Alan J. Wilensky

A randomized, double-blind study of phenytoin for the prevention of post-traumatic seizures.

BACKGROUND Antiepileptic drugs are commonly used to prevent seizures that may follow head trauma. However, previous controlled studies of this practice have been inconclusive. METHODS To study further the effectiveness of phenytoin (Dilantin) in preventing post-traumatic seizures, we randomly assigned 404 eligible patients with serious head trauma to treatment with phenytoin (n = 208) or placebo (n = 196) for one year in a double-blind fashion. An intravenous loading dose was given within 24 hours of injury. Serum levels of phenytoin were maintained in the high therapeutic range (3 to 6 mumol of free phenytoin per liter). Follow-up was continued for two years. The primary data analysis was performed according to the intention to treat. RESULTS Between drug loading and day 7, 3.6 percent of the patients assigned to phenytoin had seizures, as compared with 14.2 percent of patients assigned to placebo (P less than 0.001; risk ratio, 0.27; 95 percent confidence interval, 0.12 to 0.62). Between day 8 and the end of year 1, 21.5 percent of the phenytoin group and 15.7 percent of the placebo group had seizures; at the end of year 2, the rates were 27.5 percent and 21.1 percent, respectively (P greater than 0.2 for each comparison; risk ratio, 1.20; 95 percent confidence interval, 0.71 to 2.02). This lack of a late effect could not be attributed to differential mortality, low phenytoin levels, or treatment of some early seizures in patients assigned to the placebo group. CONCLUSIONS Phenytoin exerts a beneficial effect by reducing seizures only during the first week after severe head injury.

Valproic acid dosage and plasma protein binding and clearance

Valproic acid clearance was determined in six normal subjects during a single‐dose (250‐mg) study and multiple‐dose experiments of 500, 1,000, and 1,500 mg/day. Eight consecutive oral doses were taken at 12‐hr intervals at each dosing level. Valproate levels and protein binding were determined at steady state. Clearance declined 20% from 8.33 ± 2.44 to 6.67 ± 1.25 ml/hr/kg between the single‐dose and the 500‐mg/day steps (p = 0.05). Clearance was unchanged between the 500‐ and 1,000‐mg/day steps despite a 44% increase in mean free fraction (0.0703 ± 0.0381 vs 0.1011 ± 0.0438, p < 0.05), implying a balanced opposing decline in intrinsic clearance (from 89.2 ± 71.0 to 72.0 ± 20.8 ml/hr/kg; p = 0.025). In four subjects completing the 1,500‐mg/day step, clearance increased from 6.76 ± 1.48 ml/hr/kg (1,000 mg/day) to 8.20 ± 1.62 ml/hr/kg, corresponding to a further increase in free fraction. Free fraction varied within a single dosing interval (%SD = 11% to 49%). The apparent dose‐related decline in intrinsic clearance suggests autoinhibition or saturation of metabolism.

Zonisamide in epilepsy: a pilot study.

Summary: We compared zonisamide monotherapy (12 weeks) to carbamazepine monotherapy (12 Weeks) after phenytoin baseline monotherapy (8 weeks) in an open crossover pilot study of eight adults with uncontrolled partial seizures. Zonisamide had definite antiepilepitic activity in five subjects. In two of these, response to zonisamide was superior to that to either phenytoin or carbamazepine. A third subject became seizure free on zonisamide, but had to be withdrawn after 18 days because of mild stevens‐Johnson syndrome. The other three subjects were withdrawn from the study because of drug toxicity, manifested mainly by impaired higher mental function and increased seizures. The best response to zonisamide was at doses approximating 6 mg/kg/day, with plasma levels of 20–30 mg/L. Plasma levels of > 30 mg/L usually were associated with toxicity. the pharmacokinetics of zonisamide are complex and nonlinear, with steady‐state plasma levels being approximately three times higher than those predicted from a singledose study.

