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Epilepsy is associated with increased mortality. Cardiovascular disease confers a significant portion of this increased risk. Recently there is increased interest in the burden of cardiovascular mortality in people with epilepsy. This review discusses the most common cardiovascular risk factors and their association with epilepsy including obesity, diabetes mellitus, and hyperlipidemia. Hyperlipidemia related to the use of enzyme inducing anti-seizure medications is also discussed as a topic that is of particular importance to prescribers that have patients with comorbid cardiovascular risk and epilepsy. Heart rate variability (HRV) and its association with SUDEP is discussed as well as a contributor to vascular risk. Finally, the authors discuss a potential role for neurologists who treat epilepsy to engage closer with their patient's cardiovascular risk factors using available tools such as a the ASCVD score calculator to determine the overall risk of mortality, as well as acting upon this information to guide treatment approaches integrating the information provided in this review.
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BACKGROUND AND OBJECTIVES: Mood, anxiety disorders, and suicidality are more frequent in people with epilepsy than in the general population. Yet, their prevalence and the types of mood and anxiety disorders associated with suicidality at the time of the epilepsy diagnosis are not established. We sought to answer these questions in patients with newly diagnosed focal epilepsy and to assess their association with suicidal ideation and attempts. METHODS: The data were derived from the Human Epilepsy Project study. A total of 347 consecutive adults aged 18-60 years with newly diagnosed focal epilepsy were enrolled within 4 months of starting treatment. The types of mood and anxiety disorders were identified with the Mini International Neuropsychiatric Interview, whereas suicidal ideation (lifetime, current, active, and passive) and suicidal attempts (lifetime and current) were established with the Columbia Suicidality Severity Rating Scale (CSSRS). Statistical analyses included the t test, χ2 statistics, and logistic regression analyses. RESULTS: A total of 151 (43.5%) patients had a psychiatric diagnosis; 134 (38.6%) met the criteria for a mood and/or anxiety disorder, and 75 (21.6%) reported suicidal ideation with or without attempts. Mood (23.6%) and anxiety (27.4%) disorders had comparable prevalence rates, whereas both disorders occurred together in 43 patients (12.4%). Major depressive disorders (MDDs) had a slightly higher prevalence than bipolar disorders (BPDs) (9.5% vs 6.9%, respectively). Explanatory variables of suicidality included MDD, BPD, panic disorders, and agoraphobia, with BPD and panic disorders being the strongest variables, particularly for active suicidal ideation and suicidal attempts. DISCUSSION: In patients with newly diagnosed focal epilepsy, the prevalence of mood, anxiety disorders, and suicidality is higher than in the general population and comparable to those of patients with established epilepsy. Their recognition at the time of the initial epilepsy evaluation is of the essence.
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Trastorno Depresivo Mayor , Epilepsias Parciales , Suicidio , Adulto , Humanos , Ideación Suicida , Trastornos de Ansiedad/epidemiología , Trastornos de Ansiedad/diagnóstico , Trastorno Depresivo Mayor/psicología , Comorbilidad , Epilepsias Parciales/epidemiología , Factores de RiesgoRESUMEN
Antiepileptic drugs (AEDs) are used in various pathologies such as including epilepsy, migraine, neuropathic pain, etc. They can improve symptoms but cause adverse events (ADRs). Case reports have reported that one rare but serious AED-induced adverse reaction that has appeared in case reports is myotoxicity from rhabdomyolysis. Rhabdomyolysis can be induced by a therapeutically dosed occur with therapeutic doses of antiepileptic drugs and is in most cases reversible, although rarely it can cause serious complications. Clinical manifestations of rhabdomyolysis range from a single isolated asymptomatic rise in serum CK levels to severe electrolyte imbalances, cardiac arrhythmia, acute and disseminated renal failure, intravascular coagulation, and other symptoms. Many clinical cases reported that both conventional older and newer AEDs, as well as propofol, can cause rhabdomyolysis, even if there are no conclusive data. It has recently been shown that genetic factors certainly contribute to adverse reactions of antiepileptic drugs. A study of genetic polymorphism in patients with AED-induced rhabdomyolysis may be useful to explain the rarity of this adverse event and to improve the treatment of these AED patients, in terms of AED type and dose adjustment.
