Efficacy and tolerability of the new antiepileptic drugs I: treatment of new onset epilepsy: report of the Therapeutics and Technology Assessment Subcommittee and Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society.

OBJECTIVE: To assess the evidence demonstrating efficacy, tolerability, and safety of seven new antiepileptic drugs (AEDs) (gabapentin, lamotrigine, topiramate, tiagabine, oxcarbazepine, levetiracetam, and zonisamide-reviewed in the order in which these agents received approval by the US Food and Drug Administration) in the treatment of children and adults with newly diagnosed partial and generalized epilepsies. METHODS: A 23-member committee, including general neurologists, pediatric neurologists, epileptologists, and doctors in pharmacy, evaluated the available evidence based on a structured literature review including MEDLINE, Current Contents, and Cochrane library for relevant articles from 1987 until September 2002, with selected manual searches up until 2003. RESULTS: There is evidence either from comparative or dose-controlled trials that gabapentin, lamotrigine, topiramate, and oxcarbazepine have efficacy as monotherapy in newly diagnosed adolescents and adults with either partial or mixed seizure disorders. There is also evidence that lamotrigine is effective for newly diagnosed absence seizures in children. Evidence for effectiveness of the new AEDs in newly diagnosed patients with other generalized epilepsy syndromes is lacking. CONCLUSIONS: The results of this evidence-based assessment provide guidelines for the prescription of AEDs for patients with newly diagnosed epilepsy and identify those seizure types and syndromes where more evidence is necessary.

Efficacy and tolerability of the new antiepileptic drugs II: treatment of refractory epilepsy: report of the Therapeutics and Technology Assessment Subcommittee and Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society.

OBJECTIVE: To assess the evidence demonstrating efficacy, tolerability, and safety of seven new antiepileptic drugs (AEDs) (gabapentin, lamotrigine, topiramate, tiagabine, oxcarbazepine, levetiracetam, and zonisamide) in the treatment of children and adults with refractory partial and generalized epilepsies. METHODS: A 23-member committee including general neurologists, pediatric neurologists, epileptologists, and doctors in pharmacy evaluated the available evidence based on a structured literature review including MEDLINE, Current Contents, and Cochrane library for relevant articles from 1987 until March 2003. RESULTS: All of the new AEDs were found to be appropriate for adjunctive treatment of refractory partial seizures in adults. Gabapentin can be effective for the treatment of mixed seizure disorders, and gabapentin, lamotrigine, oxcarbazepine, and topiramate for the treatment of refractory partial seizures in children. Limited evidence suggests that lamotrigine and topiramate are also effective for adjunctive treatment of idiopathic generalized epilepsy in adults and children, as well as treatment of the Lennox Gastaut syndrome. CONCLUSIONS: The choice of AED depends upon seizure and/or syndrome type, patient age, concomitant medications, AED tolerability, safety, and efficacy. The results of this evidence-based assessment provide guidelines for the prescription of AEDs for patients with refractory epilepsy and identify those seizure types and syndromes where more evidence is necessary.

Topiramate titration and tolerability.

OBJECTIVE: To evaluate the tolerability and efficacy of two titration rates for topiramate initiated as adjunctive therapy in adults with partial-onset seizures, with or without secondary generalization, in a multicenter, double-blindtrial. METHODS: After a two-week baseline phase, 188 patients were randomized to either a 50/50 titration schedule (initial dosage 50 mg/d increased in 50-mg/d increments at weekly intervals; n = 95) or to a 100/200 titration schedule (initial dosage 100 mg/d increased by 100-200 mg/d at weekly intervals; n = 93). The maximum dosage of 400 mg/d was therefore achieved in eight weeks or three weeks, respectively. RESULTS: Compared with the 100/200 titration rate, the 50/50 titration rate significantly reduced the cumulative incidence of treatment-emergent adverse events (TEAEs) leading to changes in topiramate therapy (ie., dosage reductions, interruptions or discontinuations of therapy) (p = 0.048) and significantly reduced treatment interruptions or withdrawals due to TEAEs (p = 0.040). Mild or moderate effects involving the central nervous system were the most frequent adverse events. At the final visit, therapeutic responses were comparable in the 50/50 and 100/200 titration groups: median percent seizure reduction was 42% vs. 33%, proportion of patients with 250% seizure reduction was 42% vs. 38%, and proportion of patients with no seizures during double-blind treatment was 14% vs. 10%, respectively. Seizure frequency was substantially reduced from baseline during topiramate titration. At day 22, with the 50/50 titration group receiving 150 mg/d and the 100/200 titration group receiving 400 mg/d, the mean percent seizure reduction was 51% and 54%, respectively. CONCLUSIONS: Gradual initiation of topiramate therapy can significantly enhance patient tolerability without delaying therapeutic response.

