Prevention as it pertains to epilepsy.

Prevention may be practiced at various levels in the hierarchy of epilepsy; at the level of epilepsy itself (epileptogenesis), the individual epileptic seizures (ictogenesis), or in the avoidance of the consequences of the epilepsies or their component seizures. Moreover, it also applies in the arena of psychosocial predicaments, the neurologic or other injurious side effects of recurrent seizures, and the unwanted side effects of drug therapy or surgery employed in management, where attention to the risk/benefit analysis of the treatment employed may greatly influence outcome not only of life itself but also its quality.

Self-induced photosensitive absence seizures with ictal pleasure.

A 32-year-old woman was treated for self-induced photosensitive seizures that included strong subjective feelings of pleasure and masturbatory behavior. Electroencephalograms demonstrated generalized polyphasic spike-wave discharges in response to stroboscopic stimulation. The behavioral sequences leading to seizures and the effects of treatment can be explained in terms of operant conditioning theory. Data from human and animal studies indicate a correlation between ictal pleasure or reinforcement and the subject's ability to induce seizures. Ictal pleasure is rare in spontaneous seizures that are not under the control of the patient.

Clinical and EEG estimates of absence seizure frequency.

Absence seizure frequency was estimated in 20 patients (5 to 15 years old) before and after treatment with ethosuximide. Estimates were obtained from mothers' histories, observations by nurses, intensive observation by trained observers, physical and neurological examinations, routine EEG, and 12-hour telemetered EEG. Both before treatment (high seizure frequency) and after treatment (low frequency), telemetered EEG was the most reliable method of estimation, and intensive observation was the next best method. After treatment, the mothers' and nurses' estimates of seizure frequency were significantly less than the telemetered EEG estimates. The neurological examination and routine EEG were sufficient to diagnose absence attacks in all 20 patients and to determine if the attacks were completely controlled by therapy in all but two patients.

Valproic acid hepatic fatalities. III. U.S. experience since 1986.

We report the results of a third retrospective study of the U.S. experience with fatal hepatotoxicity associated with valproic acid (VPA). In the United States, over one million patients received new prescriptions for VPA during the years 1987 to 1993, and 29 patients developed fatal hepatotoxicity. Decreased alertness, jaundice, vomiting, hemorrhage, increased seizures, anorexia, and edema were the most common presenting signs. Risk factors included young age, polytherapy, developmental delay, and coincident metabolic disorders. Patients less than 2 years old receiving VPA as polytherapy were at the greatest risk (1:600) of developing this complication.

Prognostic factors in absence seizures.

A prospective follow-up study was conducted on 48 epileptic patients (22 males and 26 females) who had participated in a collaborative study of absence seizures about 7 years earlier. Multivariate analysis showed that the significant prognostic factors for absence seizures were normal or above normal intelligence and normal electroencephalographic background activity. For any seizure type, significant prognostic factors were a negative history of generalized tonic-clonic seizures, normal or above normal intelligence, and a negative family history of seizure disorders. Nearly 90 percent of the patients with all significant prognostic factors for both absence seizures and seizures of all types ceased having seizures.

Personality of patients with pseudoseizures.

We studied personality features of 19 patients with pseudoseizures (PS) only. Scores on a personality inventory (MMPI) were compared with those of adults with generalized seizures and correlated to cognitive measures (Halstead-Reitan). Mean MMPI scores did not differ significantly, and no profile distinguished PS and epilepsy patients. MMPI abnormalities of PS patients were diverse and seldom characteristic of hysteria. Eight PS patients had cognitive impairment, two without MMPI evidence of personality disorder. These findings suggest that the etiology of pseudoseizures is multifactorial, involving different psychopathologies and sometimes cerebral dysfunction.

Valproic acid hepatic fatalities. II. US experience since 1984.

