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*Takashi Ichiyama, *Hironori Matsufuji, *Hiroshi Isumi, *Yuichi Ishikawa, and *Susumu Furukawa *Department of Pediatrics, Yamaguchi University School of Medicine, Ube, Yamaguchi, Japan .

Purpose: Convulsions associated with mild gastroenteritis sometimes occur in infants and young children. The condition is characterized by (a) previously healthy infants and young children aged 6 months to 3 years having afebrile, brief, mostly generalized tonic–clonic convulsions between the first and fifth days of mild gastroenteritis; (b) mild dehydration (<5%); (c) seizures tending to occur repetitively over several days; (d) an interictal electroencephalogram (EEG) showing no epileptic discharges; (e) normal laboratory examinations including cerebrospinal fluid, serum electrolytes, and blood glucose; and (f) always a good prognosis without sequelae. The convulsions frequently recur after the administration of diazepam (DZP) or phenobarbital (PB). We investigated the effect of 5 mg/kg of carbamazepine (CBZ) once daily on the convulsions.

Methods: There were six boys and 10 girls, aged from 9 months to 3 years (mean, 1.7 years). The day of onset of gastroenteritis was considered the first day of illness. The convulsions occurred from days 1 to 4 (mean, day 2.6). The causative microorganisms for gastroenteritis were rotavirus in seven patients, Campylobacter jejuni in one, and unknown in eight. The patients were given 5 mg/kg of CBZ once daily until diarrhea had stopped.

Results: Thirteen of the sixteen patients were given intravenous and/or suppository DZP (0.3–0.5 mg/kg/time), and patient 8 was given a suppository of 0.5 mg/kg DZP and 5.7 mg/kg PB before the administration of CBZ. In all patients who were given DZP and/or PB, the convulsions recurred after the administration of these medications. Convulsions occurred 2 to 8 times (mean, 4.1 times) before the administration of CBZ. Fifteen of the 16 patients had no seizures after the administration of CBZ. Patient 4 had one convulsion 15 min after the administration of CBZ. All patients were treated with 5 mg/kg of CBZ once daily until the diarrhea had stopped, for 2–9 days (mean, 6.4 days).

Conclusions: CBZ is effective for such convulsions, but not DZP or PB, for unknown reasons. Although the prognosis of convulsions associated with mild gastroenteritis is good, repetitive convulsions over several days not only make the family uneasy, but also lengthen the hospitalization period and increase the cost. Therefore we recommend 5 mg/kg of CBZ once daily until the diarrhea is controlled as a treatment for convulsions associated with mild gastroenteritis. Oral administration of 5 mg/kg CBZ once daily is dramatically effective for convulsions associated with mild gastroenteritis. However, further controlled study is necessary to prove this observation.

Abstract

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*Hirokazu Oguni, *Makoto Funatsuka, *Kaori Sasaki, *Tae Nakajima, *Keisuke Yoshii, and *Makiko Osawa *Department of Pediatrics, Tokyo Women's Medical University, Tokyo, Japan .

Purpose: Epileptic spasms in clusters are the main clinical seizure manifestation not only in patients with West syndrome but also in some patients with symptomatic generalized epilepsy or focal epilepsy. The epileptic spasms in the latter group also are refractory, and no treatment strategy has been established. We have long been using adrenocorticotropic hormone (ACTH) therapy for these patients, because the seizures resemble those of West syndrome. In this study, we analyzed the short-term, as well as the long-term, effects of ACTH therapy for patients with epileptic spasms who did not meet the criteria for having West syndrome.

Subjects and Methods: Subjects were recruited from patients with epileptic spasms in clusters who received ACTH therapy between 1990 and 2003. We excluded patients with West syndrome, but included those initially diagnosed as West syndrome who no longer satisfied the criteria for West syndrome (lack of hypsarrhythmia) during the period of ACTH therapy. We analyzed the short-term seizure effect at 3 months and the long-term effect at ≥1 year at the last follow-up after ACTH therapy.

Results: Twenty-eight patients (13 boys and 15 girls) were studied. The onset ages of epileptic spasms ranged from 2 to 72 months with a median of 17 months (<1 year of age in eight patients, 1–2 years of age in 14, 2–3 years in four, and >3 years in two). The eight patients who started having epileptic spasms at younger than 1 year showed intermittent generalized polyspike-and-wave discharges with preserved background activity (no hypsarrhythmia). In two patients with a history of West syndrome, epileptic spasms recurred after a long lapse after ACTH therapy for West syndrome. MRI revealed definite structural abnormality in two of the 19 patients. All cases were refractory to all available antiepileptic drugs (AEDs), and were started on ACTH at ages ranging from 11 to 86 months, with a median of 29 months. Moderate or severe psychomotor retardation was observed in 12 patients at the time of ACTH therapy. The follow-up period ranged from 8 to 365 months, with a mean of 119 ± 88 months.

