Autoimmune Epilepsy
Autoimmune Epilepsy
What Do You Need to Know?
- 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
🚩 Don’t Miss — Test-Day Priorities
- 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
🔍 Buzzwords & Pathognomonic FindingsClinical / 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
APE2 Score & RITE2 Score
APE2 Score: Antibody Prevalence in Epilepsy and Encephalopathy
| Clinical Feature | Points |
|---|---|
| New-onset seizure (within 1 year of evaluation) | +1 |
| Neuropsychiatric changes (cognitive or behavioral) | +1 |
| Autonomic dysfunction | +1 |
| Viral prodrome | +2 |
| Faciobrachial dystonic seizures | +3 |
| Facial dyskinesias or orolingual dyskinesias | +2 |
| Refractory status epilepticus (no prior epilepsy history) | +2 |
| CSF findings (pleocytosis, elevated protein, or oligoclonal bands) | +2 |
| Brain MRI suggesting autoimmune encephalitis (mesial temporal T2/FLAIR hyperintensity) | +2 |
| History of autoimmune disease (personal) | +1 |
| Total score ≥4: autoimmune evaluation recommended | — |
APE2 Score Performance
- APE2 ≥4 = 97.7% sensitivity, ~82% specificity for positive neural-specific antibodies (Dubey 2017 Epilepsia)
- Excellent screening tool with high negative predictive value
- When APE2 ≥4 is combined with immunotherapy response: 78% sensitivity, 81.4% specificity, 88.1% PPV
RITE2 Score (Response to ImmunoTherapy in Epilepsy)
- RITE2 ≥7 = 93% sensitivity, 60% specificity for predicting seizure response to immunotherapy
- Incorporates APE2 components plus additional clinical and paraclinical features
- Patients with APE2 ≥4 but negative antibodies are candidates for empiric immunotherapy trial
💎 Board Pearl
- APE2 ≥4 = send autoimmune panel. FBDS alone scores +3 — add any one additional feature (new-onset seizure, neuropsychiatric change, autonomic dysfunction) and you meet the threshold
Clinical Clues Suggesting Autoimmune Etiology
When to Suspect Autoimmune Epilepsy
- New-onset refractory seizures in a previously healthy person (especially young adult)
- Faciobrachial dystonic seizures — virtually pathognomonic for LGI1
- Limbic encephalitis features: subacute memory loss, psychiatric symptoms, MRI mesial temporal T2/FLAIR hyperintensity
- Multifocal seizures without a clear structural cause
- Rapid progression over days to weeks with drug-resistant seizures
- Associated autoimmune disease (thyroid disease, type 1 diabetes, celiac disease)
- Ovarian teratoma or other malignancy in setting of new neurological symptoms
- Psychiatric symptoms disproportionate to seizure burden (psychosis, personality change)
- Movement disorders (orofacial dyskinesias, chorea) accompanying seizures
- Hyponatremia without other clear cause — think LGI1
Diagnostic Workup
Systematic Evaluation
- Testing should be performed before immunotherapy whenever possible — treatment may reduce antibody titers and cause false negatives
| Test | Details | Key Considerations |
|---|---|---|
| Serum antibody panel | NMDA-R, LGI1, CASPR2, GABA-B, GABA-A, AMPA, DPPX; GAD65 (quantitative); ANNA-1/Hu, CV2/CRMP5, amphiphysin | Cell-based assays preferred for surface antibodies |
| CSF antibody panel | Same as serum + oligoclonal bands, IgG index, cytology | Always send BOTH serum and CSF — NMDA-R may be negative in serum but positive in CSF in ~15%; CSF is more sensitive than serum for NMDA-R (CSF positive ~100% vs serum ~85%) — always send both |
| CSF routine | Cell count, protein, glucose, cultures, HSV/VZV PCR | Lymphocytic pleocytosis (10–100 cells) common; must exclude infectious encephalitis |
| Brain MRI | Epilepsy protocol with coronal FLAIR through temporal lobes | Mesial temporal T2/FLAIR hyperintensity (LGI1, GABA-B); multifocal cortical lesions (GABA-A); may be normal in up to 50% |
| EEG | Continuous video-EEG if encephalopathic; routine EEG otherwise | Extreme delta brush (NMDA-R); temporal IEDs; subclinical seizures |
| Cancer screening | Whole-body CT or PET/CT | Mandatory in all patients; repeat at 6–12 months if initial negative with cancer-associated antibody |
