Effects of levetiracetam on seizure frequency and neuropsychological impairments in children with refractory epilepsy with secondary bilateral synchrony

PurposeIn epilepsy with continuous spikes and waves during slow sleep (CSWS), which is a representative epileptic syndrome of secondary bilateral synchrony (SBS), the urgent suppression of this electroencephalographic (EEG) abnormality may be necessary to prevent the progression of neuropsychological impairments. The purpose of this study was to determine the efficacy of levetiracetam (LEV) on SBS, seizure frequency, and neuropsychological impairments in children with refractory epilepsy.MethodsEleven (seven male and four female) patients with refractory epilepsy with SBS on EEG, aged between 4.7 years and 11.3 years, were included in this study. After a 3-month baseline period, the patients were given LEV at an initial dose of 10 mg/kg/day for the first week, followed at increments of 5 mg/kg/day every week, up to 20 mg/kg/day. The LEV dose was then adjusted up to a maximum of 60 mg/kg/day, according to the clinician's judgment. EEG recordings and clinical evaluations were performed every 3 months, focusing on SBS. The occurrence of SBS was then scored, and the relationship between the score and the response to LEV treatment was evaluated. In comparison with the baseline SBS frequency, the EEG response to LEV treatment was classified, and responders were identified as having a ≥50% reduction in SBS frequency. In addition, in comparison with the baseline seizure frequency, response to LEV treatment was classified. Responders were identified as patients with complete cessation (100% seizure control) and a response of ≥50% reduction in seizures. Furthermore, neuropsychological impairments such as hyperactivity, impulsiveness, and inattention were evaluated before and after LEV treatment.ResultsEight patients (72.7%) were considered responders. In addition, all eight patients were also considered responders for clinical seizures. Furthermore, 7 of 8 (87.5%) patients with response showed decreased hyperactivity and impulsivity after LEV administration.ConclusionsThe present data clearly indicate the usefulness of LEV in reducing both SBS on EEG and seizure frequency. LEV represents an important addition to the treatments available for refractory childhood epilepsies with SBS on EEG.     

Levetiracetam efficacy in children with epilepsy with electrical status epilepticus in sleep

PurposeEpilepsy with electrical status epilepticus in sleep (ESES) is a devastating disease, and we sought to evaluate the efficacy of levetiracetam (LEV) for the treatment of patients with this epileptic encephalopathy in China.MethodsClinical data from all patients with ESES who received LEV therapy at our pediatric neurology outpatient clinic between 2007 and 2014 (n = 71) were retrospectively analyzed. The LEV dosage was 30–50 mg/kg/day. Electroencephalography recordings and neuropsychological evaluations were performed repeatedly for 3–75 months after the start of LEV therapy.ResultsThirty-five (70%) of 50 patients who had seizures at the start of LEV therapy had a > 50% reduction in seizure frequency. Positive response on EEG was found during the first 3–4 months of LEV therapy in 32 (45%) of 71 patients, with normalization of EEG in 5 patients. Relapse occurred in 8 (25%) of the initial electrical responders. Hence, 47 patients (66%) still suffered from ESES and only 13 patients regained their baseline level of function at the last follow-up. The response to LEV was significantly associated with ESES duration, age at onset of ESES, and etiology of epilepsy. Although fatigue and anorexia were the primary adverse events, LEV was well-tolerated by all patients.ConclusionsLevetiracetam is safe and may be efficient when used to treat ESES syndrome; however, the efficacy EEG neuropsychological outcomes is limited on the whole.     

A two-year retrospective evaluation of perampanel in patients with highly drug-resistant epilepsy and cognitive impairment

