Prior Antiepileptic Drugs Research Articles

Clinical outcomes following responsive neurostimulation implantation: a single center experience.

Responsive neurostimulation (RNS) is an implantable device for persons with medically refractory focal-onset epilepsy. We report a single-center experience for RNS outcomes with special focus on stereoelectroencephalography (sEEG) for seizure onset localization. We performed retrospective review of patients with drug resistant focal epilepsy implanted with the RNS System for a minimum of six months between July 2014 and July 2019. Records were reviewed for demographic data, epilepsy duration, seizure frequency, number of prior antiepileptic drugs (AEDs), number of AEDs at RNS System implantation, prior epilepsy surgery or device use, previous seizure localization with sEEG, and RNS system information. Clinical response was defined as a 50% reduction in seizures. Differing response rates were calculated using Fisher Exact test. 30 patients met inclusion criteria. Seventeen (57%) underwent previous sEEG. Average clinical follow up was 3.0 years. Overall response rate was 70%. Median seizure reduction was 74.5%. Response rate was 82.3% for patients with sEEG compared to 53.8% without (p = 0.08); 37.5% for prior epilepsy surgery compared to 81.8% without (p = 0.02); 70% for mesial temporal onset; 50% for previous vagal nerve stimulator compared to 77.3% without (p = 0.13). Our response rates match or surpass outcome metrics of previous studies. Although limited by small study size, subpopulation analyses show positive response rates in patients with previous sEEG versus no sEEG and in temporal versus extratemporal pathology. Additional research is needed to evaluate efficacy of RNS in patients with previous epilepsy surgery, and utility of sEEG in this population.

Retention Rate and Efficacy of Perampanel with a Slow Titration Schedule in Adults.

The manufacturer of perampanel (PER) suggests an initial adult dose of 2-4 mg/day and an upward dose titration of 2 mg at no more frequently than 1- or 2-week intervals when used with enzyme-enhancing antiepileptic drugs (AEDs) or nonenzyme-enhancing AEDs, respectively. The general practice in our clinic is an initial dose of PER 2 mg/day and titrated by 2 mg/4 weeks to an initial target of 6 mg/day. Retrospective chart audit of patients starting PER in an adult epilepsy clinic between September 2013 and November 2016 with at least one 6-month follow-up visit was reviewed. Data collection included patient demographics, seizure characteristics, past and concurrent therapy, monthly seizure frequency before PER and at 6-month visit, and characteristics of PER discontinuation. Efficacy of treatment was assessed with the Engel classification and 50% responder rate. N = 102 patients; mean age = 40 years and 54% females. Focal onset seizures 85%, generalized 13%, and unknown 2%. Median prior AED exposure = 6 (range 3-20); median concomitant AED use = 2 (range 1-5). Follow-up range was 6-37 months. The median seizure frequency/month prePER treatment was 6 (range 0-30) for focal onset seizures and 1 (range 0-6) for generalized seizures. The retention rate amongst all patients at 6 months was 78.4%. At 6-month follow-up, 36% of all patients achieved Engel class I (seizure freedom) (30.7% of patients with focal onset seizures and 63.6% with generalized epilepsy). The 50% responder rate was 52% and 82% for focal and generalized epilepsy, respectively. PER has a good retention rate when titrated slowly and thus encouraging seizure freedom results in an otherwise medically refractory epilepsy population.

Improved irritability, mood, and quality of life following introduction of perampanel as late adjunctive treatment for epilepsy

ObjectiveThe objective of this study was to evaluate the efficacy and tolerability of perampanel (PER) in late adjunctive treatment of focal epilepsy. We assessed outcomes 1) according to patients' clinical profiles and the broad mechanism of action (MoA) of concomitant antiepileptic drugs (AEDs) and 2) the effects of PER on adverse events, irritability, mood, and quality of life (QOL). MethodsConsecutive patients commenced on PER at two epilepsy centers in Melbourne, Australia were identified. A nested cohort underwent detailed prospective assessment, while the remainder were retrospectively analyzed. Six- and 12-month efficacy endpoints were at least a 50% reduction in seizure frequency (responders) and complete seizure freedom. The prospective cohort underwent standardized validated questionnaires at 0, 1, 3, 6, and 12 months using the modified semi-structured seizure interview (SSI), Liverpool Adverse Events Profile (LAEP), Quality of Life in Epilepsy-Patient-Weighted (QOLIE-10-P), Neurological Disorders Depression Inventory Epilepsy (NDDI-E), and an Irritability Questionnaire. ResultsOne hundred sixty patients were followed for a median of 6 months: the mean number of prior AEDs was 6, 99% had drug-resistant epilepsy, and 72% had never experienced a prior seizure-free period of at least 6 months (=continuously refractory epilepsy). Perampanel was associated with responder and seizure freedom rates of 30.6% and 9.4% at 6 months and 19.4% and 4.4% (5.6% adjusted for the titration period) at 12 months. Having “continuously refractory epilepsy” was associated with a reduced likelihood of seizure freedom at 6 months (5% vs. 30%; p = 0.001) and 12 months (3% vs. 13%; p = 0.058). Quality of Life in Epilepsy-Patient-Weighted, irritability, and NDDI-E showed mean improvement at 6 months from baseline. SignificanceEven when used as late add-on adjunctive therapy in patients with highly refractory focal epilepsy, PER can result in 12-month seizure freedom of 5.6%. The likelihood of seizure freedom was associated with prior “continuous medication refractoriness”. Six months after introduction of PER patients reported improved mood, QOL, and decreased irritability.

