Median Seizure Frequency Research Articles

Antiepileptic Drugs: All Ages

Antiepileptic Drugs: All Ages

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.

Immediate (overnight) switching from carbamazepine to oxcarbazepine monotherapy is equivalent to a progressive switch

This study compared immediate (overnight) and progressive switching to oxcarbazepine monotherapy in patients with partial seizures unsatisfactorily treated with carbamazepine monotherapy. Patients were randomised to either an overnight ( n=140) or a progressive switch ( n=146) from carbamazepine to oxcarbazepine monotherapy at a dose ratio of 1:1.5. The difference between the two switch groups in the mean monthly seizure frequency supported the equivalence of overnight and progressive switching (difference of 0.02 excluding outliers; 95% confidence interval (CI) −0.74, 0.78). Following the switch from carbamazepine to oxcarbazepine, there was a reduction in median monthly seizure frequency in both the overnight group (from 1.5 to 0; P=0.0005) and the progressive group (from 1.0 to 0.4; P=0.003). The proportion of seizure-free patients increased from 38 to 51% ( P=0.002) and 39 to 49% ( P=−0.01) in the overnight and progressive groups, respectively. In addition, the proportion of patients experiencing no clinically significant adverse events did not differ between the two switch methods (difference of 2.5; 95% CI −4.1, 9.0). For patients who are unsatisfactorily treated with carbamazepine monotherapy, overnight switch to oxcarbazepine monotherapy is as effective and well tolerated as a progressive switch, therefore allowing simple and flexible individualised treatment. Switching to oxcarbazepine monotherapy appears to be beneficial for patients who are unsatisfactorily treated with carbamazepine monotherapy, independently of the switch method used.

Vagal nerve stimulation in refractory epilepsy: the first 100 patients receiving vagal nerve stimulation at a pediatric epilepsy center.

To determine the outcome of intermittent left vagal nerve stimulation on the first 100 consecutive patients treated at our pediatric epilepsy center. Patients were identified by means of operating room records. Data collected described the patient's epilepsy, previous and subsequent therapies, adverse events, nonepileptic changes, and outcomes. Average age was 10.4 years; years of epilepsy, 8.5; total number of antiepileptic therapies, 8.4; and median monthly seizure frequency, 120. Data on seizure frequency at follow-up were available for 96 of the 100 patients. Forty-five percent of patients achieved greater than 50% reduction; and 18% had had no seizures for the last 6 months. Response was similar in patients with more than 7 years of refractory epilepsy as compared with patients with a shorter history. Magnet-generated, on-demand current reduced seizure intensity in almost half of the patients with available data. Generator infections occurred in 3 patients. Twenty-four patients had their generators removed. Subsequently, 2 of these patients died. Seizure reduction was the same in patients younger than 12 years and 12 years or older and in patients with shorter and longer histories of refractory epilepsy. Adverse effects were few in this population, particularly in those younger than 12 years. Vagal nerve stimulation appears to be a relatively safe and potentially effective treatment for children with severely intractable epilepsy.

The anticonvulsant effect of citalopram as an indirect evidence of serotonergic impairment in human epileptogenesis

Some evidence would indicate that a serotonergic deficit may be involved in epileptogenesis. A preliminary trial of citalopram, a selective inhibitor of serotonin reuptake, was carried out. Citalopram 20 mg/day was given to 11 non-depressed patients with poorly controlled epilepsy as an add on treatment with an open label design for 8–10 months. The median seizure frequency dropped by 55.6% in the whole group, with nine patients improving by at least 50%. No adverse reactions occurred with the exception of mild drowsiness. There were no changes of post-treatment as compared to pre-treatment AED serum concentrations. Although controlled studies are required to confirm the anticonvulsant effect of citalopram, these findings may be regarded as an indirect evidence of serotonergic impairment in human epileptogenesis.

