Advertisement

Journal of Neurology

, Volume 262, Issue 8, pp 1859–1866 | Cite as

Treatment and outcome of children and adolescents with N-methyl-d-aspartate receptor encephalitis

  • Anastasia Zekeridou
  • Evgenia Karantoni
  • Aurélien Viaccoz
  • François Ducray
  • Cyril Gitiaux
  • Frédéric Villega
  • Kumaran Deiva
  • Veronique Rogemond
  • Elodie Mathias
  • Géraldine Picard
  • Marc Tardieu
  • Jean-Christophe Antoine
  • Jean-Yves Delattre
  • Jerome Honnorat
Original Communication

Abstract

The objective of this study is to describe the treatment and outcome of children and adolescents with N-methyl-d-aspartate receptor (NMDA-R) encephalitis. A retrospective study of children and adolescents with NMDA-R encephalitis was performed by the French Paraneoplastic Neurological Syndrome Reference Center between January 1, 2007 and December 31, 2012. The modified Rankin scale (mRS) was used to assess outcome. Thirty-six children and adolescents with NMDA-R encephalitis were studied. All of the patients received first-line immunotherapy (corticosteroids, intravenous immunoglobulins or plasma exchange), and 81 % received second-line immunotherapy (rituximab or cyclophosphamide). Median time between first-line and second-line treatment was 26 days. During the first 24 months, 30 of 36 patients (83 %) achieved a good outcome (mRS ≤ 2) and 20 of 36 patients (56 %) achieved complete recovery (mRS = 0). Median time to good outcome and to complete recovery was 6 and 24 months, respectively. Three patients (8 %) relapsed, one patient died. In multivariate analysis, age >12 years was a predictor of good outcome and initial mRS ≤ 3 was a predictor of complete recovery. Despite a higher rate of patients who received second-line immunotherapy, the outcome of the patients in the present series was very similar to the outcome reported in previous series. The present study highlights the need for clinical trials to determine the optimal treatment of NMDA-R encephalitis.

Keywords

Pediatric autoimmune encephalitis NMDA receptor encephalitis 

Notes

Acknowledgments

We would like to thank all of the physicians, patients and relatives who helped to collect the clinical data. CSF samples were collected with the help of Neurobiotec Bank and the Hospices Civils de Lyon.

Conflicts of interest

On behalf of all authors, the corresponding authors state that there is no conflict of interest.

Ethical standard

This study has been approved by the institutional review board and ethics committee of the University Claude Bernard Lyon 1/Hospices Civils de Lyon.

