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9 notes available
1 Last Minute Review 2 Multiple Sclerosis 3 Disease-Modifying Therapies 4 NMOSD & MOGAD 5 Systemic Diseases 6 Autoimmune Encephalitis 7 Paraneoplastic Syndromes 8 CNS Vasculitis 9 Other Neuroimmunology Topics
Clinical › Immunology

Autoimmune Encephalitis

Autoimmune Encephalitis

What You'll Learn

  • Two antibody classes: Cell-surface antibodies (NMDA-R, LGI1, CASPR2, GABA-B, AMPA, DPPX) are directly pathogenic, immunotherapy-responsive, and carry better prognosis; intracellular/onconeural antibodies are T-cell mediated, poorly responsive to immunotherapy, and require tumor treatment
  • Anti-NMDA-R encephalitis: Most common antibody-defined autoimmune encephalitis overall, particularly in patients <45 years; young women; ovarian teratoma (~38% overall, ~50% in women 18–45, <10% in girls <14 and males); staged progression (psychiatric → seizures → movement disorders → autonomic instability); extreme delta brush on EEG; 81% achieve mRS 0–2 at 24 months with first- and second-line therapy (Titulaer 2013)
  • Anti-LGI1: Older males; faciobrachial dystonic seizures (FBDS) are pathognomonic; hyponatremia (SIADH); AED-resistant but immunotherapy-responsive; rarely paraneoplastic
  • Graus 2016 criteria: Possible autoimmune encephalitis requires subacute onset (≤3 months) of working memory deficits, altered mental status, or psychiatric symptoms plus ≥1 of: new focal CNS findings, seizures, CSF pleocytosis, or MRI suggesting encephalitis; definite requires specific antibody
  • Always test BOTH serum AND CSF: NMDA-R antibodies may be negative in serum but positive in CSF in ~15% of cases
  • Treatment ladder: First-line (steroids + IVIg or PLEX) → second-line (rituximab, cyclophosphamide) → tumor removal when applicable → long-term immunosuppression for relapsing cases
  • Cancer screening is mandatory: CT body, pelvic/testicular ultrasound, whole-body PET-CT; repeat at 6–12 months if initially negative with cancer-associated antibody
HighYield Pearls
  • Anti-NMDAR in a young woman: Viral prodrome → psychiatric symptoms → seizures → orofacial dyskinesias → autonomic instability & central hypoventilation; ovarian teratoma in ~50% of women 18–45; CSF antibody more sensitive than serum; tumor removal is critical
  • HSV encephalitis is a known NMDAR trigger: Worsening at a median of ~27 days (weeks to a few months) after HSV → check NMDAR antibodies and treat with immunotherapy, NOT more acyclovir
  • LGI1 — older man + FBDS + hyponatremia: Faciobrachial dystonic seizures (brief, frequent, ASM-resistant) precede limbic encephalitis by weeks to months; SIADH-driven hyponatremia in ~60%; rarely paraneoplastic; treat early to prevent cognitive decline
  • CASPR2 — Morvan syndrome: Encephalopathy + neuromyotonia + severe insomnia + dysautonomia; thymoma in 30–40% of Morvan cases; only autoimmune encephalitis with simultaneous central AND peripheral involvement
  • GABA-B + refractory status epilepticus + older adult → screen for SCLC (~50–60% paraneoplastic); good immunotherapy response for encephalitis, prognosis driven by tumor
  • AMPAR = relapsing limbic encephalitis: ~60–65% paraneoplastic (SCLC, breast, thymoma); long-term immunosuppression usually required
  • DPPX — prodromal diarrhea/weight loss + encephalopathy + hyperekplexia/myoclonus/PERM: GI prodrome is nearly unique; minimal tumor association
  • High-titer GAD65 (>10,000 IU/mL or >20 nmol/L): Stiff-person syndrome, cerebellar ataxia, temporal lobe epilepsy ± type 1 diabetes; intracellular target → poor immunotherapy response; low titers are non-specific
  • IgLON5 = parasomnia + sleep-disordered breathing + bulbar dysfunction + gait/chorea: Tauopathy at autopsy; the major exception to the “cell-surface = immunotherapy-responsive” rule
  • GFAP astrocytopathy: Meningoencephalomyelitis with linear radial perivascular gadolinium enhancement in white matter; steroid-responsive
  • Surface vs intracellular is the highest-yield distinction: Surface (NMDAR, LGI1, CASPR2, GABA-B, AMPA, DPPX, GFAP) = pathogenic, reversible, immunotherapy-responsive; Intracellular (Hu, Yo, Ri, Ma2, CV2/CRMP5, amphiphysin, GAD) = T-cell mediated, irreversible, strongly paraneoplastic
  • Treatment ladder: First-line steroids + IVIg or PLEX + tumor screen/removal → second-line rituximab or cyclophosphamide; ICU support for autonomic instability/central hypoventilation in NMDAR
🔍 Quick ReferenceClinical · Imaging / EEG · Antibody / tumor associations
Clinical phenotype
  • Orofacial dyskinesias + autonomic storm + central hypoventilation in a young woman → anti-NMDAR
  • Faciobrachial dystonic seizures (FBDS) + hyponatremia in older man → anti-LGI1
  • Morvan syndrome (encephalopathy + neuromyotonia + insomnia + dysautonomia) → anti-CASPR2
  • Refractory status epilepticus in older adult with limbic encephalitis → anti-GABA-B
  • Relapsing limbic encephalitis → anti-AMPAR
  • PERM (progressive encephalomyelitis with rigidity & myoclonus) / hyperekplexia + prodromal diarrhea → anti-DPPX (also GlyR)
  • Stiff-person syndrome → anti-GAD65 (non-paraneoplastic) or anti-amphiphysin (paraneoplastic, breast)
  • Non-REM + REM parasomnia + sleep-disordered breathing + bulbar dysfunction → anti-IgLON5
  • Subacute cerebellar degeneration in woman with breast/ovarian cancer → anti-Yo (PCA-1)
  • Opsoclonus-myoclonus syndrome in an adult → anti-Ri (ANNA-2)
  • Brainstem/diencephalic encephalitis + narcolepsy-like hypersomnia + vertical gaze palsy in young man → anti-Ma2
  • Sensory neuronopathy + limbic encephalitis + autonomic neuropathy in smoker → anti-Hu (ANNA-1)
    • Imaging / EEG signs
  • Extreme delta brush on EEG → anti-NMDAR
  • Normal MRI in ~50% despite florid encephalopathy → anti-NMDAR
  • Bilateral mesial temporal T2/FLAIR hyperintensity (limbic encephalitis pattern) → LGI1, GABA-B, AMPA (and HSV mimicker)
  • Multifocal cortical FLAIR + refractory status → anti-GABA-A
  • Linear radial perivascular gadolinium enhancement in white matter → anti-GFAP astrocytopathy
  • Striatal T2 hyperintensity → anti-DPPX or anti-CV2/CRMP5 (chorea)
  • Diencephalic / hypothalamic / brainstem T2/FLAIR → anti-Ma2
    • Antibody / tumor associations
  • Anti-NMDAR + ovarian teratoma → anti-NMDAR encephalitis (young women)
  • Anti-LGI1 (rarely thymoma) → FBDS + limbic encephalitis + SIADH
  • Anti-CASPR2 + thymoma → Morvan syndrome
  • Anti-GABA-B + SCLC → limbic encephalitis with status epilepticus
  • Anti-AMPA + thymoma / lung / breast → relapsing limbic encephalitis
  • Anti-Ma2 + testicular germ cell tumor → limbic/diencephalic/brainstem encephalitis (young men)
  • Anti-Yo (PCA-1) + ovarian/breast → paraneoplastic cerebellar degeneration
  • Anti-Hu (ANNA-1) + SCLC → sensory neuronopathy, limbic encephalitis, autonomic neuropathy
  • Anti-Ri (ANNA-2) + breast / SCLC → opsoclonus-myoclonus / brainstem encephalitis
  • Anti-CV2 / CRMP5 + SCLC or thymoma → chorea + optic neuritis + peripheral neuropathy
  • Anti-amphiphysin + breast → SPS-like syndrome (paraneoplastic SPS)
  • Anti-Tr / DNER + Hodgkin lymphoma → paraneoplastic cerebellar degeneration
Classification — Cell-Surface vs. Intracellular Antibodies

