What is the incidence of acute necrotizing encephalopathy (ANE) in pediatric patients with influenza?

Rate of Acute Necrotizing Encephalopathy from Influenza in Pediatric Patients

Acute necrotizing encephalopathy (ANE) is an extremely rare but devastating complication of influenza in children, with precise incidence rates difficult to establish, though recent US data suggests increasing recognition with approximately 41 cases identified across 23 hospitals over two influenza seasons (2023-2025), representing a rare event even among large pediatric centers. 1

Geographic and Epidemiologic Patterns

Historical Context

• ANE occurs predominantly in Japan and other Southeast Asian countries, where it was first described in 1995 2
• In Japan, an estimated 100 deaths per annum are related to CNS complications of influenza, suggesting either genetic predisposition or variation in circulating influenza strains 2
• This geographic clustering indicates possible autosomal dominant inheritance patterns with identified genetic mutations in some families 2

Recent US Experience

• A 2025 multicenter case series identified 41 confirmed cases of influenza-associated ANE across 23 US hospitals over approximately 18 months (October 2023-May 2025) 1
• Among these cases, genetic testing revealed 47% had genetic risk alleles potentially related to ANE risk, including 34% with RANBP2 variants 1
• The median age was 5 years (IQR 2-8 years), with 76% having no significant prior medical history 1

Clinical Characteristics and Timing

Age Distribution and Presentation

• ANE primarily affects children aged 1-5 years, though cases occur across the pediatric age spectrum 2
• The condition presents with high fever (93%), encephalopathy (100%), and seizures (68%) 1
• Onset occurs 2-4 days after respiratory symptoms begin, with rapid progression 2

Diagnostic Features

• Bilateral thalamic involvement is characteristic, with symmetrical multifocal brain lesions visible on MRI involving thalami, brainstem, and cerebral white matter 2
• Laboratory abnormalities include elevated liver transaminases (78%), thrombocytopenia (63%), and elevated CSF protein (63%) 1
• CSF protein >0.48 g/L has 76.7% sensitivity and 69.7% specificity for differentiating ANE from other influenza-associated encephalopathy 3
• Serum procalcitonin >4.25 ng/ml has 73.3% sensitivity and 100% specificity for predicting ANE 3

Mortality and Morbidity Outcomes

Survival Rates

• Historically, fewer than 10% of patients survive in Japanese cohorts 2
• In the recent US series, 27% died, with median time to death of 3 days from symptom onset, primarily from cerebral herniation (91% of deaths) 1
• Among survivors at 90-day follow-up, 63% had at least moderate disability (modified Rankin Scale score ≥3) 1

Comparison to General Influenza Encephalopathy

• In a Japanese cohort of 202 children with influenza encephalopathy (1997-2001): death occurred in 31%, residual neurological deficit in 26%, and full recovery in 43% 2
• ANE represents the most severe end of the influenza encephalopathy spectrum, with worse outcomes than general encephalopathy 2

Critical Clinical Pitfalls

Recognition Challenges

• Patients rarely have viral antigens or nucleic acid in CSF, making diagnosis dependent on clinical presentation and imaging rather than direct viral detection 2
• During influenza epidemics, focus on respiratory illness may lead to missed or delayed neurological diagnoses 4
• The pathophysiology involves cytokine-mediated brain edema rather than direct viral invasion, explaining the absence of inflammatory cells in CSF and neural tissue 2

Vaccination Status

• Only 16% of patients in the recent US series had received age-appropriate seasonal influenza vaccination, highlighting a critical prevention opportunity 1
• This low vaccination rate among ANE cases emphasizes the importance of universal pediatric influenza immunization

Influenza Strain Considerations

• Influenza A (particularly H1N1 and H3N2) is most commonly associated with ANE, though influenza B can also cause this complication 2, 1
• The 2009 H1N1 strain may cause more neurological manifestations than seasonal influenza 2