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

Treatment of NMDA Receptor Encephalitis

Initiate first-line immunotherapy immediately with high-dose intravenous methylprednisolone (1g daily for 3-5 days) after ruling out infection, and strongly consider adding IVIG or plasma exchange concurrently rather than sequentially if the presentation is severe. 1

First-Line Immunotherapy Approach

Immediate Treatment Initiation

• Begin immunotherapy as soon as infection is excluded based on basic CSF results (cell count, protein, glucose), without waiting for antibody confirmation 1
• For severe presentations (decreased consciousness, dyskinetic movements, autonomic instability, seizures), use combination therapy from the outset rather than sequential monotherapy 1
• Standard severe presentation warrants pulse-dose methylprednisolone (1g IV daily for 3-5 days) plus either IVIG or plasma exchange 1, 2

Choosing Between IVIG and Plasma Exchange

• Prefer IVIG for agitated patients (easier to administer), those with bleeding disorders, or when central line placement poses risks 1
• Prefer plasma exchange (5-10 sessions every other day) for patients with severe hyponatremia, high thromboembolic risk, associated demyelination, or when corticosteroids are contraindicated 1
• Plasma exchange combined with corticosteroids shows superior modified Rankin score improvement compared to corticosteroids alone in NMDAR encephalitis 1

Second-Line Therapy

Timing and Selection

• If no meaningful clinical, radiological, or electrophysiological improvement occurs within 2-4 weeks after completing combined first-line therapy, initiate second-line agents 1
• For severe presentations with signs like loss of neck holding or rapid deterioration, consider second-line therapy within 7-10 days rather than waiting the full 2-4 weeks 2

Agent Selection

• Rituximab is preferred for NMDAR encephalitis and other antibody-mediated autoimmunity (targets B-cells and indirectly suppresses T-cell activity) 1
• Cyclophosphamide is reserved for suspected cell-mediated autoimmunity, such as classical paraneoplastic syndromes with intracellular antibodies 1
• Rituximab has a more favorable toxicity profile than cyclophosphamide, making it the first choice for most newly diagnosed cases 1

Tumor Screening and Removal

• Perform cancer screening with CT chest/abdomen/pelvis with contrast in all patients, as up to 50% of women over age 18 with NMDAR encephalitis have ovarian teratomas 1
• If initial CT is negative, consider mammogram/breast MRI, pelvic ultrasound, and/or whole body FDG-PET guided by individual cancer risk factors 1
• Tumor removal (particularly ovarian teratoma) is a critical component of treatment, as the tumor often triggers the autoimmune response 1

Refractory Cases

Third-Line Options

• For patients showing no objective or subjective improvement with conventional second-line therapies, consider novel approaches including tocilizumab (IL-6 inhibitor) or bortezomib 1, 2
• Evidence for these agents is minimal but they represent options when standard therapies fail 1
• Transfer to a specialized neuroscience center should be arranged for refractory cases 2

Bridging and Maintenance Therapy

• After acute treatment, initiate bridging therapy with gradual oral prednisone taper, monthly IVIG, or monthly IV methylprednisolone to prevent relapse 1
• The duration of maintenance therapy remains controversial, but is generally continued for several months with gradual tapering based on clinical response 3

Critical Pitfalls to Avoid

• Never delay treatment while waiting for antibody test results—begin immunotherapy immediately after excluding infection 2, 4
• Avoid using standard-dose corticosteroids (e.g., 1mg/kg prednisone) for severe presentations; pulse-dose methylprednisolone is required 2
• Do not use sequential monotherapy for severe cases—combination therapy from the outset improves outcomes 1, 2
• Monitor closely for respiratory compromise, especially if motor weakness or loss of neck holding develops, as this may precede respiratory failure requiring ICU-level care 2

Prognostic Considerations

• Prompt treatment leads to near-complete neurologic recovery in approximately 75% of patients 4
• Delays in diagnosis and treatment are associated with worse outcomes including death 4
• Early immunomodulatory therapy is essential for positive outcomes and minimizing long-term complications 5
• NMDAR encephalitis is now recognized as the single most common cause of encephalitis in patients under 30 years, exceeding HSV, West Nile virus, and varicella zoster virus combined 1