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 Table of Contents  
Year : 2021  |  Volume : 8  |  Issue : 4  |  Page : 192-196

Clinical, laboratory, radiologic profile, and outcome in acute necrotizing encephalopathy of childhood (ANEC) – A case series

1 Department of Pediatrics, ManipalHospital,Bengaluru,Karnataka, India
2 Department of Radiology,ManipalHospital,Bengaluru,Karnataka, India

Date of Submission08-Jan-2021
Date of Decision18-Apr-2021
Date of Acceptance07-May-2021
Date of Web Publication10-Jul-2021

Correspondence Address:
Dr. Sandip Gupta
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jpcc.jpcc_4_21

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Acute necrotizing encephalopathy of childhood (ANEC) is a potentially devastating illness characterized by fever, acute encephalopathy, and bilateral thalamic lesions. This case series is a retrospective review of clinical, laboratory, neuroimaging data of 19 children diagnosed with ANEC over 9 years at a single-center from south India. The median age was 84 months (interquartile range 25.5–120 months). All children had acute febrile encephalopathy, 12 had seizures and hypotension each, 8 had vomiting, and 5 had abnormal posturing. The liver transaminases were raised almost all children. All had bilateral thalamic lesions followed by lesions in cerebral white-matter, brain stem, and cerebellar white matter. Microbial etiology was established in 9 patients (7 dengue, 1 H1N1, 1 influenza A). Neurodeficits at discharge were seen in 63% and at follow-up in 33.3% cases. Neurodeficits at follow-up were seen in all cases with age <48 months, and only 11.1% with age >48 months age (P = 0.018).

Keywords: Acute necrotizing encephalopathy of childhood, neuroimaging, neurologic outcome, steroids

How to cite this article:
Gupta S, Banerjee B, Sasidharan SK, Acharya UV. Clinical, laboratory, radiologic profile, and outcome in acute necrotizing encephalopathy of childhood (ANEC) – A case series. J Pediatr Crit Care 2021;8:192-6

How to cite this URL:
Gupta S, Banerjee B, Sasidharan SK, Acharya UV. Clinical, laboratory, radiologic profile, and outcome in acute necrotizing encephalopathy of childhood (ANEC) – A case series. J Pediatr Crit Care [serial online] 2021 [cited 2021 Sep 19];8:192-6. Available from: http://www.jpcc.org.in/text.asp?2021/8/4/192/321103

  Introduction Top

Acute necrotizing encephalopathy of childhood (ANEC) is a potentially devastating illness characterized by fever, acute encephalopathy, and bilateral thalamic lesions.[1] Symptoms include fever, rapid-onset altered sensorium, seizures, and vomiting. Liver dysfunction is commonly seen. Cerebrospinal fluid (CSF) analysis reveals increased protein without pleocytosis. It often has high mortality and poor neurological outcome.[1],[2],[3] It is usually preceded by a nonspecific viral illness. Many pathogens including the influenza A virus have been associated, but the exact etiopathogenesis remains unknown. Familial ANEC due to RANBP2 mutations has also been reported.[1] It is now believed that infection-induced exaggerated immune response causes massive cytokine production (tumor necrosis factor-alpha [TNF-α], interleukin-1 [IL-1], and IL-6) which causes brain and other organ injuries; liver dysfunction, acute renal failure, shock, and disseminated intravascular coagulation.[1] NeuroimaginginANEC is characterized by multiple symmetrical lesions in thalami, putamina, cerebral, and cerebellar white matter, and brain stem tegmentum.[4] Initially, the disease was described in Japan, Taiwan, Korea but increasing cases are reported worldwide.[1] ANEC is a rare entity that can masquerade from febrile seizure to acute encephalitis syndrome leading to delayed recognition. Lack of standard treatment protocol, need for resource-intensive care in acute and posthospitalization phase with the variable outcome are other challenges. With clustering of ANEC cases during the H1N1 influenza pandemic and dengue outbreaks, we intend to describe our experience regarding the clinico-radiological profile and factors influencing survival and neurological outcome in ANEC.

