A 2008 review by our group concluded that the risk of neuropsychiatric adverse events (NPAEs) in influenza patients was not increased by oseltamivir exposure, and did not identify any mechanism by which oseltamivir or its metabolites could cause or worsen such events. The current article reviews new information on this topic. Between September 16, 2007 and May 15, 2010, 1,805 spontaneously-reported NPAEs were identified in 1,330 patients receiving oseltamivir: 767 (42.5%) from Japan, 296 (16.4%) from the USA, and 742 (41.1%) from other countries. NPAEs were more common in children: 1,072 (59.4%) events were in those aged ≤16 years. NPAEs often occurred within 48 h of treatment initiation (953 events; 52.8%). Nearly half of the events were serious in nature (838; 46.4%). The three largest categories of events were abnormal behavior (457 events, 25.3%), miscellaneous psychiatric events (370; 20.5%), and delusions/perceptual disturbances (316 events, 17.5%). A total of 1,545 events (85.6%) in eight different categories were considered to be delirium or delirium-like. Twenty-eight suicide-related events were reported. A US healthcare claims database analysis showed that the risk of NPAEs in 7,798 oseltamivir-treated patients was no higher than that in 10,411 patients not on antivirals, but a study on oseltamivir and abnormal behavior in Japan was less conclusive. NPAE frequency in oseltamivir-exposed Japanese and Taiwanese children with influenza was the same as in unexposed children. New analysis of the UK General Practice Research Database showed that the relative adjusted risk of NPAEs in influenza patients was 2.18-times higher than in the general population. Other epidemiology studies report frequent occurrence of encephalitis and similar disorders in influenza patients independently of oseltamivir exposure. The new data support the findings of the original assessment. Evidence suggests that influenza-related encephalopathies are caused by influenza-induced inflammatory responses, but more work is needed to confirm the underlying mechanisms.
Supplementary material is available on SpringerLink.com.
Toovey S, Rayner C, Prinssen E, et al. Assessment of neuropsychiatric adverse events in influenza patients treated with oseltamivir: a comprehensive review. Drug Saf. 2008;31:1097–114.
Kasai T, Togashi T, Morishima T. Encephalopathy associated with influenza epidemics. Lancet. 2000;355:1558–9.
Morishima T, Togashi T, Yokota S, et al. Encephalitis and encephalopathy associated with an influenza epidemic in Japan. Clin Infect Dis. 2002;35:512–7.
Okabe N, Yamashita K, Taniguchi K, Inouye S. Influenza surveillance system of Japan and acute encephalitis and encephalopathy in the influenza season. Pediatr Int. 2000;42:187–91.
Food and Drug Administration (FDA). Meeting of the FDA Pediatric Advisory Committee. November 16, 2006. Available at: http://www.fda.gov/OHRMS/DOCKETS/ac/oc06.htm. Accessed Sep 10 2012
Donner B, Bader-Weder S, Schwarz R, Peng MM, Smith JR, Niranjan V. Safety profile of oseltamivir during the 2009 influenza pandemic. Pharmacoepidemiol Drug Saf. 2011;20:532–43.
Smith JR, Sacks S. Incidence of neuropsychiatric adverse events in influenza patients treated with oseltamivir or no antiviral treatment. Int J Clin Pract. 2009;63:596–605.
Casscells SW, Granger E, Kress AM, Linton A. The association between oseltamivir use and adverse neuropsychiatric outcomes among TRICARE beneficiaries, ages 1 through 21 years diagnosed with influenza. Int J Adolesc Med Health. 2009;21:79–89.
Hirota Y. Survey research on the emergence of influenza-associated symptoms. 2007/2008 research subteam report. 2009. Tokyo: MHLW Scientific Research Fund.
Yorifuji T, Suzuki E, Tsuda T. Oseltamivir and abnormal behaviors: true or not? Epidemiology. 2009;20:619–21.
Peng MM, Robinson NJ. Oseltamivir and abnormal behavior. Epidemiology. 2010;21:915–6.
Kimberlin DW, Shalabi M, Abzug MJ, et al. Safety of oseltamivir compared with the adamantanes in children less than 12 months of age. Pediatr Infect Dis J. 2010;29:195–8.
