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 significantly worsens outcomes and recovery. 1 Treatment should begin once cerebrospinal fluid results exclude infection and primary CNS lymphoma or neurosarcoidosis are not considerations. 2
Corticosteroid Dosing Options:
- Standard dosing: 1-2 mg/kg/day intravenous methylprednisolone 2
- Pulse therapy for severe presentations: 1g daily for 3-5 days 2
Additional First-Line Options:
- IVIG or plasma exchange can be added if no improvement after initial corticosteroids, or in cases of severe presentation or contraindications to steroids 3
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, 3 This is not optional—surgical removal of teratoma combined with immunotherapy significantly improves outcomes and reduces relapses. 1, 4 In the landmark series of 100 patients, those who received early tumor treatment had better outcomes (p=0.004) and fewer neurological relapses (p=0.009). 4
When to Escalate to Second-Line Therapy
Escalate to rituximab after 2-4 weeks if:
- No meaningful clinical improvement despite optimized first-line therapy 1, 3
- Patient continues to deteriorate 3
- Patient remains severely impaired 3
Rituximab Dosing:
Important caveat: Improvement typically begins 1-2 weeks after first dose, but NMDA receptor encephalitis characteristically has slower response times compared to other autoimmune encephalitides. 2, 3 Do not prematurely abandon rituximab if response is delayed.
Pre-Rituximab Safety Screening:
- Screen for hepatitis B reactivation risk 3
- Check baseline immunoglobulin levels 3
- Counsel about infusion reactions and infection risk 3
Bridging and Maintenance Therapy to Prevent Relapse
After achieving clinical improvement, initiate bridging therapy with: 1, 2, 3
- Gradual oral prednisone taper, OR
- Monthly IVIG, OR
- Monthly methylprednisolone IV
Long-term immunosuppression with agents such as azathioprine may be necessary, as approximately 25-30% of patients relapse despite no evidence of tumor. 1 Serial antibody monitoring in serum and CSF should guide treatment duration, and careful weaning is essential as premature discontinuation increases relapse risk. 3
Refractory Cases - Third-Line Options
For patients who fail standard first and second-line therapies: 2, 5
- Consider experimental therapies including tocilizumab or bortezomib 2
- Intrathecal injection of methotrexate and dexamethasone has been reported successful in case reports of refractory disease 5
- Bilateral salpingo-oophorectomy may be considered if ovarian tissue remains after initial teratoma removal 5
Expected Clinical Course and Prognosis
- Median hospital stay: 160 days (range 16-850 days) with current best therapy 1
- Recovery rate: 74% achieve full or substantial recovery at 1 year after immunotherapy or tumor removal 1
- Critical timing: Treatment started within 4 weeks of symptom onset confers the best recovery 1
- Antibody correlation: Improvement is associated with a decrease of serum antibody titres 4
Common Pitfalls to Avoid
- Do not wait for antibody confirmation before starting treatment—this delays therapy and worsens outcomes 1
- Do not skip tumor screening in young females—this is a critical determinant of outcome 1, 4
- Do not abandon rituximab prematurely—NMDA receptor encephalitis has characteristically slower response times 2, 3
- Do not discontinue immunotherapy too early—25-30% relapse risk necessitates bridging therapy 1