Autoimmune Encephalitis

• Antibody-Mediated Mechanisms: Pathogenic antibodies bind to neuronal surface antigens (e.g., NMDA receptor, AMPA receptor, GABA-B receptor), leading to complement activation, antibody-dependent cellular cytotoxicity (ADCC), and receptor internalization. This results in decreased synaptic transmission and neuronal hyperexcitability. IgG antibodies cross the blood-brain barrier and directly target extracellular epitopes on ion channels and receptors. Cross-linking of surface receptors leads to their removal from the synapse via endocytosis, effectively reducing synaptic transmission. In severe cases, complement-mediated destruction of neuronal membranes occurs (classical pathway activation, C3/C5b-9 deposition).

• T Cell-Mediated Mechanisms: Cytotoxic CD8+ T lymphocytes recognize intracellular antigens (e.g., Hu, Yo, CRMP5) presented on MHC class I molecules, leading to direct neuronal destruction via granzyme/perforin pathways. CD4+ T helper cells contribute through Th1 and Th17 differentiation, producing pro-inflammatory cytokines (IFN-γ, IL-17, TNF-α) that activate microglia and perpetuate inflammation. This T cell-dominant pattern is typical of paraneoplastic encephalitis and intracellular antigen-associated disease.

• Neuroinflammatory Cascade: Activation of resident microglia and recruitment of peripheral immune cells (macrophages, dendritic cells, T cells) create a pro-inflammatory microenvironment. Cytokine release (IL-6, TNF-α, IL-1β) increases blood-brain barrier permeability, facilitates leukocyte infiltration, and causes neuronal excitotoxicity. Glutamate excitotoxicity results from both impaired reuptake and direct release from activated immune cells. Additionally, NMDAR antibodies may potentiate NMDA receptor dysfunction independent of complement, causing calcium dysregulation and neuronal death via excitotoxic mechanisms.

Surface Antigen-Associated (Potentially Reversible)

• NMDA Receptor (NMDAR) Encephalitis: Most common form; ~40% of autoimmune encephalitis cases. Strong female predominance (2-3:1). Association with ovarian teratomas in 40-60% of female patients; testicular tumors in males. Paraneoplastic in ~55% of cases.
• AMPA Receptor Encephalitis: Rare; ~1-2% of autoimmune encephalitis. Strong association with malignancy (80% paraneoplastic), especially small cell lung cancer (SCLC) and breast cancer.
• GABA-B and GABA-A Receptor Encephalitis: GABA-B associated with SCLC (50% paraneoplastic); GABA-A more rarely paraneoplastic.
• LGI1 (Leucine-Rich Glioma Inactivated Protein 1) Encephalitis: Second most common antibody-positive form; predominantly affects older males (>50 years). Associated with malignancy in <5% of cases.
• Contactin-Associated Protein 2 (CASPR2) Encephalitis: Often coexists with LGI1 antibodies; low malignancy association.
• Glycine Receptor Encephalitis: Rare; associated with SCLC and other malignancies; progressive stiffness prominent.
• Other Surface Antigens: Metabotropic glutamate receptor 5 (mGluR5), dopamine-2 receptor (D2R), α3-ATPase.

Intracellular Antigen-Associated (Paraneoplastic, Often Irreversible)

• Hu (ANNA-1): Associated with SCLC in >80% of cases; paraneoplastic in nearly all cases. Causes encephalomyelitis with prominent limbic involvement.
• Yo (PCA-1): Strongly associated with gynecologic malignancies (ovarian, breast, uterine cancer); nearly always paraneoplastic. Predominates in cerebellum causing cerebellar degeneration.
• CRMP5 (CV-2): Associated with SCLC, breast cancer, thymoma, gynecologic cancers; >90% paraneoplastic. Causes multifocal CNS involvement.
• Amphiphysin: Associated with SCLC and breast cancer; high malignancy association.
• Ma2/Ta: Associated with testicular cancer, lung cancer, and other malignancies; paraneoplastic in >80% of cases. Prominent limbic and brainstem involvement.

