Baseline Seizure Rate Research Articles

Seizure Risk Associated With the Use of Transcranial Magnetic Stimulation for Coma Recovery in Individuals With Disordered Consciousness After Severe Traumatic Brain Injury.

Repetitive Transcranial Magnetic Stimulation (rTMS) is emerging as a promising treatment for persons with disorder of consciousness (DoC) following traumatic brain injury (TBI). Clinically, however, there are concerns about rTMS exacerbating baseline seizure risk. To advance understanding of risks, this article reports evidence of DoC-TBI rTMS-related seizure risk. Acute and sub-acute hospitals. Persons in states of DoC 6.5months to 15years after TBI (n=20) who received active rTMS (n=17) or placebo rTMS (n=3). After completing placebo procedures, placebo participants completed active rTMS procedures. These 3 participants are included in the active group. Meta-analysis of data from 3 clinical trials; 2 within-subject, 1 double blind randomized placebo-controlled. Each trial used the same rTMS protocol, provided at least 30 rTMS sessions, and delivered rTMS to the dorsolateral prefrontal cortex. During each study's rTMS treatment phase, seizure occurrences were compared between active and placebo groups using logistic regression. After stratifying active group by presence/absence of seizure occurrences, sub-groups were compared using contingency chi-square tests of independence and relative risk (RR) ratios. Two unique participants experienced seizures (1 active, 1 placebo). Post seizure, both participants returned to baseline neurobehavioral function. Both participants received antiepileptics during remaining rTMS sessions, which were completed without further seizures. rTMS-related seizure incidence rate is 59 per 1000 persons. Logistic regression revealed no difference in seizure occurrence by treatment condition (active vs placebo) or when examined with seizure risk factors (P >.1). Presence of ventriculoperitoneal shunt elevated seizure risk (RR=2.0). Collectively, findings indicate a low-likelihood that the specified rTMS protocol exacerbates baseline seizure rates in persons with DoC after TBI. In presence of VP shunts, however, rTMS likely elevates baseline seizure risk and mitigation of this increased risk with pharmacological seizure prophylaxis should be considered.

Statistical efficiency of patient data in randomized clinical trials of epilepsy treatments.

Previous research suggests that natural fluctuations in seizure rates within individuals have a quantifiable impact on therapeutic clinical trial outcomes. A trial simulator estimated the statistical power of clinical trials with a typical trial design with and without patients included who exhibited a range of means (1-15 seizures/mo) and standard deviations (1-15 seizures/mo) in their baseline seizure rates. Trial outcomes were evaluated using 50% responder rates, median percentage change, and time to prerandomization. Patients with higher seizure frequencies and lower standard deviations during their baseline contribute more to the statistical power regardless of the method used to evaluate the trial. Power varied from -20% to 30% depending on baseline seizure characteristics. Patient-specific characteristics can predict the contributions to the statistical power of clinical trials for epilepsy treatments. It may be possible to characterize this contribution with baseline data, leading to more efficient clinical trials.

Correction of medication nonadherence results in better seizure outcomes than dose escalation in a novel preclinical epilepsy model of adherence

Medication nonadherence directly contributes to poor seizure control. A lack of emphasis on correcting poor adherence and failures in patient adherence can result in unwarranted alterations to a patient's drug regimen. We have modeled nonadherent patients in an animal model of epilepsy to study how alterations to pharmacotherapy, made without consideration of a patient's adherence, result in changes to seizure control. Newly diagnosed rats with epilepsy were treated with carbamazepine (CBZ) during a 4-week baseline period to establish their baseline seizure rate in the presence of 50% adherence. Next, animals were randomized to one of three treatment interventions and monitored for 6weeks. Groups included: (1) no change in therapy-rats continued the 50% adherent paradigm; (2) dose escalation-the dose of CBZ was doubled, and the 50% adherent paradigm continued; and (3) nonadherence corrected-rats continued the initial dose of CBZ, but the adherence rate was adjusted to 100% (ie, fully adherent). The rats in the no change in therapy arm displayed a 61% increase in seizure burden over the 6-week intervention phase. Similarly, rats in the dose escalation arm had a 66% worsening of their daily seizure burden. In contrast, rats in the nonadherence corrected arm displayed a 33% reduction in their daily seizure burden; a significant improvement when compared to the normalized seizure burden scores of rats in the other two treatment arms (P<0.01). We found that failure to correct medication nonadherence resulted in an increase in daily seizure burden in rats, even following dose escalation. In the presence of nonadherence, dose escalation worsened seizure control. In contrast, correcting nonadherence alone resulted in improved seizure control. These findings suggest that improving adherence should be prioritized over dose escalation in the clinical management of uncontrolled epilepsy.