An open-label study of levetiracetam at individualised doses between 1000 and 3000 mg day −1 in adult patients with refractory epilepsy

Background: The novel antiepileptic drug (AED) levetiracetam (LEV, Keppra ®) is indicated as adjunctive therapy for partial epilepsy. The primary aim of this study was to measure the safety and tolerability of LEV individualised dosing in a heterogeneous refractory epilepsy population. Methods: LEV was evaluated in a 10- to 16-week open-label, multicentre study in adult patients with epilepsy refractory to previous treatment with at least two AEDs. Individualised LEV doses up to 3000 mg day −1 were determined in an initial up-titration phase, and optimal doses were administered as adjunctive treatment during an 8- to 10-week evaluation period. Concomitant AEDs and their doses could not be changed during the study. Safety and tolerability were monitored by expression of adverse events as well as by retention rate. The effect of LEV on concomitant AED concentration was also studied. Efficacy was assessed using global clinical evaluation (GCE) scores, seizure frequency, and ≥50% responder rate. Results: LEV therapy was initiated in 219 patients; 183 had localisation-related epilepsy and 37 had generalised epilepsy. In one patient, epileptic syndrome was defined as both localisation-related and generalised. About 81.7% (179/219) continued and completed treatment throughout the study, and 79% (172/219) chose to continue LEV in a follow-up study. The most common adverse events were asthenia, dizziness, and somnolence. Most adverse events occurred during up-titration. LEV treatment did not alter the concentration of concomitant AEDs. LEV improved GCE scores in 79.5% (152/191) of patients. LEV reduced the median total seizure frequency of all patients from a median of 2.25 seizures per week at baseline ( n=219) to 1.10 seizures per week during the evaluation period ( n=191 patients with at least one seizure count during evaluation). The ≥50% responder rate was 48.2% for all seizure types, 49.4% for partial-onset, and 51.4% for generalised-onset seizures. Throughout the evaluation period (i.e. from the start of the evaluation period until completion or early discontinuation), 26/191 (13.6%) had a 100% reduction in total seizure frequency, while in a follow-up study, 10.5% (18/172) were seizure-free for at least 6 months and 6.4% (11/172) were seizure-free for at least 1 year. Conclusion: LEV was well tolerated, as evidenced by limited adverse event reporting and the high retention rate, and appeared effective in both generalised and partial epilepsy.

A placebo-controlled, double-blind cross-over trial of adjunctive one month remacemide hydrochloride treatment in patients with refractory epilepsy

The efficacy, safety and pharmacokinetics of adjunctive remacemide hydrochloride, a novel, low-affinity non-competitive NMDA receptor channel blocker, were investigated in 28 adult patients with refractory epilepsy. This was a randomized double-blind placebo-controlled cross-over study with five 4-week periods (baseline, treatment 1, washout, treatment 2, washout). Baseline median seizure frequency was reduced by 33% following adjunctive remacemide hydrochloride 150 mg q.i.d. for 4 weeks compared with placebo (P= 0.041). Seizure frequency was reduced by ≥50% in 30% of patients treated with remacemide hydrochloride compared with 9% on placebo. Mean plasma concentration of concomitant carbamazepine increased by approximately 15% following adjunctive remacemide hydrochloride. There was no correlation between increased plasma carbamazepine and reduced seizure frequency. Remacemide hydrochloride was well tolerated and only three patients withdrew due to adverse events (two remacemide hydrochloride, one placebo). Two patients died unexpectedly from their epilepsy during placebo treatment; both deaths were considered by the investigators to be unrelated to earlier remacemide hydrochloride treatment. This first specific efficacy investigation with adjunctive remacemide hydrochloride demonstrated anticonvulsant effects in patients with refractory epilepsy. More extensive clinical investigation is justified.

Efficacy and tolerability of 1000–4000 mg per day of levetiracetam as add-on therapy in patients with refractory epilepsy

The aim of this study was to determine the efficacy and tolerability of 1000–4000 mg/day of levetiracetam (LEV, Keppra™) as add-on treatment for refractory epilepsy. This was a dose-escalation study of 29 patients with refractory epilepsy. Patients received placebo for 4 weeks (baseline) followed by levetiracetam 1000 and 2000 mg per day each for 2 weeks, and then 3000 and 4000 mg per day each for 4 weeks. Primary efficacy was assessed by seizure frequency (number/week). Tolerability was assessed by adverse events, laboratory parameters, clinical evaluations, and electrocardiogram. All the study periods were completed by 27 of the 29 patients. A substantially lower median seizure frequency was observed at all levetiracetam dosing periods (1000 mg per day, 1.0 seizures per week; 2000 mg per day, 1.5 seizures per week; 3000 mg per day, 1.0 seizures per week; 4000 mg per day, 0.75 seizures per week) compared with the placebo treatment (2.06 seizures per week). In addition, 22–33% of these patients were seizure free during treatment with levetiracetam compared with only 14% with placebo. Levetiracetam was well tolerated. The most common adverse events were somnolence and asthenia; frequency and severity increased with increasing doses of levetiracetam. Levetiracetam in doses from 1000 to 4000 mg per day is effective. Somnolence and asthenia were more frequent with the highest dose, suggesting that 4000 mg per day may be the upper limit in some patients, although individual susceptibility to somnolence was variable.

