Enzyme-inducing Antiepileptic Drugs Research Articles

Excess mortality and hospitalized morbidity in newly treated epilepsy patients.

To assess the burden of mortality and hospitalized morbidity in newly treated epilepsy patients. We extracted relevant data of patients with newly treated epilepsy between September 16, 2005, and September 15, 2010, from the data repository covering all public hospitals in Hong Kong. Patients were followed up until September 15, 2011. Mortality and hospitalized morbidity were assessed, stratified by baseline comorbidities, number of antiepileptic drugs (AEDs) used, and treatment with enzyme-inducing AEDs (EIAEDs). Mortality was compared to the age- and sex-specific general population in Hong Kong. Of the 7,461 newly treated epilepsy patients (55% male; median age 60 years), 2,166 (29%) died during the study period. The standardized mortality ratio was 5.09 (95% confidence interval [CI] 4.88-5.31), and was higher among those with physical or psychiatric baseline comorbidity (5.46; 95% CI 5.22-5.71) than those without (3.28; 95% CI 2.87-3.73). Standardized hospitalization ratio was 6.76 (95% CI 6.70-6.82). Baseline physical comorbidity-free patients (n = 3,514) exhibited higher risk of developing stroke (standardized incidence ratio [SIR] 4.96; 95% CI 4.19-5.84) and ischemic heart disease (SIR 4.18; 95% CI 3.54-4.91), and male patients had elevated risk of developing cancer (SIR 2.30; 95% CI 1.75-2.97). Patients treated with EIAEDs had higher risk of being subsequently recorded with new physical comorbidities than those with non-EIAEDs (relative risk [RR] 1.48; 95% CI 1.19-1.85), especially for cerebrovascular disease (RR 1.78; 95% CI 1.14-2.77). Newly treated epilepsy patients bear excess mortality and hospitalization risks. They have higher risk of developing stroke, ischemic heart disease, and cancer. Treatment with EIAEDs was associated with increased overall morbidity.

Guideline conform initial monotherapy increases in patients with focal epilepsy: A population-based study on German health insurance data

PurposeTo examine the implementation of the clinical practice guideline ⿿first epileptic seizure and epilepsy in adulthood⿿ published in 2008 to patients with newly diagnosed epilepsy between 2008 and 2014. MethodThis retrospective, population-based analysis was performed on patient data of 4.1 million insurants from the German statutory health insurance. Prevalent and incident cases in adults were identified based on ICD-10 codes, using a hierarchical diagnosis selection algorithm. The first anticonvulsive agent in a newly diagnosed epilepsy patient was validated against the clinical practice guideline. ResultsWe determined an annual crude prevalence rate in adults between 0.946% and 1.090% and incidence rates of at least 156 per 100,000. A significant increase in guideline compliant monotherapy was found in patients with a focal epilepsy syndrome, while, among patients with idiopathic generalised epilepsies, the share of guideline noncompliant monotherapy increased. Both changes are likely due to the overall increase in prescription of levetiracetam from 19.6% in 2008 to 58.9% in 2014 in all newly treated patients. Overall, the proportion of enzyme-inducing anticonvulsants fell significantly from 20.7% in 2008 to 4.3% in 2014 (p<0.001). The likelihood to receive non-enzyme-inducing antiepileptic drugs was 5.82 (95% CI 4.62⿿7.33) higher in 2014 than in 2008. ConclusionInitial monotherapy for focal epilepsy is in line with current clinical practice guidelines and mainly implemented by prescription of levetiracetam. Further evaluations should address the question of whether patients treated in line with the guidelines have a favorable outcome, compared to patients not treated in line with current guidelines.

White Matter Hyperintensities on Brain Magnetic Resonance Imaging in People with Epilepsy: A Hospital-Based Study.