PurposeThe objective of this work was to review systematically the efficacy and tolerability of perampanel (PER) in residential patients of an epilepsy center.MethodWe adopted an industry-independent noninterventional retrospective evaluation on the basis of the paper and electronic records complemented by personal information on the part of the treating neurologists. All patients (N = 26, 15 females, mean age: 30, range 21–55 years) started on PER from its introduction to the market in September 2012 until December 15th 2013 were included. Evaluation was carried out after 6, 12, and 24 months of PER treatment. Changes in seizure frequency were calculated as the number of seizures during three months on PER compared to a three-month baseline period. The Clinical Global Impression Scale served as an instrument to record changes in seizure intensity beyond numerical values. Adverse effects were documented by means of the Liverpool Adverse Events Profile.ResultsMost patients had structural or metabolic epilepsy, 2 patients suffered from Lennox-Gastaut syndrome, 2 from other symptomatic generalized epilepsy. All patients had grade III drug-resistant epilepsy. All patients had additional cognitive deficits of different degree.The retention rates were 61.5% after 6 months, 46.2% after 12 months, and 42.3% after 24 months. The responder rates were 11.5% after 6 months, 23.1% after 12 months, and 7.7% after 24 months. Partial responders (positive CGI and/or seizure reduction < 50%) included, the respective values were 26.9%, 38.5%, and 23.1%. Only 1 patient was seizure free at 12 months (but not at 24 months). A loss of efficacy in the second year of treatment was suspected but the decrease of the responder rate could also be ascribed to a number of different circumstances. Adverse effects in the psychiatric field like irritability, aggression, increased sensitivity, and suicidal ideation/behavior occurred in 50% of the patients. They were the main reason to discontinue PER.ConclusionsAfter one year of treatment PER showed reasonable efficacy in a particularly difficult-to-treat population. Psychiatric adverse effects forced discontinuation in many cases.     

Levetiracetam in children with refractory epilepsy: Lack of correlation between plasma concentration and efficacy

PurposeThe goals of this study are to evaluate the efficacy and tolerability of levetiracetam (LEV) as add-on therapy in children with refractory epilepsies and to determine the value of LEV blood level monitoring in this population.MethodsSixty-nine children (39 males and 30 females) treated with LEV between 2006 and 2007 were selected. Their medical files were reviewed for LEV efficacy and tolerability. In a subgroup of children currently taking LEV, plasma concentrations were determined by high performance liquid chromatography by ultraviolet detection (HPLC-UV) method and correlated with the given dose per kilo as well as clinical response.ResultsFifty-one patients (74%) had a more than 50% reduction in seizure frequency with 16 patients (23%) becoming seizure free on LEV. Eighteen (26%) patients had a less than 50% reduction in seizure frequency. Adverse events due to LEV ranged from mild to moderate in only 18 patients (26%). The most frequently observed were drowsiness, behavioral difficulties, increase in seizure frequency and headaches. The majority (60.5%) of the responders received doses between 10 and 50 mg/kg/day and had a plasma concentration (PC) between 5 and 40 μg/ml. However, we found no clear correlation between PC and efficacy.ConclusionLevetiracetam given twice a day in children with refractory epilepsy reduces seizure frequency in all types of epilepsy. In children, LEV is a broad spectrum anticonvulsant with a favourable safety profile.     

Levetiracetam in the treatment of neonatal seizures: A pilot study

PurposeAt present, neonatal seizures are usually treated with Phenobarbital (PB) despite the limited efficacy and the potential risk this treatment holds for the developing brain. We report here a prospective pilot feasibility study on the use of Levetiracetam as monotherapy in the treatment of neonatal seizures.MethodsSix newborns (body weight > 2000 g, gestational age > 30 weeks) presenting with neonatal seizures were enrolled. Patients whose seizures were caused by electrolyte disturbances or hypoglycemia, or whose seizures did respond to pyridoxine were excluded. Patients previously treated with other antiepileptic drugs (AEDs), with the exception of single PB doses before and during titration, were excluded. LEV was administered orally, increasing the dose by 10 mg/(kg day) over 3 days. Endpoint was the need of any additional AEDs (or PB) after day 3, or 3 months of LEV treatment. A decision regarding further treatment was made on an individual basis and follow-up was documented up to 8 months of age.ResultsNo severe adverse effects were observed. Mild sedation was reported in one infant. All six patients treated with oral LEV became seizure free within 6 days. Five patients remained seizure free after 3 months with ongoing LEV monotherapy. One infant developed pharmacoresistent epilepsy. Seizures relapsed later in the clinical course of two more patients, one of whom was no longer under LEV therapy.DiscussionResults from our small patient group indicate that LEV may be an alternative therapeutic option in neonatal seizures.     