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Anticonvulsivantes , Epilepsia , Miotoxicidad , Neuralgia , Anticonvulsivantes/efectos adversos , Epilepsia/tratamiento farmacológico , Humanos , Neuralgia/tratamiento farmacológicoRESUMEN
PURPOSE: There are longstanding concerns about the impact of enzyme-inducing anti-seizure medications (ASMs) on vitamin D, an important molecule in both bone metabolism and inflammation pathways. The relationship between chronic use of carbamazepine and vitamin D levels has been studied, but no comprehensive review to inform practitioners and policymakers is currently available. We performed a meta-analysis on studies that measured 25-hydroxyvitamin D (25OHD) levels in persons taking carbamazepine to determine whether this drug significantly reduces circulating 25OHD. PRINCIPAL RESULTS: From a literature search of the terms "carbamazepine" and "vitamin D", we identified 12 studies that measured 25OHD levels in persons on carbamazepine monotherapy groups and controls. Persons taking carbamazepine had significantly lower 25OHD levels than persons not taking carbamazepine. The average 25OHD levels of carbamazepine-treated patients across all studies was 21.8 ng/mL (IQR 15.4,26.0) whereas 25OHD levels of control subjects was 28.0 ng/mL (IQR 20.8,30.4). The weighted difference of means was 4.00 ng/mL of 25OHD. Neither age nor sex nor duration of carbamazepine therapy had a significant impact on this finding. The effect was similar irrespective of whether the comparator group consisted of healthy controls or epilepsy patients taking non-inducing medications. MAJOR CONCLUSIONS: Carbamazepine use is associated with a reduction of 25OHD levels. In combination with other literature establishing the problematic metabolic effects of carbamazepine, this meta-analysis provides additional evidence in favor of the use of alternative ASMs as first-line agents. At minimum, vitamin D supplementation should be strongly considered for patients prescribed carbamazepine.
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Epilepsia , Deficiencia de Vitamina D , Carbamazepina/uso terapéutico , Epilepsia/complicaciones , Epilepsia/tratamiento farmacológico , Humanos , Vitamina D/uso terapéutico , Deficiencia de Vitamina D/tratamiento farmacológico , VitaminasRESUMEN
OBJECTIVE: To evaluate whether cardiovascular risk, risk awareness, and guideline concordant treatment differ in individuals with versus without epilepsy. METHODS: This was a retrospective cross-sectional study using the National Health and Nutrition Examination Survey. We included participants ≥18â¯years for 2013-2018. We classified participants as having epilepsy if reporting ≥1 medication treating seizures. We calculated 10-year atherosclerotic cardiovascular disease (ASCVD) risk using the revised pooled cohort equation. We compared unadjusted and adjusted risk for participants with versus without epilepsy. We then assessed hypertension and diabetes disease awareness and control, plus statin guideline-concordance. We assessed mediators for both ASCVD risk and cardiovascular disease awareness. RESULTS: Of 17,961 participants, 154 (0.9%) had epilepsy. Participants with epilepsy reported poorer diet (pâ¯=â¯0.03), fewer minutes of moderate-vigorous activity per day (pâ¯<â¯0.01), and increased frequency of cardiovascular conditions (e.g. coronary heart disease, myocardial infarction, stroke). There was no difference in control of individual examination and laboratory risk factors between groups (A1c, systolic blood pressure, diastolic blood pressure, high-density lipoprotein, low-density lipoprotein, total cholesterol). However, epilepsy was associated with 52% (95% confidence interval [CI]: 0-130%) increase in ASCVD risk, which became nonsignificant after adjusting for health behaviors. No single studied variable (income, Patient Health Questionnaire-9 (PHQ-9), diet, smoking) had a significant indirect effect. Participants with epilepsy reported increased hypertension awareness which was trivially but significantly mediated by having a routine place of healthcare (indirect effect: 1% absolute increase (95% CI: 0-1%), and they reported increased rates of hypertension treatment and guideline-concordant statin therapy. Participants with versus without epilepsy reported similar rates of blood pressure control and diabetes awareness, treatment, and control. CONCLUSIONS: Participants with epilepsy had increased ASCVD risk, despite similar or better awareness, treatment, and control of individual risk factors such as diabetes and hypertension. Our results suggest that epilepsy is associated with numerous health behaviors leading to cardiovascular disease, though the causal pathway is complex as these variables (income, depression, diet, exercise, smoking) generally served as confounders rather than mediators.