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.

Psychosocial and economic problems of parents of children with epilepsy

The parents of children with epilepsy (PCE) face multiple psychosocial and economic problems that are often neglected. We undertook this study to ascertain these problems among the patients attending a tertiary referral center for epilepsy in India. A structured questionnaire was administrated to parents of 50 children aged between 5–10 years and having epilepsy for more than 1 year's duration. Some 52% of the children had partial epilepsy whilst the remaining had generalized epilepsy. The median seizure frequency was one per 6 months. The majority of the patients (86%) were living in villages. The family income was less than 1000 Rs per month (1 USD = 42 INR) for 66% of the patients. A decline in social activities, after the onset of epilepsy in their children, was reported by 80% of the parents. Daily routines were significantly affected in over 75% of the parents. Parents had been experiencing frustration (52%) and hopelessness (76%), whilst 60% were in financial difficulties. The most important item of expenditure was cost of drugs or cost of travel to hospital for 54% and 36% parents respectively. Impaired emotional status and poor social adaptation were co-related with the severity of epilepsy (frequent seizures/generalized seizures/attention disorder) and low economic status of the parents. These observations need to be borne in mind while organizing rehabilitation programs for epilepsy.

Gabapentin add-on therapy with adaptable dosages in 610 patients with partial epilepsy: an open, observational study

The objectives were to evaluate gabapentin add-on therapy in a large population under conditions close to real practice and to determine the therapeutic doses as reached with adaptable dosages. A 6-month multicentre, open-label study, involved addition of gabapentin to pre-existing treatment at the initial dosage of 1200 mg and subsequent adjustment between 900 and 2400 mg/day according to efficacy and tolerability. A study group of 610 adult patients, with partial epilepsy, persistent seizures and a median seizure frequency with a baseline of 7.2 per month were recruited; one-third had less than four seizures per month. Polypharmacy was frequent, with a mean of 2.3 concomitant drugs. After 6 months, 368 patients (62%) continued on gabapentin, at a mean dosage of 1739 mg/day with 44% of responders. On an intention-to-treat basis, median reduction in frequency was 21.2%, and the responder rate was 33.9%. The responder rate increased to 40.7% in the less severe subgroup receiving only one concomitant drug. Seventy-nine patients (13.4%) remained without seizures during the last evaluation period, versus nine (1.5%) during the baseline. Most of them had initially less than four seizures per month. The most frequent adverse effects, somnolence (29.3%), asthenia (14.6%), nausea (7.9%), ataxia (7.7%) and vertigo (7.2%), occurred rapidly after initial titration to 1200 mg/day, and were usually transitory. Weight gain (8.8%) seemed to be related to gabapentin dose. The combination of two recent drugs, vigabatrin and gabapentin, in 190 patients led to similar efficacy levels, with a tendency for more frequent somnolence and asthenia.

Gabapentin and cognition: a double blind, dose ranging, placebo controlled study in refractory epilepsy.

OBJECTIVE: To assess the effect of different doses of gabapentin (GBP) on cognitive function in treated epileptic patients. METHODS: Twenty seven patients with refractory partial seizures commenced a double blind,...

Combination vigabatrin and lamotrigine therapy for intractable epilepsy

Vigabatrin (GVG) and lamotrigine (LTG) are new antiepileptic drugs (AEDs) individually effective as add-on therapy for refractory seizures. The efficacy of GVG and LTG in combination was evaluated in a prospective audit of 42 patients with intractable epilepsy. There was a statistically significant median reduction of 62% (P < 0.025) from a median baseline monthly seizure frequency (MSF) of 29 (mean 59, 95% CI 22, 96) to a median MSF of 11 (mean 23, 95% CI 8, 38) during a median treatment period of eight months, with a greater than 50% reduction in MSF in 29 patients (69%) treated with the add-on combination of GVG and LTG. The additional MSF reduction achieved by the combination amounted to 21% (18% when GVG was added to LTG and 24% when LTG was added to GVG). The median trough plasma lamotrigine concentration was 9.9 mg/l (range 3.4-19.6 mg/l). The average daily dose of LTG was 517 mg (range, 175-800 mg) and GVG 2400 mg (range, 1500-3500 mg). Adverse events requiring alteration of therapy occurred in 24 patients (57%) with a drop-out rate of 12%. The combination of GVG and LTG should be considered as a therapeutic option in patients with intractable epilepsy. The results of the present study support the need to confirm additive efficacy of GVG and LTG by conducting controlled trials of this combination therapy.

