To report the clinical features, treatment response and outcomes of patients with severe anti-N-methyl-D-aspartate receptor encephalitis (NMDARE) treated with intrathecal methotrexate (ITMTX).

NMDARE may be paraneoplastic (usually in association with ovarian teratoma), or autoimmune. Typical evolution of NMDARE is psychiatric symptoms followed by seizures, movement disorders and autonomic failure. Many patients respond well to first line immunologic therapies such as high dose steroids, along with plasma exchange (PLEX) or intravenous immunoglobulin (IVIG). Some patients require additional therapy such as cyclophosphamide or rituximab. We report the use of ITMTX in 5 patients.

Retrospective chart review identified 5 patients (2 male, 3 female) that met criteria for definite or probable NMDAR encephalitis, received at least 1 dose of ITMTX as rescue therapy, and had follow up for at least one year after their acute presentation. Severe cases were considered those patients who were persistently catatonic, comatose, or severely encephalopathic despite first line therapies.

All patients were treated with steroids, 3 received IVIG, 3 underwent PLEX, and 4 received rituximab. At their worst, 3 patients required mechanical ventilation of which 1 also had a pacemaker placed, and 2 were under consideration for transition to comfort care only, when ITMTX was administered. All patients improved and were at or near their premorbid baseline at last follow-up.  All patients tolerated methotrexate well.

This retrospective cohort review demonstrates the utility of intrathecal methotrexate in the treatment of severe NMDARE. Potential advantages of ITMTX over other options such as cyclophosphamide include less risk of systemic immune suppression and other toxicities including infertility.