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

Treatment Approach for Anti-NMDA Receptor Encephalitis

First-line immunotherapy should be initiated promptly in anti-NMDA receptor encephalitis, without waiting for antibody test results, using a combination of high-dose corticosteroids with either intravenous immunoglobulin (IVIg) or plasma exchange (PLEX), especially in severe presentations. 1

Diagnostic Considerations

• Suspect anti-NMDA receptor encephalitis in patients with:
  • Acute/subacute onset (<12 weeks) of neuropsychiatric symptoms
  • Initial phase: Headache, fever, seizures, confusion, amnesia, psychosis
  • Later phase: Involuntary movements (choreoathetosis, orofacial dyskinesia), fluctuating consciousness, dysautonomia, central hypoventilation 1
• Diagnostic workup:
  • CSF analysis (lymphocytic pleocytosis, oligoclonal bands, NMDAR antibodies)
  • MRI (often normal in 90% initially, may show hippocampal or white matter signal changes)
  • EEG (epileptiform activity early in ~50%, generalized slowing in ~80%)
  • Serum NMDAR antibody testing 1
• Thorough tumor screening is essential, particularly for ovarian teratomas in women (20-50% of female patients) 1

Treatment Algorithm

First-Line Treatment (Start Immediately)

• Combination therapy is recommended for severe presentations 1:
  • High-dose IV methylprednisolone (1g daily for 3-5 days) followed by oral prednisone taper
  • PLUS either:
    • IVIg (0.4 g/kg/day for 5 days) OR
    • Plasma exchange (5-10 sessions every other day) 1

Second-Line Treatment (If No Response After 2-4 Weeks)

• For patients who fail to respond to first-line therapy:
  • Rituximab (preferred for antibody-mediated autoimmunity like NMDAR encephalitis)
  • Cyclophosphamide (alternative option, especially for cell-mediated autoimmunity) 1
  • Consider combination of both in severe cases 1

Third-Line Treatment (For Refractory Cases)

• For patients with no clear improvement on second-line therapies:
  • Consider novel approaches such as tocilizumab or bortezomib 1, 2

Maintenance/Bridging Therapy

• After acute treatment, implement bridging therapy:
  • Gradual oral prednisone taper
  • Monthly IVIg or IV methylprednisolone 1
• Long-term immunosuppression with agents like azathioprine may be necessary due to ~30% relapse risk 1

Tumor Management

• If tumor is detected (especially ovarian teratoma), surgical removal should be performed promptly
• Patients with tumor removal plus immunotherapy have better recovery rates 1, 3
• Continue annual tumor screening for several years, particularly if treatment response is poor or relapses occur 1

Prognostic Factors

• The largest observational cohort study (577 patients) identified key prognostic factors 3:
  • Early treatment initiation significantly improves outcomes
  • Avoiding ICU admission correlates with better prognosis
  • Recovery may take up to 18 months in some patients
  • Second-line immunotherapy significantly improves outcomes when first-line treatment fails

Clinical Pearls and Pitfalls

• Pitfall: Delaying immunotherapy while waiting for antibody results can worsen outcomes
• Pitfall: Missing associated tumors, particularly in female patients
• Pearl: Treatment response may be slow in NMDAR-Ab encephalitis compared to other autoimmune encephalitides 1
• Pearl: Serial antibody level monitoring in serum and CSF can help guide treatment decisions 1
• Pearl: Relapses occur in approximately 30% of patients, necessitating consideration of long-term immunosuppression 1

This treatment approach is supported by multiple guidelines and large observational studies, with evidence showing that early aggressive immunotherapy significantly improves morbidity, mortality, and quality of life outcomes in patients with anti-NMDA receptor encephalitis.