Perampanel Study 207: long-term open-label evaluation in patients with epilepsy.

OBJECTIVES: Evaluate interim long-term tolerability, safety and efficacy of adjunctive perampanel, a novel α-amino-3-hydroxy-5-methyl-5-isoxazolepropionic acid (AMPA)-receptor antagonist, in patients with refractory partial-onset seizures. MATERIALS AND METHODS: Study 207, an open-label extension (OLE) study (ClinicalTrials.gov identifier: NCT00368472), enrolled patients (18-70 years) who completed one of two randomized, placebo-controlled, dose-escalation Phase II studies. The OLE Treatment Phase comprised a 12-week Titration Period (2 mg increments of perampanel every 2 weeks to 12 mg/day, maximum) and a Maintenance Period, during which patients continued treatment up to a planned maximum of 424 weeks (~8 years). Interim analysis data cut-off date was 1 December, 2010. RESULTS: Of 180 patients completing the Phase II studies, 138 enrolled in study 207. At the time of interim analyses (approximately 4 years after study start), over a third (n = 53, 38.4%) remained on perampanel; 41.3% (n = 57) of patients had >3 years of exposure; and 13.0% (n = 18) had at least 4 years' exposure. Mean ± standard deviation (SD) duration of exposure was 116 ± 75 weeks and mean ± SD dose during the OLE Maintenance Period was 7.3 ± 3.3 mg. No new safety signals emerged with long-term treatment. Consistent with previous studies, the most common treatment-emergent adverse events were as follows: dizziness, headache and somnolence. Overall median (range) per cent change from baseline in seizure frequency per 28 days during open-label treatment was -31.5% (-99.2 to 512.2). CONCLUSIONS: Long-term - up to 4 years - adjunctive perampanel had a favourable tolerability profile in patients with refractory partial-onset seizures. Improvements in seizure control were maintained with long-term treatment.

Randomized phase III study 306: adjunctive perampanel for refractory partial-onset seizures.

OBJECTIVE: To evaluate the efficacy and safety of perampanel 2, 4, and 8 mg/day added to 1-3 concomitant antiepileptic drugs (AEDs) in patients with uncontrolled partial-onset seizures. METHODS: During this double-blind, placebo-controlled trial, patients with persisting seizures on 1-3 AEDs were randomized to perampanel 2, 4, and 8 mg/day or placebo following a 6-week baseline phase. Perampanel was titrated weekly by 2 mg/day and maintained at the dose achieved for 13 weeks. Primary endpoints were median percent change in seizure frequency and 50% responder rate. Analysis of covariance was performed on all treated patients with any seizure data (recorded in daily diaries) in the double-blind phase. RESULTS: A total of 706 patients were randomized and received trial medication; 623 completed the trial. Median percent change in seizure frequency-the primary efficacy endpoint-was -10.7%, -13.6%, -23.3%, and -30.8% for placebo, perampanel 2, 4, and 8 mg/day, respectively. The difference from placebo was statistically significant for perampanel 4 mg/day (p = 0.0026) and 8 mg/day (p < 0.0001). The corresponding 50% responder rates were 17.9%, 20.6%, 28.5%, and 34.9%. The difference from placebo was statistically significant for perampanel 4 mg/day (p = 0.0132) and 8 mg/day (p = 0.0003). An apparent dose response was suggested for dizziness, which was the most frequent treatment-emergent adverse event. CONCLUSIONS: This trial demonstrated that adjunctive perampanel effectively reduced seizure frequency and possessed a favorable tolerability profile in patients ≥12 years with partial-onset seizures (with or without secondary generalization), with a minimum effective dose of 4 mg/day. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that 4 and 8 mg/day doses of adjunctive perampanel are effective and tolerated in reducing partial-onset seizures.

Lacosamide for the treatment of epilepsy.

Lacosamide is a third-generation antiepilepsy drug approved for adjunctive treatment of partial-onset seizures in adults. The pharmacology of lacosamide includes linear kinetics, complete bioavailability, and no major drug interactions. Lacosamide produces slow inactivation of neuronal sodium channels, which differentiates it from other sodium channel modulators, such as carbamazepine and phenytoin. The drug was effective with no major safety problems detected in three large placebo-controlled pivotal trials and has been released in Europe and the US at 200-400 mg/day, divided b.i.d.; an intravenous formulation is approved for temporary conversion from oral therapy. This article reviews the clinical development, pharmacology, and uses of lacosamide for treating partial-onset seizures in adults.

Tolerability and safety of perampanel: two randomized dose-escalation studies.

