From the Guidelines
A negative cerebrospinal fluid (CSF) NMDA receptor antibody test does not rule out autoimmune encephalitis in a patient with suspicious clinical features. Clinicians should proceed with a comprehensive evaluation including serum NMDA receptor antibody testing, as antibodies may be present in serum but absent in CSF in approximately 15% of cases 1. Additional testing should include other neuronal autoantibodies (such as LGI1, CASPR2, AMPA, and GABA-B receptor antibodies), inflammatory markers in CSF, brain MRI, and EEG.
Key Considerations
- The diagnosis of autoimmune encephalitis is based on a combination of clinical presentation, imaging, and laboratory findings, rather than a single test result 1.
- Treatment decisions should be based on the entire clinical picture rather than a single negative test result.
- In patients with a compelling clinical presentation of autoimmune encephalitis (psychiatric symptoms, seizures, movement disorders, autonomic instability), empiric immunotherapy with IV methylprednisolone (1000 mg daily for 3-5 days) or IVIG (2 g/kg divided over 2-5 days) may be warranted even with negative antibody results 1.
- The pathophysiology of autoimmune encephalitis involves antibodies targeting neuronal cell-surface or synaptic proteins, but testing sensitivity varies by antibody type and disease stage.
Next Steps
- Proceed with serum NMDA receptor antibody testing and other neuronal autoantibody tests.
- Perform brain MRI and EEG to evaluate for focal or multifocal brain abnormalities.
- Consider empiric immunotherapy with IV methylprednisolone or IVIG in patients with a compelling clinical presentation of autoimmune encephalitis, even with negative antibody results.
From the Research
Clinical Significance of Negative CSF NMDA Receptor Antibody Test
- A negative cerebrospinal fluid (CSF) N-methyl-D-aspartate (NMDA) receptor antibody test does not completely rule out the diagnosis of autoimmune encephalitis, as some patients may have false-negative results 2, 3.
- The sensitivity of NMDA receptor antibody testing is higher in CSF than in serum, with a sensitivity of 100% in CSF compared to 85.6% in serum 3.
- If clinical suspicion remains high despite negative results, repeat testing should be pursued, and clinical response should guide treatment decisions in refractory cases 2.
- Antibody-negative autoimmune encephalitis is a recognized entity, and diagnosis should only be made after comprehensive testing, including CSF and serum analysis 4.
Diagnostic Challenges
- Variable presentations, lack of awareness, and potential false-negative diagnostic studies can lead to delayed treatment and poor outcomes 2.
- Comprehensive panel-based reflexive testing based on the predominant neurological phenotypic presentation is ideal in the workup of cases of suspected autoimmune neurological disease 5.
- Testing of both CSF and serum is recommended, with few exceptions, to ensure optimal clinical sensitivity and specificity 5.
Treatment and Management
- First-line immunotherapy, often a combination of high-dose steroids, immunoglobulins, and/or plasma exchange, is strongly recommended in the acute phase of anti-NMDA receptor encephalitis 6.
- Second-line immunotherapy, particularly rituximab, can further improve outcomes and prevent relapses in cases where first-line therapy fails 6.
- Chronic maintenance therapy may be required in some cases to prevent relapses, which occur in 10-30% of cases, mostly within the first two years from onset 6.