The MCT-ketogenic diet as a treatment option in refractory childhood epilepsy: A prospective study with 2-year follow-up

The present study assessed the long-term (i.e., 24 months) efficacy of the ketogenic diet (KD) as an add-on therapy in children with refractory epilepsy, with focus on seizure frequency, seizure severity, and tolerability. Most patients were treated with the MCT-diet.At one and two years, 33% and 23%, respectively, of the 48 included patients were still on the KD. After three months, one year, and two years of treatment, 16.7% of the patients were responders. The highest responder rate (i.e., 22.9%) was seen at six and nine months of treatment. Of the fifteen patients with seizure clusters during baseline, 60% were responders after three months when looking at cluster reduction and most of them were not responders for the total seizure frequency. From three months of treatment onwards, most of the patients had a relevant decrease in seizure severity which was mainly related to the most severe seizure type.Gastrointestinal dysfunction was often reported, especially in the first six weeks of treatment. Growth deceleration was present in 30% of the patients, and weight reduction in 15%.Improved arousal was mentioned in 30% of patients. No patients developed ECG abnormalities or kidney stones. Increase in lipid profile was rare.The KD is an effective therapy for children with therapy-resistant epilepsy. Effectiveness is reflected in the reduction of seizure frequency as well as in the reduction of seizure severity. After 6 months of treatment, it is obvious which patients are responders and tolerate the treatment well. Most of these patients will continue to benefit from the KD for a longer time. Long-term use of the diet was well tolerated.     

Long-term levetiracetam treatment of epilepsy patients: Clinical audit

PurposeThe long-term efficacy and tolerability of levetiracetam (LEV) was analysed in 218 epilepsy patients. One hundred and ninety-nine patients were treated for at least 6 months. We evaluated LEV efficacy for all types of seizures together, and for simple partial, complex partial and secondary generalized seizures individually.ResultsA significant decrease in the number of seizures occurred after 6 months of treatment (p < 0.001). Mean seizure frequency (irrespective of type) before LEV was 19.2 a month. The mean monthly frequency at 6, 12, 24 and 36 months dropped to 12.7, 10.5, 9.7 and 7.1 seizures a month, respectively. The mean percentage reduction in seizures at these times was 45.7, 52.1, 59.1 and 64.2% and the number of responding patients was 51.3, 54.2, 59.8 and 62.2%. The number of patients completely seizure free was 18.6, 16.7, 15.2 and 16.2%. We found similar results in the last three categories for partial simple, complex and secondary generalized seizures individually. Side effects in 18.3% of patients caused treatment discontinuation in 6.4%. The most frequent were somnolence, moodiness and dizziness. The retention rate at 6, 12, 24 and 36 months was 0.848, 0.72, 0.62 and 0.5, respectively.ConclusionsLEV is effective and well tolerated for long-term treatment of epilepsy.     

The effects of levetiracetam on urinary 15f-2t-isoprostane levels in epileptic patients

PurposeWe aimed to investigate the effects of levetiracetam on oxidative stress which is one of the new antiepileptic drugs in epileptic patients.MethodsThe study consisted of 21 patients with cryptogenic partial epilepsy. We determined the urinary 15F-2t-isoprostane levels of the 30 patients which is a marker of oxidative stress. Morning urine samples were collected from the patients before beginning LEV and after 3 months treatment. Of these patients 9 were excluded from the study that had seizure history in the last 1 month. Urinary levels of 15-F2t-isoprostane determined by ELISA initially and after 3 months treatment for each patient.ResultsMean age of the 21 patients was 29.6, of these 11 were females and 10 males. Mean urinary 15F-2t-isoprostane level of the patients was 876 ± 447 ng/mg Cr before the treatment of LEV. After 3 months treatment the mean 15F-2t-isoprostane level of the patients was 1560 ± 630. The patients had significantly higher levels of urinary 15F-2t-isoprostane when compared with initial levels (p = 0.025).ConclusionOur results showed the increase of urinary 15F-2t-isoprostane levels in epileptic patients whom were treated with LEV which may indicate that LEV induces the oxidative stress in epileptic patients.     

