Related Experiment Video
Updated: May 3, 2026
Measuring Influenza Neuraminidase Inhibition Antibody Titers by Enzyme-linked Lectin Assay
Published on: September 6, 2016
Influenza-Associated Acute Necrotizing Encephalopathy in US Children
, Andrew Silverman1, Rachel Walsh2
1Pediatric Neurology and Neuroimmunology, Lucile Packard Children's Hospital, Stanford University, Palo Alto, California.
Insights
Acute necrotizing encephalopathy (ANE) in children is a severe condition linked to influenza, causing high morbidity and mortality. Early recognition and standardized management are crucial for better outcomes in influenza-associated ANE.
Area of Science:
- Neurology
- Infectious Diseases
- Pediatrics
Background:
- Acute necrotizing encephalopathy (ANE) is a rare but severe neurological disorder with limited epidemiological and management data.
- Anecdotal reports suggest an increase in influenza-associated ANE cases in children during recent US influenza seasons.
Purpose of the Study:
- To investigate the clinical presentation, interventions, and outcomes of influenza-associated ANE in US children.
- To understand the epidemiology and risk factors associated with ANE in pediatric populations.
Main Methods:
- A multicenter case series involving children diagnosed with ANE and confirmed influenza infection.
- Data collected included clinical symptoms, vaccination status, laboratory findings, genetic testing, interventions, and clinical outcomes (modified Rankin Scale, length of stay, mortality).
- Cases were solicited from 76 US academic centers between October 1, 2023, and May 30, 2025.
Main Results:
- The study identified 41 cases of influenza-associated ANE in children, predominantly young and previously healthy individuals.
- Common presentations included fever, encephalopathy, and seizures. Influenza A was the most frequent cause.
- High rates of morbidity and mortality were observed, with 27% of patients dying and 63% of survivors experiencing moderate to severe disability.
- Genetic risk alleles, including RANBP2 variants, were identified in a significant portion of patients, and few had received influenza vaccination.
Conclusions:
- Influenza-associated ANE is a severe condition in children, characterized by high morbidity and mortality.
- The findings highlight the importance of influenza prevention, prompt diagnosis, and intensive, standardized treatment protocols.
- Further research into genetic predispositions and optimized management strategies for ANE is warranted.
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.
Related Concept Videos
01:18Bacterial Gastroenteritis
01:18Viral Meningitis
01:25Arboviral Encephalitis
01:22Bacterial Meningitis I: Introduction
01:19Encephalitis l: Introduction
01:26Encephalitis ll: Pathophysiology