We have analyzed the usage pattern of valproate and the associated hepatic fatalities that have been reported in the 2 years since our first study evaluating US experience during the period 1978-1984. In this follow-up study (1985-1986), we have observed a nearly fivefold decrease in the incidence of hepatic fatality during a time when the overall use of valproate has increased significantly. The dramatically decreased incidence, from 0.93 per 10,000 (1/10,000) in 1978-1984 to 0.20 per 10,000 (1/49,000) in 1985-1986 appears to be due to changes in the prescribing patterns of physicians, prompted by greater awareness of low-risk versus high-risk patients. More patients are receiving valproate as monotherapy, considerably more low-risk patients are being treated with valproate, and fewer high-risk patients (0 to 2 years old) are being treated with valproate. During 1985-1986, no hepatic fatalities were reported in any patients above the age of 10 years, regardless of whether valproate was administered as monotherapy or polytherapy. The altered exposure pattern, with an increased use of monotherapy, appears to have had a positive impact on the number of hepatic fatalities (four among 198,000 patients treated during 1985-1986) and contributed to a decreased rate of valproate-associated hepatic fatality.

Long-term follow-up of absence seizures.

The prognosis of absence seizures was evaluated in 83 patients by univariate and multivariate analysis. The mean follow-up period was 9.5 years. Normal intelligence quotient (IQ) was found to be a significant prognostic factor by both methods of analysis, but multivariate analysis showed that normal IQ, no hyperventilation-induced spikes and waves, male sex, and normal neurologic findings were significant prognostic factors associated with cessation of all types of seizures. More than 90% of patients with three or more significant factors stopped having seizures. A multiple logistic regression model describes the population and can be used for estimating the outcome of patients with absence seizures.

Sodium valproate: pharmacokinetics and effectivensss in treating intractable seizures.

Sodium valproate (VPA) was first marketed in the United States in 1978. In this pilot study of pharmacokinetics and toxicity, VPA was added to the treatment regimens of 20 patients (10 adults and 10 children) with intractable seizures. The drug was absorbed and excreted rapidly; the mean half-life was 9.6 hours. Drowsiness and gastrointestinal symptoms were the most common side effects, but they were usually minor and transient. An increase in some plasma phenobarbital levels and a decrease in some plasma phenytoin levels were attributed to drug interaction. Control of absence attacks was assessed by 12-hour telemetered electroencephalograms. Sodium valproate was most efficacious in generalized seizure disorders, particularly absence seizures.

Serum clonazepam concentrations in children with absence seizures.

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.

Intensive monitoring in refractory epilepsy.

Forty patients with intractable seizures were studied in an epilepsy unit for an average of 8 weeks with video-electroencephalographic telemetry and continuous observation by trained personnel. Drugs were administered on the basis of antiepileptic drug measurements and seizure classification determined by clinical observation and telemetry. Seizure frequency was reduced in 24 patients (60%). Unrecognized seizure types were identified in 8 patients (20%), and diagnostic classification was changed in 19 patients (47.5). At least one antiepileptic drug was eliminated in 25 patients (60%), and the average drug reduction per patient--0.60--was highly significant (p less than 0.01). In patients with seizures refractory to conventional out-patient and hospital management, improvement in diagnostic accuracy and refinement in observation techniques result in significant reduction of seizure frequency, elimination of drugs, and limitation of toxicity.

Valproic acid hepatic fatalities: a retrospective review.

We reviewed all US cases of fatal hepatotoxicity coincident with valproate anticonvulsant therapy that were reported between 1978 and 1984. Thirty-seven hepatic fatalities were determined to have occurred coincident with the use of valproate. All but one patient had such other medical conditions as mental retardation, developmental delay, congenital abnormalities, and other neurologic diseases. The primary risk of fatal hepatic dysfunction (1/500) was found to be in children 0 to 2 years old receiving valproate as polytherapy. The risk declined with age and was low in patients receiving valproate as monotherapy (1/37,000). No hepatic fatalities occurred in patients above the age of 10 years receiving valproate as monotherapy.

A controlled study of progabide in partial seizures: methodology and results.

The results of a multicenter, double-blind, placebo-controlled clinical trial of the efficacy and safety of progabide (PGB) in the treatment of partial seizures are presented. This study was performed with a number of rigorous controls not usually present in clinical trials. These included uniform co-medication in which all patients received only phenytoin and carbamazepine; concentrations of these two drugs were maintained within narrow, predefined concentration ranges. There was no statistically significant difference between PGB and placebo in seizure frequency and seizure duration for most of the analyses performed. One patient was withdrawn from the study because of hepatotoxicity. PGB was associated with a significant inhibition of phenytoin but not carbamazepine clearance. The results of this study indicate that PGB was not a potent antiepileptic drug in this population of persons with intractable epilepsy.

