autoimmune encephalitis

**Definition:** Immune-mediated inflammation of the brain (mainly gray matter/limbic system) with autoantibodies against neuronal antigens. Infectious causes (HSV, etc.) must be excluded, and the two can coexist (HSV encephalitis can trigger anti-NMDAR encephalitis).

**Pathophysiology:** - *Antibodies to cell-surface/synaptic antigens* (direct pathogenic, IgG, usually antibody-mediated receptor internalization/dysfunction, generally T-cell independent, **more treatment-responsive**, lower neuronal death): NMDAR, LGI1, CASPR2, AMPAR, GABA-B receptor, GABA-A receptor, DPPX, IgLON5, mGluR5. - *Antibodies to intracellular antigens* (classic paraneoplastic; T-cell mediated cytotoxicity, **poorer response, irreversible neuronal loss**): anti-Hu (ANNA-1; small cell lung cancer), anti-Ma2 (testicular cancer; limbic/brainstem/diencephalic), anti-CV2/CRMP5, anti-amphiphysin, anti-GAD65 (often non-paraneoplastic; stiff-person, epilepsy, cerebellar ataxia).

**Key syndromes (high-yield):** - **Anti-NMDAR encephalitis:** Most common. Young women (median ~21 yr), often with **ovarian teratoma** (screen with pelvic MRI/US; testicular teratoma in males). Prodromal flu-like illness → prominent psychiatric features (psychosis, agitation, catatonia, insomnia) → memory deficits, seizures, decreased consciousness, **orofacial dyskinesias** (and other abnormal movements), autonomic instability (tachycardia, hypoventilation, labile BP, hyperthermia), central hypoventilation. Antibodies against GluN1 subunit; **CSF antibodies are more sensitive/specific than serum**. CSF: lymphocytic pleocytosis, oligoclonal bands. MRI is often normal. EEG: **extreme delta brush** (characteristic but not sensitive). - **Anti-LGI1 (VGKC-complex):** Older men; **faciobrachial dystonic seizures**, limbic encephalitis, **hyponatremia (SIADH)**, REM sleep behavior disorder. Responds well to immunotherapy; usually not paraneoplastic. - **Anti-CASPR2:** Morvan syndrome (neuromyotonia, insomnia, dysautonomia, encephalopathy); thymoma association. - **Anti-GABA-B:** Limbic encephalitis with prominent refractory seizures; associated with small cell lung cancer. - **Anti-AMPAR:** Limbic encephalitis; associated with thymoma, lung, breast cancer. - **Anti-Hu:** Limbic encephalitis, sensory neuronopathy, cerebellar degeneration; small cell lung cancer. - **Anti-Ma2:** Testicular germ cell tumors; limbic/brainstem encephalitis with hypersomnia. - **Anti-IgLON5:** Sleep disorder (NREM/REM parasomnia, stridor), bulbar dysfunction, tauopathy. - **Limbic encephalitis (general):** Subacute memory loss, confusion, seizures, mood change; **bilateral medial temporal lobe T2/FLAIR hyperintensity** on MRI.

**Diagnosis:** Subacute onset (<3 months) of working memory deficits, altered mental status, or psychiatric symptoms plus ≥1 of: new focal CNS findings, seizures not explained by prior seizure disorder, CSF pleocytosis, MRI suggestive of encephalitis; with reasonable exclusion of alternative causes. Workup: CSF (cell count, protein, oligoclonal bands, HSV PCR, antibody panel), serum antibodies, MRI brain, EEG, and **tumor screening** (CT chest/abdomen/pelvis, pelvic/testicular US or MRI, ± PET).

**Management:** - First-line: IV methylprednisolone, IVIG, and/or plasmapheresis. - Second-line (if no response in ~2 weeks): rituximab, cyclophosphamide. - **Tumor resection** when present (improves outcome). - Supportive care: seizure control, ICU for autonomic instability/hypoventilation; antipsychotics used cautiously. - Early treatment improves prognosis; relapses can occur (~12–25% in anti-NMDAR).

**Boards pearls:** - Young woman + acute psychosis + seizures + dyskinesias + autonomic instability → anti-NMDAR → look for ovarian teratoma. - Faciobrachial dystonic seizures + hyponatremia → anti-LGI1. - Surface antibody = treatable/reversible; intracellular antibody = T-cell mediated, paraneoplastic, poor response. - Differential: HSV encephalitis (temporal lobe involvement, hemorrhagic, treat empirically with acyclovir), neuroleptic malignant syndrome, primary psychiatric disorder, Creutzfeldt-Jakob disease, Hashimoto encephalopathy (SREAT; anti-TPO, steroid-responsive). - Antipsychotics may worsen symptoms in anti-NMDAR encephalitis (NMS-like reactions).