Autoimmune Encephalitis

INTRODUCTION

• Expanding group of clinical syndromes affecting all age groups.
• Preferentially affects children and young adults.
• Most common single cause of encephalitis in western countries.
• Defined by antibodies against neuronal cell surface proteins, synaptic receptors, or intracellular antigens.
• Targets mediate synaptic transmission, plasticity, and neuronal excitability.
• Severe, potentially fatal, yet highly responsive to immunotherapy.
• Necessitates multidisciplinary treatment approach due to broad symptom spectrum (behavioral, psychiatric, movement, autonomic).

PATHOPHYSIOLOGY AND ETIOLOGY

• Exact primary trigger mechanisms unknown.
• Associated with target-specific autoantibody production.
• Autoantibodies synthesized directly within central nervous system (CNS) by plasma cells localized in brain and meningeal inflammatory infiltrates.
• Blood-brain barrier often intact.

Identified Triggers

• Paraneoplastic: Tumors expressing target neuronal antigens provoke immune response.
  • Frequent in adolescents/adults; rare in prepubertal children.
• Post-infectious/Viral: Viral illnesses alter immune tolerance and increase blood-brain barrier permeability.
  • Implicated agents: Herpes simplex virus (HSV), Mycoplasma pneumoniae, Human herpesvirus 6 (HHV-6), Enterovirus, Influenza, COVID-19, Japanese encephalitis.
  • Classical post-viral complication: Choreoathetosis post-HSV encephalitis (represents anti-NMDAR encephalitis triggered by HSV).

DIAGNOSTIC CRITERIA

• Rapid symptom onset (typically <3 months).
• Classified into Possible, Probable Antibody-Negative, and Definite Antibody-Positive categories.

Diagnostic Category	Required Clinical Features	Paraclinical Evidence Required	Serology Requirement
Possible AE	Onset $\le$ 3 months in previously healthy child. $\ge$ 2 features: Altered mental status, focal deficits, cognitive decline, acute regression, movement disorder, psychiatric symptoms, unexplained seizures.	Not strictly required for initial suspicion.	Not available/required.
Probable Antibody-Negative AE	Same as Possible AE.	$\ge$ 1 feature: CSF pleocytosis/oligoclonal bands, MRI encephalitis features, Brain biopsy showing inflammation.	Negative for known autoantibodies.
Definite Antibody-Positive AE	Same as Possible AE.	Not required if CSF antibody positive. If only serum positive, $\ge$ 1 paraclinical marker required.	Positive for well-characterized autoantibodies.

Note: Alternative causes must be reasonably excluded for all categories.

CLINICAL SUBTYPES

Anti-N-Methyl-D-Aspartate Receptor (NMDAR) Encephalitis

• Most frequent autoimmune encephalitis post-ADEM in pediatric populations.
• Targets GluN1 subunit of NMDAR.
• Female predominance (80% overall); male frequency >40% in children <12 years.

Clinical Staging and Features

• Prodrome: Fever, headache, viral-like symptoms.
• Psychiatric/Behavioral Phase: Anxiety, agitation, delusions, mania, insomnia.
  • Pediatric variants: Irritability, temper tantrums, mutism, autistic-like regression.
• Neurologic Phase: Decreased consciousness, seizures, status epilepticus.
• Movement Disorders: Orofacial dyskinesias, choreoathetoid movements, limb dystonia.
  • Pediatric variants: Cerebellar ataxia, hemiparesis.
• Autonomic Instability: Tachycardia, bradycardia, blood pressure fluctuations, hypoventilation, sialorrhea.

Investigations in NMDAR Encephalitis

• CSF: Lymphocytic pleocytosis, increased protein (80% of cases). Superior sensitivity for NMDAR antibodies compared to serum (100% vs 85%).
• EEG: Abnormal in almost all patients. Focal/diffuse delta-theta slowing. “Extreme delta brush” pattern characteristic (30% adults, less frequent in children).
• MRI: Abnormal in ~35%. Nonspecific cortical/subcortical T2-FLAIR hyperintensities.
• Tumor Screening: Ovarian teratoma in 40% of females >12 years. Rare in young children. Screen via abdominal/pelvic ultrasound or MRI.

Encephalitis with GABA-A Receptor Antibodies

• Targets $\alpha 1$, $\beta 3$, or $\gamma 2$ subunits of GABA-A receptor.
• Frequent in children (40% of cases <18 years).
• Features: Refractory seizures, epilepsia partialis continua, limb/orofacial dyskinesias.
• MRI: Multifocal cortical-subcortical FLAIR/T2 hyperintensities (77% of patients).
• Tumor association: Thymoma in adults; extremely rare in children.

Autoimmune Limbic Encephalitis

• Inflammatory process of limbic system (medial temporal lobes, amygdala, cingulate gyri).
• LGI1 Antibodies (Leucine-rich glioma-inactivated 1):
  • Adults: Hyponatremia, faciobrachial dystonic seizures.
  • Children: Extremely rare. Lacks classic adult symptoms.
• Caspr2 Antibodies (Contactin-associated protein-like 2):
  • Features: Encephalopathy, neuromyotonia, sleep disorders (Morvan syndrome).
  • Children: Flaccid paresis, hypertensive encephalopathy, palmoplantar erythema/eczema. No tumor association.

