Richard H. Mattson

Comparison of Carbamazepine, Phenobarbital, Phenytoin, and Primidone in Partial and Secondarily Generalized Tonic–Clonic Seizures

We conducted a 10-center, double-blind trial to compare the efficacy and toxicity of four antiepileptic drugs in the treatment of partial and secondarily generalized tonic-clonic seizures in 622 adults. Patients were randomly assigned to treatment with carbamazepine, phenobarbital, phenytoin, or primidone and were followed for two years or until the drug failed to control seizures or caused unacceptable side effects. Overall treatment success was highest with carbamazepine or phenytoin, intermediate with phenobarbital, and lowest with primidone (P less than 0.002). Differences in failure rates of the drugs were explained primarily by the fact that primidone caused more intolerable acute toxic effects, such as nausea, vomiting, dizziness, and sedation. Decreased libido and impotence were more common in patients given primidone. Phenytoin caused more dysmorphic effects and hypersensitivity. Control of tonic-clonic seizures did not differ significantly with the various drugs. Carbamazepine provided complete control of partial seizures more often than primidone or phenobarbital (P less than 0.03). Overall, carbamazepine and phenytoin are recommended drugs of first choice for single-drug therapy of adults with partial or generalized tonic-clonic seizures or with both.

ILAE Treatment Guidelines: Evidence‐based Analysis of Antiepileptic Drug Efficacy and Effectiveness as Initial Monotherapy for Epileptic Seizures and Syndromes

Summary:  Purpose: To assess which antiepileptic medications (AEDs) have the best evidence for long‐term efficacy or effectiveness as initial monotherapy for patients with newly diagnosed or untreated epilepsy.

A Comparison of Valproate with Carbamazepine for the Treatment of Complex Partial Seizures and Secondarily Generalized Tonic–Clonic Seizures in Adults

BACKGROUND Valproate is approved for use primarily in patients with absence seizures, but the drug has a broad spectrum of activity against seizures of all types. Partial or secondarily generalized tonic-clonic seizures are often difficult to control adequately with standard treatment, usually carbamazepine or phenytoin. METHODS We conducted a multicenter, double-blind trial that compared valproate with carbamazepine in the treatment of 480 adults with complex partial seizures (206 patients) or secondarily generalized tonic-clonic seizures (274 patients). The patients were randomly assigned to treatment with carbamazepine or divalproex sodium (valproate) at doses adjusted to achieve blood levels in the middle of the therapeutic range. Patients were followed for one to five years or until seizures became uncontrollable, treatment had unacceptable adverse effects, or both these events occurred. RESULTS For the control of secondarily generalized tonic-clonic seizures, carbamazepine and valproate were comparably effective (in 136 patients and 138 patients, respectively). For complex partial seizures, four of five outcome measures favored carbamazepine (100 patients) over valproate (106 patients): the total number of seizures (2.7 vs. 7.6, P = 0.05), the number of seizures per month (0.9 vs. 2.2, P = 0.01), the time to the first seizure (P less than 0.02), and the seizure-rating score (P = 0.04). Carbamazepine was also superior according to a composite score that combined scores for the control of seizures and for adverse effects (P less than 0.001). Valproate was associated more frequently than carbamazepine with a weight gain of more than 5.5 kg (12 lb) (20 percent vs. 8 percent, P less than 0.001), with hair loss or change in texture (12 percent vs. 6 percent, P = 0.02), and with tremor (45 percent vs. 22 percent, P less than 0.001). Rash was more often associated with carbamazepine (11 percent vs. 1 percent, P less than 0.001). CONCLUSIONS Valproate is as effective as carbamazepine for the treatment of generalized tonic-clonic seizures, but carbamazepine provides better control of complex partial seizures and has fewer long-term adverse effects.