Risk Factors

• Underlying malignancy (paraneoplastic forms)
• Female sex (NMDAR, female predominance)
• Age >50 years (higher malignancy risk)
• History of autoimmune disease (increased susceptibility)
• Genetic predisposition (HLA associations, e.g., HLA-A2 with Hu antibodies)

Cardinal Neuropsychiatric Symptoms

• Acute behavioral/psychiatric changes: Personality alteration, aggression, inappropriate behavior, paranoia, hallucinations (visual or auditory); often precedes neurological symptoms by days to weeks. In NMDAR encephalitis, severe psychiatric manifestations are nearly universal, sometimes misdiagnosed as primary psychiatric illness.
• Cognitive dysfunction: Memory impairment, difficulty with concentration, confusion, altered mental status progressing to encephalopathy
• Sleep disturbance: Insomnia, sleep inversion, REM sleep abnormalities, hypersomnia
• Autonomic instability: Temperature dysregulation, hypertension/hypotension, tachycardia, excessive salivation, pupillary abnormalities

Seizures

• Present in 60-90% of cases depending on antigen
• Often refractory to standard antiepileptic drugs (major diagnostic clue)
• Can be focal or generalized; status epilepticus occurs in severe cases
• May precede other manifestations by weeks

• Orofacial dyskinesias: Stereotyped lip smacking, grimacing, tongue protrusion; highly characteristic
• Limb dyskinesias: Choreoathetoid movements, ballism
• Dystonia: Sustained abnormal postures, trunk/extremity involvement
• Hypokinetic movement disorder: Bradykinesia, rigidity, akinetic mutism (later in disease)
• Catatonia: Mutism, waxy flexibility, posturing, negativism

Speech and Language

• Dysarthria, dysphonia, palilalia
• Speech slowing, reduced verbal output
• Rarely, selective speech arrest with preserved comprehension

Sensory and Motor Findings

• Usually preserved early (helps distinguish from other encephalitides)
• Variable weakness if encephalomyelitis present
• Hyperreflexia, pyramidal signs if pyramidal involvement
• Normal or mildly elevated tone unless dystonia present

• Faciobrachial dystonic seizures (FBDS): Brief, stereotyped seizures with dystonic posturing of arm/face, highly specific for LGI1
• Autonomic symptoms including cardiac arrhythmias

Disease Progression Timeline

• Prodromal phase (days): Fever, headache, malaise, psychiatric symptoms
• Acute phase (weeks 1-4): Progressive neuropsychiatric decline, seizures, movement disorders peak
• Plateau phase: Symptoms stabilize (untreated or inadequately treated)
• Chronic phase: Residual deficits if inadequately treated; potential recovery with treatment

Clinical Diagnosis (Required First Step)

• Subacute onset (hours to weeks) of encephalopathy (altered mental status, psychiatric symptoms, memory impairment)
• PLUS at least one of: new focal CNS finding, seizure, movement disorder, hypokinetic movement disorder, or psychiatric symptoms requiring hospitalization
• PLUS objective evidence of brain inflammation (CSF pleocytosis, brain MRI abnormality, EEG with seizures or slowing)

Cerebrospinal Fluid (CSF) Analysis

• Cell count: Pleocytosis (typically 10-500 cells/μL; can be higher) with lymphocytic predominance (>80% lymphocytes)
• Protein: Elevated (50-200 mg/dL, sometimes >500 mg/dL)
• Glucose: Normal or mildly reduced (CSF:serum glucose ratio >0.40, unlike bacterial meningitis)
• Oligoclonal bands (OCBs): Often present; highly specific for CNS inflammation
• Cultured sterile: Rules out infectious encephalitis (bacterial, fungal); viral PCR negative (though enterovirus/HSV can coexist)
• Antibody detection in CSF: More sensitive and specific than serum; aquaporin-4 (AQP4) and MOG antibodies particularly important to exclude if present

• NMDAR: ELISA, cell-based assays, immunofluorescence on HEK293 cells expressing NMDAR; serum positive in ~90%, CSF in near 100%
• LGI1: Radioimmunoassay most sensitive; serum and CSF testing
• CASPR2: Similar methodologies to LGI1
• AMPA Receptor: ELISA and cell-based assays; lower prevalence
• GABA-B/GABA-A Receptor: Cell-based assays
• CRMP5, Hu, Yo, Ma2, Amphiphysin: Immunoprecipitation assays, immunoblotting, ELISA; commercial labs available

• Seropositivity with typical clinical syndrome: Definite autoimmune encephalitis
• Seronegative (CSF or serum negative): Does not exclude autoimmune encephalitis; may represent undetected antibodies or T cell-mediated disease (~50% of cases are antibody-negative)
• Clinical + CSF evidence + typical imaging = probable autoimmune encephalitis even if seronegative

