Choreiform movements associated with the use of valproate.

OBJECTIVE: To describe the association of choreiform movements with the use of valproic acid. DESIGN: Case series. PATIENTS: Three patients who developed chorea during long-term treatment with valproic acid. All patients had severe brain damage; one had a preexisting unilateral vascular lesion in the caudate nucleus. At the time chorea developed, two patients were also receiving phenytoin sodium. RESULTS: Chorea developed between 30 minutes and 3 hours after ingestion of valproic acid, and the duration of the episodes varied between 30 minutes and 8 hours. The episodes of chorea occurred frequently for several days followed by asymptomatic periods lasting several weeks. Choreic movements involved the head, mouth, tongue, trunk, and limbs bilaterally in two cases and contralaterally in the patient with the caudate lesion. In one case, it was necessary to withdraw valproic acid treatment, while in the other two cases, replacement of valproic acid by divalproex sodium sprinkles presumably decreased peak concentrations and resulted in resolution with no recurrence of the chorea. CONCLUSIONS: Valproic acid-associated chorea occurred in patients with severe epilepsy and brain damage. It may occur after several years of valproic acid use and may be more likely to develop if valproic acid is taken together with phenytoin. Because valproic acid-associated chorea seemed to be dose related, avoiding excessive fluctuations of serum levels by the use of divalproex sodium sprinkles may be an effective solution in these cases.

Predictive value of induction of psychogenic seizures by suggestion.

Induction by suggestion has previously been reported to be effective in the diagnosis of psychogenic seizures (PS). However, the sensitivity and specificity of this procedure has not previously been studied. Results of induction of PS by suggestion were analyzed in 93 patients with purely PS. The diagnosis of PS was based on the recording of a clinical event on video-electroencephalography, the absence of clinical or electroencephalography the absence of clinical or electroencephalographic evidence of epilepsy, and the subsequent followup and withdrawal of anticonvulsants supporting the diagnosis of PS. A control-group was composed of 20 patients with epilepsy in which induction was tried. Both groups were comparable for age, sex, and educational level. Induction was performed following a standardized protocol. The test was carried out placing a colored patch on the neck. The test was considered positive when the induced clinical events were typical, according to a witness familiar with the patient's seizures. Induction was positive in 72 of 93 cases with PS and in none with epilepsy. Sensitivity of this test for the diagnosis of PS was 77.4%, specificity 100%, positive predictive value 100%, and negative predictive value 48.7%.

Clinical and EEG asymmetries in juvenile myoclonic epilepsy.

We reviewed records of 85 patients with juvenile myoclonic epilepsy (JME) for significant asymmetries in clinical seizures or the EEG. We noted asymmetries in 26 of 85 patients (30.6%). Only 2 patients had both clinical and EEG asymmetries; 12 had clinical asymmetries and 12 had EEG asymmetries exclusively. Analysis of patients with and without asymmetries showed no statistically significant differences in comparisons of sex, age at seizure onset, family history of epilepsy, seizure type, or response to treatment. The delay in diagnosis was greater in JME patients with asymmetries (9.5 years) than in JME patients with no asymmetries (7.5 years), but this difference was not statistically significant. Fourteen of the 26 patients with asymmetries (53.8%) were initially misdiagnosed as having partial seizures. Asymmetries in JME patients are not only common, but are also a frequent cause of misdiagnosis.

Psychogenic seizures in adults: a longitudinal analysis.

The clinical characteristics, psychosocial background, neuropsychological testing, clinical and social outcome were analysed in 93 adults with psychogenic seizures (PS). Thirteen (14%) were males and 80 (86%) were females. Mean age was 31.7 years (range 16 to 55 years). Lack of responsiveness associated with motor activity was the most common finding. Neuropsychological testing done in 46 cases revealed hysteroid traits and coping mechanisms and depression to be the most prevalent underlying problems. History of sexual abuse was evident in 10 (10.7%) cases. Social impact analysis revealed that of 62 patients who were working at the onset of PS, 34 were not working at the time of the diagnosis of PS. In 25 cases, PS were the reason for not working. After a mean follow-up of 60.7 months done in 63 patients, 16 (25.4%) patients were seizure-free. There were no obvious significant predictors of poor prognosis.