Efficacy, retention, and safety of brivaracetam in adult patients with genetic generalized epilepsy

ObjectiveThe aim of this study was to evaluate the efficacy, tolerability, and retention of brivaracetam (BRV) in genetic generalized epilepsy (GGE) in real-life practice. MethodsThis is a retrospective cohort study of adult patients with GGE in whom BRV was started between 2016 and 2018, completing a follow-up period of ≥6 months. Clinical and electroencephalogram (EEG) characteristics were analyzed at baseline and at follow-up as outcome measures. ResultsBrivaracetam was started in 37 patients (mean age: 29.9 ± 12.3 years; 73% women). Juvenile myoclonic epilepsy was the most common syndrome (43.2%). The primary indications for starting BRV were lack of efficacy (51.4%) and adverse events (AEs) (27%) of other antiepileptic drugs (AEDs). In total, 32.4% of patients received BRV monotherapy. Retention rate at 6 months was 81.1%; 83.8% of patients were considered responders, and 62.2% achieved seizure freedom. The primary reasons for withdrawal were treatment-emergent adverse events (TEAEs, 57.1%) and lack of efficacy (42.9%). The higher number of prior AED use was a risk factor for a lack of response [median = 4 (interquartile range (IQR): 3–4) vs 2 (IQR: 1–3); p < 0.05]. Patients with a previous response to valproic acid tended to have a higher response rate to BRV (86.7% vs 50%, p = 0.169). Eighty-three point eight percent (83.8%) of previous levetiracetam (LEV) responders also showed a good response to BRV. In terms of patients who presented LEV-related AEs, AE resolution was observed in 79.8%, particularly with regard to psychiatric AEs. Follow-up EEGs were compared with baseline EEGs in 25 patients (67.6%) during follow-up. Most patients showed a reduction (52%) or no change (36%) in interictal epileptiform discharge (IED) frequency. SignificanceBrivaracetam shows good responder and retention rates in GGE and is generally well tolerated. It is an appropriate alternative treatment for GGE, especially in refractory epilepsy and when other AEDs are not tolerated.

Effectiveness of perampanel as a first add-on antiepileptic drug for the treatment of partial epilepsy

BackgroundPerampanel (PER) is a newly introduced antiepileptic drug (AED) and is used in over 50 countries. In the current study, we analyzed the efficacy of PER for patients with partial epilepsy who were recruited from two hospitals that had both an epilepsy center and a general neurosurgical unit over a 1-year period. MethodsThe present study was a retrospective observational study that evaluated the effects of PER for the treatment of partial epilepsy in 51 patients. We analyzed the effects of PER at two checkpoints, i.e., 6 and 12 months after starting adjunctive PER treatment. Following this, we analyzed the effects of PER as a first add-on (only one prior AED) and late add-on (≥2 prior AEDs) therapy, and focused on the characteristics of the patients who achieved seizure freedom. ResultsOf the initial 51 patients, 45 and 39 patients were evaluated at the 6- and 12-month checkpoints, respectively. Overall, after starting treatment with PER, 29% (13/45) and 28% (11/39) of patients were seizure-free at 6 and 12 months, respectively. The tolerance rate of PER was 67% (30/45) at 6 months and 53.8% (21/39) at 12 months following treatment. The seizure-free rate of the 30 patients who were continuously treated with PER for 6 months was significantly higher in the patients who used PER as a first add-on treatment (75.0%, 6/8) than it was in the patients who used PER as a late add-on treatment (31.8%, 7/22) (p = 0.049). The seizure-free rate of the 21 patients who were continuously treated with PER for 12 months was significantly higher in the patients who used PER as a first add-on treatment (100%, 5/5) than it was in the patients who used PER as a late add-on treatment (37.5%, 6/16) (p = 0.035). Among the patients who achieved seizure freedom, the most frequently administered dose of PER was 2 mg at 6 (62%, 8/13) and 12 months (64%, 7/11). Levetiracetam was the most frequently administered concomitant AED at both 6 (92%, 12/13) and 12 months (91%, 10/11). ConclusionThis retrospective observational study provides evidence supporting the effectiveness of PER as a first add-on therapy in patients with partial epilepsy. Importantly, the seizure-free rate was better when PER was used as a first, rather than a second or later, add-on treatment.