Quality of life,mood and seizure control in patients with brain tumor related epilepsy treated with lacosamide as add-on therapy: A prospective explorative study with a historical control group

ObjectiveBrain tumor-related epilepsy (BTRE) is often drug resistant and patients can be forced to take polytherapy that can adversely affect their quality of life (QoL). Lacosamide (LCM) is a new antiepileptic drug (AED) used as adjunctive therapy in patients with partial seizures with or without secondary generalization, with a favorable pharmacokinetic profile that seems to be effective and well tolerated.Therefore it represents a possible therapeutic choice for patients with BTRE. We propose a prospective study with a historical control group to evaluate the effect of LCM as add-on therapy on seizure control and quality of life in patients with BTRE. This study has been designed to test the superiority of Lacosamide over Levetiracetam as an add-on. We compared a prospective cohort of 25 patients treated with Lacosamide with a historical control group (n = 19) treated with Levetiracetam as an add-on.MethodsWe recruited 25 adult patients (M 18, F 7; mean age 41.9) affected by BTRE with uncontrolled partial-onset seizures treated with AED polytherapy. We added LCM as an add-on. Patients were evaluated at baseline, after 3 months and at 6 months.This population has been compared with a historical control group of 19 BTRE adult patients (M 13, F 6; median age 48.0, range: 28–70) with uncontrolled partial-onset seizures treated with LEV as add-on.The patients underwent QoL, mood and adverse events tests (Adverse Event Profile-AEP) and evaluation of seizure frequency.ResultsTwelve patients had high grade gliomas, and thirteen had low grade gliomas. During follow-up, thirteen patients underwent chemotherapy, three radiotherapy and five patients had disease progression. Nine patients had simple partial seizures, eight had complex partial seizures, and eight had secondary generalized seizures. Fifteen patients were in monotherapy and ten in polytherapy with AEDs. LCM was added up to reach the maximum dosage of 400 mg/die (mean final dose 300 mg/die). Four patients dropped out due to poor compliance and 1 for inefficacy.In the historical control group treated with LEV (mean final dose 2000 mg/die) 12 patients had high-grade gliomas, and 7 had low grade gliomas. Thirteen patients were in monotherapy and 6 in polytherapy with AEDs.In the 22 patients evaluable of 25 patients treated with LCM, we observed at final follow-up 7 patients seizure free, 12 with a significant reduction of seizures ≥ 50%, 2 stable and 1 patient with number of seizures increased.Mean seizure frequency at baseline compared with baseline period: the mean number of seizures significantly decreased from baseline (9.4) to final follow-up (1.2) (P = 0.005). The Responder Rate was 86.4%.Comparing responder rate of 22 evaluable patients with LCM with responder rate of 19 patients with LEV we didn't observe significant differences (p = 0.31).In our patients treated with LCM we didn't observe significant difference at 3 and 6 months in QoL tests results; we observe a significant reduction in the mean score of Karnofsky Performance Status (KPS) and Barthel Index (BI) between baseline and 6 months of follow-up (KPS p = 0.003; BI p = 0.007).No clinical side effects were observed.ConclusionComparing the LCM with the historical group treated with LEV in add-on, we observed that LCM seems to have a higher clinical efficacy than LEV.In our patients, we did not observe any significant changes in QoL tests, indicating stability in all quality of life domains explored, despite the objective worsening in their functional status. Although this is a small series with a relatively short follow-up, our data indicates that LCM in add-on in patients with BTRE appears to be as effective as LEV in add-on, without impact on mood and quality of life.     

Prospective audits with newer antiepileptic drugs in focal epilepsy: Insights into population responses?

