Journal of Neurology

, Volume 263, Issue 8, pp 1620–1625 | Cite as

Natalizumab discontinuation is associated with a rebound of cognitive impairment in multiple sclerosis patients

  • Pietro Iaffaldano
  • Rosa Gemma Viterbo
  • Maria Trojano
Original Communication

Abstract

Natalizumab discontinuation is associated with a disease reactivation in multiple sclerosis (MS) patients. Whether this reactivation involves also cognitive functions is not known to date. To assess the persistence of the effect of natalizumab on cognitive functions 1 year after its discontinuation, we compared the longitudinal changes of cognitive performances in two groups of patients. The interrupters, 30 MS patients, have stopped natalizumab due to PML concern, and the continuers, 28 MS patients, continued the treatment. The cognitive impairment index (CII) was used as main outcome measure. As expected, during the natalizumab treatment, we observed a significant reduction of the relapse rate and the number of gadolinium-enhancing lesions along with a reduction of the CII. After 1 year of discontinuation, the beneficial effect on cognitive functions was lost in the interrupters group, as the mean CII increased in comparison with the mean at the end of natalizumab treatment (12.2 ± 7.9 vs 9.3 ± 8.1, p < 0.0001). As opposite, in the continuers group, the CII further decreased after an additional year of treatment (8.4 ± 5.1 vs 9.8 ± 4.6, p = 0.007). A multivariate logistic regression model revealed as predictors of cognitive worsening male sex, disease duration, and the treatment discontinuation. The worsening of cognitive functions after natalizumab discontinuation goes in parallel with the clinical/radiological disease reactivation. Our data reinforce the hypothesis that, in the short-term, natalizumab exerts its positive impact on cognitive functions by means of its anti-inflammatory properties.

Keywords

Multiple sclerosis Cognitive functions Natalizumab discontinuation Disease reactivation Cognitive impairment index 

