Current Neurology and Neuroscience Reports

, Volume 12, Issue 5, pp 618–627 | Cite as

Cognitive Impairment in Multiple Sclerosis

  • Jesus Lovera
  • Blake Kovner
Demyelinating Disorders (DN Bourdette and V Yadav, Section Editors)


Cognitive impairment (CI) is a serious complication of multiple sclerosis (MS), and the domains affected are well established, but new affected domains such as theory of mind are still being identified. The evidence that disease-modifying therapies (DMTs) improve and prevent the development of CI in MS is not solid. Recent studies on the prevalence of CI in MS among people treated with DMT, although not as solid as studies completed prior to DMT introduction, suggest that CI remains a problem even among people on DMTs and that CI occurs frequently even at the very earliest stages of MS. Functional MRI studies and studies using diffusion tractography show that the impact of lesions on cognition depends on the particular cortical networks affected and their plasticity. Cognitive rehabilitation and L-amphetamine appear promising symptomatic treatments for CI in MS, while, cholinesterase inhibitors and memantine have failed, and data on Ginkgo and exercise are limited. We need more work to understand better CI in MS and develop treatments for this serious complication of MS.


Multiple sclerosis (MS) Cognitive impairment Assessment Neuropsychological tests Processing speed Memory Disease-modifying therapies (DMTs) Interferon Amphetamine Cholinesterase inhibitors Exercise Yoga Symptomatic treatment Cognitive rehabilitation Complementary and alternative treatments Functional connectivity MRI fMRI Lesion load Theory of mind Imaging correlates of MS Domains of impairment Prevalence Incidence Cortical pathology 



