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.

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

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.

• [Neurology/Common Movement Disorders in Children#^OMAS2|Opsoclonus-Myoclonus Ataxia Syndrome ]: ^ OMAS1

  • 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.

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).