysfunction in multiple sclerosis. Brain 2009;132(Pt 1):239‐49. - PubMed
Feuillet 2007
    1. Feuillet L, Reuter F, Audoin B, Malikova I, Barrau K, Cherif AA, et al. Early cognitive impairment in patients with clinically isolated syndrome suggestive of multiple sclerosis. Multiple Sclerosis 2007;13(1):124‐7. - PubMed
Fischer 1999
    1. Fischer JS, LaRocca NG, Miller DM, Ritvo PG, Andrews H, Paty D. Recent developments in the assessment of quality of life in multiple sclerosis (MS). Multiple Sclerosis 1999;5(4):251‐9. - PubMed
Foong 1998
    1. Foong J, Rozewicz L, Quaghebeur G, Thompson AJ, Miller DH, Ron MA. Neuropsychological deficits in multiple sclerosis after acute relapse. Journal of Neurology Neurosurgery and Psychiatry 1998;64(4):529‐32. - PMC - PubMed
Geurts 2012
    1. Geurts JJ, Calabrese M, Fisher E, Rudick RA. Measurement and clinical effect of grey matter pathology in multiple sclerosis. Lancet Neurology 2012;11(12):1082‐92. - PubMed
Glanz 2012
    1. Glanz BI, Healy BC, Hviid LE, Chitnis T, Weiner HL. Cognitive deterioration in patients with early multiple sclerosis: a 5‐year study. Journal of Neurology Neurosurgery and Psychiatry 2012;83(1):38‐43. - PubMed
Higgins 2011
    1. Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane‐handbook.org.
Huang 2004
    1. Huang SH, Duke RK, Chebib M, Sasaki K, Wada K, Johnston GA. Ginkgolides, diterpene trilactones of Ginkgo biloba, as antagonists at recombinant alpha1beta2gamma2L GABAA receptors. European Journal of Pharmacology 2004;494:131‐8. - PubMed
Huijbregts 2004
    1. Huijbregts SC, Kalkers NF, Sonneville LM, Groot V, Reuling IE, Polman CH. Differences in cognitive impairment of relapsing remitting, secondary, and primary progressive MS. Neurology 2004;63(2):335‐9. - PubMed
Kinsinger 2010
    1. Kinsinger SW, Lattie E, Mohr DC. Relationship between depression, fatigue, subjective cognitive impairment, and objective neuropsychological functioning in patients with multiple sclerosis. Neuropsychology 2010;24(5):573‐80. - PMC - PubMed
Kuczenski 1995
    1. Kuczenski R, Segal DS, Cho AK, Melega W. Hippocampus norepinephrine, caudate dopamine and serotonin, and behavioral responses to the stereoisomers of amphetamine and methamphetamine. The Journal of Neuroscience 1995;15:1308‐17. - PMC - PubMed
Leocani 2000
    1. Leocani L, Locatelli T, Martinelli V, Rovaris M, Falautano M, Filippi M, et al. Electroencephalographic coherence analysis in multiple sclerosis: correlation with clinical, neuropsychological, and MRI findings. Journal of Neurology Neurosurgery and Psychiatry 2000;69(2):192‐8. - PMC - PubMed
Lezak 2004
    1. Lezak MD, Howieson DB, Loring DW. Neuropsychological Assessment. 4th Edition. New York: Oxford University Press, 2004.
McDonald 2001
    1. McDonald WI, Compston A, Edan G, Goodkin D, Hartung HP, Lublin FD, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the Diagnosis of Multiple Sclerosis. Annals of Neurology 2001;50(1):121‐7. - PubMed
Mesaros 2012
    1. Mesaros S, Rocca MA, Kacar K, Kostic J, Copetti M, Stosic‐Opincal T, et al. Diffusion tensor MRI tractography and cognitive impairment in multiple sclerosis. Neurology 2012;78(13):969‐75. - PubMed
Morgen 2006
    1. Morgen K, Sammer G, Courtney SM, Wolters T, Melchior H, Blecker CR, et al. Evidence for a direct association between cortical atrophy and cognitive impairment in relapsing‐remitting MS. Neuroimage 2006;30(3):891‐8. - PubMed
Morrow 2011
    1. Morrow SA, Jurgensen S, Forrestal F, Munchauer FE, Benedict RH. Effects of acute relapses on neuropsychological status in multiple sclerosis patients. Journal of Neurology 2011;258(9):1603‐8. - PubMed
Nathan 2000
    1. Nathan P. Can the cognitive enhancing effects of Ginkgo biloba be explained by its pharmacology?. Medical Hypotheses 2000;55:491‐93. - PubMed
Paulesu 1996
    1. Paulesu E, Perani D, Fazio F, Comi G, Pozzilli C, Martinelli V, et al. Functional basis of memory impairment in multiple sclerosis: a [18F] FDG PET study. Neuroimage 1996;4(2):87‐96. - PubMed
Pitt 2000
    1. Pitt D, Werner P, Raine CS. Glutamate excitotoxicity in a model of multiple sclerosis. Nature Medicine 2000;6(1):67‐70. - PubMed
Polman 2005
    1. Polman CH, Reingold SC, Edan G, Filippi M, Hartung HP, Kappos L. Diagnostic criteria for multiple sclerosis: 2005 revisions to the "McDonald Criteria". Annals of Neurology 2005;58(6):840‐6. - PubMed
Polman 2011
    1. Polman CH, Reingold SC, Banwell B, Clanet M, Cohen JA, Filippi M, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Annals of Neurology 2011;69(2):292‐302. - PMC - PubMed
Poser 1983
