Safety and efficacy of intrathecal methotrexate in severe anti-NMDAR encephalitis: a single-institution retrospective study
- 1Department of Neurology, Wuhan Zhongnan Hospital of Wuhan University
- 2Hubei Provincial Clinical Research Center for Dementia and Cognitive Impairment
- 3Department of Neurology, Wuhan Fourth Hospital
Abstract
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.
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BibTeX
@article{tuo2026safety,
title = {{Safety and efficacy of intrathecal methotrexate in severe anti-NMDAR encephalitis: a single-institution retrospective study}},
author = {Minghui Tuo and Jiabin Fang and Yuanteng Fan and Yan Xu},
journal = {Frontiers in Immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1936870},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1936870/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Safety and efficacy of intrathecal methotrexate in severe anti-NMDAR encephalitis: a single-institution retrospective study
AU - Minghui Tuo
AU - Jiabin Fang
AU - Yuanteng Fan
AU - Yan Xu
PY - 2026
DA - 2026/10/26
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1936870
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1936870/full
AB - 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.
SN - 1664-3224
ER -