The main aim of this study was to reinvestigate the initial therapeutic level of sodium valproate (VPA). For the purpose, the author carried out VPA monotherapy on 39 untreated epileptic patients with 52 seizure types, and followed them up for an average of 2.8 years. The initial dose of VPA was 200mg/day for adults and 100mg/day for children. The doses were gradually increased until the seizures were well controlled. The satisfactory effect of the treatment, which was defined as a reduction of seizure frequency at least to 25% or complete suppression for more than one and a half years, was achieved in 75% of the 52 seizure types. In these seizures, the mean serum concentration of VPA (initial therapeutic level) was 37μg/ml, which was lower than those reported in literatures. Especially, 93% of the seizures which were not caused by organic etiology (typical absence, tonic-clonic seizure, seizures in benign epilepsy of children with centro-temporal EEG foci) showed an excellent response. The initial therapeutic level of the seizure group was lower (24μg/ml) than that of the other types. The serum VPA concentration showed a linear correlation with daily dose per body weight. Also the correlation was clear between age (in cases below 20 years old) and level/dose ratio, and between body weight and level/dose ratio. The daily fluctuation of serum concentrations in patients administered twice a day showed the same max./min. concentration ratio as that in patients administered three times a day. However, the difference was that the concentrations in the former group of patients showed an afternoon dip around 15:00.

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A study was conducted to find a dose-schedule of a rectal administration of phenobarbital sodium, in which the effective serum level of phenobarbital was attained rapidly as possible and the effective serum level could be maintained.
(1) Repeated rectal administration of phenobarbital more than 4.04mg/kg/day in divided doses brought its serum level above 10μg/ml within 48 hours and remained between 10 and 25μg/ml in 72 hours.
(2) This effective serum level of phenobarbital was maintained with either an oral or a rectal administration of 1.53-2.53mg/kg/day phenobarbital in divided doses.
(3) This dose-schedule was equivalent to that in which an intramuscular administration of 4.50-6.06mg/kg/day phenobarbital for the first 72 hours, followed by an oral administration 2.26-3.03mg/kg/day phenobarbital thereafter.

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Fluorescence Polarization Immunoassay (FPIA) is a competitive binding assay requiring no sample treatment, extraction, or phase separation for analysis of antiepileptic drugs. To confirm the reliability of the data by FPIA, it was compared to high performance liquid chromatography (HPLC) for determing serum phenytoin (PHT), phenobarbital (PB) and carbamazepine (CBZ) levels, and also compared to gaschromatography (GLC) for valproic acid (VPA). The correlation coefficient between the data by FPIA and chromatographical methods were PHT: 0.99, PB: 0.99, CBZ: 0.98, VPA: 0.99. Furthermore, the coefficient of variation of each of four antiepileptic drugs was less than 5% between assay by FPIA. Therefore, it is concluded that FPIA is very useful for therapeutic monitoring of antiepileptic drugs.

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This paper was based on 37 cases with the West syndrome and 29 cases with the Lennox syndrome, which were followed for more than five years. The materials were divided into the following groups: 14 cases which were converted from the West to the Lennox syndrome, 23 cases with the West syndrome excluding the patients with the conversion to the Lennox syndrome and 15 cases with the Lennox syndrome which were not converted from the West syndrome. On the above-mentioned three groups long-term prognosis and factors influencing the prognosis were investigated.
The patients with the conversion from the West to the Lennox syndrome were the worst about the prognosis of seizure control, EEG findings and abilities of daily life. Risk factors influencing the conversion from the West to the Lennox syndrome were age of onset of the West syndrome, treatment lag, initial effects of steroids and neurological development before the attacks. The factors influencing the prognosis of the abilities of daily life were initial effects of steroids and relapse or long duration of attacks in the West syndrome, and continuance of seizures, presence of underlying etiologies and continuous appearance of proxysmal discharges in EEG in the Lennox syndrome

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Seventy one children with nonfebrile generalized convulsions were followed for three years to 6 years and 10 months.
The results were summarized as follows.
1) Fifty cases out of 71 (70.4%) were free of seizures and 64 cases (90.1%) had normal psychomotor and mental status.
2) Ten cases out of 71 (14.1%) had other types of seizures.
Three had simple partial seizures, 6 had complex partial seizures and one had complex partial seizures and atypical absence. Of those, 9 (90.0%) still had seizures, and 7 (70.0%) had psychomotor or mental retardation.
3) Factors associated with prognosis of seizures were psychomotor or mental retardation (p<0.01), lag time between onset and the first visit (p<0.05), and past history of nonfebrile generalized convulsions which lasted for more than 30 minutes (p<0.05).
We found no association between prognosis of seizures and sex, family history of febrile convulsions or epilepsy, past history of neoratal asphyxia or febrile convulsions, age of onset, abnormal landings on CT scan, or complication of otner types oi seizures before the first visit.
The relation between prognosis of seizures and the epileptic discharges at the first EEG recording was obscure, because many factors influenced the EEG findings.

