Seizure Reduction Rate Research Articles

Evaluation of Open-Label Topiramate as Primary or Adjunctive Therapy in Infantile Spasms

A multicenter open-label clinical trial was conducted to evaluate the clinical usefulness of topiramate (TPM) as primary or adjunctive therapy for infantile spasms in the postmarketing period in China. Thirty-four centers participated in the trial. Patients included in the study had 1 or more seizures per day before treatment. One hundred twenty (22.1%) very young patients with an age younger than 6 month and 64.2% of patients were younger than 1 year at start of treatment. All patients received a starting dose of 0.5 to 1 mg kg d TPM twice daily. The dosage was increased by 0.5 to 1 mg kg d every 5 to 7 days up to 3 to 5 mg kg d. The resulting range of the total TPM dosage was 25 to 200 mg d (3.57-20 mg kg d), with a median value of 73.9 mg d. Seizure outcomes were measured by intention-to-treat analysis. Patients were seen by a neurologist, and their data were evaluated at the day of inclusion and after 4, 8, 12, 16, and 20 weeks (from visit 1 to visit 5) of treatment. Five hundred forty-four patients entered the study. After 20 weeks of TPM treatment, 239 patients (43.9%) were seizure-free. A higher proportion of patients in the monotherapy group than in the add-on therapy group showed a seizure rate reduction. An increase in seizure frequency was observed in 8 patients (1.5%) during the 20-week treatment period. Nineteen patients were withdrawn before completing the study, and in 46 cases, some data of the structured data files and questionnaires were missing. No efficacy of TPM treatment was recorded in these cases. Adverse effects occurred in 211 patients (38.8%). Most frequent side effects were anorexia and somnolence. Topiramate proved to be an effective and safe monotherapy and add-on therapy in patients with infantile spasms younger than 1 year.

Vagus Nerve Stimulation in Intractable Childhood Epilepsy: a Korean Multicenter Experience

We evaluated the long-term outcome of vagus nerve stimulation (VNS) in 28 children with refractory epilepsy. Of these 28 children, 15 (53.6%) showed a >50% reduction in seizure frequency and 9 (32.1%) had a >75% reduction. When we compared seizure reduction rates according to seizure types (generalized vs. partial) and etiologies (symptomatic vs. cryptogenic), we found no significant differences. In addition, there was no correlation between the length of the stimulation period and treatment effect. The seizure reduction rate, however, tended to be inversely related to the seizure duration before VNS implantation and age at the time of VNS therapy. VNS also improved quality of life in this group of patients, including improved memory in 9 (32.1%), improved mood in 12 (42.9%), improved behavior in 11 (39.3%), improved altertness in 12 (42.9%), improved achievement in 6 (21.4%), and improved verbal skills in 8 (28.6%). Adverse events included hoarseness in 7 patients, dyspnea at sleep in 2 patients, and wound infection in 1 patient, but all were transient and successfully managed by careful follow-up and adjustment of parameters. These results indicate that VNS is a safe and effective alternative therapy for pediatric refractory epilepsy, without significant adverse events.

Evaluation of quality of life and clinical status of children operated on for intractable epilepsy

The aim of the study was evaluation of surgical treatment of epilepsy measured by changes in quality of life (QOL) and in seizure frequency and severity. Examined group consists of 24 boys and 9 girls. We performed corpus callosotomy, lesionectomy, vagal nerve stimulation, temporal lobectomy and multiple subpial transections. Age at surgery ranged from 5 months to 19 years, with mean follow-up of 11.9 months. QOL was evaluated on the basis of the questionnaire created by us, in which parents were asked to assess the following variables before and after the surgical procedure: communication, socialization, daily living skills, movement abilities and behavioural problems. The seizure frequency was assessed with the Engel's scale, the modified Engel's scale and the Seizure Scoring System. Clinical state of all the patients was evaluated as well. There were no patients with stable and worsening QOL status. In the whole group treated with callosotomy, the considerable improvement in QOL concerned 36.4% of cases. In more than 95% of cases, the reduction in seizures frequency is greater than 75%. In more than 43% of patients, there are no seizures after surgery. Surgical treatment of intractable epilepsy is an effective method in terms of both seizure control and QOL improvement. Our results indicate the improvement in QOL of all operated patients. The improvement in QOL was accompanied by decrease in frequency and 'positive' changes in morphology of seizures. Improvement in QOL, as equivalent to seizure reduction rate, may influence further differentiation of qualification methods and surgical procedures of epilepsy.

