Child's Nervous System

, Volume 34, Issue 2, pp 335–347 | Cite as

Neuroinfluenza: evaluation of seasonal influenza associated severe neurological complications in children (a multicenter study)

  • Muhammet Sukru PaksuEmail author
  • Kerim Aslan
  • Tanil Kendirli
  • Basak Nur Akyildiz
  • Nazik Yener
  • Riza Dincer Yildizdas
  • Mehmet Davutoglu
  • Ayhan Yaman
  • Sedat Isikay
  • Gulnar Sensoy
  • Haydar Ali Tasdemir
Original Paper



Although influenza primarily affects the respiratory system, in some cases, it can cause severe neurological complications. Younger children are especially at risk. Pediatric literature is limited on the diagnosis, treatment, and prognosis of influenza-related neurological complications. The aim of the study was to evaluate children who suffered severe neurological manifestation as a result of seasonal influenza infection.


The medical records of 14 patients from six hospitals in different regions of the country were evaluated. All of the children had a severe neurological manifestations related to laboratory-confirmed influenza infection.


Median age of the patients was 59 months (6 months—15.5 years) and nine (64.3%) were male. Only 4 (28.6%) of the 14 patients had a comorbid disease. Two patients were admitted to hospital with influenza-related late complications, and the remainder had acute complication. The most frequent complaints at admission were fever, altered mental status, vomiting, and seizure, respectively. Cerebrospinal fluid (CSF) analysis was performed in 11 cases, and pleocytosis was found in only two cases. Neuroradiological imaging was performed in 13 patients. The most frequent affected regions of nervous system were as follows: cerebellum, brainstem, thalamus, basal ganglions, periventricular white matter, and spinal cords. Nine (64.3%) patients suffered epileptic seizures. Two patients had focal seizure, and the rest had generalized seizures. Two patients developed status epilepticus. Most frequent diagnoses of patients were encephalopathy (n = 4), encephalitis (n = 3), and meningitis (n = 3), respectively. The rate of recovery without sequelae from was found to be 50%. At discharge, three (21.4%) patients had mild symptoms, another three (21.4%) had severe neurological sequelae. One (7.1%) patient died. The clinical findings were more severe and outcome was worse in patients <5 years old than patients >5 years old and in patients with comorbid disease than previously healthy group.


Seasonal influenza infection may cause severe neurological complications, especially in children. Healthy children are also at risk such as patients with comorbid conditions. All children who are admitted with neurological findings, especially during the influenza season, should be evaluated for influenza-related neurological complications even if their respiratory complaints are mild or nonexistent.


Influenza Infection Neurological complication Children 


Authors’ contributions

Muhammet Sukru Paksu was performed literature search and writing and submitting of the manuscript.

Kerim Aslan was evaluated neuroradiological images of study patients.

Tanil Kendirli was recorded patient medical data of hospital 2 and he edited of manuscript.

Basak Nur Akyildiz was recorded patient medical data of hospital 3 she edited of manuscript.

Nazik Yener was recorded patient medical data of hospital 1 and she searched the literature.

Riza Dincer Yildizdas was recorded patient medical data of hospital 4 and he edited of manuscript.

Mehmet Davutoglu was recorded patient medical data of hospital 5 and he edited of manuscript.

Ayhan Yaman was recorded patient medical data of hospital 6.

Sedat Isikay was recorded patient medical data of hospital 5.

Gulnar Sensoy was edited and approved the final version of the manuscript.

Haydar Ali Tasdemir was edited and approved the final version of the manuscript.

Compliance with ethical standards


This study was not funded by any institution, organization, or company. No honorarium, grant, or other form of payment was given to anyone to produce the manuscript.

Conflict of interest

The authors declare that they have no conflict of interest associated with this study.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The study was approved by the local ethics committee of Ondokuz Mayis University (Samsun, Turkey).

According to local ethical standards, informed consent is not needed for retrospective study.