    1. Poser CM, Paty DW, Scheinberg L, McDonald WI, Davis FA, Ebers GC, et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Annals of Neurology 1983;13(3):227‐31. - PubMed
Potagas 2008
    1. Potagas C, Giogkaraki E, Koutsis G, Mandellos D, Tsirempolou E, Sfagos C, et al. Cognitive impairment in different MS subtypes and clinically isolated syndromes. Journal of the Neurological Sciences 2008;267(1‐2):100‐6. - PubMed
Rao 1990a
    1. Rao SM, in collaboration with the Cognitive Function Study Group of the National Multiple Sclerosis Society. A Manual for the Brief, Repeatable Battery of Neuropsychological Tests in Multiple Sclerosis. Milwaukee: WI: Section of Neuropsychology, Medical College of Wisconsin, 1990.
Rao 1990b
    1. Rao SM. Cognitive Function Study Group, NMSS. A Manual for the Brief Repeatable Battery of Neuropsychological Tests in Multiple Sclerosis. New York: National Multiple Sclerosis Society, 1990.
Rao 1991a
    1. Rao SM, Leo GJ, Bernardin L, Unverzagt F. Cognitive dysfunction in multiple sclerosis. I. Frequency, patterns, and prediction. Neurology 1991;41(5):685‐91. - PubMed
Rao 1991b
    1. Rao SM, Leo GJ, Ellington MS, Nauertz T, Bernardin L, Unverzagt F. Cognitive dysfunction in multiple sclerosis: II. Impact on employment and social functioning. Neurology 1991;41:692‐6. - PubMed
Rao 1991c
    1. Rao SM. Neuropsychological Screening Battery for Multiple Sclerosis. Milwaukee, WI: Medical College of Wisconsin, 1991.
Rao 1993
    1. Rao SM, Grafman J, DiGiulio D, Mittenberg W, Bernardin L, Leo GJ, et al. Memory dysfunction in multiple sclerosis: its relation to working memory, semantic encoding, and implicit learning. Neuropsychology 1993;7(3):364‐74.
Review Manager 2012 [Computer program]
    1. The Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager (RevMan). Version 5.2. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2013.
Rossi 2012
    1. Rossi F, Giorgio A, Battaglini M, Stromillo ML, Portaccio E, Goretti B, et al. Relevance of brain lesion location to cognition in relapsing multiple sclerosis. PLoS One 2012;7(11):e44826. - PMC - PubMed
Ruberg 1987
    1. Ruberg M, Villageois A, Bonnet AM, Rieger F, Agid Y, Fahn S. Acetylcholinesterase and butyrylcholinesterase activity in the cerebrospinal fluid of patients with neurodegenerative diseases involving cholinergic systems. Journal of Neurology Neurosurgery and Psychiatry 1987;50(5):538‐43. - PMC - PubMed
Ruet 2013
    1. Ruet A, Deloire M, Charré‐Morin J, Hamel D, Brochet B. Cognitive impairment differs between primary progressive and relapsing‐remitting MS. Neurology 2013;80(16):1501‐8. - PubMed
Sanfilipo 2006
    1. Sanfilipo MP, Benedict RH, Weinstock‐Guttman B, Bakshi R. Gray and white matter brain atrophy and neuropsychological impairment in multiple sclerosis. Neurology 2006;66(5):685‐92. - PubMed
Schünemann 2009
    1. Schünemann H, Brożek J, Oxman A, editors. GRADE Handbook for Grading Quality of Evidence and Strength of Recommendation. Version 3.2 [updated March 2009]. The GRADE Working Group. http://www.cc‐ims‐net/gradepro 2009.
Smith 1982
    1. Smith, A. Symbol Digit Modalities Test (SDMT). Los Angeles: Western Psychological Services, 1982.
Thornton 2002
    1. Thornton AE, Raz N, Tucke KA. Memory in multiple sclerosis: contextual encoding deficits. Journal of the International Neuropsychological Society 2002;8(3):395‐409. - PubMed
Vercellino 2005
    1. Vercellino M, Plano F, Votta B, Mutani R, Giordana MT, Cavalla P. Grey matter pathology in multiple sclerosis. Journal of Neuropathology and Experimental Neurology 2005;64(12):1101‐7. - PubMed
Vickrey 1995
    1. Vickrey BG, Hays RD, Harooni R, Myers LW, Ellison GW. A health‐related quality of life measure for multiple sclerosis. Quality of Life Research 1995;4(3):187‐206. - PubMed
Ware 1992
    1. Ware JE Jr, Sherbourne CD. The MOS 36‐item short‐form health survey (SF‐36). I. Conceptual framework and item selection. Medical Care 1992;30(6):473‐83. - PubMed
Wechsler 1987
    1. Wechsler D. Wechsler Memory Scale‐Revised. San Antonio: Psychological Corporation, 1987.
Wechsler 1997a
    1. Wechsler D. Wechsler Memory Scale ‐ Third Edition (WMS‐III). San Antonio: Psychological Corporation, 1997.
Wechsler 1997b
    1. Wechsler D. Wechsler Adult Intelligence Scale. 3rd Edition. San Antonio: The Psychological Corporation, 1997.

References to other published versions of this review

He 2011
    1. He D, Zhou H, Guo D, Hao Z, Wu B. Pharmacologic treatment for memory disorder in multiple sclerosis. Cochrane Database of Systematic Reviews 2011, Issue 10. [DOI: 10.1002/14651858.CD008876] - DOI - PubMed

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