Treatment of epilepsy by stimulation of the vagus nerve.

We treated 14 patients with medically refractory partial seizures by stimulation of the vagus nerve in two single-blind pilot studies. Patients received stimulation through an implantable, programmable NeuroCybernetic Prosthesis, consisting of a pulse generator and a lead-electrode assembly. The mean reduction in seizure frequency after 14 to 35 months of vagal stimulation was 46.6%. Of the 14 patients, five (35.7%) had a 50% or greater reduction in seizure frequency. Two patients, one of whom had had 10 to 100 seizures per day before stimulation, have been seizure-free for over 1 year. Adverse events were primarily limited to initial hoarseness and a tingling sensation at the electrode site in the neck when the device was activated. Most patients tolerated the device and stimulation well. There were no permanent adverse events. Some cases of medically refractory partial seizures are improved by vagal stimulation.

Efficacy and safety of zonisamide: results of a multicenter study.

The safety and efficacy of zonisamide (ZNS), a new antiepileptic drug, was tested in 167 adult participants who entered a historical-controlled 16-week open label, multicenter study. The median percent reduction from baseline of partial seizures was 51.8% in the fourth month of the study (baseline median = 11.5 sz/month; treatment weeks 13-16 = 5.5 sz/month). Persons completing the efficacy study successfully were eligible for a long-term safety study; 113 entered this study. Adverse effects involved principally the CNS and were similar to those seen with other antiepileptic drugs. Four persons (3.7%) developed kidney stones and were withdrawn from the study 250-477 days after starting ZNS. Because of the high percentage of kidney stones, development of ZNS was stopped in the United States but was continued in Japan.

Quality of life in epilepsy: the clinician's view.

Quality of life in patients with epilepsy may be impaired by seizures, side effects of medication, and psychosocial problems. Doctors tend to focus their attention on managing the seizures and the side effects, but may not be meeting all of the patient's needs because of differences between their perception of these concerns and the patient's. Further, psychosocial problems often are addressed only superficially or not at all during office visits. The challenge is to integrate quality-of-life issues into clinical practice and to better assess the patient's perception of the disorder, the seizures, and the medications, as they impact on cognitive function, emotional well-being, and social and economic functioning.

Valproate-associated pancreatitis.

To assess the clinical characteristics of valproate (VPA)-associated pancreatitis, information from three sources was gathered: (a) a survey among 507 physicians with a special interest in treatment of epilepsy, (b) a review of the authors' patient population, and (c) a review of the literature. Of 366 physicians answering the survey, 53 (14.5%) reported a case of pancreatitis. Thirty-nine cases were available for review (24 from the medical literature, 12 from the survey, and 3 from the authors). Pancreatitis appeared to be more frequent in young persons (mean age 16.4 years) but may occur at any age. The highest risk appears to exist during the first months of treatment: 43.8% of the cases developed during the first 3 months, and 68.8% developed during the first year. Seventy-six percent of patients were receiving polytherapy, and 41% had some form of associated chronic encephalopathy. In most patients, the reaction was rapidly reversible when VPA was discontinued. It was severe in 6 patients, with 3 deaths reported. Rechallenge with VPA was attempted in 9 patients, with a high incidence of relapses. Asymptomatic elevation of serum amylase in patients receiving VPA was reported by 40 (10.9%) of the physicians surveyed. Awareness of the problem and early discontinuation of VPA may be effective in preventing serious reactions.

Relationship between serum concentration and dose of valproic acid during monotherapy in adult outpatients.