Oral administration of the casein kinase 2 inhibitor TBB leads to persistent KCa2.2 channel up-regulation in the epileptic CA1 area and cortex, but lacks anti-seizure efficacy in the pilocarpine epilepsy model

Temporal lobe epilepsy (TLE) is the most common epileptic syndrome in adults and often presents with seizures that prove intractable with currently available anticonvulsants. Thus, there is still a need for new anti-seizure drugs in this condition. Recently, we found that the casein kinase 2 inhibitor 4,5,6,7-tetrabromotriazole (TBB) prevented the emergence of spontaneous epileptic discharges in an acute in vitro epilepsy model. This prompted us to study the anti-seizure effects of TBB in the pilocarpine model of chronic epilepsy in vivo. To this end, we performed long-term video-EEG monitoring lasting 78–167 days of nine chronically epileptic rats and obtained a baseline seizure rate of 3.3 ± 1.3 per day (baseline of 27–80 days). We found a significant age effect with more pronounced seizure rates in older animals as compared to younger ones. However, the seizure rate increased to 6.3 ± 2.2 per day during the oral TBB administration (treatment period of 21–50 days), and following discontinuation of TBB, this rate remained stable with 5.2 ± 1.4 seizures per day (follow-up of 30–55 days). After completing the video-EEG during the follow-up the hippocampal tissue was prepared and studied for the expression of the Ca2+-activated K+ channel KCa2.2. We found a significant up-regulation of KCa2.2 in the epileptic CA1 region and in the neocortex, but in no other hippocampal subfield. Hence, our findings indicate that oral administration of TBB leads to persistent up-regulation of KCa2.2 in the epileptic CA1 subfield and in the neocortex, but lacks anti-seizure efficacy in the pilocarpine epilepsy model.

T14. Potential electrocorticographic seizure biomarkers

Identifying electrographic features that differentiate patients with the most favorable response to epilepsy treatments will aid in discovering disease biomarkers and treatment endpoints, and could enhance patient selection. The RNS® System provides responsive direct-brain stimulation and is FDA approved for the treatment of medically refractory focal epilepsies in adults. The median percent seizure reduction in clinical trials reaches 72% at 7 years with 30% experiencing a reduction in seizures of ⩾90% based on most recent 3 months of follow-up. The device also provides chronic ambulatory electrocorticographic data. The objective of this study was to assess electrographic and demographic differences between patients treated with the RNS® System (NeuroPace, Inc.) who had the greatest and the least reductions in clinical seizure frequency. 179 adults within clinical trials of the RNS System had ⩾6 months of clinical seizure data at year 7 of treatment and were included in this analysis. Patients in the upper (n = 45: MTL = 16, Neocortical = 27, MTL + neocortical = 2) and lower (n = 45: MTL = 16, Neocortical = 26, MTL + neocortical = 3) clinical seizure response quartiles were determined by ranking mean change in clinical seizure rates in year 7 compared to baseline. Electrographic features (interictal spikes, total spectral power and band spectral power) were extracted from 76,570 scheduled (putatively interictal baseline) ambulatory 4-channel electrocorticographic (ECoG) records (each ∼90 s) collected over 7 years. Differences in electrographic features and clinical seizures over time in the upper and lower response quartile patients were measured. Demographic characteristics (gender, age at enrollment, age of onset, number of onsets, baseline seizure rate, and presence or absence of previous resection, callosotomy, subpial transection and prior intracranial monitoring) were compared. ECoG feature trends over time (6 months to 7 years) closely followed clinical seizure rate trends in both MTL and neocortical groups, with higher feature values significantly (p < 0.05) correlated with higher clinical seizure rates. Ranking features according to their ability to differentiate upper and lower response quartile patients revealed spike rate as the strongest feature in the MTL group. In the neocortical group, high gamma (50–125 Hz) emerged as the strongest feature. There were no significant differences in the demographic characteristics between upper and lower quartile patients when considered as one group or when divided into MTL and neocortical onset groups. Chronic ambulatory ECoG data obtained from a trial of the RNS System revealed electrophysiological differences between patients in the upper and lower quartiles of clinical seizure response. Changes in spike frequency and in high gamma could be potential seizure biomarkers.