References

  1. 1.
    Dalmau J, Tu E, Rossi JE, Voloschin A, Baehring JM, Shimazaki H, Koide R, King D, Mason W, Sansing LH, Dichter MA, Rosenfeld MR, Lynch DR (2007) Paraneoplastic anti—N-methyl-d-aspartate receptor encephalitis associated with ovarian teratoma. Ann Neurol 61:25–36. doi: 10.1002/ana.21050 PubMedCentralCrossRefPubMedGoogle Scholar
  2. 2.
    Florance NR, Davis RL, Lam C, Szperka C, Zhou L, Ahmad S, Campen CJ, Moss H, Peter N, Gleichman AJ, Glaser CA, Lynch DR, Rosenfeld MR, Dalmau J (2009) Anti—N-methyl-d-aspartate receptor (NMDAR) encephalitis in children and adolescents. Ann Neurol 66:11–18. doi: 10.1002/ana.21756 PubMedCentralCrossRefPubMedGoogle Scholar
  3. 3.
    Irani SR, Bera K, Waters P, Zuliani L, Maxwell S, Zandi MS, Friese Ma, Galea I, Kullmann DM, Beeson D, Lang B, Bien CG, Vincent A (2010) N-methyl-d-aspartate antibody encephalitis: temporal progression of clinical and paraclinical observations in a predominantly non-paraneoplastic disorder of both sexes. Brain 133:1655–1667. doi: 10.1093/brain/awq113 PubMedCentralCrossRefPubMedGoogle Scholar
  4. 4.
    Dalmau J, Lancaster E, Martinez-Hernandez E, Rosenfeld MR, Balice-Gordon R (2011) Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis. Lancet Neurol 10:63–74. doi: 10.1016/S1474-4422(10)70253-2 PubMedCentralCrossRefPubMedGoogle Scholar
  5. 5.
    Titulaer MJ, McCracken L, Gabilondo I, Armangué T, Glaser C, Iizuka T, Honig LS, Benseler SM, Kawachi I, Martinez-Hernandez E, Aguilar E, Gresa-Arribas N, Ryan-Florance N, Torrents A, Saiz A, Rosenfeld MR, Balice-Gordon R, Graus F, Dalmau J (2013) Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol 12:157–165. doi: 10.1016/S1474-4422(12)70310-1 PubMedCentralCrossRefPubMedGoogle Scholar
  6. 6.
    Armangue T, Titulaer MJ, Málaga I, Bataller L, Gabilondo I, Graus F, Dalmau J (2013) Pediatric anti-N-methyl-d-aspartate receptor encephalitis-clinical analysis and novel findings in a series of 20 patients. J Pediatr 162:850–856. doi: 10.1016/j.jpeds.2012.10.011 PubMedCentralCrossRefPubMedGoogle Scholar
  7. 7.
    Wright S, Hacohen Y, Jacobson L, Agrawal S, Gupta R, Philip S, Smith M, Lim M, Wassmer E, Vincent A (2015) N-methyl-d-aspartate receptor antibody-mediated neurological disease: results of a UK-based surveillance study in children. Arch Dis Child. doi: 10.1136/archdischild-2014-306795 Google Scholar
  8. 8.
    Mikasova L, De Rossi P, Bouchet D, Georges F, Rogemond V, Didelot A, Meissirel C, Honnorat J, Groc L (2012) Disrupted surface cross-talk between NMDA and Ephrin-B2 receptors in anti-NMDA encephalitis. Brain 135:1606–1621. doi: 10.1093/brain/aws092 CrossRefPubMedGoogle Scholar
  9. 9.
    Dalmau J, Gleichman AJ, Hughes EG, Rossi JE, Peng X, Dessain SK, Rosenfeld MR, Balice-gordon R, Lynch DR (2008) Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurol 7:1091–1098. doi: 10.1016/S1474-4422(08)70224-2.Anti-NMDA-receptor PubMedCentralCrossRefPubMedGoogle Scholar
  10. 10.
    Hacohen Y, Absoud M, Hemingway C, Jacobson L, Lin J-P, Pike M, Pullaperuma S, Siddiqui A, Wassmer E, Waters P, Irani SR, Buckley C, Vincent A, Lim M (2014) NMDA receptor antibodies associated with distinct white matter syndromes. Neurol Neuroimmunol Neuroinflamm 1:e2. doi: 10.1212/NXI.0000000000000002 PubMedCentralCrossRefPubMedGoogle Scholar
  11. 11.
    Dale RC, Brilot F, Duffy LV, Twilt M, Waldman AT, Narula S, Muscal E, Deiva K, Andersen E, Eyre MR, Eleftheriou D, Brogan Pa, Kneen R, Alper G, Anlar B, Wassmer E, Heineman K, Hemingway C, Riney CJ, Kornberg A, Tardieu M, Stocco A, Banwell B, Gorman MP, Benseler SM, Lim M (2014) Utility and safety of rituximab in pediatric autoimmune and inflammatory CNS disease. Neurology 83:142–150. doi: 10.1212/WNL.0000000000000570 PubMedCentralCrossRefPubMedGoogle Scholar
  12. 12.
    Manto M, Dalmau J, Didelot A, Rogemond V, Honnorat J (2010) In vivo effects of antibodies from patients with anti-NMDA receptor encephalitis: further evidence of synaptic glutamatergic dysfunction. Orphanet J Rare Dis 5:31. doi: 10.1186/1750-1172-5-31 PubMedCentralCrossRefPubMedGoogle Scholar
  13. 13.
    Lancaster E, Dalmau J (2012) Neuronal autoantigens-pathogenesis, associated disorders and antibody testing. Nat Rev Neurol 8:380–390. doi: 10.1038/nrneurol.2012.99 PubMedCentralCrossRefPubMedGoogle Scholar
  14. 14.
