Autoimmune Epilepsy
Autoimmune Epilepsy
What You'll Learn
- Prevalence: Autoimmune etiologies account for ~5–7% of all epilepsies and up to 20% of epilepsies of unknown cause
- Two antibody classes: Cell-surface antibodies (NMDA-R, LGI1, CASPR2, GABA-B, GABA-A, AMPA) are directly pathogenic and treatment-responsive; intracellular antibodies (GAD65, ANNA-1/Hu, CV2/CRMP5, amphiphysin) are T-cell mediated, poorly immunotherapy-responsive, and strongly paraneoplastic
- Clinical clues: Subacute onset, drug-resistant seizures, new psychiatric symptoms, FBDS, hyponatremia, autonomic dysfunction, temporal FLAIR changes
- APE2 score ≥4: 97% sensitivity for predicting positive neural-specific antibodies — validated screening tool
- Treatment paradigm: Immunotherapy (steroids, IVIg, PLEX) targets the cause; ASMs alone are often insufficient; early treatment improves outcomes
- Seronegative cases: Up to 40–50% of suspected autoimmune epilepsy is antibody-negative; empiric immunotherapy trial warranted if APE2 ≥4
HighYield Pearls
- APE2 ≥4 / RITE2 ≥7: Screen for autoimmune epilepsy — 97% sensitivity; key clues are subacute onset (<1 yr), drug-resistance, encephalopathy, psychiatric/autonomic features, viral prodrome, cancer history, autoimmune comorbidity
- LGI1 = FBDS + hyponatremia: Faciobrachial dystonic seizures (brief asymmetric arm/face jerks, up to 100/day, ASM-resistant) in an older man with SIADH-related hyponatremia — treat early to prevent limbic encephalitis; rarely paraneoplastic
- NMDAR = young woman + ovarian teratoma: Psychiatric onset → seizures → orofacial dyskinesias → autonomic instability; extreme delta brush on EEG; pelvic US/MRI for teratoma is mandatory
- GABA-B = SCLC + status epilepticus: Severe drug-resistant focal seizures and limbic encephalitis in older smoker — chest CT/PET for SCLC
- CASPR2 = Morvan / thymoma: Encephalopathy + insomnia + neuromyotonia + autonomic dysfunction — screen chest CT for thymoma
- GAD65 high-titer (>10× ULN or >100,000 U/mL): Drug-resistant TLE ± stiff person syndrome, type 1 DM, cerebellar ataxia; low titer = nonspecific (DM, thyroid)
- Rasmussen encephalitis: Child with progressive unilateral hemispheric atrophy + epilepsia partialis continua + hemiparesis + cognitive decline — hemispherotomy/hemispherectomy is definitive
- SREAT (Hashimoto encephalopathy): Encephalopathy + seizures + myoclonus + stroke-like episodes with high anti-TPO/Tg; dramatic steroid response is the hallmark (titers alone are not pathognomonic)
- Treatment ladder: First-line steroids (methylpred 1 g × 5 d) + IVIG (2 g/kg) or PLEX; second-line rituximab or cyclophosphamide; maintenance mycophenolate/azathioprine + treat underlying tumor
- Seronegative responders: ~50% of antibody-negative suspected autoimmune epilepsy respond to empiric immunotherapy when APE2 ≥4 — do not wait for antibody confirmation
🔍 Quick ReferenceClinical / semiology · Antibody / imaging / EEG · Treatment
Clinical / semiology
- Faciobrachial dystonic seizures (FBDS) → LGI1 encephalitis
- Orofacial dyskinesias + psychiatric prodrome in young woman → NMDAR encephalitis (ovarian teratoma)
- Morvan syndrome (encephalopathy + insomnia + neuromyotonia + autonomic) → CASPR2 (thymoma)
- Epilepsia partialis continua + progressive hemiparesis in a child → Rasmussen encephalitis
- Stiff person syndrome + drug-resistant TLE + type 1 DM → GAD65
- Progressive encephalomyelitis with rigidity and myoclonus (PERM) → GlyR antibody
- Opsoclonus-myoclonus in a toddler → Neuroblastoma (OMS); in adult woman → anti-Ri (breast/SCLC)
- Encephalopathy + myoclonus + stroke-like episodes + dramatic steroid response → SREAT / Hashimoto encephalopathy
Antibody / imaging / EEG
- Extreme delta brush on EEG → NMDAR encephalitis
- Hyponatremia (SIADH) + limbic encephalitis in older man → LGI1
- Mesial temporal T2/FLAIR hyperintensity → Limbic encephalitis (LGI1, GABA-B, AMPA, GAD65, Ma2)
- Unilateral hemispheric atrophy on MRI → Rasmussen encephalitis
- GAD65 titer >10× ULN or >100,000 U/mL → Autoimmune-relevant (vs. low-titer DM/thyroid)
- CSF lymphocytic pleocytosis + oligoclonal bands + cell-based antibody panel positive → Autoimmune encephalitis
- Temporal lobe hypermetabolism on PET (early) / hypometabolism (late) → Autoimmune limbic encephalitis
