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Analysis of a child who developed abnormal neuropsychiatric symptoms after administration of oseltamivir: a case report.

Morimoto K, Nagaoka K, Nagai A, Kashii H, Hosokawa M, Takahashi Y, Ogihara T, Kubota M - BMC Neurol (2015)

Bottom Line: Neuropsychiatric side effects of oseltamivir occur occasionally, especially in infants and young patients, but nothing is known about possible contributory factors.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, Graduate School, Takasaki University of Health and Welfare, 60 Nakaorui-machi, Takasaki-city, Gunma, Japan. morimoto@tohoku-pharm.ac.jp.

ABSTRACT

Background: Neuropsychiatric side effects of oseltamivir occur occasionally, especially in infants and young patients, but nothing is known about possible contributory factors.

Case presentation: 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.

No MeSH data available.


Related in: MedlinePlus

SPECT with 123I-iomazenil 10 days after admission revealed decreased benzodiazepine receptor binding in the right medial temporal area (arrows)
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Fig1: SPECT with 123I-iomazenil 10 days after admission revealed decreased benzodiazepine receptor binding in the right medial temporal area (arrows)

Mentions: This previously healthy 15-year-old Japanese girl developed fever and was diagnosed with influenza A virus infection based on a positive result with a rapid detection kit in 2009, during the pandemic influenza (H1N1) period. She had not previously taken oseltamivir, and had not developed neuropsychiatric symptoms in her previous influenza infection; this was her first admission to a neurological ward. The day after oseltamivir was started, her fever subsided, but the family noticed unusual behavior, such as doing her makeup at midnight and littering her room. She took 5 doses of 2 mg/kg (150 mg/day, b.i.d., 36 kg in weight) of oseltamivir every twelve hours and concomitantly took dihydrocodeine, ambroxol, benproperine, azithromycin and clarithromycin. There is no report of neuropsychiatric symptoms associated with these concomitant medications, except clarithromycin (clarithromycin occasionally induces altered mental status accompanied with electroencephalogram (EEG) abnormality, mostly in adults with psychiatric illness [2]). The symptoms did not fluctuate according to oseltamivir dosing times. After 3 days, she suddenly left her home and was found standing in front of an unknown apartment. Her family discontinued oseltamivir at that point. Because her bizarre behaviors continued after cessation of oseltamivir (for example, she complained of hearing voices of strange men), she was admitted to our hospital with suspected influenza encephalopathy. She developed delirium-like symptoms, such as insomnia, disorientation, visual hallucinations, a long-term memory deficit, abnormal behaviors (e.g., persistent ritual sneezing) and delusion (e.g., insisting that she was pregnant), but showed normal responses intermittently, especially during benzodiazepine infusion (diazepam or midazolam). Midazolam infusion (1 mg) enabled her to give correct verbal responses to questions about her name, her friends’ names, her age, and her address, as well as to perform mental calculations (additions and subtractions). Seizures were not observed and abnormal slowing in the EEG, which is characteristic of influenza-associated encephalopathy, was not observed in repeated recordings. Cerebrospinal fluid (CSF) study and repeated brain MRIs showed no abnormality. SPECT with 99mTc-ethyl cysteinate dimer showed no abnormal cerebral perfusion, while SPECT with 123I-iomazenil (performed 3 days after discontinuation of benzodiazepine) showed decreased benzodiazepine receptor binding in the right medial temporal area (Fig. 1).Fig. 1


Analysis of a child who developed abnormal neuropsychiatric symptoms after administration of oseltamivir: a case report.

Morimoto K, Nagaoka K, Nagai A, Kashii H, Hosokawa M, Takahashi Y, Ogihara T, Kubota M - BMC Neurol (2015)

SPECT with 123I-iomazenil 10 days after admission revealed decreased benzodiazepine receptor binding in the right medial temporal area (arrows)
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4526296&req=5

Fig1: SPECT with 123I-iomazenil 10 days after admission revealed decreased benzodiazepine receptor binding in the right medial temporal area (arrows)
Mentions: This previously healthy 15-year-old Japanese girl developed fever and was diagnosed with influenza A virus infection based on a positive result with a rapid detection kit in 2009, during the pandemic influenza (H1N1) period. She had not previously taken oseltamivir, and had not developed neuropsychiatric symptoms in her previous influenza infection; this was her first admission to a neurological ward. The day after oseltamivir was started, her fever subsided, but the family noticed unusual behavior, such as doing her makeup at midnight and littering her room. She took 5 doses of 2 mg/kg (150 mg/day, b.i.d., 36 kg in weight) of oseltamivir every twelve hours and concomitantly took dihydrocodeine, ambroxol, benproperine, azithromycin and clarithromycin. There is no report of neuropsychiatric symptoms associated with these concomitant medications, except clarithromycin (clarithromycin occasionally induces altered mental status accompanied with electroencephalogram (EEG) abnormality, mostly in adults with psychiatric illness [2]). The symptoms did not fluctuate according to oseltamivir dosing times. After 3 days, she suddenly left her home and was found standing in front of an unknown apartment. Her family discontinued oseltamivir at that point. Because her bizarre behaviors continued after cessation of oseltamivir (for example, she complained of hearing voices of strange men), she was admitted to our hospital with suspected influenza encephalopathy. She developed delirium-like symptoms, such as insomnia, disorientation, visual hallucinations, a long-term memory deficit, abnormal behaviors (e.g., persistent ritual sneezing) and delusion (e.g., insisting that she was pregnant), but showed normal responses intermittently, especially during benzodiazepine infusion (diazepam or midazolam). Midazolam infusion (1 mg) enabled her to give correct verbal responses to questions about her name, her friends’ names, her age, and her address, as well as to perform mental calculations (additions and subtractions). Seizures were not observed and abnormal slowing in the EEG, which is characteristic of influenza-associated encephalopathy, was not observed in repeated recordings. Cerebrospinal fluid (CSF) study and repeated brain MRIs showed no abnormality. SPECT with 99mTc-ethyl cysteinate dimer showed no abnormal cerebral perfusion, while SPECT with 123I-iomazenil (performed 3 days after discontinuation of benzodiazepine) showed decreased benzodiazepine receptor binding in the right medial temporal area (Fig. 1).Fig. 1

Bottom Line: Neuropsychiatric side effects of oseltamivir occur occasionally, especially in infants and young patients, but nothing is known about possible contributory factors.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, Graduate School, Takasaki University of Health and Welfare, 60 Nakaorui-machi, Takasaki-city, Gunma, Japan. morimoto@tohoku-pharm.ac.jp.

ABSTRACT

Background: Neuropsychiatric side effects of oseltamivir occur occasionally, especially in infants and young patients, but nothing is known about possible contributory factors.

Case presentation: 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.

No MeSH data available.


Related in: MedlinePlus