Q&A: A deep dive into influenza-associated acute necrotizing encephalopathy

Q: In pediatric patients presenting with acute necrotizing encephalopathy (ANE), what early clinical and imaging findings should raise suspicion for ANE, and how can timely recognition alter management and prognosis?

A: When a child presents with sudden-onset encephalopathy in the midst of a viral illness—particularly with fever, seizures, or altered mental status—ANE should be on the radar. It is rare, but it progresses quite quickly and can be devastating. Seizures are common, and many children show dramatic neurologic decline within even a day or 2 of initial infectious symptoms.

Imaging is key to diagnosis and, in addition to the clinical picture, reflects the defining feature. MRI of the brain typically shows prominent bilateral lesions in the thalami—often considered the hallmark finding of ANE. A subset of these patients has a specific pattern called trilaminar necrosis of the thalami, and if that is seen, the diagnosis is ANE. These thalamic lesions in general are critical because the thalamus is the brain's central relay station, or switchboard, and is highly implicated in disorders of consciousness. ANE lesions may also be seen in the brain stem, cerebellum, and white matter, and often show restricted diffusion or hemorrhagic changes. These findings, especially when paired with elevated liver enzyme [levels], normal ammonia [levels], low platelet [counts], and high cerebrospinal fluid protein [levels], are strong diagnostic clues.

Recognizing ANE early matters. Prompt diagnosis allows for early intensive care support and the initiation of immunotherapy. In our US multicenter case series of influenza-associated ANE, early steroid use may be linked to better outcomes. Delays in recognition and treatment can lead to cerebral edema and herniation, which, unfortunately, can result in death within the first week of illness—actually within the first few days in most fatal cases.¹

Q: How should pediatricians approach the risk of ANE in children with recent viral infections—particularly influenza or COVID-19—and what additional considerations apply if there is a known familial RANBP2 variant or other genetic predisposition?

A: Most children who get the flu or other common viruses recover without complication—but a very small subset may develop ANE, particularly with influenza A (and especially, as our data suggest, the H1N1/2009 strain). Pediatricians should be extra vigilant during peak respiratory virus season (ie, October through March, though cases have been observed outside this window) when a child with a recent infection starts showing neurologic symptoms such as confusion, lethargy, seizures, or focal neurologic deficits. We know that vaccination is key to helping prevent severe illness with influenza, and our findings suggest that vaccination may be one factor in preventing ANE. Only a small percentage of patients with ANE in our series were vaccinated, much lower than the national rates of influenza vaccination in children.

In some cases, there are genetic associations that predispose children to ANE. The most well characterized of these is a gene called RANBP2. Children with known RANBP2 variants are at higher risk for familial ANE, which can recur with future viral illnesses. In families with RANBP2 variants, individuals who carry a problematic change, also known as a pathogenic variant in the gene, may have about a 40% lifetime risk of ANE. It is important to remember that this pathogenic variant is very rare in the general population, but it’s not uncommon among people who develop ANE. As mentioned, there are other genes in addition to RANBP2 that can be associated with an increased risk of ANE. This makes family history particularly important—if a sibling or parent has had unexplained encephalopathy, genetic testing should be performed for all first-degree family members. If there is suspicion for ANE, broad genetic testing should be done as soon as possible (eg, whole-genome sequencing). If you are encountering a case post hospitalization, we maintain that a referral to a geneticist should be done for all cases of ANE, regardless of family history.

There are no formal guidelines for [treating] children with RANBP2 variants, but some clinicians recommend early antiviral and steroid treatment during febrile illnesses, and prioritizing influenza vaccination for these children and their households.

In light of our national data collection and analysis, for any child with ANE (genetic or sporadic), we strongly endorse early intensive care, alongside immunomodulatory (eg, intravenous pulse-dose corticosteroids, plasmapheresis, tocilizumab, etc) and antiviral (eg, oseltamivir) therapy. Because most children in our national case series of influenza-associated ANE had not received the seasonal influenza vaccine, we also strongly recommend annual influenza vaccination.²

Q: What are the current recommendations for acute management of ANE in children, and when should pediatricians consider initiating or referring for immunomodulatory treatments such as steroids, intravenous immunoglobulin, or plasmapheresis?

A: While there is no universal treatment protocol for ANE, most experts agree on starting high-dose intravenous steroids as early as possible. Other treatments such as intravenous immunoglobulin, tocilizumab, and plasmapheresis are also often used, but data remain limited on the efficacy of the myriad possible immunotherapies. What is clear is that early recognition and prompt treatment are critical.

Any child suspected of having ANE should be referred emergently for high-acuity medical attention. Nearly all patients with ANE will require [treatment] in a pediatric intensive care unit. These children often need airway protection, watchful neurocritical care, and sometimes intracranial pressure monitoring. Emergency and critical care providers should be wary of cerebral edema and take concrete steps to lower intracranial pressure as indicated. Pediatricians should not wait for confirmatory imaging or [laboratory results] to initiate care or transfer [the patient] to a pediatric intensive care unit with the capacity to further [treat] children with ANE—time is brain.³

Q: For survivors of ANE, what are the key neurologic and developmental concerns pediatricians should monitor long term, and how can they coordinate multidisciplinary care to support recovery and function?

A: When children survive ANE, recovery can be long, grueling, and complex. Many are left with challenges such as spasticity, movement disorders, seizures, or cognitive delays. In our US case series encompassing the 2023-2024 and 2024-2025 influenza seasons, approximately 60% of the children followed beyond 3 months had moderate to severe disability. Nearly half regained the ability to walk independently, and 40% returned to school. Another way of thinking of this is that a fair percentage of survivors recover to some degree, and many recover quite significantly. While this is a critical illness with high morbidity and mortality, early recognition and immediate treatment may help improve outcomes. For survivors, long-term recovery will require rigorous support.

This makes close, ongoing follow-up essential. Pediatricians can play a key role in coordinating multidisciplinary care, including neurology, physiatry, rehabilitation, nutrition, and educational support. Many children will need [a Section] 504 or individualized education plan, physical and occupational therapy, and neuropsychological assessments and support.

Lastly, of course, it is also important to support families through this process. ANE is traumatic, and the path forward can be overwhelming. Helping families access services—while setting realistic but hopeful expectations—can make enormous differences in long-term outcomes.⁴

References

1. Influenza-Associated Acute Necrotizing Encephalopathy (IA-ANE) Working Group; Silverman A, Walsh R, Santoro JD, et al. Influenza-associated acute necrotizing encephalopathy in US children. JAMA. 2025;334(8);692-701. doi:10.1001/jama.2025.11534
2. Uyeki TM. Pediatric influenza-associated acute necrotizing encephalopathy-gaps need to be addressed. JAMA. 2025;334(8)677-679. doi:10.1001/jama.2025.13003
3. Silverman A, Sasaki M, Espíndola Lima JE, et al. Child neurology: remarkable recovery from severe acute necrotizing encephalopathy. Neurology. 2024;103(8):e209877. doi:10.1212/WNL.0000000000209877
4. Fazal A, Reinhart K, Huang S, et al. Reports of encephalopathy among children with influenza-associated mortality - United States, 2010-11 through 2024-25 influenza seasons. MMWR Morb Mortal Wkly Rep. 2025;74(6):91-95. doi:10.15585/mmwr.mm7406a3