What are the treatment recommendations for a patient diagnosed with NMDAR (N-methyl-D-aspartate receptor) encephalitis?

Treatment Recommendations for NMDAR Encephalitis

Immediate First-Line Immunotherapy

Start high-dose intravenous methylprednisolone (IVMP) immediately once CSF excludes infection, without waiting for antibody confirmation, as delayed treatment significantly worsens outcomes. 1, 2, 3

• Dosing options: Standard 1-2 mg/kg/day or pulse therapy 1g daily for 3-5 days in severe presentations 3
• Treatment must begin as soon as infection is ruled out based on basic CSF results (cell count, protein, glucose) 1
• Do not delay for antibody results—turnaround time is often weeks, and early treatment is critical for recovery 2, 3

Combination First-Line Therapy for Severe Presentations

For severe initial presentations (severe agitation, status epilepticus, dysautonomia, mechanical ventilation requirement), combine IVMP with either IVIG or plasma exchange from the beginning rather than sequentially. 1, 4

• IVIG preferred for: Agitated patients, bleeding disorders 1
• Plasma exchange (5-10 sessions) preferred for: Severe hyponatremia, high thromboembolic risk, contraindication to steroids, or associated demyelination 1, 4
• If starting with steroids alone, add IVIG or plasma exchange if no improvement by end of initial treatment cycle 1

Critical Tumor Screening

Screen all young females for ovarian teratoma using pelvic ultrasound or MRI, as 20-50% will have an associated tumor—surgical removal combined with immunotherapy significantly improves outcomes. 2, 3, 5

• Teratoma removal is as important as immunotherapy for recovery 2
• Consider broader oncologic screening (mammogram, whole body FDG-PET) guided by age and cancer risk factors 1

Second-Line Therapy: When and What

Escalate to rituximab after 2-4 weeks if there is no meaningful clinical, radiological, or electrophysiological improvement despite optimized first-line therapy. 1, 2, 3, 5

Rituximab Dosing and Expectations

• Standard dosing: 375 mg/m² IV weekly for 4 weeks OR 1000 mg on days 1 and 15 2, 3, 5
• Improvement typically begins 1-2 weeks after first dose, though NMDAR encephalitis characteristically has slower response times than other autoimmune encephalitides 3, 5
• Rituximab is preferred over cyclophosphamide (80% vs 10% expert preference) for antibody-mediated autoimmunity like NMDAR encephalitis 1

Alternative Second-Line Options

• Cyclophosphamide: Consider if rituximab unavailable or for cell-mediated features 1, 6
• Repetitive first-line therapy: For patients with mRS ≥4 after initial first-line who cannot access second-line agents, repeating IVMP plus IVIG is superior to oral prednisolone alone 7, 8

Bridging and Maintenance Therapy

After achieving clinical improvement, initiate bridging therapy with gradual oral prednisone taper, monthly IVIG, or monthly IV methylprednisolone to prevent relapse. 1, 2, 3, 5

• Approximately 25-30% of patients relapse despite no evidence of tumor 2
• Duration guided by serial antibody monitoring in serum and CSF 3, 5
• Long-term immunosuppression (azathioprine, mycophenolate) may be needed for severe cases or those with relapses 2, 9
• Premature discontinuation increases relapse risk—careful weaning is essential 5

Refractory Cases

For patients refractory to standard first and second-line therapies after 1-3 months, consider experimental therapies including tocilizumab or bortezomib, though evidence is minimal. 1, 6, 9

• Immunoadsorption may be effective for severe, refractory cases requiring ICU support 4
• Some patients require repeated and alternating use of rituximab and cyclophosphamide 6

Expected Clinical Course and Outcomes

• Median hospital stay: 160 days (range 16-850 days) with current best therapy 2
• Overall 74% achieve full or substantial recovery at 1 year after immunotherapy or tumor removal 2
• Treatment started within 4 weeks of symptom onset confers the best recovery 2
• Median ICU time for severe cases: 46 days 8

Common Pitfalls to Avoid

• Do not wait for antibody confirmation to start treatment—this is the single most critical error that worsens outcomes 2, 3
• Do not use oral prednisolone alone for patients with mRS ≥4 after first-line therapy—this has higher rates of poor outcomes compared to second-line or repetitive first-line therapy 7
• Do not skip tumor screening in young females—missing a teratoma significantly impacts recovery 2, 3
• Do not discontinue immunotherapy prematurely—relapses are common and require prolonged maintenance 2, 5