Median Reduction In Seizure Frequency Research Articles

A Comparison of Vagal Nerve Stimulation and Responsive Neurostimulation for the Treatment of Medically Refractory Complex Partial Epilepsy

Background: Neuromodulatory applications such as vagus nerve stimulation (VNS) and responsive neurostimulation (RNS) are safe and effective strategies for medically intractable epilepsy secondary to complex partial seizures, but researchers have yet to compare their efficacies. Objective: The goal of this study is to compare VNS and RNS efficacy at reducing seizure frequency and complication rates in subjects with medically intractable epilepsy secondary to complex partial seizures. Methods: This is a retrospective chart review of 30 patients with medically intractable complex partial epilepsy, who underwent either VNS or RNS placement at a single institution between June 2012 and January 2016. There was a mean follow-up of 19 months. Seizure frequency reduction and complications were identified. Results: The median seizure frequency reduction was similar for VNS (66%) and RNS (58%). There was no major morbidity or mortality, and the frequency of minor complications was similar between VNS (15%) and RNS (18%). Conclusion: We found that VNS and RNS reduced the median seizure frequency similarly with no difference in morbidity or mortality. Further prospective studies are warranted as VNS and RNS therapy improves over time.

Adjunctive everolimus for children and adolescents with treatment-refractory seizures associated with tuberous sclerosis complex: post-hoc analysis of the phase 3 EXIST-3 trial

Epilepsy occurs in 70-90% of patients with tuberous sclerosis complex. We aimed to assess the efficacy and safety of adjunctive everolimus for treatment-refractory seizures associated with tuberous sclerosis complex in paediatric patients enrolled in the EXIST-3 trial, a double-blind, placebo-controlled, randomised, phase 3 study. This post-hoc analysis focused on paediatric patients (age <18 years) in the EXIST-3 trial, which consisted of baseline (8 weeks), core (18 weeks), and extension phases (≥48 weeks) and was done at 99 centres in 25 countries worldwide. Briefly, patients with tuberous sclerosis complex-associated treatment-refractory seizures, who were receiving a stable dose of one to three antiepileptic drugs, were randomly assigned (1:1:1) to receive placebo, low-exposure everolimus (3-7 ng/mL), or high-exposure everolimus (9-15 ng/mL). Following the core phase, patients could enter the extension phase to receive everolimus at a targeted exposure range of 3-15 ng/mL up to 48 weeks after the last patient had completed the core phase. Efficacy endpoints were response rate (≥50% of reduction from baseline in average weekly seizure frequency) and median percentage reduction in seizure frequency during the 12-week maintenance period of the core phase, and at 12-week intervals throughout the extension phase. This study is registered with ClinicalTrials.gov, number NCT01713946. Between July 3, 2013, and May 29, 2015, 299 paediatric patients enrolled in the trial. In the younger subgroup (<6 years; n=104), 34 received placebo, 33 low-exposure everolimus, and 37 high-exposure everolimus; in the older subgroup (≥6 years to <18 years; n=195), 62 received placebo, 63 low-exposure everolimus, and 70 high-exposure everolimus. At the end of the core phase, response rate was higher in the treatment groups than placebo in both the younger subgroup (17·6% [6·8-34·5] for placebo vs 30·3% [95% CI 15·6-48·7; p=0·2245] for low-exposure everolimus vs 59·5% [42·1-75·2; p=0·0003] for high-exposure everolimus) and the older subgroup (12·9% [5·7-23·9] vs 27·0% [16·6-39·7; p=0·0491] vs 30·0% [19·6-42·1; p=0·0179]), as were median reduction in seizure frequency (12·3% [95% CI -10·1 to 24·8] vs 29·3% [95% CI 13·4 to 46·3; p=0·0474] vs 54·7% [43·5 to 73·1; p<0·0001] in younger patients; 13·5% [-3·0 to 26·8] vs 31·0% [16·1 to 42·9; p=0·0128] vs 34·8% [26·7 to 41·3; p=0·0006] in older patients). The efficacy persisted, with sustained seizure reduction after 1 year of treatment across both paediatric subgroups (response rate 48·9% [95% CI 38·1-59·8] for the younger subgroup vs 47·2% [39·3-55·2] for the older subgroup; median percentage reduction in seizure frequency 48·4% [95% CI 34·3-73·6] vs 48·0% [38·2-57·5]). At the cutoff date for the extension phase, grade 3 or 4 adverse events were reported in 45 (45%) younger patients (commonly pneumonia [n=16]) and 74 (38%) older patients (commonly pneumonia [n=8] and stomatitis [n=6]). Two deaths (pneumonia, which was suspected to be treatment-related, and sudden unexplained death due to epilepsy) were reported. Adjunctive everolimus resulted in sustained reductions in seizure frequency after 1 year and was well tolerated in paediatric patients with treatment-refractory seizures associated with tuberous sclerosis complex. Novartis Pharmaceuticals Corporation.

