To present two cases of early, simultaneous multi-level initiation of immunotherapy in patients with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis (NMDARE).

NMDARE is characterized by neuropsychiatric symptoms and presence of CSF antibodies against the GluN1 subunit of NMDAR. Despite widely accepted treatment protocols for NMDARE, long-term patient outcomes remain suboptimal, involving prolonged hospitalization, persistent neurological deficits, and relapses. Traditional immunotherapy increases the risk of extensive tissue damage during the interval between therapies.

We report a case series of two young women diagnosed with NMDARE at a tertiary care center in South Asia. Inclusion criteria were fulfillment of Graus et al.’s diagnostic criteria and availability of complete clinical data. Patients received early, simultaneous immunotherapy targeting multiple levels of the autoimmune pathway, including corticosteroids, intravenous immunoglobulin, rituximab, tocilizumab, and bortezomib. Clinical outcomes were assessed using the modified Rankin Scale (mRS) score at presentation and at one year follow-up.

Both patients presented with seizures, behavioral abnormalities, movement disorders, and autonomic instability, requiring ICU admission. Early initiation of multi-level immunotherapy led to rapid clinical improvement. Patient 1 was discharged after 20 days with mRS 3, improving to mRS 0 at 1-year follow-up. Patient 2 was discharged after 4 weeks with mRS 3, improving to mRS 0 at 10-month follow-up. Both patients remained seizure-free and exhibited no residual neurological deficits.

Simultaneous multi-level immunotherapy in NMDARE may limit ICU duration, reduce hospital stay, and prevent long-term neurological deficits. Early targeting of different steps in the autoimmune cascade appears to enhance functional outcomes. These findings support further studies with larger sample sizes to improve treatment protocols for NMDARE.