We aim to explore whether people with epilepsy have increased white matter hyperintensities (WMHs). Eligible patients were categorized into newly diagnosed epilepsy (NE) and chronic epilepsy (CE); the latter were subdivided to those treated with enzyme-inducing antiepileptic drugs (EIAEDs) with or without non-enzyme-inducing antiepileptic drugs (NEIAEDs) and those with NEIAEDs only. WMHs were measured using age-related white matter changes (ARWMC) scale and compared between patients and healthy control group. Higher scores indicate greater WMH changes. The strengths of associations were estimated as incidence rate ratios (IRRs) with 95% confidence interval (CI). A total of 217 patients were included in the analysis, of whom 67 had NE, 45 had CE treated with NEIAEDs, and 105 had CE treated with EIAEDs. Age was positively associated with ARWMC score (IRR per year, 1.03; 95%CI, 1.03-1.04, P < 0.001). Compared with the healthy control group (n = 23), all patient groups had higher ARWMC score (P < 0.05). The difference was greatest in patients receiving EIAEDs (IRR, 2.13; 95%CI, 1.22-3.70, P = 0.007). WMHs tended to be observed in people with epilepsy, especially in those treated with EIAEDs. People with epilepsy with white matter changes should be evaluated for stroke risk, particularly if they are receiving EIAEDs.

Perampanel Serum Concentrations in Adults With Epilepsy: Effect of Dose, Age, Sex, and Concomitant Anti-Epileptic Drugs.

Perampanel (PMP), a noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor antagonist, is a novel anti-epileptic drug (AED) licensed for the adjunctive treatment of focal and generalized epilepsy. There is limited information on PMP's pharmacokinetics and drug interaction characteristics with concomitant AEDs. We have investigated the effects of PMP dose, age, sex, and coprescribed AEDs on serum PMP concentrations. We used the database of a therapeutic drug monitoring unit at a tertiary epilepsy referral center to identify patients who had PMP as part of their treatment and extracted clinical information from their medical notes. Sera PMP concentrations were determined using liquid chromatography/mass spectroscopy. In total, 160 sera from 107 patients (66 females) aged 18-70 years and weighing 40-125 kg were identified. They were prescribed a median PMP dose of 6 mg/d (range 2-12 mg/d) and were coprescribed a variety of AEDs, including enzyme-inducing [carbamazepine (CBZ) and oxcarbazepine (OXC)] and enzyme-inhibiting (valproic acid) AEDs. A linear relationship was observed between PMP dose and serum concentrations (r = 0.714, P < 0.0005). Sex and age were found not to influence PMP serum concentration. Enzyme-inducing AEDs dose-dependently decreased PMP concentrations, with CBZ and OXC decreasing mean values by 69% and 37%, respectively. In contrast, although topiramate and phenytoin also decreased mean PMP concentrations by 18% and 13%, respectively, these changes did not achieve statistical significance. PMP exhibits a linear dose-concentration relationship, with serum PMP concentrations being age and sex independent. CBZ and OXC can significantly decrease PMP concentrations, probably through an induction of CYP3A4-mediated metabolism.

One-year clinical experience of perampanel in Spain: a multicentre study of efficacy and tolerability.

Perampanel, a non-competitive antagonist of the α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptors, is the most recent antiepileptic drug available in Spain, marketed in January2014. It was initially approved by the European Medicines Agency as adjunctive treatment for partial-onset seizures in patients 12 years and older, but recently also for primary generalized tonic-clonic seizures. Although clinical trials provide essential information about the drug, they do not reflect daily clinical practice. This retrospective study shows the initial experience with perampanel in 11 Spanish hospitals during its first year post-commercialisation. All patients who started perampanel treatment were included, but efficacy and tolerability were only assessed in those patients with a minimum follow-up period of six months. In total, 256 patients were treated with perampanel before September2014, and 253 had an observational period of one year. After six months, 216/256 patients (84%) continued on perampanel and 180/253 (71.1%) completed one year of treatment. The mean number of previous antiepileptic drugs used was 6.83 and the median number of concomitant antiepileptic drugs was 2. The mean perampanel dose was 7.06mg and 8.26mg at six and 12 months, respectively. The responder rate was 39.5% and 35.9% at both follow-up points, respectively. Adverse events were experienced by 91/253 (35.5%) and resulted in withdrawal in 37 (14.6%). The most common adverse events were somnolence, dizziness, and irritability. We found no significant differences between concomitant use of enzyme-inducing and non-inducing antiepileptic drugs, regarding efficacy, adverse effects, or withdrawals. Irritability was not influenced by concomitant use of levetiracetam, relative to other drugs, but was more frequently observed in patients with a history of psychiatric problems or learning disabilities.