Despite the availability of a wide range of new antiepileptic drugs (AEDs), there is little evidence that their introduction has substantially altered outcomes. This paper reviews data from 5 consecutive prospective audits with new AEDs using similar methodology. Prospective audits with topiramate (TPM; n = 135), levetiracetam (LEV; n = 136), zonisamide (ZNS; n = 141), pregabalin (PGB; n = 135), and lacosamide (LCM; n = 160) were undertaken in treated patients with uncontrolled partial-onset seizures. Follow-up continued until one of four endpoints was reached: seizure freedom for ≥ 6 months on unchanged dosing; ≥ 50% reduction (responder) in seizure frequency on the highest tolerated dose compared with baseline; < 50% seizure frequency reduction (marginal response) compared with baseline in patients wishing to continue treatment with the new AED; or withdrawal due to lack of efficacy, side effects, or both. A greater proportion of seizure-free patients occurred with LEV (23.5%), LCM (21.9%), and TPM (20.7%) than with ZNS (12.8%) and PGB (10.4%). A higher percentage discontinued treatment with ZNS (41.8%) and PGB (50.4%) than with LEV (32.4%), TPM (31.1%), and LCM (22.5%). Most seizure-free patients responded to the new agent as first or second add-on (TPM 96%; LEV 97%; ZNS 89%; PGB 86%; LCM 97%) often at modest or moderate dosing (TPM 68%, ≤ 200 mg/day; LEV 63%, ≤ 1000 mg/day; ZNS 61%, ≤ 100 mg/day; PGB 86%, ≤ 300 mg/day; LCM 74%, ≤ 200 mg/day). With < 10% of patients discontinuing all AEDs due to lack of efficacy, tolerability was the major factor influencing the number of patients remaining on treatment. Lacosamide was the best (77% patients continued treatment), while PGB was the worst (50% continued treatment) tolerated AED. Overall, seizure freedom was achieved in < 25% of patients in each audit, mainly as a first or second add-on, with best tolerated AEDs producing a higher number of good outcomes. Seizures in very few patients with drug-resistant epilepsy, as defined by the International League Against Epilepsy task force, responded to any of the 5 newer AEDs. These data support the suggestion that the introduction of modern agents has not importantly impacted the outcomes in refractory epilepsy.     

Can an early 24-hour EEG predict the response to the ketogenic diet? A prospective study in 34 children and adults with refractory epilepsy treated with the ketogenic diet

PurposeWe examined whether early EEG changes in a 24-h EEG at 6 weeks of treatment were related to the later clinical response to the ketogenic diet (KD) in a 6-month period of treatment.MethodsWe examined 34 patients with heterogeneous epilepsy syndromes (21 children, 13 adults) and found 9 clinical responders (≥50% seizure reduction); this is a responder rate of 26%. We visually counted the interictal epileptic discharge index (IED index) in % during 2 h of wakefulness and in the first hour of sleep (method 1), and also globally reviewed EEG changes (method 2), while blinded to the effect of the KD.ResultsAt group level we saw a correlation between nocturnal reduction of IED-index at 6 weeks and seizure reduction in the follow-up period. A proportional reduction in IED index of 30% from baseline in the sleep EEG, was associated with being a responder to the diet (Pearson Chi-square p = 0.04). EEG scoring method 2 observed a significantly larger proportion of patients with EEG-improvement in sleep in KD responders than in non-responders (p = 0.03). At individual level, however, EEG changes did not correlate very strongly to the response to the diet, as IED reduction in sleep was also seen in 15% (method 1) to 26% (method 2) of the non-responders.ConclusionNocturnal reduction of IEDs is related to the response to the KD, however in daily clinical practice, an early EEG to predict seizure reduction should not be advised for individual patients.     

Evaluation of levetiracetam and valproic acid as low-dose monotherapies for children with typical benign childhood epilepsy with centrotemporal spikes (BECTS)

PurposeThis study aimed to compare the monotherapeutic efficacies of levetiracetam (LEV) and valproic acid (VPA) in a cohort of newly diagnosed children with typical benign childhood epilepsy with centrotemporal spikes (BECTS).MethodsA total of 56 children with typical BECTS were retrospectively reviewed in the analyses. Thirty-three children received LEV and 23 received VPA as initial monotherapy, and the treatments lasted for at least 18 months.ResultsThe average dosage of LEV was 22.7 ± 4.7 mg/kg/day, and that of VPA was 18.7 ± 5.7 mg/kg/day. The seizure-freedom rates were not significantly different between the two groups at 6 (57.5% vs. 60.9%), 12 (81.8% vs. 73.9%) or 18 months (100% vs. 100%). However, a greater number of the children taking VPA achieved Electroencephalography (EEG) normalization compared to those taking LEV both at 12 (78.3% vs. 45.5%) and 18 months (95.7% vs. 72.7%; p < 0.05). No children discontinued therapy due to adverse effects during the follow-up. Only one child (4.7%) in the VPA group exhibited mild weight gain (BMI increase of 2 at the end of follow-up) but did not withdraw from treatment.ConclusionLow-dosage VPA and LEV monotherapies are equally effective in controlling seizures, but VPA exhibited better efficacy than LEV in improving the electrophysiological abnormalities of children with BECTS. None of the patients discontinued therapy, which was likely due to the administration of low dosages.     