Long-term effects of adjunctive perampanel on cognition in adolescents with partial seizures

ObjectiveThe aim of this study was to evaluate long-term effects of adjunctive perampanel on cognition, efficacy, growth, safety, and tolerability in adolescents with inadequately controlled partial seizures. MethodsStudy 235, a multicenter, randomized, double-blind, placebo-controlled, parallel-group, Phase II study with an open-label extension phase (NCT01161524), was primarily designed to assess the effects of adjunctive perampanel on cognition. Patients (aged ≥12 to <18years) had a diagnosis of epilepsy with inadequately controlled partial seizures, with or without secondary generalization, despite receiving 1–3 antiepileptic drugs. During the double-blind phase, adjunctive perampanel or placebo was administered over a 6-week titration period and a 13-week maintenance period up to 12mg/day. During the extension phase, all patients received perampanel. Data from the extension phase are presented here. Study endpoints included change from baseline in Cognitive Drug Research (CDR) measures of cognition, seizure frequency, growth, development, the occurrence of treatment-emergent adverse events (TEAEs), and laboratory values. ResultsA total of 114 patients entered the extension phase (prior double-blind treatment: placebo, n=41; perampanel, n=73). Perampanel had no effect on the CDR system global cognition score, continuity of attention, quality of episodic memory, quality of working memory, or speed of memory but was associated with a significant decline in power of attention at end of treatment compared with baseline (p=0.03). There were no effects on language skills or manual dexterity from baseline to end of treatment. At Weeks 40–52, median reduction in seizure frequency was 74.1%, and 50% responder rate was 66.0%. There were no clinically relevant effects of perampanel on growth or development at end of treatment compared with baseline. Overall, 84.2% of patients experienced at least one TEAE and 70.2% experienced at least one treatment-related TEAE. The most common TEAEs were dizziness (29.8%) and somnolence (19.3%). The TEAEs resulted in the discontinuation of treatment in 6.1% of patients. ConclusionsIn keeping with the 19-week double-blind phase, long-term adjunctive treatment with perampanel did not have any significant overall effects on the CDR system global cognition score in adolescent patients with inadequately controlled partial seizures. Similar trends were observed across the individual CDR system domains. Adjunctive perampanel showed sustained long-term seizure control and had a safety and tolerability profile similar to that observed in prior clinical studies.

Safety and efficacy of perampanel in children and adults with various epilepsy syndromes: A single-center postmarketing study.

Perampanel is an AMPA receptor antagonist recently approved for the treatment of partial and generalized epilepsies with tonic-clonic seizures as an add-on therapy. This single-center postmarketing study retrospectively evaluated the efficacy of perampanel in patients with partial onset and other seizure types, with a special emphasis on its efficacy, safety, and tolerability. Review of medical records revealed that adequate data were available on 101 patients taking perampanel. Fifty-seven patients were female. Sixteen patients were of pediatric age range. The average dose of perampanel was 6.5mg, and average treatment duration was 8.2months. After treatment, median seizure frequency reduction was 50% overall, 50% in children, and 33% in adults; 44% in primary generalized, 38% in secondarily generalized, and 33% in partial seizures. Responder rate (50% seizure frequency reduction) was 51% overall, 63% in children, and 49% in adults; 60% in partial seizures, 43% in secondarily generalized tonic-clonic seizures, 53% in primary generalized tonic-clonic seizures, and 56% in other seizure types. Seizure freedom was attained in 6% of cases. Most common adverse events were sleepiness/fatigue (35%), behavioral problems (30%), and dizziness (22%). Adverse events were correlated with dosage. Average dose was 7.3mg in patients with adverse events vs. 5.5mg in those without adverse events. Patients who developed fatigue, cognitive decline, headaches, and weight gain were more likely to discontinue perampanel than those patients who experienced coordination issues and behavioral problems. These findings suggest that perampanel is safe, well-tolerated, and effective in treatment of various types of adult and pediatric epilepsy syndromes. Fatigue, cognitive decline, headache and weight gain were the main causes of perampanel discontinuation.