Population dose-response analysis of daily seizure count following vigabatrin therapy in adult and pediatric patients with refractory complex partial seizures.

Vigabatrin is an irreversible inhibitor of γ-aminobutyric acid transaminase (GABA-T) and is used as an adjunctive therapy for adult patients with refractory complex partial seizures (rCPS). The purpose of this investigation was to describe the relationship between vigabatrin dosage and daily seizure rate for adults and children with rCPS and identify relevant covariates that might impact seizure frequency. This population dose-response analysis used seizure-count data from three pediatric and two adult randomized controlled studies of rCPS patients. A negative binomial distribution model adequately described daily seizure data. Mean seizure rate decreased with time after first dose and was described using an asymptotic model. Vigabatrin drug effects were best characterized by a quadratic model using normalized dosage as the exposure metric. Normalized dosage was an estimated parameter that allowed for individualized changes in vigabatrin exposure based on body weight. Baseline seizure rate increased with decreasing age, but age had no impact on vigabatrin drug effects after dosage was normalized for body weight differences. Posterior predictive checks indicated the final model was capable of simulating data consistent with observed daily seizure counts. Total normalized vigabatrin dosages of 1, 3, and 6 g/day were predicted to reduce seizure rates 23.2%, 45.6%, and 48.5%, respectively.

Stable dosages of clobazam for Lennox‐Gastaut syndrome are associated with sustained drop‐seizure and total‐seizure improvements over 3 years

ObjectiveTo determine long-term safety and efficacy of adjunctive clobazam for patients with Lennox-Gastaut syndrome (LGS).MethodsEligible patients from two randomized controlled trials (Phase II OV-1002 and Phase III OV-1012) were able to enroll in open-label extension (OLE) study OV-1004 beginning in December 2005 and received clobazam until they discontinued (mandatory at 2 years for patients outside the United States) or until study completion in March 2012. Patients in the United States could have received clobazam for 6 years before it became commercially available. Efficacy assessments included changes in rates of drop seizures and total seizures, responder rates (≥50%, ≥75%, or 100% decreases in seizure frequency vs. baseline), sustained efficacy over time, concomitant antiepileptic drug (AED) use, and global evaluations. Safety assessments included exposure to clobazam, laboratory assessments, physical and neurologic examinations, vital sign monitoring, electrocardiography monitoring, and adverse event reporting.ResultsOf 267 patients who enrolled in the OLE, 188 (70%) completed the trial. Two hundred seven patients were from the United States, which was the only country in which patients could be treated with clobazam for >2 years. Forty-four patients were treated with clobazam for 5 years, and 11 for 6 years. Because of the low number of Year 6 patients, this group is not reported separately. Improvements in baseline seizure rates were very stable over the course of the study, with a median 85% decrease in drop seizures at Year 1, 87% at Year 2, 92% at Year 3, 97% at Year 4, and a 91% decrease for patients who had reached Year 5. Similar results were observed for total seizures (79% decrease at both Years 1 and 2, 82% decrease at Year 3, 75% decrease at Year 4, and 85% decrease at Year 5). Responder rates were also stable for the duration of the trial. Of patients who had achieved a ≥50% decrease in median drop-seizure frequency from baseline to Month 3, 86% still had that degree of drop-seizure reduction at Year 3 (and 14% lost their initial responses), and 47% were drop-seizure–free. Most patients who had achieved drop-seizure freedom in the original controlled trials remained drop-seizure–free in the OLE. Based on parents' and physicians' ratings of global evaluations, 80% of patients were “very much improved” or “much improved” after 3 years. Of the 43 patients with concomitant AED data who were treated for 5 years, 30% increased, 19% decreased, and 51% had no change in numbers of AEDs versus their Week 4 regimens. The mean modal clobazam dosage was 0.90 mg/kg/day at Year 1 and 0.97 mg/kg/day at Year 5, suggesting that study patients did not need significant increases in dosage over time. The safety profile was what would be expected for clobazam for LGS patients over a 5-year span, and no new safety concerns developed over time.SignificanceIn this largest and longest-running trial in LGS, adjunctive clobazam sustained seizure freedom and substantial seizure improvements at stable dosages through 3 years of therapy in this difficult- to-treat patient population.