  Case Series Top

This is a retrospective chart review at a tertiary-care hospital in South India for over 9 years (January 1, 2010 to December 31, 2018). The institutional ethics committee approved the study. All children <18 years of age admitted with a diagnosis of ANEC were included. Clinical, laboratory, and radiological data were retrieved from patients' electronic medical records which are securely stored in the hospital severs, and factors predicting outcomes were analyzed. Diagnosis of ANEC was based on acute febrile encephalopathy with neuroimaging showing symmetrical lesions involving bilateral thalami [Figure 1] and clinical absence of diseases resembling ANEC.[5] Etiologic work-up and other laboratory tests were done at the discretion of treating clinicians. Testing for dengue involved detection of NS1 antigen and IgM and IgG antibodies by ELISA and influenza A and H1N1 by reverse transcriptase-polymerase chain reaction method. Analysis of CSF was done if not contraindicated All cases were managed in the pediatric intensive care unit in consultation with a pediatric neurologist.
Figure 1: a) Axial non-contrast CT head shows bilateral thalamic hypodensities with central hyper densities. b) The axial diffusion-weighted sequence shows hyperintense foci in bilateral thalami c) Axial T1 weighted sequence shows hypointensity with central hyperintense foci in bilateral thalami d) Coronal T2 weighted sequence shows hyperintensities in bilateral thalamus e) Axial FLAIR sequences show hyperintensities in bilateral thalami, internal capsule, and f) cerebellar white mater pontine tegmentum

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An initial computed tomography (CT) head or magnetic resonance imaging (MRI) brain was performed on all patients. A neuroradiologist and pediatric neurologist reviewed neuroimages. ANE-Severity Score (ANE-SS) was used for scoring the severity of illness.[6] Neurological scores at discharge and 6 or 12 months follow-up whichever available were determined based on the Glasgow outcome scale (GOS).[7] For analysis, these groups were categorized into good (GOS 4,5), fair (GOS 3), poor outcome (GOS 1, 2). Outcome at later follow-up was considered because many children were young and had ongoing neurologic recovery with maximum neurologic recovery in 6–12 months. The minimum and maximum follow-up duration were 9.5 and 96 months, respectively. Variables analyzed for association with neurologic outcome included age, brainstem lesions, ANE-SS, and early use (within 24 h) of steroids.

Nineteen children (12 boys, 7 girls) with a median age of 84 months (interquartile range 24.5–120 months) were evaluated. All presented with fever and altered sensorium; median duration of illness at presentation being, 2 days (range 1–4). Clinical and laboratory features are enumerated in [Table 1] and [Table 2]. The most common etiology identified was dengue fever (7.36.9%). Five patients were diagnosed during the H1N1 Influenza pandemic; however, they were not tested.
Table 1: Patient's clinical characteristics

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Table 2: Clinical, laboratory, radiology and outcome data of all 19 children with acute necrotizing encephalopathy of childhood

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Initial neuroimaging was MRI brain in 12 and CT head in 7. The average time to initial neuroimaging was 2.27 ± 1.27 days. Findings are shown in [Table 2] and image 1. Of the 19 patients, 12 (63%) had high ANE-SS, 6 (31.5%) medium ANE-SS and 1 (5.9%) low ANE-SS. All received standard general supportive care for raised intracranial pressure and osmotherapy. Intubation and ventilation for poor sensorium were needed in 18 patients. Eleven received pulse methylprednisolone (30 mg/kg/day intravenous infusion for 5 days); 8 within 24 h of neurologic symptoms. Three patients required tracheostomy.

The mean duration of hospitalization was 1.8 weeks. There were 14 (73.7%) survivors and 5 (26.3%) deaths. Severe neurodeficits at discharges were seen in 12 (63%) survivors. Of 14 survivors, 2 were lost to follow-up. At median follow-up of 25 months (interquartile range 10.4–37 months) 1 (8.3%) had poor, 3 (25%) fair and 8 (66.6%) good neurologic outcome (no disability) [Table 2].

Age was one of the variables analyzed for outcome. At admission, six were younger than 48 months and 13 were older than 48 months. Poor outcomes were seen in 6 (100%) younger than 48 months age (2 had high, 3 medium ANE-SS and1 low ANE-SS, 3 brain-stem lesion) as against 8 (61.5%) older than 48 months age (10 high and 3 medium ANE-SS, 9 brain-stem lesions); however this was not statistically significant (P = 0.07). Continued neurologic improvement was seen in survivors during follow-up. At follow-up, persistent neurodeficits (fair/poor outcomes) were seen in all younger than 48 months, and in only 11.1% (1/9) patients >48 months age (P = 0.018); no statistically significant difference in outcome at discharge and follow-up was seen with respect to ANE-SS and presence/absence of brain stem lesion.

