What is the appropriate workup for a patient suspected of having N-methyl-D-aspartate (NMDA) receptor encephalitis?

Workup for NMDA Receptor Encephalitis

When NMDA receptor encephalitis is suspected, immediately obtain brain MRI with contrast, CSF analysis with NMDAR antibodies, serum NMDAR antibodies, EEG, and tumor screening—particularly pelvic imaging in young females—while simultaneously excluding infectious causes. 1

Initial Diagnostic Steps

Brain Imaging

• Obtain MRI brain with and without contrast as the preferred modality (CT is insufficient) 1
• Look for bilateral limbic involvement (temporal lobes), cortical/subcortical changes, or multifocal abnormalities 1
• MRI may be completely normal in up to 50% of cases, so negative imaging does not exclude the diagnosis 1
• If MRI is contraindicated or negative with high clinical suspicion, obtain brain FDG-PET scan which is more sensitive 1

Cerebrospinal Fluid Analysis

• Collect at least 20 cc of CSF if possible 1
• Essential tests include: opening pressure, cell count with differential, protein, glucose, Gram stain, bacterial culture 1
• CSF NMDAR antibodies are the gold standard diagnostic test and are more sensitive than serum 1, 2, 3
• Send oligoclonal bands and IgG index 1
• Exclude infectious causes: HSV-1/2 PCR, VZV PCR, enterovirus PCR, cryptococcal antigen, VDRL 1
• CSF may show lymphocytic pleocytosis and elevated protein, but can be completely normal 1

Serum Testing

• Serum NMDAR antibodies (less sensitive than CSF but more accessible for preliminary screening) 1, 2
• Comprehensive autoimmune panel: FBC, ESR, CRP, ANA, ENA, dsDNA, ANCA, C3, C4 1
• Thyroid antibodies (thyroglobulin, thyroperoxidase) 1
• Hold acute serum and collect convalescent serum 10-14 days later for paired antibody testing 1
• HIV serology, treponemal testing (RPR) 1

Electroencephalogram

• Obtain EEG to exclude subclinical status epilepticus, which is common in NMDAR encephalitis 1
• Look for focal slowing, lateralized periodic discharges, or extreme delta brush (highly suggestive of NMDAR encephalitis) 1, 4
• Normal EEG does not exclude the diagnosis but can help differentiate from primary psychiatric disorders 1

Tumor Screening - Critical Component

Mandatory in Young Females

• Screen all young females with pelvic ultrasound or pelvic MRI for ovarian teratoma 5, 6, 7
• 20-50% of young women with NMDAR encephalitis have an associated ovarian teratoma 7
• Surgical removal combined with immunotherapy significantly improves outcomes 5, 6, 7

Broader Tumor Screening

• CT chest, abdomen, and pelvis 1
• Mammogram/breast MRI in appropriate age groups 1
• Testicular ultrasound in males 1
• If initial screening is negative, obtain whole-body PET scan 1

Additional Investigations Based on Clinical Features

If Psychiatric Symptoms Predominate

• Consider anti-neuronal and onconeuronal antibodies panel 1
• Voltage-gated potassium channel complex antibodies 1
• Screen for other surface antigen antibodies (AMPAR, LGI1, CASPR2, GABAR) 1

If Seizures or Movement Disorders Present

• Male patients with seizures as initial symptom should raise high suspicion 3
• Look for preceding headaches or fever 3
• Repeat EEG if initial study normal but clinical suspicion remains high 1

If Initial Antibody Testing Negative

• Repeat CSF and serum NMDAR antibodies if clinical suspicion remains high, as initial testing can be falsely negative 4
• Consider brain and meningeal biopsy if diagnosis remains uncertain despite comprehensive workup 1

Critical Pitfalls to Avoid

• Do not wait for antibody confirmation to initiate treatment—delayed treatment worsens outcomes 7
• Do not rely solely on serum antibodies—CSF testing is mandatory and more sensitive 2, 3
• Do not exclude diagnosis based on normal MRI or CSF—both can be normal in confirmed cases 1
• Do not miss tumor screening in young females—this is a treatable cause that dramatically improves prognosis 5, 6, 7
• Total CSF protein elevation is more common in middle and late stages, so early normal protein does not exclude diagnosis 3

Timing Considerations

• Initiate workup immediately once infection is excluded from CSF 5, 7
• Treatment should begin within 4 weeks of symptom onset for best recovery 7
• The median hospital stay with current best therapy is 160 days, emphasizing the importance of early diagnosis 7