Safety and efficacy of intrathecal methotrexate in severe anti-NMDAR encephalitis: a single-institution retrospective study

Background Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is one of the most common forms of autoimmune encephalitis (AE). Most cases can achieve clinical relief with first- and second-line immunotherapies, while approximately 25% are resistant to these immunotherapies and require further immunomodulatory therapy. Intrathecal methotrexate (IT-MTX) is one of the escalation treatments. This study aimed to analyze the safety and efficacy of IT-MTX in severe cases of anti-NMDAR encephalitis. Methods A retrospective observational analysis was performed on 10 patients with severe anti-NMDAR encephalitis who received IT-MTX weekly for 4 consecutive weeks in our institution between 2021 and 2024. We reviewed patients’ baseline clinical characteristics, cerebrospinal fluid antibody titers, modified Rankin Scale (mRS) scores, and Clinical Assessment Scale in Autoimmune Encephalitis (CASE) scores before and after IT-MTX. The entire follow-up observation lasted for 12 months. Results Nine of 10 patients experienced significant clinical relief at the 12-month follow-up after IT-MTX, with a significant decrease in CASE scores (6–24 to 0-2) and mRS scores (4–5 to 0-1) in survivors, and six of 10 patients had a parallel decrease in antibody titers at the 12-month follow-up. No IT-MTX-related neurotoxicity or recurrences were observed during the 1-year follow-up. One patient who did not complete the standard IT-MTX treatment died from a severe systemic infection, which was considered unrelated to IT-MTX. When patients receiving IT-MTX within 2 weeks were compared with those receiving IT-MTX >2 weeks after conventional immunotherapy, reductions in CASE and mRS scores were larger in the early-treatment group (p < 0.05). Conclusion Our findings suggest that IT-MTX may be an effective and relatively safe escalation option for severe anti-NMDAR encephalitis. Early and aggressive application of IT-MTX may improve the prognosis. Further large prospective studies are needed to better illustrate the safety, efficacy, and optimal timing of IT-MTX in severe anti-NMDAR encephalitis.