The Role of 5-ALA in Low-Grade Gliomas and the Influence of Antiepileptic Drugs on Intraoperative Fluorescence.

Objectives: Intraoperative tumor visualization with 5-aminolevulinic acid (5-ALA) induced protoporphyrin IX (PpIX) fluorescence is widely applied for improved resection of high-grade gliomas. However, visible fluorescence is present only in a minority of low-grade gliomas (LGGs) according to current literature. Nowadays, antiepileptic drugs (AEDs) are frequently administered to LGG patients prior to surgery. A recent in-vitro study demonstrated that AEDs result in significant reduction of PpIX synthesis in glioma cells. The aim of this study was thus to investigate the role of 5-ALA fluorescence in LGG surgery and the influence of AEDs on visible fluorescence.Patients and Methods: Patients with resection of a newly diagnosed suspected LGG after 5-ALA (25 mg/kg) administration were initially included. During surgery, the presence of visible fluorescence (none, mild, moderate, or bright) within the tumor and intratumoral fluorescence homogeneity (diffuse or focal) were analyzed. Tissue samples from fluorescing and/or non-fluorescing areas within the tumor and/or the assumed tumor border were collected for histopathological analysis (WHO tumor diagnosis, cell density, and proliferation rate). Only patients with diagnosis of LGG after surgery remained in the final study cohort. In each patient, the potential preoperative intake of AEDs was investigated.Results: Altogether, 27 patients with a histopathologically confirmed LGG (14 diffuse astrocytomas, 6 oligodendrogliomas, 4 pilocytic astrocytomas, 2 gemistocytic astrocytomas, and one desmoplastic infantile ganglioglioma) were finally included. Visible fluorescence was detected in 14 (52%) of 27. In terms of fluorescence homogeneity (n = 14), 7 tumors showed diffuse fluorescence, while in 7 gliomas focal fluorescence was noted. Cell density (p = 0.03) and proliferation rate (p = 0.04) was significantly higher in fluorescence-positive than in fluorescence-negative samples. Furthermore, 15 (56%) of 27 patients were taking AEDs before surgery. Of these, 11 patients (73%) showed no visible fluorescence. In contrast, 10 (83%) of 12 patients without prior AEDs intake showed visible fluorescence. Thus, visible fluorescence was significantly more common in patients without AEDs compared to patients with preoperative AED intake (OR = 0,15 (CI 95% 0.012–1.07), p = 0.046).Conclusions: Our study shows a markedly higher rate of visible fluorescence in a series of LGGs compared to current literature. According to our preliminary data, preoperative intake of AEDs seems to reduce the presence of visible fluorescence in such tumors and should thus be taken into account in the clinical setting.

Long-Term Safety, Tolerability, and Efficacy of Cannabidiol in Children with Refractory Epilepsy: Results from an Expanded Access Program in the US.