Designing a new proof-of-principle trial for treatment of partial seizures to demonstrate efficacy with minimal sample size and duration—A case study

The ideal proof-of-principle study design provides a strong efficacy signal over the shortest duration, while exposing the fewest patients possible. Data from a large database (Pfizer Inc) which studied add-on pregabalin for the treatment of partial seizures was used to model how duration of baseline, post-randomization treatment period, and number of subjects impact the likelihood of an interpretable efficacy signal. Data from four double-blind, randomized, placebo-controlled, phase III studies that had at least one 600 mg/day treatment arm were combined. The common 6-week baseline period was divided into weekly intervals, as was the 12-week post-randomization period. Two methods of analysis were used: logistic regression performed on 50% responder rate and the Hodges-Lehmann estimate on percentage reduction from baseline seizure rate. A simulation-based re-sampling approach was used to determine sufficient sample size. Four weeks of baseline with 3 weeks of treatment were determined to be clinically and statistically sufficient. A reasonable sample size was estimated to be 40-50 patients per group, if a highly efficacious drug was used. These modeling results indicate that the efficacy of an antiepileptic drug can be demonstrated in a relatively short period of time with a reasonable sample size.

Reduction of seizure occurrence from exposure to auditory stimulation in individuals with neurological handicaps: a randomized controlled trial.

BackgroundThe purpose of this work was to determine in a clinical trial the efficacy of reducing or preventing seizures in patients with neurological handicaps through sustained cortical activation evoked by passive exposure to a specific auditory stimulus (particular music). The specific type of stimulation had been determined in previous studies to evoke anti-epileptiform/anti-seizure brain activity.MethodsThe study was conducted at the Thad E. Saleeby Center in Harstville, South Carolina, which is a permanent residence for individuals with heterogeneous neurological impairments, many with epilepsy. We investigated the ability to reduce or prevent seizures in subjects through cortical stimulation from sustained passive nightly exposure to a specific auditory stimulus (music) in a three-year randomized controlled study. In year 1, baseline seizure rates were established. In year 2, subjects were randomly assigned to treatment and control groups. Treatment group subjects were exposed during sleeping hours to specific music at regular intervals. Control subjects received no music exposure and were maintained on regular anti-seizure medication. In year 3, music treatment was terminated and seizure rates followed. We found a significant treatment effect (p = 0.024) during the treatment phase persisting through the follow-up phase (p = 0.002). Subjects exposed to treatment exhibited a significant 24% decrease in seizures during the treatment phase, and a 33% decrease persisting through the follow-up phase. Twenty-four percent of treatment subjects exhibited a complete absence of seizures during treatment.Conclusion/SignificanceExposure to specific auditory stimuli (i.e. music) can significantly reduce seizures in subjects with a range of epilepsy and seizure types, in some cases achieving a complete cessation of seizures. These results are consistent with previous work showing reductions in epileptiform activity from particular music exposure and offers potential for achieving a non-invasive, non-pharmacologic treatment of epilepsy.Trial RegistrationClinicaltrials.gov NCT01459692

Perampanel, a Selective, Non-Competitive AMPA Receptor Antagonist, Prolongs Time to Seizure Recurrence in Patients with Epilepsy: Results of Pooled Phase III Clinical Trial Data (S56.005)

