Influenza-Associated Encephalopathy and Acute Necrotizing Encephalopathy in Children: A Retrospective Single-Center Study

Yongling Song, Suyun Li, Weiqiang Xiao, Jun Shen, Wencheng Ma, Qiang Wang, Haomei Yang, Guangming Liu, Yan Hong, Peiqing Li, Sida Yang, Yongling Song, Suyun Li, Weiqiang Xiao, Jun Shen, Wencheng Ma, Qiang Wang, Haomei Yang, Guangming Liu, Yan Hong, Peiqing Li, Sida Yang

Abstract

BACKGROUND Although influenza primarily affects the respiratory system, it can cause severe neurological complications, especially in younger children, but knowledge about the early indicators of acute necrotizing encephalopathy (ANE) is limited. The main purpose of this article is to summarize the clinical characteristics, diagnosis, and treatment of neurological complications of influenza in children, and to identify factors associated with ANE. MATERIAL AND METHODS This was a retrospective study of children with confirmed influenza with neurological complications treated between 01/2014 and 12/2019 at Guangzhou Women and Children's Medical Center. A receiver operating characteristics curve analysis was performed to determine the prognostic value of selected variables. RESULTS Sixty-three children with IAE (n=33) and ANE (n=30) were included. Compared with the IAE group, the ANE group showed higher proportions of fever and acute disturbance of consciousness, higher alanine aminotransferase, higher aspartate aminotransferase, higher creatinine kinase, higher procalcitonin, higher cerebrospinal fluid (CSF) protein, and lower CSF white blood cells (all P<0.05). The areas under the curve (AUCs) for procalcitonin and CSF proteins, used to differentiate IAE and ANE, were 0.790 and 0.736, respectively. The sensitivity and specificity of PCT >4.25 ng/ml to predict ANE were 73.3% and 100.0%, respectively. The sensitivity and specificity of CSF protein >0.48 g/L to predict ANE were 76.7% and 69.7%, respectively. Thirteen (43.3%) children with ANE and none with IAE died (P<0.0001). CONCLUSIONS High levels of CSF protein and serum procalcitonin might be used as early indicators for ANE. All children admitted with neurological findings, especially during the influenza season, should be evaluated for influenza-related neurological complications.

Conflict of interest statement

Conflict of interests

None.

Figures

Figure 1
Figure 1
Distribution of the neurological complications in children with influenza during 2014–2019.
Figure 2
Figure 2
Epidemic trend of brain injury caused by influenza in 2014–2019.
Figure 3
Figure 3
Using ROC curve analysis of PCT and cerebrospinal fluid protein to differentiate ANE from IAE.
Figure 4
Figure 4
A 3-year-old boy with acute necrotizing encephalitis, with fever for 2 days and convulsion once. The thalamus was swollen. Symmetrical and multifocal involvement was observed in bilateral thalamus and paraventricular (A. T1WI; B. T2WI; C. T2WI-FLAIR), and no enhancement was observed in all lesions (D) (T1WI contrast enhancement). Axial T1WI (A) showed the tricolor pattern in thalamic lesions.
Figure 5
Figure 5
A 11-month-old girl with influenza-associated encephalopathy (IAE), with fever for 2 days, no convulsion. Multiple gyrus swelling and abnormal signals were observed in bilateral cerebral hemispheres, with low signal on T1WI (A) and high signal on T2WI (B) and T2WI-FLAIR (C), more obviously on the left side. Diffuse enhancement was observed on T1WI contrast enhancement (D) in lesions of the gyrus and pia meninges.

