What is the primary cause of acute necrotizing encephalopathy of childhood?

Primary Cause of Acute Necrotizing Encephalopathy of Childhood

Acute Necrotizing Encephalopathy of Childhood (ANEC) is primarily caused by viral infections, particularly influenza viruses, which trigger an abnormal immune response leading to cytokine-mediated brain edema rather than direct viral invasion of the brain. 1, 2

Viral Etiology and Pathophysiology

• Influenza viruses: Most commonly associated with ANEC

  • Influenza A (including H1N1 strain) 2
  • Influenza B 3
  • The H1N1 strain that emerged in 2009 may cause more neurological manifestations than seasonal flu 2

• Other viral triggers:

  • Parainfluenza virus 4
  • Other respiratory viruses

• Pathophysiological mechanism:

  • Cytokine-mediated brain edema rather than direct viral invasion 2
  • Typically occurs 2-4 days after respiratory symptoms 1

Genetic Predisposition

• Genetic susceptibility: Some families show autosomal dominant inheritance pattern 2
  • Mutations in RANBP2 (Ran-binding protein 2) gene have been identified 5
  • These mutations can occur de novo or be inherited 5
  • Genetic predisposition may explain recurrent episodes in some patients 5

Clinical Presentation

• Affects primarily children aged 1-5 years 1
• Presents with:
  • High fever
  • Convulsions
  • Rapid progression to altered consciousness or coma
  • Occurs after a short febrile illness (typically respiratory) 1, 6

Diagnostic Features

• Neuroimaging: Characteristic bilateral thalamic lesions on MRI 1, 6

  • Additional lesions may be seen in:
    • Brainstem tegmentum
    • Cerebral periventricular white matter
    • Cerebellar medulla

• CSF findings: Increased protein without pleocytosis 1

Geographical Distribution

• Initially reported predominantly in Japan and Taiwan 7
• Now recognized worldwide but may be underdiagnosed in Western countries 5

Prognosis

• Generally poor prognosis with high mortality (25% in some series) 6
• Less than 10% of patients recover completely 3
• Survivors often have significant neurological sequelae 1

Treatment Approach

• Initial empirical treatment with antibiotics and antiviral agents (acyclovir) 1, 6
• Immunomodulatory therapy:
  • High-dose intravenous methylprednisolone (1g daily for 3-5 days)
  • Intravenous immunoglobulin (IVIG) at 2g/kg over 5 days
  • Early intervention with these therapies may improve outcomes 1, 6

Key Distinctions from Other Encephalopathies

• Unlike viral encephalitis, ANEC shows no CSF pleocytosis 1
• Unlike Reye's syndrome, ANEC is not specifically associated with aspirin use 2
• Unlike ADEM, ANEC has characteristic bilateral thalamic involvement 1

ANEC remains a rare but devastating condition with limited treatment options. Early recognition through characteristic MRI findings and prompt initiation of immunomodulatory therapy are crucial for improving outcomes.