| Sex-specific imaging | Pelvic MRI/ultrasound (women); testicular ultrasound (men) | Ovarian teratoma (NMDA-R in women); testicular germ cell tumor (men with NMDA-R) |
Treatment
First-Line Immunotherapy
- IV methylprednisolone: 1 g/day × 5 days, then oral prednisone taper over 3–6 months
- IVIg: 0.4 g/kg/day × 5 days (total 2 g/kg); may repeat monthly
- PLEX: 5–7 exchanges on alternate days; most effective for cell-surface antibodies; consider first-line in fulminant presentations
- First-line agents are typically combined (steroids + IVIg or steroids + PLEX)
Second-Line Immunotherapy
- Rituximab: 375 mg/m2 weekly ×4 or 1000 mg ×2 (2 weeks apart); B-cell depletion within 2–4 weeks; preferred first second-line agent
- Cyclophosphamide: IV pulse 750 mg/m2 monthly × 3–6; reserved for rituximab-refractory cases; significant toxicity
- Add if no clinical improvement after ~10–14 days of first-line therapy (Titulaer 2013)
Tumor Removal
- Essential when paraneoplastic etiology identified — immunotherapy alone is often insufficient
- Ovarian teratoma resection in NMDA-R encephalitis
- Thymectomy for thymoma-associated CASPR2 or AMPA
- SCLC treatment for GABA-B, AMPA, ANNA-1 syndromes
Long-Term Immunosuppression
- Rituximab: every 6 months, guided by CD19/CD20 recovery or clinical relapse
- Mycophenolate mofetil: 1000–1500 mg BID; onset 2–3 months; steroid-sparing
- Azathioprine: 2–3 mg/kg/day; onset 3–6 months; check TPMT genotype
- Continue immunotherapy ≥1–2 years; taper ASMs cautiously after sustained seizure freedom
Relapse Rates
- NMDA-R: 12–20% relapse; higher if tumor not removed or no second-line therapy given; ~81% achieve good outcome (mRS 0–2) at 24 months with first- and second-line therapy (Titulaer 2013)
- LGI1: 20–35% relapse; most during steroid taper; many require prolonged immunosuppression
- GAD65: poor immunotherapy response overall; chronic ASMs usually required
Seronegative Autoimmune Epilepsy
- Up to 40–50% of suspected autoimmune epilepsy cases are antibody-negative
- Does NOT exclude the diagnosis — novel antibodies continue to be discovered
- Empiric immunotherapy trial warranted if APE2 ≥4 and clinical suspicion high
- Response to immunotherapy supports diagnosis of probable autoimmune epilepsy
- Trial should be of adequate duration (at least 3–6 months) with escalation through first- and second-line agents
Diagnostic Classification
- Definite: APE2 ≥4 + positive validated neural antibody
- Probable: APE2 ≥4 + negative antibodies + clinical response to immunotherapy
- Possible: APE2 ≥4 + negative antibodies + immunotherapy not yet attempted or response inconclusive
Board Pearls & Clinical Pearls
💎 Board Pearl
- FBDS = LGI1 until proven otherwise — brief (<3 sec), frequent (up to 100/day), ASM-resistant, immunotherapy-responsive; pathognomonic for LGI1 antibody encephalitis
- Extreme delta brush on EEG = NMDA-R encephalitis — rhythmic delta activity at 1–3 Hz with superimposed bursts of beta activity; seen in ~30% of NMDA-R cases; low sensitivity — absence does not exclude NMDA-R
- Hyponatremia + seizures + older adult = think LGI1 — hyponatremia occurs in 60–70% of LGI1 encephalitis due to SIADH
- Post-HSV worsening at 2–6 weeks = NMDA-R antibodies — not HSV relapse; requires immunotherapy, not more acyclovir
- Multifocal cortical FLAIR + status epilepticus = GABA-A — unique MRI pattern distinguishing GABA-A from other autoimmune encephalitides
- Cell-surface = treatable, intracellular = search for tumor — the single most important distinction in autoimmune epilepsy is the antibody target location
- GAD65 titers <20 nmol/L are NOT specific for autoimmune epilepsy — found in 5–8% of the general population (type 1 diabetes); only high titers (≥20 nmol/L) are meaningful
Clinical Pearl
Do not delay immunotherapy while awaiting antibody results in patients with rapidly progressive encephalopathy, refractory status epilepticus, or high clinical suspicion (APE2 ≥4). Early treatment is associated with significantly better seizure and cognitive outcomes, particularly for NMDA-R and LGI1 encephalitis. Obtain samples before treatment whenever possible, but treatment should not be withheld for pending results.