Purified cannabidiol is a new antiepileptic drug that has recently been approved for use in patients with Lennox-Gastaut and Dravet syndromes, but most published studies have not extended beyond 12-16weeks. The objective of this study was to evaluate the long-term safety, tolerability, and efficacy of cannabidiol in children with epilepsy. Patients aged 1-17years with refractory epilepsy were enrolled in an open-label prospective study through individual patient and expanded access programs between April 2013 and December 2014. Seizure types were video-electroencephalogram confirmed prior to enrollment. After a 28-day evaluation period, during which baseline seizure frequency was assessed, cannabidiol was given as add-on therapy at 5mg/kg/day and titrated weekly by 5-mg/kg increments to a dose of 25mg/kg/day. Blood tests were performed at baseline, after 1, 2, and 3months, and every 3months thereafter. Trough concentrations of concomitant antiepileptic drugs were measured at baseline, after 1, 2, and 3months of therapy, and as clinically indicated afterwards. Concomitant antiepileptic drugs, ketogenic diet ratio, and vagal nerve stimulator settings remained unchanged during the baseline period and the first 3months of treatment, unless there was a significant increase in plasma concentrations. Seizure frequency was reported daily in seizure diaries by parents or caregivers. Clinical assessments occurred after 15days of treatment, at 1month, at 3months, and every 3months thereafter. Diaries of seizure frequency and adverse events were reviewed at each visit. The primary efficacy outcome was a reduction in seizure frequency and responders were defined as those patients achieving a > 50% reduction in motor seizures. Twenty-six children were enrolled. Most had genetic epilepsies with daily or weekly seizures and multiple seizure types. All were refractory to prior antiepileptic drugs (range 4-11, mean 7), and were taking two antiepileptic drugs on average. Duration of therapy ranged from 4 to 53months (mean 21months). Adverse events were reported in 21 patients (80.8%), including reduced appetite in ten (38.4%), diarrhea in nine (34.6%), and weight loss in eight (30.7%). Four (15.4%) had changes in antiepileptic drug concentrations and three had elevated aspartate aminotransferase and alanine aminotransferase levels when cannabidiol was administered together with valproate. Serious adverse events, reported in six patients (23.1%), included status epilepticus in three, catatonia in two, and hypoalbuminemia in one. Fifteen patients (57.7%) discontinued cannabidiol for lack of efficacy, one because of status epilepticus, and one for severe weight loss. The retention rate declined rapidly in the first 6months and more gradually thereafter. At 24months, the number of patients continuing cannabidiol as adjunctive therapy was nine of the original 26 (34.6%). Of these patients, seven (26.9%) had a sustained> 50% reduction in motor seizures, including three (11.5%) who remain seizure free. Over a 4-year period, cannabidiol was effective in 26.9% of children with otherwise refractory epilepsy. It was well tolerated in about 20% of patients, but 80.8% had adverse events, including 23.1% with serious adverse events. Decreased appetite and diarrhea were frequent along with weight loss that became evident only later in the treatment.

Perampanel in routine clinical use in idiopathic generalized epilepsy: The 12-month GENERAL study.

To analyze the effectiveness and tolerability of perampanel across different seizure types in routine clinical care of patients with idiopathic generalized epilepsy (IGE). This multicenter, retrospective, 1-year observational study collected data from patient records at 21 specialist epilepsy units in Spain. All patients who were aged ≥12 years, prescribed perampanel before December 2016, and had a confirmed diagnosis of IGE were included. The population comprised 149 patients with IGE (60 with juvenile myoclonic epilepsy, 51 generalized tonic-clonic seizures [GTCS] only, 21 juvenile absence epilepsy, 10 childhood absence epilepsy, 6 adulthood absence epilepsy, and one Jeavons syndrome). Mean age was 36 years. The retention rate at 12 months was 83% (124/149), and 4 mg was the most common dose. At 12 months, the seizure-free rate was 59% for all seizures (88/149); 63% for GTCS (72/115), 65% for myoclonic seizures (31/48), and 51% for absence seizures (24/47). Seizure frequency was reduced significantly at 12 months relative to baseline for GTCS (78%), myoclonic (65%), and absence seizures (48%). Increase from baseline seizure frequency was seen in 5.2% of patients with GTCS seizures, 6.3% with myoclonic, and 4.3% with absence seizures. Perampanel was effective regardless of epilepsy syndrome, concomitant antiepileptic drugs (AEDs), and prior AEDs, but retention and seizure freedom were significantly higher when used as early add-on (after ≤2 prior AEDs) than late (≥3 prior AEDs). Adverse events were reported in 50% of patients over 12 months, mostly mild or moderate, and irritability (23%), somnolence (15%), and dizziness (14%) were most frequent. In routine clinical care of patients with IGE, perampanel improved seizure outcomes for GTCS, myoclonic seizures, and absence seizures, with few discontinuations due to adverse events. This is the first real-world evidence with perampanel across different seizure types in IGE.

Perampanel in routine clinical use across Europe: Pooled, multicenter, observational data.