Objective: Evaluate new endpoints and identify those most sensitive to earlier outcome determinations. Background New study designs requiring less patient exposure are needed. Design/Methods: Patients (≥12 years with uncontrolled partial-onset seizures, despite 1-3 concomitant antiepileptic drugs) had individual Baseline (6-week) 28-day seizure rates determined. Patients were then randomized to once-daily double-blind treatment (6-week Titration; 13-week Maintenance) with placebo or perampanel 2, 4, 8, 12 mg. Seizure frequency was recorded. Kaplan-Meier analyses of pooled phase III data assessed both median time to reach individual Baseline 28-day seizure rates and time to the next seizure event during double-blind treatment (ITT analysis set: all North American, European, Asia/Pacific, South African, and Australian patients. Central/South American patients were excluded due to a treatment-by-region interaction [high placebo responses]). Results: Numbers of patients at each randomized dose were: placebo n=393, and perampanel 2 mg n=180; 4 mg n=172, 8 mg n=372, and 12 mg n=201. Perampanel prolonged median times to Baseline 28-day seizure rate (32 [p=0.0672], 33 [p=0.0019], 36 [p Conclusions: Perampanel (4-12 mg/day) prolonged time to Baseline seizure rate and time to next event vs placebo, suggesting potential new study designs for earlier assessment of outcomes. These results support the dose range assessed in prior phase III studies and identification of 4 mg as the minimally effective dose. Supported by: Eisai Inc. Disclosure: Dr. Laurenza has received personal compensation for activities with Eisai as an employee. Dr. French has nothing to disclose. Dr. Gil-Nagel has received personal compensation for activities with Bial, Eisai Inc., GlaxoSmithKline, Inc., UCB Pharma and Medtronic as a speaker and/or consultant. Dr. Gil-Nagel has received research support from UCB Pharma. Dr. Guerrini has received personal compensation for activities with Biocodes, UCB Pharma, Eisai Inc, ValueBox, Biocodex, Japanese Epilepsy Society, Weill Cornell Medical College and European Medicine Agency as a speaker and/or participating on an advisory board. Dr. Guerrini has received personal compensation in an editorial capacity for Epilepsia, Progress in Epileptic Disorders, Neuropediatrics, Journal of Child Neurology, Seizure, BMC Medical Genetics, Topics in Epilepsy, Journal of Pediatric Epilepsy,Epileptic Disorders and European Neurological Journal. Dr. Squillacote has received personal compensation for activities with Eisai as an employee. Dr. Yang has received personal compensation for activities with Eisai, Inc. as an employee. Dr. Kumar has received personal compensation for activities with Eisai Inc. as an employee.

A 21-week open-label clinical trial of pregabalin as adjunctive therapy in partial seizures at multiple centers in Mexico (PREPS Mexico)

To investigate the efficacy of pregabalin in the treatment of refractory partial seizures. This was a 21-week, open-label study of pregabalin (150-600 mg/day) as an adjunctive therapy in adults with refractory partial seizures. The study included an 8-week baseline period, a 9-week dose-optimization period, and a 12-week treatment-observation period. The primary assessment was mean percentage change in 28-day seizure rate between baseline and the last 12 weeks of treatment. In total, 136 Mexican patients were included in this study (55.9% women; mean age/epilepsy duration, 35.2/22.9 years). The median and mean (95% confidence interval [CI]) 28-day baseline seizure rates were 3.9 and 7.8 (5.4-10.2), respectively. The mean (95% CI) reduction in seizure frequency was 51.2% (43.0-59.3) over the last 12 weeks of treatment, while the median reduction was 57.9%. The percentage of patients with a ≥ 5 0% or ≥ 75% reduction in seizure frequency was 63.6% and 48.8%, respectively. The percentage of patients who were seizure-free during the last 4 and 12 weeks of treatment was 40.5% and 20.7%, respectively. The most common adverse events were somnolence (39.7%), dizziness (16.2%), and weight gain (14.0%). Pregabalin was well tolerated and associated with significant reductions in seizure frequency.

Transient suppression of seizures by repetitive transcranial magnetic stimulation in a case of Rasmussen’s encephalitis

Repetitive transcranial magnetic stimulation (rTMS) has been applied with variable success to terminate the seizures of epilepsia partialis continua. The rationale for using this technique to suppress ongoing seizures is the capacity of rTMS to interrupt ongoing neuronal activity, and to produce a lasting decrease in cortical excitability with low-frequency (⩽1 Hz) stimulation. We report a case of epilepsia partialis continua in a child with Rasmussen’s encephalitis, in whom seizures were transiently suppressed by 1-Hz rTMS delivered in nine daily 30-minute sessions. In this case, total ictal time was significantly reduced during stimulation, but the daily baseline seizure rate remained unchanged. Notably, the detection and quantification of this short-lived improvement were enabled by recording EEG continuously during the rTMS session. Thus, we present this case to illustrate a potential utility of combined continuous EEG recording and rTMS in seizure treatment.