References

    1. Grohskopf LA, Alyanak E, Broder KR, et al. Prevention and control of seasonal influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices – United States, 2019–20 Influenza Season. MMWR Recomm Rep. 2019;68:1–21.
    1. Treanor JJ. Influenza (Including avian influenza and swine influenza) In: Bennett J, Dolin R, Blaser M, editors. Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases. eighth edition. New York: Saunders; 2015.
    1. Kash JC, Taubenberger JK. The role of viral, host, and secondary bacterial factors in influenza pathogenesis. Am J Pathol. 2015;185:1528–36.
    1. Yildizdas D, Kendirli T, Arslankoylu AE, et al. Neurological complications of pandemic influenza (H1N1) in children. Eur J Pediatr. 2011;170:779–88.
    1. Akins PT, Belko J, Uyeki TM, et al. H1N1 encephalitis with malignant edema and review of neurologic complications from influenza. Neurocrit Care. 2010;13:396–406.
    1. Morishima T, Togashi T, Yokota S, et al. Encephalitis and encephalopathy associated with an influenza epidemic in Japan. Clin Infect Dis. 2002;35:512–17.
    1. Takahashi M, Yamada T, Nakashita Y, et al. Influenza virus-induced encephalopathy: Clinicopathologic study of an autopsied case. Pediatr Int. 2000;42:204–14.
    1. Wong AM, Simon EM, Zimmerman RA, et al. Acute necrotizing encephalopathy of childhood: Correlation of MR findings and clinical outcome. Am J Neuroradiol. 2006;27:1919–23.
    1. Ekstrand JJ. Neurologic complications of influenza. Semin Pediatr Neurol. 2012;19:96–100.
    1. Wu X, Wu W, Pan W, et al. Acute necrotizing encephalopathy: An underrecognized clinicoradiologic disorder. Mediators Inflamm. 2015;2015 792578.
    1. Seo HE, Hwang SK, Choe BH, et al. Clinical spectrum and prognostic factors of acute necrotizing encephalopathy in children. J Korean Med Sci. 2010;25:449–53.
    1. Kim YN, You SJ. A case of acute necrotizing encephalopathy associated with parainfluenza virus infection. Korean J Pediatr. 2012;55:147–50.
    1. Okumura A, Mizuguchi M, Kidokoro H, et al. Outcome of acute necrotizing encephalopathy in relation to treatment with corticosteroids and gammaglobulin. Brain Dev. 2009;31:221–27.
    1. San Millan B, Teijeira S, Penin C, et al. Acute necrotizing encephalopathy of childhood: Report of a Spanish case. Pediatr Neurol. 2007;37:438–41.
    1. Tabarki B, Thabet F, Al Shafi S, et al. Acute necrotizing encephalopathy associated with enterovirus infection. Brain Dev. 2013;35:454–57.
    1. Vargas WS, Merchant S, Solomon G. Favorable outcomes in acute necrotizing encephalopathy in a child treated with hypothermia. Pediatr Neurol. 2012;46:387–89.
    1. Lyon JB, Remigio C, Milligan T, Deline C. Acute necrotizing encephalopathy in a child with H1N1 influenza infection. Pediatr Radiol. 2010;40:200–5.
    1. Aydin H, Ozgul E, Agildere AM. Acute necrotizing encephalopathy secondary to diphtheria, tetanus toxoid and whole-cell pertussis vaccination: Diffusion-weighted imaging and proton MR spectroscopy findings. Pediatr Radiol. 2010;40:1281–84.
    1. Okumura A, Mizuguchi M, Aiba H, et al. Delirious behavior in children with acute necrotizing encephalopathy. Brain Dev. 2009;31:594–99.
    1. Ohsaka M, Houkin K, Takigami M, Koyanagi I. Acute necrotizing encephalopathy associated with human herpesvirus-6 infection. Pediatr Neurol. 2006;34:160–63.
    1. Mastroyianni SD, Voudris KA, Katsarou E, et al. Acute necrotizing encephalopathy associated with parainfluenza virus in a Caucasian child. J Child Neurol. 2003;18:570–72.
    1. Kim JH, Kim IO, Lim MK, et al. Acute necrotizing encephalopathy in Korean infants and children: Imaging findings and diverse clinical outcome. Korean J Radiol. 2004;5:171–77.