Vagus nerve stimulation: Longitudinal follow-up of patients treated for 5 years

We performed a retrospective, multicenter, open-label study to evaluate the efficacy of vagus nerve stimulation (VNS) in all patients in the Czech Republic who have received this treatment for at least 5 years (n = 90). The mean last follow-up was 6.6 ± 1.1 years (79 ± 13 months). The median number of seizures among all patients decreased from 41.2 seizures/month in the prestimulation period to 14.9 seizures/month at 5 years follow-up visit. The mean percentage of seizure reduction was 55.9%. The responder rate in these patients is in concordance with the decrease of overall seizure frequency. At 1 year after beginning the stimulation, 44.4% of patients were responders; this percentage increased to 58.7% after 2 years. At the 5 years last follow-up 64.4% of patients were responders, 15.5% experienced ≥90% seizure reduction, and 5.5% were seizure-free. A separate analysis of patients younger than 16 years of age showed lower efficacy rates of VNS in comparison to the whole group. Complications and chronic adverse effects occurred in 13.3% of patients. VNS is an effective and safe method to refractory epilepsy in common clinical practice.     

A prospective long-term study of external trigeminal nerve stimulation for drug-resistant epilepsy

BackgroundExternal trigeminal nerve stimulation (eTNS) is an emerging noninvasive therapy for drug-resistant epilepsy (DRE). We report the long-term safety and efficacy of eTNS after completion of a phase II randomized controlled clinical trial for drug-resistant epilepsy.MethodsThis was a prospective open-label long-term study. Subjects who completed the phase II randomized controlled trial of eTNS for DRE were offered long-term follow-up for 1 year. Subjects who were originally randomized to control settings were crossed over to effective device parameters (30 s on, 30 s off, pulse duration of 250 s, frequency of 120 Hz). Efficacy was assessed using last observation carried forward or parametric imputation methods for missing data points. Outcomes included change in median seizure frequency, RRATIO, and 50% responder rate.ResultsThirty-five of 50 subjects from the acute double-blind randomized controlled study continued in the long-term study. External trigeminal nerve stimulation was well tolerated. No serious device-related adverse events occurred through 12 months of long-term treatment. At six and twelve months, the median seizure frequency for the original treatment group decreased by -2.39 seizures per month at 6 months (-27.4%) and -3.03 seizures per month at 12 months (-34.8%), respectively, from the initial baseline (p < 0.05, signed-rank test). The 50% responder rates at three, six, and twelve months were 36.8% for the treatment group and 30.6% for all subjects.ConclusionThe results provide long-term evidence that external trigeminal nerve stimulation is a safe and promising long-term treatment for drug-resistant epilepsy.     

Lacosamide in pediatric and adult patients: Comparison of efficacy and safety

PurposeThis multicenter, prospective study investigates the efficacy and safety of lacosamide adjunctive therapy in pediatric and adult patients with uncontrolled epilepsy.MethodThis study was carried out between September 2010 and December 2011 at 16 Italian and 1 German neurologic centers. Lacosamide was added to the baseline therapy at a starting dose of 1 mg/kg/day in patients aged <16 years (group A) and 100 mg daily in subjects aged 16 and older (group B), and titrated to the target dose, ranging from 3 to 12 mg/kg/day or from 100 to 600 mg daily, respectively. After completing the titration period, patients entered a 12-month maintenance period and they were followed up at 3, 6 and 12 months. The primary assessment of efficacy was based on the change from baseline in seizure frequency per 28 days and was evaluated at 3, 6 and 12 months as follows: number and proportion of 100% responders, 50% responders, non-responders and worsening patients. Safety evaluation was also performed at 3, 6 and 12 months.ResultsA total of 118 patients (59 group A, 59 group B) with uncontrolled generalized and focal epilepsy were enrolled. Patient mean ± SD age was 15.9 ± 6.80 years and the age range was 4–38 years. At 3-month evaluation, of 118 treated patients 56 subjects (47.4% group A; 47.4% group B; p = 0.8537) experienced at least a 50% reduction in seizure frequency. At 6 and 12-month follow-up, the 50% responders were 57 (52.5% group A; 44.1% group B; p = 0.4612) and 51 (47.4% group A; 39% group B; p = 0.4573), respectively. Thirty-five subjects (30.5% group A; 28.8% group B; p = 1) experienced side effects during the treatment period. The most common adverse events were dyspepsia for group A and dizziness for group B.ConclusionLacosamide may be a useful and safe pharmacological treatment option for both pediatric and adult patients with uncontrolled seizures.     

