Should we still explore the possibility of autoimmune epilepsy?

Should You Still Explore Autoimmune Epilepsy?

Yes, you should absolutely continue to explore the possibility of autoimmune epilepsy, as this represents a potentially treatable cause of seizures that can significantly impact morbidity and quality of life if left undiagnosed and untreated. 1

Why Autoimmune Epilepsy Warrants Investigation

The field has evolved substantially, revealing that autoimmune mechanisms may underlie a considerable proportion of epilepsy cases previously classified as "unknown etiology." 2 Population-level evidence demonstrates that patients with autoimmune diseases have a 3.8-fold increased risk of epilepsy (5.2-fold in children), with elevated risk consistently observed across 12 different autoimmune conditions. 3

Autoimmune epilepsy is not merely an academic consideration—it represents a treatable cause of seizures where early immunotherapy can prevent cognitive dysfunction and progression to more widespread seizures. 1

Clinical Features That Should Prompt Evaluation

You should pursue autoimmune epilepsy workup when patients present with: 2, 4

• New-onset refractory seizures with subacute progressive cognitive decline
• Behavioral or psychiatric dysfunction accompanying seizures
• Distinctive seizure semiology (such as faciobrachial dystonic seizures, which respond rapidly to immunotherapy and may prevent progression to full limbic encephalitis) 1
• Seizures as an isolated feature without full encephalitis syndrome—the concept of autoimmune epilepsy as a distinct entity is now well-established 1, 4

Diagnostic Approach

Initial Antibody Screening

Most autoimmune epilepsy cases are covered by testing for NMDAR antibodies and VGKC-complex antibodies (LGI1 and CASPR2). 1 Additional commonly associated antibodies include GAD65, AMPA receptor, and GABA-B receptor antibodies. 2, 4

The gold standard for neuronal surface antibody detection is cell-based assays using transfected mammalian cells, with serum diluted 1:10 or greater (or CSF diluted 1:1 to 1:10). 1

Supporting Evidence to Look For

Beyond antibody testing, seek: 1

• CSF inflammatory changes (elevated WBC with lymphocytic predominance, elevated protein, oligoclonal bands)
• MRI findings (medial temporal lobe inflammation in ~60% of limbic encephalitis cases, though MRI can be normal) 1
• History of other autoimmune conditions or organ-specific autoimmunity
• EEG abnormalities consistent with epileptogenic activity

Important Caveats

Very low antibody titers (<1:50) can occur in unrelated conditions and may be misleading. 1 The diagnosis should integrate clinical presentation, antibody results, and response to immunotherapy rather than relying on antibodies alone.

Classification Framework

Use this algorithmic approach for diagnosis: 1

Definite autoimmune epilepsy:

• Known neuronal surface antibodies present in serum or CSF AND
• Response to immunotherapy

Probable autoimmune epilepsy:

• Known neuronal surface antibodies present OR
• Other neuronal antibody markers (GAD-Ab, unknown neuronal surface/neuropil antibodies) or clinical supportive features AND
• Response to immunotherapy

Possible autoimmune epilepsy:

• Other neuronal antibody markers or clinical supportive features OR
• Response to immunotherapy alone (when antibodies not found but clinical suspicion high)

Treatment Implications

The critical point is that autoimmune epilepsy responds to immunotherapy, not just antiepileptic drugs. 1, 4 Patients respond within weeks to intense immunotherapies with good or very good outcomes. 1

First-line treatment includes: 5

• High-dose corticosteroids (methylprednisolone 1-2 mg/kg/day)
• IVIG (0.4 g/kg/day for 5 days) or plasma exchange (5-10 sessions)
• Treatment should begin once infection is ruled out

Early recognition and treatment can prevent permanent cognitive dysfunction and progression of seizures. 1 For example, faciobrachial dystonic seizures respond rapidly to immunotherapy and treating them early may prevent the onset of full limbic encephalitis. 1

Distinguishing from Other Conditions

Do not confuse autoimmune epilepsy with the inflammatory processes seen in neurodegenerative diseases like Alzheimer's disease. 6 True autoimmune epilepsy is characterized by:

• Acute or subacute onset (typically <3 months) 6
• Specific neural autoantibodies targeting cell surface or synaptic proteins 6
• Response to immunotherapy 6

This contrasts with chronic progressive neurodegenerative conditions that have inflammatory components but are not antibody-mediated. 6

Practical Algorithm

When epilepsy etiology is unclear: 1

1. Screen for onconeural antibodies and tumors (paraneoplastic workup)
2. Test for neuronal surface antibodies (NMDAR, VGKC-complex/LGI1/CASPR2, GAD65, AMPA-R, GABA-B-R)
3. Perform lumbar puncture for CSF analysis (cell count, protein, oligoclonal bands, autoimmune encephalitis panel)
4. Obtain brain MRI with contrast
5. Consider trial of immunotherapy even while awaiting antibody results if clinical suspicion is high
6. Assess for sustained improvement (modified Rankin score improvement of ≥1 point) 1

The potential for reversible, treatable epilepsy mandates that autoimmune etiology be systematically examined in patients with unexplained seizures, particularly those with refractory epilepsy or accompanying cognitive/psychiatric features. 1, 3