References

  1. 1.
    Chiaravalloti ND, DeLuca J (2008) Cognitive impairment in multiple sclerosis. Lancet Neurol 7:1139–1151CrossRefPubMedGoogle Scholar
  2. 2.
    Rao SM (1995) Neuropsychology of multiple sclerosis. Curr Opin Neurol 8:216–220CrossRefPubMedGoogle Scholar
  3. 3.
    Amato MP, Zipoli V, Portaccio E (2006) Multiple sclerosis-related cognitive changes: a review of cross-sectional and longitudinal studies. J Neurol Sci 245:41–46CrossRefPubMedGoogle Scholar
  4. 4.
    He D, Zhang Y, Dong S et al (2013) Pharmacological treatment for memory disorder in multiple sclerosis. Cochrane Database Syst Rev 17(12):CD008876Google Scholar
  5. 5.
    Pliskin NH, Hamer DP, Goldstein DS, Towle VL, Reder AT et al (1996) Improved delayed visual reproduction test performance in multiple sclerosis patients receiving interferon b-1b. Neurology 47:1463–1468CrossRefPubMedGoogle Scholar
  6. 6.
    Fischer JS, Priore RL, Jacobs LD, Cookfair DL, Rudick RA et al (2000) Neuropsychological effects of interferon b-1a in relapsing multiple sclerosis. Ann Neurol 48:885–892CrossRefPubMedGoogle Scholar
  7. 7.
    Cohen JA, Cutter GR, Fischer JS, Goodman AD, Heidenreich FR et al (2002) Benefit of interferon b-1a on MSFC progression in secondary progressive MS. Neurology 59:679–687CrossRefPubMedGoogle Scholar
  8. 8.
    Kappos L, Freedman MS, Polman CH, Edan G, Hartung HP et al (2009) Long-term effect of early treatment with interferon beta-1b after a first clinical event suggestive of multiple sclerosis: 5-year active treatment extension of the phase 3 BENEFIT trial. Lancet Neurol 8:987–997CrossRefPubMedGoogle Scholar
  9. 9.
    Patti F, Amato MP, Bastianello S, Caniatti L, Di Monte E et al (2010) Effects of immunomodulatory treatment with subcutaneous interferon beta-1a on cognitive decline in mildly disable patients with relapsing remitting multiple sclerosis. Mult Scler 16:68–77CrossRefPubMedGoogle Scholar
  10. 10.
    Mattioli F, Stampatori C, Capra R (2011) 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 32:83–88CrossRefPubMedGoogle Scholar
  11. 11.
    Iaffaldano P, Viterbo RG, Paolicelli D et al (2012) Impact of Natalizumab on cognitive performances and fatigue in relapsing multiple sclerosis: a prospective, open-label. Two years observational study. PLoS One 7(4):e35843. doi:10.1371/journal.pone.0035843 CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Kunkel A, Fischer M, Faiss J et al (2015) Impact of Natalizumab treatment on fatigue, mood, and aspects of cognition in relapsing-remitting multiple sclerosis. Front Neurol 11(6):97Google Scholar
  13. 13.
    Mattioli F, Stampatori C, Bellomi F, Scarpazza C, Capra R (2015) Natalizumab significantly improves cognitive impairment over 3 years in MS: pattern of disability progression and preliminary MRI findings. PLoS One 10(7):e0131803CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Killestein J, Vennegoor A, Strijbis EM et al (2010) Natalizumab drug holiday in multiple sclerosis: poorly tolerated. Ann Neurol 68:392–395CrossRefPubMedGoogle Scholar
  15. 15.
    West TW, Cree BA (2010) Natalizumab dosage suspension: are we helping or hurting? Ann Neurol 68:395–399CrossRefPubMedGoogle Scholar
  16. 16.
    Borriello G, Prosperini L, Marinelli F, Fubelli F, Pozzilli C (2011) Observations during an elective interruption of Natalizumab treatment: a post-marketing study. Mult Scler 17:372–375CrossRefPubMedGoogle Scholar
  17. 17.
    Borriello G, Prosperini L, Mancinelli C, Gianni C, Fubelli F, Pozzilli C (2012) Pulse monthly steroids during an elective interruption of Natalizumab: a post-marketing study. Eur J Neurol 19:783–787CrossRefPubMedGoogle Scholar
  18. 18.
    Havla J, Gerdes LA, Meinl I et al (2011) De-escalation from Natalizumab in multiple sclerosis: recurrence of disease activity despite switching to glatiramer acetate. J Neurol 258:1665–1669CrossRefPubMedGoogle Scholar
  19. 19.
    Kaufman MD, Lee R, Norton HJ (2011) Course of relapsing remitting multiple sclerosis before, during and after Natalizumab. Mult Scler 17:490–494CrossRefPubMedGoogle Scholar
  20. 20.
    Kerbrat A, Le Page E, Leray E et al (2011) Natalizumab and drug holiday in clinical practice: an observational study in very active relapsing remitting multiple sclerosis patients. J Neurol Sci 308:98–102CrossRefPubMedGoogle Scholar
  21. 21.
    Magraner MJ, Coret F, Navarre A et al (2011) Pulsed steroids followed by glatiramer acetate to prevent inflammatory activity after cessation of Natalizumab therapy: a prospective, 6-month observational study. J Neurol 258:1805–1811CrossRefPubMedGoogle Scholar
  22. 22.
    O’Connor PW, Goodman A, Kappos L, Lublin FD, Miller DH, Polman C et al (2011) Disease activity return during Natalizumab treatment interruption in patients with multiple sclerosis. Neurology 76(22):1858–1865CrossRefPubMedGoogle Scholar
  23. 23.