Hama R. Fatal neuropsychiatric adverse reactions to oseltamivir: case series and overview of causal relationship. Int J Risk Saf Med. 2008;20:5–36.
Huang YC, Li WC, Tsao KC, et al. Influenza-associated central nervous system dysfunction in Taiwanese children: clinical characteristics and outcomes with and without administration of oseltamivir. Pediatr Infect Dis J. 2009;28:647–8.
Tanabe T, Hara K, Nakajima M, Shimakawa S, Tamai H. Oseltamivir treatment for children showing abnormal behavior during influenza virus infection. Brain Dev. 2010;32:440–4.
Takanashi J, Tada H, Kuroki H, Barkovich AJ. Delirious behavior in influenza is associated with a reversible splenial lesion. Brain Dev. 2009;31:423–6.
Baltagi SA, Shoykhet M, Felmet K, Kochanek PM, Bell MJ. Neurological sequelae of 2009 influenza A (H1N1) in children: a case series observed during a pandemic. Pediatr Crit Care Med. 2010;11:179–84.
Rellosa N, Bloch KC, Shane AL, Debiasi RL. Neurologic manifestations of pediatric novel H1N1 influenza infection. Pediatr Infect Dis J. 2011;30:165–7.
Tan K, Prerna A, Leo YS. Surveillance of H1N1-related neurological complications. Lancet Neurol. 2010;9:142–3.
Wiwanitkit V. Swine flu encephalitis: a comment on the first case in Thailand. J Neurol Sci. 2009;26:518–9.
Calitri C, Gabiano C, Garazzino S, et al. Clinical features of hospitalised children with 2009 H1N1 influenza virus infection. Eur J Pediatr. 2010;169:1511–5.
Centers for Disease Control and Prevention (CDC). Neurologic complications associated with novel influenza A (H1N1) virus infection in children — Dallas, Texas, May 2009. MMWR Morb Mortal Wkly Rep. 2009;58:773–8.
Chen YC, Lo CP, Chang TP. Novel influenza A (H1N1)-associated encephalopathy/encephalitis with severe neurological sequelae and unique image features — A case report. J Neurol Sci. 2010;298:110–3.
Citerio G, Sala F, Patruno A, et al. Influenza A (H1N1) encephalitis with severe intracranial hypertension. Minerva Anestesiol. 2010;76:459–62.
German-Diaz M, Pavo-Garcia R, Diaz-Diaz J, Giangaspro-Corradi E, Negreira-Cepeda S. Adolescent with neuropsychiatric symptoms associated with novel influenza A (H1N1) virus infection. Pediatr Infect Dis J. 2010;29:570–1.
Gonzalez BE, Brust DG. Novel influenza A (H1N1) presenting as an acute febrile encephalopathy in a mother and daughter. Clin Infect Dis. 2009;49:1966–7.
Haktanir A. MR imaging in novel influenza A(H1N1)-associated meningoencephalitis. AJNR Am J Neuroradiol. 2010;31:394–5.
Kedia S, Stroud B, Parsons J, et al. Pediatric neurological complications of 2009 pandemic influenza A (H1N1). Arch Neurol. 2011;68:455–62.
Kwong KL, Hiu H, Hui CM, Que TL. A tragic case of flu. HK J Paediatr. 2007;12:199–201.
Lee N, Wong CK, Chan PK, et al. Acute encephalopathy associated with influenza A infection in adults. Emerg Infect Dis. 2010;16:139–42.
Li X, Du Y. Neurologic complications associated with novel influenza A (H1N1) virus infection in Nanchong, Chengdu, November 2009. J Exp Clin Med. 2010;2:254–6.
Mariotti P, Iorio R, Frisullo G, et al. Acute necrotizing encephalopathy during novel influenza A (H1N1) virus infection. Ann Neurol. 2010;68:111–4.
Martin A, Reade EP. Acute necrotizing encephalopathy progressing to brain death in a pediatric patient with novel influenza A (H1N1) infection. Clin Infect Dis. 2010;50:e50–e52.
Noriega LM, Verdugo RJ, Araos R, et al. Pandemic influenza A (H1N1) 2009 with neurological manifestations, a case series. Influenza Other Respi Viruses. 2010;4:117–20.