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Enfermedades Cardiovasculares , Epilepsia , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Enfermedades Cardiovasculares/epidemiología , Estudios Transversales , Epilepsia/tratamiento farmacológico , Epilepsia/epidemiología , Humanos , Encuestas Nutricionales , Estudios Retrospectivos , Factores de RiesgoAsunto(s)
Autoanticuerpos/inmunología , Enfermedades Autoinmunes/etiología , Carcinoma de Células Escamosas/complicaciones , Encefalitis Límbica/etiología , Neoplasias Pulmonares/complicaciones , Anciano , Carcinoma de Células Escamosas/inmunología , Carcinoma de Células Escamosas/cirugía , Femenino , Humanos , Péptidos y Proteínas de Señalización Intracelular/inmunología , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/cirugíaRESUMEN
Phenytoin is an antiepileptic drug with a narrow therapeutic index and large interpatient pharmacokinetic variability, partly due to genetic variation in CYP2C9. Furthermore, the variant allele HLA-B*15:02 is associated with an increased risk of Stevens-Johnson syndrome and toxic epidermal necrolysis in response to phenytoin treatment. We summarize evidence from the published literature supporting these associations and provide therapeutic recommendations for the use of phenytoin based on CYP2C9 and/or HLA-B genotypes (updates on cpicpgx.org).
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Citocromo P-450 CYP2C9/genética , Antígenos HLA-B/genética , Fenitoína/administración & dosificación , Alelos , Anticonvulsivantes/administración & dosificación , Variación Genética/genética , Genotipo , Humanos , Farmacogenética/métodos , Síndrome de Stevens-Johnson/tratamiento farmacológico , Síndrome de Stevens-Johnson/genéticaRESUMEN
OBJECTIVE: We compared long-term seizure outcome, neuropsychological outcome, and occupational outcome of anterior temporal lobectomy (ATL) with and without sparing of mesial structures to determine whether mesial sparing temporal lobectomy prevents memory decline and thus disability, with acceptable seizure outcome. METHODS: We studied patients (nâ¯=â¯21) and controls (nâ¯=â¯21) with no evidence of mesial temporal sclerosis (MTS) on MRI who had surgery to treat drug-resistant epilepsy. Demographic and pre- and postsurgical clinical characteristics were compared. Patients had neuropsychological assessment before and after surgery. Neuropsychological analyses were limited to patients with left-sided surgery and available data (nâ¯=â¯14 in each group) as they were at risk of verbal memory impairment. The California Verbal Learning Test II (CVLT-II) (sum of trials 1-5, delayed free recall) and the Logical Memory subtest of the Wechsler Memory Scale III or IV (WMS-III or WMS-IV) (learning and delayed recall of prose passages) were used to assess verbal episodic learning and memory. Seizure and occupational outcomes were assessed. RESULTS: The chance of attaining seizure freedom was similar in the two groups, so sparing mesial temporal structures did not lessen the chance of stopping seizures. Sparing mesial temporal structures mitigated the extent of postoperative verbal memory impairment, though some of these individuals suffered decline as a consequence of surgery. Occupational outcome was similar in both groups. SIGNIFICANCE: Mesial temporal sparing resections provide a similar seizure outcome as ATL, while producing a better memory outcome. Anterior temporal lobectomy including mesial structure resection did not increase the risk of postoperative disability.