To pool observational data on the routine use of perampanel to obtain information on real-world outcomes and data in populations typically underrepresented in clinical trials. Individual-level data of people with epilepsy treated with perampanel at 45 European centers were merged into a single dataset. Prespecified outcomes were: 1-year retention rate, 1-year seizure freedom rate (duration≥6months), and incidence of treatment-emergent adverse events (TEAEs). In addition, relationships were explored with logistic regression analyses. The full analysis set comprised 2396 people: 95% had focal seizures; median epilepsy duration was 27years; median number of concomitant antiepileptic drugs (AEDs) was 2; and median prior AEDs was 6. One-year retention rate was 48% (1117/2332; 95% confidence interval [CI] 46-50%), and 1-year seizure-free rate (≥6-month duration) was 9.2% (74/803; 95% CI 7-11%). Median treatment duration was 11.3months (1832 patient-years); median dose was 8mg. In 388 individuals with available data at 3, 6, and 12months, responder rates were 42%, 46%, and 39%, respectively. During the first year, TEAEs were reported in 68% of participants (1317/1497; 95% CI 66-70%). Logistic regression found higher age at perampanel initiation was associated with higher seizure-free rate, and higher number of prior AEDs with lower seizure-free rate and lower rates of somatic TEAEs. In 135 individuals aged ≥65years, 1-year retention rate was 48% and seizure-free rate was 28%. Across a large, treatment-resistant population, add-on perampanel was retained for ≥1year by 48% of individuals, and 9% were seizure-free for ≥6months. TEAEs were in line with previous reports in routine clinical use, and less frequent than in the clinical trial setting. No new or unexpected TEAEs were seen. Despite the limitations of observational studies, our data indicate that some individuals may derive a marked benefit from the use of perampanel.

Antiepileptic drugs and suicide-related behavior: Is it the drug or comorbidity?

We sought to compare trends of suicide-related behavior (SRB) before and after initiation of antiepileptic drug (AED) therapy among AED users (with and without epilepsy) to that of individuals without AED use controlling for sociodemographic characteristics and mental health comorbidity. We used national Veterans Health Administration (VHA) data for post-9/11 veterans who received VHA care (2013-2014) without prior AED use. We conducted generalized estimation equation (GEE) analyses, stratified by epilepsy status and type of AED received, to assess the trend of SRB prevalence the year prior to and after the index date (date of first AED prescription/date of first health care encounter for non-AED users) controlling for sociodemographic factors and mental health comorbidity. The GEE analysis showed significant curvilinear trends of SRB prevalence over the 24-month study period among the AED users, indicating that the probability of SRB diagnoses increased over time with a peak before the index month and decreased thereafter. Similar patterns were observed among non-AED users, but significantly lower odds for SRB. Among AED users, there were no significant differences by epilepsy status; however, higher SRB prevalence and differential SRB trajectory measures were observed among those who received AEDs with mood-stabilizing action. The peak of SRB prior to and rapid reduction in SRB after initiation of AED, and the finding that individuals eventually prescribed a mood-stabilizing AED (vs other AED or levetiracetam) had higher odds of SRB, suggests a strong possibility that the relationship of AED and SRB is one of residual confounding.

Efficacy and tolerability of adjunctive brivaracetam in patients with prior antiepileptic drug exposure: A post-hoc study

Brivaracetam (BRV), a selective, high-affinity ligand for synaptic vesicle protein 2A, is a new antiepileptic drug (AED) for adjunctive treatment of focal (partial-onset) seizures in adults with epilepsy. This post-hoc analysis was conducted to explore the efficacy of adjunctive BRV in patients with prior levetiracetam (LEV) exposure and whether changes in efficacy were related to the similar mechanism of action of these two drugs. Data were pooled from three Phase III studies (NCT00490035; NCT00464269; NCT01261325) of adults with focal seizures taking 1–2 AEDs who received placebo or BRV 50–200mg/day without titration over a 12-week treatment period. Patients taking concomitant LEV at enrollment were excluded from this analysis. Patients were categorized by their status of prior exposure to LEV, carbamazepine (CBZ), topiramate (TPM), or lamotrigine (LTG), to investigate any consistent trend towards reduced response in AED-exposed subgroups compared to AED-naïve subgroups, regardless of the mechanism of action. Study completion rates, percent reduction from baseline in focal seizure frequency over placebo, ≥50% responder rates, and tolerability were evaluated for each subgroup. A total of 1160 patients were investigated. Study completion rates were similar in the AED-exposed subgroups and AED-naïve subgroups. In subgroups with (531 patients) or without (629 patients) prior LEV exposure, ≥50% responder rates for each dose of BRV compared with placebo were generally higher among the LEV-naïve subgroups than the previously LEV-exposed subgroups. LEV-exposed subgroups receiving BRV doses ≥50mg/day showed greater ≥50% responder rates than those receiving placebo. Similar results were observed for CBZ, TPM, and LTG. Previous treatment failure with commonly prescribed AEDs (LEV, CBZ, TPM, or LTG) is associated with a reduced response to BRV irrespective of the mechanism of action. Hence, this post-hoc analysis indicates that previous treatment failure with LEV does not preclude the use of BRV in patients with epilepsy.