New Statistical Method for Analyzing Time to First Seizure: Example Using Data Comparing Carbamazepine and Valproate Monotherapy

Time to first seizure is a common outcome in antiepileptic drug (AED) studies. Previous studies have typically failed to find statistically significant differences between carbamazepine (CBZ) and valproate (VPS). We re-analyzed a meta-analysis comparing CBZ and VPS monotherapy with new powerful statistical methods that incorporate baseline seizure rate information. Individual patient data were available on 1,265 patients from a meta-analysis of five trials. The outcome measure was time to first seizure after randomization, adjusted for background variables and baseline seizure rate. We found strong evidence of an interaction between treatment and epilepsy type, and between treatment and age. For generalized onset seizures, VPS was statistically significantly better than CBZ: VPS delayed the first seizure after treatment 58%, 52%, 44%, and 36% longer than CBZ for individuals aged 10, 20, 30, or 40, respectively. For partial onset seizures in individuals older than 30, CBZ was significantly better then VPS; CBZ delayed the time to first seizure by 9%, 25%, 44%, and 66% longer than VPS for individuals aged 20, 30, 40, or 50, respectively. The results show clear age-varying differences between the effectiveness of CBZ and VPS for generalized onset and partial onset seizures, which have not been identified in previous studies using standard statistical methods. In future trials of AED monotherapy or add-on where time to first or Nth seizure is an outcome, methodology that can incorporate baseline seizure rate information would allow more powerful comparisons between treatments or between treatment and placebo.

Vagus nerve stimulation for epilepsy

In two prospective, double-blind, 3-month trials with 300 patients, chronic intermittent high intensity electrical stimulation of the cervical vagus nerve with a subcutaneous surgically implanted device (vagus nerve stimulation, VNS) reduced medication-resistant partial onset seizures by 24–28%, compared with seizure rate reductions of 6–15% in the low intensity control group. Side effects in the first 3 months of treatment were hoarseness (60%), cough (38%), parasthesias (20%) and dyspnea (20%); after 3 years of VNS, less than 5% of patients experience side effects. Seizure rates decline further with increasing VNS treatment durations (43% of patients have a 50% or more seizure rate reduction after 3 years); this seems independent of later antiepileptic drug (AED) and stimulation parameter changes. Antiepileptic effects of VNS may persist after termination of the therapy. The following clinical features are not predictive of seizure rate responsiveness to VNS: epilepsy duration, epilepsy syndrome, age, gender, epilepsy onset age, baseline seizure rate, prior epilepsy surgery, number and type of concomitant AEDs, number of prior AEDs, and number of seizure types. In one small study, increased thalamic blood flow seen on PET scans performed upon VNS initiation was predictive of later clinical responsiveness. Better methods to identify preoperatively probable VNS responders need to be developed.

A pooled analysis of adjunctive topiramate in refractory partial epilepsy.

To evaluate the impact of different dosages of topiramate (TPM) add-on to stable antiepileptic therapy for refractory partial epilepsy in adults. Pooled intention-to-treat analysis of six similarly designed double-blind, placebo-controlled trials, including 481 patients treated with doses of TPM 200, 400, 600 and 800 mg/day, and 265 patients receiving placebo. Seizures were reduced by >/=50% from baseline in 41% of TPM-treated patients and 15% of placebo-treated patients (P < 0.001); 5 and 0.8%, respectively, were seizure-free (P < 0.003). TPM was significantly better than placebo regardless of gender, age, baseline seizure rate as well as number and type of concomitant antiepileptic drugs. Efficacy was statistically significant in favour of TPM at all dose levels: at least 50% seizure reduction was achieved in 40% of patients with 200 mg, 41% with 400 mg, 44% with 600 mg and 41% with 800 mg TPM when compared with 15% with placebo (P </= 0.001 for each dosage arm vs placebo). The median reduction in monthly seizure frequency was 38%, 42%, 45% and 38% vs 8%, respectively (P </= 0.001). Moreover, response to TPM was significantly superior to placebo at each of the dose levels tested for most of the baseline variables. The total percentage of withdrawals increased with the dosage, and the withdrawals caused by adverse events increased from 3% with placebo to 7% with 200 mg TPM (not significant vs placebo), 15% with 400 mg TPM (P = 0.08), 16% with 600 mg TPM (P = 0.002) and 15% with 800 mg TPM (P = 0.003). The efficacy of TPM add-on in partial epilepsy is consistent across efficacy endpoints and independent of study population characteristics. The response at 200 mg TPM is similar to the response at higher doses, but as drop-outs caused by adverse events are more frequent above the 200 mg dose, this pooled analysis supports that 200 mg daily is a good target dose for add-on therapy in most patients with partial epilepsy, showing an excellent balance between efficacy and tolerability.