Electroencephalography (EEG)

• Shows non-specific abnormalities in most cases
• Extreme delta brush pattern: Highly characteristic of NMDAR encephalitis; burst of delta activity (1-4 Hz) with superimposed 20-40 Hz activity
• Generalized slowing, focal slowing, seizure activity
• Serial EEGs may show evolution; therapeutic response correlates with improvement

Brain Imaging

• Conventional MRI (initial modality):
• T2/FLAIR hyperintense lesions in medial temporal lobes (limbic encephalitis pattern), particularly involved in Hu, Ma2, LGI1 encephalitis
• May show involvement of amygdala, anterior insula, mesial temporal structures
• MRI can be normal in NMDAR encephalitis (up to 50% of cases)
• White matter involvement less common than in infectious etiologies
• Cortical involvement when present (ovarian teratoma-associated NMDAR encephalitis)

• Advanced Imaging:
• PET imaging: FDG-PET may show hypometabolism in affected brain regions (more sensitive than MRI in early stages)
• Brain SPECT: Can demonstrate areas of hypoperfusion/hyperemia

Screening for Associated Malignancy

• Chest CT/CXR: Screen for lung cancer (SCLC, adenocarcinoma)
• Pelvic ultrasound and CT: Ovarian teratomas (NMDAR encephalitis in women)
• Mammography/breast MRI: Breast cancer (Yo antibodies, AMPA receptor)
• Testicular ultrasound: Testicular seminoma or teratoma (NMDAR in men, Ma2)
• Age-appropriate cancer screening: Based on antibody profiles and epidemiology
• Repeat imaging if initial negative: ~10% of malignancies emerge months to years after diagnosis
• FDG-PET body scan: May detect occult malignancy in paraneoplastic cases

• One or more of: NMDAR, LGI1, CASPR2 antibodies in serum or CSF (high-tier diagnosis)
• Other antibodies (AMPA-R, GABA-B, Hu, Yo, CRMP5, Ma2, amphiphysin) if compatible clinical syndrome AND absence of alternative explanations

• Clinical presentation highly suggestive of autoimmune encephalitis
• CSF pleocytosis (>4 WBC/μL)
• Brain MRI abnormality consistent with encephalitis
• Absence of alternative diagnoses
• Seronegative cases may be classified as probable despite negative antibodies if clinical and paraclinical findings are compelling

• Intravenous Corticosteroids:
• Mechanism: Broad immunosuppression, reduced B and T cell activation, decreased cytokine production, increased Treg differentiation
• Dosing: Methylprednisolone 1 g IV daily for 3-5 days, followed by oral corticosteroid taper (prednisone 1 mg/kg/day initially, then gradual taper over weeks to months)
• Efficacy: Cornerstone of acute treatment; response may take 1-2 weeks
• Monitoring: Check for hyperglycemia, infection, osteoporosis with prolonged use

• Intravenous Immunoglobulin (IVIG):
• Mechanism: Blocks Fc receptors on macrophages (reducing ADCC), neutralizes antibodies, modulates complement activation, increases regulatory T cells
• Dosing: 2 g/kg divided over 3-5 days (typical: 0.4 g/kg/day), or 1 g/kg daily for 2-3 days; may repeat monthly if needed
• Indication: Often combined with corticosteroids for enhanced efficacy; particularly useful for antibody-mediated disease
• Advantages: Rapid onset (days), well-tolerated, can be repeated
• Monitor: Renal function, volume status, thrombosis risk (rare but serious)

• Plasmapheresis (Plasma Exchange):
• Mechanism: Direct removal of circulating pathogenic antibodies

