What immune work‑up should be obtained when febrile infection‑related epilepsy syndrome (FIRES) is suspected?

Immune Work-Up for Suspected FIRES

When FIRES is suspected, obtain comprehensive CSF analysis including cell count, protein, glucose, oligoclonal bands, IgG index, and neuronal autoantibodies, along with serum neuronal autoantibodies and cytokine profiling, while simultaneously ruling out infectious and neoplastic causes. 1

Core Diagnostic Testing

Cerebrospinal Fluid Analysis

• Perform lumbar puncture immediately to support inflammatory etiology and exclude infectious/neoplastic causes 1
• Test for:
  • Cell count and differential (lymphocytic pleocytosis supports autoimmune etiology) 1
  • Protein and glucose levels 1
  • Oligoclonal bands 1
  • IgG index and IgG synthesis rate 1
  • CSF-specific oligoclonal bands 1
  • Neuronal autoantibodies in CSF (including NMDAR, AMPA, GABA-B receptors, LGI1, CASPR2, and GAD antibodies) 1, 2

Serum Testing

• Neuronal autoantibodies in serum (same panel as CSF) 1
• Cytokine profiling should be performed early in the clinical course, as this can guide targeted immunotherapy 3, 4
  • Elevated IL-6, IL-1RA, monocyte chemoattractant protein-1, macrophage inflammatory protein 1β, and interferon γ may indicate cytokine release syndrome 3
  • Serial cytokine profiles can monitor treatment response 3

Additional Immunological Investigations

Screening for Onconeural Antibodies

• Screen for onconeural antibodies in all cases, as these conditions can associate with tumors 1
• If positive or if tumor found, classify as paraneoplastic neurological syndrome 1

Advanced Antibody Testing

• Immunohistochemistry on rat brain slices should be considered when standard antibody panels are negative, as novel anti-neuronal antibodies may be detected 5
• This is particularly important since approximately 50% of FIRES cases remain cryptogenic despite standard testing 6, 7

Critical Caveats

Timing Considerations

• Do not delay immunotherapy while awaiting antibody results 1
• Antibody testing is frequently negative in FIRES (all tested antibodies were negative in one cohort of 12 patients) 2
• The absence of detectable autoantibodies does not exclude FIRES or preclude immunotherapy 2

Interpretation Pitfalls

• Very low antibody titers (<1:50) can be found in patients with unrelated conditions and may be misleading 1
• Positive antibodies alone do not confirm diagnosis; clinical context and immunotherapy response are essential 1

Exclusion of Alternative Diagnoses

Rule Out Infectious Causes

• Basic CSF results (cell count) must exclude infection before starting immunotherapy 1
• Complete infectious workup including viral PCR panels 1

Rule Out Other Etiologies

• Exclude metabolic, toxic, traumatic, demyelinating, or structural causes 1
• Consider mitochondrial encephalopathy in the differential, particularly when antibody testing is negative 2

Diagnostic Classification Framework

Once testing is complete, classify as:

• Definite autoimmune: Known neuronal surface antibodies present AND response to immunotherapy 1
• Probable autoimmune: Known antibodies OR other neuronal antibody markers (GAD-Ab, unknown neuronal surface antibodies) with clinical supportive features AND immunotherapy response 1
• Possible autoimmune: Other neuronal antibody markers or supportive features present OR immunotherapy response, even without identified antibodies 1