Anticonvulsant therapy in brain-tumor related epilepsy

SummaryBackground. The lifetime risk of patients with brain tumors to have focal epileptic seizures is 10-100%; the risk depends on different histology. Specific guidelines for drug treatment of brain tumor-related seizures have not yet been established.Aim. This review addresses the special aspects of antiepileptic drug (AED) therapy in brain tumor-related epilepsy.Methods. We analyzed the literature up to December 2015.Results. Based on current evidence the management of tumor-related seizures does not differ substantially from that applied to epilepsies from other etiologies. Therefore, the choice of an AED is based, above all, on tolerability and pharmacokinetic interactions with chemotherapeutic drugs. Levetiracetam is recommended by many authors as first-line therapy in brain tumor-related epilepsy. Due to the possibility of interactions, the combination of enzyme-inducing AEDs and chemotherapeutic drugs, is usually not recommended as a first choice. Currently there is no evidence that prophylactic prescription of long-term AEDs in brain tumor-patients who did not present with seizures is justified. Because of the high risk of recurrence, however, AED treatment should be strongly considered after a single brain tumor-related seizure. The decision to withdraw AEDs must carefully consider the risk of seizure recurrence.Conclusion. At present levetiracetam is the preferred drug in brain tumor-related epilepsy, especially when drug interactions need to be avoided. In the future we hope to acquire more targeted drugs against this disorder by uncovering its pathogenesis.

Markers of Bone Turnover and Lipid Metabolism During Eslicarbazepine Acetate (ESL) Monotherapy in Patients Taking or Not Taking Enzyme-Inducing Antiepileptic Drugs (EIAEDs) at Baseline (BL) (P2.030)

Markers of Bone Turnover and Lipid Metabolism During Eslicarbazepine Acetate (ESL) Monotherapy in Patients Taking or Not Taking Enzyme-Inducing Antiepileptic Drugs (EIAEDs) at Baseline (BL) (P2.030)

Prevalencia de prescripción conjunta incorrecta de fármacos anticonvulsivantes y anticonceptivos hormonales Colombia, 2014

&lt;p&gt;&lt;strong&gt;Objetivo:&lt;/strong&gt; determinar la prevalencia de prescripción conjunta de fármacos antiepilépticos para identificar formulación incorrecta que podría afectar la efectividad de los anticonceptivos hormonales en un grupo de mujeres afiliadas al Sistema General de Seguridad Social en Salud de Colombia.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Materiales y métodos:&lt;/strong&gt; estudio de corte transversal, en el que se seleccionaron registros de mujeres de 15 a 45 años que recibían al menos un fármaco antiepiléptico, entre el 1 y el 31 de marzo de 2014, en una base de datos poblacional de dispensación de medicamentos de un operador logístico en Colombia, para población perteneciente al régimen contributivo y subsidiado en el Sistema General de Seguridad Social en Salud de Colombia. Se evaluaron el tipo de anticonceptivo hormonal y de fármaco antiepiléptico. Se utilizó estadística descriptiva.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Resultados:&lt;/strong&gt; de un total de 2092 pacientes usuarias de fármacos antiepilépticos, se identificaron 89 (4,3 %) casos que tenían por lo menos un antiepiléptico y un anticonceptivo simultáneamente. En 48 mujeres (54 %) se encontró formulación incorrecta de métodos de planificación, como el uso de fármacos antiepilépticos inductores enzimáticos e inyectables combinados (20 casos), el uso de anticonceptivos orales combinados de bajas dosis de estrógenos (16 casos), de progestinas orales (10 casos), y el uso de antiepilépticos no inductores enzimáticos y anticonceptivos orales combinados y dosis altas de estrógenos (2 casos).&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusiones:&lt;/strong&gt; un importante número de mujeres usuarias de medicamentos antiepilépticos utiliza métodos hormonales de anticoncepción, y cerca de la mitad de ellas tenían una prescripción anticonceptiva incorrecta, lo que podría resultar en embarazos no deseados o incremento del riesgo de enfermedad tromboembólica.&lt;/p&gt;

Concentrations of carbamazepine and carbamazepine-10,11-epoxide in maternal and umbilical cord blood at birth: Influence of co-administration of valproic acid or enzyme-inducing antiepileptic drugs