Disease-related — emergencies

• Refractory and super-refractory status epilepticus: antibody-mediated receptor internalization (NMDAR) plus cortical inflammation produces seizures poorly responsive to sodium-channel and GABAergic agents. Refractory status epilepticus is ongoing seizure activity despite an adequately dosed benzodiazepine plus a second-line agent (levetiracetam, fosphenytoin, or valproate); it becomes super-refractory when seizures persist or recur ≥24 h after starting an anesthetic infusion, including on weaning. Suspect nonconvulsive status on continuous EEG in a patient who fails to awaken. Manage with anesthetic infusion and continuous EEG monitoring per the Neurocritical Care Society status epilepticus guideline, alongside escalating immunotherapy.
• Central hypoventilation and airway loss: brainstem and hypothalamic involvement in NMDAR encephalitis; heralded by rising PaCO2, apneic pauses, or inability to protect the airway during catatonia. Intubation is often needed for weeks.
• Autonomic storm: dysautonomia produces alternating hypertension/hypotension, hyperthermia, and bradyarrhythmia or asystole — the reason these patients need telemetry; some require temporary pacing.
• Neuroleptic hypersensitivity: NMDAR patients treated as primary psychosis may develop rigidity, hyperthermia, and rhabdomyolysis resembling neuroleptic malignant syndrome; signaled by CK elevation after dopamine blockade. Withdraw the antipsychotic.

Disease-related — subacute

• Hyponatremia: characteristic of LGI1 encephalitis (SIADH-like); lowers seizure threshold further.
• Relapse and residual deficit: a minority of NMDAR patients relapse, often when tumor is missed or immunotherapy was brief; memory impairment, disinhibition, and hippocampal atrophy with chronic temporal lobe epilepsy are the usual residua of limbic encephalitis.
• Delayed malignancy: tumor may surface months to years later — hence scheduled repeat screening.

Treatment-related

• Corticosteroids: hyperglycemia, steroid psychosis (mimics disease relapse), infection, osteoporosis, avascular necrosis.
• IVIG: aseptic meningitis (mimics relapse), volume overload, acute kidney injury, hemolysis, and thrombosis; anaphylaxis in IgA deficiency.
• Plasma exchange: citrate-induced hypocalcemia, hypotension, coagulopathy, and central line infection/pneumothorax.
• Rituximab: hypogammaglobulinemia and hepatitis B reactivation — AASLD advises HBsAg/anti-HBc screening with antiviral prophylaxis before anti-CD20 therapy; rare PML.
• Cyclophosphamide: hemorrhagic cystitis (mesna and hydration), cytopenias, infertility, late malignancy.
• Opportunistic infection: consider Pneumocystis prophylaxis with trimethoprim-sulfamethoxazole when prednisone ≥20 mg/day is expected for ≥4 weeks, or with combined agents such as rituximab or cyclophosphamide — extrapolated from other immunosuppression settings; no autoimmune encephalitis–specific guideline exists.

• Young woman, psychosis then seizures then orofacial dyskinesia: this triad in sequence is anti-NMDA receptor encephalitis until proven otherwise. The single best next step after CSF is pelvic imaging for an ovarian teratoma — tumor resection is itself immunotherapy and predicts better outcome.
• Send CSF, not just serum: NMDAR antibodies are more sensitive and specific in CSF; a negative serum assay does not exclude the diagnosis. LGI1 and CASPR2 antibodies are often detected at higher titer in serum (assay-dependent), so paired serum and CSF testing is standard.
• Extreme delta brush on EEG is the buzzword for NMDAR encephalitis; faciobrachial dystonic seizures plus hyponatremia in an older man is the buzzword pair for LGI1.
• Do not wait for antibody results to treat: first-line immunotherapy (corticosteroids, IVIG, plasma exchange) is started on clinical and CSF grounds, as framed by the Graus criteria. Simultaneously give empiric acyclovir until HSV PCR returns negative — untreated HSV encephalitis is the lethal miss.
• The association examiners test: surface-antigen antibodies (NMDAR, LGI1, CASPR2, AMPAR, GABA-B) are antibody-mediated and reversible with immunotherapy; intracellular-antigen antibodies (Hu, Yo, Ma2, CRMP5, amphiphysin) are markers of a cytotoxic T-cell process, respond poorly to immunotherapy, and management pivots to finding and treating the underlying cancer — SCLC for Hu/CRMP5/amphiphysin, ovarian or breast for Yo, testicular germ cell tumor for Ma2.
• Common distractor — primary psychiatric illness: a first psychotic break does not cause seizures, dyskinesias, autonomic instability, or CSF pleocytosis. Giving an antipsychotic instead can precipitate a neuroleptic malignant syndrome–like reaction.
• Second distractor — antiseizure drug escalation alone: seizures refractory to appropriate antiseizure medications should prompt immunotherapy, not a fourth agent.
• Post-HSV relapse: new choreoathetosis and behavioral regression weeks after treated HSV encephalitis suggests secondary NMDAR autoimmunity, not viral relapse — retest CSF for both.