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.

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.

Cognitive effects of lamotrigine compared with topiramate in patients with epilepsy.

OBJECTIVE: To compare the cognitive effects of lamotrigine vs topiramate as adjunctive therapy in adults with epilepsy. METHODS: A multicenter, double-blind, randomized, prospective study was conducted in adults with partial seizures. Lamotrigine or topiramate was introduced as an adjunctive therapy to carbamazepine or phenytoin and titrated over 8 weeks to target doses. These drugs were maintained another 8 weeks (maintenance phase) without dosage changes. The primary endpoint was change from screening to the end of the maintenance phase in a combined analysis of standardized measures of cognition (Controlled Oral Word Association Task [COWA]; Stroop Color-Word Interference; Digit Cancellation; Lafayette Grooved Pegboard, dominant hand; Rey Auditory Verbal Learning Test, delayed recall; and Symbol-Digit Modalities test). RESULTS: For the primary endpoint, cognitive performance at the end of the maintenance phase was better with lamotrigine than with topiramate (415.3 vs 315.1; p < 0.001). On the individual cognitive tests, performance was better with lamotrigine than with topiramate in mean changes from screening on the COWA (p < 0.001), Stroop Color-Word Interference (p = 0.038), and Symbol-Digit Modalities tests (p < 0.001). The treatment effect exceeded the minimum clinically important difference for the COWA and the Symbol-Digit Modalities test. Mean changes from screening in the Performance-On-Line test simulating driving skills reflected better performance with lamotrigine than with topiramate (p = 0.021). The median percentage change from baseline in seizure frequency was lower with lamotrigine than with topiramate during the escalation phase (-80% vs -100%; p = 0.028) but not during the maintenance phase (-75% vs -100%; p = 0.062). The frequencies of cognitive adverse events and of premature withdrawals related to cognitive decline were higher with topiramate than with lamotrigine (6% vs 0%; p = 0.013). CONCLUSION: Lamotrigine had significantly less impact than topiramate on measures of cognition when used as adjunctive therapy for partial seizures.

Double-blind, placebo-controlled study of lamotrigine in primary generalized tonic-clonic seizures.

OBJECTIVE: To evaluate the efficacy and tolerability of adjunctive lamotrigine in primary generalized tonic-clonic (PGTC) seizures in a randomized, double-blind, placebo-controlled trial. METHODS: Patients with a diagnosis of epilepsy with PGTC seizures who were receiving one or two antiepileptic drugs at study entry were eligible. Patients with partial seizures were excluded on the basis of seizure history and screening EEGs. The study comprised a baseline phase, an escalation phase during which study medication was titrated to a target dose, and a 12-week maintenance phase during which doses of lamotrigine/placebo and concomitant antiepileptic drugs were maintained. RESULTS: Of the 121 randomized patients ages 2 to 55 years, 117 (58 lamotrigine, 59 placebo) entered the escalation phase and received study medication. During the escalation and maintenance phases combined, median percent reduction in PGTC seizure frequency was 66.5% with lamotrigine compared with 34.2% with placebo (p = 0.006). The corresponding numbers for lamotrigine and placebo were 60.6% and 32.8% (p = 0.038) during the escalation phase and 81.9% and 43.0% (p = 0.006) during the maintenance phase. During the maintenance phase, 72% of lamotrigine-treated patients compared with 49% of placebo-treated patients experienced a > or = 50% reduction in frequency of PGTC seizures (p = 0.014). A similar pattern of results was observed for all generalized seizures. The most common drug-related adverse events were dizziness (5% lamotrigine, 2% placebo), somnolence (5% lamotrigine, 2% placebo), and nausea (5% lamotrigine, 3% placebo). CONCLUSIONS: Adjunctive lamotrigine is effective in the treatment of primary generalized tonic-clonic seizures and has a favorable tolerability profile.

A dose-comparison trial of topiramate as monotherapy in recently diagnosed partial epilepsy.

OBJECTIVE: To evaluate topiramate as monotherapy in adults and children with recently diagnosed, localization-related epilepsy, comparing two dosages of topiramate in a multicenter, randomized, double-blind study. METHODS: Adults and children (>/=3 years of age) were eligible if the maximum interval since epilepsy diagnosis was 3 years and patients had one to six partial-onset seizures during a 3-month retrospective baseline. At study entry, patients (N = 252) were untreated or receiving one antiepileptic drug for less than 1 month. After randomization to 50 or 500 mg/d topiramate (25 or 200 mg/d if weight

Weight change associated with valproate and lamotrigine monotherapy in patients with epilepsy.

