Initial Treatment for NMDA Receptor Encephalitis
Start high-dose intravenous methylprednisolone (IVMP) immediately as first-line therapy once infection is ruled out, with standard dosing at 1-2 mg/kg/day or pulse dosing at 1g daily for 3-5 days in severe cases. 1, 2
First-Line Immunotherapy Approach
The American Academy of Neurology recommends initiating acute immunotherapy immediately once cerebrospinal fluid results exclude infection and primary CNS lymphoma or neurosarcoidosis are not considerations. 2, 3 The treatment hierarchy is clear:
Primary Agent: Corticosteroids
- IVMP is the most commonly used and preferred first-line agent for NMDA receptor encephalitis 4, 1, 2
- Dosing options include:
Adding IVIG or Plasma Exchange
If no improvement occurs after initial corticosteroids, or in severe presentations, add either IVIG or plasma exchange (PLEX) to the corticosteroid regimen. 1, 2, 3
- Patient is agitated or combative
- Bleeding disorders or coagulopathy present
- Difficulty with central line placement
- Standard dosing: 0.4 g/kg/day for 5 days (total 2 g/kg) 2, 3
- Severe hyponatremia present
- High thromboembolic risk
- Associated brain or spinal demyelination
- Standard protocol: 5-10 sessions every other day 2, 3
A retrospective study showed patients receiving both corticosteroids and PLEX had better modified Rankin score improvement than corticosteroids alone, with the largest sustained improvement typically occurring after the third-fifth exchange. 5
Tumor Screening
Screen all young females with NMDA receptor encephalitis for ovarian teratoma using pelvic ultrasound or MRI, as surgical removal combined with immunotherapy significantly improves outcomes. 1 The American Academy of Neurology emphasizes this high association warrants immediate investigation. 1
Escalation to Second-Line Therapy
Administer rituximab if no meaningful clinical improvement occurs after 2-4 weeks of optimized first-line therapy, or if the patient continues to deteriorate or remains severely impaired. 1, 2 The American Academy of Neurology and American Society of Clinical Oncology recommend rituximab as the preferred second-line agent for autoimmune encephalitis with inadequate first-line response. 1, 2
Rituximab Dosing and Monitoring
- Standard dosing: 375 mg/m² weekly for 4 weeks OR 1000 mg on days 1 and 15 1
- Screen for hepatitis B reactivation risk and baseline immunoglobulin levels before administration 1
- Improvement typically begins 1-2 weeks after first dose, though NMDA receptor encephalitis characteristically has slower response times 1, 6
Alternative Second-Line Option
Cyclophosphamide can be considered as an alternative second-line agent, particularly for cell-mediated autoimmunity, though rituximab is preferred for antibody-mediated disease. 2, 6 Most patients show gradual improvement within weeks of second-line therapy initiation, though repeated or alternating use of both drugs may be required. 6, 7
Critical Timing Considerations
Early treatment is a significant predictor of good outcome (odds ratio 0.62, p<0.0001), and avoiding ICU admission correlates with better prognosis. 7 In a large observational cohort of 501 patients, 53% improved within 4 weeks of first-line therapy, and among those who didn't improve initially, second-line immunotherapy resulted in significantly better outcomes (odds ratio 2.69, p=0.012). 7
Recovery can take up to 18 months, with 81% of patients achieving good outcome (mRS 0-2) at 24 months follow-up. 7 This prolonged recovery timeline underscores the importance of not prematurely abandoning treatment.
Bridging and Maintenance Therapy
After achieving clinical improvement, initiate bridging therapy with gradual oral prednisone taper or monthly IVIG to prevent relapse. 1, 3 Serial antibody monitoring in serum and CSF can guide treatment duration, as premature discontinuation increases the 12% two-year relapse risk. 1, 7
Severe and Refractory Cases
For patients refractory to standard first and second-line therapies, consider: