Management of NMDA Receptor Encephalitis
Initiate high-dose intravenous methylprednisolone immediately as first-line therapy once CSF excludes infection, and escalate to rituximab after 2-4 weeks if there is no meaningful clinical improvement. 1, 2
Immediate First-Line Immunotherapy
- Start treatment immediately without waiting for antibody confirmation, as delayed treatment worsens outcomes and recovery. 1
- High-dose intravenous methylprednisolone (IVMP) is the preferred first-line agent, with dosing options of standard 1-2 mg/kg/day or pulse therapy 1g daily for 3-5 days in severe presentations. 2, 3
- In severe presentations or if no improvement after initial corticosteroids, add IVIG (0.4 g/kg/day) or plasma exchange to the steroid regimen. 4, 3
- The combination of two immunosuppressive agents is important for optimal outcomes. 4
Critical Tumor Screening - Do Not Skip This Step
- Screen all young females for ovarian teratoma using pelvic ultrasound or MRI, as 20-50% will have an associated tumor. 1, 2
- Male patients and children have lower rates of associated tumors but should still be screened. 4
- Surgical removal of teratoma combined with immunotherapy significantly improves outcomes. 1, 2
- Continue annual tumor screening for several years, particularly if treatment response is poor or relapses occur. 4
When and How to Escalate to Second-Line Therapy
- Escalate to rituximab after 2-4 weeks if there is no significant clinical, radiological, or electrophysiological improvement despite optimized first-line therapy, or if the patient continues to deteriorate or remains severely impaired. 1, 3
- The mean time between first- and second-line treatment in clinical practice is approximately 13 days. 5
- Standard rituximab dosing is 375 mg/m² IV weekly for 4 weeks, OR 1000 mg on days 1 and 15. 1, 2, 3
- Improvement typically begins 1-2 weeks after the first rituximab dose, though NMDA receptor encephalitis characteristically has slower response times. 2, 3
- Cyclophosphamide is an alternative second-line option for patients who cannot tolerate or do not respond to rituximab. 4, 5
Severe and Refractory Cases
- For patients refractory to standard first and second-line therapies, consider a three-combined immunotherapy approach with high-dose steroid, IVIG, and rituximab administered simultaneously rather than sequentially. 6
- Experimental therapies including tocilizumab or bortezomib may be considered for truly refractory cases. 2
Bridging and Long-Term Maintenance Therapy
- After achieving clinical improvement, initiate bridging therapy to prevent relapse, which may include gradual oral prednisone taper, monthly IVIG, or monthly methylprednisolone IV. 1, 2, 3
- Long-term immunosuppression with agents such as azathioprine may be helpful, as approximately 25-30% of patients relapse despite no evidence of tumor. 4, 1
- Serial antibody monitoring in serum and CSF can guide treatment duration, and careful weaning is essential as premature discontinuation increases relapse risk. 3
Expected Clinical Course and Outcomes
- The median hospital stay is 160 days (range 16-850 days) with current best therapy, and many patients require ICU admission for assisted ventilation. 4, 1
- Overall, 74% achieve full or substantial recovery at 1 year after immunotherapy or tumor removal. 1
- Treatment started within 4 weeks of symptom onset confers the best recovery. 1
- During the first 6 months, approximately 83% achieve a good outcome (modified Rankin Scale score ≤2) and 62.5% completely recover. 5
Common Pitfalls to Avoid
- Do not delay treatment while waiting for antibody confirmation—start immunotherapy based on clinical suspicion. 1
- Do not use regular IVIG alone without steroids, as this may be less effective at reducing antibody levels with associated poorer clinical outcomes. 4
- Do not miss tumor screening in young females, as this is a critical component of treatment. 1, 2
- Do not discontinue immunosuppression too early, as relapse rates are significant (approximately 30%) even without tumor presence. 4, 1