Refractory Pediatric NMDA Receptor Encephalitis: A Case Series

Abstract

Objective To characterize clinical features of our institution's refractory pediatric NMDA receptor encephalitis (NMDARE) patients, in the hopes of identifying predictive risk factors and specific treatment escalation targets. Background Management protocols for pediatric NMDARE increasingly recommend anti-CD-20 agents following first-line treatment with high-dose corticosteroids, intravenous immunoglobulin (IVIg), and/or plasma exchange therapy (PLEX). Even with early, aggressive treatment, some patients exhibit refractory disease or recurrences. Identification of clinical predictors for refractory disease course may allow earlier, targeted treatment escalation in these patients. Design/Methods We performed IRB-approved retrospective, descriptive review of patients in our institutional NMDARE database (2011-2021). Refractory disease was defined as lack of neurological improvement within 1-3 months, or recurrent relapse, after standardized treatment protocol (steroids, IVIg or PLEX, and two doses of rituximab 500 mg/m2). Demographics, clinical information, and diagnostic results from refractory patients were collected. Results 8/73 (10.9%) patients met criteria for refractory NMDARE (median age 10.0 years, IQR 8.3-14.0. 2 male, 6 female). Median days from symptom onset to first treatment was 12.5 (IQR 8.5-18.8), to detection of +NMDA Ab was 20.5 (17.8-24.0), and to rituximab was 27.5 (26.5-31.0). All were critically ill at disease onset, with seizures, encephalopathy, and respiratory failure. 2 (25%) had associated ovarian teratoma. Oligoclonal bands were tested in 6, with 4 resulting positive (67%). 7 had confirmed B-cell depletion after rituximab. Post-rituximab NMDA titers persisted in serum in 5 (63%) and CSF in 8 (100%). Immune therapy escalation was varied, and included repeat rituximab, mycophenolate, cyclophosphamide, and tocilizumab. Conclusions Severe initial presentation is a consistent feature among our refractory patients. The contribution of other factors such as oligoclonal bands and time to diagnosis/treatment are less clear, and warrant inter-group comparison with non-refractory patients. Persistence of serum and CSF titers despite B-cell depletion may suggest utility in targeting CD-20-negative mature plasma cells which may continue to produce disease-causing antibodies.