Is NMDA (N-methyl-D-aspartate) receptor antibody (serum) testing indicated in the diagnosis of epilepsy?

NMDA Receptor Antibody Testing in Epilepsy

NMDA receptor antibody testing is indicated in patients with epilepsy when there are features suggestive of autoimmune encephalitis, particularly in cases of new onset refractory status epilepticus (NORSE), but is not routinely recommended for all epilepsy patients. 1

When to Consider NMDA Receptor Antibody Testing

• NMDA receptor antibody encephalitis should be considered in the differential diagnosis of patients with epilepsy who present with additional features such as:

  • Psychiatric symptoms (psychosis, behavioral changes) 1
  • Cognitive dysfunction (memory deficits) 1
  • Movement disorders (dyskinesias, choreoathetosis) 1
  • Autonomic instability 1
  • Decreased level of consciousness 1
  • Refractory seizures or status epilepticus 1

• Testing is particularly important in young patients with epilepsy, as anti-NMDAR encephalitis has been identified as the single most common cause of encephalitis in patients under 30 years of age, exceeding the combined incidence of herpes simplex virus, West Nile virus, and varicella zoster virus encephalitis in this population 1

Diagnostic Approach

• CSF testing for NMDA receptor antibodies is more sensitive than serum testing:

  • CSF has 100% sensitivity compared to 85.6% sensitivity in serum 2
  • When testing for anti-NMDAR antibodies, CSF should be the preferred specimen 1, 2

• A comprehensive diagnostic algorithm for suspected autoimmune encephalitis with seizures should include:

  1. Confirming focal or multifocal brain pathology suggestive of autoimmune encephalitis:

     • Brain MRI with and without contrast 1
     • EEG to exclude subclinical status epilepticus and identify patterns suggestive of autoimmune encephalitis (e.g., extreme delta brush in NMDAR encephalitis) 1
     • Brain FDG-PET if MRI is negative but clinical suspicion remains high 1, 3

  2. Confirming inflammatory etiology:

     • Lumbar puncture with CSF testing for NMDAR antibodies 1
     • Blood tests including serum NMDAR antibodies 1
     • CSF should also be tested for infections, inflammatory markers (IgG index, oligoclonal bands) 1

  3. Screening for associated neoplasms (particularly ovarian teratoma in young women) 1

Clinical Relevance and Outcomes

• Anti-NMDAR antibodies are pathogenic for seizures, as demonstrated in animal models where antibody exposure induced seizures in 33 of 36 mice 4

• Higher antibody titers in CSF and serum correlate with poorer clinical outcomes 2

• Treatment response can be significant even with delayed therapy:

  • Immunotherapy can lead to improvement even when initiated months after symptom onset 5
  • Changes in CSF antibody titers correlate more closely with relapses than serum titers 2

Important Considerations and Pitfalls

• A negative serum NMDAR antibody test does not exclude the diagnosis; CSF testing is essential 2

• NMDAR antibodies can sometimes be detected in serum but not in CSF, particularly in early stages of the disease 3

• Interpretation of positive antibody results should be made in the proper clinical context, as NMDAR antibodies have been detected in 30% of patients during the course of herpes simplex encephalitis without clinical relapse 1

• Anti-NMDAR encephalitis can develop following viral infections (HSV, VZV, EBV, influenza A), so consider testing in patients with viral encephalitis who exhibit slow response to treatment or develop recrudescent symptoms 1

• The underlying pathophysiology of seizures in NMDAR antibody encephalitis involves reduction of synaptic excitatory neurotransmission rather than decreased inhibition as might be expected 6