OBJECTIVE: To compare the incidence and magnitude of change in body weight associated with lamotrigine or divalproex sodium monotherapy in patients with epilepsy. METHODS: A randomized, double-blind study with 8-week escalation phase and 24-week maintenance phase was conducted. Target maintenance dosage was 200 mg/day (lamotrigine) and 20 mg/kg/day (valproic acid), with adjustment from 100 to 500 mg/day (lamotrigine) and 10 to 60 mg/kg/day (valproate) based on investigators' judgment. Eligible patients were > or = 12 years old with new-onset or previously diagnosed partial or generalized seizures. Weight change was primary and seizure frequency and tolerance were secondary outcome measures. RESULTS: For the lamotrigine group, 65 patients (mean age 34.5 years) were investigated; for the valproate group, 68 patients (mean age 30.1 years) were investigated. Weight remained stable in lamotrigine-treated patients. Significant weight gain occurred in valproate-treated patients by the 10th week of treatment; weight continued to increase throughout the study. After 32 weeks of treatment, mean weight gain was significantly higher in valproate-treated (12.8 +/- 9.3 lb) than lamotrigine-treated (1.3 +/- 11.9 lb) patients. Similar proportions of patients in lamotrigine (29%) and valproate (26%) groups were seizure-free. Overall frequency of adverse events was similar between the two treatment groups. Mean time to withdrawal from the study due to adverse events was 103 +/- 70 days for the lamotrigine group and 79 +/- 48 days for the valproate group. CONCLUSION: Valproate monotherapy was associated with significantly greater weight gain than lamotrigine monotherapy. Weight gain associated with valproate was significant within 10 weeks after initiating therapy and continued throughout the study. Efficacy of lamotrigine was comparable with that of valproate; lamotrigine tended to be better tolerated.

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.

Efficacy and safety of recombinant human nerve growth factor in patients with diabetic polyneuropathy: A randomized controlled trial. rhNGF Clinical Investigator Group.

CONTEXT: Nerve growth factor is a neurotrophic factor that promotes the survival of small fiber sensory neurons and sympathetic neurons in the peripheral nervous system. Recombinant human nerve growth factor (rhNGF) has demonstrated efficacy as treatment for peripheral neuropathy in experimental models and phase 2 clinical trials. OBJECTIVE: To evaluate the efficacy and safety of a 12-month regimen of rhNGF in patients with diabetic polyneuropathy. DESIGN: Randomized, double-blind, placebo-controlled phase 3 trial conducted from July 1997 through May 1999. SETTING: Eighty-four outpatient centers throughout the United States. PATIENTS: A total of 1019 men and women aged 18 to 74 years with either type 1 or type 2 diabetes and a sensory polyneuropathy attributable to diabetes. INTERVENTIONS: Patients were randomly assigned to receive either rhNGF, 0.1 microg/kg (n = 504), or placebo (n = 515) by subcutaneous injection 3 times per week for 48 weeks. Patients were assessed at baseline, 12 weeks, 24 weeks, and 48 weeks. MAIN OUTCOME MEASURES: The primary outcome measure was a change in neuropathy between baseline and week 48, demonstrated by the Neuropathy Impairment Score for the Lower Limbs, compared between the 2 groups. Secondary outcome measures included quantitative sensory tests using the CASE IV System, the Neuropathy Symptom and Change questionnaire, the Patient Benefit Questionnaire (PBQ), and a global symptom assessment, as well as nerve conduction studies and occurrence of new plantar foot ulcers. Patients also were evaluated for presence of adverse events. RESULTS: Among patients who received rhNGF, 418 (83%) completed the regimen compared with 461 (90%) who received placebo. Administration of rhNGF was safe, with few adverse events attributed to treatment apart from injection site pain/hyperalgesia and other pain syndromes. However, neither the primary end point (P =.25) nor most of the secondary end points demonstrated a significant benefit of rhNGF. Exceptions were the global symptom assessment (P =.03) and 2 of 32 comparisons within the PBQ, which showed a modest but significant benefit of rhNGF (P =.05 for severity of pain in the legs and P =.003 for 6-month symptoms in the feet and legs). CONCLUSION: Unlike previous phase 2 trials, this phase 3 clinical trial failed to demonstrate a significant beneficial effect of rhNGF on diabetic polyneuropathy. JAMA. 2000;284:2215-2221.

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.

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.

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.

Preliminary open-label experience with topiramate in primary generalized seizures.

Preliminary data concerning the effectiveness of topiramate (TPM) in the management of resistant primary generalized seizures were obtained from the open-label extension of a double-blind, placebo-controlled trial of TPM. The controlled trial enrolled patients experiencing three or more primary generalized tonic-clonic seizures (PGTCS) during an 8-week baseline period. Twelve of 13 patients who completed double-blind treatment elected to receive extended open therapy with TPM and were followed for periods ranging from 2 to 11 months. Of the 12 patients, 11 (92%) experienced a 50% or greater reduction in tonic-clonic seizures during their last 2 months of open-label TPM therapy compared to their pre-double-blind baseline period, and 7 (58%) were seizure-free during the open extension. Of five patients reporting absence seizures at baseline, four (80%) demonstrated a 50% or greater reduction in seizures. In seven of the 12 patients, a concomitant antiepileptic drug (AED) was discontinued or its dosage was reduced during open TPM treatment. The most common adverse events observed in the open study extension were weight reduction (five patients), weight increase (two patients), and drowsiness (two patients). The results of controlled trials are needed to determine the efficacy of TPM in primary generalized seizures. However, these preliminary findings are encouraging.