J. Lovera: EMD Serono and TEVA (consultant); B. Kovner: none.


Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. 1.
    • Benedict RH, Zivadinov R. Risk factors for and management of cognitive dysfunction in multiple sclerosis. Nat Rev Neurol. 2011;7:332–42. Important recent review on CI in MS. PubMedCrossRefGoogle Scholar
  2. 2.
    • Julian LJ. Cognitive functioning in multiple sclerosis. Neurol Clin. 2011;29:507–25. Important recent review on CI in MS. PubMedCrossRefGoogle Scholar
  3. 3.
    Rao SM, Leo GJ, Bernardin L, Unverzagt F. Cognitive dysfunction in multiple sclerosis: I. Frequency, patterns, and prediction. Neurology. 1991;41:685–91.PubMedCrossRefGoogle Scholar
  4. 4.
    Benedict RH, Fischer JS, Archibald CJ, et al. Minimal neuropsychological assessment of MS patients: a consensus approach. Clin Neuropsychol. 2002;16:381–97.PubMedCrossRefGoogle Scholar
  5. 5.
    Banati M, Sandor J, Mike A, et al. Social cognition and theory of mind in patients with relapsing–remitting multiple sclerosis. Eur J Neurol. 2009;17:426–33.PubMedCrossRefGoogle Scholar
  6. 6.
    • Jehna M, Langkammer C, Wallner-Blazek M, et al. Cognitively preserved MS patients demonstrate functional differences in processing neutral and emotional faces. Brain Imaging Behav. 2011;5:241–51. Interesting new findings on the changes in cortical networks responsible theory of mind processes in patients with MS. PubMedCrossRefGoogle Scholar
  7. 7.
    Amato MP, Ponziani G, Siracusa G, Sorbi S. Cognitive dysfunction in early-onset multiple sclerosis: a reappraisal after 10 years. Arch Neurol. 2001;58:1602–6.PubMedCrossRefGoogle Scholar
  8. 8.
    • Morrow SA, Drake A, Zivadinov R, et al. Predicting loss of employment over three years in multiple sclerosis: clinically meaningful cognitive decline. Clin Neuropsychol. 2010;24:1131–45. This important paper helps determine a level of change in cognitive tests that has important implications for employability and will be useful in the design of clinical trials. PubMedCrossRefGoogle Scholar
  9. 9.
    D'Orio VL, Foley FW, Armentano F, et al. Cognitive and motor functioning in patients with multiple sclerosis: neuropsychological predictors of walking speed and falls. J Neurol Sci. 2012;316:42–6.PubMedCrossRefGoogle Scholar
  10. 10.
    Fischer JS, Priore RL, Jacobs LD, et al. Neuropsychological effects of interferon beta-1a in relapsing multiple sclerosis. Multiple Sclerosis Collaborative Research Group. Ann Neurol. 2000;48:885–92.PubMedCrossRefGoogle Scholar
  11. 11.
    Pliskin NH, Hamer DP, Goldstein DS, et al. Improved delayed visual reproduction test performance in multiple sclerosis patients receiving interferon beta-1b. Neurology. 1996;47:1463–8.PubMedCrossRefGoogle Scholar
  12. 12.
    Panitch H, Miller A, Paty D, Weinshenker B. Interferon beta-1b in secondary progressive MS: results from a 3-year controlled study. Neurology. 2004;63:1788–95.PubMedCrossRefGoogle Scholar
  13. 13.
    Weinstein A, Schwid SR, Schiffer RB, et al. Neuropsychologic status in multiple sclerosis after treatment with glatiramer. Arch Neurol. 1999;56:319–24.PubMedCrossRefGoogle Scholar
  14. 14.
    Polman CH, O’Connor PW, Havrdova E, et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med. 2006;354:899–910.PubMedCrossRefGoogle Scholar
  15. 15.
    Rudick RA, Stuart WH, Calabresi PA, et al. Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. N Engl J Med. 2006;354:911–23.PubMedCrossRefGoogle Scholar
  16. 16.
    • Weinstock-Guttman B, Galetta SL, Giovannoni G, et al. Additional efficacy endpoints from pivotal natalizumab trials in relapsing-remitting MS. J Neurol. 2012;259:898–905. Important although limited assessment of the impact of Natalizumab on CI. PubMedCrossRefGoogle Scholar
  17. 17.
    Lang C, Reiss C, Maurer M. Natalizumab may improve cognition and mood in multiple sclerosis. Eur Neurol. 2012;67:162–6.PubMedCrossRefGoogle Scholar
  18. 18.
    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. Neurol Sci. 2011;32:83–8.PubMedCrossRefGoogle Scholar
  19. 19.