Hippocampal deep brain stimulation in nonlesional refractory mesial temporal lobe epilepsy

PurposeTo evaluate the efficacy of chronic continuous hippocampal deep brain stimulation (DBS) in nonlesional refractory mesial temporal lobe epilepsy. MethodsThree adult patients with medically intractable epilepsy treated with hippocampal DBS were studied. Two patients underwent invasive recordings with depth stereo-electroencephalography (SEEG) electrodes to localize ictal onset zone prior to implantation of DBS electrodes. All the patients with no lesion in brain magnetic resonance imaging (MRI) scan received bilateral implantation of DBS electrodes. Chronic continuous high-frequency hippocampal stimulation was applied during treatment. The number of seizures in each patient before and after stimulation was compared. ResultsLong-term hippocampal stimulation produced a median reduction in seizure frequency of 93%. Two out of these patients received unilateral activation of the electrodes and experienced a 95% and 92% reduction in seizure frequency after hippocampal DBS respectively. The last patient had bilateral electrode activation and had a seizure-frequency reduction of 91%. None of the patients had neuropsychological deterioration and showed side effects. Generalized tonic–clonic seizures disappeared completely after hippocampal DBS. ConclusionsChronic continuous hippocampal DBS demonstrated a potential efficiency and safety in nonlesional refractory mesial temporal lobe epilepsy and might represent an effective therapeutic option for these patients.

OP53 – 2462: The role of mTOR inhibitors in TSC associated epilepsy

We evaluated prospectively the effect of Everolimus on epilepsy in children and adolescents with TSC treated with Everolimus for SEGA at our center. Methods This is a retrospective analysis of prospectively collected data: included were patients ≤19 years with epilepsy, treated with Votubia, who had regular prospective follow-up every 3 months at the study center (clinical inspection and EEG, seizure diaries, blood sampling). Everolimus is orally administered once per day, starting with 4.5 mg/m 2 and titration to achieve blood trough concentrations of 5–15 ng/ml. Response was defined as ≥50% reduction in seizure count. Results We present pilot data of 12 patients (4 female, 8 male), with genetically confirmed diagnosis of TSC (3 TSC1, 9 TSC2 mutations). The median age at initiation of Votubia was 10 years (y) (range: 2–19 y). The median duration of epilepsy prior to treatment was 9.5 y (range: 1.75–16.75 y). The median number of AEDs prior to treatment was 1 (range: 1–3). The median seizure frequency prior to treatment was 30 seizures/month (range: 2–1470 seizures/month). 8/12 (66%) patients were responders. The median follow up after initiation of Everolimus was 13.5 months (range: 2–31 months). The median reduction in seizure frequency was 93% (range: 0–100%). Four patients became seizure free. The median number of AED after treatment was 1 (range: 1–2). The effect on seizure frequency was accompanied by significant developmental progress in all seizure free children. 4 patients were non-responders, one of them was incompliant. Side effects were observed in 7 patients (58%). The most common side effects were aphtae (7/7); 1 patient was hospitalized because of angina herpetica and pneumonia. In no case the Everolimus treatment had to be interrupted or withdrawn. Conclusions Everolimus seems to be effective and safe in treating TSC associated epilepsy in pediatric patients (even in cases prior refractory to AEDs).

Safety and retention rate of rufinamide in 300 patients: a single pediatric epilepsy center experience.

