WFN Neuroinfectious Disease Update [August '25]

B. Jeanne Billioux, MD, and Avindra Nath, MD

This WFN Neuroinfectious disease update describes a recent article published on influenza-associated encephalopathy (IAE) and acute necrotizing encephalopathy (ANE), H5N1-related encephalitis, and the recent Nipah virus outbreak in Kerala State in India.

Influenza-associated encephalopathy (IAE) is a range of neurologic symptoms triggered by infection with influenza, with acute necrotizing encephalopathy (ANE) as the most severe form. ANE is characterized by a viral prodrome followed by rapid neurologic deterioration with altered consciousness, seizures, and focal neurologic deficits; imaging typically shows diffuse cerebral inflammation and distinctive symmetric thalamic and deep gray matter lesions. Although this is a rare complication, during the last two flu seasons, pediatricians in the US noted what seemed to be a rise in cases of ANE, prompting a multicenter investigation.

Recently reported in JAMA, the Influenza-Associated Acute Necrotizing Encephalopathy Working Group detailed their findings of a case series of 41 children diagnosed with ANE across 23 US hospitals between October 2023 and May 2025. The majority of the cases (n=31, 76%) had no prior significant medical history, and most patients with ANE also had not received age-appropriate immunization against influenza (n=32, 78%). In the cohort, presenting symptoms included a typical viral prodrome with subsequent mental status changes (median Glasgow Coma Scale at presentation of 6); seizures were frequent at presentation (n=28, 68%). Most (n=39, 95%) patients tested positive for Influenza A; subtypes H1 2009 and H3, and of the 32 patients with genetic testing, 15 patients had a gene with possible or likely relevance to ANE (with variant in RANBP2 being the most common abnormality identified, in 11 patients). Of those imaged with MRI, all patients had typical findings with T2 signal intensity changes in the thalamus bilaterally, as well as associated changes in the subcortical white matter, basal ganglia, and brainstem; restricted diffusion was seen in the majority of patients (n=37, 97%), with 27 patients (73%) showing susceptibility-weighted imaging findings, and 17 (46%) with trilaminar necrosis of the thalami. Management typically included a dual antiviral and immunotherapeutic strategy, with 31 patients (76%) receiving oseltamivir and 39 (95%) receiving intravenous methylprednisolone as first-line therapy. Other immunotherapies included intravenous immunoglobulin, tocilizumab, plasmapheresis, and anakinra; other antivirals used included acyclovir, peramivir, and remdesivir. Anecdotally, a senior author noted that “early, intensive management of brain swelling and immune response really seemed to help children with this condition recover,” (clinicallab.com 2025). Unfortunately, mortality was high at 27% (n=11). Most of these patients died shortly after admission (median 3 days), often due to cerebral herniation due to cerebral edema (n=10). Of the patients who died, only one had received a seasonal flu vaccine. Of the 27 survivors who were followed up to 90 days, most (n=17, 63%) had moderate to severe disability. These included various levels of neurologic symptomatology such as spasticity (n=18, 60%), dystonia (n=9, 30%), and epilepsy (n=6, 20%). This study highlights the fact that influenza can lead to ANE even in previously healthy children, and that seasonal influenza vaccination may be preventative for this deadly complication (Influenza-Associated Acute Necrotizing Encephalopathy (IA-ANE) Working Group 2025).

In other influenza-related news, a case of H5N1 avian flu-related encephalitis was reported in Vietnam this past April (Schnirring, Cidrap.umn.edu 2025). A 3-year-old girl in Mexico died in April 2025 after getting infected with H5N1 bird flu, according to a report by the World Health Organization. The strain of bird flu circulating in wild birds throughout North America, known as D1.1. This is also implicated in the death of a person in Louisiana earlier this year, and in the case of a 13-year-old Canadian who was placed on life-support for several weeks before recovering. Two others, a person in Wyoming and a poultry worker in Ohio, were also reported to have severe disease after exposure to this strain of the virus.