    1. Yamamoto H, Okumura A, Natsume J, et al. A severity score for acute necrotizing encephalopathy. Brain Dev. 2015;37:322–27.
    1. Goenka A, Michael BD, Ledger E, et al. Neurological manifestations of influenza infection in children and adults: Results of a National British Surveillance Study. Clin Infect Dis. 2014;58:775–84.
    1. Sugaya N. Influenza-associated encephalopathy in Japan. Semin Pediatr Infect Dis. 2002;13:79–84.
    1. Shiomi M. [Pathogenesis of acute encephalitis and acute encephalopathy]. Nihon Rinsho. 2011;69:399–408. [in Japanese]
    1. Howard A, Uyeki TM, Fergie J. Influenza-associated acute necrotizing encephalopathy in siblings. J Pediatric Infect Dis Soc. 2018;7:e172–77.
    1. Lafond KE, Nair H, Rasooly MH, et al. Global role and burden of influenza in pediatric respiratory hospitalizations, 1982–2012: A systematic analysis. PLoS Med. 2016;13:e1001977.
    1. Halasa NB. Update on the 2009 pandemic influenza A H1N1 in children. Curr Opin Pediatr. 2010;22:83–87.
    1. Flannery B, Reynolds SB, Blanton L, et al. Influenza vaccine effectiveness against pediatric deaths: 2010–2014. Pediatrics. 2017;139:e20164244.
    1. Newland JG, Laurich VM, Rosenquist AW, et al. Neurologic complications in children hospitalized with influenza: Characteristics, incidence, and risk factors. J Pediatr. 2007;150:306–10.
    1. Britton PN, Blyth CC, Macartney K, et al. The spectrum and burden of influenza-associated neurological disease in children: Combined encephalitis and influenza sentinel site surveillance from Australia, 2013–2015. Clin Infect Dis. 2017;65:653–60.
    1. To KF, Chan PK, Chan KF, et al. Pathology of fatal human infection associated with avian influenza A H5N1 virus. J Med Virol. 2001;63:242–46.
    1. Rothberg MB, Pekow PS, Liu F, et al. Potentially inappropriate medication use in hospitalized elders. J Hosp Med. 2008;3:91–102.
    1. Surana P, Tang S, McDougall M, et al. Neurological complications of pandemic influenza A H1N1 2009 infection: European case series and review. Eur J Pediatr. 2011;170:1007–15.
    1. Kimura S, Ohtuki N, Nezu A, et al. Clinical and radiological variability of influenza-related encephalopathy or encephalitis. Acta Paediatr Jpn. 1998;40:264–70.
    1. Voudris KA, Skaardoutsou A, Haronitis I, et al. Brain MRI findings in influenza A – associated acute necrotizing encephalopathy of childhood. Eur J Paediatr Neurol. 2001;5:199–202.
    1. Khandaker G, Zurynski Y, Buttery J, et al. Neurologic complications of influenza A(H1N1)pdm09: Surveillance in 6 pediatric hospitals. Neurology. 2012;79:1474–81.
    1. Mizuguchi M, Yamanouchi H, Ichiyama T, Shiomi M. Acute encephalopathy associated with influenza and other viral infections. Acta Neurol Scand. 2007;115:45–56.
    1. Kawashima H, Togashi T, Yamanaka G, et al. Efficacy of plasma exchange and methylprednisolone pulse therapy on influenza-associated encephalopathy. J Infect. 2005;51:E53–56.
    1. Turgut M, Sagirogluo S. Suboccipital decompressive craniectomy in a case of complex Chiari malformation complicated with influenza A (H1N1) necrotizing encephalopathy. Childs Nerv Syst. 2020;36:1335–36.
    1. Çiftçi E, Tuygun N, Özdemir H, et al. Clinical and epidemiological features of Turkish children with 2009 pandemic influenza A (H1N1) infection: Experience from multiple tertiary paediatric centres in Turkey. Scand J Infect Dis. 2011;43:923–29.
    1. Teke T, Coskun R, Sungur M, et al. 2009 H1N1 influenza and experience in three critical care units. Int J Med Sci. 2011;8:270–77.

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