Reports of studies evaluating rufinamide as an add-on therapy in children and adolescents with refractory epilepsy are restricted to a few publications. Prospective multicenter studies including children and adults have yielded important information about several types of epilepsies and syndromes. We evaluated the use of rufinamide in a single pediatric center with a large cohort and long-term follow-up period. We retrospectively included patients taking rufinamide from November 2008 to March 2013. Response was defined by a seizure reduction of ≥50% compared to baseline. Three hundred patients with a median age of 9.1 years (range 0.4-29.6 years) were reviewed. Median follow-up was 9 months (range 1-37 months). Epilepsy etiology was classified as genetic (23.7%), structural/metabolic (41%), and unknown cause (35.3%). Overall, rufinamide treatment led to a median seizure frequency reduction of 59.2% from responders to baseline. Seizure reduction was greater in patients with genetic etiology compared to structural/metabolic (66.2% vs. 45.5% responders, p = 0.005). Rufinamide was discontinued in 110 (36.7%) of 300 patients: 63 (21%) due to unsatisfactory response, 47 (15.7%) due to side effects, and in 18 (6%) of those due to both. Most common adverse effects were sleepiness, vomiting, mood changes, nausea, and loss of appetite. Median time to loss of efficacy was 11.6 months (range 3-28 months). Rufinamide provides satisfactory seizure reduction as an adjunctive treatment in refractory epilepsy. Results need to be interpreted in the setting of data acquisition, including inherent biases of retrospective studies. Patients with a known genetic etiology may have better responses than patients with structural/metabolic etiology.

Long‐term efficacy and tolerability of topiramate as add‐on therapy in refractory partial epilepsy: An observational study

To evaluate the long-term efficacy and tolerability of topiramate (TPM) as add-on therapy in patients with refractory partial epilepsy. This is a retrospective, single-center, long-term observational study. Patients fulfilling the criteria of medical intractability proposed by Berg et al. were entered into the study if they were newly prescribed TPM as add-on therapy between January 2000 and June 2002. The usual starting dosage of TPM was 50 mg/day and optimal-dose adjustments were made according to individual clinical responses. Efficacy and tolerability were analyzed every year during 5-year follow-up in the "intention-to-treat (ITT) population." Retention rate was estimated by Kaplan-Meyer analysis. A total of 125 patients were included in the study and 107 patients (85.6%) were followed for 5 years. Retention rate was 87.2% at 1 year and 64% at 5 years. At the end of 5 years, the median seizure frequency reduction rate was 69.0% and responder rate was 43.2% in the ITT population. Cumulative seizure-free rate (SFR) was 30.4% and the terminal 1-year SFR was 12.8% in the ITT population (20.0% in completers) at 5-year follow-up. Adverse events (AEs) occurred in 39.2% of patients, including significant AEs leading to antiepileptic drug (AED) withdrawal in 14.4%. The most common AEs were anorexia (16.0%), weight loss (10.4%), and gastrointestinal symptoms (8.8%). Concomitant AEDs were reduced in 25.0% of the completers. Low-dose and slow-dose escalation of TPM in add-on therapy for patients with refractory partial epilepsy is effective and well tolerated in long-term, individualized clinical practice.

Lacosamide

Lacosamide is a new chemical entity being investigated as an adjunctive treatment for epilepsy, as well as monotherapy for diabetic neuropathic pain. Lacosamide appears to have a dual mode of action: selective enhancement of sodium channel inactivation and modulation of collapsin response mediator protein-2. Rapidly and completely absorbed after oral administration, lacosamide has an elimination half-life of approximately 13 hours and a low potential for drug interactions. Additionally, lacosamide exhibits linear, dose-proportional pharmacokinetics with low intra- and interpatient variability. Randomized controlled trials of adjunctive lacosamide (200, 400, and 600 mg/day) have demonstrated statistically significant reduction in median seizure frequency compared with placebo. In addition, 50% responder rates for lacosamide (400 and 600 mg/day) were statistically superior to placebo. The most frequently reported adverse events (> or =10% of lacosamide-treated patients) included dizziness, headache, and nausea. A double-blind, double-dummy randomized trial of intravenous lacosamide (30- and 60-minute infusion) as replacement for oral lacosamide showed that the safety and tolerability profiles were comparable for intravenous and oral lacosamide. The efficacy and safety results from completed clinical trials, as well as the favorable pharmacokinetic profile, suggest that lacosamide may represent a significant advance in antiepileptic drug therapy.

