There is debate in the literature regarding the magnitude, nature, and influence of cognitive impairment in individuals with relapsing-remitting multiple sclerosis (RRMS). Therefore, we conducted a meta-analysis that quantified the overall magnitude of cognitive impairment in individuals with RRMS and identified the domains of cognition and clinical/demographic variables that were moderators of the overall effect. We included 57 studies with 3891 participants that yielded a total of 755 effect sizes. Overall, there was a moderate decline in cognitive functioning in individuals with RRMS compared with healthy controls. Larger effects were observed in cognitive domains of motor functioning, mood status and memory and learning. Regarding demographic and clinical variables, age and gender were moderators of cognitive impairment in all cognitive domains, whereas neurological disability and disease duration primarily moderated performance on tasks assessing memory and learning.
1 Devins GM Seland TP . Emotional impact of multiple sclerosis: recent findings and suggestions for future research. Psychol Bull1987; 101: 363–375.
2.
2 Lester K Stepleman L Hughes M . The association of illness severity, self-reported cognitive impairment, and perceived illness management with depression and anxiety in a multiple sclerosis clinic population. J Behav Med2007; 30: 177–186.
3.
3 Calabrese P; . Neuropsychology of multiple sclerosis: an overview. J Neurol 2006; 253(Suppl. 1): I/10–I/15.
4.
4 Bobholz JA Rao SM . Cognitive dysfunction in multiple sclerosis: a review of recent developments. Curr Opin Neurol2003; 16: 283–288.
5.
5 Achiron A Barak Y . Cognitive changes in early MS: a call for a common framework. J Neurol Sci2006; 245(Special Issue): 47–51.
6.
6 Thornton AE Naftali R . Memory impairment in multiple sclerosis: a quantitative review. Neuropsychology1997; 11: 357–366.
7.
7 *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 Neurol Scand1998; 97: 366–369.
8.
8 Janculjak D Mubrin Z Brzovic Z . Changes in short-term memory processes in patients with multiple sclerosis. Eur J Neurol1999; 6: 663–668.
9.
9 *Gaudino EA Chiaravalloti ND Deluca J Diamond BJ . A comparison of memory performance in relapsing-remitting, primary progressive and secondary progressive, multiple sclerosis. Neuropsychiatry Neuropsychol Behav Neurol2001; 14: 32–44.
10.
10 *Wishart HA Saykin AJ McDonald BC . Brain activation patterns associated with working memory in relapsing-remitting MS. Neurology2004; 62: 234–238.
11.
11 Arnett PA Rao SM Hussain M Swanson SJ Hammeke TA . Conduction aphasia in multiple sclerosis: a case report with MRI findings. Neurology1996; 47: 576–578.
12.
12 *Denney DR Sworowski LA Lynch SG . Cognitive impairment in three subtypes of multiple sclerosis. Arch Clin Neuropsychol2005; 20: 967–981.
13.
13 *LaPointe LL Maitland CG Blanchard AA Kemker BE Stierwalt JAG Heald GR . The effects of auditory distraction on visual cognitive performance in multiple sclerosis. J Neuroophthalmol2005; 25: 92–94.
14.
14 Lengenfelder J Bryant D Diamond BJ Kalmer JH Moore NB DeLuca J . Processing speed interacts with working memory efficiency in multiple sclerosis. Arch Clin Neuropsychol2006; 21: 229–238.
15.
15 *Rosti E Hämäläinen P Koivisto K Hokkanen L . PASAT in detecting cognitive impairment in relapsing-remitting MS. Appl Neuropsychol2007; 14: 101–112.
16.
16 Foong J Rozewicz L Quaghebeur G . Executive function in multiple sclerosis: the role of frontal lobe pathology. Brain1997; 120: 15–26.
17.
17 Nocentini U Rossini PM Carlesimo GA . Patterns of cognitive impairment in secondary progressive stable phase of multiple sclerosis: correlations with MRI findings. Eur Neurol2001; 45: 11–18.