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Epilepsia Refractaria , Epilepsia del Lóbulo Temporal , Lobectomía Temporal Anterior , Epilepsia Refractaria/cirugía , Epilepsia del Lóbulo Temporal/cirugía , Hipocampo/cirugía , Humanos , Pruebas Neuropsicológicas , Lóbulo Temporal/cirugía , Resultado del TratamientoRESUMEN
OBJECTIVE: The effects of anticonvulsants on lipids are the subject of considerable concern and investigation, but there are almost no data on this issue from randomized trials. We evaluated serum lipid profiles in adults with newly diagnosed epilepsy, following randomization to lacosamide (LCM) or carbamazepine (CBZ) monotherapy. METHODS: We analyzed data from a Phase 3, international, randomized, double-blind trial of LCM vs CBZ for the initial treatment of focal epilepsy. Serum lipid profiles in patients not taking lipid-lowering agents and providing blood samples under fasting conditions before treatment, and following 3 or 12 months of treatment with LCM or CBZ at various doses were analyzed. RESULTS: At 12 months, 271 patients satisfied the inclusion criteria for the analysis. No change was observed in LCM-treated patients for total cholesterol, cholesterol fractions, or triglycerides. CBZ-treated patients showed an increase of 21.1 mg/dL in total cholesterol, 12.6 mg/dL in low-density lipoprotein (LDL) cholesterol, 12.5 mg/dL in non-high density lipoprotein (non-HDL) cholesterol, and 8.5 mg/dL in HDL cholesterol; triglycerides remained unchanged. The proportion of patients with elevated total cholesterol levels (above the upper limit of the reference range) did not change in the LCM treatment group (37.0% at Baseline; 34.8% at 12 months), but increased from 30.8% (at Baseline) to 49.6% (at 12 months) in the CBZ treatment group. SIGNIFICANCE: This study provides Class II evidence that CBZ elevates serum lipids, whereas LCM has no effect on lipids. It supports LCM as an appropriate choice for new-onset focal epilepsy.
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Anticonvulsivantes/uso terapéutico , Carbamazepina/uso terapéutico , Epilepsia/tratamiento farmacológico , Lacosamida/uso terapéutico , Lípidos/sangre , Anticonvulsivantes/efectos adversos , Carbamazepina/efectos adversos , Colesterol/sangre , HDL-Colesterol/sangre , LDL-Colesterol/sangre , Método Doble Ciego , Epilepsia/sangre , Humanos , Lacosamida/efectos adversos , Triglicéridos/sangreRESUMEN
OBJECTIVE: To determine the incidence of hyperlipidemia after first anticonvulsant treatment for seizures, using a large US administrative claims database. METHODS: We obtained data from the MarketScan Commercial and Medicare databases for 2005-2009 for all adult patients newly treated with an anticonvulsant for seizures who had no previous history of hyperlipidemia or treatment with a lipid-lowering agent. We divided the population based upon whether they were treated with an enzyme-inducing anticonvulsant (phenytoin, carbamazepine, phenobarbital, primidone) or a noninducing anticonvulsant (all others). The primary outcome measure was a new diagnosis of hyperlipidemia during subsequent follow-up. We accounted for a large number of demographic and clinical covariates. RESULTS: Of 11 374 subjects, 8778 (77%) were prescribed noninducers and 2596 (23%) were prescribed inducers. New hyperlipidemia diagnoses were seen in 14.6% of the patients started on inducing anticonvulsants and 10.7% of the patients started on noninducing anticonvulsants (P < .001). Both hyperlipidemia and the use of inducers were significantly associated with older age and male gender. After accounting for covariates, inducer prescription was still associated with 23% higher odds of a subsequent diagnosis of hyperlipidemia (odds ratio = 1.225, 95% confidence interval = 1.066-1.408, P < .001). SIGNIFICANCE: The use of enzyme-inducing anticonvulsants in patients with newly diagnosed epilepsy was associated with a significant increase in subsequent diagnoses of hyperlipidemia, suggesting that the lipid-elevating properties of these agents are of genuine clinical importance. This adds to the body of data demonstrating that these agents are likely associated with additional hassle, cost, and morbidity.