Zonisamide as adjunctive therapy for refractory partial seizures

Zonisamide (Zonegran ®) has been used extensively worldwide (>2 million patient-years experience) for the effective treatment of a broad range of epilepsy indications. Four randomised, placebo-controlled trials (duration ≤6 months) in the United States and Europe (848 patients in total) have shown doses of zonisamide ≥300 mg/day to be efficacious in treating refractory partial seizures in adults. In a pivotal European study, zonisamide 500 mg/day was significantly superior to placebo in reducing the frequency of complex partial seizures (−51% versus −16%), all partial seizures and all seizures, with dose-dependent benefit provided over a 100–500 mg/day dose range. Supporting trials have confirmed significant increases in reduction in median seizure frequency (up to 41%) and responder rates (35–42%) compared with placebo following zonisamide 400–600 mg/day, enabling 20–27% of patients to attain ≥75% reduction in seizure frequency. Pooled data from all four placebo-controlled trials demonstrate an excellent tolerability and safety profile; adverse events are generally of mild–moderate severity with few leading to discontinuation, and incidence of serious adverse events is comparable to placebo. These data support the use of zonisamide in combination with commonly used antiepileptic drugs to provide efficacious and well-tolerated treatment for patients with refractory partial seizures.

Vagus Nerve Stimulation Therapy after Failed Cranial Surgery for Intractable Epilepsy: Results from the Vagus Nerve Stimulation Therapy Patient Outcome Registry

To determine the effectiveness of vagus nerve stimulation (VNS) therapy among patients with persistent or recurrent seizures after lobar resection, callosotomy, and other cranial operations for intractable epilepsy. Data were obtained from the VNS therapy patient outcome registry, which was established after United States Food and Drug Administration approval of the VNS device in 1997 as a means of capturing open-label clinical data outside of protocol. The integrity of the systems for collecting and processing registry data was authenticated by an independent auditing agency. The effect of potential selection bias, however, remains uncertain. Two nonconsecutive cohorts were compared: patients tracked in the registry who had previously undergone cranial surgery for epilepsy (CS group, n = 921) and those who had not (non-CS group, n = 3822). For the CS group, the median reduction in seizure frequency was 42.5% after 3 months of VNS therapy, 42.9% at 6 months, 45.7% at 12 months, 52.0% at 18 months, and 50.5% at 24 months. For the non-CS group, analogous rates were 47.0%, 52.9%, 60.0%, 62.7%, and 66.7%, respectively. In the CS group, seizures were reduced by at least 50% in 55.1% of patients, at least 75% in 31.4% of patients, at least 90% in 17.3% of patients, and 100% in 5.1% of patients after 24 months of VNS therapy. Response rates were more pronounced in the non-CS group: at least 50% in 62.2% of patients, at least 75% in 43.7% of patients, at least 90% in 26.8% of patients, and 100% in 8.3% of patients. Patients in both groups experienced marked improvements in quality of life parameters. The effectiveness of VNS is maintained during prolonged stimulation, and overall seizure control continues to improve with time. Patients in whom prior cranial surgery had failed did not respond as favorably as all other patients receiving VNS therapy. Nonetheless, many of the former group improved substantially. Thus, on the basis of these open-label data, VNS therapy represents a potentially palliative treatment option for patients with refractory seizures after failed cranial surgery.

Vagus Nerve Stimulation Therapy for Patients with Persistent Seizures after Epilepsy Surgery

Background: This study reports the effectiveness of vagus nerve stimulation (VNS) among patients who failed cranial surgery for intractable epilepsy. Methods: Data were obtained from the Cyberonics VNS therapy patient outcome registry. The integrity of the systems for collecting and processing registry data was authenticated by an independent auditing agency. Results: Two nonconsecutive cohorts were compared: patients who had had prior cranial surgery (CS group, n = 921) and those who had not (non-CS group, n = 3,822). For the CS group, the median reduction in seizure frequency was 42.5% after 3 months of VNS therapy, 42.9% at 6 months, 45.7% at 12 months, 52.0% at 18 months and 50.5% at 24 months. For the non-CS group, analogous rates were 47.0, 52.9, 60.0, 62.7 and 66.7%, respectively. Conclusion: The effectiveness of VNS is maintained during prolonged stimulation. Patients who failed prior cranial surgery did not respond quite as favorably as all other patients receiving VNS therapy.