OBJECTIVES: To evaluate, for the first time in patients with epilepsy, the tolerability and safety of escalating doses of oral perampanel, a novel, selective, non-competitive AMPA antagonist, as adjunctive therapy for refractory partial-onset seizures. MATERIALS AND METHODS: Two consecutive, randomized, double-blind, dose-escalation studies recruited adults (18-70 years) with uncontrolled partial-onset seizures receiving one to three concomitant antiepileptic drugs. In study 206, patients were treated for 12 weeks (8-week dose-titration, 4-week dose-maintenance) with placebo or perampanel (up to 4 mg/day, dosed once- or twice-daily). In study 208, patients received placebo or perampanel once-daily (up to 12 mg) for 16 weeks (12-week titration, 4-week maintenance). RESULTS: Overall, 153 patients were randomized into study 206 (perampanel twice-daily, n = 51; perampanel once-daily, n = 51; placebo, n = 51). Study 208 included 48 patients (perampanel once-daily, n = 38; placebo, n = 10). The highest dose in study 206 - 4 mg/day - was well tolerated, with similar proportions of patients tolerating once-daily (82.4%) and twice-daily (82.4%) perampanel and placebo (82.4%) treatments. In study 208 most patients tolerated doses of ≥ 6 mg perampanel once-daily in a Kaplan-Meier analysis. In both studies, the most common adverse events were CNS-related; most were of mild/moderate severity. CONCLUSIONS: Perampanel was well tolerated across doses of 4-12 mg/day. The studies showed preliminary evidence of efficacy and identified doses to be evaluated in larger clinical studies.

Minimizing pharmacodynamic interactions of high doses of lacosamide.

OBJECTIVES: To determine whether pharmacodynamic interactions between high doses of lacosamide (400-800 mg/day) and concomitant sodium channel antiepilepsy drugs (AEDs) can be minimized in patients with drug-resistant partial-onset seizures. MATERIALS AND METHODS: Patients were rapidly initiated with high-dose lacosamide (100 mg/week; increases to 400 to 800 mg/day), while simultaneously tapering concomitant sodium channel AEDs. Seizure frequency and side effects were evaluated at six time points: baseline, titration, 3, 6, 9 and 12 months. RESULTS: Twenty-three patients had a baseline median of 4 seizures/month with persisting partial-onset seizures, despite previous treatment with an average of 6.8 AEDs. Mean decreases in monthly seizure frequency were as follows: 3 months 49.9% (P = 0.011), 6 months 55.4% (P = 0.010), 9 months 60.8% (P = 0.002) and 12 months 58.2% (P = 0.011). Most adverse events were mild CNS-related symptoms and occurred transiently only during titration - there was no significant relationship (χ(2) < 1.5, P > 0.1) between lacosamide dose and the presence of side effects at 3, 6, 9 or 12 months. CONCLUSIONS: Drug-resistant patients rapidly titrated to high doses of lacosamide with simultaneous tapering of traditional sodium channel AEDs had marked reduction in CNS-related adverse events compared with patients treated in three previous pivotal trials that used fixed doses of concomitant AEDs.

Cerebellar and thalamic stimulation treatment for epilepsy.

The present chapter describes the most important available experimental and clinical evidence on the role of electrical stimulation of the cerebellum or the thalamus in the control of epilepsy. Cerebellum serves as an integrator of sensory information and regulator of motor coordinating and training. The sole output of the cerebellum is inhibitory Purkinje cell projections to deep cerebellar nuclei in the brainstem. Cerebellar stimulation in animal models of epilepsy has given mixed results. Nevertheless, more than 130 epileptic patients have been subjected to cerebellar stimulation and the results from uncontrolled studies have been encouraging. The anterior thalamic nucleus (ATN) is part of the Papez circuit, a group of limbic structures with demonstrated role in epilepsy. The centromedian thalamic nucleus (CMN) is considered part of the thalamic reticular system. Stimulation of either of these nuclei in experimental animals has been associated with considerable antiepileptic effects. On the basis of the research evidence, numerous studies have been done on humans, which gave promising results. Currently, a multicenter trial on stimulation of the ATN, the SANTE trial is in progress in the USA. On the basis of the reported studies, the authors aim to provide insights into how the electrical stimulation of the above structures exerts an antiepileptic effect and also provide suggestions regarding the future progress in this field.

Clinical and EEG features of patients with EEG wicket rhythms misdiagnosed with epilepsy.

