Autoimmune Encephalitis

Definition: A heterogeneous group of non-infectious inflammatory disorders of the brain mediated by antibodies against neuronal cell surface proteins, ion channels, or receptors.
Paradigm Shift: Formerly diagnosed as "idiopathic encephalitis" or "viral negative encephalitis." It is a rapidly evolving field in neurology/pediatrics.
Key Characteristic: Subacute onset of memory deficits, altered mental status, or psychiatric symptoms.

Classified based on the location of the target antigen, which dictates response to immunotherapy and cancer association.

Feature	Neuronal Surface Antibody Syndrome	Paraneoplastic (Intracellular) Syndrome
Target	Surface receptors (NMDAR, AMPAR, GABA-B) or Synaptic proteins (LGI1, CASPR2).	Intracellular antigens (Hu, Ma2, Yo, Ri).
Mechanism	Antibody-mediated disruption of synaptic function (internalization of receptors). Direct pathogenic effect.	T-cell mediated cytotoxicity. Antibodies are markers, not directly pathogenic.
Cancer Association	Variable (e.g., NMDAR + Teratoma). Lower risk than intracellular.	High association (e.g., Small cell lung cancer, Neuroblastoma).
Response to Rx	Good to Excellent. Potentially reversible.	Poor/Limited.

Presentation varies by antibody type, but a general clinical course (especially Anti-NMDAR) follows a characteristic progression.

Prodromal Phase: Fever, headache, malaise (viral-like) 1–2 weeks prior.
Psychiatric Phase: Anxiety, agitation, psychosis, hallucinations, insomnia, mania. (Often misdiagnosed as acute psychosis).
Neurologic Phase:
- Seizures: Focal or generalized.
- Movement Disorders: Orofacial dyskinesias (chewing/licking), choreoathetosis, dystonia.
- Autonomic Instability: Tachycardia, hypertension, hyperthermia.
- Hypoventilation: Central hypoventilation requiring ventilation.
- Language: Mutism, echolalia.

Anti-LGI1 (Limbic Encephalitis): Older children/adults. Hallmark: Faciobrachial Dystonic Seizures (FBDS) – brief (<3 sec) dystonic posturing of face and arm. Hyponatremia (SIADH).
Anti-GABA-B: Prominent seizures, limbic features.
Hashimoto Encephalopathy: Associated with Thyroid antibodies (Anti-TPO); Steroid-responsive tremor/myoclonus.

Diagnosis relies on a combined clinical approach. Antibody results should not delay treatment.

Subacute onset (rapid progression of < 3 months) of working memory deficits, altered mental status, or psychiatric symptoms.
At least one of:
- New focal CNS findings.
- Seizures not explained by a known seizure disorder.
- CSF pleocytosis (>5 WBC/mm³).
- MRI suggestive of encephalitis (T2/FLAIR hyperintensities).
Reasonable exclusion of alternative causes (HSV, Metabolic, Toxic).

NMDAR: Often normal (50%) or nonspecific T2/FLAIR hyperintensities in hippocampus/cortex.
Limbic Encephalitis (LGI1/GABA): T2/FLAIR hyperintensity in medial temporal lobes (uni/bilateral).
Exclusion: Rule out stroke, tumor, ADEM.

Routine: Lymphocytic pleocytosis (mild-moderate), Normal/mildly elevated protein, Normal glucose.
Oligoclonal Bands: Positive in ~60%.
Autoimmune Panel: CSF is more sensitive than Serum for NMDAR. Test for NMDAR, LGI1, CASPR2, AMPAR, GABA.

General: Generalized slowing, epileptiform discharges.
Specific: "Extreme Delta Brush" pattern (beta activity superimposed on delta waves) – highly specific for NMDAR encephalitis (seen in ~30%).

CT Chest/Abdomen/Pelvis or Whole Body PET scan.
Ovarian Ultrasound/MRI: Mandatory in females (search for Ovarian Teratoma).

Infectious: HSV Encephalitis (Acute, fever high, temporal lobe necrosis), Tuberculosis, JE.
Vascular: Primary CNS Vasculitis.
Metabolic: Wernicke encephalopathy, Inborn errors (Porphyria).
Psychiatric: Primary Schizophrenia or Bipolar disorder (AIE patients usually have neuro soft signs/seizures).

"Time is Brain" – Start immunotherapy empirically if "Possible AIE" criteria are met and infection ruled out.

Corticosteroids: IV Methylprednisolone (Pulse: 30 mg/kg/day x 3–5 days) followed by oral taper.
IVIG: 2 g/kg over 2–5 days.
Plasmapheresis (PLEX): 5–7 cycles. (If severe or no response to Steroids/IVIG).

(If no improvement after 2 weeks of 1st line)

Rituximab: Anti-CD20 monoclonal antibody. (375 mg/m² weekly x 4). Standard of care for NMDAR.
Cyclophosphamide: Alkylating agent (often used in adults/severe paraneoplastic).

Resection: Immediate removal of teratoma or associated tumor is curative and essential for preventing relapse.

NMDAR: Generally good with treatment. Recovery is slow (months to years) and occurs in reverse order of symptom onset.
Mortality: ~5–7% (due to autonomic instability/ICU complications).
Relapse: 12–20%. Higher risk if tumor is not removed or no immunotherapy given.