Topiramate as add-on therapy: pooled analysis of randomized controlled trials in adults.

Six double-blind, placebo-controlled trials were conducted with topiramate (TPM) initiated as adjunctive therapy in adults with treatment-resistant partial-onset seizures with or without secondary generalization. Because protocols and study populations were similar, data from the studies were pooled and analyzed for 527 patients treated with TPM and 216 treated with placebo. Seizures were reduced > or =50% in 43% of TPM-treated patients and in 12% of placebo-treated patients (p < 0.001); 5% of TPM-treated patients, but no placebo-treated patients, were seizure free during 11-19 weeks of double-blind treatment (p < 0.001). The therapeutic effect was consistent regardless of seizure type, age, gender, baseline seizure rate, or concomitant antiepileptic drug (AED). With 100 mg/day TPM as a starting dosage and weekly dosage increments of 100-200 mg/day added to maximally tolerated dosages of AEDs, the most common treatment-emergent adverse events (TEAEs) were dizziness, somnolence, fatigue, psychomotor slowing, nervousness, paresthesia, ataxia, memory difficulty and speech problems. These central nervous system effects were generally mild to moderate in severity, usually occurred early in treatment, often during titration, and resolved with continued treatment. Other notable TEAEs were weight loss and, in a small percentage of patients, renal calculi.

Vagus nerve stimulation for symptomatic generalized epilepsy: a pilot study.

Patients with symptomatic generalized epilepsy (SGE) may have antiepileptic drug (AED)-resistant mixed generalized seizures. Vagus nerve stimulation (VNS) reduces partial seizures and may help SGE. We added VNS to stable AED therapy in five SGE patients. Nine-month postoperative VNS treatment seizure rates were compared to a 1-month preoperative baseline. All patients had mixed generalized seizures, EEG generalized slow spike-and-wave and behavioral abnormalities. Median number of previous AEDs taken was 6 (range 5-12). Median baseline seizure rate was 75/month (range 29-110). VNS produced a median seizure rate production of -41% (range -40% - -85%). Adverse events reported in one patient each were: incisional infection, choking sensation and voice change; and coughing (noted by two patients). One patient discontinued VNS due to coughing. We conclude that VNS may be useful add-on therapy for SGE. A larger, controlled, and blinded trial may be warranted.

Double-blind crossover comparison of Tegretol-XR and Tegretol in patients with epilepsy

This multicenter, double-blind, crossover study compared Tegretol-XR and Tegretol tablets with respect to trough plasma carbamazepine (CBZ) concentrations, seizure control, tolerability, and safety. We randomized 96 patients with epilepsy to 56-day monotherapy with their usual daily CBZ dose administered as (1) Tegretol-XR 200-mg tablets every 12 hours plus placebo or (2) Tegretol 200-mg tablets three or four times daily plus placebo. Upon completion, patients immediately switched to the alternate treatment for 56 days. During the study, 98% of patients had plasma CBZ concentrations within the recommended therapeutic range during Tegretol-XR treatment and 97% did during Tegretol treatment. The seizure rate during treatment, compared with the baseline seizure rate, decreased in 26% of patients both during treatment with Tegretol-XR and during treatment with Tegretol, and it remained the same in 48% of patients during Tegretol-XR therapy and in 52% of patients during Tegretol therapy. We did not observe any pattern of change in seizure frequency. We switched patients on a milligram-per-milligram basis from multiple-daily-dose Tegretol to Tegretol-XR twice daily from one day to the next without reiterating the daily dose.