    Rossi S, Motta C, Studer V et al (2013) Effect of glatiramer acetate on disease reactivation in MS patients discontinuing Natalizumab. Eur J Neurol 20:87–94CrossRefPubMedGoogle Scholar
  24. 24.
    Cohen M, Maillart E, Tourbah A, De Sèze J, Vukusic S, Brassat D et al (2014) Switching from Natalizumab to fingolimod in multiple sclerosis: a French prospective study. JAMA Neurol. doi:10.1001/jamaneurol.2013.6240 PubMedCentralGoogle Scholar
  25. 25.
    Jokubaitis VG, Li V, Kalincik T, Izquierdo G, Hodgkinson S, Alroughani R et al (2014) Fingolimod after Natalizumab and the risk of short-term relapse. Neurology 82(14):1204–1211. doi:10.1212/WNL.0000000000000283 CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Iaffaldano P, Lucisano G, Pozzilli C, et al. (2015) Fingolimod versus interferon beta/glatiramer acetate after Natalizumab suspension in multiple sclerosis. Brain 138(11):3275–3286. doi:10.1093/brain/awv260 CrossRefPubMedGoogle Scholar
  27. 27.
    Clerico M, Schiavetti I, De Mercanti SF, Piazza F, Gned D, Brescia Morra V et al (2014) Treatment of relapsing-remitting multiple sclerosis after 24 doses of Natalizumab: evidence from an Italian spontaneous, prospective, and observational study (the TY-STOP Study). JAMA Neurol. doi:10.1001/jamaneurol.2014.1200 Google Scholar
  28. 28.
    Fox RJ, Cree BA, De Sèze J, Gold R, Hartung HP, Jeffery D et al (2014) MS disease activity in RESTORE: a randomized 24-week Natalizumab treatment interruption study. Neurology 82(17):1491–1498CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Morrow SA, Jurgensen S, Forrestal F, Munchauer FE, Benedict RH (2011) Effects of acute relapses on neuropsychological status in multiple sclerosis patients. J Neurol 258(9):1603–1608CrossRefPubMedGoogle Scholar
  30. 30.
    McGuigan C, Craner M, Guadagno J, Kapoor R, Mazibrada G, Molyneux P et al (2016) Stratification and monitoring of Natalizumab-associated progressive multifocal leukoencephalopathy risk: recommendations from an expert group. J Neurol Neurosurg Psychiatry 87(2):117–125. doi:10.1136/jnnp-2015-311100 (Epub 2015 Oct 22) PubMedGoogle Scholar
  31. 31.
    Amato MP, Portaccio E, Goretti B, Zipoli V, Ricchiuti L et al (2006) The Rao’s brief repeatable battery and stroop test: normative values with age, education and gender corrections in an Italian population. Mult Scler 12:787–793CrossRefPubMedGoogle Scholar
  32. 32.
    Camp SJ, Stevenson VL, Thompson AJ, Miller DH, Borras C et al (1999) Cognitive function in primary progressive and transitional progressive multiple sclerosis. A controlled study with MRI correlates. Brain 122:1341–1348CrossRefPubMedGoogle Scholar
  33. 33.
    Amato MP, Goretti B, Ghezzi A, Hakiki B, Niccolai C, Lori S et al (2014) Neuropsychological features in childhood and juvenile multiple sclerosis: five-year follow-up. Neurology 83(16):1432–1438. doi:10.1212/WNL.0000000000000885 CrossRefPubMedGoogle Scholar
  34. 34.
    Goretti B, Patti F, Cilia S, Mattioli F, Stampatori C et al (2014) The Rao’s Brief Repeatable Battery version B: normative values with age, education and gender corrections in an Italian population. Neurol Sci 35(1):79–82. doi:10.1007/s10072-013-1558-7 Epub 2013 Oct 8 CrossRefPubMedGoogle Scholar
  35. 35.
    Mandolesi G, Grasselli G, Musumesi G, Centonze D (2010) Cognitive deficits in experimental autoimmune encephalomyelitis: neuroinflammation and synaptic degeration. Neurol Sci 31(Suppl 2):S255–S259CrossRefPubMedGoogle Scholar
  36. 36.
    Centonze D, Muzio L, Rossi S, Cavasinni F, De Chiara V et al (2009) Inflammation triggers synaptic alteration and degeneration in experimental autoimmune encephalomyelitis. J Neurosci 29:3442–3452CrossRefPubMedGoogle Scholar
  37. 37.
    Gunnarsson M, Malmestro¨m C, Axelsson M, Sundstro¨m P, Dahle C et al (2010) Axonal damage in relapsing multiple sclerosis is markedly reduced by Natalizumab. Ann Neurol 69:83–89CrossRefPubMedGoogle Scholar
  38. 38.
    Khademi M, Bornsen L, Rafatnia F, Andersson M, Brundin L et al (2009) The effects of Natalizumab on inflammatory mediators in multiple sclerosis: prospects for treatment-sensitive biomarkers. Eur J Neurol 16:528–536CrossRefPubMedGoogle Scholar
  39. 39.
    Mellergard J, Edstrom M, Vrethem M, Erneurdh J, Dahle C (2010) Natalizumab treatment in multiple sclerosis: marked decline of chemokines and cytokines in cerebrospinal fluid. Mult Scler 16:208–217CrossRefPubMedGoogle Scholar
  40. 40.
    Iaffaldano P, Ruggieri M, Viterbo RG, Mastrapasqua M, Trojano M (2014) The improvement of cognitive functions is associated with a decrease of plasma osteopontin levels in Natalizumab treated relapsing multiple sclerosis. Brain Behav Immun 35:176–181CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Pietro Iaffaldano
    • 1
  • Rosa Gemma Viterbo
    • 1
  • Maria Trojano
    • 1
  1. 1.Department of Basic Medical Sciences, Neurosciences and Sense OrgansUniversity of Bari “Aldo Moro”BariItaly

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