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Anticonvulsivantes/efectos adversos , Hiperlipidemias/inducido químicamente , Hiperlipidemias/epidemiología , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Anticonvulsivantes/uso terapéutico , Bases de Datos Factuales , Epilepsia/complicaciones , Epilepsia/tratamiento farmacológico , Femenino , Humanos , Hiperlipidemias/tratamiento farmacológico , Hipolipemiantes/uso terapéutico , Incidencia , Masculino , Medicare , Persona de Mediana Edad , Población , Convulsiones/complicaciones , Convulsiones/tratamiento farmacológico , Factores Sexuales , Factores Socioeconómicos , Resultado del Tratamiento , Estados Unidos/epidemiología , Adulto JovenRESUMEN
OBJECTIVE: To evaluate the impact of eslicarbazepine acetate (ESL) monotherapy on markers of bone and lipid metabolism. METHODS: We conducted a post-hoc analysis of data pooled from two Phase III, dose-blind, conversion-to-ESL (1600â¯mg and 1200â¯mg) monotherapy studies in patients with focal seizures. Laboratory measurements included lipids (total cholesterol [TC]; high-density lipoprotein cholesterol [HDL-C]; low-density lipoprotein cholesterol; and triglycerides) and markers of bone metabolism (alkaline phosphatase; 25-hydroxyvitamin D; osteocalcin; and parathyroid hormone [PTH]); measurements were taken at baseline, Week 18, and Month 12, and analyzed according to enzyme-inducing antiepileptic drugs (EIAEDs) use at baseline (+EIAED and -EIAED subgroups). RESULTS: Data from 337 treatment-compliant patients were used for the Week 18 analyses (+EIAED subgroup, nâ¯=â¯119; -EIAED subgroup, nâ¯=â¯218); data from 161 treatment-compliant patients were used for the Month 12 analyses (+EIAED subgroup, nâ¯=â¯53; -EIAED subgroup, nâ¯=â¯108). At baseline, alkaline phosphatase and PTH concentrations were higher in theâ¯+â¯EIAED versus -EIAED subgroup. Changes from baseline in markers of bone turnover were generally insignificant, except for some elevation in alkaline phosphatase in the -EIAED subgroup (18 weeks and 12 months) and osteocalcin in both subgroups (18 weeks only). Regarding lipids, TC and HDL-C concentrations were higher in theâ¯+â¯EIAED versus -EIAED subgroup at baseline. Concentrations of markers of lipid metabolism fell in theâ¯+â¯EIAED group and rose in the -EIAED group, reaching very similar values that were intermediate between the -EIAED andâ¯+â¯EIAED baseline values. CONCLUSIONS: Based on this retrospective analysis, ESL seems to have had only a modest and primarily clinically insignificant impact on plasma lipids. More prospective data are needed to definitively ascertain the effects of ESL on bone metabolism.