Valproic acid clearance: Unbound fraction and diurnal variation in young and elderly adults

Six young (22 to 25 years old) and six elderly (60 to 88 years old) healthy adults took valproic acid, 250 mg by mouth, at 8 AM and 8 PM for 5 days. On the fifth day, blood samples were drawn over each dosage interval. Both young and elderly subjects exhibited diurnal variability. Total and unbound clearances in the young and elderly subjects were about 10% and 15% higher during the evening. These changes led to lower total and unbound steady‐state and peak concentrations during the nighttime dosage interval. There were no differences in total steady‐state concentrations and kinetics computed from total concentrations between the young and elderly, but there were differences in unbound steady‐state concentrations and kinetics. Unbound clearances were 65% lower, which resulted in unbound steady‐state concentrations 67% higher in the elderly. The average unbound fractions in the elderly and young were 10.7% and 6.4%. To minimize the influence of diurnal variability, drug concentrations should be determined at the same time each day. Total valproic acid concentration data may be less useful in elderly patients; unbound concentrations may be more reliable in this population.

Outcome after surgery in patients with refractory temporal lobe epilepsy and normal MRI.

Our purpose is to determine predictors of outcome in patients with refractory temporal lobe epilepsy and normal high resolution magnetic resonance imaging (MRI) who undergo surgical therapy. We identified 23 patients who underwent temporal lobectomy and had normal pre-operative MRI, including surface coil phased array temporal lobe imaging. All were followed at least 2 years after surgery. We graded outcome as seizure-free, > 75% reduction in seizures, or < 75% reduction in seizures. We examined pre-operative interictal and ictal electroencephalographic (EEG) findings, age of onset, gender, duration of epilepsy, risk factors, family history, physical findings, age at operation, side of operation, and pathology of resected tissue in order to determine if any of these factors were associated with outcome. Overall, 48% (11/23) of patients were seizure-free, 39% (9/23) had > 75% reduction in seizures, while 13% (3/23) had < 75% reduction in seizures. Only the EEG findings were useful in predicting outcome. When ictal onsets arose from basal-temporal regions, 61% (11/18) of patients were seizure-free, while none (0/5) were seizure-free when seizures arose from mid-posterior temporal regions (P = 0.04). Interictally, if all epileptiform patterns were localized exclusively to one basal-temporal region, a finding that invariably correlated with ictal onsets, 78% (7/9) of patients were seizure-free, while only 29% (4/14) were seizure-free if discharges were bilateral or multifocal (P = 0.04). We conclude that surgery may be a reasonable treatment for some patients with intractable temporal lobe seizures and normal MRI. The best outcomes occur when seizure onsets and interictal epileptiform patterns are exclusive to one basal-temporal region. Unfavorable outcomes are most likely to occur when ictal origins are from mid-posterior temporal regions and when interictal discharges are bitemporal or multifocal in distribution.

Effects of polytherapy with phenytoin, carbamazepine, and stiripentol on formation of 4‐ene‐valproate, a hepatotoxic metabolite of valproic acid

The incidence of valproic acid hepatotoxicity has been reported to increase in patients who are receiving polytherapy. A minor valproic acid metabolite, 2‐propyl‐4‐pentenoic acid (4‐ene‐VPA), formed by a cytochrome P450‐mediated reaction, has been shown to be a potent inducer of microvesicular steatosis in rats. This study tested the hypothesis that formation of 4‐ene‐VPA would be increased in patients taking valproic acid with carbamazepine or with phenytoin but decreased with coadministration of an inhibitor of cytochrome P450 (the antiepileptic drug stiripentol in 300 to 1200 mg daily doses) in healthy subjects. Blood and urine samples in the studies were collected during a dosing interval at steady state. Valproic acid was assayed in plasma by capillary gas chromatography; valproic acid and 15 metabolites were measured in urine by gas chromatography/mass spectrometry. The formation clearance (CLf) of 4‐ene‐VPA was increased twofold in the valproic acid‐carbamazepine and valproic acid‐phenytoin groups. In the valproic acid/stiripentol studies, the CLf of 4‐ene‐VPA decreased by 32% in the 1200 mg/day stiripentol study. Similar findings were obtained at 600 and 300 mg/day stiripentol. These findings provide evidence supporting a role for cytochrome P450 in the formation of the hepatotoxic metabolite, 4‐ene‐VPA, in humans. The increased formation of 4‐ene‐VPA associated with carbamazepine and phenytoin is striking in relation to the epidemiologic finding of increased incidence of valproic acid–related hepatotoxicity during polytherapy with P450 inducers.