Improvement in neuropsychological performance in patients with refractory seizures after intensive diagnostic and therapeutic intervention.

Tests of cognitive, perceptual, motor, and memory function were administered to patients with refractory seizures before and after intensive treatment on a specialized epilepsy unit. Improved test performance related to withdrawal of barbiturates and an overall reduction in the number of antiepileptic drugs but not with reduction of seizure frequency.

Ethosuximide in the treatment of absence (peptit mal) seizures.

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.

Patients with pseudoseizures: intellectual and cognitive performance.

We compared cognitive and intellectual performance of patients with pseudoseizures (pseudoseizure-only group), pseudoseizures and epilepsy (mixed seizure group), and generalized epileptic seizures (generalized seizure group). The pseudoseizure-only group performed significantly better on all measures except those of simple motor function. There were no significant differences between those with mixed and generalized seizures. Therefore, cognitive and intellectual performances of patients with pseudoseizures are influenced by the presence or absence of concomitant epilepsy, and suggest that it is necessary to distinguish patients with and without epilepsy in studies of pseudoseizures.

Felbamate for partial seizures: results of a controlled clinical trial.

Felbamate (2-phenyl-1,3-propanediol dicarbamate) has a favorable preclinical profile in animal models of epilepsy. We present the results of a double-blind, randomized, placebo-controlled clinical trial in patients with partial seizures. Criteria for entry included a requirement for four or more partial seizures per month despite concomitant therapeutic blood levels of phenytoin and carbamazepine. Fifty-six patients (mean age, 31.4 years; 32 men, 24 women) completed the trial. The mean seizure frequencies for the 8-week periods analyzed were felbamate = 34.9, placebo = 40.2. Felbamate was statistically superior to placebo in seizure reduction, percent seizure reduction, and truncated percent seizure reduction. The mean felbamate dosage was 2,300 mg/d. Plasma felbamate concentrations ranged from 18.4 to 51.9 mg/l, mean = 32.5 mg/l. Adverse experiences during felbamate therapy were minor and consisted primarily of nausea and CNS effects. This trial indicates that felbamate is safe and effective in the treatment of comedicated patients with severely refractory epilepsy.

Side effects of valproate.

In the management of epilepsy, selecting an antiepileptic drug appropriate for each individual patient requires matching the patient's clinical needs with the agent's specific pharmacologic attributes. In many situations, the final choice of an antiepileptic drug is based upon an agent's side-effect profile. Because side-effect profiles emerge gradually as the number of patients treated expands from the thousands to the hundreds of thousands, it is helpful to periodically update our perspective of side effects of antiepileptic drugs. For valproate, the frequency of side effects has been reduced by monitoring serum levels, using improved formulations, and limiting use in patients who have been identified as having a high risk for the development of a serious side effect.

Teratogenicity of anticonvulsant drugs. II: A prospective study.

To 468 women with epilepsy enrolled in the study, 171 children were born and evaluated prospectively. The mothers in this group were characterized by low socioeconomic status, high frequency of tonic-clonic generalized seizures, and use of combinations of anticonvulsants. Approximately 30% of infants exposed to diphenylhydantoin in utero had minor craniofacial and digital changes. The infants did not show an increased rate of growth retardation, mental retardation, or major malformations. It is suggested that the nature of the association of birth defects and maternal epilepsy is complex and that the teratogenicity of anticonvulsant drugs plays only a minor role in this association. The sample size necessary to demonstrate a two- to threefold increase in malformations is beyond the capability of a single center.

Classification and recognition of seizures.

Inappropriate drug therapy for epilepsy may do more harm than good. Therefore it is important that the clinician appreciate differences among the various forms of epilepsy and choose the safest and most effective drug for the individual. The currently used classification of seizure types is summarized, and conditions that need to be distinguished from epilepsy are mentioned.