Topiramate for the Treatment of Infantile Spasms

Topiramate is a new antiepileptic drug with a broad spectrum of efficacy. Reports on the use of topiramate for treatment of infantile spasms are limited. We prospectively followed 15 children with recently diagnosed infantile spasms treated with topiramate for efficacy and tolerability. Twelve patients had symptomatic infantile spasms, and two patients had cryptogenic infantile spasms. Topiramate was started at a dose of 3 mg/kg/day and titrated up to a dose of 27 mg/kg/day in 2 to 3 weeks. The primary efficacy measure was comparison of the seizure rate during the 2-week baseline with the median seizure rate during the first 2 months of treatment with topiramate. We also compared baseline electroencephalograms (EEGs) with post-treatment EEGs. The median seizure rate reduction during the first 2 months of treatment was 41% (P = .002). Three patients became spasm free (20%), five had > 50% reduction, and three had at least 25% reduction. Four patients did not respond. Three of 15 patients had clearing of hypsarrhythmia. Topiramate was generally well tolerated, with irritability being the most common side effect. Topiramate was efficacious and well tolerated; one patient discontinued the medication because of adverse effects. (J Child Neurol 2006;21:17-19).

Fasting versus Gradual Initiation of the Ketogenic Diet: A Prospective, Randomized Clinical Trial of Efficacy

The ketogenic diet (KD) is a 90% fat diet that is an effective treatment for intractable epilepsy. Rapid initiation of the KD requires hospital admission because of the complexity of the protocol and frequent mild and moderate adverse events. The purpose of the study was to compare the efficacy of a gradual KD initiation with the standard KD initiation preceded by a 24- to 48-h fast. Children ages 1 to 14 years with intractable epilepsy were randomized to a fasting initiation (FAST-KD) or gradual initiation (GRAD-KD). Baseline seizure activity was recorded daily for 28 days before admission and continued for the 3-month duration of the study. Effectiveness was measured in two ways: (a) the proportion of subjects with >50% reduction in target seizure type from baseline to 3-month evaluation, and (b) percentage reduction in the frequency of the target seizure type from baseline to 3-month evaluation. Blood glucose was assessed q4 to 6h, and weights, electrolytes, hydration status, vomiting, acid balance, need for interventions (citric acid and sodium citrates (Bicitra) and IV fluids) were assessed daily. Fisher's exact tests were used to examine the association between protocol and occurrence of adverse events, and longitudinal mixed-effects models were used to look for trends in tolerability data over time. Forty-eight subjects, 24 in each arm, were randomized. In the FAST-KD protocol, 58% of the children had >50% reduction in the target seizure type at 3 months, and 21% were seizure free. In the GRAD-KD protocol, 67% had a >50% reduction at 3 months, and 21% were seizure free. The two protocols were equivalent in efficacy (p = 0.033). At 3 months, the FAST-KD median percentage seizure reduction rate was 78% (ranging from 100% reduction to 73% increase in seizures per week) and was 94% (ranging from 100% reduction to 161% increase in seizures per week) for the GRAD-KD protocol. By using a logarithmic transformed percentage reduction rate and an equivalence limit difference of 20%, the efficacy of the two protocols was equivalent (p = 0.0002). Children in the GRAD protocol lost significantly less weight (p = 0.006), and had fewer and less-severe episodes of hypoglycemia (p < 0.001), fewer treatments for acidosis (citric acid and sodium citrates) (p < 0.04) and dehydration (IV fluids) (p < 0.04), but no difference in vomiting was noted. These data suggest that in children with intractable epilepsy, a gradual initiation results in fewer adverse events and is tolerated better overall while maintaining the efficacy of the KD.

Clinical Epilepsy: Adult

Clinical Epilepsy: Adult

Vagus nerve stimulation in pharmacoresistant epilepsy of childhood and adolescence

Since five years the vagus nerve stimulation therapy (VNS) is used in Germany, Austria and Switzerland for the treatment of pharmacoresistant epilepsy of childhood and adolescence. About 300 children were implanted with the VNS device, nearly 200 patients were followed using an open, not randomized, prospective protocol up to 24 months. Mainly mentally retarded children with a psychomotor retardation suffering from a catasrophic epilepsy are candidates for the VNS, if epilepsy surgery is not possible. It was shown, that 50 percent of these patients improved with this adjunctive, palliative and non pharmacological, antiepileptic therapy in terms of at least 50% seizure reduction. Less than 6% of patients became seizure free. Subgroups with Lennox-Gastaut syndrome and patients with previous unsuccessful epilepsy surgery presented with similar seizure reduction rates as the entire cohort. Patients with an early onset of epilepsy before the age of 12 months seemed to benefit more often compared to patients with later seizure onset. Also patients without significant seizure reduction showed improvements of quality of life concerning vigilance and mood. Recent EEG findings revealed differences in responders versus nonresponders concerning frequencies of the delta, alpha and beta band as well as very slow cortical potentials.