  1. 1.
    Yildizdas D, Kendirli T, Arslankoylu AE, Horoz OO, Incecik F, Ince E, Ciftci E (2011) Neurological complications of pandemic influenza (H1N1) in children. Eur J Pediatr 170:779–788PubMedPubMedCentralGoogle Scholar
  2. 2.
    Akins PT, Belko J, Uyeki TM, Axelrod Y, Lee KK, Silverthorn J (2010) H1N1 encephalitis with malignant edema and review of neurologic complications from influenza. Neurocrit Care 13:396–406PubMedPubMedCentralGoogle Scholar
  3. 3.
    Newland JG, Laurich VM, Rosenquist AW, Heydon K, Licht DJ, Keren R, Zaoutis TE, Watson B, Hodinka RL, Coffin SE (2007) Neurologic complications in children hospitalized with influenza: characteristics, incidence, and risk factors. J Pediatr 150:306–310PubMedPubMedCentralGoogle Scholar
  4. 4.
    Morishima T, Togashi T, Yokota S, Okuno Y, Miyazaki C, Tashiro M, Okabe N, Collaborative Study Group on Influenza-Associated Encephalopathy in J (2002) Encephalitis and encephalopathy associated with an influenza epidemic in Japan. Clin Infect Dis 35:512–517PubMedPubMedCentralGoogle Scholar
  5. 5.
    Surana P, Tang S, McDougall M, Tong CY, Menson E, Lim M (2011) Neurological complications of pandemic influenza A H1N1 2009 infection: European case series and review. Eur J Pediatr 170:1007–1015PubMedPubMedCentralGoogle Scholar
  6. 6.
    Chiu SS, Tse CY, Lau YL, Peiris M (2001) Influenza A infection is an important cause of febrile seizures. Pediatrics 108:E63PubMedPubMedCentralGoogle Scholar
  7. 7.
    Maricich SM, Neul JL, Lotze TE, Cazacu AC, Uyeki TM, Demmler GJ, Clark GD (2004) Neurologic complications associated with influenza A in children during the 2003-2004 influenza season in Houston, Texas. Pediatrics 114:e626–e633PubMedPubMedCentralGoogle Scholar
  8. 8.
    Belay ED, Bresee JS, Holman RC, Khan AS, Shahriari A, Schonberger LB (1999) Reye's syndrome in the United States from 1981 through 1997. N Engl J Med 340:1377–1382PubMedPubMedCentralGoogle Scholar
  9. 9.
    Landau YE, Grisaru-Soen G, Reif S, Fattal-Valevski A (2011) Pediatric neurologic complications associated with influenza A H1N1. Pediatr Neurol 44:47–51PubMedPubMedCentralGoogle Scholar
  10. 10.
    Nakamura Y, Ikeda K, Yoshii Y, Ito H, Hirayama T, Kawabe K, Kano O, Iwasaki Y (2011) Influenza-associated monophasic neuromyelitis optica. Intern Med 50:1605–1609PubMedPubMedCentralGoogle Scholar
  11. 11.
    Lehmann HC, Hartung HP, Kieseier BC, Hughes RA (2010) Guillain-Barre syndrome after exposure to influenza virus. Lancet Infect Dis 10:643–651PubMedPubMedCentralGoogle Scholar
  12. 12.
    Khandaker G, Zurynski Y, Buttery J, Marshall H, Richmond PC, Dale RC, Royle J, Gold M, Snelling T, Whitehead B, Jones C, Heron L, McCaskill M, Macartney K, Elliott EJ, Booy R (2012) Neurologic complications of influenza A(H1N1)pdm09: surveillance in 6 pediatric hospitals. Neurology 79:1474–1481PubMedPubMedCentralGoogle Scholar
  13. 13.
    Wong AM, Simon EM, Zimmerman RA, Wang HS, Toh CH, Ng SH (2006) Acute necrotizing encephalopathy of childhood: correlation of MR findings and clinical outcome. AJNR Am J Neuroradiol 27:1919–1923PubMedPubMedCentralGoogle Scholar
  14. 14.
    Isikay S (2016) Influenza A (H1N1) infection associated acute necrotizing encephalopathy in a child with periodic lateralized epileptiform discharges. Pediatr Emerg Care 32:e14–e15PubMedPubMedCentralGoogle Scholar
  15. 15.
    Sachedina N, Donaldson LJ (2010) Paediatric mortality related to pandemic influenza a H1N1 infection in England: an observational population-based study. Lancet 376:1846–1852Google Scholar
  16. 16.