Use and cost comparison of clobazam to other antiepileptic drugs for treatment of Lennox-Gastaut syndrome

ABSTRACTBackground: Lennox-Gastaut syndrome (LGS) is a severe form of childhood-onset epilepsy associated with serious injuries due to frequent and severe seizures. Of the antiepileptic drugs (AEDs) approved for LGS, clobazam is a more recent market entrant, having been approved in October 2011. Recent AED budget impact and cost-effectiveness analyses for LGS suggest that adding clobazam to a health plan formulary may result in decreased medical costs; however, research on clinical and economic outcomes and treatment patterns with these AED treatments in LGS is limited.Objectives: To compare the baseline characteristics and treatment patterns of new initiators of clobazam and other AEDs among LGS patients and compare healthcare utilization and costs before and after clobazam initiation among LGS patients.Methods: A retrospective study of probable LGS patients was conducted using the MarketScan® Commercial, Medicare Supplemental, and Medicaid databases (10/1/2010-3/31/2014).Results: In the Commercial/Medicare Supplemental population, clobazam users were younger, had fewer comorbidities, and more prior AED use than non-clobazam users. In the 12 months pre-treatment initiation, clobazam users had significantly more seizure-related inpatient stays and outpatient visits and higher total seizure-related (P < 0.001) and all-cause (P < 0.001) costs than non-clobazam users. Among clobazam users, when compared to the 12 months pre-clobazam initiation, seizure-related medical utilization and costs were lower in the 12 months post-clobazam initiation (P = 0.004). Total all-cause (P < 0.001) and seizure-related (P = 0.029) costs increased post-clobazam initiation mainly due to the increase in outpatient pharmacy costs. Similar results were observed in the Medicaid population.Conclusions: Baseline results suggest a prescribing preference for clobazam in severe LGS patients. Clobazam users had a reduction in seizure-related medical utilization and costs after clobazam initiation. The improvement in medical costs mostly offset the higher prescription costs following clobazam initiation.

NEOPLASM study: Real-life use of lacosamide in patients with brain tumor-related epilepsy.

The choice of antiepileptic drug (AED) therapy in patients with brain tumor-related epilepsy (BTRE) is complicated, and there are a lack of robust clinical trial data to date. The NEOPLASM (Neuroncologic Patients treated with LAcoSaMide) study was a 6-month, multicenter, retrospective, observational study in patients with BTRE treated with lacosamide. Patients were started on lacosamide because of a lack of efficacy or adverse events (AEs) with prior AEDs or suitability versus other AEDs, according to clinical practice. The primary efficacy variable was the seizure-free rate at 6months. Safety variables included the proportion of patients with an AE and the proportion with an AE that led to discontinuation. Overall, 105 patients from 14 hospital centers were included in the analysis. Treatment with lacosamide for 6months resulted in a 30.8% seizure-free rate, and 66.3% of patients had a ≥50% seizure reduction (responders). In the subset of patients included because of a lack of efficacy with prior AEDs, seizure-free rates were 28.0%, and 66.7% of patients were responders. No statistically significant differences in efficacy were observed according to the mechanism of action or enzyme-inducing properties of concomitant AEDs. Adverse events were reported by 41.9% of patients at 6months, and 4.7% of them led to discontinuation. The most common AEs were somnolence/fatigue and dizziness. Notably, 57.1% of the patients who were switched to lacosamide because of AEs with their previous therapy did not report any AE at 6-month follow-up. In this open-label, observational study, lacosamide appeared to be effective and well tolerated in a large population of patients with BTRE. Lacosamide may therefore be a promising option for the treatment of patients with BTRE.

Safety, efficacy and outcome-related factors of perampanel over 12 months in a real-world setting: The FYDATA study

BackgroundReal-world data of current antiepileptic drugs (AEDs) used to treat focal seizures is of importance to understand the efficacy and safety outside of the clinical trial setting. Here we report real-world data from a large series of patients treated with perampanel for 1year. MethodsFYDATA was a multicentre, retrospective, 1-year observational study assessing the efficacy and safety of adjuvant perampanel in patients ≥12 years of age with focal epilepsy in a real-world setting. At 12 months, the proportion of patients who were seizure free, median percentage seizure reduction, proportion of responders, retention rate and proportion of patients with adverse events (AEs) were assessed. Analyses were also performed to identify any patient-, medication- and disease-related factors associated with a large clinical response or carry a risk for AEs. ResultsA total of 464 patients were included in the study with a retention rate of 60.6% at 1year. The mean number of prior AEDs was 7.8. The median percentage reduction in overall seizures was 33.3% (75% for secondary generalised seizures) after 1year, with 7.2% of patients achieving seizure freedom. Furthermore, patients on non-enzyme-inducing AEDs were more likely to achieve seizure freedom, and logistic regression revealed that patients aged ≥65 years, those with epilepsy due to a vascular aetiology and those who had received fewer prior AEDs showed a better clinical response to perampanel. A total of 62.9% of the patients experienced AEs at 12 months; dizziness, somnolence and irritability were the most frequent AEs. Patients with prior psychiatric comorbidities (hyperactivity and personality disorder) were more likely to experience psychiatric AEs with perampanel, and slower titration schedules were associated with less AEs overall. ConclusionPerampanel, for the treatment of focal epilepsy in a real-world setting in a refractory population, over 1year, demonstrates a similar efficacy and safety profile to that observed in clinical trials. Our results have implications for the optimisation of perampanel use in a clinical setting.

