What lab tests are recommended for diagnosing autoimmune epilepsy?

Laboratory Tests for Diagnosing Autoimmune Epilepsy

Testing for autoimmune epilepsy should include both serum and cerebrospinal fluid (CSF) neuronal autoantibody panels, along with inflammatory markers and neuroimaging to confirm the diagnosis and guide treatment. 1

Diagnostic Algorithm

Step 1: Confirm focal or multifocal brain pathology

• Brain MRI with and without contrast

  • Look for bilateral limbic encephalitis (sufficient to diagnose definite autoimmune encephalitis when CSF viral studies are negative)
  • Other patterns: cortical/subcortical, striatal, diencephalic, brainstem abnormalities

• EEG (especially if MRI is negative or patient has encephalopathy/frequent seizures)

  • Look for: focal slowing/seizures, lateralized periodic discharges, extreme delta brush (seen in NMDAR encephalitis)
  • Can help differentiate from metabolic encephalopathy

• Brain FDG-PET (if MRI is negative but clinical suspicion remains high)

  • May reveal abnormalities earlier than MRI
  • Common patterns: bilateral temporal hypermetabolism (limbic encephalitis) or bilateral occipito-parietal hypometabolism (NMDAR encephalitis)

Step 2: Confirm inflammatory etiology

CSF Analysis (most important test)

• Cell count and differential (look for mild to moderate lymphocytic pleocytosis, 20-200 cells)
• Protein (often elevated)
• Glucose and CSF/serum glucose ratio
• Albumin quotient
• IgG index and synthesis rate
• Oligoclonal bands (unmatched in serum)
• Neuronal autoantibody panel including:
  • Surface antigen antibodies: NMDAR, AMPAR, LGI1, CASPR2, GABAR A/B, DPPX, glycine receptor
  • Intracellular antigen antibodies: GAD65 (high titers clinically relevant)
  • Other antibodies: AQP4, MOG, GFAP
• Viral studies (HSV1/2 PCR, VZV PCR, IgG/IgM)
• Bacterial/fungal cultures when appropriate
• Cytology and flow cytometry
• Prion disorder panel (RTQuIC) when appropriate

Serum Testing

• Neuronal autoantibody panel (same as CSF)
  • Some antibodies more sensitive in serum (onconeuronal, LGI1, AQP4)
  • Others more sensitive in CSF (NMDAR, GFAP)
• Additional blood tests based on clinical presentation:
  • Antithyroid antibodies
  • Inflammatory markers
  • Antinuclear antibodies, extractable nuclear antigen antibodies
  • Antiphospholipid and lupus anticoagulant antibodies
  • Immunoglobulins
  • Sodium levels (hyponatremia common in LGI1-antibody encephalitis)
  • Toxicology screen, ammonia, vitamin B1/B12 levels when appropriate

Step 3: Screen for associated neoplasm

• CT chest, abdomen, and pelvis
• Mammogram/breast MRI (in women)
• Pelvic or testicular ultrasound
• Body PET if initial screen negative

Clinical Features That Suggest Autoimmune Epilepsy

An Antibody Prevalence in Epilepsy (APE) score ≥4 has 97.7% sensitivity and 77.9% specificity for predicting autoimmune epilepsy 2. Key clinical features include:

• New-onset epilepsy (especially drug-resistant)
• Autonomic dysfunction
• Viral prodrome
• Faciobrachial dystonic seizures or oral dyskinesia
• Inflammatory CSF profile
• Mesial temporal MRI abnormalities
• Multifocal seizures or seizure semiologies that change over time 3
• Seizures that fail to respond to conventional antiepileptic drugs

Important Considerations

• Collect blood samples before treatment with intravenous immunoglobulins or plasmapheresis to avoid false results 1
• GAD65 antibodies are clinically relevant at high titers but usually irrelevant at low titers 1
• Early immunotherapy initiation (within 4 months of seizure onset) is associated with better outcomes 3
• Patients with voltage-gated potassium channel complex antibodies have better response to treatment compared to those with GAD65 antibodies 4
• In children, neuronal surface antibodies (NMDAR, VGKC-complex) and GAD antibodies are present in a proportion of suspected autoimmune epilepsy cases and may define a treatable subgroup 5

Pitfalls to Avoid

• Relying solely on serum testing without CSF analysis (some antibodies are more sensitive in CSF)
• Delaying immunotherapy while waiting for antibody results in patients with high clinical suspicion
• Misinterpreting a normal CSF analysis as excluding autoimmune epilepsy (routine CSF studies may be normal in some patients)
• Failing to recognize that autoimmune epilepsy can occur beyond the spectrum of recognized syndromes like limbic encephalitis and NMDAR encephalitis 5
• Not distinguishing between acute autoimmune encephalitis with seizures and autoimmune encephalitis-associated epilepsy, which may require different treatment approaches 6

By following this comprehensive testing approach, clinicians can identify patients with autoimmune epilepsy who may benefit from immunotherapy, potentially improving seizure control and overall outcomes.