18.
18 Beatty WW . Fluency in multiple sclerosis: which measure is best. Mult Scler2002; 8: 261–264.
19.
19 Parry AMM Scott RB Palace J Smith S Matthews PM . Potentially adaptive functional changes in cognitive processing for patients with multiple sclerosis and their acute modulation by rivastigmine. Brain2003; 126: 2750–2760.
20.
20 Henry JD Beatty WW . Verbal fluency deficits in multiple sclerosis. Neuropsychologia2006; 44: 1166–1174.
21.
21 Wishart H Sharpe D . Neuropsychological aspects of multiple sclerosis – a quantitative review. J Clin Exp Neuropsychol1997; 19: 810–824.
22.
22 Zakzanis KK . Distinct neurocognitive profiles in multiple sclerosis subtypes. Arch Clin Neuropsychol2000; 15: 115–136.
23.
23 Stroup DF Berlin JA Morton SC . Meta-analysis of obeservational studies in epidemiology: a proposal for reporting. JAMA2000; 283: 2008–2012.
24.
24 Poser CM Paty DW Scheinberg L . New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol1983; 13: 227–231.
25.
25 Roberts BW; Kuncel NR; Viechtbauer W; Bogg T; . Meta-analysis in personality psychology. In RW Robins, RC Fraley and RF Kruger (Eds.), Handbook of Research Methods in Personality Psycology. New York, NY: Guilford Press, 2007..
27 Strauss E Sherman E Spreen O . A compendium of neuropsychological tests.Oxford University Press, New York; 2006.
28.
28 Kurtzke JF . Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology1983; 33: 1444–1452.
29.
29 Confavreux C Vukusic S Adeleine P . Early clinical predictors and progression of irreversible disability in multiple sclerosis: an amnesic process. Brain2003; 126: 770–782.
30.
30 Hedges L . Advances in statistical methods for meta-analysis. In: WH Yeaton PM Wortman , (eds), Issues in data synthesis: new directions for program evaluation.San Francisco: Academic Press; 1984. pp. 25–42.
31.
31 Borenstein M Hedges L Higgins J Rothstein H . Comprehensive meta-analysis.Englewood, NJ: Biostat; 2005.
32.
32 Cohen J . A power primer. Psychol Bull1992; 112: 155–159.
33.
33 Rosenthal R . The “file drawer problem” and tolerance for null results. Psychol Bull1979; 86: 638–641.
34.
34 *Andrade VM . Cognitive profile of patients with relapsing remitting multiple sclerosis. Arq Neuropsiquiatr1999; 57: 775–783.
35.
35 *Andrade VM Oliveira MGM Miranda MC Oliveira ASB Oliveira EML Bueno OFA . Semantic relations and repetition of items enhance the free recall of words by multiple sclerosis patients. J Clin Exp Neuropsychol2003; 25: 1070–1078.
36.
36 *Archibald CJ Fisk JD . Information processing efficiency in patients with multiple sclerosis. J Clin Exp Neuropsychol2000; 22: 686–701.
37.
37 *Arnett PA Rao SM Grafman J . Executive functions in multiple sclerosis: an analysis of temporal ordering, semantic encoding, and planning abilities. Neuropsychology1997; 11: 535–544.
38.
38 *Arnott WL Jordan FM Murdoch BE Lethlean JB . Narrative discourse in multiple sclerosis: an investigation of conceptual structure. Aphasiology1997; 11: 969–991.
39.
39 *Barkhof F Elton M Lindeboom J . Functional correlates of callosal atrophy in relapsing-remitting multiple sclerosis patients: a preliminary study. J Neurol1998; 245: 153–158.
40.
40 *Beatty WW Goodkin DE Monson N Beatty PA . Cognitive disturbances in patients with relapsing-remitting multiple sclerosis. Arch Neurol1989; 46: 1113–1119.
41.