Access to the Posterior Medial Temporal Lobe Structures in the Surgical Treatment of Temporal Lobe Epilepsy

The authors describe a surgical technique that allows access to the posterior temporal horn of the lateral ventricle with preservation of the most functional lateral temporal cortex. Development of the technique was stimulated by the need to resect posteromedial temporal lobe structures in patients with intractable complex partial epilepsy and well-identified unilateral posterior hippocampal foci. This technique has also been of value in the resection of some lateral ventricular and posteromedial temporal lobe masses. The operation consists of three steps. No more than 4.5 cm of the anterolateral temporal lobe is removed en bloc such that the most anterior aspect of the temporal horn is entered. An incision is carried from the floor of the temporal horn through the inferior longitudinal fasciculus to the middle fossa dura mater and posteriorally into the lateral ventricular atrium. The lateral temporal cortex and white matter are then elevated with a self-retaining retractor. This exposes the posteromedial temporal horn or intraaxial mass for excision or allows en bloc resection of the entire hippocampus and medial temporal lobe structures while preserving the functional association areas of the lateral temporal cortex, including speech and visual spatial function.

Memory Function in Focal Epilepsy: A Comparison of Non-Surgical, Unilateral Temporal Lobe and Frontal Lobe Samples

Three well-matched groups of non-surgical, pharmacologically controlled epileptic patients with unilateral seizure foci in either the left temporal lobe, the right temporal lobe or a frontal lobe, and a normal control group were compared on several verbal and non-verbal memory tasks. Results revealed significant impairment of verbal memory in left temporal epileptic subjects, and significant impairment of non-verbal, visual memory in right temporal epileptic subjects. Seizure patients with unilateral frontal lobe foci did not differ from the control sample on any measure. Results support previous research which emphasizes the importance of temporal lobe systems in memory function. The findings are discussed with regard to the nature and specificity of the observed deficits.

Updated ILAE evidence review of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes

The purpose of this report was to update the 2006 International League Against Epilepsy (ILAE) report and identify the level of evidence for long‐term efficacy or effectiveness for antiepileptic drugs (AEDs) as initial monotherapy for patients with newly diagnosed or untreated epilepsy. All applicable articles from July 2005 until March 2012 were identified, evaluated, and combined with the previous analysis (Glauser et al., 2006) to provide a comprehensive update. The prior analysis methodology was utilized with three modifications: (1) the detectable noninferiority boundary approach was dropped and both failed superiority studies and prespecified noninferiority studies were analyzed using a noninferiority approach, (2) the definition of an adequate comparator was clarified and now includes an absolute minimum point estimate for efficacy/effectiveness, and (3) the relationship table between clinical trial ratings, level of evidence, and conclusions no longer includes a recommendation column to reinforce that this review of efficacy/evidence for specific seizure types does not imply treatment recommendations. This evidence review contains one clarification: The commission has determined that class I superiority studies can be designed to detect up to a 20% absolute (rather than relative) difference in the point estimate of efficacy/effectiveness between study treatment and comparator using an intent‐to‐treat analysis. Since July, 2005, three class I randomized controlled trials (RCT) and 11 class III RCTs have been published. The combined analysis (1940–2012) now includes a total of 64 RCTs (7 with class I evidence, 2 with class II evidence) and 11 meta‐analyses. New efficacy/effectiveness findings include the following: levetiracetam and zonisamide have level A evidence in adults with partial onset seizures and both ethosuximide and valproic acid have level A evidence in children with childhood absence epilepsy. There are no major changes in the level of evidence for any other subgroup. Levetiracetam and zonisamide join carbamazepine and phenytoin with level A efficacy/effectiveness evidence as initial monotherapy for adults with partial onset seizures. Although ethosuximide and valproic acid now have level A efficacy/effectiveness evidence as initial monotherapy for children with absence seizures, there continues to be an alarming lack of well designed, properly conducted epilepsy RCTs for patients with generalized seizures/epilepsies and in children in general. These findings reinforce the need for multicenter, multinational efforts to design, conduct, and analyze future clinically relevant adequately designed RCTs. When selecting a patients AED, all relevant variables and not just efficacy and effectiveness should be considered.