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Anticonvulsivantes/uso terapéutico , Huesos/metabolismo , Dibenzazepinas/farmacología , Metabolismo de los Lípidos/efectos de los fármacos , Adolescente , Adulto , Biomarcadores/análisis , Femenino , Humanos , Lípidos , Masculino , Persona de Mediana Edad , Triglicéridos/metabolismo , Adulto JovenRESUMEN
OBJECTIVE: To examine serologic markers of vascular risk under treatment with commonly used antiepileptic drugs (AEDs) in the elderly in a randomized setting, and to determine whether the reduced exposure to hydroxymethylglutaryl-CoA reductase inhibitors ("statins") caused by carbamazepine reduces the effectiveness of the drugs as lipid-lowering agents. METHODS: Standard lipid fractions, lipoprotein(a), and C-reactive protein (CRP) were examined in a subset of those participating in the STEP-ONE trial, in which elderly patients with new epilepsy were randomized to treatment with carbamazepine, lamotrigine, or levetiracetam. Separate comparisons were made by individual AED, among those treated with statins, and, for CRP, among those treated with anti-inflammatory drugs. RESULTS: One hundred ninety-four patients had the aforementioned serologic measurements. In patients not taking statins, those treated with carbamazepine had higher total cholesterol than those treated with levetiracetam (+16.6 mg/dL, P = 0.053), with values from patients on lamotrigine intermediate, whereas cholesterol fractions were subject to drug-gender interactions which did not show a consistent pattern. Lipoprotein(a) was significantly lower in lamotrigine patients than in the carbamazepine and levetiracetam groups. After accounting for the effects of steroids, CRP was higher in carbamazepine patients than in other patients. Patients taking a statin had lower lipid levels than those not taking a statin regardless of AED, but the differences between statin-treated and non-statin-treated patients were much larger (50%-100% or more) in the lamotrigine and levetiracetam groups than in the carbamazepine group (P = 0.035 for interaction effect of statin use and AED on total cholesterol). SIGNIFICANCE: Here, we demonstrate that carbamazepine significantly interferes with the ability of statins to lower total cholesterol, thus making it a poor choice for hyperlipidemic patients or those with cardiovascular disease. Native AED effects on lipids were inconsistent and subject to drug-gender interaction, in contrast with other studies; further investigation is necessary to determine if these latter findings are genuine or spurious.
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Anticonvulsivantes/uso terapéutico , Proteína C-Reactiva/metabolismo , Epilepsia/tratamiento farmacológico , Epilepsia/metabolismo , Metabolismo de los Lípidos/efectos de los fármacos , Lipoproteínas/metabolismo , Anciano , Anciano de 80 o más Años , Carbamazepina/uso terapéutico , LDL-Colesterol/metabolismo , Método Doble Ciego , Interacciones Farmacológicas , Femenino , Humanos , Lamotrigina/uso terapéutico , Levetiracetam/uso terapéutico , Masculino , Triglicéridos/metabolismoRESUMEN
Perampanel, a selective, non-competitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist, is approved for adjunctive treatment of focal seizures, with or without secondarily generalized seizures, and for primary generalized tonic-clonic seizures in patients with epilepsy aged ≥ 12 years. Perampanel was recently approved for monotherapy use for focal seizures in the U.S.A. Anti-seizure drug monotherapy may be preferable to polytherapy, which is generally associated with increased toxicity, non-compliance, and cost. Here, we report cases where patients had converted to perampanel monotherapy during open-label extension (OLEx) portions of 9 Phase II and III studies. Of 2245 patients who enrolled in the OLEx studies, we identified 7 patients with drug-resistant focal seizures who discontinued all non-perampanel anti-seizure drugs and were maintained on perampanel monotherapy for ≥ 91 days until the end of data cut-off. Patients received perampanel monotherapy for up to 1099 days (157 weeks), most at a modal dose of 12 mg. Seizure data were available for 6 patients, of whom 5 had a ≥ 90% reduction in overall seizure frequency between baseline and their last 13-week period of monotherapy (3 were seizure-free). Perampanel monotherapy was generally well tolerated and the safety profile during perampanel monotherapy was consistent with clinical and post-marketing experience in the adjunctive setting. This analysis included a small proportion of patients with highly drug-resistant focal seizures who converted to monotherapy during OLEx studies. While these limited data are encouraging in suggesting that perampanel might be useful as a monotherapy, further studies are required to explore outcomes in a less drug-resistant population, where a larger proportion of patients might benefit from monotherapy.
