Highlight
– Influenza-associated acute necrotizing encephalopathy (ANE) in US children showed a 27% mortality rate and 63% moderate-to-severe disability among survivors at 90 days.
– Most affected children were previously healthy, but nearly half of those tested carried genetic risk alleles, including RANBP2 variants.
– Only 16% of cases had received seasonal influenza vaccination, and the 2009 H1N1 influenza A strain predominated.
– Early recognition, prevention, and standardized treatment protocols are urgently needed.
Background
Acute necrotizing encephalopathy (ANE) is a rare but catastrophic neurologic disorder, most often triggered by viral infections in children. Characterized by rapid-onset encephalopathy and distinctive bilateral thalamic lesions on MRI, ANE can rapidly progress to coma, cerebral herniation, and death. Although first described in East Asian populations, recent influenza seasons in the United States have seen clusters of pediatric ANE cases, raising concern among clinicians about potential under-recognition, genetic susceptibility, and optimal management strategies. The disease burden is compounded by its predilection for previously healthy children and its frequent association with significant long-term neurological disability or fatal outcomes.
Study Overview and Methodological Design
The referenced study is a national multicenter case series conducted over the 2023-2025 influenza seasons. Investigators coordinated with 76 US academic centers to identify children (≤21 years) diagnosed with ANE, using a combination of case calls to professional societies, public health agencies, and direct outreach to pediatric subspecialists. Inclusion criteria required documented acute encephalopathy with radiologic evidence of acute thalamic injury and laboratory confirmation of influenza infection. The study collected data on demographics, medical history, clinical presentation, laboratory and genetic findings, management strategies, and clinical outcomes, including the modified Rankin Scale (mRS) at 90 days.
Of 58 reported cases, 41 met strict inclusion criteria. Data were analyzed descriptively, with medians and interquartile ranges for continuous variables and proportions for categorical outcomes.
Key Findings
– Demographics: Median age was 5 years (IQR, 2-8); 56% were female.
– Most children (76%) had no significant prior medical history; 12% were medically complex.
– Clinical Presentation: All had encephalopathy, 93% had fever, and 68% experienced seizures.
– Influenza Subtypes: 95% had influenza A (predominantly H1N1pdm2009 and H3N2), 5% had influenza B.
– Laboratory Abnormalities: Elevated liver enzymes (78%), thrombocytopenia (63%), elevated CSF protein (63%).
– Genetic Findings: Among 32 tested, 47% had potentially predisposing alleles, including RANBP2 variants (34%).
– Vaccination: Only 16% of 38 patients with available data had received age-appropriate influenza vaccination.
– Interventions: Nearly all received high-dose corticosteroids (95%), with frequent use of IVIG (66%), tocilizumab (51%), plasmapheresis (32%), and less commonly anakinra or intrathecal steroids.
– Outcomes: 27% mortality (median time to death: 3 days post-symptom onset, mainly from cerebral herniation). Of the 27 survivors with 90-day data, 63% had moderate or severe disability (mRS ≥3).
– ICU and hospital stays were prolonged (median: 11 and 22 days, respectively).
Mechanistic Insights and Pathophysiological Context
ANE is linked to a hyperinflammatory response, with cytokine storm and blood-brain barrier disruption leading to symmetric thalamic necrosis and cerebral edema. The association with RANBP2 gene variants—encoding a nuclear pore protein—suggests a genetic predisposition that may exacerbate susceptibility to inflammatory or metabolic insults during viral infections. The predominance of H1N1pdm2009 is notable, aligning with previous reports linking this influenza strain to a higher risk of neurologic complications.
Clinical Implications
This study underscores the devastating impact of influenza-associated ANE on young, previously healthy children in the US. The high rates of mortality and lasting disability, despite aggressive and multimodal immunomodulatory interventions, highlight the need for:
– Increased vigilance for ANE in children presenting with influenza and new-onset encephalopathy or seizures, particularly in the presence of rapid neurological deterioration or thalamic MRI lesions.
– Early and aggressive supportive care, including neurocritical management to prevent secondary brain injury.
– Consideration of genetic testing in all pediatric ANE cases to inform prognosis, counseling, and possible familial risk.
– Promotion and broader uptake of annual influenza vaccination, as vaccine coverage among affected children was alarmingly low.
– Development and implementation of standardized treatment protocols, as therapeutic approaches remain heterogeneous and evidence for specific interventions is limited.
Limitations and Controversies
– The study’s case series design lacks a comparison group, limiting causal inference regarding therapies or risk factors.
– Reporting bias may have occurred, as more severe or fatal cases are more likely to be captured at tertiary centers.
– Genetic risk alleles were not uniformly tested, and their pathogenicity remains incompletely understood.
– The optimal immunomodulatory regimen is still unclear, and controlled trials are lacking.
– Long-term neurodevelopmental and quality-of-life outcomes beyond 90 days were not assessed.
Expert Commentary or Guideline Positioning
Current guidelines, including from the American Academy of Pediatrics and CDC, emphasize influenza vaccination and prompt recognition of severe neurologic complications, but do not provide specific recommendations for ANE management. Expert consensus supports early use of high-dose corticosteroids, but data on adjunctive immunotherapies (e.g., IVIG, tocilizumab) are limited. Ongoing international registries and collaborative trials are needed to define optimal management strategies.
Conclusion
Influenza-associated acute necrotizing encephalopathy is an uncommon but highly morbid complication of pediatric influenza, primarily affecting previously healthy children and leading to death or severe disability in most cases. Prevention through vaccination and rapid clinical recognition are critical, as is the establishment of standardized, evidence-based treatment pathways. Further research should focus on elucidating pathophysiology, refining genetic risk stratification, and evaluating therapeutic strategies in prospective studies.
References
1. Influenza-Associated Acute Necrotizing Encephalopathy (IA-ANE) Working Group; Silverman A, Walsh R, Santoro JD, et al. Influenza-Associated Acute Necrotizing Encephalopathy in US Children. JAMA. 2025 Jul 30. doi: 10.1001/jama.2025.11534 IF: 55.0 Q1 .2. Mizuguchi M. Acute necrotizing encephalopathy of childhood: a novel form of acute encephalopathy prevalent in Japan and Taiwan. Brain Dev. 1997;19(2):81-92.
3. Centers for Disease Control and Prevention. Influenza Vaccination: A Summary for Clinicians. Updated October 2023. https://www.cdc.gov/flu/professionals/vaccination/index.htm
4. Neilson DE. The interplay of infection and genetics in acute necrotizing encephalopathy. Curr Opin Pediatr. 2010;22(6):751-7.