Effect of vagus nerve stimulation on adults with pharmacoresistant generalized epilepsy syndromes

Introduction: Although vagus nerve stimulation (VNS) therapy is approved for the treatment of partial onset seizures, its efficacy for generalized seizures has not been fully evaluated. This Investigational Device Exemption assessed the outcome of VNS therapy among patients with generalized epilepsy syndromes. Methods: Sixteen patients with pharmacoresistant generalized epilepsy syndromes and stable antiepileptic drug (AED) regimens were implanted with the VNS therapy device and were evaluated for changes in seizure frequency and type between baseline and follow-up of 12–21 months. Results: The patients experienced a statistically significant overall median seizure frequency reduction of 43.3% ( P=0.002, Wilcoxon signed rank test) after 12–21 months of VNS therapy. Types of seizures that may involve a fall or collapse decreased with reductions in the frequency of myoclonic (60% reduction, n=9; P=0.016, Wilcoxon signed rank test), tonic (75% reduction, n=8, NS), atonic (98.6%, n=3, NS), and clonic seizures (86.7%, n=1, NS). Conclusion: The benefits of reduced seizure frequency and reduced risk of injury merit consideration of VNS therapy for patients with pharmacoresistant generalized seizure syndromes.

Earlier use of adjunctive vagus nerve stimulation therapy for refractory epilepsy.

Recent studies suggest that epilepsy that is unresponsive to medical therapy is likely to be refractory from the onset. Identifying such patients early and treating them with nonpharmacologic therapies may improve their outcome. We hypothesized that patients who had adjunctive therapy with vagus nerve stimulation (VNS) earlier in the course of their epilepsy would have a better response compared with patients who had VNS therapy instituted later in the course. Patients in the VNS patient outcome registry who were more than 5 years post onset of their seizure disorder at implantation and had seizure frequency data available at both baseline and 3 months comprised the control group (n = 2785). These data were obtained retrospectively. Patients who were implanted between August 15, 2000 and July 31, 2001 who had epilepsy for 5 years or less at implantation or who had tried four or fewer standard antiepileptic drugs (AEDs) before implantation, and who were evaluated at baseline and at 3-month intervals for seizure frequency and quality of life, comprised the early adjunctive registry (EAR group; n = 120). This group was identified prospectively by participating physicians at multiple centers. The data describe patient demographics, medical history, seizure frequency, and physician-graded quality of life measures. The two populations were demographically similar except for statistically significant differences in age, duration of epilepsy, institutionalized patients, and seizure type (partial and generalized). Although the median reduction in seizure frequency for all patients at 3 months was similar between groups (48.2% control versus 50.0% EAR), 15.0% of the patients in the EAR group reported no seizures at 3 months compared with 4.4% of those in the control group (p < 0.001). In addition, significantly more patients in the EAR group (20% versus 8%; p < 0.001) reported no seizures with alteration or loss of consciousness, and 32% of EAR patients reported no complex partial seizures compared with 17% in the control group (p = 0.002). Improvements in all areas of quality of life were reported by both populations, but more patients in the EAR group were reported as "much better/better" for postictal state (p = 0.030) and seizure clustering (p = 0.002). Typically, 5% of patients report having no seizures after 3 months of VNS therapy. The proportion increased threefold, from 5% to 15%, for patients who received VNS therapy earlier in the treatment process. Patients reported even higher rates of no seizures when simple partial seizures were excluded from the analysis or when only complex partial seizures were considered. Although these results are preliminary, they offer promise of success in achieving seizure control among patients with refractory seizures who have been diagnosed with epilepsy for less than 5 years or who have tried four or fewer AEDs. We suggest future prospective studies evaluating VNS therapy versus best medical therapy after the first two to three AEDs have failed, which typically occurs within 2 years of seizure onset.