Previous outbreaks of highly pathogenic avian influenza virus (HPAI) have been rarely associated with encephalitis as evidenced by a handful of case reports (Mak 2017, Rajabali 2015). H5N1 is an avian flu virus that is widespread in wild birds, currently causing outbreaks in poultry farms as well as dairy cows. Of note, H5N1 and other HPAIs have been known to infect other species such as felines and sea mammals, often causing neurologic symptoms (Mainenti 2025, Mirolo 2023). Occasional zoonotic crossover into humans occurs, typically in poultry or dairy workers, with no known person-to-person spread at this time (CDC.gov). In 2025, there have been 22 cases reported, with 8 fatalities, with the largest number in Cambodia (11) (WHO H5N1 Emergency Situation Update 1 July 2025). The WHO assessment of global public health risk of H5 influenza is currently low (WHO influenza A(H5) Update 28 Jul 2025).

Regarding other neurotropic virus outbreaks, a new outbreak of Nipah virus has been reported in Kerala State, India, with 4 confirmed cases between May 17 and July 12, 2025, according to a recent WHO Disease Outbreak News report. Since 2018, Kerala has had 9 outbreaks, all small in nature. Nipah virus is a zoonotic disease with a high fatality, ranging from 40-100%, with either an encephalitic or a pneumonic presentation. It is typically transmitted from fruit bats (Pteropus), often through contamination of date palm sap and fruit, although person-to-person transmission may also occur. There is currently no vaccine or approved therapy for treatment (WHO Nipah Virus DON 6 Aug 2025).

References

• 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 Jul 30:e2511534. Epub ahead of print.
  DOI: 10.1001/jama.2025.11534 ⧉
  
  
• “Rapid Treatment Improves Outcomes in Children with Rare Flu Brain Complication. ⧉” Today’s Clincal Lab. Published Aug 07, 2025, accessed Aug 12, 2025.
  
• Schnirring, Lisa. “Vietnam reports H5N1 avian flu case with encephalitis. ⧉” CIDRAP.unm.edu. Published April 21, 2025. Accessed August 12, 2025. 
  
  
• Mak GCK, Kwan MY, Mok CKP, Lo JYC, Peiris M, Leung CW. Influenza A(H5N1) Virus Infection in a Child With Encephalitis Complicated by Obstructive Hydrocephalus. ⧉ Clin Infect Dis. 2018 Jan 6;66(1):136-139. doi: 10.1093/cid/cix707. PMID: 29020163; PMCID: PMC5850530.
  
  
• Rajabali N, Lim T, Sokolowski C, Prevost JD, Lee EZ. Avian influenza A (H5N1) infection with respiratory failure and meningoencephalitis in a Canadian traveller. ⧉ Can J Infect Dis Med Microbiol. 2015 Jul-Aug;26(4):221-3. doi: 10.1155/2015/961080. PMID: 26361492; PMCID: PMC4556185.
  
  
• Mainenti M, Siepker C, Magstadt DR, Gauger P, Baum D, Petersen B, Aubrey T, Sett K, Burrough ER. Distribution of lesions and detection of influenza A(H5N1) virus, clade 2.3.4.4b, in ante- and postmortem samples from naturally infected domestic cats on U.S. dairy farms. ⧉ J Vet Diagn Invest. 2025 Jan;37(1):27-35. doi: 10.1177/10406387241300464. Epub 2024 Dec 14. PMID: 39673479; PMCID: PMC11645685.
  
  
• Mirolo M, Pohlmann A, Ahrens AK, Kühl B, Rubio-Garcìa A, Kramer K, Meinfelder U, Rosenberger T, Morito HL, Beer M, Ludlow M, Wohlsein P, Baumgärtner W, Harder T, Osterhaus A. Highly pathogenic avian influenza A virus (HPAIV) H5N1 infection in two European grey seals (Halichoerus grypus) with encephalitis. ⧉ Emerg Microbes Infect. 2023 Dec;12(2):e2257810. doi: 10.1080/22221751.2023.2257810. Epub 2023 Sep 8. PMID: 37682060; PMCID: PMC10768861.
  
  
• “H5 Bird Flu: Current Situation. ⧉” CDC.gov. Published 1 Aug 2025, accessed 12 August 2025.
  
  
• “Cumulative number of confirmed human cases for avian influenza A (H5N1) reported to WHO, 2003-2025, 1 July 2025. ⧉” The World Health Organization. 
  
  
•  “Updated joint FAO/WHO/WOAH public health assessment of recent influenza A(H5) virus events in animals and people. ⧉” The World Health Organization. 28 July 2025.