BACKGROUND: EEG wicket rhythms are 6- to 11-Hz medium-to-high voltage bursts that are sometimes misidentified as epileptogenic activity. The authors determined the clinical and EEG features of patients with wicket rhythms who had been incorrectly diagnosed with epilepsy. METHODS: Electroencephalographers at an epilepsy center re-read EEGs for patients referred for epilepsy management and identified patients with wicket rhythms. On further evaluation, the majority (54%; 25/46) of these patients were found not to have epilepsy. The authors compared the clinical and EEG features for the 25 patients with wickets and nonepileptic episodes with those of age- and sex-matched patients with partial-onset epilepsy using univariate and multivariate analysis. RESULTS: Several features distinguished patients with EEG wicket patterns and nonepileptic episodes (n = 25) from age- and sex-matched patients with epilepsy (n = 25): mid-adult age at onset of episodes (mean 38.4 years vs 19.8 years), prolonged clinical episodes (mean 155 minutes vs 2.3 minutes), and long duration of EEG wicket patterns (mean 0.66 seconds vs 0.11 second spikes). After controlling for other factors, patients without major confusion during episodes were unlikely to have epilepsy. CONCLUSION: Wicket patterns are often interpreted as epileptogenic. This distinctive EEG pattern should be considered in patients with clinical episodes atypical for epilepsy.

Improved CNS tolerability following conversion from immediate- to extended-release carbamazepine.

OBJECTIVES: Tolerability of 'narrow therapeutic ratio' (NTR) antiepileptic drugs may improve with uniform drug delivery. We determined whether conversion from immediate-release carbamazepine (IR-CBZ) to extended-release carbamazepine (ER-CBZ) decreased the incidence of CNS side-effects associated with drug concentration oscillations. METHODS: We compared CNS side effects and seizure frequency for patients with partial-onset seizures (n = 61) treated with IR-CBZ for > or =1 year with conversion to ER-CBZ for > or =1 year. We compared tolerability findings with absorption variability of the formulations. RESULTS: Incidence of CNS side-effects decreased from 49% during IR-CBZ treatment to 20% following conversion to ER-CBZ. Patients also had improved tolerability of high doses (> or =1200 mg/day) during ER-CBZ treatment. Pharmacokinetic analysis showed absorption and drug concentration were much more variable for the immediate-release formulation. CONCLUSIONS: This study suggests that ER-CBZ formulations, with smoother drug delivery and less variable absorption, provide improved CNS tolerability compared with immediate-release formulations.

A controlled study comparing visual function in patients treated with vigabatrin and tiagabine.

OBJECTIVE: Vigabatrin treatment is frequently associated with irreversible retinal injury and produces retinal electrophysiological changes in nearly all patients. Concern has been raised that tiagabine and other antiepilepsy drugs (AEDs) that increase brain gamma-aminobutyric acid (GABA) might produce similar electrophysiological and clinical changes in visual function. The study compared visual function between groups of patients with epilepsy treated long term with tiagabine, vigabatrin, and patients treated with other AEDs. METHODS: A cross sectional study comparing visual acuity, colour vision, static and kinetic perimetry, and electroretinograms between groups of patients treated with tiagabine, vigabatrin, and other AEDs (control patients). Patients were adults receiving stable AED treatment for >6 months. RESULTS: Vigabatrin treated patients had marked visual field constrictions in kinetic perimetry (mean radius 39.6 degrees OD, 40.5 degrees OS), while tiagabine patients had normal findings (mean 61 degrees OD, 62 degrees OS) (differences OD and OS, p=0.001), which were similar to epilepsy control patients (mean 60 degrees OD, 61 degrees OS). Vigabatrin patients had abnormal electroretinographic photopic B wave, oscillatory, and flicker responses, which correlated with visual field constrictions. These electroretinographic responses were normal for tiagabine patients and control patients. Patients were treated with vigabatrin for a median of 46 months compared with 29 months for tiagabine. Patients taking other AEDs that may change brain GABA had normal visual function. CONCLUSION: Unlike vigabatrin, tiagabine treatment is associated with normal electroretinography and visual fields and ophthalmological function similar to epilepsy control patients. Differences between vigabatrin and other GABA modulating AEDs in retinal drug concentrations and other effects might explain why tiagabine increases in GABA reuptake do not cause retinal injury.

Individual state driving restrictions for people with epilepsy in the US.