Various parameters on initial neuroimaging (lesions in brain stem, cerebral/cerebellar white matter lesions, hemorrhages) were studied for their correlation with the neurologic score at discharge and follow-up. However, no apparent correlation was noted with respect to the radiologic score at diagnosis.

  Discussion Top

In this hospital-based series of ANEC, we observed that all presented with a short febrile illness with encephalopathy and bilateral symmetric thalamic lesions along with seizures and hypotension in about two-third each, abnormal posturing in one-fourth which is comparable to the Japanese cohort by Mizuguchi et al.[5] In this study, mortality was 26.3% and neurodeficits were seen in 63%, and 33.3% at discharge and follow-up respectively. Similar mortality (25%) was seen in a Korean study by Lee et al.;[8] better outcomes were seen in another Korean study by Kim et al.[2] with 100% survival, no or mild sequelae in 57% of patients. Better outcomes arepossibly attributed to earlier recognition and management as a result of increased awareness about the disease. Continued neurologic recovery was noted at follow-up as previously described.[3],[8]

Among the determinants of the outcome at follow-up (12 months in all but one), age <48 months correlated with poor outcomes at 1-year follow-up, possibly owing to delayed recognition of “irritability” and “sleepiness” asencephalopathy. In the context of cytokine storm which is the pathomechanism in ANEC, this delay in diagnosis and initiation of treatment may contribute to neuronal injury.[1] This is in contrast to the Japanese study by Yamamoto et al., where older children had poor outcomes.[6] We found supratentorial white matter lesions in 89.4% as compared to 64.3%-68%, in previous reports, cerebellar lesions in 52.6% compared to 14.3%–71% in prior studies, and brain stem lesions in 63.1%, as compared to 73%–85.7% in previous studies.[2],[4],[5] Hemorrhagic lesions were seen in 42% compared to 41.6%–100% in previous reports. As most had early neuroimaging at a mean of 2.27 days hence we did not see cases with necrosis/cavitation as described in the score by Wong et al.[4] We did not find a correlation of radiologic score with outcome in contrast to the findings of Wong et al.

Procalcitonin (PCT) was found to be elevated in 7 out of 9 patients tested. This elevation was seen more in nonsurvivors (60%) versus 28.6% in survivors. Though a marker of severe bacterial infection, it may also be increased in inflammatory conditions like Kawasaki's disease, acute pancreatitis. Endotoxins like IL-6, TNF-α (implicated in ANEC) may induce its production. In a study on Acute Encephalopathy with Biphasic Seizures and Late Reduced Diffusion (AESD), PCT and PCT/C-reactive protein ratio were high in the AESD group compared to the febrile seizure group.[9] ANEC has been etiologically associated with viruses like Influenza A and HHV6.[2],[3],[8] Recently, COVID-19 has been associated with ANEC.[10] In this study Dengue fever was most common, contributing 37% of total cases along with 1 case each of H1N1 and Influenza A. However, the under-representation of influenza/H1N1 may be due to inadequate testing as five ANEC cases were during the H1N1 pandemic. Case reports of ANEC associated with H1N1 have been reported from India,[11],[12] but no Indian study of dengue infection is associated with ANEC. Neurological complications of Dengue are known, but there are few descriptions of ANEC.[13],[14],[15] This study to the best of our knowledge which reports the largest cluster of ANEC with dengue fever in India. With recent outbreaks of Dengue infection in the Indian subcontinent, uncommon neurologic manifestation has been seen possibly, secondary to an immune response mediated pathology causing ANEC. In this cohort, none had relapsed and they were not checked for RANBP2 mutation.

Treatment of ANEC is primarily, neuroprotection often requiring intensive care, along with antiepileptic drugs, and immunomodulatory agents.[1] The specific benefit of early pulse steroids (within 24 h of onset) in cases without brainstem lesions was reported by Okumura et al.[16] The benefit of early steroid therapy was not observed in this study, rather, they were seen to have poor outcomes at discharge. However, this group also had children with high ANE-SS and brainstem lesions wherein the benefits of steroids have been reported to be limited. Due to smaller numbers, subgroup analysis for benefit in those without brainstem lesions could not be done. Furthermore, some might have received steroids later than 24 h of the onset of encephalopathy which is difficult to time on history.

