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Objective: To characterize pretreatment behavioral problems and differential effects of initial therapy in children with childhood absence epilepsy (CAE)., Methods: The Child Behavior Checklist (CBCL) was administered at baseline, week 16-20, and month 12 visits of a randomized double-blind trial of ethosuximide, lamotrigine, and valproate. Total problems score was the primary outcome measure., Results: A total of 382 participants at baseline, 310 participants at the week 16-20 visit, and 168 participants at the month 12 visit had CBCL data. At baseline, 8% (95% confidence interval [CI] 6%-11%) of children with CAE had elevated total problems scores (mean 52.9 ± 10.91). At week 16-20, participants taking valproic acid had significantly higher total problems (51.7 [98.3% CI 48.6-54.7]), externalizing problems (51.4 [98.3% CI 48.5-54.3]), attention problems (57.8 [98.3% CI 55.6-60.0]), and attention-deficit/hyperactivity problems (55.8 [98.3% CI 54.1-57.6]) scores compared to participants taking ethosuximide (46.5 [98.3% CI 43.4-49.6]; 45.8 [98.3% CI 42.9-48.7]; 54.6 [98.3% CI 52.4-56.9]; 53.0 [98.3% CI 51.3-54.8]). Lack of seizure freedom and elevated week 16-20 Conner Continuous Performance Test confidence index were associated with worse total problems scores. At month 12, participants taking valproic acid had significantly higher attention problems scores (57.9 [98.3% CI 55.6-60.3]) compared to participants taking ethosuximide (54.5 [95% CI 52.1-56.9])., Conclusions: Pretreatment and ongoing behavioral problems exist in CAE. Valproic acid is associated with worse behavioral outcomes than ethosuximide or lamotrigine, further reinforcing ethosuximide as the preferred initial therapy for CAE., Clinicaltrialsgov Identifier: NCT00088452., Classification of Evidence: This study provides Class II evidence that for children with CAE, valproic acid is associated with worse behavioral outcomes than ethosuximide or lamotrigine., (© 2017 American Academy of Neurology.)

Sodium valproate and ethosuximide are anticonvulsants employed in the treatment of petit mal epilepsy; both drugs are considered to be thalamically active. Valproate and ethosuximide both decreased the average evoked response following the second of two stimuli delivered to the ventrolateral thalamus at stimulus frequencies in the region of 3 Hz. Ethosuximide, but not valproate, enhanced the average evoked response at high stimulus frequencies an action shared with several convulsant treatments having different modes of action. The clinical effects of valproate and ethosuximide can be related to this differential modulation of thalamocortical excitability.

Clonazepam, a chlorinated derivative of nitrazepam, was administered to 10 children with absence seizures. Serum concentrations were measured after 8 weeks of treatment, at steady state. Seizure frequency reports and the 12-hour telemetered electroencephalogram were studied before and after 8 weeks of treatment to determine the frequency and duration of generalized spike-wave paroxysms. The clonazepam dosage ranged from 0.028 to 0.111 mg per kilogram and was reflected in serum levels ranging from 13 to 72 ng per milliliter, with an excellent correlation between dose and serum level. Eight of the 10 patients showed a significant decrease in seizure frequency, with three experiencing no seizures at all. Six patients had side effects, predominantly drowsiness and ataxia. This preliminary study shows clonazepam to be useful in the treatment of absence seizures in children and to merit further study.

Conditioning stimuli to the coronal gyrus or periventricular gray matter inhibit the activity of spinal trigeminal neurons. Valproate decreased the corticofugal inhibition of the spinal trigeminal nucleus, as did ethosuximide, trimethadione, and imipramine. Valproate and ethosuximide also decreased the periventricular inhibition of the spinal trigeminal nucleus, indicating that antiabsence drug depress subcortical inhibitory pathways as well as pathways of cortical origin. These results support the hypothesis that ability to depress inhibitory pathways is an important characteristic of antiabsence drugs. The effect of valproate and ethosuximide on periventricular inhibition also suggests that these anticonvulsants may act by preventing the spread of seizure activity through subcortical pathways.

Thirty-seven patients with previously untreated absence seizures were treated with ethosuximide. Seizures were completely controlled in 7 patients (19 percent); 90 to 100 percent control was achieved in 18 patients (49 percent) and 50 to 100 percent control in 35 (95 percent). Plasma ethosuximide concentration increased with dose, but variability in the plasma concentration produced by a given ethosuximide dose made it impossible to predict a patient's plasma concentration from the dose. The therapeutic range of plasma ethosuximide concentration was 40 to 100 mug per milliliter. Patients with evidence of structural central nervous system abnormalities responded as well or better to the drug as patients without such evidence. Ethosuximide did not impair psychometric performance, but rather resulted in improved performance in 17 cases. The side effects of ethosuximide were minor, and rarely required withdrawal of the drug.

We evaluated the effects of phenytoin, carbamazepine, phenobarbital, sodium valproate, and ethosuximide on penicillin-induced spike foci. Phenytoin, carbamazepine, and phenobarbital at blood levels within or slightly above the human therapeutic range in humans increased spike frequency, decreased spike duration, and abolished after discharges. Ethosuximide and sodium valproate had no statistically significant effect even at blood levels considered toxic in humans. The experimental spike focus and the method of analysis appear useful for: (1) detection of new potentially anticonvulsant drugs, (2) classifying new potentially anticonvulsant drugs according to the type of clinical seizure for which benefit is most likely, and (3) comparing different anticonvulsant drugs.

The effects of ethosuximide and diphenylhydantoin sodium on feline generalized penicillin epilepsy, a model of human generalized corticoreticular (centreccephalic) epilepsy, were significantly reduced following administration of ethosuximide with plasma levels of 60 mug per milliliter, and there was a linear correlation between the plasma level and antiephilepileptic effect (p less than 0.01). Diphenylhydantoin produced a lesser reduction in epileptic activity, and there was no correlation between the plasma level and effect. Four cats that received both drugs successively responded well to ethosuximide, while only two responded to diphenylhdantoin. The good response to ethosuximide is in accord with clinical experience in human generalized corticoreticular epilepsy.