The relationship between serum concentration and dose of valproic acid (VPA) is reported to be variable and inconsistent. However, studies evaluating this relationship have included individuals of varying ages and patients receiving potentially interacting medications. In this study, the relationship between VPA serum concentration and dose was evaluated in a homogeneous patient population. Medical records of 60 adult outpatients with epilepsy receiving VPA monotherapy were examined retrospectively for VPA dose (milligrams per kilogram) and corresponding serum VPA concentrations. A significant linear correlation was found in the relationship between VPA dose and serum concentration among all patients (r = 0.63; p less than 0.01). However, considerable interindividual variability in this ratio was demonstrated [coefficient of variation (CV) = 28.9%], and the ratio was significantly dependent on VPA dose. In three selected individual patients, a significant linear correlation was also demonstrated in the VPA serum concentration:dose relationship over time (r = 0.91, 0.94, 0.96; p less than 0.05 for all three patients) with substantially less variability (CV = 10.2-14.6%) and without significant dose dependency, suggesting that this parameter may be useful for guiding VPA dosage adjustment and monitoring patient compliance. Further study is required to evaluate the utility of the serum concentration:dose ratio in monitoring VPA therapy.

Serum and tissue carnitine assay based on dialysis.

Carnitine (L-beta-hydroxy-gamma-trimethylaminobutyric acid) aids mitochondrial energy production by transferring fatty acids across the membranes for beta-oxidation. We describe here a modified enzymatic assay for free serum and tissue carnitine based on dialysis to remove interfering substances in the serum, with subsequent conversion of carnitine to the acyl derivative by carnitine acetyltransferase (EC 2.3.1.7) in the presence of 5,5'-dithiobis-(2-nitrobenzoic acid). The method compared well with a radioenzymatic assay. The reference interval for serum is 28-70 mumol/L. Patients with advanced diabetes and those undergoing valproic acid treatment displayed lower mean values; a statistically significant number of them showed serum carnitine values below the reference interval. The method was also applied to carnitine measurement in cerebrospinal fluid and human tissues.

Therapeutic bioequivalency study of brand name versus generic carbamazepine.

We performed a randomized double-blind crossover therapeutic bioequivalency study of a generic (Epitol) versus a brand name (Tegretol) carbamazepine product under steady-state conditions in 40 epileptic patients. Each patient received 90-day supplies of Epitol or Tegretol and placebo, which replaced the usual dosage of the alternate product. Group A consisted of 20 seizure-free (from 5 months to 2 years) patients and group B of 20 patients with seizures refractory to drug therapy. In group A, four patients had seizures, two on both Epitol and Tegretol and two on Tegretol. In group B, the average seizure frequencies were 0.25 seizures per day on Epitol and 0.22 seizures per day on Tegretol. Average seizure frequencies were statistically the same (at a 20% difference, p less than 0.05). Areas under the curve were statistically the same (at a 20% difference, p = 0.05). Average peak heights were statistically the same (at a 20% difference, p less than 0.05). Average time to peak was earlier with Epitol. Epitol and Tegretol performed equally well in clinical efficacy and bioequivalency.

Poststroke seizures in the elderly.

Strokes are the most common cause of epilepsy in the elderly. Seizures after an acute stroke have been estimated to occur in 5% to 10% of cases. A distinction between early and late seizures should be made. Early seizures are more common, occur very early in the evolution of the stroke, and tend to be focal motor, brief, and isolated. They are likely to be the result of an acute local brain metabolic alteration induced by the cerebrovascular event, and once these derangements are reversed, seizures disappear. Epilepsy usually does not follow early seizures, but the risk is probably increased. Late seizures occur months to years after the stroke and are probably due to structural brain abnormalities leading to the development of an epileptic focus. The majority of these cases develop epilepsy. The risk of seizures is markedly increased when the cerebrovascular event involves the cerebral cortex. Deep-seated hemispheric or infratentorial lesions rarely produce seizures or epilepsy. It is possible that hemorrhagic stroke carries a higher incidence of seizures, but the issue remains controversial. It has also been suggested that embolic infarction has a higher incidence of seizures that does thrombotic infarction, but definitive evidence is lacking. The presence of seizures in an acute stroke does not seem to correlate with the size of the lesion, functional outcome, or mortality. Prophylactic treatment with antiepileptic drugs is probably not indicated in most types of strokes, except for subarachnoid hemorrhage after a ruptured intracranial aneurysm. When early seizures develop, treatment is indicated but may not be necessary for a prolonged period of time. If late seizures develop, chronic anticonvulsant therapy is recommended.