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.

Nitrazepam for the treatment oflennox-gastaut syndrome

Lennox-Gastaut syndrome is a severe childhood epileptic syndrome with encephalopathy and multiple seizure types, which are often intractable to treatment. Most of these children will ultimately become mentally retarded and dependent on others for their daily care. Antiepileptic drugs are the mainstay of treatment, however, no particular drug is entirely effective. Apart from the use of antiepileptic drugs, nonpharmacologic treatments are also considered (i.e., callosotomy, ketogenic diet, and vagus nerve stimulation), which have proven to be partially effective. We prospectively studied 14 children (11 months-8 years of age) with medication-resistant Lennox-Gastaut syndrome, being treated with nitrazepam (open-label compassionate protocol). We compared the 1-month baseline seizure frequency with the median seizure rate reduction during the first 12 months of treatment with nitrazepam. The median seizure rate reduction during the first 12 months of treatment with nitrazepam was 41% ( P = 0.001), with more than 50% seizure reduction in 60% of patients. Two patients became seizure free, five patients demonstrated at least 50% reduction in seizure rates, six patients had at least 25% seizure rate reduction, and one patient did not respond. No patient had any serious adverse effects. Side effects included sedation in six children (40%) and drooling in nine patients (60%).

Antiepileptic drug treatment in the developmentally disabled: treatment considerations with the newer antiepileptic drugs

Epilepsy is a common comorbidity among developmentally disabled (DD) patients, and special considerations apply to its treatment. In particular, clinicians should try to avoid antiepileptic drugs (AEDs) with sedating properties or adverse cognitive effects that might further diminish quality of life for DD patients. Behavioral changes due to medication and significant pharmacokinetic interactions with other medications are also concerns. The newer AEDs, approved in the 1990s, offer new options for the treatment of individuals with developmental disability and epilepsy. Gabapentin does not interact with the hepatic metabolism of other AEDs or psychotropic agents, results in a statistically significant reduction in seizure frequency in mentally retarded children, and is generally well tolerated. Felbamate is an effective broad-spectrum AED, but has serious toxicity issues limiting its use. Lamotrigine has been extensively studied in the DD population, achieving seizure reduction rates of up to 50% in some trials. Although it is usually well tolerated in this population, its pharmacokinetic profile is influenced by concomitant medications. Levetiracetam has been found to be effective against kindled seizures and has been approved as adjunctive therapy for partial epilepsies. It does not cause any pharmacokinetic interactions, but may have behavioral side effects. Oxcarbazepine is a homologue of carbamazepine that has fewer drug interactions. It is approved for mono- or adjunctive therapy in patients with partial seizures, and its use in DD individuals appears to be worthwhile. Tiagabine is extensively bound to plasma proteins and is therefore subject to protein-binding displacement interactions by other highly protein-bound drugs, such as sodium valproate. While there are trial data showing its efficacy as adjunctive therapy in partial epilepsy in adults and children, there is a paucity of data specific to the DD population. Common side effects include sedation. Topiramate is a broad-spectrum AED approved as adjunctive therapy for partial and primary generalized tonic–clonic seizures. It appears to be particularly effective in patients with Lennox–Gastaut syndrome and those with cognitive disabilities. It appears to be better tolerated in the DD population than in the general population. Zonisamide has been effective in the DD population, yielding a seizure reduction of 50% in 41% of children in 1 trial. It has been associated with renal stone formation, sedation, and cognitive effects, however. The new AEDs have a role in treating seizures in the DD. Side effects that limit their use include anorexia, behavioral changes, and sedation. Seizure exacerbation can occur with the new AEDs and success is defined empirically and by improvements in quality of life.

Tiagabine (gabitril) experience in children.

