ANE is a rare but fulminant neurologic complication of viral infections, most frequently caused by influenza. The illness is marked by acute encephalopathy and thalamic damage, resulting in progressive neurological deterioration. Due to its rarity, clinicians are frequently uncertain in diagnosing and managing ANE, with resultant variable treatment strategies and outcomes. This research offers one of the largest US case series available to date, providing important insight into the clinical spectrum, treatment, and prognosis of influenza-associated ANE.
This study was a multicenter series of cases coordinated across academic societies, pediatric experts, and public health organizations. Reporting of cases was solicited from 76 US academic institutions, with participation restricted to patients aged 21 years and younger who had acute encephalopathy, radiologic thalamic injury, and laboratory-confirmed influenza infection from October 1, 2023, through May 30, 2025.
Data on clinical presentation, vaccination history, laboratory results, genetic testing, treatments, and outcomes were collected, with emphasis on the modified Rankin Scale (mRS) as an outcome measure of neurological disability (0: no symptoms; 6: death).
Key Findings
Patient demographics: Median age 5 years (IQR, 2–8); 23 were female (56%).
Medical history: 76% (31 patients) had no pre-existing medical conditions; 12% (5 patients) were medically complex.
Clinical presentation:
Influenza subtypes:
39 patients (95%) had influenza A (14 A/H1pdm/2009, 7 A/H3N2, 18 untyped).
2 patients had influenza B.
Laboratory abnormalities:
Elevated liver enzymes: 78%
Thrombocytopenia: 63%
Elevated CSF protein: 63%
Genetic testing: Done in 32 patients (78%); 15 (47%) had potential genetic susceptibility, including 11 (34%) with RANBP2 variants.
Vaccination history: Of 38 patients with information, only 6 (16%) had been age-appropriately vaccinated against influenza.
Treatment given:
Hospitalization:
Median stay in ICU: 11 days (IQR, 4–19)
Median hospital stay: 22 days (IQR, 7–36)
Outcome:
11 patients (27%) died within a median of 3 days (IQR, 2–4) from onset, largely as a result of cerebral herniation (91%).
Among the 27 survivors with 90-day follow-up, 63% had moderate-to-severe disability (mRS ≥3).
The majority of the patients were healthy before the disease and had not been vaccinated, stressing the importance of influenza prophylaxis, prompt diagnosis, intensive supportive management, and creation of standard management guidelines.
Reference:
Influenza-Associated Acute Necrotizing Encephalopathy (IA-ANE) Working Group. Influenza-Associated Acute Necrotizing Encephalopathy in US Children. JAMA. 2025;334(8):692–701. doi:10.1001/jama.2025.11534
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