41 *Birnboim S Miller A . Cognitive strategies application of multiple sclerosis patients. Mult Scler2004; 10: 67–73.
42.
42 *Blum D Yonelinas AP Luks T . Dissociating perceptual and conceptual implicit memory in multiple sclerosis patients. Brain Cogn2002; 50: 51–61.
43.
43 *Bobholz JA Rao SM Lobeck L . fMRI study of episodic memory in relapsing-remitting MS: correlation with T2 lesion volume. Neurology2006; 67: 1640–1645.
44.
44 *Deloire MSA Salort E Bonnet MC . Cognitve impairment as marker of diffuse brain abnormalities in early relapsing remitting multiple sclerosis. J Neurol Neurosurg Psychiatry2005; 76: 519–526.
45.
45 *Denney DR Lynch SG Parmenter BA Horne N . Cognitive impairment in relapsing and primary progressive multiple sclerosis: mostly a matter of speed. J Int Neuropsychol Soc2004; 10: 948–956.
46.
46 *Drake MA Carra A Allegri RF Luetic G . Differential patterns of memory performance in relapsing-remitting and secondary progressive multiple sclerosis. Neurol India2006; 54: 370–376.
47.
47 *Dujardin K Donze AC Hautecoeur P . Attention impairment in recently diagnosed multiple sclerosis. Eur J Neurol1998; 5: 61–66.
48.
48 *Fisk JD Archibald CJ . Limitations of the Paced Auditory Serial Addition Test as a measure of working memory in patients with multiple sclerosis. J Int Neuropsychol Soc2001; 7: 363–372.
49.
49 *Forn C Barros-Loscertales A Escudero J . Cortical reorganization during PASAT task in MS patients with preserved working memory functions. Neuroimage2006; 31: 686–691.
50.
50 *Forn C Barros-Loscertales A Escudero J . Compensatory activations in patients with multiple sclerosis during preserved performance on the auditory N-back test. Hum Brain Mapp2007; 28: 424–430.
51.
51 *Friend KB Rabin BM Groninger L Deluty RH Bever C Grattan L . Language functions in patients with multiple sclerosis. Clin Neuropsychol1999; 13: 78–94.
52.
52 *Gilad R Sadeh M Boaz M Lampl Y . Visual spatial neglect in multiple sclerosis. Cortex2006; 42: 1138–1142.
53.
53 *Gonzalez-Rosa JJ Vazquez-Marrufo M Vaquero E . Differential cognitive impairment for diverse forms of multiple sclerosis. BMC Neuroscience2006; 7: 39–49.
54.
54 *Grigsby J Kaye K Busenbark D . Alphanumeric sequencing: a report on a brief measure of information processing used among persons with multiple sclerosis. Percept Mot Skills1994; 78: 883–887.
55.
55 *Haase CG Tinnefeld M Lienemann M Ganz RE Faustmann PM . Depression and cognitive impairment in disability-free early multiple sclerosis. Behav Neurol2003; 14: 39–45.
56.
56 *Haase CG Tinnefeld M Daum I Ganz RE Haupts M Faustmann PM . Cognitive, but not mood dysfunction develops in multiple sclerosis during 7 years of follow-up. Eur Neurol2004; 52: 92–95.
57.
57 *Heaton RK Nelson LM Thompson DS Burks JS Franklin GM . Neuropsychological findings in relapsing-remitting and chronic-progressive multiple sclerosis. J Consult Clin Psychol1985; 53: 103–110.
58.
58 *Huijbregts SCJ Kalkers NF De Sonneville LMJ De Groot V Reuling IEW Polman CH . Differences in cognitive impairment of relapsing remitting, secondary, and primary progressive MS. Neurology2004; 63: 335–339.
59.
59 *Kolonoff H Clark C Oger J Paty D Li D . Neuropsychological performance in patients with mild multiple sclerosis. J Nerv Ment Dis1991; 179: 127–131.
60.
