Childhood Anti-NMDA Receptor Encephalitis

Abstract

Objectives

To study the clinical profile, and outcome of children with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis.

Methods

This is a retrospective case series of children <12 y of age, diagnosed with anti-NMDAR encephalitis at a tertiary care institute during the period, May 2013 through June 2015.

Results

Twenty patients were tested for suspected anti-NMDAR encephalitis over this 2 y period. Of these, six children were positive for anti-NMDAR antibodies. Four of these six children had completed treatment and two are currently receiving immunotherapy. Behavioral changes, psychosis, seizures and oro-lingual-facial dyskinesia were the presenting features. Extreme irritability, insomnia and mutism were noted in all the children. The symptoms were persistent, and the course was progressive over 4–8 wk duration. Neuroimaging and electroencephalography were non-specific. Intravenous pulse methylprednisolone and immunoglobulins were used as first-line therapeutic agents. Only one patient responded to first line immunotherapy; five out of six children required second-line immunotherapy. One patient recovered following rituximab, and two patients showed a good response to cyclophosphamide pulse therapy; two patients are currently under treatment with second line immunotherapeutic agents. Tumor screen was negative in all children.

Conclusions

Anti-NMDAR encephalitis is rare but a potentially treatable condition. Timely recognition is essential because treatment is entirely different from other viral encephalitis. Aggressive immunotherapy is the key to a favourable outcome.

This is a preview of subscription content, log in to check access.

References

  1. 1.

    Vitaliani R, Mason W, Ances B, Zwerdling T, Jiang Z, Dalmau J. Paraneoplastic encephalitis, psychiatric symptoms, and hypoventilation in ovarian teratoma. Ann Neurol. 2005;58:594–604.

    Article  PubMed  PubMed Central  Google Scholar 

  2. 2.

    Dalmau J, Lancaster E, Martinez-Hernandez E, Rosenfeld MR, Balice-Gordon R. Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis. Lancet Neurol. 2011;10:63–74.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Dalmau J, Tüzün E, Wu HY, et al. Paraneoplastic anti-N-methyl-D-aspartate receptor encephalitis associated with ovarian teratoma. Ann Neurol. 2007;61:25–36.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Gable MS, Sheriff H, Dalmau J, Tilley DH, Glaser CA. The frequency of autoimmune N-methyl-D-aspartate receptor encephalitis surpasses that of individual viral etiologies in young individuals enrolled in the California encephalitis project. Clin Infect Dis. 2012;54:899–904.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Wandinger KP, Saschenbrecker S, Stoecker W, Dalmau J. Anti-NMDA-receptor encephalitis: a severe, multistage, treatable disorder presenting with psychosis. J Neuroimmunol. 2011;231:86–91.

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    Raha S, Gadgil P, Sankhla C, Udani V. Nonparaneoplastic anti-N-methyl-D-aspartate receptor encephalitis: a case series of four children. Pediatr Neurol. 2012;46:246–9.

    Article  PubMed  Google Scholar 

  7. 7.

    Chakrabarty B, Tripathi M1, Gulati S, et al. Pediatric anti-N-methyl-D-aspartate (NMDA) receptor encephalitis: experience of a tertiary care teaching center from north India. J Child Neurol. 2014;29:1453–9.

    Article  PubMed  Google Scholar 

  8. 8.

    Titulaer MJ, McCracken L, Gabilondo I, et al. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol. 2013;12:157–65.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Irani SR, Bera K, Waters P, et al. N-methyl-D-aspartate antibody encephalitis: temporal progression of clinical and paraclinical observations in a predominantly non-paraneoplastic disorder of both sexes. Brain. 2010;133:1655–67.

    Article  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Peery HE, Day GS, Dunn S, et al., anti-NMDA receptor encephalitis. The disorder, the diagnosis and the immunobiology. Autoimmun Rev. 2012;11:863–72.

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    Florance NR, Davis RL, Lam C, et al. Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis in children and adolescents. Ann Neurol. 2009;66:11–8.

    Article  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Armangue T, Titulaer MJ, Málaga I, et al. Pediatric anti-N-methyl-D-aspartate receptor encephalitis-clinical analysis and novel findings in a series of 20 patients. J Pediatr 2013;162:850–6. e2.

  13. 13.

    Goldberg EM, Titulaer M, de Blank PM, Sievert A, Ryan N. Anti-N-methyl-D-aspartate receptor-mediated encephalitis in infants and toddlers: case report and review of the literature. Pediatr Neurol. 2014;50:181–4.

    Article  PubMed  Google Scholar 

  14. 14.

    DeSena AD, Greenberg BM, Graves D.”light switch” mental status changes and irritable insomnia are two particularly salient features of anti-NMDA receptor antibody encephalitis. Pediatr Neurol. 2014;51:151–3.

    Article  PubMed  Google Scholar 

  15. 15.

    Stamelou M, Plazzi G, Lugaresi E, et al. The distinct movement disorder in anti-NMDA receptor encephalitis may be related to status dissociatus: a hypothesis. Mov Disord. 2012;27:1360–3.

