title: Analysis of a child who developed abnormal neuropsychiatric symptoms after administration of oseltamivir: a case report.
abstract: BACKGROUND
  Neuropsychiatric side effects of oseltamivir occur occasionally, especially in infants and young patients, but nothing is known about possible contributory factors.
  
  
  METHODS
  We report a case of a 15-year-old Japanese female with influenza infection who developed abnormal psychiatric symptoms after administration of standard doses of oseltamivir. She had no history of neurological illness, had never previously taken oseltamivir, and had not developed psychiatric reactions during previous influenza infection. Her delirium-like symptoms, including insomnia, visual hallucinations, and a long-term memory deficit, disappeared after cessation of oseltamivir and administration of benzodiazepine. Detailed assessment was performed, including neurological examination (electroencephalogram, brain magnetic resonance imaging, single photon emission computed tomography with 99mTc-ethyl cysteinate dimer and with (123)I-iomazenil, cerebrospinal fluid analysis and glutamate receptor autoantibodies), drug level determination and simulation, and genetic assessment (OAT1, OAT3, CES1, Neu2).
  
  
  CONCLUSIONS
  Abnormal slowing in the electroencephalogram, which is characteristic of influenza-associated encephalopathy, was not observed in repeated recordings. The serum level determination of active metabolite Ro 64-0802 determined at 154 h after final dosing of oseltamivir was higher than the expected value, suggesting delayed elimination of Ro 64-0802. Thus, abnormal exposure to Ro 64-0802 might have contributed, at least in part, to the development of neuropsychiatric symptoms in this patient. The score on Naranjo's adverse drug reaction probability scale was 6. Mutation of c.122G > A (R41Q) in the sialidase Neu2 gene, increased CSF glutamate receptor autoantibodies, and limbic GABAergic dysfunction indicated by SPECT with (123)I-iomazenil were found as possible contributory factors to the CNS side effects.
authors.affiliation: Department of Pharmacology, Graduate School, Takasaki University of Health and Welfare, 60 Nakaorui-machi, Takasaki-city, Gunma, Japan. morimoto@tohoku-pharm.ac.jp.|Department of Drug Absorption and Pharmacokinetics, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai-city, Miyagi, Japan. morimoto@tohoku-pharm.ac.jp.
authors.forename: Kaori
authors.initials: K
authors.lastname: Morimoto
authors.affiliation: Department of General Pediatrics and Interdisciplinary Medicine, National Center for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo, 157-8535, Japan. nagaoka-k@khe.biglobe.ne.jp.
authors.forename: Kei
authors.initials: K
authors.lastname: Nagaoka
authors.affiliation: Department of General Pediatrics and Interdisciplinary Medicine, National Center for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo, 157-8535, Japan. nagai-ak@ncchd.go.jp.
authors.forename: Akira
authors.initials: A
authors.lastname: Nagai
authors.affiliation: Division of Neurology, National Center for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo, 157-8535, Japan. kashii-tky@umin.ac.jp.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Kashii
authors.affiliation: Faculty of Pharmaceutical Sciences, Chiba Institute of Science, 15-8 Shiomi-cho, Choshi-city, Chiba, Japan. masakiyo@cis.ac.jp.
authors.forename: Masakiyo
authors.initials: M
authors.lastname: Hosokawa
authors.affiliation: Department of Pediatrics, National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders, Urushiyama 886, Aoi-ku, Shizuoka, 420-8688, Japan. yukito@hosp.go.jp.
authors.forename: Yukitoshi
authors.initials: Y
authors.lastname: Takahashi
authors.affiliation: Department of Pharmacology, Graduate School, Takasaki University of Health and Welfare, 60 Nakaorui-machi, Takasaki-city, Gunma, Japan. togihara@takasaki-u.ac.jp.
authors.forename: Takuo
authors.initials: T
authors.lastname: Ogihara
authors.affiliation: Division of Neurology, National Center for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo, 157-8535, Japan. mkmegped@opal.plala.or.jp.
authors.forename: Masaya
authors.initials: M
authors.lastname: Kubota
mesh_terms: D000293:Adolescent; D000998:Antiviral Agents / Q000009:adverse effects*; D005260:Female; D006212:Hallucinations / Q000139:chemically induced*; D006801:Humans; D007251:Influenza, Human / Q000188:drug therapy*; D008569:Memory Disorders / Q000139:chemically induced*; D001523:Mental Disorders / Q000139:chemically induced; D053139:Oseltamivir / Q000009:adverse effects* / Q000493:pharmacokinetics; D007319:Sleep Initiation and Maintenance Disorders / Q000139:chemically induced*
chemical_list: D000998:Antiviral Agents; D053139:Oseltamivir