Flu-linked necrotizing encephalopathy in children carries high risks | Image Credit: © Alexis Scholtz/peopleimages.com- stock.adobe.com.
A recent multicenter case series published in JAMA underscores the severity and rapid progression of influenza-associated acute necrotizing encephalopathy (ANE) in children. The study, led by Molly Wilson-Murphy, MD, and Rachel Walsh, MD, of Boston Children’s Neuroimmunology Center, examined 41 pediatric cases from 23 U.S. hospitals during the 2023 to 2025 influenza seasons and found a 27% mortality rate, with most deaths occurring within three days of symptom onset.1,2
ANE is a rare but life-threatening neurologic condition that can occur in otherwise healthy children following influenza infection. Characterized by brain inflammation, encephalopathy, and distinctive thalamic lesions, ANE often presents with fever, seizures, and altered mental status. “While rare, ANE is potentially devastating and can progress very quickly,” said Wilson-Murphy. “It is incredibly important for providers to be able to recognize ANE and to act immediately, as rapid treatment may save lives and minimize long-term difficulties.”
The majority of children in the study had no prior medical history. Median patient age was 5 years, and 76% had no preexisting conditions. Of the 41 patients, 95% had influenza A and 5% had influenza B. Among those with influenza A, the H1N1 2009 strain was most common. Despite the severity of illness, only 16% of patients had received an age-appropriate influenza vaccination for the season in which they were diagnosed, and only one of the 11 children who died had been vaccinated.
The investigation revealed that nearly all patients experienced encephalopathy and fever, and 68% presented with seizures. Neuroimaging findings commonly showed thalamic injury, with 88% of patients displaying brainstem involvement. Additionally, 63% of patients had thrombocytopenia, and elevated cerebrospinal fluid (CSF) protein was present in an equal proportion. Electroencephalography indicated generalized slowing in 95% of patients.
Despite aggressive treatment efforts, including corticosteroids (95%), intravenous immunoglobulin (66%), tocilizumab (51%), and plasmapheresis (32%), the mortality rate remained high. Among survivors, outcomes were also concerning. At 90-day follow-up, 63% of survivors had moderate to severe disability. Functional limitations included spasticity (60%), epilepsy (20%), and the need for feeding or breathing support. Only 43% of patients regained the ability to walk unassisted within three months.
“These findings emphasize the need for prevention, early recognition, intensive treatment, and standardized management protocols,” the authors wrote. The study also found genetic predispositions in a subset of patients, with 47% of those tested carrying variants potentially linked to ANE, including heterozygous RANBP2 mutations in 34%.
The data highlight a critical gap in influenza prevention through vaccination. “Vaccination may be important in helping to prevent ANE,” Wilson-Murphy noted. The results support earlier findings from international studies, such as a large Japanese epidemiologic analysis, which demonstrated that mass influenza vaccination of school-aged children significantly reduced mortality from influenza-associated encephalopathy, likely due to reduced viral transmission within communities.
The authors called for improved public health surveillance of ANE and more research into treatment strategies. Given that most deaths occurred rapidly after presentation, with a median of three days from symptom onset to death, largely due to cerebral herniation, the need for rapid diagnosis and aggressive critical care is paramount. “There is still so much we have yet to learn about ANE, but we hope this study has helped raise awareness and pave the way for more surveillance and recognition and, ultimately, to advances in treatment,” said Wilson-Murphy.
References:
- Boston Children’s Hospital. Study highlights the severity of acute necrotizing encephalopathy in kids with the flu. Eurekalert. July 30, 2025. August 4, 2025. https://www.eurekalert.org/news-releases/1093106
- Silverman A, Walsh R, Santoro JD, et al. Influenza-Associated Acute Necrotizing Encephalopathy in US Children. JAMA. Published online July 30, 2025. doi:https://doi.org/10.1001/jama.2025.11534