BackgroundCarbamazepine is one of the three most frequently prescribed antiepileptic drugs in pregnancy. However, data relating to both carbamazepine and carbamazepine-10,11-epoxide transplacental passage remain sparse. Material and methodsWe have analysed in a cohort of 114 women carbamazepine and carbamazepine-10,11-epoxide levels in maternal and umbilical cord serum at birth during 25 years retrospectively. The carbamazepine maternal apparent oral clearance, ratio of the umbilical cord/maternal level and ratio of the carbamazepine-10,11-epoxide/carbamazepine ratio were estimated. The influence of co-medication with valproic acid or enzyme-inducing antiepileptic drugs was evaluated. ResultsThe maternal carbamazepine levels varied from 0.6 to 11.8mg/L (carbamazepine-10,11-epoxide 0.1–2.5mg/L) and in umbilical cord between 0.1 and 10.5mg/L (carbamazepine-10,11-epoxide 0.1–2.2mg/L). The ratio the of umbilical cord/maternal level of carbamazepine ranged from 0.03 to 2.23 (median 0.80) and of carbamazepine-10,11-epoxide between 0.17 and 2.00 (median 0.83). Concomitant administration with enzyme inducers significantly increased the maternal apparent oral clearance by approximately 50% and co-administration with valproic acid approximately by 70%. Combination with valproic acid significantly increased the rate of carbamazepine-10,11-epoxide to the parent drug both in maternal serum (by approximately 80%) and in umbilical cord (by 100%). ConclusionsThe data showed the wide interindividual variability of the ratio of the umbilical cord/maternal level of both carbamazepine and carbamazepine-10,11-epoxide. It is the first study showing the significant increase of the ratio of umbilical cord/maternal level of carbamazepine-10,11-epoxide and carbamazepine-10,11-epoxide/carbamazepine ratio not only in maternal serum but also in umbilical cord in addition of valproic acid. The present study demonstrates that a concomitant administration of enzyme-inducing antiepileptics and valproic acid increases the maternal apparent oral clearance of carbamazepine significantly.

Preliminary evidence for gender effects of levetiracetam monotherapy duration on bone health of patients with epilepsy.

Enzyme-inducing antiepileptic drugs AEDs have adverse effects on bone mineral density (BMD), whereas studies on levetiracetam (LEV), a nonenzyme-inducing agent, have showed conflicting results. The aim of this study was to further elucidate the role of LEV in bone health. A sample of forty-six patients with epilepsy (mean age: 35.7 years, range: 20.2-64.2 years, 39.1% males) on LEV monotherapy for at least one year (range: 1.5-14.5 years, median 5.5 years) underwent femoral neck (FN) and lumbar spine (LS) BMD measurements. The T- and Z-scores were calculated. Results showed that 15.2% of the patients were identified with osteopenia and none with osteoporosis. Pearson's correlations revealed a negative but not significant association of LEV duration with bone-related measurements (range of rhos: from -0.004 to -0.23), except for LS T-scores. In terms of FN BMD measurements, Z-scores, and T-scores, longer LEV therapy duration had adverse but not significant effects on bone health after adjusting for age and gender. With regard to LS BMD measurements, Z-scores, and T-scores, men taking LEV for at least 5.5 years had better, although not significant, bone health compared with men with shorter LEV exposure, after adjusting for age. The opposite was found in women, although differences did not reach significance. These preliminary results are indicative of a differential effect of LEV therapy duration in men and women, which could presumably account for the incongruity of the already published studies. Also, LS assessments were more sensitive to these gender differences. Future larger studies should validate these results.

Contraception in women with epilepsy: Potential drug interactions between contraceptive hormones and enzyme inducing antiepileptic drugs

Contraception is essential for a woman as it helps to achieve autonomy in personal life and avoid unwanted pregnancy. Adequate contraception is even more essential for women with epilepsy (WWE) due to potential maternal and fetal risks of antiepileptic drugs (AEDs) and poor seizure control. There are several hormonal and nonhormonal contraceptive options available for WWE, with combined oral hormonal pills being used most commonly. The choice of contraception in WWE is influenced by many factors, chief among these being potential drug interactions between contraceptive hormones and enzyme inducing antiepileptic drugs (EIAEDs). While EIAEDs may increase metabolism of contraceptive hormones leading to contraceptive failure, contraceptive hormones in turn may increase metabolism of AEDs resulting in their faster elimination and breakthrough seizures. The co-administration of lamotrigine and oral hormonal pills is especially complicated by unpredictable interactions and requires several considerations. In this review, we try to address various issues concerning the use of different contraceptive modalities in WWE. In addition, we review the current guidelines for concurrent use of hormonal contraception and AEDs in WWE.