BACKGROUND: States in the United States vary widely in their approaches to restricting driving for patients with epilepsy. Many states have shortened seizure-free restrictions or have adopted flexible regulations that consider individual clinical factors in determining driving privileges. The authors summarized state driving restrictions for patients with seizures, particularly unpublished regulatory practices, and determined the role and liability of physicians in judging driving safety for patients with epilepsy. METHODS: The authors surveyed motor vehicle administration bureaus in the 50 states and the District of Columbia and compared the laws, regulations, and practices restricting driving for people with epilepsy. Key responses from a questionnaire were confirmed by state motor vehicle administrations with phone interviews and by a signed executive summary. RESULTS: Twenty-eight states, including the District of Columbia, have laws requiring patients with epilepsy to be free of seizures for single fixed periods, with a median restriction of six months (range, 3 to 12 months). Twenty-three states have adopted more flexible approaches to restricting driving, such as varying seizure-free restrictions based on individual clinical factors. Many states allow patients to drive after shorter seizure-free periods than stated in their laws. These practices, however, are usually unpublished and not easily accessible. Physicians helped determine when their patients may drive in 13 states and were not legally shielded for their assessments in six of these states. CONCLUSIONS: States vary widely in how they regulate driving for patients with seizures. These varied regulatory approaches present potentially valuable models to determine how driving might be best regulated to protect public and patient safety optimally while permitting patients with controlled seizures to drive.

Human "memories" can be evoked by stimulation of the lateral temporal cortex after ipsilateral medial temporal lobe resection.

A patient with medically intractable seizures and mesial temporal sclerosis underwent a left anterior temporal lobectomy and amygdalohippocampectomy. After 4 months, his seizures recurred and a left temporal, subdural grid of electrodes was placed to localise his seizure focus. Stimulation through the grid evoked four distinct "memories", or experiential phenomena, despite absence of the ipsilateral medial temporal lobe. To our knowledge, this is the first documented case of experiential phenomena evoked by cortical stimulation in the absence of the ipsilateral medial temporal lobe.

Visual function is stable in patients who continue long-term vigabatrin therapy: implications for clinical decision making.

PURPOSE: Vigabatrin (VGB) has been shown to cause visual field constriction and other forms of mild visual dysfunction. We determined the safety of continuing VGB therapy in patients who had received prolonged treatment (>2 years) with the drug by serially monitoring changes in visual function over a 1-year period of continued therapy. We also followed up patients who discontinued VGB to see whether alternative therapies are effective. METHODS: Fifteen of 17 patients who continued VGB therapy had visual-function testing (visual acuity, color vision, kinetic and static perimetry) every 3 months for 1 year. Eighteen patients who discontinued VGB were given alternative antiepileptic drugs (AEDs); their seizure responses were measured after > or =3 months of treatment. RESULTS: Patients continuing VGB showed no worsening of visual acuity, color vision, or visual-field constriction beyond that measured in the initial test. Many patients who discontinued VGB had good seizure control with either newer or previously unsuccessful AEDs. CONCLUSIONS: For patients who have an excellent response to VGB and only mild visual changes, continued therapy may be safe with close visual monitoring. Patients who do not have a significant reduction in seizures or who experience considerable visual dysfunction with VGB may respond well to alternative therapies.

Suppression of post-hypoxic and post-encephalitic myoclonus with levetiracetam.

Posthypoxic and postencephalitic myoclonus is often poorly controlled with current treatments. The authors successfully treated three patients with posthypoxic and postencephalitic myoclonus by using levetiracetam, a new antiepileptic drug. Levetiracetam appears to be a promising agent for treating action myoclonus caused by hypoxic and encephalitic brain injury-the degree of functional improvement may depend on the severity of associated motor dysfunction.

Oxcarbazepine monotherapy for partial-onset seizures: a multicenter, double-blind, clinical trial.

OBJECTIVE: To evaluate the safety and efficacy of oxcarbazepine (OXC) 2,400 mg/day versus OXC 300 mg/day monotherapy in patients with medically refractory partial epilepsy. BACKGROUND: OXC is primarily metabolized by reductase enzymes and, consequently, has a low propensity to inhibit or induce oxidative enzymes and a minimal potential for drug-drug interactions. The efficacy of OXC as monotherapy was shown in several comparative trials in patients with newly diagnosed epilepsy and in hospitalized patients undergoing evaluation for epilepsy surgery. METHODS: A multicenter, double-blind, randomized, parallel-group trial design was chosen to assess the antiepileptic efficacy of OXC as monotherapy in a refractory epilepsy patient population. Outpatients aged 12 years or older with inadequately controlled partial seizures, with or without secondarily generalized seizures, were enrolled. Patients finished the trial by completing the double-blind phase or by meeting one of four predefined exit criteria: a twofold increase in partial seizure frequency in any 28-day period relative to baseline; a twofold increase in the highest consecutive 2-day partial seizure frequency relative to baseline; occurrence of a single generalized seizure if none occurred during the 6 months prior to randomization; or prolongation or worsening of generalized seizure duration or frequency requiring intervention. Adverse events (AEs), vital signs, and clinical laboratory tests were evaluated. RESULTS: The percentage of patients meeting one of the exit criteria was significantly lower (p < 0.0001) for the OXC 2400 mg/day group (14/34; 41%) than the OXC 300 mg/day group (42/45; 93%). In addition, there was a significant difference in time to exit in favor of the OXC 2400 mg/day group (p = 0.0001). In the intent-to-treat analysis, 12% of patients in the OXC 2400 mg/day group were seizure-free compared with none in the 300 mg/day group. OXC was well-tolerated, with dizziness, fatigue, somnolence, and nausea being the most frequent AEs. Most of these AEs were transient and rated as mild to moderate in intensity. CONCLUSION: OXC is safe and effective in the treatment of patients with partial epilepsy previously receiving treatment with other antiepileptic drugs. The results of this trial are consistent with previous monotherapy trials with OXC.

