Mycophenolate mofetil, azathioprine and methotrexate usage in paediatric anti-NMDAR encephalitis: A systematic literature review

Eur J Paediatr Neurol. 2019 Jan;23(1):7-18. doi: 10.1016/j.ejpn.2018.09.008. Epub 2018 Sep 27.


Background: Available data on mycophenolate mofetil (MMF), azathioprine (AZA) and methotrexate (MTX) for paediatric-onset anti-N-methyl-d-aspartate receptor encephalitis (anti-NMDARE) is limited.

Methods: Systematic literature review on patients treated with MMF/AZA/MTX for paediatric-onset anti-NMDARE, with focus on modes of use, efficacy and safety.

Results: 87 patients were included (age at onset median 11 years, range 0.8-18 years; 69% females). 46% had a relapsing course. 52% received MMF, 27% AZA, 15% MTX, and 6% a combination of MMF/AZA/MTX (7 patients received intrathecal MTX). Before MMF/AZA/MTX, 100% patients received steroids, 83% intravenous immunoglobulin and 45% plasma exchange, and 50% received second-line treatments (rituximab/cyclophosphamide). MMF/AZA/MTX were administered >6 months from onset in 51%, and only after relapse in 40%. Worst mRS before MMF/AZA/MTX was median 4.5 (range 3-5). At last follow-up (median 2 years, range 0.2-8.6), median mRS was 1 (range 0-6). Median annualised relapse rate was 0.4 (range 0-6.7) pre-MMF/AZA/MTX (excluding first events), and 0 on MMF/AZA/MTX (mean 0.03, range 0-0.8). 7% patients relapsed on MMF/AZA/MTX. These relapsing patients had low rate of second-line treatments before MMF/AZA/MTX (25%), long median time between onset and MMF/AZA/MTX usage (18 months), and frequently they were started on MMF/AZA/MTX only after relapse (75%). Relapse rate was lower among patients who received first immune therapy ≤30 days (25%) than later (64%), who received second-line treatments at first event (14%) rather than not (64%), who were started on MMF/AZA/MTX after the first (12%) rather than subsequent events (17%), and who were started on MMF/AZA/MTX ≤3 months from onset (33%) rather than later (53%). Adverse reactions to MMF/AZA/MTX occurred in 2 cases (cytomegalovirus colitis and respiratory infection), of grade 3 Common Terminology Criteria for Adverse Events v4.0.

Discussion: Our literature review disclosed heterogeneity in the use of MMF/AZA/MTX in paediatric-onset anti-NMDARE. MMF/AZA/MTX usage is mostly restricted to retrospective cohort descriptions. These agents may reduce risk of relapse, and have a reasonable safety profile, however data on larger cohorts are required to definitively determine effect.

Keywords: Anti-NMDAR encephalitis; Azathioprine; Children; Methotrexate; Mycophenolate mofetil; Steroid sparing agents.

Publication types

  • Systematic Review

MeSH terms

  • Adolescent
  • Anti-N-Methyl-D-Aspartate Receptor Encephalitis / drug therapy*
  • Azathioprine / therapeutic use*
  • Child
  • Child, Preschool
  • Female
  • Humans
  • Immunosuppressive Agents / adverse effects
  • Immunosuppressive Agents / therapeutic use*
  • Infant
  • Male
  • Methotrexate / therapeutic use*
  • Mycophenolic Acid / therapeutic use*


  • Immunosuppressive Agents
  • Mycophenolic Acid
  • Azathioprine
  • Methotrexate