What is the treatment approach for conditions related to N-methyl-D-aspartate receptor (NMDAR) dysfunction, such as NMDAR encephalitis?

Treatment of NMDAR Encephalitis

Start immunotherapy immediately once infection is ruled out, without waiting for antibody confirmation, using first-line therapy with high-dose corticosteroids combined with either IVIG or plasma exchange, and escalate to second-line agents (rituximab or cyclophosphamide) if no meaningful improvement occurs within 2-4 weeks. 1, 2

First-Line Immunotherapy

Initiate treatment as soon as CSF results exclude infection and primary CNS lymphoma or neurosarcoidosis are not considerations. 2 The timing is critical—early treatment is a significant predictor of good outcome. 3

Corticosteroid Dosing

• High-dose intravenous methylprednisolone is the cornerstone of first-line therapy 1, 2
• Standard dosing: 1-2 mg/kg/day 1
• Pulse dosing for severe presentations: 1g daily for 3-5 days 1, 4
• Follow with gradual oral prednisone taper as bridging therapy 2

Adding IVIG or Plasma Exchange

Choose based on specific patient factors: 2

Use IVIG (0.4 g/kg/day for 5 days, total 2 g/kg) when: 1, 2

• Patient is agitated or combative
• Bleeding disorders or coagulopathy present
• Difficulty with central line placement

Use plasma exchange (5-10 sessions every other day) when: 1, 2

• Severe hyponatremia present
• High thromboembolic risk
• Associated brain or spinal demyelination

Combination vs Sequential Therapy

For severe initial presentations (e.g., loss of neck holding, decreased consciousness, severe dyskinetic movements), use combination therapy with steroids PLUS IVIG or steroids PLUS plasma exchange from the beginning, rather than sequential therapy. 2, 4 This is particularly important as responses can be slow in NMDAR encephalitis compared to other neuronal surface antibody syndromes. 5

Tumor Screening

Conduct tumor screening concurrently with immunotherapy initiation, not before. 5 In NMDAR encephalitis:

• Ovarian teratoma occurs in up to 50% of patients after age 18 years 5
• Rare in children 5
• Screen with CT chest/abdomen/pelvis with contrast, and pelvic ultrasound in females 4
• Tumor removal, when present, is part of first-line treatment 3

Second-Line Immunotherapy

If no clinical, radiological, or electrophysiological improvement after 2-4 weeks of optimized first-line therapy, add second-line agents without further delay. 1, 4

Agent Selection

• Rituximab is preferred for NMDAR encephalitis (antibody-mediated autoimmunity), chosen by 80% of experts 1
• Cyclophosphamide for suspected cell-mediated components 1
• Second-line therapy significantly improves outcomes (OR 2.69, CI 1.24-5.80; p=0.012) compared to those who do not receive it 3

Evidence for Second-Line Efficacy

In a cohort of 577 patients, 57% of those who failed first-line treatment received second-line immunotherapy and achieved better outcomes than those who did not. 3 Recovery can take up to 18 months, with outcomes continuing to improve throughout this period. 3

Critical Clinical Scenarios

Loss of Neck Holding or Severe Motor Weakness

This represents a medical emergency requiring immediate escalation: 4

• Use pulse-dose methylprednisolone (1g daily for 3-5 days) immediately 4
• Add IVIG or plasma exchange concurrently, not sequentially 4
• Obtain ICU evaluation for potential airway protection 4
• Perform urgent MRI brain/spine with attention to brainstem 4
• Monitor closely for respiratory compromise, as progression can be rapid 4
• If no improvement within 7-10 days, initiate second-line therapy without waiting the full 2-4 weeks 4

Maintenance and Relapse Prevention

After acute treatment, start bridging therapy with: 2

• Gradual oral prednisone taper, OR
• Monthly IVIG, OR
• Monthly intravenous methylprednisolone

Relapse risk is approximately 12% within 2 years. 3 Patients not treated with immunotherapy at first presentation have higher relapse risk. 5 When relapses occur, 67% are less severe than initial episodes. 3

Wean immunotherapy very carefully, with serial antibody level monitoring in serum and CSF when available. 5

Predictors of Good Outcome

The strongest predictors of favorable outcome (mRS 0-2) are: 3

• Early treatment initiation (OR 0.62, CI 0.50-0.76; p<0.0001)
• No ICU admission (OR 0.12, CI 0.06-0.22; p<0.0001)

At 24 months follow-up, 81% of patients achieve good outcome (mRS 0-2), with median time to good outcome of 6 months (IQR 2-12). 3

Common Pitfalls to Avoid

• Never delay treatment while waiting for antibody results—start once infection is excluded 1, 4
• Do not use standard-dose corticosteroids for severe presentations—use pulse dosing 4
• Avoid sequential therapy in severe cases—use combination therapy from onset 4
• Do not wait the full 2-4 weeks before escalating in rapidly deteriorating patients (e.g., loss of neck holding) 4
• Do not assume lack of response means treatment failure—recovery can take up to 18 months 3
• Do not abruptly discontinue immunotherapy—taper carefully to prevent relapses 5

Pediatric Considerations

In 177 children studied, predictors of good outcome and magnitude of second-line immunotherapy effect were similar to the entire cohort. 3 Epilepsy and abnormal movements are more frequent at onset in children compared to adults. 5