Levetiracetam for partial seizures: results of a double-blind, randomized clinical trial.

OBJECTIVE: To evaluate the efficacy and safety of 500 mg bid and 1500 mg bid levetiracetam as adjunctive therapy for refractory partial seizures in a double-blind, randomized, placebo-controlled, parallel-group, multicenter trial. METHODS: The authors studied patients with uncontrolled partial seizures (minimum 12 per 12 weeks), regardless of whether they became secondarily generalized, for 38 weeks. A 12-week baseline was followed by random assignment to adjunctive therapy with placebo (n = 95), levetiracetam 1000 mg/day (n = 98), or levetiracetam 3000 mg/day (n = 101). Upward titration over 4 weeks was followed by 14 weeks of fixed dose treatment, and concluded with an 8-week medication withdrawal period or entering a follow-up study. RESULTS: Of 294 patients randomized, 268 completed the study. Partial seizure frequency during the entire evaluation period (primary efficacy variable) was lower with levetiracetam compared to placebo (p /=10%), mostly mild to moderate in severity, with incidences higher than placebo were asthenia, dizziness, flu syndrome, headache, infection, rhinitis, and somnolence. CONCLUSION: Adjunctive therapy with levetiracetam was effective and well tolerated in controlling partial seizures.

L-carnitine supplementation in childhood epilepsy: current perspectives.

In November 1996, a panel of pediatric neurologists met to update the consensus statement issued in 1989 by a panel of neurologists and metabolic experts on L-carnitine supplementation in childhood epilepsy. The panelists agreed that intravenous L-carnitine supplementation is clearly indicated for valproate (VPA)-induced hepatotoxicity, overdose, and other acute metabolic crises associated with carnitine deficiency. Oral supplementation is clearly indicated for the primary plasmalemmal carnitine transporter defect. The panelists concurred that oral L-carnitine supplementation is strongly suggested for the following groups as well: patients with certain secondary carnitine-deficiency syndromes, symptomatic VPA-associated hyperammonemia, multiple risk factors for VPA hepatotoxicity, or renal-associated syndromes; infants and young children taking VPA; patients with epilepsy using the ketogenic diet who have hypocarnitinemia; patients receiving dialysis; and premature infants who are receiving total parenteral nutrition. The panel recommended an oral L-carnitine dosage of 100 mg/kg/day, up to a maximum of 2 g/day. Intravenous supplementation for medical emergency situations usually exceeds this recommended dosage.

A comparison of rectal diazepam gel and placebo for acute repetitive seizures.

BACKGROUND: Acute repetitive seizures are readily recognizable episodes involving increased seizure frequency. Urgent treatment is often required. Rectal diazepam gel is a promising therapy. METHODS: We conducted a randomized, double-blind, parallel-group, placebo-controlled study of home-based treatment for acute repetitive seizures. Patients were randomly assigned to receive either rectal diazepam gel, at a dosage varying from 0.2 to 0.5 mg per kilogram of body weight on the basis of age, or placebo. Children received one dose at the onset of acute repetitive seizures and a second dose four hours later. Adults received three doses -- one dose at onset, and two more doses 4 and 12 hours after onset. Treatment was administered by a care giver, such as a parent, who had received special training. The number of seizures after the first dose was counted for 12 hours in children and for 24 hours in adults. RESULTS: Of 125 study patients (64 assigned to diazepam and 61 to placebo) with a history of acute repetitive seizures, 91 (47 children and 44 adults) were treated for an exacerbation of seizures during the study period. Diazepam treatment was superior to placebo with regard to the outcome variables related to efficacy: reduced seizure frequency (P<0.001) and improved global assessment of treatment outcome by the care giver (frequency and severity of seizures and drug toxicity) (P<0.001). Post hoc analysis showed diazepam to be superior to placebo in reducing seizure frequency in both children (P<0.001) and adults (P=0.02), but only in children was it superior with regard to improvement in global outcome (P<0.001). The time to the first recurrence of seizures after initial treatment was longer for the patients receiving diazepam (P<0.001). Thirty-five patients reported at least one adverse effect of treatment; somnolence was the most frequent. Respiratory depression was not reported. CONCLUSIONS: Rectal diazepam gel, administered at home by trained care givers, is an effective and well-tolerated treatment for acute repetitive seizures.

Lamotrigine in childhood epilepsies.