    Morrow SA, O’Connor PW, Polman CH, et al. Evaluation of the symbol digit modalities test (SDMT) and MS neuropsychological screening questionnaire (MSNQ) in natalizumab-treated MS patients over 48 weeks. Mult Scler. 2010;16:1385–92.PubMedCrossRefGoogle Scholar
  20. 20.
    Cohen JA, Barkhof F, Comi G, et al. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med. 2010;362(5):402–15.PubMedCrossRefGoogle Scholar
  21. 21.
    Kappos L, Radue EW, O'Connor P, et al. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med. 2010;362:387–401.PubMedCrossRefGoogle Scholar
  22. 22.
    Schwid SR, Goodman AD, Weinstein A, et al. Cognitive function in relapsing multiple sclerosis: minimal changes in a 10-year clinical trial. J Neurol Sci. 2007;255:57–63.PubMedCrossRefGoogle Scholar
  23. 23.
    Patti F, Amato MP, Bastianello S, et al. Effects of immunomodulatory treatment with subcutaneous interferon beta-1a on cognitive decline in mildly disabled patients with relapsing–remitting multiple sclerosis. Mult Scler. 2009;16:68–77.PubMedCrossRefGoogle Scholar
  24. 24.
    Duque B, Sepulcre J, Bejarano B, et al. Memory decline evolves independently of disease activity in MS. Mult Scler. 2008;14:947–53.PubMedCrossRefGoogle Scholar
  25. 25.
    Brooks JB, Borela MC, Fragoso YD. Assessment of cognition using the Rao's Brief Repeatable Battery of Neuropsychological Tests on a group of Brazilian patients with multiple sclerosis. Arq Neuropsiquiatr. 2012;69:887–91.CrossRefGoogle Scholar
  26. 26.
    Baumstarck-Barrau K, Simeoni MC, Reuter F, et al. Cognitive function and quality of life in multiple sclerosis patients: a cross-sectional study. BMC Neurol. 2011;11:17.PubMedCrossRefGoogle Scholar
  27. 27.
    Brissart H, Morele E, Baumann C, Debouverie M. Verbal episodic memory in 426 multiple sclerosis patients: impairment in encoding, retrieval or both? Neurol Sci. 2012.Google Scholar
  28. 28.
    Glanz BI, Healy BC, Hviid LE, et al. Cognitive deterioration in patients with early multiple sclerosis: a 5-year study. J Neurol Neurosurg Psychiatry. 2011;83:38–43.PubMedCrossRefGoogle Scholar
  29. 29.
    Feuillet L, Reuter F, Audoin B, et al. Early cognitive impairment in patients with clinically isolated syndrome suggestive of multiple sclerosis. Mult Scler. 2007;13:124–7.PubMedCrossRefGoogle Scholar
  30. 30.
    Kocer B, Unal T, Nazliel B, et al. Evaluating sub-clinical cognitive dysfunction and event-related potentials (P300) in clinically isolated syndrome. Neurol Sci. 2008;29:435–44.PubMedCrossRefGoogle Scholar
  31. 31.
    Feinstein A, Kartsounis LD, Miller DH, et al. Clinically isolated lesions of the type seen in multiple sclerosis: a cognitive, psychiatric, and MRI follow up study. J Neurol Neurosurg Psychiatry. 1992;55:869–76.PubMedCrossRefGoogle Scholar
  32. 32.
    Reuter F, Zaaraoui W, Crespy L, et al. Frequency of cognitive impairment dramatically increases during the first 5 years of multiple sclerosis. J Neurol Neurosurg Psychiatry. 2010;82:1157–9.PubMedCrossRefGoogle Scholar
  33. 33.
    • Lebrun C, Blanc F, Brassat D, et al. Cognitive function in radiologically isolated syndrome. Mult Scler. 2010;16:919–25. This interesting study documents the presence of cognitive changes before other symptoms occur among people with incidental findings of brain lesions typical of MS. PubMedCrossRefGoogle Scholar
  34. 34.
    • Amato MP, Hakiki B, Goretti B, et al. Association of MRI metrics and cognitive impairment in radiologically isolated syndromes. Neurology. 2012;78:309–14. Another recent interesting study documenting CI in patients with RIS. PubMedCrossRefGoogle Scholar
  35. 35.
    • Mesaros S, Rocca MA, Kacar K, et al. Diffusion tensor MRI tractography and cognitive impairment in multiple sclerosis. Neurology. 2012;78:969–75. This study clarifies the long-standing paradox of why lesion burden does not correlate with CI. PubMedCrossRefGoogle Scholar
  36. 36.
    • Hawellek DJ, Hipp JF, Lewis CM, et al. Increased functional connectivity indicates the severity of cognitive impairment in multiple sclerosis. Proc Natl Acad Sci U S A. 2011;108:19066–71. This study documents changes in the default and control networks in patients with MS and correlates these changes with CI. PubMedCrossRefGoogle Scholar