ANEC is a cause of acute febrile encephalopathy with specific neuroimaging findings. Increasing public and physician awareness by running educational campaigns about the disease, on ANE awareness day, July 31st can promote early diagnosis and appropriate treatment which can be life-saving. Local/institutional protocols will facilitate timely treatment. Multicenter trials are needed to establish the role of steroids, other immunotherapy, hypothermia in reducing mortality and morbidity in this potentially devastating illness. Rehabilitation needs to be standardized as these children tend to make gradual recovery leading to improved quality of life.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient (s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Wu X, Wu W, Pan W, Wu L, Liu K, Zhang HL. Acute necrotizing encephalopathy: An underrecognized clinicoradiologic disorder. Mediators Inflamm 2015;2015:792578.  Back to cited text no. 1
Kim JH, Kim IO, Lim MK, Park MS, Choi CG, Kim HW, et al. Acute necrotizing encephalopathy in Korean infants and children: Imaging findings and diverse clinical outcomes. Korean J Radiol 2004;5:171-7.  Back to cited text no. 2
Lim HY, Ho VP, Lim TC, Thomas T, Chan DW. Serial outcomes in acute necrotising encephalopathy of childhood: A medium and long term study. Brain Dev 2016;38:928-36.  Back to cited text no. 3
Wong AM, Simon EM, Zimmerman RA, Wang HS, Toh CH, Ng SH. Acute necrotizing encephalopathy of childhood: Correlation of MR findings and clinical outcome. AJNR Am J Neuroradiol 2006;27:1919-23.  Back to cited text no. 4
Mizuguchi M, Abe J, Mikkaichi K, Noma S, Yoshida K, Yamanaka T, et al. Acute necrotising encephalopathy of childhood: A new syndrome presenting with multifocal, symmetric brain lesions. J Neurol Neurosurg Psychiatry 1995;58:555-61.  Back to cited text no. 5
Yamamoto H, Okumura A, Natsume J, Kojima S, Mizuguchi M. A severity score for acute necrotizing encephalopathy. Brain Dev 2015;37:322-7.  Back to cited text no. 6
Jennett B, Bond M. Assessment of outcome after severe brain damage: A practical scale. Lancet 1975;305:480-4.  Back to cited text no. 7
Lee YJ, Hwang SK, Kwon S. Acute necrotizing encephalopathy in children: A long way to go. J Korean Med Sci 2019;34:e143.  Back to cited text no. 8
Fujii Y, Yashiro M, Yamada M, Kikkawa T, Nosaka N, Saito Y, et al. Serum Procalcitonin Levels in Acute Encephalopathy with Biphasic Seizures and Late Reduced Diffusion. Disease markers. 2018;2018:2380179.  Back to cited text no. 9
Poyiadji N, Shahin G, Noujaim D, Stone M, Patel S, Griffith B. COVID-19-associated acute hemorrhagic necrotizing encephalopathy: Imaging features. Radiology. 2020;296.  Back to cited text no. 10
Yoganathan S, Sudhakar SV, James EJ, Thomas MM. Acute necrotising encephalopathy in a child with H1N1 influenza infection: a clinicoradiological diagnosis and follow-up. BMJ Case Reports. 2016 Jan 11;2016:bcr-2015-213429.  Back to cited text no. 11
Takia L, Patra N, Nallasamy K, Saini L, Suthar R, Angurana SK, et al. Acute necrotizing encephalopathy of childhood with H1N1 infection. J Pediatr Intensive Care 2020;9:222-4.  Back to cited text no. 12
Carod-Artal FJ, Wichmann O, Farrar J, Gascón J. Neurological complications of dengue virus infection. Lancet Neurol 2013;12:906-19.  Back to cited text no. 13
Puccioni-Sohler M, Rosadas C, Cabral-Castro MJ. Neurological complications in dengue infection: A review for clinical practice. Arq Neuropsiquiatr 2013;71:667-71.  Back to cited text no. 14
Abbas Q, Jafri SK, Ishaque S, Jamil MT. Acute necrotizing encephalopathy of childhood secondary to dengue infection: A case report from Pakistan. J Pediatr Neurosci 2017;12:165-7.  Back to cited text no. 15
[PUBMED]  [Full text]  
Okumura A, Mizuguchi M, Kidokoro H, Tanaka M, Abe S, Hosoya M, et al. Outcome of acute necrotizing encephalopathy in relation to treatment with corticosteroids and gammaglobulin. Brain Dev 2009;31:221-7.  Back to cited text no. 16


  [Figure 1]

  [Table 1], [Table 2]


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