    Article  PubMed  Google Scholar 

  16. 16.

    Hacohen Y, Dlamini N, Hedderly T, et al. N-methyl-D-aspartate receptor antibody-associated movement disorder without encephalopathy. Dev Med Child Neurol. 2014;56:190–3.

    Article  PubMed  Google Scholar 

  17. 17.

    Titulaer MJ, Höftberger R, Iizuka T, et al. Overlapping demyelinating syndromes and anti-N-methyl-D-aspartate receptor encephalitis. Ann Neurol. 2014;75:411–28.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Titulaer MJ, Leypoldt F, Dalmau J. Antibodies to N-methyl-D-aspartate and other synaptic receptors in choreoathetosis and relapsing symptoms post-herpes virus encephalitis. Mov Disord. 2014;29:3–6.

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    Prüss H, Finke C, Höltje M, et al. N-methyl-D-aspartate receptor antibodies in herpes simplex encephalitis. Ann Neurol. 2012;72:902–11.

    Article  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Benarroch EE. NMDA receptors: recent insights and clinical correlations. Neurology. 2011;76:1750–7.

    Article  PubMed  Google Scholar 

  21. 21.

    Zhang Q, Tanaka K, Sun P, et al. Suppression of synaptic plasticity by cerebrospinal fluid from anti-NMDA receptor encephalitis patients. Neurobiol Dis. 2012;45:610–5.

    CAS  Article  PubMed  Google Scholar 

  22. 22.

    Moscato EH, Peng X, Jain A, Parsons TD, Dalmau J, Balice-Gordon RJ. Acute mechanisms underlying antibody effects in anti-N-methyl-D-aspartate receptor encephalitis. Ann Neurol. 2014;76:108–19.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  23. 23.

    da Silva-Júnior FP, Castro LH, Andrade JQ, et al. Serial and prolonged EEG monitoring in anti-N-methyl-d-aspartate receptor encephalitis. Clin Neurophysiol. 2014;125:1541–4.

    Article  PubMed  Google Scholar 

  24. 24.

    Schmitt SE, Pargeon K, Frechette ES, Hirsch LJ, Dalmau J, Friedman D. Extreme delta brush: a unique EEG pattern in adults with anti-NMDA receptor encephalitis. Neurology. 2012;79:1094–100.

    Article  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Finke C, Kopp UA, Scheel M, et al. Functional and structural brain changes in anti-N-methyl-D-aspartate receptor encephalitis. Ann Neurol. 2013;74:284–96.

    CAS  PubMed  Google Scholar 

  26. 26.

    Pillai SC, Gill D, Webster R, Howman-Giles R, Dale RC. Cortical hypometabolism demonstrated by PET in relapsing NMDA receptor encephalitis. Pediatr Neurol. 2010;43:217–20.

    Article  PubMed  Google Scholar 

  27. 27.

    Gresa-Arribas N, Titulaer MJ, Torrents A, et al. Antibody titres at diagnosis and during follow-up of anti-NMDA receptor encephalitis: a retrospective study. Lancet Neurol. 2014;13:167–77.

    CAS  Article  PubMed  Google Scholar 

  28. 28.

    Appu M, Noetzel M. Clinically significant response to zolpidem in disorders of consciousness secondary to anti-N-methyl-D-aspartate receptor encephalitis in a teenager: a case report. Pediatr Neurol. 2014;50:262–4.

    Article  PubMed  Google Scholar 

  29. 29.

    Kashyape P, Taylor E, Ng J, Krishnakumar D, Kirkham F, Whitney A. Successful treatment of two pediatric cases of anti-NMDA receptor encephalitis with cyclophosphamide: the need for early aggressive immunotherapy in tumour negative pediatric patients. Eur J Paediatr Neurol. 2012;16:74–8.

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

The authors wish to thank Dr. Josep Dalmau, (ICREA Senior Investigator, Institutd’InvestigacionsBiomèdiques August Pi iSunyer (IDIBAPS), Hospital Clinic, University of Barcelona, Spain) for his support in testing the samples.

Contributions

RS, AGS: Patient management, draft of manuscript and review of literature; JKS: Patient management, critical review of manuscript for important intellectual content and final approval of the version to be published; NS: Patient management, critical review of manuscript for important intellectual content and final approval of the version to be published; PS: Clinician-in-charge, concept and design of the study, critical review of manuscript for important intellectual content and final approval of the version to be published. She will act as guarantor for the paper.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Pratibha Singhi.

Ethics declarations

Conflict of Interest

None.

Source of Funding

None.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Suthar, R., Saini, A.G., Sankhyan, N. et al. Childhood Anti-NMDA Receptor Encephalitis. Indian J Pediatr 83, 628–633 (2016). https://doi.org/10.1007/s12098-015-1988-8

Download citation

Keywords

  • Autoimmune encephalitis
  • Encephalopathy
  • Neuropsychiatric
  • Neuroimmunology