Visual function loss from vigabatrin: effect of stopping the drug.

OBJECTIVE: To determine if visual function loss from vigabatrin use recovers after the drug is discontinued. BACKGROUND: Vigabatrin is an effective antiepileptic drug, but it is known to cause a variety of changes in visual function, including reductions in the visual field, visual acuity, color vision, and in electroretinogram (ERG) and electro-oculogram amplitudes. It is not known whether these changes are reversible. METHODS: Measurements of static and kinetic visual fields, visual acuity, color vision, and the ERG were recorded while patients were taking vigabatrin and again in 13 patients who had discontinued the drug because of lack of efficacy or reductions in visual field. Most of the patients had been off the drug for 3 to 6 months, although two patients had been drug-free for almost 1 year. RESULTS: Although ERG cone implicit time improved, most of the patients did not show improvement in either clinical measures of visual function (i.e., visual acuity, color vision, visual fields) or in ERG amplitudes. However, several patients who showed minimal visual field loss while on the drug had substantial recovery of ERG amplitudes. There was no statistical association between recovery of function and either duration of treatment or cumulative dosage. The multifocal ERG showed a diffuse loss of function that was not isolated to the periphery. CONCLUSIONS: Although the visual deficits in patients taking vigabatrin tend to be mild, most patients do not show improvement after they stop taking the drug. Visual field loss resulting from vigabatrin was not reversible. Visual acuity, color vision, and ERG amplitude loss may be reversible in patients with minimal or no field loss.

"The scarlet E": the presentation of epilepsy in the English language print media.

OBJECTIVE: To examine the coverage of epilepsy in English language newspapers and magazines to determine how they portray the medical risks associated with epilepsy, whether they report research and treatment advances accurately, whether stigmatizing biases toward persons with epilepsy persist, and to examine the sources of errors in reporting about epilepsy. BACKGROUND: The print media reflect and shape current views about epilepsy and other neurologic conditions. They also have the potential to further misconceptions about neurologic issues and particular brain disorders. Persistent myths about epilepsy, such as the ancient belief that it is a demonic disorder, can result in discrimination, emotional difficulties, and reluctance to seek effective treatment. METHODS: A large commercial database was used to search for stories about epilepsy from approximately 2,000 English language newspapers and popular magazines. Two epileptologists independently classified story themes and main sources, and screened for the presence of gross errors in 210 stories about epilepsy or seizures. The authors analyzed the metaphors and terminology used to describe seizures and epilepsy. RESULTS: The majority of English language print stories about epilepsy were accurate depictions of social and medical issues regarding the disorder, most commonly depictions of persons overcoming epilepsy and announcements of new therapies and reports of scientific advances. Thirty-one percent of the stories, however, contained gross errors, most commonly scientific inaccuracy, exaggerated treatment claims, and overestimates of the risks of dying during a seizure. New drug therapies were often described inaccurately by physicians and pharmaceutical spokespersons as curative and without side effects. Patients and their families frequently overemphasized the risk of dying during a seizure and misstated medical issues. Most celebrities with recurring seizures denied having epilepsy. Seizures were described with demonic imagery in 6% of stories. United States epilepsy associations discourage labeling patients as "epileptics"; however, the term was used in 45% of stories. CONCLUSION: Physicians and reporters should be aware of both professional and popular biases that influence the print media's presentation of the causes and consequences of epilepsy.

Aggression and violence in patients with epilepsy.

Violence has been associated with epilepsy. However, the links between violent behaviors and epilepsy involve multiple factors. These range from behaviors associated with underlying brain dysfunction to postictal delirious and psychotic states and rare cases of ictal aggression. This review describes the differential diagnosis of violent acts in epilepsy and the features that can be used to evaluate these behaviors.