    Surtees R, DeSousa C (2006) Influenza virus associated encephalopathy. Arch Dis Child 91:455–456PubMedPubMedCentralGoogle Scholar
  17. 17.
    Dawood FS, Chaves SS, Perez A, Reingold A, Meek J, Farley MM, Ryan P, Lynfield R, Morin C, Baumbach J, Bennett NM, Zansky S, Thomas A, Lindegren ML, Schaffner W, Finelli L, Emerging Infections Program N (2014) Complications and associated bacterial coinfections among children hospitalized with seasonal or pandemic influenza, United States, 2003-2010. J Infect Dis 209:686–694Google Scholar
  18. 18.
    Wilking AN, Elliott E, Garcia MN, Murray KO, Munoz FM (2014) Central nervous system manifestations in pediatric patients with influenza A H1N1 infection during the 2009 pandemic. Pediatr Neurol 51:370–376PubMedGoogle Scholar
  19. 19.
    Zeng H, Quinet S, Huang W, Gan Y, Han C, He Y, Wang Y (2013) Clinical and MRI features of neurological complications after influenza A (H1N1) infection in critically ill children. Pediatr Radiol 43:1182–1189Google Scholar
  20. 20.
    Steininger C, Popow-Kraupp T, Laferl H, Seiser A, Godl I, Djamshidian S, Puchhammer-Stockl E (2003) Acute encephalopathy associated with influenza A virus infection. Clin Infect Dis 36:567–574PubMedPubMedCentralGoogle Scholar
  21. 21.
    Omari I, Breuer O, Kerem E, Berger I (2011) Neurological complications and pandemic influenza A (H1N1) virus infection. Acta Paediatr 100:e12–e16PubMedPubMedCentralGoogle Scholar
  22. 22.
    Glaser CA, Gilliam S, Schnurr D, Forghani B, Honarmand S, Khetsuriani N, Fischer M, Cossen CK, Anderson LJ, California Encephalitis P (2003) In search of encephalitis etiologies: diagnostic challenges in the California Encephalitis Project, 1998-2000. Clin Infect Dis 36:731–742PubMedPubMedCentralGoogle Scholar
  23. 23.
    Frobert E, Sarret C, Billaud G, Gillet Y, Escuret V, Floret D, Casalegno JS, Bouscambert M, Morfin F, Javouhey E, Lina B (2011) Pediatric neurological complications associated with the A(H1N1)pdm09 influenza infection. J Clin Virol 52:307–313PubMedPubMedCentralGoogle Scholar
  24. 24.
    Kwon S, Kim S, Cho MH, Seo H (2012) Neurologic complications and outcomes of pandemic (H1N1) 2009 in Korean children. J Korean Med Sci 27:402–407PubMedPubMedCentralGoogle Scholar
  25. 25.
    Kedia S, Stroud B, Parsons J, Schreiner T, Curtis DJ, Bagdure D, Brooks-Kayal AR, Glode MP, Dominguez SR (2011) Pediatric neurological complications of 2009 pandemic influenza A (H1N1). Arch Neurol 68:455–462PubMedPubMedCentralGoogle Scholar
  26. 26.
    Toovey S (2008) Influenza-associated central nervous system dysfunction: a literature review. Travel Med Infect Dis 6:114–124PubMedPubMedCentralGoogle Scholar
  27. 27.
    Centers for Disease C, Prevention (2009) Surveillance for pediatric deaths associated with 2009 pandemic influenza A (H1N1) virus infection—United States, April-August 2009. MMWR Morb Mortal Wkly Rep 58:941–947Google Scholar
  28. 28.
    Bhat N, Wright JG, Broder KR, Murray EL, Greenberg ME, Glover MJ, Likos AM, Posey DL, Klimov A, Lindstrom SE, Balish A, Medina MJ, Wallis TR, Guarner J, Paddock CD, Shieh WJ, Zaki SR, Sejvar JJ, Shay DK, Harper SA, Cox NJ, Fukuda K, Uyeki TM, Influenza Special Investigations T (2005) Influenza-associated deaths among children in the United States, 2003-2004. N Engl J Med 353:2559–2567PubMedPubMedCentralGoogle Scholar
  29. 29.
    McSwiney P, Purnama J, Kornberg A, Danchin M (2014) A severe neurological complication of influenza in a previously well child. BMJ Case Rep. doi: 10.1136/bcr-2014-206930 Google Scholar
  30. 30.
    Ozkan M, Tuygun N, Erkek N, Aksoy A, Yildiz YT (2011) Neurologic manifestations of novel influenza A (H1N1) virus infection in childhood. Pediatr Neurol 45:72–76PubMedPubMedCentralGoogle Scholar