Lacosamide use in children with epilepsy: Retention rate and effect of concomitant sodium channel blockers in a large cohort.

To evaluate the effectiveness of lacosamide (LCM) in pediatric patients, using time to treatment failure as the outcome measure, and to assess the impact of concomitant sodium channel blocker (SCB) use on LCM retention. This is a retrospective cohort study of patients <21 years old receiving LCM from 2010 to 2015. Kaplan-Meier survival curves were generated for time to LCM failure, defined as discontinuation of LCM or addition of another antiepileptic therapy. The impact of concomitant use of traditional SCB agents (phenytoin, carbamazepine, oxcarbazepine, and/or lamotrigine) and other factors including age, seizure types, fast drug titration, and prior antiepileptic drug history were evaluated using Cox regression. The analysis cohort included 223 patients, of whom 116 were taking one or more SCBs, with median follow-up of 7.4 months (1-53 months). For all patients, the probability of remaining on LCM without addition of another therapy was 44.7% at 12 months and 25.6% at 24 months. Concomitant SCB use was an independent predictor of time to LCM failure (hazard ratio [HR] 1.91, 95% confidence interval [CI] 1.38-2.65, p < 0.001).Although treatment emergent adverse effects were reported more often in patients taking SCB (65% vs. 39%, p < 0.001), intolerability was rarely the sole reason cited for LCM discontinuation, and SCB use was strongly associated with LCM failure, even when controlling for presence of treatment emergent adverse effects (adjusted HR 1.99, 95% CI 1.36-2.90, p < 0.001). This study provides observational evidence for treatment persistence of LCM in children, in a large cohort with long-term follow-up, using time to treatment failure as the outcome measure. Concomitant SCB use was a key factor increasing risk of LCM failure, but not due to treatment-emergent adverse effects alone.

Plasma carnitine levels in children with idiopathic epilepsy treated with old and new antiepileptic drugs

Prolonged antiepileptic drugs (AEDs) treatment can result in secondary carnitine deficiency. Clinical studies indicate a decrease in free and total carnitine levels in children treated with old-generation AEDs (especially valproate). A number of studies on the effect of valproic acid and/or other AEDs on carnitine concentrations yielded contradictory results. The effect of new AEDs as oxcarbazepine and lamotrigine on carnitine metabolism has not been reported previously. The aim of this study was to evaluate the plasma carnitine level in children with idiopathic epilepsy treated with old AEDs (valproic acid and carbamazepine) and new AEDs (lamotrigine and oxcarbazepine). Fifty children with newly diagnosed idiopathic epilepsy were selected from those at- tending the pediatric neurology out-patient clinic at Tanta University Hosptial. Thirty-four males and 16 females were enrolled in the study with the mean age was (6.8 ± 3.1 yr). Patients were grouped according to their antiepileptic treatment into: group 1, 20 patients received valproic acid as monotherapy with no prior AEDs use. Group 2, 10 patients received valproic acid as poly- therapy after 3 mo treatment with carbamazepine. Group 3, 10 patients received lamotrigine as monotherapy, and group 4, 10 patients received oxcarbazepine as monotherapy. Twenty healthy children served as control group with mean age was (8.5 ± 2.3 yr). Estimation of the plasma carnitine levels were done for all the studied groups. Group 1 and group 2 epileptic children, treated with valproic acid monotherapy and polytherapy respectively had significantly lower plasma carnitine levels than that of the control group (P 0.05). In conclusion, carnitine deficiency is not uncommon among children with epilepsy and is mainly linked to valproate therapy. In contrast, new-generation AEDs probably do not cause carnitine deficiency. These findings suggest a need to monitor serum carnitine levels in children treated with valproic acid therapy.