Psychogenic seizures in children: long-term analysis of 43 cases.

Forty-three patients exhibiting psychogenic seizures with onset before the age of 16 years were studied. All patients underwent intensive electroencephalography and video-electroencephalography monitoring. Thirty-two were female and 11 male. Mean age of the population at seizure onset was 12.4 years (range, 5 to 16 years). Twenty-one patients (48.8%) were taking anticonvulsants. Neurologic past history was abnormal in nine cases. Family history of epilepsy was found in 15 cases (34.9%). Median seizure frequency was one seizure every 5 days. Clinical characteristics of the seizures varied. However, unresponsiveness with generalized violent and uncoordinated movements involving the whole body (n = 19) or with generalized trembling (n = 11) were the most common features. Neuropsychological testing, carried out in 22 cases, failed to show major abnormalities in most of the cases. Significant personal and family distress was found in most of the cases. An important impact on patient's quality of life was evident when the seizures were present as compared to the seizure-free periods. There were no statistically significant predictors of clinical outcome.

Effects of vigabatrin on partial seizures and cognitive function.

Forty five patients with refractory partial seizures were studied in a prospective, randomised, placebo controlled, add on, parallel group, double blind trial of the new antiepileptic drug vigabatrin (1.5 g twice daily) followed by open treatment. Seizure frequency was monitored throughout an eight week baseline, 20 weeks double blind, and up to 18 months of open vigabatrin treatment. Cognitive function, including measures of memory and concentration, mood, and behaviour were assessed at baseline and again during the 20th week of treatment. Vigabatrin was associated with a significant reduction in a measure of motor speed and overall score on a design learning test in the first 20 weeks of treatment. In comparison with the baseline period, vigabatrin treatment was associated with a significant reduction in median complex partial seizure frequency four to 12 and 12 to 20 weeks after commencing vigabatrin (-66% and -69% in the vigabatrin group, +50% and +25% in the placebo group). Ten of 20 patients on vigabatrin and four of 23 on placebo showed a > 50% reduction in complex partial seizure frequency in the last eight weeks of double blind treatment. At least 60% of responders had maintained the response to vigabatrin when assessed during the open phase of the trial at 44 weeks. Two patients discontinued vigabatrin because of depression, which resolved on drug withdrawal.

Lamotrigine in Resistant Childhood Epilepsy

Fourteen children (6 M, 8 F) suffering from refractory epilepsy received LTG as add-on therapy. LTG was administered twice daily at dosages increasing up to 2 mg/kg/day (for patients taking VPA) or to 10 mg/kg/day for patients taking AEDs that induce hepatic metabolism. The drug was withdrawn for side effects in 3 cases (rash: two cases, hirsutism: one), because of increased seizure frequency in 2 cases and because of unchanged seizure frequency in one. One patient died from acute respiratory failure, after repeated respiratory tract infections. A decrease in seizure frequency after one year of treatment with LTG was observed in 6 of the 7 patients who completed the study. The median total seizure frequency decreased from 10.7 +/- 7.3 to 3.8 +/- 4.6 seizures per day. At the end of the study, seizure frequency had decreased by more than 50% in 2 patients, by more than 75% in 2 patients, and 2 patients were seizure-free; in the remaining patient seizure frequency was unchanged. The best results were obtained with plasma LTG concentrations ranging from 0.5 to 5.4 micrograms/ml; no further improvement was observed at higher LTG concentrations.