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To evaluate the risk of relapse in children with epilepsy or febrile convulsion whose chronic anticonvulsant therapy has been withdrawn after prolonged control, we studied 115 such children for more than 2 years or until relapse. Anticonvulsant therapy was discontinued in 77 children with epilepsy (51 cases with generalized tonic clonic seizure, cases with Sylvian seizure, 4 cases with other partial seizure, 3 cases with absence seizure) whose seizures had been easily controlled by treatment and who had had no seizures for 2 or more years, and in 38 children with febrile convulsion who had had seizures for 1 or more years and had reached more than 4 years of age. Medication was gradually withdrawn over six to twelve months. The 77 patients with epilepsy and 38 patients with febrile convulsion ranged in age from 4 to 23 years and from 4 to years respectively when their medications were discontinued. Only five (4%) of 115 patients had a recurrence of seizures. Seizure recurred in 2 patients with generalized tonic clonic seizure and in 3 patients with febrile convulsion. These seizures recurred at from 4 months to 2 years and 8 months (mean 1 year and 7 months) after discontinuation of therapy.
In 44 patients (23 cases with epilepsy and 21 cases with febrile convulsion) epileptiform EEG activities were found at time of withdrawal of therapy and/or after drug withdrawal. We found that abnormal electroencephalographic tracings did not contraindicate slow elimination of medication in children who had not had seizures for many years.

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By using forty pregnant rats and 47 non-pregnant female rats, generalized seizure triggering threshold and serum concentration of phenobarbital (PB) were measured. The results obtained were as follows:
1) On the experiment of amygdaloid kindled rats, generalized seizure triggering threshold of pregnant group was significantly higher than that of non-pregnant group.
2) As for the experiment of rats taking oral 4 mg/kg phenobarbital once every day corresponding with the increased body weight, there was no significant difference of serum levels between pregnant group and non-pregnant group.
3) In the experiment of amygdaloid kindled rats taking oral 4 mg/kg phenobarbital once every day as same as (2), generalized seizure triggering threshold of pregnant group was significantly higher than that of non-pregnant group as well as (1).So, it was likely suggested that the rise of threshold by gestational physiological changes may act antagonistically to the fall of threshold by decreased serum levels of anticovulsants according to increasing distribution volume by increasing body weight during pregnancy when the drug dose is the same.

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Recently, intracerebral folic acid (FA) injection was reported to produce status epilepticus (SE) associated with extensive neuronal damage considered to reflect primalily lesion of GABA-ergic neurons in rats. Since earlier studies in our laboratory suggested the possibility that substantia innominata (SI) plays an important role in amygdaloid kingdling (Am K), we planned to examine (1) the effect of SE, induced by FA injection into the Am upon subsequent seizure development at the same Am site by kindling, and (2) the possible role of GABA-ergic neurons, reported to be selectively vulnerable to FA when injected into SI, play in Am K in cats. The present study was undertaken to investigate acute effects of SE induced by microinjection of FA into Am or SI through chronic canula. EEG, EKG, and urinary samples were obtained continuously before, during, and after SE.
Regardless of where FA was injected, all the animals developed SE with recurrent stage 1-6 Am K seizure manifestations reaching a peak in about 3 hrs, gradually subsiding within 5 days. Motor seizure symptom appeared relating with reactive after discharge in motor cortex and hippocampus. Generalization followed appearance of reactive afterdischarge in midbrain reticular formation as reported in Am K.
There was no significant change in EKG except for a marked increase of cardiac rate during SE. Similarly transient myoglobuinuria and significant increase of urinary output of noradrenaline were observed at the time of SE. At the 14th day after FA injection all animals were sacrificed and examined histopathologically. There was a little evidence characterized by shrinkage and pyknosis of nerve cells with some macrophage proriferations localizing in the pyriform cortex and hippocampus. Other organs including the heart were normal. Thus no evidence of severe neuronal damage reported in rats was found, suggesting a significant species difference.

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We report “unexpected death” following what appears to have been complete recovery from status epilepticus induced by intracerebral microinjection of folic acid (FA) into either amygdala or substantia innominata through chronic canula. These experiments were originally designed to study the effect of status epilepticus upon subsequent amygdaloid kindling. With FA injection all the animals developed “limbic” seizure leading to convulsive status epilepticus reaching its peak at about 3 hrs but dissipating over 1-4 days. One cat died in prolonged convulsive status epilepticus, while five cats recovered. completely only to become acutely ill in 2-4 weeks and died rather suddenly. Histopathological findings of the brain showed inconsistently lateralized edema and shrinkage and pyknosis of nerve cells localizing in the hippocampus and front-temporal corticies. The most impressive pathological finding was myocardiac damage caracterized by an extensive “wavy fibre pattern” of both the left and right ventricle with numerous “transverse contraction bands”. Cause of deth was considered as acute myocardial ischemia related with increase of catecholamine release at the sympathetic nerve terminals of the heart.
While intracerebral microinjection of FA into amygdala of cats under nembutal anesthesia produced electrographic discharge readily propagating mainly into the ipsilataral hemisphere with minimal clinical manifestations leaving no evidence of lasting change in behavior and seizure susceptibility as examined by kindling at the same site.
We concluded as follows:
1) Status epilepticus can have not only immediate but also remote and serious consequences.
2) Rapid and effective control of status epilepticus is vital for prevention of delayed and untoward consequences.
3) Intracerebral folic acid injection may be a useful tool to study the poorly understood phenomenon “SUD in epileptics”.

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