Results: Of the 28 patients, 17 (60%) showed an excellent response, and the remaining 11 exhibited a poor response as short-term outcome. Among 15 of the 17 patients with excellent response and a follow-up period >1 year after ACTH therapy, nine patients had seizure recurrence from 9 to 198 months (median, 49 months) after ACTH therapy. The seizure types of the nine patients consisted of generalized tonic seizures in four, complex partial seizures in three, and epileptic spasms in two. The diagnoses were frontal lobe epilepsy in three patients, symptomatic generalized epilepsy with focal features in three, Lennox–Gastaut syndrome in two, and occipitotemporal lobe epilepsy in one. Thus the long-term seizure-control effect was maintained only in six (23%) of the 26 patients. One patient with frontal lobe epilepsy undergoing epilepsy surgery showed a significant improvement of seizures.

Conclusions: ACTH therapy is worth trying for patients with resistant epileptic spasms, even without features of West syndrome. However, the long-term effect should be monitored because recurrence of various types of seizures, including focal, is frequently observed. Among them, patients with focal epilepsy emerging after ACTH therapy may be good candidates for epilepsy surgery.

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*Yuko Sakaue, *Junko Abe, *Tomoyuki Takano, *Masaki Oono, *Yoshihiro Takeuchi, and *Kashiro Nisizawa *Shiga University of Medical Science, Shiga, Japan .

Purpose: Three cases of a peculiar type of postencephalitic/encephalopathic epilepsy (Awaya/Fukuyama type) are presented. Treatments of these three cases are reviewed to evaluate the treatment for controlling intractable seizures in this disease.

Case Report: Case 1 was a 10-year-old boy. He had been healthy with normal development before disease onset. Five days after the onset of upper respiratory infection (URI), he had a severe generalized seizure that evolved into intractable seizures. At first he was treated with phenobarbital (PB), phenytoin (PHT), and pentobarbital (PTB), but these antiepileptic drugs (AEDs) were not effective for the refractory seizures. Thiopental (TP) was tried, and his seizures were successfully controlled. Case 2 was an 11-year-old girl. She had fever and tonsillitis due to an Epstein–Barr virus infection. Five days later, she had a severe complex partial seizure, which was secondarily generalized. She was treated with PB, lidocaine, TP, and midazolam (MDL), but the seizures were highly refractory to these drugs. She died of multiple organ failure due to methicillin-resistant Staphylococcus aureus (MRSA) infection. Case 3 was a 12-year-old girl. She had been healthy previously. Five days after the onset of a URI, status epilepticus developed. The seizures were highly refractory to treatment with PHT, lidocaine, PTB, and TP. Inhalation anesthesia with isoflurane also was tried; however, seizures reappeared after discontinuation of anesthesia. Nonintravenous high-dose phenobarbital therapy (NIHDPB) was started, which successfully controlled her seizures. Anesthesia was discontinued.

Conclusions: The observations in the three cases suggest that NIHDPB is one of the effective therapies to treat a peculiar type of postencephalitic/encephalopathic (Awaya/Fukuyama type) epilepsy.

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*†Kenji Takei, *†Hisao Miura, *Wataru Sunaoshi, *†Nozomi Hosoda, and *Toshiyuki Iwasaki *Department of Pediatrics, Kitasato University School of Medicine , and †Sagamihara Ryouikuen, Institute for Severely Disabled, Sagamihara, Japan .

Purpose: To examine the metabolic pathway of clonazepam (CZP) and to determine the collective pharmacokinetic parameters, we measured the plasma concentrations of CZP and its main metabolite, 7-aminoclonazepam (7-amino-CZP), in patients who were treated with CZP monotherapy or combined with other antiepileptic drugs (AEDs). CZP undergoes nitroreduction to 7-amino-CZP, followed by acetylation to 7-acetamidoclonazepam. Hepatic cytochrome P-450 3A4 has been implicated in the nitroreduction of CZP.

Methods: The subjects comprised 181 patients aged 2–37 years (mean, 17 years) whose seizures were controlled with CZP therapy. They were divided into four groups: 72 patients treated with CZP monotherapy (group A), 45 patients treated with CZP combined with sodium valproate (VPA) (group B), 53 patients treated with CZP combined with carbamazepine (CBZ) (group C), and 11 patients treated with CZP combined with both VPA and CBZ (group D). CZP was taken twice daily, and blood samples for determination of plasma concentrations were taken 2–4 h after the morning dose, representing the peak level in a day. The daily dosage of CZP was 0.035 ± 0.021 mg/kg in group A, 0.056 ± 0.056 mg/kg in group B, 0.050 ± 0.019 mg/kg in group C, and 0.059 ± 0.025 mg/kg in group D.