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PURPOSE: To evaluate the effects of eslicarbazepine acetate (ESL) on lipid metabolism and to determine whether reduced statin exposure during ESL therapy has clinical consequences. SUBJECTS AND METHODS: We conducted a post-hoc analysis of pooled data for serum lipids (laboratory values) from three phase III, multicenter, randomized, double-blind, placebo-controlled trials of adjunctive ESL therapy (400, 800, or 1200â¯mg once daily) in patients with treatment-refractory partial-onset seizures. Changes from baseline in serum lipid levels were analyzed according to use of statins and/or enzyme-inducing antiepileptic drugs (EIAEDs) during the baseline period. KEY FINDINGS: In total, 426 and 1021 placebo- and ESL-treated patients, respectively, were included in the analysis. With regard to the changes from baseline in serum concentrations, there were statistically significant differences between the placebo and ESL 1200â¯mg QD groups, for both total cholesterol (TC) and high-density lipoprotein cholesterol (HDL-C), but the effect sizes were small (+4.1â¯mg/dL and +1.8â¯mg/dL, respectively). A small but significant difference in low-density lipoprotein cholesterol (LDL-C; -5.0â¯mg/dL) was observed between the ESL 400â¯mg QD group and the placebo group. In patients not taking a concomitant EIAED, there were no changes with ESL 400â¯mg QD, but modest and statistically significant increases in cholesterol fractions (TC, LDL-C and HDL-C) with ESL 800â¯mg QD (<6â¯mg/dL) and ESL 1200â¯mg QD (<10â¯mg/dL). ESL had no consistent effect on lipids in patients taking a concomitant EIAED. In patients taking statins during baseline, there were no clinically relevant changes in serum lipids during use of ESL, although the subgroups were small. SIGNIFICANCE: These results suggest that ESL does not appear to have clinically significant effects on serum lipids, nor does the pharmacokinetic interaction between ESL and statins have an impact on serum lipid concentrations.
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Anticonvulsivantes/uso terapéutico , Dibenzazepinas/uso terapéutico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/administración & dosificación , Lípidos/sangre , Convulsiones/sangre , Convulsiones/tratamiento farmacológico , Adolescente , Adulto , Anciano , Anticonvulsivantes/farmacología , Dibenzazepinas/farmacología , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Inducción Enzimática/efectos de los fármacos , Femenino , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Masculino , Persona de Mediana Edad , Resultado del Tratamiento , Adulto JovenRESUMEN
INTRODUCTION: Patients with partial-onset seizures and comorbid cardiovascular disease may concomitantly receive eslicarbazepine acetate (ESL), an antiepileptic drug, and rosuvastatin, an HMG-CoA reductase inhibitor. This study evaluated the effect of multiple-dose ESL on the pharmacokinetic (PK) parameters of a single dose of rosuvastatin in healthy subjects. METHODS: This was a Phase I, single-center, fixed-sequence, open-label study. Healthy subjects received two treatments, in sequence. Treatment A: a single 40mg oral dose of rosuvastatin on Day 1, followed by a washout period (Days 1-4); treatment B: titration of ESL (400-800mg once daily) on Days 5-18, followed by ESL 1200mg once daily on Days 19-35, with a single dose of rosuvastatin (40mg) on Day 32. Subjects then entered a 2-week follow-up period. Plasma concentrations of rosuvastatin were quantified for PK analyses. Safety and tolerability were assessed throughout the study. RESULTS: Thirty-three healthy subjects were enrolled and 30 completed the study. Mean rosuvastatin (standard deviation) t1/2 was similar when rosuvastatin was used concomitantly with ESL and when it was used alone (26.5 [16.3]h, and 22.4 [9.5]h, respectively). The geometric least squares mean ratios (90% confidence intervals) of rosuvastatin exposure levels between rosuvastatin used concomitantly with ESL and rosuvastatin used alone were as follows: Cmax, 64.0% (55.9-73.3%); AUC(0-∞), 63.0% (57.1-69.4%); and AUC(0-last), 60.9% (55.2-67.1%). Concomitant use of ESL and rosuvastatin was generally well tolerated. CONCLUSIONS: Rosuvastatin exposure was 36-39% lower with steady-state administration of ESL, potentially due to reduced oral bioavailability of rosuvastatin. Consequently, when rosuvastatin is used with ESL, a rosuvastatin dose adjustment may be necessary if a clinically significant change in lipids is noted.