Identification of states of consciousness from trancendencies in EEG

Perampanel (PER) was first licensed in the United Kingdom in 2012 for the adjunctive treatment of focal seizures with or without secondary generalization in adults and children over 12 years of age. It has recently also been approved for use as add-on therapy for patients with primary generalized tonic–clonic seizures. This prospective audit reports preliminary outcomes with adjunctive PER in patients with focal-onset seizures in everyday clinical practice using a standard design.To date, 54 patients (38 males, 16 females; 21–65 years, median: 48 years) have completed the study. The median monthly seizure frequency was 4 (range: 1–60). At baseline, patients were taking a median of 2 other antiepileptic drugs (range: 1–4 drugs), with their seizures having previously failed to improve on a median of 3 schedules (range: 1–15 schedules). After 12 weeks of stable dosing, PER was added, aiming at a target range of 6–12 mg/daily. Review took place every 6–8 weeks until one of 4 endpoints was reached: seizure freedom for ≥ 6 months on a given PER dose, ≥ 50% (responder) or < 50% (marginal effect) seizure reduction over 6 months, compared with the prospective baseline, on the highest tolerated PER dose, or withdrawal of PER due to a lack of efficacy or side effects.Three (5.6%) patients have remained seizure-free, with 8 (14.8%) demonstrating a ≥ 50% response and a further 17 (31.5%) reporting a marginal effect. Of the 26 (48.1%) dropping out of PER treatment, 21 (38.9%) did so because of side effects. The commonest problems were nausea, vomiting, ataxia, dizziness, and sedation. Overall, 6 (11%) patients developed neuropsychiatric problems, with 3 reporting irritability and/or aggression. Two patients had substantial weight gain, and another patient suffered recurrent falls. Treatment with enzyme-inducing AEDs had no effect on PER dosing in patients responding to PER or withdrawing due to side effects.These data support the value of adjunctive PER in some patients with pharmacoresistant epilepsy in everyday clinical practice.

Therapeutic drug monitoring improves seizure control and reduces anticonvulsant side-effects in patients with refractory epilepsy

The benefit to patients of an on-site antiepileptic drug monitoring service, in which physicians' decisions were recorded before and after the concentration became available, have been assessed retrospectively. In 109 patients with refractory epilepsy monitored on three ( n = 61) or four ( n = 48) occasions between 1986 and 1990, one or more assay result was rated as ‘unexpected’ by the consulting doctor. In 51 of these, revision of the dose was undertaken as a consequence (active group). Their clinical outcomes were compared with those of the other 54 patients in whom the initial management plan was left unchanged (passive group). Median seizure frequency decreased in both groups, but this was statistically significant only for the actively treated patients [active group: first visit 1 (0 to 26) seizures/month, last visit 0 (0 to 19) seizures/month, P < 0.01, 95% CI −2 to −0.5; passive group: first visit 2.5 (0 to 57) seizures/month, last visit 1.5 (0 to 44) seizures/month, NS, 95% CI −1 to +10]. The number of patients reporting one or more episodes of drug-related toxicity also favoured the actively managed patients (active group 25%, passive group 56%, P < 0.01). Within this selected group of patients, the anticonvulsant concentration was a better guide to clinical management than the physician's assessment.

Vigabatrin in drug‐resistant partial epilepsy

We treated 75 patients with drug-resistant complex partial seizures and secondarily generalized seizures with vigabatrin as additional therapy for 6 months. Twenty-one patients either showed no benefit from vigabatrin treatment or had side effects. The remaining 54 patients entered into the long-term study. The median monthly seizure frequency decreased from 12.5 at baseline to 3.3 at the 3-month visit, and was 3.9 after 5 years of therapy in 28 patients who continued using the drug after the 5-year period. During 5 years of therapy with vigabatrin, 26 patients have withdrawn from the study because of various reasons: loss of efficacy (14), suspected side effects (5), noncompliance (3), administrative reasons (2), pregnancy (1), and epilepsy surgery (1). In all, 19 patients had a greater than 50% seizure frequency reduction at 5 years, representing 35% of the 54 patients who entered the long-term study, or 25% of the 75 patients who were initially recruited into the efficacy study.

Progressive relaxation for seizure reduction

It is widely accepted that stress and other environmental factors often trigger seizures in people with epilepsy. It is thus reasonable to hypothesize that behavioral approaches could minimize stress and improve seizure control, yet there have been very few controlled studies of this hypothesis and none that has involved long-term follow-up. To implement such a study, we involved 12 people with epilepsy in a training program for progressive relaxation therapy (PRT). Baseline seizure frequency of 8 weeks was compared to three 8-week follow-up periods. Median seizure frequency for the group decreased 21% after the first follow-up interval, from 19.5 to 15.5 (p = 0.07) and 54% after the third and final follow-up interval, from 19.5 to 9.0 (p = 0.02). This study also tried to answer two methodological questions. First, is it possible to abbreviate the most common protocol for PRT so that only three training sessions are required instead of 107 Second, is it possible that comparative newcomers to this field can become effective trainers? Both of these questions were answered in the affirmative by this study, although it is acknowledged that much more work needs to be done in these areas.