Lamotrigine (LTG) is one of the new generation of antiepileptic drugs (AEDs) that have been designed to perform specific physiological or pharmacological functions. Early laboratory testing revealed an AED profile auguring success in the management of generalized tonic-clonic seizures, partial seizures, and also absence, thus suggesting a broad spectrum of activity. The drug blocks voltage-sensitive sodium channels resulting in inhibition of excitatory neurotransmitter release. Randomized, controlled clinical trials confirmed effectiveness and the side effect profile was favorable. The use of LTG in childhood is based largely on anecdotal open-label derived information. To date it appears to have been successful in many of the most devastating childhood epilepsy syndromes but controlled trial information is needed to confirm that it may be not only successful as add-on in partial seizures but also in primary and secondarily generalized epilepsies as a primary agent.

Epilepsy: standards of medical care.

This paper acknowledges that the majority of doctors who care for those with epilepsy are not specialists in epileptology. It then provides standard guidelines to patient management and provides a flow chart for diagnosis, examination, investigations and treatment to assist in decision making. The paper argues that excessively rigid formalized programmes result in loss of flexibility to respond to changing circumstances, which may require further investigation to confirm the diagnosis and the appropriateness of selected therapy. The paper reaffirms that guidelines could cause unnecessary inhibitions to optimal delivery of care but those who deviate from standard practice must be able to substantiate and justify the approach adopted.

Epilepsies with partial seizures in childhood.

Individual seizures are described as either partial (localization related) or generalized depending on whether a localized area of cerebral cortex is symptomatically involved sufficient to impart to the seizure a focal signature or whether sufficient cortex is involved sufficiently rapidly to appear as if generalized from the outset. This distinction is of some diagnostic and therapeutic importance. However, it has become evident that the prognosis of the patient's epilepsy is less a function of the seizure type than it is of the etiology and of the nature of the syndrome that the seizures represent. This approach is stressed in this chapter as is the regret that there is frequently a delay in the acknowledgment of the usefulness of a new drug in childhood epilepsies, as exemplified by lamotrigine.

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.

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.

New antiepileptic drug development.

The development of new antiepileptic drugs is poised on the cusp between empiricism and the rational scientific development of medicaments designed to perform specific neurophysiologic functions in keeping with modern ideas of epilepsy generation and spread. It takes into account the difference between seizures and their underlying disorder known as epilepsies and the fact that, although seizures can be effectively treated with pharmacologic agents, the development of epilepsy requires both a predisposition (which may be innate or preventable) and precipitating factors that determine the timing of the individual seizures. The local membrane phenomena or cellular substrates of epilepsy can be described, as can the process of epileptogenesis. New antiepileptic development can be viewed in the light of these concepts.

Prognosis of childhood seizure disorders: present and future.

The prognoses for seizure disorders have been examined since the beginnings of epileptology, and only recently has the realization emerged that, ultimately, prognosis depends on causation, which, in turn, determines whether a condition is self-limited or progressive. This factor is more important than either mode or alacrity of therapeutic intervention. The epilepsies are a series of conditions that have the final common path of either increasing cerebral irritability or synchronizing normally occurring electrical activity in such a manner that seizures result. In turn, some seizure disorders are characterized by secondary changes in neuronal synaptogenesis, leading to the development of circuits of predilection, which then render the process autonomous. Epileptogenesis has then become epilepsy, which is the norm in acquired rather than genetic epileptogenesis. An understanding of the basic differences between the primary (idiopathic) epilepsies and the secondary (acquired or symptomatic) epilepsies is basic to a discussion concerning prognosis and to the development of a definitive individualized treatment plan. An elucidation of the genetic factors in idiopathic epilepsy and their neurochemical consequences represents a major frontier in epileptology.

Changes in red blood cells with valproate therapy.

Increase in the red blood cell mean corpuscular volume (MCV), and mean corpuscular haemoglobin (MCH) values in patients receiving Valproate as mono or polytherapy was noted. To investigate this situation 41 epileptic patients were studied on Valproate alone (Group 1) and 20 patients on Valproate added to another antiepileptic drug (AED), (Group 4), and compared with 19 patients on carbamazepine (CBZ) (Group 2) and 12 patients on phenytoin (PHT), (Group 3). The results showed significant rise in MCV values in Groups 1 and 4. The peripheral blood smear and other tests including reticulocyte counts of the patients with abnormal values ruled out macrocytic anemias. We postulate a generalized effect which is the result of alteration in erythrocyte membrane phospholipids.

Differential diagnosis in pseudoepileptic seizures.

With increasing use of intensive video-EEG monitoring, publications concerning pseudoepileptic seizures have burgeoned, but without clarification concerning differing psychopathologic mechanisms and without distinction of different syndromic varieties. The frequent concurrence of pseudoepileptic and epileptic seizures has not been sufficiently recognized, and an undue reliance on clinical experience on the one hand and individual tests such as EEG on the other has proven equally misleading in this group of cases.

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.