What is the treatment for N-methyl-D-aspartate (NMDA) receptor encephalitis?

Treatment 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

First-Line Immunotherapy

Begin treatment immediately without waiting for antibody confirmation, as delayed treatment worsens outcomes and recovery. 3

Corticosteroids as Primary Agent

• Intravenous methylprednisolone (IVMP) is the preferred first-line agent, with two dosing options: 1, 2
  • Standard dosing: 1-2 mg/kg/day
  • Pulse therapy: 1g daily for 3-5 days in severe presentations

Combination First-Line Therapy

• Add IVIG (0.4 g/kg/day for 5 days) or plasma exchange (5-10 sessions on alternate days) if: 2, 3
  • No improvement after initial corticosteroids alone
  • Severe presentation at onset
  • Contraindications to steroids exist
• Combination therapy (steroids + IVIG or steroids + plasma exchange) from the start is preferred in severe cases rather than steroid monotherapy 3, 4

Tumor Screening - Critical Step

Screen all young females for ovarian teratoma using pelvic ultrasound or MRI, as 20-50% will have an associated tumor. 5, 1, 2

• 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 5
• Men and children have lower rates of associated tumors 5

Second-Line Therapy - When to Escalate

Escalate to rituximab after 2-4 weeks if:

• No significant clinical, radiological, or electrophysiological improvement despite optimized first-line therapy 2, 3
• Patient continues to deteriorate or remains severely impaired 2
• Failure to respond to more than one first-line agent 3

Rituximab Administration

• Standard dosing options: 1, 2
  • 375 mg/m² IV weekly for 4 weeks, OR
  • 1000 mg on days 1 and 15
• Expected response timeline: Improvement typically begins 1-2 weeks after first dose, though NMDA receptor encephalitis characteristically has slower response times compared to other autoimmune encephalitides 1, 2
• Rituximab is preferred by 80% of specialists for antibody-mediated autoimmune encephalitis 3

Pre-Rituximab Safety Screening

• Screen for hepatitis B reactivation risk 2
• Check baseline immunoglobulin levels 2
• Counsel about infusion reactions and infection risk 2

Bridging and Maintenance Therapy

After achieving clinical improvement, initiate bridging therapy to prevent relapse: 1, 2

• Gradual oral prednisone taper, OR
• Monthly IVIG, OR
• Monthly methylprednisolone IV 3

Duration and Monitoring

• Use serial antibody monitoring in serum and CSF to guide treatment duration 1, 2
• Careful weaning is essential as premature discontinuation increases relapse risk 2
• Long-term immunosuppression with agents such as azathioprine may be helpful, as approximately 25-30% of patients relapse despite no evidence of tumor 5

Refractory Cases

For patients unresponsive to standard first and second-line therapies:

• Consider cyclophosphamide as an alternative second-line agent, particularly for suspected T-cell mediated mechanisms 3
• Experimental therapies including tocilizumab or bortezomib may be considered 1, 6

Critical Pitfalls to Avoid

• Do not wait for antibody results to initiate immunotherapy - treatment should begin immediately once infection is excluded 3
• Do not underestimate the need for early escalation - 32% of specialists add second-line agents after failure of only one first-line agent 3
• Do not use steroid monotherapy in severe cases - combination therapy from the start improves outcomes 3, 4
• Do not neglect tumor screening - failure to identify and remove teratomas compromises treatment success 3
• Do not assume linear recovery - improvement can be severely delayed (up to 18-30 months after treatment initiation) and may occur in a non-linear fashion 7

Expected Clinical Course

• Median hospital stay is 160 days (range 16-850 days) with current best therapy 5
• Many patients require ICU admission for assisted ventilation due to central hypoventilation 5
• Overall, 74% achieve full or substantial recovery at 1 year after immunotherapy or tumor removal 5
• Treatment started within 4 weeks of symptom onset confers the best recovery 5