Nonfocal generalized tonic-clonic seizures: response during long-term topiramate treatment. Topiramate YTC/YTCE Study Group.

PURPOSE: A total of 131 adults and children (mean age, 27 years; range, 3-59 years) with generalized tonic-clonic seizures (GTCS) of nonfocal origin resistant to other antiepileptic drugs (AEDs) were treated with open-label topiramate (TPM) after completing double-blind placebo-controlled trials. RESULTS: The mean duration of open-label TPM treatment was 387 days (range, 14-909 days); the mean TPM dose was 7 mg/kg/day (range, 1-16 mg/kg/day). At the last study visit, the frequency of GTCS was reduced > or =50% from baseline in 63% of patients and by > or =75% in 44%. Among patients treated > or =6 months, 16% were GTCS free > or =6 months despite a pretreatment seizure frequency of one GTCS/week (median). Treatment with TPM was being continued in 82% of patients (n = 107) at the last visit. During treatment periods of up to 2.5 years, 11 (8%) patients discontinued TPM because of adverse events and seven (5%) because of inadequate seizure control. CONCLUSIONS: TPM therapy was well tolerated, and seizure control was maintained with long-term, open-label therapy in patients with GTCS, leading to prolonged seizure-free intervals in some patients with seizures previously resistant to AED therapy.

How will primary care physicians, specialists, and managed care treat epilepsy in the new millennium?

Epilepsy is a complex disorder that requires specialized knowledge for correct diagnosis, classification, and treatment. As we enter the millennium, changes in the health-care environment have created potential problems and opportunities as managed care organizations (MCOs), primary care practitioners (PCPs), and specialists work to improve the diagnosis and treatment of patients with seizure disorders. In the United States, only 17% of patients with new-onset epilepsy are examined by neurologists. Consequently, PCPs have a significant role in the care of patients with seizures. However, these practitioners may not be aware of newer diagnostic and therapeutic measures. Although practice guidelines have been promoted by MCOs as a cost-control and quality measure, their existence provides a cautionary note about the importance of consultations in patients with epilepsy. Specialists in epilepsy constitute an important resource to ensure that patients are correctly diagnosed and adequately treated. Consultation of a seizure-disorder patient by a specialist should be encouraged and never questioned by MCOs. The patient's best interests are served when PCPs, specialists, and MCOs establish a cooperative relationship and respect and recognize each other's expertise and common goals. This approach should help to deliver the best medical care to patients with epilepsy as we enter the next millennium.

New developments in the treatment of epilepsy.

Epilepsy is a medical disorder that presents with single or clustered seizures. There are several new drugs that effectively treat epilepsy with few side effects, and treatments of children, women, and the elderly are discussed. In the special population of children, there is a strong emphasis on the cognitive and behavioral benefits of specific therapies. In the population of epileptic women, seizures most often occur at the start of puberty and menarche, and worsen periodically with each menstrual cycle. Relief of symptoms often occurs at menopause, but a possibility of exacerbation also exists. Women with epilepsy often battle a fear of becoming pregnant. This is a fallacy which must be widely dispelled, as the risk is less than supposed. Among the elderly, epilepsy often presents after trauma, particularly stroke, and the incidence is three times greater for those over 60 years of age than the general population. Due to various conditions specific to the elderly, misdiagnosis is common. The greatest challenge in treating the elderly is adverse side effects.

A randomized, placebo-controlled study of topiramate in primary generalized tonic-clonic seizures. Topiramate YTC Study Group.