O’Leary MF, Chappell JD, Stratton CW, et al. Complex febrile seizures followed by complete recovery in an infant with high-titer 2009 pandemic influenza A (H1N1) virus infection. J Clin Microbiol. 2010;48:3803–5.
Ormitti F, Ventura E, Summa A, Picetti E, Crisi G. Acute necrotizing encephalopathy in a child during the 2009 influenza A(H1N1) pandemia: MR imaging in diagnosis and follow-up. AJNR Am J Neuroradiol. 2010;31:396–400.
Samuel N, Attias O, Tatour S, Brik R. Novel influenza A (H1N1) and acute encephalitis in a child. Isr Med Assoc J. 2010;12:446–7.
Tada H, Takanashi JI, Terada H, Tajima K. Severe form of acute influenza encephalopathy with biphasic seizures and late reduced diffusion. Neuropediatrics. 2008;39:134–6.
Webster RI, Hazelton B, Suleiman J, et al. Severe encephalopathy with swine origin influenza A H1N1 infection in childhood: case reports. Neurology. 2010;74:1077–8.
Yamashita S, Kouzaki Y, Kawano R, Tokunaga M, Uchino M. Acute ophthalmoparesis accompanied with influenza A infection. Intern Med. 2008;47:1627–9.
Yildizdas D, Kendirli T, Arslankoylu AE, et al. Neurological complications of pandemic influenza (H1N1) in children. Eur J Pediatr. 2011;170:779–88.
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.
Choi SY, Jang SH, Kim JO, et al. Novel swine-origin influenza A (H1N1) viral encephalitis. Yonsei Med J. 2010;51:291–2.
Costiniuk CT, Le SN, Sell E, et al. Miller Fisher syndrome in a toddler with influenza A (pH1N1) infection. J Child Neurol. 2011;26:385–8.
Gadoth A, Aizenstein O, Mosek A. Influenza A/H1N1 encephalitis. Neurology. 2010;75:666–7.
Kimura E, Okamoto S, Uchida Y, et al. A reversible lesion of the corpus callosum splenium with adult influenza-associated encephalitis/encephalopathy: a case report. J Med Case Reports. 2008;2:220.
Sanchez-Torrent L, Trivino-Rodriguez M, Suero-Toledano P, et al. Novel influenza A (H1N1) encephalitis in a 3-month-old infant. Infection. 2010;38:227–9.
Fugate JE, Lam EM, Rabinstein AA, Wijdicks EF. Acute hemorrhagic leukoencephalitis and hypoxic brain injury associated with H1N1 influenza. Arch Neurol. 2010;67:756–8.
Gonzalez-Duarte A, Magana ZL, Cantu BC, Garcia-Ramos G. Hypothalamic abnormalities and Parkinsonism associated with H1N1 influenza infection. J Neuroinflammation. 2010;7:47.
Data on file. Basel: Roche; 2010.
Okabe N. Research on Abnormal Behaviour Accompanying Influenza — Report of the 2008–2009 season. Available at: http://www.mhlw.go.jp/shingi/2009/06/dl/s0603-6b.pdf. Accessed 23 Sep 2012
Fowler A, Stodberg T, Eriksson M, Wickstrom R. Childhood encephalitis in Sweden: etiology, clinical presentation and outcome. Eur J Paediatr Neurol. 2008;12:484–90.
Hjalmarsson A, Blomqvist P, Brytting M, Linde A, Skoldenberg B. Encephalitis after influenza in Sweden 1987-1998: a rare complication of a common infection. Eur Neurol. 2009;61:289–94.
Amin R, Ford-Jones E, Richardson SE, et al. Acute childhood encephalitis and encephalopathy associated with influenza: a prospective 11-year review. Pediatr Infect Dis J. 2008;27:390–5.
Ekstrand JJ, Herbener A, Rawlings J, et al. Heightened neurologic complications in children with pandemic H1N1 influenza. Ann Neurol. 2010;68:762–6.
Fukumoto Y, Okumura A, Hayakawa F, et al. Serum levels of cytokines and EEG findings in children with influenza associated with mild neurological complications. Brain Dev. 2007;29:425–30.