60 *Kotterba S Orth M Eren E Fangerau T Sindern E . Assessment of driving performance in patients with relapsing-remitting multiple sclerosis by a driving simulator. Eur Neurol2003; 50: 160–164.
61.
61 *Kraus JA Schutze C Brokate B Kroger B Schwendemann G Hildebrandt H . Discriminant analysis of the cognitive performance profile of MS patients differentiates their clinical course. J Neurol2005; 252.
62.
62 *Lethlean JB Murdoch BE . Performance of subjects with multiple sclerosis on tests of high-level language. Aphasiology1997; 11: 39–57.
63.
63 *Liguori M Fera F Gioia MC . Investigating the role of brain-derived neurotrophic factor in relapsing-remitting multiple sclerosis. Genes Brain Behav2007; 6: 177–183.
64.
64 *Ling ND Selby MJ . Assessment of memory in multiple sclerosis patients using the memory assessment scale. Percept Mot Skills1998; 86: 987–998.
65.
65 *Mainero C Caramia F Pozzilli C . fMRI evidence of brain reorganization during attention and memory tasks in multiple sclerosis. Neuroimage2004; 21: 858–867.
66.
66 *Manson SC Palace J Frank JA Matthews PM . Loss of interhemispheric inhibition in patients with multiple sclerosis is related to corpus callosum atrophy. Exp Brain Res2006; 174: 728–733.
67.
67 *Moore AC MacLeod AK Barnes D Langdon DW . Future-directed thinking and depression in relapsing-remitting multiple sclerosis. Br J Health Psychol2006; 11: 663–675.
68.
68 *Morgen K Sammer G Courtney SM . Evidence for a direct association between cortical atrophy and cognitve impairment in relapsing-remitting MS. Neuroimage2006; 30: 891–898.
69.
69 *Nagy H Bencsik K Rajda C . The effects of reward and punishment contingencies on decision-making in multiple sclerosis. J Int Neuropsychol Soc2006; 12: 559–565.
70.
70 *Olivares T Nieto A Sanchez MP Wollmann T Hernandez MA Barroso J . Pattern of neuropsychological impairment in the early phase of relapsing-remitting multiple sclerosis. Mult Scler2005; 11: 191–197.
71.
71 *Parmenter BA Shucard JL Shucard DW . Information processing deficits in multiple sclerosis: a matter of complexity. J Int Neuropsychol Soc2007a; 13: 417–423.
72.
72 *Parmenter BA Zivadinov R Kerenyi L Gavett R Weinstock-Guttmann B . Validity of the Wisconsin Card Sorting and Delis-Kaplan Executive Function System (DKEFS) sorting tests in multiple sclerosis. J Clin Exp Neuropsychol2007; 29: 215–223.
73.
73 *Pelletier J Suchet L Witjas T . A longitudinal study of callosal atrophy and interhemispheric dysfunction in relapsing-remitting multiple sclerosis [Reprint].Arch Neurol2001; 58: 105–111.
74.
74 *Pozzilli C Passafiume D Bernardi S . SPECT, MRI and cognitive functions in multiple sclerosis. J Neurol Neurosurg Psychiatry1991; 54: 110–115.
75.
75 *Randolph JJ Wishart HA Saykin AJ . FLAIR lesion volume in multiple sclerosis. J Int Neuropsychol Soc2005; 11: 205–209.
76.
76 *Rocca MA Falini A Colombo B Scotti G Comi G Filippi M . Adaptive functional changes in the cerebral cortex of patients with nondisabling multiple sclerosis correlate with the extent of brain structural damage. Ann Neurol2002; 51: 330–339.
77.
77 *Rosti E Hamalainen P Koivisto K Hokkanen L . The PASAT performance among patients with multiple sclerosis: analysis of responding patterns using different scoring methods. Mult Scler2006; 12: 586–593.
78.