BACKGROUND AND OBJECTIVE: Topiramate is effective as adjunctive treatment of partial-onset seizures in adults. The efficacy and safety of topiramate as adjunctive therapy for the treatment of primary generalized tonic-clonic (PGTC) seizures were investigated in a randomized, double-blind, placebo-controlled study. METHODS: Eighty patients, 3 to 59 years old, who experienced three or more PGTC seizures during an 8-week baseline phase were randomly assigned to treatment with either topiramate (n = 39) or placebo (n = 41). Topiramate was titrated to target doses of approximately 6 mg/kg/day over 8 weeks and maintained for another 12 weeks. RESULTS: The median percentage reduction from baseline in PGTC seizure rate was 56.7% for topiramate patients and 9.0% for placebo patients (p = 0.019). The proportion of patients with 50% or higher reduction in PGTC seizure rate was 22/39 (56%) and 8/40 (20%) for the topiramate and placebo groups, respectively (p = 0.001). The median percentage reduction in the rate of all generalized seizures was 42.1% for topiramate patients and 0.9% for placebo patients (p = 0.003). The proportions of patients with 50% or higher reductions in generalized seizure rate were 18/39 (46%) and 7/41 (17%) for the topiramate and placebo groups, respectively (p = 0.003). The most common adverse events were somnolence, fatigue, weight loss, difficulty with memory, and nervousness. Treatment-limiting adverse events occurred in one patient in the topiramate group (anorexia and weight loss) and one in the placebo group (granulocytopenia and thrombocytopenia). CONCLUSION: Topiramate is well-tolerated and effective for the adjunctive treatment of PGTC seizures.

Oxcarbazepine: double-blind, randomized, placebo-control, monotherapy trial for partial seizures.

OBJECTIVE: To evaluate the efficacy and safety of oxcarbazepine in a placebo-control trial. METHODS: A multicenter, double-blind, randomized, placebo-control, two-arm parallel group, monotherapy design was used to compare oxcarbazepine administered 1,200 mg twice daily to placebo in hospitalized patients with refractory partial seizures, including simple and complex partial seizures and partial seizures evolving to secondarily generalized seizures. Patients exited the trial after completing the 10-day double-blind treatment phase or after experiencing four partial seizures, two new-onset secondarily generalized seizures, serial seizures, or status epilepticus, whichever came first. RESULTS: Analysis of the primary efficacy variable--time to meeting one of the exit criteria--showed a statistically significant effect in favor of oxcarbazepine (p = 0.0001). The secondary efficacy variables--percentage of patients who met one of the exit criteria (p = 0.0001) and total partial seizure frequency per 9 days during the double-blind treatment (p = 0.0001)--were also statistically significant in favor of oxcarbazepine. CONCLUSION: These results demonstrate that oxcarbazepine given as monotherapy is effective and safe for the treatment of partial seizures in this paradigm.

Spitting automatism in complex partial seizures: a nondominant temporal localizing sign?

PURPOSE: Spitting as an ictal automatism has been rarely reported. We aimed to establish its potential lateralizing and localizing significance. METHODS: Review of patients undergoing surgery for intractable epilepsy at two comprehensive epilepsy centers. RESULTS: Five patients were found who had spitting as a stereotyped automatism of their complex partial seizures. All had evidence of right temporal ictal onset and underwent resective surgery. Two had tumors; one, a cavernous angioma; one, hippocampal gliosis, and one, hippocampal sclerosis. We found no instances of ictal spitting in patients with left hemisphere onset. CONCLUSIONS: Spitting as an automatism in complex partial seizures, although uncommon, may be a localizing sign to the nondominant temporal lobe.

Practical insights and clinical experience with combinations of the new antiepileptic drugs.

Physicians must decide which new antiepileptic drug to select for a given type of epilepsy. Screening characteristics and patient profiles obtained from compassionate-use trials with felbamate and lamotrigine, as well as from monotherapy trials with gabapentin, have helped in determining which agent to use when initiating therapy. Factors to consider include age, age at seizure onset, type of seizure(s), level of functioning, and cause of epilepsy. Also important are medications previously used, including their associated adverse effects; concurrent medical and psychiatric history; and factors that may affect patient compliance, such as type and number of medications, dosing regimen, and reliability in self-administration of medication.

The pregnant epileptic: a review and recommendations.

The major concerns in the pregnant epileptic patient are loss of seizure control and the teratogenic effects of antiepileptic drugs on the fetus. Loss of seizure control is usually caused by a progressive decline of antiepileptic plasma levels throughout pregnancy. This decline can be prevented by monthly dose adjustments based on plasma level determinations. Although infant malformations are a more prevalent outcome of the pregnancies of epileptics than of nonepileptics, the role of antiepileptic drugs in teratogenicity is not fully established. Only trimethadione has been convincingly linked to fetal malformation. Recommendations for the management of epilepsy in pregnancy are made.