Results: Plasma concentrations of CZP and 7-amino-CZP were 20.2 ± 13.4 and 14.5 ± 10.6 ng/ml, respectively, in group A. The ratio of 7 amino-CZP to CZP in group A was 0.76 ± 0.29. Plasma concentrations of CZP in groups B, C, and D were 25.6 ± 14.7, 21.7 ± 8.3, and 23.6 ± 11.4 ng/ml; and those of 7-amino-CZP were 29.2 ± 21.7, 8.9 ± 5.0, and 19.2 ± 9.3 ng/ml, respectively. The ratios of 7-amino-CZP to CZP in groups B, C, and D were 1.12 ± 0.35, 0.40 ± 0.12, and 0.85 ± 0.31, respectively.

Conclusions: In patients treated with CZP, plasma concentrations of CZP and 7-amino-CZP have been reported to be almost the same in the steady state. Considering the pharmacologic activity of 7-amino-CZP, it is interesting that the ratio of 7-amino-CZP to CZP was higher in group B than in group A, and the ratio was lower in group C than in group A. The results suggest that frequent withdrawal seizures may be seen in the cases with high plasma concentration of 7-amino-CZP before stopping CZP therapy.

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*Motohiro Okada, *Gang Zhu, *†Shukuko Yoshida, ‡Fumiaki Mori, ‡Koichi Wakabayashi, and *Sunao Kaneko *Department of Neuropsychiatry, Hirosaki University ; †Institute of Neuroscience and Molecular Biology, Shibata IRIKA ; and ‡Department of Neuropathology, Institute of Brain Science, Hirosaki University, Hirosaki, Japan .

Purpose: Release of synaptic vesicles containing neurotransmitters is triggered by influx of Ca2+ through voltage-sensitive Ca2+ channel (VSCC). The Ca2+ influx via VSCC activates endoplasmic reticulum–associated intracellular Ca2+ signal transduction, “Ca2+-induced Ca2+ releasing systems” (CICRs), which regulate a wide variety of neuronal processes including neurotransmitter exocytosis. Two types of CICRs have been identified in neurons; the inositol 1,4,5-trisphosphate receptor (IP3R)-sensitive and ryanodine receptor (RyR)-sensitive stores. The effects of therapeutic concentrations of carbamazepine (CBZ) on CICR-associated neurotransmitter exocytosis mechanisms remain to be clarified. To explore novel pharmacologic mechanisms of the antiepileptic action of CBZ, the present study examined the interaction between CBZ and CICRs on hippocampal serotonin (5-HT) exocytosis by using in vivo microdialysis.

Methods: All of the experiments described in this report were performed in accordance with the specifications of the Animal Research Committee of Hirosaki University and complied with the Guidelines Animal Experimentation of Hirosaki University. Each rat was placed in a stereotaxic frame and kept under halothane anesthesia (1.5% mixture of halothane and O2 with N2O). A concentric I-type dialysis probe (0.22 mm diameter; 3 mm exposed membrane) was implanted in the hippocampus (A =−5.8 mm, L = 4.8 mm, V =−4.0 mm relative to the bregma), and the perfusion experiments were started 18 h after the rats had recovered from anesthesia. The hippocampal extracellular 5-HT level was determined by in vivo microdialysis by using the ECD-high-performance liquid chromatography (HPLC) system. After confirming the stabilization of extracellular 5-HT level, the perfusion medium was switched from modified Ringer's solution (MRS) to MRS containing target agents (agonists and antagonists of CICR or therapeutic concentrations of CBZ) for 120 min. After this study, experiments were continued to examine the interaction between CICR and CBZ on 5-HT release. After confirming stabilization, the perfusion medium was switched to MRS containing a different target agent.

Results: Basal 5-HT release was decreased by IP3R antagonists, whereas RyR antagonists had no effect. Agonists of IP3R and RyR as well as therapeutic concentration of CBZ increased basal 5-HT release. The stimulatory effect of RyR agonists was stronger than that of IP3R agonists. Pretreatment with CBZ reduced the stimulatory effects of RyR agonists on basal 5-HT release, whereas CBZ enhanced the stimulatory effect of IP3R agonists. Pretreatment with RyR antagonists did not affect the stimulatory effect of therapeutic concentrations of CBZ on 5-HT release, whereas pretreatment with IP3R antagonists reduced the effect of CBZ.