Specific Autoimmune Syndromes and Antibodies

Syndrome/Antibody	Target Type	Core Clinical Features	Tumor Association / Prognosis
Ophelia Syndrome (mGluR5)	Cell Surface	Abnormal behavior, seizures, memory deficits.	Hodgkin lymphoma. Favorable recovery with treatment.
Bickerstaff Encephalitis (GQ1b)	Cell Surface	Rapid bilateral ophthalmoplegia, ataxia, altered consciousness, hyperreflexia.	Good response to steroids/IVIG/Plasmapheresis.
GABABR	Cell Surface	Encephalitis, seizures, cerebellar ataxia.	Rare in children.
DPPX	Cell Surface	CNS hyperexcitability, Progressive encephalomyelitis with rigidity and myoclonus (PERM).	Rare in children.
GlyR	Cell Surface	PERM, stiff person syndrome.	Rare in children.
GluK2	Cell Surface	Cerebellitis, prominent ataxia.	Post-viral trigger typical.
Hu, Ma2, Amphiphysin	Intracellular	Brainstem/limbic encephalitis, opsoclonus-myoclonus.	Neuroblastoma (Hu). Poor immunotherapy response.
GAD65	Intracellular	Encephalitis with refractory epilepsy.	Poor immunotherapy response.

Autoimmune Encephalopathies Associated with Specific Phenotypes

• Hashimoto Encephalopathy (SREAT):
  • Associated with Thyroid Peroxidase (TPO) antibodies.
  • Features: Strokelike episodes, tremor, myoclonus, aphasia, subclinical hypothyroidism (48%).
  • Highly steroid-responsive.
• Rasmussen Encephalitis:
  • Unknown immune mechanism; T-cell mediated suspicion.
  • Features: Progressive refractory focal seizures, cognitive decline, progressive unilateral hemispheric atrophy.
  • Management: Functional hemispherectomy. Poor response to standard immunotherapy.
• Opsoclonus-Myoclonus Ataxia Syndrome (OMAS):
  • Autoimmune B-cell trafficking disorder.
  • Features: Subacute irritability, tremor, ataxia, chaotic eye movements (opsoclonus).
  • Tumor Association: Neuroblastoma (~40% cases).
  • Treatment: ACTH, IVIG, Rituximab, tumor resection.
• Basal Ganglia Encephalitis:
  • Infrequent Dopamine-2 Receptor (D2R) antibodies.
  • Features: Dystonia, chorea, parkinsonism, psychosis.
  • MRI: Basal ganglia T2/FLAIR abnormalities (normal in 50%).

DIFFERENTIAL DIAGNOSIS

Differentiating AE from other etiologies is critical due to rapid treatment implications.

Diagnosis Category	Differentiating Features
Viral Encephalitis	Acute onset, severe hyperthermia. Psychosis and dyskinesias significantly less frequent than in AE. Higher CSF pleocytosis/protein.
New-Onset Psychosis	Initial presentation of AE mimics psychosis; evolution of neurologic symptoms (seizures, dyskinesias) confirms AE.
Childhood Disintegrative Disorder	Rapid loss of language, autistic features mimic AE. Unlike CDD, AE responds to immunotherapy.
Kleine-Levin Syndrome	Hypersomnia, hyperphagia, hypersexuality. Relapsing-remitting course (unlike AE).
CNS Vasculitis	Elevated systemic inflammatory markers (ESR, CRP). MRI shows ischemic microhemorrhages, leptomeningeal enhancement. Angiography/biopsy required.
Genetic/Metabolic	HLH, Autoinflammatory syndromes (Aicardi-Goutières). Systemic features present (rash, cytopenias).
Acquired Demyelinating Syndromes	ADEM, NMOSD. Distinguishable via MRI patterns and MOG/AQP4 antibody detection.

INVESTIGATIONS AND EVALUATION

• Neuroimaging (MRI Brain):
  • Modality of choice. Findings vary by subtype.
  • Limbic encephalitis: Bilateral medial temporal lobe abnormalities.
  • GABA-A Encephalitis: Multifocal corticosubcortical hyperintensities.
  • Often normal or nonspecific in NMDAR encephalitis.
• Cerebrospinal Fluid (CSF) Analysis:
  • Essential for identifying autoantibodies. CSF more sensitive than serum for specific antibodies (e.g., NMDAR).
  • Typical profile: Mild/moderate lymphocytic pleocytosis, normal to elevated protein, normal glucose, possible oligoclonal bands.
• Electroencephalogram (EEG):
  • Rule out nonconvulsive status epilepticus.
  • Identifies characteristic patterns (e.g., extreme delta brush in NMDAR encephalitis).
• Tumor Surveillance:
  • Ultrasound/MRI of abdomen, pelvis, and testes to rule out occult malignancies (teratoma, neuroblastoma, Hodgkin lymphoma). Whole-body PET-CT for paraneoplastic suspicion.

MANAGEMENT

Early, aggressive immunotherapy improves neurologic outcomes and reduces relapse rates.

First-Line Immunotherapy

• Corticosteroids: Intravenous Methylprednisolone (Pulse therapy).
• Intravenous Immunoglobulin (IVIG): Often combined with steroids.
• Plasmapheresis: Mechanical removal of autoantibodies; utilized in severe/refractory cases.

Second-Line Immunotherapy

• Indicated if first-line therapy fails (~50% of NMDAR patients).
• Rituximab: Anti-CD20 monoclonal antibody. Highly effective; prevents relapses.
• Cyclophosphamide: Alkylating agent used in refractory cases.

Tumor Management

• Prompt surgical removal of associated tumors (e.g., ovarian teratoma) mandatory. Delays worsen neurologic prognosis.

Prognosis

• Variable dependent on antibody target. Cell-surface targets (NMDAR, GABA-A) exhibit substantially better immunotherapy responses than intracellular targets (Hu, GAD65).
• NMDAR Encephalitis: ~80% substantial/full recovery. Recovery prolonged (up to 2 years). Relapse rate ~15%; reduced by comprehensive immunotherapy.
• Mortality: ~5% (typically secondary to autonomic dysregulation or secondary infections).