78 *Ruggieri RM Palermo R Vitello G Gennuso M Settipani N Piccoli F . Cognitive impairment in patients suffering from relapsing-remitting multiple sclerosis with EDSS <= 3.5. Acta Neurol Scand2003; 108: 323–326.
79.
79 Ryan L Clark CM Klonoff H Li D Paty D . Patterns of cognitive impairment in relapsing-remitting multiple sclerosis and their relationship to neuropathology on magnetic resonance images. Neuropsychology1996; 10: 176–193.
80.
80 *Selby MJ Ling N Williams JM . Interferon beta 1-b in verbal memory functioning of patients with relapsing-remitting multiple sclerosis. Percept Mot Skills1998; 86: 1099–1106.
81.
81 *Stablum F Meligrana L Sgaramella T Bortolon F Toso V . Endogenous task shift processes in relapsing-remitting multiple sclerosis. Brain Cogn2004; 56: 328–331.
82.
82 *Staffen W Mair A Zauner H . Cognitive function and fMRI in patients with multiple sclerosis: evidence for compensatory cortical activation during an attention task. Brain2002; 125: 1275–1282.
83.
83 *Staffen W Zauner H Mair A . Magnetic resonance spectroscopy of memory and frontal brain region in early multiple sclerosis. J Neuropsychiatry Clin Neurosci2005; 17: 357–363.
84.
84 *Sweet LH Rao SM Primeau M Durgerian S Cohen RA . Functional magnetic resonance imaging response to increased verbal working memory demands among patients with multiple sclerosis. Hum Brain Mapp2006; 27: 28–36.
85.
85 Hedges LV Olkin I . Statistical methods for meta-analysis.Orlando, FL: Academic; 1985.
86.
86 Mathias JL Wheaton P . Changes in attention and information-processing speed following severe traumatic brain injury: a meta-analytic review. Neuropsychology2007; 21: 212–223.
87.
87 Amato MP Ponziani G Pracucci G Bracco L Siracusa G Amaducci L . Cognitive impairment in early-onset multiple sclerosis: pattern, predictors, and impact on everyday life in a 4-year follow-up. Arch Neurol1995; 52: 168–172.
88.
88 Ling S . Driving accident frequency increased in patients with multiple sclerosis. Acta Neurol Scand2002; 105: 169–173.
89.
89 Shawaryn MA Schultheis MT Garay E DeLuca J . Assessing functional status: exploring the relationship between the multiple sclerosis functional composite and driving. Arch Phys Med Rehabil2002; 83: 1123–1129.
90.
90 Schultheis MT Garay E DeLuca J . The influence of cognitive impairment on driving performance in multiple sclerosis. Neurology2001; 56: 1089–1094.
91.
91 Baum HM Rothschild BB . The incidence and prevalence of reported multiple sclerosis. Ann Neurol1981; 10: 420–428.
92.
92 Minden SL Schiffer RB . Affective disorders in MS: review and recommendations for clinical research. Arch Neurol1991; 47: 98–104.
93.
93 Riether AM . Anxiety in patients with multiple sclerosis. Semin Clin Neuropsychiatry1999; 4: 103–113.
94.
94 Mohr D Cox D . Multiple sclerosis: empirical literature for the clinical health psychologist. J Clin Psychol2001; 57: 479–499.
95.
95 Patten SB Beck CA Williams JVA . Major depression in multiple sclerosis: a population-based perspective. Neurology2003; 61: 1524–1527.
96.
96 Rodgers D Khoo K MacEachen M Oven M Beatty WW . Cognitive therapy for multiple sclerosis: a preliminary study. Altern Ther Health Med1996; 2: 70–74.
97.
97 Lublin FD Reingold SC . Defining the clinical course of multiple sclerosis: results of an international study. Neurology1996; 46: 907–910.
98.
98 Minden SL Moes EJ Orav J Kaplan E Reich P . Memory impairment in multiple sclerosis. J Clin Exp Neuropsychol1990; 12: 566–586.