Conclusions: Judging from the action of CICR agents on hippocampal 5-HT release, the present results indicate that hippocampal 5-HT release is regulated by CICR-associated exocytosis mechanisms. A part of the detectable basal 5-HT release was generated by IP3R-associated exocytosis mechanisms; whereas RyR-associated mechanisms did not affect basal release. However, the potential effect of the RyR-associated system in neurotransmitter exocytosis may be greater than that of IP3R, because the stimulatory effects of RyR agonists on 5-HT release was greater than that of IP3R agonists. Therapeutic concentrations of CBZ increased basal 5-HT release and enhanced the stimulatory effects of IP3R agonists on 5-HT release. The stimulatory effect of CBZ on basal release was inhibited by IP3R antagonists. These data suggest that CBZ acts as an indirect stimulatory modulator for the IP3R-associated exocytosis mechanisms. Contrary to IP3R, CBZ directly blocks RyR-associated mechanisms. These findings suggest that IP3R- and RyR-associated CICRs are new pharmacologic targets for CBZ in association with the regulation of hippocampal neurotransmitter exocytosis.

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*Toshio Hiyoshi, *Masaki Tanaka, *Katsuhisa Uruno, *Katsuyuki Fukushima, *Yushi Inoue, and *Tateki Fujiwara *National Epilepsy Center, Shizuoka Medical Institute of Neurological Disorders, Shizuoka, Japan .

Purpose: Because the therapeutic range of the plasma phenytoin (PHT) level is close to the toxic range, and the elimination half-life increases with the plasma level because of saturation of metabolism, acute intoxication is relatively common in patients treated with PHT. In such circumstances, in principle, PHT is withheld until the plasma level has fallen back to the therapeutic range. However, reduction of the daily dose may be an alternative, considering seizure exacerbation during PHT withdrawal. To obtain a guide for rational management of PHT intoxication, we retrospectively reviewed the time course of seizures and plasma levels after discontinuation or dose reduction of PHT.

Methods: Fifteen patients admitted to our hospital with acute PHT intoxication were studied. All but one received polytherapy with up to three drugs, including PHT. Before intoxication, the seizure frequency was daily in six patients, weekly in one, monthly in three, yearly in one, and seizure free in four. On admission, the mean PHT level was 45.3 (range, 31.6–64.5) μg/ml. Despite such high PHT levels, seizures occurred daily in two patients. The remaining 13 patients had no seizure on admission.

Results: In 10 patients, PHT was discontinued for a mean of 3.7 (range, 1.5–7) days, during which the mean PHT level decreased from 45.6 to 17.7 μg/ml. PHT was restarted at doses reduced to on average 74% of those at admission. However, PHT levels further decreased in some patients, and the mean trough level reached 15.6 μg/ml. In five patients, PHT was not discontinued, but the doses were reduced to a mean of 77% for a mean duration of 12.8 (range, 3–22) days, during which the mean PHT level decreased from 44.6 to 21.2 μg/ml. Thereafter, the PHT doses were readjusted. In four patients who had been seizure free before intoxication, seizures did not recur after discontinuation (three patients) or dose reduction (one patient). In eight patients whose daily to monthly seizures ceased under intoxication, the seizures recurred in all five patients on discontinuation and in two of three patients on dose reduction; the mean PHT levels at recurrence were 22.5 and 20.3 μg/ml, respectively. In two patients who had daily seizures even under intoxication, one who discontinued PHT developed tonic status when the PHT level decreased to 22.9 μg/ml and was treated with rectal diazepam. The other, who had reduced PHT, began to have secondarily generalized convulsive seizures every 2–3 days when the PHT level decreased to 21.8 μg/ml, but was controlled by adding phenobarbital to his prescription. After PHT discontinuation, the plasma level decreased at a mean rate of 7.8 (4.3–12.3) μg/ml/day. The mean plasma half-life was 3.2 (2.1–4.9) days.

Conclusions: On PHT discontinuation due to intoxication, the risk of seizure recurrence or exacerbation is low until the PHT level decreases to ∼20 μg/ml, when patients have recovered from acute intoxication. In patients with seizures controlled before intoxication, PHT should be discontinued. In patients whose seizures have not been controlled but cease under intoxication, it is practical to discontinue PHT. Patients with recurrent seizures even under intoxication require careful management. The finding in this study that under intoxication, the plasma level decreases at a rate of 7.8 μg/ml/day with an elimination half-life of 3 days is a useful reference to forecast the duration of discontinuation. Drug-level monitoring should be continued after recovery from intoxication to avoid further decline in PHT level.