Li WC, Shih SR, Huang YC, et al. Clinical and genetic characterization of severe influenza B-associated diseases during an outbreak in Taiwan. J Clin Virol. 2008;42:45–51.
Chung B, Wong V. Relationship between five common viruses and febrile seizure in children. Arch Dis Child. 2007;92:593.
Chung BH, Tsang AM, Wong VC. Neurologic complications in children hospitalized with influenza: comparison between USA and Hong Kong. J Pediatr. 2007;151:e17–8.
Kwong KL, Lung D, Wong SN, Que TL, Kwong NS. Influenza-related hospitalisations in children. J Paediatr Child Health. 2009;45:660–4.
Hon KL, Leung E, Tang J, et al. Premorbid factors and outcome associated with respiratory virus infections in a pediatric intensive care unit. Pediatr Pulmonol. 2008;43:275–80.
Louie JK, Gavali S, Acosta M, et al. Children hospitalized with 2009 novel influenza A(H1N1) in California. Arch Pediatr Adolesc Med. 2010;164:1023–31.
Parakh A, Kumar A, Kumar V, Dutta AK, Khare S. Pediatric hospitalizations associated with 2009 pandemic influenza A (H1N1): an experience from a tertiary care center in North India. Indian J Pediatr. 2010;77:981–5.
Stein M, Tasher D, Glikman D, et al. Hospitalization of children with influenza A(H1N1) virus in Israel during the 2009 outbreak in Israel: a multicenter survey. Arch Pediatr Adolesc Med. 2010;164:1015–22.
Zheng Y, He Y, Deng J, et al. Hospitalized children with 2009 influenza a (H1N1) infection in Shenzhen, China, November–December 2009. Pediatr Pulmonol. 2010; Oct 20. [Epub ahead of print.]
Shin SY, Kim JH, Kim HS, et al. Clinical characteristics of Korean pediatric patients critically ill with influenza A (H1N1) virus. Pediatr Pulmonol. 2010;45:1014–20.
Zhao C, Gan Y, Sun J. Radiographic study of severe Influenza-A (H1N1) disease in children. Eur J Radiol 2011;79:447–51.
Wada T, Morishima T, Okumura A, et al. Differences in clinical manifestations of influenza-associated encephalopathy by age. Microbiol Immunol. 2009;53:83–8.
Nagao T, Morishima T, Kimura H, et al. Prognostic factors in influenza-associated encephalopathy. Pediatr Infect Dis J. 2008;27:384–9.
Wang CC, Chen PY, Wang JD, et al. Clinical and laboratory analysis of influenza B infection in children in Taichung, Taiwan during the 2006–2007 flu season. Pediatr Neonatol. 2009;50:54–8.
Terada K, Kawai Y, Monju A, Wakabayashi T, Ouchi K. Adolescent jump case in Japan associated with influenza but not oseltamivir. Pediatr Infect Dis J. 2008;27:88–9.
Takayanagi M, Umehara N, Watanabe H, et al. Acute encephalopathy associated with influenza C virus infection. Pediatr Infect Dis J. 2009;28:554.
Okumura A, Abe S, Kidokoro H, Mizuguchi M. Acute necrotizing encephalopathy: a comparison between influenza and non-influenza cases. Microbiol Immunol. 2009;53:277–80.
Gika AD, Rich P, Gupta S, Neilson DE, Clarke A. Recurrent acute necrotizing encephalopathy following influenza A in a genetically predisposed family. Dev Med Child Neurol. 2010;52:99–102.
Lyon JB, Remigio C, Milligan T, Deline C. Acute necrotizing encephalopathy in a child with H1N1 influenza infection. Pediatr Radiol. 2010;40:200–5.
Ng WF, Chiu SC, Lam DS, et al. A 7-year-old boy dying of acute encephalopathy. Brain Pathol. 2010;20:261–4.
Troedson C, Gill D, Dale RC. Emergence of acute necrotising encephalopathy in Australia. J Paediatr Child Health. 2008;44:599–601.
Neilson DE, Adams MD, Orr CM, et al. Infection-triggered familial or recurrent cases of acute necrotizing encephalopathy caused by mutations in a component of the nuclear pore, RANBP2. Am J Hum Genet. 2009;84:44–51.