  31. 31.
    Prerna A, Lim JY, Tan NW, Isa MS, Oh HM, Yassin N, Low CY, Chan DW, Chong CY, Leo YS, Chow AL, Tambyah PA, Tan K (2015) Neurology of the H1N1 pandemic in Singapore: a nationwide case series of children and adults. J Neuro-Oncol 21:491–499Google Scholar
  32. 32.
    Ishida Y, Kawashima H, Morichi S, Yamanaka G, Okumura A, Nakagawa S, Morishima T (2015) Brain magnetic resonance imaging in acute phase of pandemic influenza A (H1N1) 2009—associated encephalopathy in children. Neuropediatrics 46:20–25PubMedPubMedCentralGoogle Scholar
  33. 33.
    Nakai Y, Itoh M, Mizuguchi M, Ozawa H, Okazaki E, Kobayashi Y, Takahashi M, Ohtani K, Ogawa A, Narita M, Togashi T, Takashima S (2003) Apoptosis and microglial activation in influenza encephalopathy. Acta Neuropathol 105:233–239PubMedPubMedCentralGoogle Scholar
  34. 34.
    Takahashi M, Yamada T, Nakashita Y, Saikusa H, Deguchi M, Kida H, Tashiro M, Toyoda T (2000) Influenza virus-induced encephalopathy: clinicopathologic study of an autopsied case. Pediatr Int 42:204–214PubMedPubMedCentralGoogle Scholar
  35. 35.
    Goenka A, Michael BD, Ledger E, Hart IJ, Absoud M, Chow G, Lilleker J, Lunn M, McKee D, Peake D, Pysden K, Roberts M, Carrol ED, Lim M, Avula S, Solomon T, Kneen R (2014) Neurological manifestations of influenza infection in children and adults: results of a National British Surveillance Study. Clin Infect Dis 58:775–784PubMedPubMedCentralGoogle Scholar
  36. 36.
    Mizuguchi M, Yamanouchi H, Ichiyama T, Shiomi M (2007) Acute encephalopathy associated with influenza and other viral infections. Acta Neurol Scand 115:45–56PubMedGoogle Scholar
  37. 37.
    Kumakura A, Iida C, Saito M, Mizuguchi M, Hata D (2011) Pandemic influenza A-associated acute necrotizing encephalopathy without neurologic sequelae. Pediatr Neurol 45:344–346PubMedPubMedCentralGoogle Scholar
  38. 38.
    Kawashima H, Togashi T, Yamanaka G, Nakajima M, Nagai M, Aritaki K, Kashiwagi Y, Takekuma K, Hoshika A (2005) Efficacy of plasma exchange and methylprednisolone pulse therapy on influenza-associated encephalopathy. J Inf Secur 51:E53–E56Google Scholar
  39. 39.
    Kimberlin DW, Shalabi M, Abzug MJ, Lang D, Jacobs RF, Storch G, Bradley JS, Wade KC, Ramilo O, Romero JR, Shelton M, Leach C, Guzman-Cottrill J, Robinson J, Abughali N, Englund J, Griffin J, Jester P, Cloud GA, Whitley RJ, Group NCAS (2010) Safety of oseltamivir compared with the adamantanes in children less than 12 months of age. Pediatr Infect Dis J 29:195–198PubMedPubMedCentralGoogle Scholar
  40. 40.
    Nagao T, Morishima T, Kimura H, Yokota S, Yamashita N, Ichiyama T, Kurihara M, Miyazaki C, Okabe N (2008) Prognostic factors in influenza-associated encephalopathy. Pediatr Infect Dis J 27:384–389Google Scholar
  41. 41.
    Randolph AG, Vaughn F, Sullivan R, Rubinson L, Thompson BT, Yoon G, Smoot E, Rice TW, Loftis LL, Helfaer M, Doctor A, Paden M, Flori H, Babbitt C, Graciano AL, Gedeit R, Sanders RC, Giuliano JS, Zimmerman J, Uyeki TM, Pediatric Acute Lung I, Sepsis Investigator’s N, the National Heart L, Blood Institute ACTN (2011) Critically ill children during the 2009-2010 influenza pandemic in the United States. Pediatrics 128:e1450–e1458PubMedPubMedCentralGoogle Scholar
  42. 42.
    Fuchigami T, Imai Y, Hasegawa M, Ishii W, Endo A, Arakawa C, Kohira R, Hashimoto K, Fujita Y, Inamo Y, Mugishima H (2012) Acute encephalopathy with pandemic (H1N1) 2009 virus infection. Pediatr Emerg Care 28:998–1002PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany 2017