Tiagabine (TGB) is indicated as adjunctive therapy for partial seizures in adults and children aged 12 years and older. Double-blind, placebo-controlled studies of TGB treatment are under way in younger children with various forms of epilepsy. The results of pediatric pharmacokinetic trials indicate patterns similar to those seen in adults. An open-label study was conducted in the United States in 31 children with refractory complex partial seizures, with doses escalated every 2 weeks by 0.25 mg/kg up to a maximal daily dose of 1 mg/kg. Twenty-nine patients were treated with TGB for >1 year; 26 completed the study, of whom 18 were receiving monotherapy at study completion. A European dose-escalation study evaluated TGB (0.25-1.5 mg/kg/day) as add-on therapy in 52 children aged 2-15 years. TGB appeared to be more effective in localization-related epilepsy syndromes, with 17 of 23 patients with localization-related epilepsy having a 33% median reduction of seizure rate compared with baseline in the fourth month of treatment, and six patients having > or =50% seizure rate reduction. In this study, myoclonic seizures and spasms showed a poor response as opposed to encouraging findings reported by other groups with these seizure types. The adverse effect profile of TGB in children with epilepsy is similar to that in adults. In the U.S. study, most common adverse events were related to the central nervous system (CNS) and decreased over time. In the European study, mostly mild to moderate adverse events, including asthenia (19%), nervousness (19%), dizziness (17%), and somnolence (17%), were reported by 83% of TGB-treated children (39% of children reported adverse events during the single-blind placebo period). In summary, preliminary pediatric data with TGB suggest particular efficacy against epilepsy characterized by partial seizures or other syndromes, and further investigation is warranted.

Topiramate: a review of its use in childhood epilepsy.

Topiramate is an antiepileptic drug (AED) which appears to have a broad range of antiseizure activity in humans. A previous overview focused primarily on results of trials of topiramate in adults with epilepsy, and this review highlights the use of topiramate in children. Clinical trials have shown that topiramate is effective when used adjunctively in children with refractory partial-onset seizures and generalised tonic-clonic seizures. The drug significantly reduced seizure frequency compared with placebo in children with partial-onset epilepsy after 16 weeks of double-blind adjunctive treatment (33.1 vs 10.5%); the frequency of secondarily generalised seizures was also markedly reduced. During a nonblind extension of this trial, the mean dosage was titrated from 4.8 to 9 mg/kg/day and further reductions in the frequency of seizures were observed (71% compared with prestudy levels). In 2 mixed adult/paediatric populations with primary generalised tonic-clonic seizures, topiramate (target dosage 5.2 to 9.3 mg/kg/day) reduced the seizure rate compared with those receiving placebo. This difference was significant in one trial (56.7 vs 9%) but not in another (57.1 vs 33.2%). A subanalysis of the paediatric patients found that the favourable effect of topiramate on seizure rates was not age-related. Topiramate (median average dosage 5.1 mg/kg/day) was also found to be useful as adjunctive therapy in the management of Lennox-Gastaut syndrome and significantly reduced the mean frequency of drop attacks by 14.8% compared with an increase of 5.1% with placebo. Further gains in seizure control were made in a nonblind extension of this trial where the mean topiramate dosage was 10 mg/kg/day. Nine of 11 patients in 1 pilot trial of children with otherwise intractable West syndrome, and 5 of 10 in another, achieved a > or =50% reduction in seizure rate with topiramate (target dosage up to 24 mg/kg/day). In an 18-month extension of the former trial (mean dosage 29 mg/kg/day) a > or =50% reduction in seizures was maintained in 7 of 11 children. Adverse events associated with adjunctive topiramate therapy in children were predominantly neuropsychiatric and generally mild to moderate in severity. Behavioural and cognitive problems do occur and are a limiting factor in some children. Also, weight loss can be problematical in some individuals. Withdrawal rates were low in the controlled trials (4.8%), but appear to be more frequent in noncomparative and post-marketing studies. Well controlled studies have demonstrated that topiramate is an effective agent for the adjunctive therapy of partial and generalised tonic-clonic seizures in children. Treatment-limiting adverse events do occur, but these may be managed by slow titration. Although comparative studies with the other newer AEDs used in adjuntive therapy are required, topiramate is an important extension to the range of drugs that may be used to treat refractory epilepsy in children.

Sensorimotor rhythm feedback training and epilepsy: Some methodological and conceptual issues

This study examined the hypothesis that the enhancement of a 12–16 Hz sensorimotor rhythm in the EEG is inhibitory to epileptic seizure activity. The effects of training to enhance 12–16 Hz central EEG, to enhance 8–10 Hz central EEG, to suppress high voltage EEG activity, and of random feedback were compared over a period of 12 months in three adult patients suffering from chronic, drug-refractory epilepsy. All three patients experienced a significant reduction in seizure rate by the end of the study, but this was not related to any one particular training condition. It is suggested that the therapeutic mechanism might involve placebo effects, relaxation training, or a facilitation of EEG desynchronization, the effect being idiosyncratic to the individual patient.