Pharmacodynamic and pharmacokinetic interactions of perampanel and other antiepileptic drugs in a rat amygdala kindling model

PurposeThis study explored the pharmacodynamic and pharmacokinetic effects of combining perampanel (PER) with commonly co-administered AEDs.MethodA strong stimulus intensity (three-fold higher than after-discharge threshold) was used to elicit drug-resistant seizures in a rat amygdala kindling model. Vehicle, low-dose PER (0.75 mg/kg), or high-dose PER (1.5 mg/kg), in combination with vehicle, levetiracetam (LEV) 50 mg/kg, lamotrigine (LAM) 20 mg/kg, carbamazepine (CBZ) 20 mg/kg, or valproic acid (VPA) 200 mg/kg, were administered intraperitoneally to groups of 6–13 rats. Seizure score, electroencephalography (EEG) seizure duration, and motor seizure duration were evaluated, with pharmacodynamic interactions determined by two-way analysis of variance (ANOVA). Motor impairment was evaluated by rotarod test and two-way ANOVA.ResultsHigh-dose PER, but not low-dose PER, LEV, LAM, CBZ, or VPA, reduced EEG seizure duration, motor seizure duration, and seizure score compared with vehicle alone. However, when low-dose PER was administered in combination with LEV, LAM, CBZ, or VPA, seizure severity parameters were reduced compared with the concomitant AEDs alone. These pharmacodynamic interactions were statistically significant in some cases, but the same AED combinations were not associated with statistically significant neurotoxic interactions. Efficacy may have been slightly affected by changes in PER plasma concentrations in the presence of other AEDs:PER plasma concentrations increased with LEV or LAM co-administration, and decreased with CBZ or VPA co-administration.ConclusionOverall, these data support published Phase III data demonstrating the efficacy of PER as adjunctive therapy for the treatment of refractory partial-onset seizures in patients aged ≥12 years.     

An estimate of placebo effect of repetitive transcranial magnetic stimulation in epilepsy

ObjectiveLow-frequency repetitive transcranial magnetic stimulation (rTMS) is emerging as a therapeutic tool in epilepsy. In recent years, several open-label trials have shown an encouraging reduction in seizure frequency in patients with epilepsy. However, the data from controlled trials are mixed with respect to antiepileptic rTMS efficacy, and the field would benefit from further carefully controlled trials. Prior to initiating new trials, it is important assess the magnitude of the placebo effect of presently used sham rTMS methods.MethodsWe systematically analyzed individual subject data from three placebo-controlled trials and measured the placebo effect at follow-up intervals of 2, 4, and 8 weeks after sham rTMS treatment. Given the relatively small subgroup sample size, placebo condition data were pooled for analysis.ResultsThree methods for sham rTMS were employed in the reviewed studies: (1) coil positioning orthogonal to the scalp, (2) a spring-loaded sham coil, and (3) a double active-sham coil. The placebo response overall was consistently low across follow-up intervals, both for median change in seizure frequency (Kruskal–Wallis, P > 0.4, df = 2) and for responder (defined as ≥ 50% seizure frequency reduction) rate (Fisher's exact rest, P > 0.9, df = 2). The aggregate effect of the placebo condition was a 0–2% median seizure reduction rate and a responder rate of 16–20%.ConclusionWe anticipate that these data will contribute to future power analysis as well as selection and design of sham rTMS methods for controlled rTMS trials.     