Authors and Affiliations

  • Muhammet Sukru Paksu
    • 1
    • 2
    Email author
  • Kerim Aslan
    • 3
  • Tanil Kendirli
    • 4
  • Basak Nur Akyildiz
    • 5
  • Nazik Yener
    • 1
  • Riza Dincer Yildizdas
    • 6
  • Mehmet Davutoglu
    • 7
  • Ayhan Yaman
    • 8
  • Sedat Isikay
    • 9
  • Gulnar Sensoy
    • 10
  • Haydar Ali Tasdemir
    • 11
  1. 1.Pediatric Intensive Care UnitOndokuz Mayis University Faculty of MedicineSamsunTurkey
  2. 2.Ondokuz Mayis Universitesi Tip Fakultesi Cocuk Yogun Bakim UnitesiSamsunTurkey
  3. 3.Department of RadiologyOndokuz Mayis University Faculty of MedicineSamsunTurkey
  4. 4.Pediatric Intensive Care UnitAnkara University Faculty of MedicineAnkaraTurkey
  5. 5.Pediatric Intensive Care UnitErciyes University Faculty of MedicineKayseriTurkey
  6. 6.Pediatric Intensive Care UnitCukurova University Faculty of MedicineAdanaTurkey
  7. 7.Pediatric Intensive Care UnitSutcu Imam University Faculty of MedicineKahramanmarasTurkey
  8. 8.Pediatric Intensive Care UnitObstetrics and Gynecology and Children’s HospitalGaziantepTurkey
  9. 9.Pediatric NeurologySutcu Imam University Faculty of MedicineKahramanmarasTurkey
  10. 10.Department of Pediatric Infection DiseasesOndokuz Mayis University Faculty of MedicineSamsunTurkey
  11. 11.Department of Pediatric NeurologyOndokuz Mayis University Faculty of MedicineSamsunTurkey

Personalised recommendations