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Anticonvulsivantes/farmacocinética , Dibenzazepinas/farmacocinética , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacocinética , Rosuvastatina Cálcica/farmacocinética , Administración Oral , Adolescente , Adulto , Anticonvulsivantes/efectos adversos , Área Bajo la Curva , Disponibilidad Biológica , Dibenzazepinas/efectos adversos , Interacciones Farmacológicas , Femenino , Estudios de Seguimiento , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/administración & dosificación , Inhibidores de Hidroximetilglutaril-CoA Reductasas/efectos adversos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/sangre , Análisis de los Mínimos Cuadrados , Masculino , Proteínas de Transporte de Membrana/metabolismo , Persona de Mediana Edad , Rosuvastatina Cálcica/administración & dosificación , Rosuvastatina Cálcica/efectos adversos , Rosuvastatina Cálcica/sangre , Adulto JovenRESUMEN
Objective: To develop a novel software method (AR2) for reducing muscle contamination of ictal scalp electroencephalogram (EEG), and validate this method on the basis of its performance in comparison to a commercially available software method (AR1) to accurately depict seizure-onset location. Methods: A blinded investigation used 23 EEG recordings of seizures from 8 patients. Each recording was uninterpretable with digital filtering because of muscle artifact and processed using AR1 and AR2 and reviewed by 26 EEG specialists. EEG readers assessed seizure-onset time, lateralization, and region, and specified confidence for each determination. The two methods were validated on the basis of the number of readers able to render assignments, confidence, the intra-class correlation (ICC), and agreement with other clinical findings. Results: Among the 23 seizures, two-thirds of the readers were able to delineate seizure-onset time in 10 of 23 using AR1, and 15 of 23 using AR2 (p<0.01). Fewer readers could lateralize seizure-onset (p<0.05). The confidence measures of the assignments were low (probable-unlikely), but increased using AR2 (p<0.05). The ICC for identifying the time of seizure-onset was 0.15 (95% confidence interval (CI), 0.11-0.18) using AR1 and 0.26 (95% CI 0.21-0.30) using AR2. The EEG interpretations were often consistent with behavioral, neurophysiological, and neuro-radiological findings, with left sided assignments correct in 95.9% (CI 85.7-98.9%, n=4) of cases using AR2, and 91.9% (77.0-97.5%) (n=4) of cases using AR1. Conclusions: EEG artifact reduction methods for localizing seizure-onset does not result in high rates of interpretability, reader confidence, and inter-reader agreement. However, the assignments by groups of readers are often congruent with other clinical data. Utilization of the AR2 software method may improve the validity of ictal EEG artifact reduction.
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PURPOSE: Frequent interictal epileptiform abnormalities may correlate with poor prognosis after temporal lobe resection for refractory epilepsy. To date, studies have focused on limited resections such as selective amygdalohippocampectomy and apical temporal lobectomy without hippocampectomy. However, it is unclear whether the frequency of spikes predicts outcome after standard anterior temporal lobectomy. METHOD: Preoperative scalp video-EEG monitoring data from patients who subsequently underwent anterior temporal lobectomy over a three year period and were followed for at least one year were reviewed for the frequency of interictal epileptiform abnormalities. Surgical outcome for those patients with frequent spikes (>60/h) was compared with those with less frequent spikes. Additionally, spike frequency was evaluated as a continuous variable and correlated with outcome to determine if increased spike frequency correlated with worse outcome, as assessed by modified Engel Class outcome. RESULTS: Forty-seven patients (18 men, 29 women; mean age 40 years at surgery) were included. Forty-six patients had standard anterior temporal lobectomy (24 right, 22 left) and one had a modified left temporal lobectomy. There was no significant difference in seizure outcome between those with frequent (57% Class I) vs. those with less frequent (58% Class I) spikes. Increased spike frequency did not correlate with worse outcome. Greater than 20 complex partial seizures/month and generalized tonic-clonic seizures within one year of surgery correlated with worse outcome. CONCLUSIONS: This study suggests that absolute spike frequency does not predict seizure outcome after anterior temporal lobectomy unlike in selective procedures, and should not be used as a prognostic factor in this population.