Combined depth and subdural electrode investigation in uncontrolled epilepsy

We used both depth and subdural electrodes to obtain localization of the seizure focus in 47 medically refractory epileptic patients. Seizures were localized in 33 patients. Onset was consistently localized by the depth electrodes in 23 patients, was variable or simultaneous in depth and subdural electrodes in 6 (in the same lobe), and was consistently localized to subdural electrodes in 4. All patients localized with subdural electrodes were extratemporal and 3 of the 4 had lesions on imaging studies which helped guide location of electrode placement. Eighty-seven percent of temporal lobe seizures began in hippocampus (recorded by the depth electrode), and 80% were eventually propagated to the ipsilateral temporal neocortex (recorded by the subdural electrode). In 8 patients with bilateral temporal depth and subdural recording, seizures never spread to the contralateral neocortex before the ipsilateral neocortex. Subdural electrodes were 20% less sensitive than depth electrodes in detection of seizures beginning in hippocampus but were accurate when lateralized. Variable or simultaneous unilateral neocortical versus hippocampal temporal lobe seizure onset, determined by the combined study, was significantly correlated with less favorable seizure control after anteromedial temporal lobectomy and hippocampectomy.

Topiramate, carbamazepine and valproate monotherapy: double-blind comparison in newly diagnosed epilepsy.

Objectives – To compare topiramate (TPM) with investigators choice of carbamazepine (CBZ) or valproate (VPA) for initial treatment in patients with newly diagnosed epilepsy.

Lamotrigine Therapy for Partial Seizures: A Multicenter, Placebo‐Controlled, Double‐Blind, Cross‐Over Trial

Summary: The efficacy and safety of lamotrigine (LTG), a new antiepileptic drug (AED), were evaluated in a multicenter, randomized, double‐blind, placebo‐controlled, cross‐over study of 98 patients with refractory partial seizures. Each treatment period lasted 14 weeks. Most patients were titrated to a LTG maintenance dose of 400 mglday. Seizure frequency with LTG decreased by ≥50%, as compared with placebo, in one fifth of patients. Overall median seizure frequency decreased by 25% with LTG as compared with placebo (p < 0.001). With LTG, the number of seizure days decreased by 18% as compared with placebo (p < 0.01), and investigator global evaluation of overall patient clinical status favored LTG by 2: 1 (p = 0.013). Plasma LTG concentrations appeared to be linearly related to dosage. LTG had no clinically important effects on the plasma concentrations of concomitant AEds. Adverse experiences were generally minor and most frequently were CNS‐related (e.g., ataxia, dizziness, diplopia, headache). Most were transient and resolved without discontinuing treatment. Five patients withdrew as a result of adverse experiences while receiving LTG, including 3 patients with rash. One placebo patient was also withdrawn because of rash. The addition of twice‐daily LTG to an existing AED regimen was safe, effective, and well tolerated in these medically refractory partial seizure patients.

Results of a Nationwide Veterans Administration Cooperative Study Comparing the Efficacy and Toxicity of Carbamazepine, Phenobarbital, Phenytoin, and Primidone

Summary: : In 1985 a 5‐year multicenter Veterans Administration Cooperative Study was completed that compared the efficacy and toxicity of phenobarbital, carbamazepine, phenytoin, and primidone in a double‐blind prospective study design. A total of 622 patients, either previously untreated or undertreated, were entered into the study. Strict exclusion criteria limited confounding factors such as drug or alcohol abuse. Results showed that each of the four drugs used as monotherapy were similarly effective in the treatment of generalized tonic‐clonic seizures, but carbamazepine was significantly more effective in the treatment of complex partial seizures as measured by 100% control. When the results for all four drugs were combined, the data showed that approximately 80% of the patients were adequately managed on monotherapy. Differences in toxicity were the most significant factor that discriminated between these four drugs. Both carbamazepine and phenytoin were associated with significantly lower incidences of intolerable side effects than were primidone or phenobarbital. A behavioral toxicity battery was performed whenever possible prior to administration of any antiepileptic drug and at 1, 3, 6, and 12 months after initiation of monotherapy. Significant differences in performance on all subtests of the battery were found between patients with epilepsy and a control group matched by age, sex, and education. When the differential effects of all four drugs on behavioral toxicity were compared, few statistically significant differences emerged. However, carbamazepine consistently produced fewer adverse effects on tests of attention/concentration and motor performance than did the other three antiepileptic drugs.