Abstract
Importance: Acute necrotizing encephalopathy (ANE) is a rare, but severe, neurologic condition for which epidemiologic and management data remain limited. During the 2024-2025 US influenza season, clinicians at large pediatric centers anecdotally reported an increased number of children with influenza-associated ANE, prompting this national investigation.
Objective: To understand the clinical presentation, interventions, and outcomes among US children diagnosed with influenza-associated ANE.
Design, setting, and participants: This study was a multicenter case series of children diagnosed with ANE with longitudinal follow-up. A call for cases was issued via academic societies, public health agencies, and by directly contacting pediatric specialists at 76 US academic centers, requesting cases between October 1, 2023, and May 30, 2025. Inclusion criteria required acute encephalopathy with radiologic evidence of acute thalamic injury and laboratory confirmation of influenza infection in individuals aged 21 years or younger.
Exposure: Influenza-associated ANE.
Main outcomes and measures: Presenting symptoms, vaccination history, laboratory and genetic findings, interventions, and clinical outcomes, including modified Rankin Scale score (0: no symptoms; 1-2: mild disability; 3-5: moderate to severe disability; 6: death), length of stay, and functional outcomes.
Results: Of 58 submitted cases, 41 cases (23 females; median age, 5 years [IQR, 2-8]) from 23 US hospitals met inclusion criteria. Thirty-one cases (76%) had no significant medical history; 5 (12%) were medically complex. Clinical presentation included fever in 38 patients (93%), encephalopathy in 41 (100%), and seizures in 28 (68%). Thirty-nine patients (95%) had influenza A (14 with A/H1pdm/2009, 7 with A/H3N2, and 18 with no subtype) and 2 had influenza B. Laboratory deviations included elevated liver enzymes (78%), thrombocytopenia (63%), and elevated cerebrospinal fluid protein (63%). Among 32 patients (78%) with genetic testing, 15 (47%) had genetic risk alleles potentially related to risk of ANE including 11 (34%) with RANBP2 variants. Among 38 patients with available vaccination history, only 6 (16%) had received age-appropriate seasonal influenza vaccination. Most patients received multiple immunomodulatory treatments, including methylprednisolone (95%), intravenous immunoglobulin (66%), tocilizumab (51%), plasmapheresis (32%), anakinra (5%), and intrathecal methylprednisolone (5%). Median intensive care unit and hospital lengths of stay were 11 days (IQR, 4-19) and 22 days (IQR, 7-36), respectively. Eleven patients (27%) died a median of 3 days (IQR, 2-4) from symptom onset, primarily from cerebral herniation (91%). Among the 27 survivors with 90-day follow-up, 63% had at least moderate disability (modified Rankin Scale score ≥3).
Conclusions and relevance: In this case series of children with influenza-associated ANE from the 2 most recent influenza seasons in the US, the condition was associated with high morbidity and mortality in this cohort of predominantly young and previously healthy children. The findings emphasize the need for prevention, early recognition, intensive treatment, and standardized management protocols.
Fazal A, Harker EJ, Neelam V, Olson SM, Rolfes MA, Reinhart K, Kniss K, Frutos A, Leonard J, Reed C, Dugan VG, Safi H, Dulski TM, Stanley-Downs A, Bhatti A, Armistead I, Rao S, Torres-Diaz C, Thomas A, Weigel A, Patten M, Sinner M, Nims D, Mattingly C, Gosack V, Voris A, Redkey J, Scaggs Huang FA, DeCesaris D, Tuggle C, Betters KA, Hand J, Krueger A, Potter DZ, Kim C, Park R, Hong S, Edelman HE, Kim S, Henderson J, McMahon M, Sanders J, Hunstad DA, Doran EL, Harbi K, Julian D, Ball H, Dreisig J, Thomas D, Faybusovich J, Shaw YP, Eisenberg N, Chaturvedi R, Faulstich A, Wester RE, Gowie DL, Fisher N, Sutton M, Boktor SW, Long JM, Marshall P, Berns AL, McAda L, Winders S, Gomez Pinedo P, Murray J, Westbrook T, Unutzer A, Lindquist S, Haupt TE, Baum K, Wilson-Murphy M, Glaser C, Harriman K, Antoon JW, Van Haren KP, Randolph AG, Silverman A, de St Maurice A, Ellington S, Uyeki TM, Garg S; CDC Influenza-Associated Encephalopathy Collaborators. Pediatric Influenza-Associated Encephalopathy and Acute Necrotizing Encephalopathy - United States, 2024-25 Influenza Season. MMWR Morb Mortal Wkly Rep. 2025 Sep 25;74(36):556-564. doi: 10.15585/mmwr.mm7436a1. PMID: 40996921; PMCID: PMC12463191.
Abstract
In January 2025, CDC received several reports of deaths among children aged <18 years with a severe form of influenza-associated encephalopathy (IAE) termed acute necrotizing encephalopathy (ANE). Because no national surveillance for IAE currently exists, CDC requested notification of U.S. pediatric IAE cases from clinicians and health departments during the 2024-25 influenza season, a high-severity season with a record number of pediatric influenza-associated deaths. Among 192 reports of suspected IAE submitted to CDC, 109 (57%) were categorized as IAE, 37 (34%) of which were subcategorized as ANE, and 72 (66%) as other IAE; 82 reports did not meet IAE criteria and were categorized as other influenza-associated neurologic disease. The median age of children with IAE was 5 years and 55% were previously healthy, 74% were admitted to an intensive care unit, and 19% died; 41% of children with ANE died. Only 16% of children with IAE who were vaccination-eligible had received the 2024-25 influenza vaccine. Health care providers should consider IAE in children with encephalopathy or altered level of consciousness and a recent or current febrile illness when influenza viruses are circulating. Annual influenza vaccination is recommended for all children aged ≥6 months to prevent influenza and associated complications, potentially including severe neurologic disease such as IAE and ANE.
Silverman A, Sasaki M, Espíndola Lima JE, Cheronis C, Lin GL, Johnson A, Dahmoush H, Archer E, Grekov K, LaRocca TJ, Van Haren K. Child Neurology: Remarkable Recovery From Severe Acute Necrotizing Encephalopathy. Neurology. 2024 Oct 22;103(8):e209877. doi: 10.1212/WNL.0000000000209877. Epub 2024 Sep 19. PMID: 39298704.
Abstract
A previously healthy 6-year-old girl presented with several days of fever before a generalized seizure. Laboratory investigation revealed elevated liver enzymes, normal ammonia, and positive influenza A through respiratory PCR. Brain MRI demonstrated extensive, bilateral lesions in the cerebral and cerebellar white matter, thalami, basal ganglia, and brainstem. She was diagnosed with acute necrotizing encephalopathy, a rare parainfectious encephalitis commonly associated with influenza. Genetic variants have been implicated (e.g., RANBP2 and RNH1), but our patient's rapid genome was nondiagnostic. Her 1-month hospitalization was complicated by prolonged encephalopathy and intracranial pressure crises requiring hyperosmolar therapy, sedation, intermittent paralysis, and hypothermia. Concomitantly, she received pulse corticosteroids, plasmapheresis, and oseltamivir. Three months after illness onset, she achieved a remarkable recovery with a normal neurologic examination. Although prognosis may comprise considerable morbidity and mortality, prompt recognition, immunotherapy, and intensive care can achieve positive neurodevelopmental outcomes. Our discussion concludes with a focus on the intrinsic uncertainties of neuroprognostication in the pediatric intensive care unit.
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