How is anti‑N‑methyl‑D‑aspartate receptor (anti‑NMDA) encephalitis tested?

Testing for Anti-NMDA Receptor Encephalitis

Test both CSF and serum for anti-NMDA receptor antibodies using cell-based assays (CBA) combined with rat brain immunohistochemistry, with CSF testing being mandatory as it has 100% sensitivity compared to only 85.6% for serum alone 1.

Antibody Testing Approach

The diagnostic workup requires a two-pronged antibody testing strategy:

CSF Testing (Primary - Most Sensitive)

• CSF antibody testing is essential and should never be skipped - it detects antibodies in 100% of confirmed cases 1
• Use both immunohistochemistry and cell-based assays (CBA) with NMDA receptor-expressing cells
• CSF is more sensitive than serum for NMDAR antibodies specifically 2
• A patient is considered antibody-positive only if samples test positive with BOTH immunohistochemistry AND CBA techniques 1

Serum Testing (Adjunctive)

• Serum testing alone misses approximately 14% of cases (85.6% sensitivity) 1
• Still valuable as an adjunct and for monitoring treatment response
• Immunohistochemistry on serum shows better agreement with CBA using fixed cells (71%) versus live cells (58%) 1

Critical pitfall: Never rely on serum testing alone - you will miss confirmed cases. Always obtain CSF 1.

Complete Diagnostic Algorithm

Beyond antibody testing, the full workup includes 2:

Step 1: Brain Imaging

• MRI brain with or without contrast (first-line)
• Look for T2/FLAIR hyperintensities in medial temporal lobes, hippocampus, frontal cortex, basal ganglia, or cerebellum
• Note: MRI can be normal in up to 63% of non-infection-related cases 3
• Brain FDG-PET if MRI is negative but clinical suspicion remains high 2

Step 2: Additional CSF Studies

Beyond antibody testing, CSF should include:

• HSV1/2 and VZV PCR (to exclude viral encephalitis)
• Cell count and differential (expect mild-moderate lymphocytic pleocytosis, typically 20-200 cells) 2
• Protein (often elevated)
• IgG index/synthesis rate and oligoclonal bands (often positive) 2
• Bacterial/fungal cultures when appropriate
• Cytology if malignancy suspected

Step 3: EEG

• Exclude subclinical status epilepticus
• Look for focal slowing, lateralized periodic discharges, or extreme delta brush (occasionally seen in NMDAR encephalitis) 2
• Normal EEG does not exclude the diagnosis 2

Step 4: Tumor Screening

Young and middle-aged adults with suspected NMDAR encephalitis require targeted screening for ovarian teratoma 2:

• Transvaginal or transabdominal pelvic ultrasound (first-line for females)
• Testicular ultrasound for males
• If ultrasound negative but suspicion high: pelvic MRI
• CT chest/abdomen/pelvis for broader cancer screening
• Consider whole-body FDG-PET if initial screening negative 2

Monitoring and Follow-up Testing

Antibody titers have clinical utility 1:

• Higher CSF and serum titers correlate with poor outcome and presence of teratoma
• CSF titer changes correlate better with relapses than serum (14/19 vs 7/16 cases) 1
• Antibodies often remain detectable even after recovery (24/28 CSF samples, 17/23 serum samples) 1
• Serial titers can complement clinical assessments during treatment

Key Testing Pitfalls to Avoid

1. Never skip CSF testing - serum alone misses 14% of cases 1
2. Don't wait for antibody results to start treatment - if clinical suspicion is high based on presentation (psychiatric prodrome, seizures, movement disorders, dysautonomia), begin immunotherapy while awaiting confirmation 2
3. Don't assume negative MRI excludes diagnosis - up to 63% may have normal imaging 3
4. Don't forget tumor screening - especially pelvic ultrasound in young women, as ovarian teratoma is a common trigger 2