Retention rate of pregabalin in drug-resistant epilepsy: 1-year follow-up, single-centre observation in 105 consecutive, adult patients

ObjectivesPregabalin (PGB) is a newer antiepileptic drug (AED) licensed as add-on treatment for partial epilepsy in adults. Efficacy and safety have been proven in several controlled clinical studies. These trials, however, only partially reflect clinical practice. Retention rate has been established as a marker for efficacy and safety of AEDs in long-term follow-up studies.MethodsWe evaluated the data of the first 105 patients treated with PGB at Bethel Epilepsy Centre, a tertiary referral centre for epilepsy. The patients were interviewed after 3, 6 and 12 months.Results105 adult patients (aged 38 ± 13 years) were treated with PGB, on average in combination with 2.1 AEDs (mean observation period 232 days). 76.2% had focal epilepsy, 19.0 multifocal epilepsy, and 3.8% epilepsy with both focal and generalised seizures. 40% continued PGB with the following outcome: 5.7% seizure-free for at least 1 month (4.8% for at least 3 months, 2.4% for at least 6 months; one of the seizure-free patients, however, had had epilepsy surgery during the observational period), 17.1% responders (≥50% reduction of seizure frequency but not seizure-free), 13.3% with unchanged or increased seizure frequency. Reasons for withdrawal were lack of efficacy (47.6%) or side-effects (12.7%).ConclusionsPGB is a new therapeutic option as add-on therapy for patients with highly refractory focal epilepsies although the therapeutic success that can be expected in this group of patients is limited.     

Long-term outcome and tolerability of the ketogenic diet in drug-resistant childhood epilepsy—The Austrian experience

PurposeTo evaluate the long-term efficacy/tolerability of the ketogenic diet (KD) in paediatric drug-resistant epilepsies.MethodsData from children who were treated between 1999 and 2008 and had continuous follow-up of at least 6 months after initiation of the KD were analysed retrospectively. Response was defined as ≥50% seizure reduction. Treatment effects on EEG, developmental outcome and the “outcome-predictive” value of various clinical factors were also assessed.Results50 children (22 boys; mean age 4.5 years ± 3.55) were included. Mean follow-up was 3.93 ± 2.95. 50% of the patients were responders, 48% of them became seizure free. 50% were non-responders, 20% of them deteriorated. In responders, EEG background activity improved significantly (p = 0.014) and a significantly lower rate of epileptic discharges (p = 0.009) was seen after 6 months. In addition, neurological examination findings demonstrated significant developmental progress (p = 0.038).Favourable treatment outcome was associated with a shorter disease duration (p = 0.025) and generalised tonic clonic seizures (p = 0.059). No further significant outcome predictors were detected. However, response was 44% in patients with infantile spasms, 62.5% in those with Dravet syndrome and 50% in Lennox-Gastaut-syndrome.Side effects occurred in 28%, but discontinuation of the KD was not required in any case. They most often observed with concomitant topiramate (p = 0.001) and valproate (p = 0.046).ConclusionDespite the retrospective nature of the study and the inhomogeneous patient sample, we found good long-term effects of the KD on seizure frequency, EEG and neurological development.     

A retrospective evaluation of retigabine in patients with cognitive impairment with highly drug-resistant epilepsy

PurposeThe purpose of this study was to evaluate retrospectively the efficacy and tolerability of retigabine (RTG) in residential patients of an epilepsy center.MethodWe used an industry-independent noninterventional retrospective evaluation on the basis of paper and electronic records plus interrogation of the treating neurologists. All patients (N = 20; 7 females; mean age: 31.8, range: 18–54 years) started on RTG between May 2011 and March 2012 were included. Evaluation was carried out after 6, 12, and 24 months. Changes in seizure frequency were measured as the number of seizures during three months on RTG compared with a three-month baseline period. The Clinical Global Impression scale was applied to include qualitative changes in seizure severity. All but one patient had symptomatic (structural; one patient: metabolic) or cryptogenic focal or multifocal epilepsy. All had grade III drug-resistant epilepsy and cognitive deficits of different degrees.ResultsThe retention rates were 60% after 6 months, 35% after 12 months, and 20% after 24 months. At 12 months, there were 2 responders (10%): one had a > 90% seizure reduction and the other had a > 50% seizure reduction. Another 5 patients were still on RTG because of minor improvements. The reasons for discontinuation in 13 patients were adverse effects (6), lack of effect (6), and both (1). Cognitive or emotional changes were the side effects that most frequently led to discontinuation. Beyond the 12-month evaluation, 3 patients were discontinued as a consequence of the FDA warning regarding retinal pigmentation and discoloration of skin and nails in patients exposed to RTG. One patient had a moderate blue–gray finger coloring. Ophthalmological changes were not discovered.ConclusionRetigabine proved to be useful only for a small minority of patients in a sample of patients with particularly difficult-to-treat epilepsy.