  37. 37.
    Fink F, Rischkau E, Butt M, et al. Efficacy of an executive function intervention programme in MS: a placebo-controlled and pseudo-randomized trial. Mult Scler. 2010;16:1148–51.PubMedCrossRefGoogle Scholar
  38. 38.
    Chiaravalloti ND, DeLuca J, Moore NB, Ricker JH. Treating learning impairments improves memory performance in multiple sclerosis: a randomized clinical trial. Mult Scler. 2005;11:58–68.PubMedCrossRefGoogle Scholar
  39. 39.
    • Stuifbergen AK, Becker H, Perez F, et al. A randomized controlled trial of a cognitive rehabilitation intervention for persons with multiple sclerosis. Clin Rehabil. 2012. This study shows promising results from cognitive rehabilitation strategy. Google Scholar
  40. 40.
    Harel Y, Appleboim N, Lavie M, Achiron A. Single dose of methylphenidate improves cognitive performance in multiple sclerosis patients with impaired attention process. J Neurol Sci. 2009;276:38–40.PubMedCrossRefGoogle Scholar
  41. 41.
    Benedict RH, Munschauer F, Zarevics P, et al. Effects of l-amphetamine sulfate on cognitive function in multiple sclerosis patients. J Neurol. 2008;255:848–52.PubMedCrossRefGoogle Scholar
  42. 42.
    Sumowski JF, Chiaravalloti N, Erlanger D, et al. L-amphetamine improves memory in MS patients with objective memory impairment. Mult Scler. 2011;17:1141–5.PubMedCrossRefGoogle Scholar
  43. 43.
    Wilken JA, Sulliven C, Wallin M, et al. Treatment of multiple sclerosis–related cognitive problems with adjunctive modafinil. Int J MS Care. 2008;10:1–10.CrossRefGoogle Scholar
  44. 44.
    Moller F, Poettgen J, Broemel F, et al. HAGIL (Hamburg Vigil Study): a randomized placebo-controlled double-blind study with modafinil for treatment of fatigue in patients with multiple sclerosis. Mult Scler. 2011;17:1002–9.PubMedCrossRefGoogle Scholar
  45. 45.
    Huolman S, Hamalainen P, Vorobyev V, et al. The effects of rivastigmine on processing speed and brain activation in patients with multiple sclerosis and subjective cognitive fatigue. Mult Scler. 2011;17:1351–61.PubMedCrossRefGoogle Scholar
  46. 46.
    Krupp LB, Christodoulou C, Melville P, et al. Donepezil improved memory in multiple sclerosis in a randomized clinical trial. Neurology. 2004;63:1579–85.PubMedCrossRefGoogle Scholar
  47. 47.
    • Krupp LB, Christodoulou C, Melville P, et al. Multicenter randomized clinical trial of donepezil for memory impairment in multiple sclerosis. Neurology. 2011;76:1500–7. This is an important randomized placebo-controlled trial that, unfortunately, showed no benefit with donepezil. PubMedCrossRefGoogle Scholar
  48. 48.
    Villoslada P, Arrondo G, Sepulcre J, et al. Memantine induces reversible neurologic impairment in patients with MS. Neurology. 2009;72:1630–3.PubMedCrossRefGoogle Scholar
  49. 49.
    • Lovera JF, Frohman E, Brown TR, et al. Memantine for cognitive impairment in multiple sclerosis: a randomized placebo-controlled trial. Mult Scler. 2010;16:715–23. Our randomized multicenter trial with memantine also failed to show any beneficial effect. PubMedCrossRefGoogle Scholar
  50. 50.
    Lovera J, Bagert B, Smoot K, et al. Ginkgo biloba for the improvement of cognitive performance in multiple sclerosis: a randomized, placebo-controlled trial. Mult Scler. 2007;13:376–85.PubMedGoogle Scholar
  51. 51.
    Lovera J, Howieson D, Wild K, et al. Randomized placebo controlled trial of Ginkgo biloba for cognitive impairment in multiple sclerosis. Neurology 2011 Suppl 4: A546Google Scholar
  52. 52.
    Motl RW, Gappmaier E, Nelson K, Benedict RH. Physical activity and cognitive function in multiple sclerosis. J Sport Exerc Psychol. 2011;33:734–41.PubMedGoogle Scholar
  53. 53.
    Oken BS, Kishiyama S, Zajdel D, et al. Randomized controlled trial of yoga and exercise in multiple sclerosis. Neurology. 2004;62:2058–64.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Department of NeurologyLouisiana State University Health Sciences Center-New OrleansNew OrleansUSA

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