Clinical Pearl
FBDS as an early treatment window: Faciobrachial dystonic seizures typically precede cognitive decline and full limbic encephalitis by weeks to months. Recognizing FBDS and initiating immunotherapy at this stage may prevent progression to overt encephalitis with memory impairment — one of the few scenarios where a specific seizure semiology directly dictates immune-targeted treatment that can alter disease course.
Clinical Pearl
Paraneoplastic cancer screening should not stop after one negative scan. Repeat imaging at 6-month intervals for at least 2 years in patients with high-risk antibody profiles (ANNA-1, CV2, GABA-B). Tumors may be occult at initial presentation. PET/CT has higher sensitivity than CT alone for small tumors.
References
- Dubey D, Pittock SJ, Kelly CR, et al. Autoimmune encephalitis epidemiology and a comparison to infectious encephalitis. Ann Neurol 2018;83(1):166–177.
- Dubey D, Singh J, Britton JW, et al. Predictive models in the diagnosis and treatment of autoimmune epilepsy. Epilepsia 2017;58(7):1181–1189.
- Dalmau J, Graus F. Antibody-mediated encephalitis. N Engl J Med 2018;378(9):840–851.
- Graus F, Titulaer MJ, Balu R, et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol 2016;15(4):391–404.
- Irani SR, Michell AW, Lang B, et al. Faciobrachial dystonic seizures precede LGI1 antibody limbic encephalitis. Ann Neurol 2011;69(5):892–900.
- Titulaer MJ, McCracken L, Gabilondo I, et al. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis. Lancet Neurol 2013;12(2):157–165.
- Toledano M, Britton JW, McKeon A, et al. Utility of an immunotherapy trial in evaluating patients with presumed autoimmune epilepsy. Neurology 2014;82(18):1578–1586.
- de Bruijn MAAM, Bastiaansen AEM, Thijs RD, et al. Antibody prevalence in epilepsy and encephalopathy score: increased immunotherapy utilization and improved outcome. Neurology 2022;98(11):e1167–e1178.
- Bien CG, Holtkamp M. Autoimmune epilepsy: encephalitis with autoantibodies for neurologists. Epilepsy Curr 2017;17(3):134–141.
- Scheffer IE, Berkovic S, Capovilla G, et al. ILAE classification of the epilepsies: position paper. Epilepsia 2017;58(4):512–521.
- Finke C, Pruss H, Heine J, et al. Evaluation of cognitive deficits and structural hippocampal damage in encephalitis with leucine-rich, glioma-inactivated 1 antibodies. JAMA Neurol 2017;74(1):50–59.
- Falip M, Rodriguez-Bel L, Casasnovas C, et al. Prevalence and immunological spectrum of temporal lobe epilepsy with glutamic acid decarboxylase antibodies. Eur J Neurol 2012;19(6):827–833.
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