    Camdessanché J-P, Streichenberger N, Cavillon G, Rogemond V, Jousserand G, Honnorat J, Convers P, Antoine J-C (2011) Brain immunohistopathological study in a patient with anti-NMDAR encephalitis. Eur J Neurol 18:929–931. doi: 10.1111/j.1468-1331.2010.03180.x CrossRefPubMedGoogle Scholar
  15. 15.
    Martinez-Hernandez E, Horvath J, Shiloh-Malawsky Y, Sangha N, Martinez-Lage M, Dalmau J (2011) Analysis of complement and plasma cells in the brain of patients with anti-NMDAR encephalitis. Neurology 77:589–593PubMedCentralCrossRefPubMedGoogle Scholar
  16. 16.
    Kosmidis ML, Dalakas MC (2010) Practical considerations on the use of rituximab in autoimmune neurological disorders. Ther Adv Neurol Disord 3:93–105. doi: 10.1177/1756285609356135 PubMedCentralCrossRefPubMedGoogle Scholar
  17. 17.
    Martin Mdel P, Cravens PD, Winger R, Kieseier BC, Cepok S, Eagar TN, Zamvil SS, Weber MS (2009) Depletion of B lymphocytes from cerebral perivascular spaces by rituximab. Arch Neurol 66:1016–1021PubMedGoogle Scholar
  18. 18.
    Binstadt B, Caldas A, Turvey S, Weinstein H, Jackson J, Fuhlbrigge R, Sundel R (2003) Rituximab therapy for multisystem autoimmune diseases in pediatric patients. J Pediatr 143:598–604CrossRefPubMedGoogle Scholar
  19. 19.
    Nowak RJ, Dicapua DB, Zebardast N, Goldstein JM (2011) Response of patients with refractory myasthenia gravis to rituximab: a retrospective study. Ther Adv Neurol Disord 4:259–266. doi: 10.1177/1756285611411503 PubMedCentralCrossRefPubMedGoogle Scholar
  20. 20.
    Kim S-H, Huh S-Y, Lee SJ, Joung A, Kim HJ (2013) A 5-year follow-up of rituximab treatment in patients with neuromyelitis optica spectrum disorder. JAMA Neurol 70:1110–1117. doi: 10.1001/jamaneurol.2013.3071 CrossRefPubMedGoogle Scholar
  21. 21.
    Fekete R, Jankovic J (2012) Childhood stiff-person syndrome improved with rituximab. Case Rep Neurol 4:92–96. doi: 10.1159/000339446 PubMedCentralCrossRefPubMedGoogle Scholar
  22. 22.
    Battaglia T, De Grandis E, Mirabelli-Badenier M, Boeri L, Morcaldi G, Barabino P, Intra C, Naselli F, Pistoia V, Veneselli E, Conte M (2012) Response to rituximab in 3 children with opsoclonus-myoclonus syndrome resistant to conventional treatments. Eur J Paediatr Neurol 16:192–195. doi: 10.1016/j.ejpn.2011.05.013 CrossRefPubMedGoogle Scholar
  23. 23.
    Tatencloux S, Chretien P, Rogemond V, Honnorat J, Tardieu M, Deiva K (2015) Intrathecal treatment of anti-N-methyl-d-aspartate receptor encephalitis in children. Dev Med Child Neurol. 57(1):95–99.  doi: 10.1111/dmcn.12545 CrossRefPubMedGoogle Scholar
  24. 24.
    DeSena AD, Greenberg BM, Graves D (2014) Three phenotypes of anti-N-methyl-d-aspartate receptor antibody encephalitis in children: prevalence of symptoms and prognosis. Pediatr Neurol 51:542–549. doi: 10.1016/j.pediatrneurol.2014.04.030 CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Anastasia Zekeridou
    • 1
  • Evgenia Karantoni
    • 1
    • 4
  • Aurélien Viaccoz
    • 1
    • 2
    • 3
  • François Ducray
    • 1
    • 2
    • 3
  • Cyril Gitiaux
    • 5
  • Frédéric Villega
    • 6
  • Kumaran Deiva
    • 7
  • Veronique Rogemond
    • 1
    • 2
  • Elodie Mathias
    • 1
    • 2
  • Géraldine Picard
    • 1
  • Marc Tardieu
    • 7
  • Jean-Christophe Antoine
    • 1
    • 8
  • Jean-Yves Delattre
    • 4
  • Jerome Honnorat
    • 1
    • 2
    • 3
    • 9
  1. 1.French Reference Center of Paraneoplastic Neurological SyndromesHospices Civils de Lyon, Hôpital NeurologiqueBronFrance
  2. 2.Lyon Neuroscience Research CenterINSERM U1028/CNRS UMR 5292LyonFrance
  3. 3.Université de Lyon, Université Claude Bernard Lyon 1LyonFrance
  4. 4.Service de Neurologie Mazarin, Groupe Hospitalier Pitié-Salpêtrière, APHP, UMR S975, CNRS, UMR 7225, Centre de Recherche de l’Institut du Cerveau et de la Moelle épinièreUniversité Pierre et Marie Curie-Paris 6ParisFrance
  5. 5.Service de Neurologie Pédiatrique, Hôpital Necker Enfants Malades, APHP, INSERM U1016-CNRS8104Université Paris-DescartesParisFrance
  6. 6.Service de Neurologie PédiatriqueCHU BordeauxBordeauxFrance
  7. 7.Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris Sud, Neurologie PédiatriqueUniversité Paris Sud et INSERM U1012OrsayFrance
  8. 8.Service de NeurologieCHU de Saint-Etienne et Université de LyonSaint-EtienneFrance
  9. 9.Neuro-OncologieHôpital Neurologique Pierre WertheimerBron CedexFrance

Personalised recommendations