Bartynski WS, Upadhyaya AR, Petropoulou KA, Boardman JF. Influenza A encephalopathy, cerebral vasculopathy, and posterior reversible encephalopathy syndrome: combined occurrence in a 3-year-old child. AJNR Am J Neuroradiol. 2010;31:1443–6.
Bartynski WS, Upadhyaya AR, Boardman JF. Posterior reversible encephalopathy syndrome and cerebral vasculopathy associated with influenza A infection: report of a case and review of the literature. J Comput Assist Tomogr. 2009;33:917–22.
Henry J, Smeyne RJ, Jang H, Miller B, Okun MS. Parkinsonism and neurological manifestations of influenza throughout the 20th and 21st centuries. Parkinsonism Relat Disord. 2010;16:566–71.
Toovey S, Jick SS, Meier CR. Parkinson’s disease or Parkinson symptoms following seasonal influenza. Influenza Other Respi Viruses. 2011;5:328–33.
Hoffmann G, Funk C, Fowler S, et al. Nonclinical pharmacokinetics of oseltamivir and oseltamivir carboxylate in the central nervous system. Antimicrob Agents Chemother. 2009;53:4753–61.
Hatori A, Arai T, Yanamoto K, et al. Biodistribution and metabolism of the anti-influenza drug [11C] oseltamivir and its active metabolite [11C]Ro 64-0802 in mice. Nucl Med Biol. 2009;36:47–55.
Jhee SS, Yen M, Ereshefsky L, et al. Low penetration of oseltamivir and its carboxylate into cerebrospinal fluid in healthy Japanese and Caucasian volunteers. Antimicrob Agents Chemother. 2008;52:3687–93.
Ose A, Ito M, Kusuhara H, et al. Limited brain distribution of [3R,4R,5S]-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate phosphate (Ro 64-0802), a pharmacologically active form of oseltamivir, by active efflux across the blood-brain barrier mediated by organic anion transporter 3 (Oat3/Slc22a8) and multidrug resistance-associated protein 4 (Mrp4/Abcc4). Drug Metab Dispos. 2009;37:315–21.
Uchida Y, Ohtsuki S, Katsukura Y, et al. Quantitative targeted absolute proteomics of human blood-brain barrier transporters and receptors. J Neurochem. 2011;117:333–45.
Oshima S, Nemoto E, Kuramochi M, Saitoh Y, Kobayashi D. Penetration of oseltamivir and its active metabolite into the brain after lipopolysaccharide-induced inflammation in mice. J Pharm Pharmacol. 2009;61:1397–400.
Lindemann L, Jacobsen H, Schuhbauer D, et al. In vitro pharmacological selectivity profile of oseltamivir prodrug (Tamiflu®) and active metabolite. Eur J Pharmacol. 2010;628:6–10.
Izumi Y, Tokuda K, O’Dell KA, Zorumski CF, Narahashi T. Neuroexcitatory actions of Tamiflu and its carboxylate metabolite. Neurosci Lett. 2007;426:54–8.
Knoflach F, Trube G, Buisson B, Steidl-Armougom E, Prinssen P, Lindemann L. Evaluation of pharmacological activities of oseltamivir on paired-pulse inhibition in the CA1 region of adult rat hippocampus. p. 822.18. Available at: http://www.sfn.org/skins/main/pdf/abstracts/am2009/poster_presentations/PosterPresentation_WedPM.pdf. Accessed Sep 10 2012
Usami A, Sasaki T, Satoh N, et al. Oseltamivir enhances hippocampal network synchronization. J Pharmacol Sci. 2008;106:659–62.
Satoh K, Nonaka R, Ogata A, Nakae D, Uehara S. Effects of oseltamivir phosphate (Tamiflu) and its metabolite (GS4071) on monoamine neurotransmission in the rat brain. Biol Pharm Bull. 2007;30:1816–8.
Data on file. Basel: Roche; 1998.
Izumi Y, Tokuda K, O’Dell K, Zorumski C, Narahashi T. Synaptic and behavioral interactions of oseltamivir (Tamiflu) with neurostimulants. Hum Exp Toxicol. 2008;27:911–7.
