Influenza-Associated Encephalopathy or Encephalitis (IAE) and Acute Necrotizing Encephalopathy (ANE)

On February 27, 2025, the CDC released a Morbidity and Mortality Weekly Report (MMWR) on Reports of Encephalopathy among Children with Influenza- Associated Mortality. At least 20 hospitals across the United States have reported pediatric patients presenting with severe neurological complications of influenza, including influenza-associated encephalopathy or encephalitis (IAE) and acute necrotizing encephalopathy (ANE) during the 2023-24 and 2024-25 seasons. Because there is no dedicated U.S. surveillance for IAE (including ANE) among children, it is currently not known whether these reported cases vary from expected numbers.

Children age <5 years, and especially age <2 years, and those who have not received the seasonal influenza vaccine are at higher risk for complications from influenza. Neurological complications, such as encephalopathy and encephalitis (distinct from post-influenza immune-mediated complications such as acute disseminated encephalomyelitis), are among the most severe non-pulmonary complications of influenza. IAE is a spectrum of neurologic syndromes thought to be the result of a dysregulated host inflammatory response to the virus. ANE is the most severe form of IAE and is associated with a high morbidity and mortality rate.

Key Points: Neurological complications of influenza, including ANE, can occur in previously healthy children. Vaccination against seasonal influenza strains may represent a prevention strategy. Early recognition is important to provide the supportive care and immunomodulation necessary to reduce morbidity and mortality.

Rapid neurological deterioration during or following a febrile systemic illness.

• Patients with ANE present with neurological decompensation 1-3 days following onset of influenza symptoms of fever, respiratory symptoms, and/or gastrointestinal symptoms.
• Seizures or focal neurologic deficits
• More commonly found in children compared to adults
• Following febrile/hyperthermic systemic illness, with fever as high as 103 F

Laboratory and Imaging Findings:

• Lab abnormalities: elevated liver enzymes, low platelets, normal ammonia, and elevated CSF protein (often >100 mg/dL) Cytokine panel may be helpful in determination of adjunctive therapies.
• Characteristic neuroimaging findings: symmetric involvement of bilateral thalami in addition to possible involvement of cerebral white matter, brainstem tegmentum, and the cerebellum. Thalamic injury, which is thought to incite abrupt neurological deterioration and decline in consciousness, often involves edema and necrosis.

Treatment

• Pediatric neurology and/or neurocritical care consultation is recommended
• High quality evidence for treatment strategies does not exist. Small retrospective studies suggest a potential benefit of high-dose methylprednisolone and plasma exchange.
  • Early high-dose methylprednisolone therapy is associated with better outcomes in children with acute necrotizing encephalopathy
  • Plasma exchange therapy for acute necrotizing encephalopathy of childhood

Risk factors for poor outcomes:

• Low Glasgow Coma Scale scores on presentation
• Metabolic acidosis
• Evidence of DIC and/or organ dysfunction
• Presence of brainstem involvement

1. The American Academy of Pediatrics (AAP) provides influenza prevention and treatment recommendations for routine influenza vaccination and use of antiviral agents in children.
2. Because there are no reliable predictors for the development of neurological complications, anticipatory guidance provided to caregivers of all children with influenza should include monitoring for neurological symptoms such as lethargy, disturbances in consciousness, and convulsions.
3. Patients hospitalized with influenza should also be monitored for the development of any neurological signs or symptoms.
4. Recommendations on antiviral treatment are available from the American Academy of Pediatrics – oseltamivir is the preferred antiviral medication.
   1. Although best results are observed when the child is treated within 48 hours of symptom onset, antiviral therapy should still be considered beyond 48 hours in certain cases (see below).
   2. Antiviral treatment should be offered as early as possible to the following individuals, regardless of influenza vaccination status and duration of symptoms^*:
      • Any child hospitalized with suspected or confirmed influenza disease.
      • Any child with severe, complicated, or progressive influenza disease, regardless of health care setting (i.e., inpatient or outpatient).
      • Any child with suspected or confirmed influenza disease of any severity if they are younger than 5 years or they belong to other high-risk groups for influenza complications, regardless of health care setting (i.e., inpatient or outpatient)
   3. Treatment may be considered for the following individuals in the outpatient setting after discussing benefits and risks with parents or guardians:
      • Any child with suspected or confirmed influenza disease who is not at high risk for influenza complications if treatment can be initiated within 48 hours of illness onset.
      • Any child with suspected or confirmed influenza disease whose siblings or household contacts are either younger than 6 months or at high risk for influenza complications

Because there is no dedicated U.S. surveillance for IAE (including ANE) among children, it is currently not known whether reported cases vary from expected numbers. Enhanced surveillance to systematically identify and report pediatric IAE cases, including ANE, in the United States during the remainder of the 2024–25 season would improve understanding of the incidence of this influenza complication and the frequency of severe outcomes, including long-term neurologic sequelae or death. CDC has posted a national call for possible pediatric IAE/ANE cases identified during this influenza season on EPI-X and can be contacted at severeflu@cdc.gov.

An additional effort led by teams at Stanford and Boston Children’s is also underway to report cases of influenza-associated ANE. To report and submit case(s) of influenza-associated ANE from the 2023-24 and/or 2024-25 seasons, please contact Dr. Andrew Silverman andrew.silverman@stanford.edu and Dr. Keith Van Haren kpv@stanford.edu.

1. Age <18 years
2. Admitted to an acute care hospital or pronounced dead in an emergency department between October 1, 2024, and May 30, 2025
3. Laboratory-confirmed influenza virus infection within 14 days preceding hospital presentation, during hospitalization, or in respiratory specimens collected post-mortem
4. Documented neurologic abnormalities (meets one or more of the following):
   1. Diagnosis of encephalopathy or encephalitis
   2. Neurologic signs or symptoms including but not limited to seizures, altered mental status, delirium, decreased level of consciousness, lethargy, hallucinations, or personality changes lasting >24 hours
   3. Neuroimaging abnormalities such as brain edema, brain inflammation, or brain lesions
   4. Electroencephalogram abnormalities
   5. Abnormal brain autopsy findings, if available, for children who died

Note that the “influenza A” criteria have been removed, and any diagnosis of influenza should now be reported.

1. 2018 IDSA Clinical Practice Guidelines
2. 2025 CDC MMWR Encephalopathy Among Children with Influenza-Associated Mortality
3. 2024-2025 AAP Recommendations for Prevention and Control of Influenza in Children
4. Yen W-L, Lee K-H, Huang H-J, Tsai M-J. Influenza A-Associated Acute Necrotizing Encephalopathy. J Acute Med. 2020 Jun 1;10(2):96–97.
5. Fischell S-Z, et al. Case report: Acute necrotizing encephalopathy: a report of a favorable outcome and systematic meta-analysis of outcomes with different immunosuppressive therapies. Front Neurol. 2023 Sep 1;14:12397546.
6. Zhang H, et al. Clinical characteristics and associated factors of pediatric acute necrotizing encephalopathy: a retrospective study. Clin Exp Pediatr. 2024 Nov 11;68(2):153-162.
7. Takia L, et al. Acute Necrotizing Encephalopathy of Childhood with H1N1 Infection. J Pediatric Intensive Care. 2020 Mar 6;9(3):222-224.
8. Fang Y. et al. Clinical characteristics and prognostic analysis of acute necrotizing encephalopathy of childhood: a retrospective study at a single center in China over 3 years. Front Neurol. 2023 Dec 20:14:1308044.