What is the next step in managing a 15-year-old female patient with NMDA (N-methyl-D-aspartate) receptor encephalitis, who is currently on pulse intravenous (IV) methylprednisolone (MP) and IV immunoglobulin (IVIG) and has received 1 gram IV rituximab (rituximab), with prominent behavioral abnormalities and on risperidone (risperidone), despite negative magnetic resonance imaging (MRI) and computed tomography (CT) scans for teratoma?

Management of Refractory NMDA Receptor Encephalitis in Adolescent Female

This patient requires immediate escalation to second-line immunotherapy with additional rituximab, given the lack of adequate response to first-line therapy (pulse methylprednisolone and IVIG) plus only a single dose of rituximab, combined with persistent severe behavioral abnormalities. 1

Immediate Treatment Escalation

Complete the rituximab course immediately - the patient has received only 1 gram IV rituximab, which is insufficient. 1, 2

• Standard rituximab dosing for NMDA receptor encephalitis is 375 mg/m² weekly for 4 weeks, or two doses of 1000 mg separated by 2 weeks 1, 2
• The single 1-gram dose represents incomplete second-line therapy, not treatment failure 2
• Monitor CD19+ B cell counts to confirm adequate B-cell depletion (target: reduction to near 0) 2

Consider adding plasma exchange (PLEX) concurrently if no improvement occurs within 2-4 weeks of completing rituximab. 1

• PLEX (5-10 sessions every other day) is particularly effective for refractory NMDA receptor encephalitis 1
• Combined rituximab plus PLEX may be superior to either alone in severe, unresponsive cases 1, 3
• PLEX should be prioritized if the patient develops severe dysautonomia or further neurological deterioration 1

Critical Tumor Screening

Repeat comprehensive tumor screening immediately, despite negative initial imaging. 1, 4

• Perform transvaginal or transabdominal pelvic ultrasound specifically for ovarian teratoma - this is the most critical test, as 20-50% of female adolescents with NMDA receptor encephalitis harbor an ovarian teratoma 4, 5
• If ultrasound is negative or equivocal, obtain pelvic MRI for higher sensitivity 4
• Consider whole-body FDG-PET if initial screening remains negative, as it has superior sensitivity for small or early neoplasms 1, 4
• Tumor screening must be repeated annually for several years, particularly given poor treatment response 1, 4

The absence of tumor on initial CT does not exclude teratoma - ultrasound and MRI are superior for pelvic imaging in adolescent females. 4

Monitoring for Severe Deterioration

Assess daily for signs of severe neurological progression requiring ICU-level care. 6

• Monitor for loss of neck holding, respiratory muscle weakness, or central hypoventilation - these indicate brainstem involvement and potential respiratory failure 6, 5
• If severe motor weakness develops, escalate immediately to pulse-dose methylprednisolone 1g daily for 3-5 days plus IVIG or PLEX concurrently (not sequentially) 6
• Arrange ICU evaluation if any signs of respiratory compromise emerge 6

Psychiatric Symptom Management

Continue risperidone for behavioral control while pursuing aggressive immunotherapy. 5, 2

• Prominent behavioral abnormalities are expected in NMDA receptor encephalitis and typically improve with effective immunotherapy 5, 2
• Antipsychotics provide symptomatic control but do not address the underlying autoimmune process 2
• Avoid attributing psychiatric symptoms to primary psychiatric illness - they reflect active encephalitis requiring immunotherapy escalation 1

Treatment Timeline and Prognosis

Recovery is typically prolonged, often requiring months to years. 5, 7

• 74% of pediatric patients achieve full or substantial recovery at 1 year with appropriate immunotherapy 1
• Relapses occur in 25-30% of pediatric/adolescent patients, requiring retreatment 1, 5
• Treatment initiated within 4 weeks of symptom onset confers the best recovery 1

Initiate bridging/maintenance therapy once acute phase resolves to prevent relapse. 1

• Options include gradual oral prednisone taper, monthly IVIG, or monthly IV methylprednisolone 1
• Long-term immunosuppression may be necessary in 40-45% of severe cases 7

Third-Line Options for Refractory Disease

If no improvement after completing rituximab course plus PLEX, consider cyclophosphamide. 1, 3

• Cyclophosphamide is effective for refractory NMDA receptor encephalitis unresponsive to rituximab 1, 3
• Combination rituximab plus cyclophosphamide has shown marked improvement in drug-resistant cases 3
• Novel agents (tocilizumab, bortezomib) remain experimental with minimal evidence 1

Common Pitfalls to Avoid

• Do not delay second-line therapy completion - a single rituximab dose is inadequate; complete the full course immediately 1, 2
• Do not attribute behavioral symptoms to primary psychiatric illness - they reflect active encephalitis requiring immunotherapy escalation, not just antipsychotic management 1
• Do not rely solely on CT for tumor screening in adolescent females - pelvic ultrasound is mandatory for ovarian teratoma detection 4
• Do not use sequential therapy in severe cases - if further deterioration occurs, use combination therapy (steroids + IVIG or PLEX) from the outset 1, 6