Transient magnetic resonance imaging abnormalities during partial status epilepticus.

Magnetic resonance imaging is an important tool in the evaluation of patients with seizures. Frequently, abnormalities are found that lead to further, invasive testing. The first child with transient abnormal findings on magnetic resonance imaging during a time of frequent partial seizures is presented. This lesion disappeared with seizure control. The imaging literature is reviewed concerning transient findings on any imaging modality during frequent seizures. Caution in recommending invasive procedures is suggested when abnormalities are found on magnetic resonance imaging during frequent seizures.

Multicenter long-term safety and efficacy study of vigabatrin for refractory complex partial seizures: an update.

We followed 66 patients with refractory complex partial seizures and a favorable initial response to vigabatrin for 5 to 72 (median, 43) months. Thirty-seven patients discontinued vigabatrin for the following reasons: benefit-to-risk evaluation, 8; seizure breakthrough, 6; adverse events, 6; seizure breakthrough and adverse events, 5; moved or lost, 4; no longer eligible for study, 2; non-drug-related death, 2; narcotic abuse, 1; and patient request, three. There were no clinically significant abnormalities in laboratory studies including SMA 12, complete blood count, ECG, EEG, and visual evoked response testing, and no toxicity other than reversible, dose-dependent side effects. Based on this and other long-term data, clinical trials of vigabatrin have resumed in the United States and Canada.

Prevention of intractable partial seizures by intermittent vagal stimulation in humans: preliminary results.

Intermittent stimulation of the vagus nerve in four patients resulted in complete seizure control in two, a 40% reduction of seizure frequency in one, and no change in seizure frequency in the other. Side effects (hoarseness, stimulation sensation in the neck, and hiccups) were transient and occurred concomitantly with stimulation. All patients tolerated increasing stimulation parameters well. The results, however, are inconclusive because of the brief duration (6-12 months) of follow-up. Vagal stimulation represents a novel approach for seizure control in patients who have intractable epilepsy, but additional studies are needed to clarify the efficacy and safety of the procedure and to define selection criteria for patients.

Catastrophic neurologic signs due to drug interaction: Tegretol and Darvon.

Eight cases of carbamazepine toxicity from interaction with propoxyphene are reported. Serum concentrations of carbamazepine increased up to sixfold. All patients were symptomatic and two were hospitalized. Practitioners prescribing propoxyphene acutely for pain should be aware of this significant interaction.

The scope and use of valproate in epilepsy.

Valproate has rapidly advanced as an antiepileptic drug in the last 15 years. This simple branched-chain fatty acid is strikingly different from previous antiepileptic drugs. Numerous clinical studies have found valproate to be highly effective in controlling generalized seizures, particularly as monotherapy. Ideally, valproate is given in three to four doses per day, because the elimination half-life varies from 6 to 15 hours, depending on concomitantly administered drugs and metabolic variations. Increasing the dosage raises the peak serum level and also increases the duration of time during which a minimum effective serum concentration is obtained. Drug interactions occur when valproate is administered with other drugs, especially other antiepileptic drugs. Side effects attributed to valproate include tremor, weight gain, hair loss, hair growth, hepatotoxicity, and neural tube defects in offspring of mothers. Monitoring serum valproate concentrations and seizure frequency are essential aspects of patient follow-up.

Phenytoin and phenobarbital concentrations in serum: a comparison of Ames Seralyzer with GLC, TDX, and EMIT.

A recently developed system for measuring antiepileptic drug concentrations was evaluated for phenytoin and phenobarbital. The apoenzyme reactive immunoassay system was compared with gas-liquid chromatography, EMIT, and TDX systems. Comparisons were performed with control specimens and with sera obtained from patients at three facilities. Precision for all methods was similar, with within-run and between-run coefficients of variation generally 5%. The accuracy of all methods was acceptable, but bias was present in some. However, measurements obtained by a nontechnical person (physician) in a clinical setting were sometimes inaccurate.