Uchimura N, Kuwahara H, Kumagai Y, et al. Absence of adverse effects of oseltamivir on sleep: a double-blind, randomized study in healthy volunteers in Japan. Basic Clin Pharmacol Toxicol. 2011;109:309–14.
Doucette KE, Aoki FY. Oseltamivir: a clinical and pharmacological perspective. Expert Opin Pharmacother. 2001;2:1671–83.
He G, Massarella J, Ward P. Clinical pharmacokinetics of the prodrug oseltamivir and its active metabolite Ro 64-0802. Clin Pharmacokinet. 1999;37:471–84.
Shi D, Yang J, Yang D, et al. Anti-influenza prodrug oseltamivir is activated by carboxylesterase human carboxylesterase 1, and the activation is inhibited by antiplatelet agent clopidogrel. J Pharmacol Exp Ther. 2006;319:1477–84.
Zhu HJ, Markowitz JS. Activation of the antiviral prodrug oseltamivir is impaired by two newly identified carboxylesterase 1 variants. Drug Metab Dispos. 2009;37:264–7.
Yang D, Pearce RE, Wang X, et al. Human carboxylesterases HCE1 and HCE2: ontogenic expression, inter-individual variability and differential hydrolysis of oseltamivir, aspirin, deltamethrin and permethrin. Biochem Pharmacol. 2009;77:238–47.
Zhu HJ, Appel DI, Jiang Y, Markowitz JS. Age- and sex-related expression and activity of carboxylesterase 1 and 2 in mouse and human liver. Drug Metab Dispos. 2009;37:1819–25.
Oo C, Barrett J, Hill G, et al. Pharmacokinetics and dosage recommendations for an oseltamivir oral suspension for the treatment of influenza in children. Paediatr Drugs. 2001;3:229–36.
Acosta EP, Jester P, Gal P, et al. Oseltamivir dosing for influenza infection in premature neonates. J Infect Dis. 2010;202:563–6.
Aiba H, Mochizuki M, Kimura M, Hojo H. Predictive value of serum interleukin-6 level in influenza virus-associated encephalopathy. Neurology. 2001;57:295–9.
Ichiyama T, Isumi H, Ozawa H, et al. Cerebrospinal fluid and serum levels of cytokines and soluble tumor necrosis factor receptor in influenza virus-associated encephalopathy. Scand J Infect Dis. 2003;35:59–61.
Cisse Y, Wang S, Inoue I, Kido H. Rat model of influenza-associated encephalopathy (IAE): studies of electroencephalogram (EEG) in vivo. Neuroscience. 2010;165:1127–37.
Tanaka T, Sunden Y, Sakoda Y, et al. Lipopolysaccharide treatment and inoculation of influenza A virus results in influenza virus-associated encephalopathy-like changes in neonatal mice. J Neurovirol. 2010;16:125–32.
Riazi K, Galic MA, Kuzmiski JB, et al. Microglial activation and TNFalpha production mediate altered CNS excitability following peripheral inflammation. Proc Natl Acad Sci USA. 2008;105:17151–6.
Tsuge M, Yasui K, Ichiyawa T, et al. Increase of tumor necrosis factor-alpha in the blood induces early activation of matrix metalloproteinase-9 in the brain. Microbiol Immunol. 2010;54:417–24.
Serrats J, Schiltz JC, Garcia-Bueno B, et al. Dual roles for perivascular macrophages in immune-tobrain signaling. Neuron. 2010;65:94–106.
Holmes C, Cunningham C, Zotova E, et al. Systemic inflammation and disease progression in Alzheimer disease. Neurology. 2009;73:768–74.
Steinman L. Nuanced roles of cytokines in three major human brain disorders. J Clin Invest. 2008;118:3557–63.
Raison CL, Capuron L, Miller AH. Cytokines sing the blues: inflammation and the pathogenesis of depression. Trends Immunol. 2006;27:24–31.
Bentivoglio M, Kristensson K. Neural-immune interactions in disorders of sleep-wakefulness organization. Trends Neurosci. 2007;30:645–52.
