Three patients with anti-NMDA encephalitis were refractory to first- and second-line treatments. Third-line treatments, bortezomib and tocilizumab, achieved disease control.

A 41-year-old male presented with behavioral changes and seizures in 2016. CSF showed lymphocytic pleocytosis. He developed lethargy and orofacial dyskinesias. Anti-NMDA antibody IgG CSF was 1:320. He underwent plasmapheresis, corticosteroids, IVIG, cyclophosphamide, and rituximab without improvement. He remained comatose on a ventilator for 18 months. Anti-NMDA serum titer was 1:640. Initiation of bortezomib lead to rapid improvement in mental status and reduced anti-NMDA titers. Four months later, he was off mechanical ventilation and three years later is at baseline.

A 20-year-old woman presented with psychosis, worsening cognition, orofacial dyskinesias, and seizures in 2020, became stuporous, and was intubated. CSF displayed lymphocytic pleocytosis. Anti-NMDA antibody CSF was 1:40; her ovarian teratoma was resected. She received corticosteroids, IVIG, rituximab without improvement. Mental status improved with bortezomib in 2021. Anti-NMDA antibody titer was 1:10, but cognitive impairment persisted. Bortezomib infusions were repeated with rapid improvement followed by rituximab. Repeat anti-NMDA titer was 1:5 and she returned to baseline. 

A 31-year-old woman presented with insomnia, cognitive, behavioral changes, and seizures in 2023. CSF showed lymphocytic pleocytosis with anti-NMDA antibody CSF 1:1024 and serum 1:2560. She received corticosteroids, plasmapheresis, and IVIG without improvement; an associated ovarian teratoma was resected. She remained in long-term-care for one year. Elevated serum anti-NMDA led to bortezomib treatment with mild improvement. Tocilizumab was started with improvement in clinical status and antibody titers at 1:160. She continues tocilizumab and rituximab therapy.

Anti-N-methyl d-aspartate-receptor encephalitis standard therapy includes corticosteroids, IVIG, plasmapheresis, tumor removal, cyclophosphamide, and rituximab. Only half of patients respond to standard therapy.

This case series highlights that third-line treatments (bortezomib and tocilizumab) were effective in refractory NMDA encephalitis. Consider these early interventions in refractory cases.