Vagus nerve stimulation and late-onset bradycardia and asystole: Case report

Vagus nerve stimulation (VNS) therapy is approved in the United States by the FDA in 1997 for medically refractory partial epilepsy in patients of ages 12 years and above. The most common stimulation-associated side effects are voice alteration, hoarseness, throat and neck pain, headache, cough, and dyspnea. Four patients with VNS had late-onset bradycardia and asystole, attributed to VNS stimulation. Their ages were 13, 17, 47, and 55. Cardiac symptoms were noted after 2.33–9 years postimplantation [1–4]. Three cases had symptoms correlated with stimulation, monitored by electrocardiogram [1,2,4]. This new case report highlights cardiac syncope with very similar clinical presentation as previous four cases, and raises the concern for cardiac symptoms, even many years after VNS implantation.

Early add-on lacosamide in a real-life setting: results of the REALLY study.

Many patients with epilepsy are treated with antiepileptic drug (AED) polytherapy. Several factors influence the choice of early add-on therapy, and deciding on the most appropriate drug can be difficult. This study aimed to assess the efficacy and tolerability of lacosamide as early add-on therapy in patients with partial-onset seizures. REALLY (REtrospective study of lAcosamide as earLy add-on aLong one Year) was a multicenter, retrospective, 1-year, real-life study. Patients included were aged older than 16years, had partial-onset seizures, and were treated with lacosamide as add-on therapy after one or two prior AEDs. Data were collected retrospectively from clinical records. The primary study objective was to assess the efficacy of lacosamide over 12months (seizure-free and responder rates), and the secondary objective was to assess the tolerability of lacosamide at 3, 6, and 12months [adverse events (AEs) and discontinuation]. One hundred and ninety-nine patients were enrolled in the study; 89 patients (44.7%) had tried one AED and 110 patients (55.3%) had tried two AEDs before lacosamide. At 12months, the proportion of patients who were seizure free was 44.9%, and 76% of patients were responders. The seizure-free rate at 12months for patients who had previously received one or two AEDs was 58 and 34.3%, and the responder rate at 12months was 83.0 and 70.4%, respectively. The AE rate was 21.5% at 3months, 27.1% at 6months, and 31.2% at 12months, with 7.0% of patients discontinuing treatment because of an AE. The most common AE reported was dizziness (11.6%). Cryptogenic epilepsy, a higher number of prior AEDs, and the use of a sodium channel blocker at onset were associated with a worse outcome. The number of concomitant AEDs decreased over 1year (Z=5.89; p<0.001). Twenty-two patients were converted to lacosamide monotherapy with at least one evaluation ≥6months from the beginning of monotherapy conversion. Lacosamide was effective and well tolerated as early add-on treatment in patients who had received one or two previous AEDs.

Control of seizures in different stages of partial epilepsy: LACO-EXP, a Spanish retrospective study of lacosamide

Lacosamide is approved as adjunctive therapy for focal epilepsies. The number of antiepileptic drugs (AEDs) tried is associated with prognosis. This multicenter, retrospective, observational study (LACO-EXP) in Spain in 500 adult patients with focal epilepsies examined the efficacy and tolerability of add-on lacosamide. Factors associated with better efficacy/tolerability were analyzed. After 12months, the responder rate (≥50% reduction in seizure frequency) was 57.1%, and the seizure-free rate was 14.9%. Efficacy was better when lacosamide was the first or second add-on AED, although there was a small chance to be seizure-free even for patients who had received ≤10 prior AEDs. The mechanism of action of concomitant AEDs is important in all the stages, but differences are smaller in the early stages. Lacosamide was generally well tolerated. A slower dosage–titration schedule was associated with a lower adverse event rate. Further investigation of the timing of initiation of lacosamide add-on therapy and ideal combinations of AEDs is required.

Adjunctive Madopar for ultrarefractory epilepsy? Preliminary observations

BackgroundThe optimum drug treatment for ultrarefractory epilepsy after failure of seven prior antiepileptic drugs (AEDs) remains uncertain. Prompted by reports that adjunctive amantadine or l-dopa has been useful for children with refractory absence seizures and Lennox–Gastaut syndrome, we studied the utility of dopaminergic agents for adults with ultrarefractory epilepsy. MethodsWe assessed seizure control following adjunctive treatment for up to 12months with the dopaminergic agent Madopar© in three adult patients with ultrarefractory epilepsy following brain injury or with Lennox–Gastaut syndrome, who had not achieved sustained seizure remission during past treatment with at least seven lifetime AEDs. FindingsThe adjunctive use of Madopar was associated with a reduction or remission of tonic–clonic seizures in two patients. However, Madopar seemed to have aggravated absence seizures in the patient with Lennox–Gastaut syndrome. InterpretationAlthough our preliminary observations do not and cannot establish the efficacy or safety of adjunctive Madopar, it may be an option for treatment of ultrarefractory focal seizures in adults if confirmed by randomized controlled trials.