The effects of adjunctive topiramate therapy on seizure severity and health-related quality of life in patients with refractory epilepsy—a Canadian study

Although reduction in seizure frequency is the most common endpoint used to assess the antiepileptic efficacy, seizure frequency alone does not provide a complete picture of effectiveness, particularly in patients with refractory epilepsy. The aim of our study was to assess the effects of topiramate on seizure severity and health-related quality of life (HRQL), in addition to standard efficacy measures, in an open, multicentre, 6-month trial of patients with epilepsy uncontrolled on antiepileptic drugs other than topiramate. Two hundred and nine patients were enrolled and received topiramate for up to 6 months (initiated at 50 mg/day and titrated to a recommended dose of 200–400 mg/day) in addition to existing medication. The median reduction in seizure frequency from baseline to the post-titration period was 40.9% (P < 0.0001). Patients also demonstrated a mean reduction in the Liverpool Seizure Severity Scale (LSSS) of 5.3 ( P< 0.0001), which was considered clinically significant. Statistically significant changes in HRQL were not observed with the SF-36, a generic measure. Tolerability of antiepileptic medication was good, with a low incidence of cognitive adverse events. The results indicate that topiramate significantly reduces seizure severity—an important aspect of HRQL—when administered as adjunctive therapy to anticonvulsant therapy.

Use of topiramate in childhood generalized seizure disorders.

Topiramate is a sulfamate derivative of the naturally occurring monosaccharide D-fructose. It was initially approved in the United States as adjunctive therapy for partial seizures in 1997. However, there is increasing evidence that it is effective in the treatment of generalized seizures and epilepsy syndromes. Initially, open-label studies using topiramate as add-on therapy in children with refractory generalized seizure types were performed. These showed improvement in patients with the following generalized seizure types: typical and atypical absence, atonic, myoclonic, generalized tonic-clonic, and juvenile myoclonic epilepsy. Double-blind, placebo-controlled multicentered studies in patients with refractory primary generalized tonic-clonic seizures and epilepsy syndromes were performed. The median reduction in seizure frequency for primary generalized tonic-clonic seizures was 56.7% for topiramate and 9% for placebo. Additionally, 13.6% of topiramate-treated patients were primary generalized tonic-clonic seizure free for the study period. In the topiramate-treated juvenile myoclonic epilepsy patients, primary generalized tonic-clonic seizures were reduced > 50% in 73% of patients. Open-label extension showed that primary generalized tonic-clonic seizures were reduced >50% in 63% of topiramate-treated patients for > or = 6 months, and 16% were primary generalized tonic-clonic seizure free > or = 6 months. Accumulating evidence suggests that topiramate has a broad spectrum of antiepileptic effect. Moreover, life-threatening organ toxicity has not been attributed to topiramate. Topiramate is an effective treatment for refractory generalized seizure types and epilepsy syndromes encountered in children.

Topiramate (Topamax). Pharmacological characteristics and current use in epilepsy treatment

Topiramate (Topamax) has been registered since July 1998 and has market authorization for the Federal Republic of Germany as an additive drug for the treatment of patients (age 12 or older) suffering from intractable partial and secondarily generalized seizures. The anticonvulsant effect of topiramate is based on three mechanisms: (a) modulating the blocking of the Na channels activated by voltage, depending on status, (b) potentiation of GABAA-mediated inhibiting neurotransmission, and (c) inhibition of excitatory neurotransmission by blocking APMA glutamate receptors. Topiramate exhibits a substantial anticonvulsive effect on partial seizures both with and without secondary generalization. The median reduction in seizure frequency using topiramate as adjunct therapy was 44%. In 44% of patients, seizure frequency was reduced by more than 50%, and seizure reduction was more than 75% in nearly half of these (i.e., in 21% of all patients), while 5% of patients remained completely free of seizures. Adverse events most often caused central nervous disturbances. Weight loss, the development of renal calculi, and impairment of cognitive functions may occur. It is recommended to start therapy with topiramate at a daily dosage of 25 mg, increasing by 25 mg every week up to 200-400 mg/day but not exceeding 1000 mg/day.