Fundamental Distinction

The single most important distinction in autoimmune encephalitis is antibody target location — this determines pathogenesis, treatment strategy, cancer association, and prognosis.

Feature Cell-Surface Antibodies Intracellular/Onconeural Antibodies
Targets NMDA-R, LGI1, CASPR2, GABA-B, GABA-A, AMPA, DPPX, IgLON5 Hu (ANNA-1), Yo (PCA-1), Ri (ANNA-2), CV2/CRMP5, amphiphysin, Ma2
Pathogenic mechanism Directly pathogenic — receptor internalization, blockade, complement-mediated damage T-cell mediated cytotoxicity — antibodies are biomarkers, not direct effectors
Neuronal damage Potentially reversible — receptor dysfunction without neuronal death Irreversible — cytotoxic T cells destroy neurons
Cancer association Variable: NMDA-R (teratoma ~38% overall, ~50% in women 18–45); GABA-B (SCLC ~50–60%); LGI1 (<5%) Strongly paraneoplastic: Hu (SCLC >80%); Yo (ovarian/breast); amphiphysin (breast, SCLC)
Immunotherapy response Often excellent — >70% improve with first-line immunotherapy Usually limited — neuronal damage is irreversible
Primary treatment strategy Immunotherapy ± tumor removal Tumor removal is primary; immunotherapy is adjunctive
Prognosis Generally favorable with prompt treatment Guarded — depends on tumor status and extent of neuronal loss
💎 Board Pearl
  • Cell-surface = treatable, intracellular = search for tumor — this is the highest-yield distinction on boards
  • Cell-surface antibodies cause receptor dysfunction (reversible) while intracellular antibodies mark T-cell-mediated neuronal death (irreversible)
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