Outcome following surgery in patients with bitemporal interictal epileptiform patterns

We reviewed outcome at least 1 year after temporal lobectomy in 44 patients with bitemporal, independent, interictal epileptiform patterns on EEG. All 44 underwent preoperative intracranial monitoring. Twenty-two (50%) were seizure-free, 14 (32%) had at a least 75% reduction in seizures, and eight (18%) had less than a 75% reduction in seizures. We analyzed age of seizure onset, duration of epilepsy, gender, side of operation, history and clinical findings, findings on MRI, results of intracranial EEG-video monitoring, presence or absence of lateralizing neuropsychological deficits, and pathology of resected tissue to identify factors associated with outcome. Three factors emerged as independently associated with a good outcome: concordance of MRI abnormality and side of operation (p = 0.01), history of febrile seizures (p = 0.04), and 100% lateralization of intracranially recorded ictal onsets to the side of operation (p = 0.05). A seizure-free outcome was much more likely to occur if more than one of these factors was present: with at least two factors co-existing, 83% (15/18) of patients were seizure-free, while only 35% (7/20) were seizure-free with a single factor present (p = 0.0009). Of the six patients without any of the three factors, none were seizure-free. We conclude that it is possible to predict reasonably which patients with bitemporal epileptiform abnormalities will have a good outcome after surgery.

Cognitive impairment is not equal in patients with epileptic and psychogenic nonepileptic seizures.

Summary:  Purpose: Patients with psychogenic nonepileptic seizures (PNES) and those with epileptic seizures (ES) purportedly have roughly equal neurocognitive deficits. However, recent findings suggest that patients with somatoform disorders exhibit more variable effort on neurocognitive testing than do controls. We reexamined neurocognitive function in patients with ESs and PNES by using symptom validity testing to control for variability in effort.

Neuropsychological abilities before and after 5 years of stable antiepileptic drug therapy

Summary: Detailed neuropsychological evaluations were conducted on 198 adults with epilepsy before and after a 5‐year study period. Of these, three groups of 11 persons each were formed in which the patients did not change their medication: (a) phenytoin (PHT) monotherapy; (b) PHT and other drug(s); (c) drug regimens exclusive of PHT. The typical patient had few seizures during the study period. Examination of data from 20 neuropsychological and intellectual variables obtained at the beginning and end of the 5‐year study period revealed few statistically significant changes in mental abilities and no losses. Thus, we were unable to find evidence for insidious cognitive losses with PHT and other drugs over time with normal therapeutic serum levels and in the absence of active seizure disorders.

Inhibition of human liver microsomal epoxide hydrolase by valproate and valpromide: In vitro/in vivo correlation

On the basis of drug interactions with carbamazepine epoxide, it has been hypothesized that valproic acid and valpromide are inhibitors of epoxide hydrolase, but the role of epoxide hydrolase in these interactions has not been clearly established. In this study, therapeutic concentrations of valproic acid (<1 mmol/L) and valpromide (<10 µmol/L) inhibited hydrolysis of carbamazepine epoxide and styrene oxide in human liver microsomes and in preparations of purified human liver microsomal epoxide hydrolase. Valpromide (K1 = 5 µmol/L) was 100 times more potent than valproic acid (K1 = 550 µmol/L) as an inhibitor of carbamazepine epoxide hydrolysis in microsomes. After administration of carbamazepine epoxide to volunteers, the transdihydrodiol formation clearance was decreased 20% by valproic acid (blood concentration ≈ 113 µmol/L) and 67% by valpromide (blood concentration < 10 µmol/L). For both valproic acid and valpromide, a striking similarity exists between in vitro and in vivo inhibitory potencies. Valproic acid and valpromide are the first drugs known to inhibit microsomal epoxide hydrolase, an important detoxification enzyme, at therapeutic concentrations.