Silverman Andrew, Walsh Rachel, Santoro Jonathan D, Thomas Katherine, Ballinger Elizabeth, Fisher Kristen S, Thomas Ajay X, Appavu Brian, Kruer Michael C, Neilson Derek, Knoll Jasmine, Sharp April N, Edelman Hannah E, Otallah Scott, Morgan Alexandra, Grzezulkowska Aniela, Nguyen John, Rao Lekha M, Hecht Shaina M, Catalano Laura, Daigle Hunter, Kronfol Catherine, Wharton Jessica, Adams David, Kalawi Adam Z, Kung Michael, Arellano Janetta L, Smith Lauren, Segal Devorah, Feja Kristina, Broomall Eileen, Jayakar Anuj, Arnold Sandra R, Retallack Hanna, Press Craig A, Gombolay Grace, McLaughlin Madeleine H, Kannan Varun, Thakkar Kavita, Rezwan Tasmia, Hulfish Erin, Eid Dalia, Meylor Jennifer, Peng Diane, Hurtado Ryan, Nickerson Taylor, Mandell Iris, Carbonell Abigail U, Kerner-Rossi Mallory, Jayaraman Divya, Davis Mallory, Olivero Rosemary, Shah Neel, Osborne Christina M, Zhang Bo, Cortina Christopher, Randolph Adrienne G, Rao Suchitra, LaRocca Thomas, Van Haren Keith P, Wilson-Murphy Molly
Pediatric Neurology and Neuroimmunology, Lucile Packard Children's Hospital, Stanford University, Palo Alto, California.
Department of Neurology and Pediatric Neuroimmunology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
JAMA. 2025 Jul 30. doi: 10.1001/jama.2025.11534.
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.
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.
Influenza-associated ANE.
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.
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).
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.
急性坏死性脑病（ANE）是一种罕见但严重的神经系统疾病，其流行病学和管理数据仍然有限。在2024 - 2025年美国流感季节，大型儿科中心的临床医生 anecdotal（原文有误，推测可能是anecdotally，意为“轶事地，非官方地”）报告称，与流感相关的ANE患儿数量有所增加，促使开展了这项全国性调查。
了解美国诊断为与流感相关的ANE的儿童的临床表现、干预措施和结局。
设计、背景和参与者：本研究是一项对诊断为ANE的儿童进行纵向随访的多中心病例系列研究。通过学术团体、公共卫生机构以及直接联系美国76个学术中心的儿科专家发出病例征集通知，要求提供2023年10月1日至2025年5月30日期间的病例。纳入标准要求21岁及以下个体出现急性脑病且有急性丘脑损伤的影像学证据以及流感感染的实验室确诊。
与流感相关的ANE。
呈现的症状、疫苗接种史、实验室和基因检测结果、干预措施以及临床结局，包括改良Rankin量表评分（0：无症状；1 - 2：轻度残疾；3 - 5：中度至重度残疾；6：死亡）、住院时间和功能结局。
在提交的58例病例中，来自美国23家医院的41例病例（23名女性；中位年龄5岁[四分位间距，2 - 8岁]）符合纳入标准。31例（76%）无重大病史；5例（12%）病情复杂。临床表现包括38例（93%）发热、41例（100%）脑病和28例（68%）癫痫发作。39例（95%）感染甲型流感（14例感染A/H1pdm/2009、7例感染A/H3N2、1例未分型），2例感染乙型流感。实验室异常包括肝酶升高（78%）、血小板减少（63%）和脑脊液蛋白升高（63%）。在32例（78%）进行基因检测的患者中，15例（47%）具有可能与ANE风险相关的基因风险等位基因，包括11例（34%）具有RANBP2变异。在38例有可用疫苗接种史的患者中，只有6例（16%）接种了适合年龄的季节性流感疫苗。大多数患者接受了多种免疫调节治疗，包括甲基强的松龙（95%）、静脉注射免疫球蛋白（66%）、托珠单抗（51%）、血浆置换（32%）、阿那白滞素（