- Mayo PAVAL/RAVE panel (NMDAR/LGI1/CASPR2/GABA-B/AMPA/DPPX/IgLON5/GlyR; ANNA-1/Hu, Ri, Yo, Ma2, CV2/CRMP5, amphiphysin) → Serum + CSF testing standard
Treatment / pearls
- APE2 ≥4 / RITE2 ≥7 → High probability of autoimmune etiology / immunotherapy response
- Methylprednisolone 1 g × 5 d + IVIG 2 g/kg or PLEX → First-line immunotherapy
- Rituximab or cyclophosphamide → Second-line for refractory autoimmune encephalitis
- Mycophenolate / azathioprine → Maintenance immunotherapy
- Hemispherotomy / hemispherectomy → Definitive treatment for Rasmussen encephalitis
- Tumor screen (PET-CT, mammogram, pelvic/testicular US) → Mandatory in suspected paraneoplastic syndromes
- FBDS often resistant to ASMs, responsive to steroids/IVIG → LGI1 pearl
- Empiric immunotherapy trial → Seronegative autoimmune epilepsy with APE2 ≥4 (~50% respond)
Antibody Classification
Cell-Surface vs. Intracellular Antibodies
| Feature | Cell-Surface Antibodies | Intracellular Antibodies |
|---|---|---|
| Targets | NMDA-R, LGI1, CASPR2, GABA-B, GABA-A, AMPA | GAD65, ANNA-1 (Hu), CV2/CRMP5, amphiphysin |
| Pathogenic mechanism | Directly pathogenic — receptor internalization, blockade, or complement-mediated damage | T-cell mediated cytotoxicity — antibodies are biomarkers, not direct effectors |
| Cancer association | Variable: NMDA-R (ovarian teratoma 20–50% in women); GABA-B (SCLC ~50%); AMPA (SCLC, breast, thymoma); LGI1 rarely paraneoplastic | Strongly paraneoplastic: ANNA-1 (SCLC >80%); CV2 (SCLC, thymoma); amphiphysin (breast, SCLC) |
| Immunotherapy response | Often excellent — >70% improve with first-line immunotherapy | Usually limited — neuronal damage is irreversible; tumor removal is primary treatment |
| Prognosis | Generally favorable with prompt immunotherapy | Guarded — depends on tumor status and extent of neuronal loss |
Key Antibodies & Clinical Syndromes
| Antibody | Seizure Prevalence | Hallmark Feature | Cancer Association |
|---|---|---|---|
| NMDA-R | 70–80% | Stereotyped progression: psychiatric onset → seizures → movement disorder (orofacial dyskinesias) → autonomic instability → decreased consciousness/coma; extreme delta brush on EEG | Ovarian teratoma (20–50% in women); rare in men/children |
| LGI1 | >90% | FBDS pathognomonic — <3 sec, up to 100/day, ASM-resistant, immunotherapy-responsive; hyponatremia 60–70%; may prevent limbic encephalitis if treated early | Rare (~5–10%); no consistent tumor association |
| CASPR2 | 30–50% | Morvan syndrome: insomnia + autonomic dysfunction + neuromyotonia + encephalopathy; older males predominate | Thymoma ~20% overall; up to 40% in Morvan syndrome phenotype |
| GABA-B | >90% | Early refractory seizures, often temporal; status epilepticus common; older adults | SCLC (~50%) |
| GABA-A | >90% | Refractory status epilepticus; multifocal cortical FLAIR abnormalities on MRI; rapidly progressive encephalopathy | Thymoma (occasional); often non-paraneoplastic |
| AMPA | 40–60% | Limbic encephalitis with relapsing course; memory impairment | SCLC, breast, thymoma (~60–65%) |
| GAD65 | Variable | Only high titers (≥20 nmol/L by RIA, or >1000 IU/mL by ELISA) — assay-dependent; associated with stiff-person syndrome, cerebellar ataxia, drug-resistant TLE; poor immunotherapy response | Rarely paraneoplastic |
Faciobrachial Dystonic Seizures (FBDS)
- Virtually pathognomonic for LGI1 antibody encephalitis
- Brief (<3 sec), very frequent (up to 100/day) dystonic contractions of face + ipsilateral arm
- Often precede cognitive decline by weeks to months — critical early treatment window
- ASM-resistant but respond rapidly to immunotherapy (corticosteroids, IVIg)
- EEG may be normal in >50% — frequently misdiagnosed as myoclonus, tics, or PNES
- Prompt immunotherapy may prevent progression to full limbic encephalitis
Post-HSV NMDA-R Encephalitis
- NMDA-R antibodies develop 2–6 weeks after HSV encephalitis due to exposure of neuronal antigens during viral tissue destruction
- Presents as clinical worsening weeks after initial HSV improvement
- Always test for HSV before attributing relapse solely to autoimmune encephalitis
- Requires immunotherapy, not additional antiviral treatment
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