Long-Term Multicenter Experience with Vagus Nerve Stimulation for Intractable Partial Seizures

Objective: Intermittent stimulation of the left cervical vagus nerve trunk (VNS) with the NeuroCybernetic Prosthesis (NCP) is emerging as a novel adjunct in the management of medically refractory epilepsy. We review the safety and efficacy of VNS 1 year after completion of the E05 study, the largest controlled clinical trial of VNS to date. Methods: One hundred and ninety-nine patients with intractable epilepsy and at least 6 complex partial or secondarily generalized seizures per month enrolled in a randomized, double-blinded, partial crossover trial of high versus low parameters of stimulation (E05). After 3 months, all patients received high stimulation during an open-label, nonblinded extension trial (XE5). Seizure frequency, adverse events and multiple physiologic variables were monitored at regular intervals. Results: At 3 months, the mean reduction in seizure frequency among patients receiving high stimulation during E05 was 28%. Of the 199 subjects participating in this acute-phase trial, 195 continued in the long-term protocol. Among the latter patients, 21 subsequently exited the study due to lack of efficacy, and 2 others died from causes unrelated to VNS. Complete data were obtained for 164 of the remaining subjects. Using a declining N analysis, the mean and median reduction in seizure frequency at 15 months was 37 and 45%, respectively. A last visit carried forward analysis, which controls for dropouts and incomplete follow-up, yielded comparable results (34 and 45%, respectively), indicating little potential for selection bias. At 15 months, 39% of the subjects had a greater than 50% reduction in seizures, including 21% who had a greater than 75% reduction, and 2% have remained seizure free. Few serious adverse events, physiological perturbation or device failures were reported. Conclusions: The long-term multicenter safety, efficacy, feasibility and tolerability of VNS, as well as the durability of the NCP device have been confirmed. Unlike chronic therapy with antiepileptic medication, the efficacy of VNS is maintained during prolonged stimulation, and overall seizure control continues to improve with time.

Left vagal nerve stimulation in children with medically refractory epilepsy

Objective: To assess the use of intermittent left vagal nerve stimulation in a large population of children with pharmacoresistant epilepsy. Study design: Sixty children who were entered into controlled or compassionate use protocols of left vagal nerve stimulation all had been monitored for at least 3 months after their left vagal nerve stimulators were activated. Results: The age range was 3½ to 18 years (median 15 years). Sixteen of these 60 patients were younger than 12 years. Fifty-seven percent of the patients had partial complex seizures, and generalized tonic clonic seizures occurred in 27%. After 3 months of intermittent stimulation of the left vagal nerve, a median reduction in seizure frequency of 23% occurred in 60 patients. At 6 months the median reduction was 31% in 55 patients, at 12 months 34% in 51 patients, and at 18 months 42% in 46 patients. Improvement was not associated with any seizure type or seizure cause. Adverse events during stimulation included fever, coughing, colds, and voice alteration. None of these necessitated cessation of stimulation. Complications included aspiration pneumonia and necrosis of skin overlying the generator. Conclusions: Intermittent stimulation of the left vagal nerve appears to be a safe, adjunctive therapy for the treatment of children with epilepsy intractable to available antiepileptic drugs. The reduction in seizure frequency in children was similar to that reported in adults. (J Pediatr 1999;134:563-6)

Rectal diazepam gel for treatment of acute repetitive seizures

The purpose of these investigations was to determine from combined data the response to rectal diazepam (DZP) gel (Diastat [Athena Neurosciences, South San Francisco, CA]) in home treatment of children with episodes of acute repetitive seizures (ARS). A subset of patients aged 2-17 years were selected from two prospective placebo-controlled studies of children and adults. In both studies a prospective, double-blind, placebo-controlled design was used. The treatment groups (68 DZP; 65 placebo) did not differ significantly in age, race, seizure type or etiology, or in the median number of ARS episodes per month before study entry. DZP-treated children demonstrated a significant reduction in median seizure frequency compared with the placebo group (0.00 vs 0.25 seizures per hour, P = 0.001). Significantly more DZP-treated children remained seizure free during the observation period (40 vs 20, P = 0.001). Somnolence was the only adverse effect present significantly more often in the DZP-treated children (25.0% vs 7.7%, P = 0.0095). There were no instances of serious respiratory depression. Rectal DZP was demonstrated to be an effective and safe treatment to abort an episode of ARS in a child and, additionally, lessened the likelihood of seizure recurrence within the next 12 hours.