Matsubara K, Kodera M, Nigami H, Yura K, Fukaya T. Reversible splenial lesion in influenza virus encephalopathy. Pediatr Neurol. 2007;37:431–4.
Fluss J, Ferey S, Menache-Starobinski C, et al. Mild influenza-associated encephalopathy/encephalitis with a reversible splenial lesion in a Caucasian child with additional cerebellar features. Eur J Paediatr Neurol. 2010;14:97–100.
Ganapathy S, Ey EH, Wolfson BJ, Khan N. Transient isolated lesion of the splenium associated with clinically mild influenza encephalitis. Pediatr Radiol. 2008;38:1243–5.
Iwata A, Matsubara K, Nigami H, Kamimura K, Fukaya T. Reversible splenial lesion associated with novel influenza A (H1N1) viral infection. Pediatr Neurol. 2010;42:447–50.
Tsuji M, Yoshida T, Miyakoshi C, Haruta T. Is a reversible splenial lesion a sign of encephalopathy? Pediatr Neurol. 2009;41:143–5.
Kotan D. Widespread subarachnoidal pneumocephalus development as a complication of influenza: a case report. Arch Med Sci. 2008;4:471–3.
Sumikoshi M, Hashimoto K, Kawasaki Y, et al. Human influenza virus infection and apoptosis induction in human vascular endothelial cells. J Med Virol. 2008;80:1072–8.
Wang G, Zhang J, Li W, et al. Apoptosis and proinflammatory cytokine responses of primary mouse microglia and astrocytes induced by human H1N1 and avian H5N1 influenza viruses. Cell Mol Immunol. 2008;5:113–20.
Kawada J, Kimura H, Ito Y, et al. Systemic cytokine responses in patients with influenza-associated encephalopathy. J Infect Dis. 2003;188:690–8.
van Zeijl JH, Bakkers J, Wilbrink B, et al. Influenza-associated encephalopathy: no evidence for neuroinvasion by influenza virus nor for reactivation of human herpesvirus 6 or 7. Clin Infect Dis. 2005;40:483–5.
Morishima T. Influenza-associated encephalopathy. No To Shinkei. 2006;58:561–9. In Japanese.
Shinohara M, Saitoh M, Takanashi JI, et al. Carnitine palmitoyl transferase II polymorphism is associated with multiple syndromes of acute encephalopathy with various infectious diseases. Brain Dev. 2011;33:512–7.
Yao D, Mizuguchi H, Yamaguchi M, et al. Thermal instability of compound variants of carnitine palmitoyltransferase II and impaired mitochondrial fuel utilization in influenza-associated encephalopathy. Hum Mutat. 2008;29:718–27.
Chen Y, Mizuguchi H, Yao D, et al. Thermolabile phenotype of carnitine palmitoyltransferase II variations as a predisposing factor for influenza-associated encephalopathy. FEBS Lett. 2005;579:2040–4.
Hosoya M, Kawasaki Y, Katayose M, et al. Prognostic predictive values of serum cytochrome c, cytokines, and other laboratory measurements in acute encephalopathy with multiple organ failure. Arch Dis Child. 2006;91:469–72.
Purevsuren J, Hasegawa Y, Kobayashi H, Endo M, Yamaguchi S. Urinary organic metabolite screening of children with influenza-associated encephalopathy for inborn errors of metabolism using GC/MS. Brain Dev. 2008;30:520–6.
Okamoto E. Incidence of injuries after influenza using health insurance claims. Jpn J Pharmacoepidemiol. 2009;21:50–1.
Berger JR, Houff SA. Neurological infections: the year of PML and influenza. Lancet Neurol. 2010;9:14–7.
To view enhanced content go to www.advancesintherapy.com
This article is published with open access at Springerlink.com
Electronic supplementary material
Rights and permissions
Open Access This article is distributed under the terms of the Creative Commons Attribution 2.0 International License (https://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
About this article
Cite this article
Toovey, S., Prinssen, E.P., Rayner, C.R. et al. Post-Marketing Assessment of Neuropsychiatric Adverse Events in Influenza Patients Treated with Oseltamivir: An Updated Review. Adv Therapy 29, 826–848 (2012). https://doi.org/10.1007/s12325-012-0050-8
- Adverse events
- Central nervous system