Results of temporal lobectomy for the treatment of partial complex epilepsy.

Epilepsy is the third most common cause of neurologic disability. The disease carries a 15 prevalence and a 3.5% lifetime risk. Seventy percent of patients can achieve good seizure control with medication. The remaining 30%, some 360,000 people across the United States, have intractable epilepsy and would benefit from evaluation at an epilepsy specialty center where surgical intervention is an option. The following report reviews a series of 50 patients referred to the Arkansas Comprehensive Epilepsy Program for treatment of intractable complex partial epilepsy. In this series, we evaluate results of temporal lobectomy, commenting upon factors in the patients' histories which may influence their outcomes.

Multiple sclerosis: genetic versus environmental aetiology: epidemiology in Israel updated.

The incidence and prevalence of multiple sclerosis (MS) were compared, controlling for age, in native-born Israelis of different origins and in immigrants to Israel. This comparison was carried out in two populations, countrywide and in Jerusalem. In the countrywide population, ascertainment was based mainly on hospitalizations; it included 252 patients who were native-born and 150 who had immigrated from Africa-Asia (AA immigrants). The 89 MS patients of Jerusalem also included patients diagnosed in outpatient clinics. In native-born Israelis whose father was born in Europe-America (I-EA), the incidence and prevalence of MS were found to be as high as or even higher than that found previously in immigrants from Europe-America. Among native-born Israelis whose father was born in Africa or Asia (I-AA), the yearly age-adjusted incidence and prevalence rates were found to be 1.4- to 1.8-fold higher than among AA immigrants, pointing to environmental factors. The incidence and prevalence rates in the I-EA were 1.2- to 1.6-fold higher than in the I-AA, pointing to genetic factors. These results seem to point to both environmental and genetic factors in the aetiology of MS. Further research is needed, however, to disentangle the genetic factors from possible environmental differences in the two ethnic groups.

Adjunctive therapy for intractable epilepsy with ethotoin.

In a retrospective study, records of 46 patients (24 women and 22 men aged 17-51 years; mean 29.2 years), who had been treated with ethotoin (EHN) as adjunctive therapy for control of intractable seizures were reviewed. Overall, approximately 51% of this highly selected patient population had a reduction greater than 50% in overall seizure frequency 1 month after initiation of treatment. This was reduced to approximately 25% for the last 3 months of follow-up (mean follow-up period 10.6 months). Tonic seizure frequency was reduced most dramatically, by greater than 50%, in 60% of patients at 1 month and in 35% of patients for the last 3 months of follow-up. This study suggests that prospective controlled trials of EHN, especially for tonic seizures, are needed.

Prolonged postictal encephalopathy.

Eleven patients (6 males, 5 females; ages 7.5 to 40 years, mean 27.8) had prolonged postictal confusion lasting from 4 to 10 days. During that time, the EEG showed a typical encephalopathic pattern. Comprehensive evaluation ruled out the possibility of metabolic, toxic, drug-related, or ongoing nonconvulsive status epilepticus. We have designated this syndrome as prolonged postictal encephalopathy (PPIE). Nine of 11 patients were mildly to borderline mentally retarded. Ten had previous episodes of status epilepticus. Nine of 11 had minimal structural abnormalities (mainly diffuse cortical atrophy). Nine patients had multiple recurrent episodes of PPIE. All episodes occurred following a cluster of seizures: in 8 patients after a cluster of generalized tonic-clonic seizures, in 2 after complex partial seizures, and in 1 patient after a cluster of atypical absence seizures. This series suggests that vulnerability to develop PPIE exists in patients with diffuse structural abnormalities, mild to borderline mental retardation, a history of status epilepticus, and a tendency of seizures to cluster.

Central auditory tests and auditory nerve-brainstem evoked responses in multiple sclerosis.

In 43 multiple sclerosis (MS) patients and an equal number of age- and sex-matched normal controls, auditory nerve-brainstem evoked responses (ABR), audiometric tests, central auditory tests (CAT) and clinical-neurological examinations were conducted. The CAT included rapid alternating speech perception, masking level differences to tones and to words and lateralization based on interaural time and intensity differences. The results in the MS group on the ABR and each of the CAT differed significantly from those in the control group. The ABR results and the lateralization test results were each abnormal in 50% of the MS patients. The ABR, CAT and clinical examination results were all mutually correlated. These findings are probably related to the fact that the demyelination in MS induces a decrease in impulse velocity, to temporal dispersion and to desynchrony of impulses in groups of affected axons and to the fact that the ABR and the CAT tests chosen are dependent on synchronous impulse firing and on the precise timing of the arrival of impulses from each ear at some brain centre. These tests may therefore contribute to neurological and to audiological diagnosis.