Chapter 16 - Epilepsy and brain tumors

Seizures are common in patients with brain tumors, and epilepsy can significantly impact patient quality of life. Therefore, a thorough understanding of rates and predictors of seizures, and the likelihood of seizure freedom after resection, is critical in the treatment of brain tumors. Among all tumor types, seizures are most common with glioneuronal tumors (70-80%), particularly in patients with frontotemporal or insular lesions. Seizures are also common in individuals with glioma, with the highest rates of epilepsy (60-75%) observed in patients with low-grade gliomas located in superficial cortical or insular regions. Approximately 20-50% of patients with meningioma and 20-35% of those with brain metastases also suffer from seizures. After tumor resection, approximately 60-90% are rendered seizure-free, with most favorable seizure outcomes seen in individuals with glioneuronal tumors. Gross total resection, earlier surgical therapy, and a lack of generalized seizures are common predictors of a favorable seizure outcome. With regard to anticonvulsant medication selection, evidence-based guidelines for the treatment of focal epilepsy should be followed, and individual patient factors should also be considered, including patient age, sex, organ dysfunction, comorbidity, or cotherapy. As concomitant chemotherapy commonly forms an essential part of glioma treatment, enzyme-inducing anticonvulsants should be avoided when possible. Seizure freedom is the ultimate goal in the treatment of brain tumor patients with epilepsy, given the adverse effects of seizures on quality of life.

Perampanel for focal epilepsy: insights from early clinical experience.

Perampanel is approved for adjunctive therapy of focal epilepsy with or without secondarily generalized seizures in patients aged >12 years. This narrative review uses real‐world and clinical trial data to elucidate perampanel's role in the clinic. Audit data show good tolerability with perampanel and higher freedom‐from‐seizure rates in elderly vs younger patients. When using perampanel in elderly patients, special attention should be given to comorbidities and co‐medication to avoid potential interactions or adverse events. Slower titration is generally recommended, and seizure control should be reassessed at a dose of 4 mg before further dose increases. Perampanel efficacy is similar in adolescents and adults; however, somnolence, nasopharyngitis, and aggression are more frequent in adolescents vs the overall population. Individualized and slow‐dose titration can minimize adverse events. Low serum concentrations of perampanel may occur in patients also receiving some enzyme‐inducing anti‐epileptic drugs; a perampanel dose increase may be required. Adverse events of importance with perampanel include dizziness; anger, aggression, and hostile behavior (particularly in adolescents); and falls (particularly in patients >65 years). An individualized approach to dosing, including slower up‐titration and bedtime dosing, reduces dizziness risk. Other drugs may cause or aggravate dizziness; reducing concomitant drugs may be necessary when up‐titrating perampanel. It would seem clinically appropriate to give due consideration to avoiding use in patients with a history of anger or hostile/aggressive behavior. The possibility of such behaviors should be discussed with patients before starting perampanel, with monitoring during up‐titration. Slower up‐titration of perampanel in older patients helps reduce fall risk.

Changing incidence of hyperammonemia in Japan from 2006 to 2013: expansion of new antiepileptic drugs reduces the risk of hyperammonemia.

The purpose of the present study was to examine the relationship between the incidence of hyperammonemia and changes in the prescribing of concomitant antiepileptic drugs (AEDs) in patients receiving valproic acid. We evaluated 40,363 plasma samples from 6009 epilepsy patients obtained from 2006 to 2013. Hyperammonemia was defined as a plasma ammonia level exceeding 100μg/dL. In 2006, 32.6% of the plasma samples were from patients with concomitant use of phenytoin but this decreased to 16.0% in 2013. Lamotrigine and levetiracetam were approved in 2008 and 2010, respectively, and were prescribed for patients who provided 27.8 and 14.9% of the plasma samples in 2013. The incidence rate of hyperammonemia (per 100 person years) decreased markedly from 40.8(95% confidence interval (CI), 37.7-43.9) in 2006 to 14.2 (95% CI, 12.5-15.9) in 2013. In any year reviewed, concomitant use of phenytoin, phenobarbital, carbamazepine, or carbonic anhydrase inhibitors was a risk factor for hyperammonemia. Among enzyme-inducing AEDs, concomitant use of phenytoin was associated with the highest risk of hyperammonemia. Drug interactions caused by enzyme-inducing AEDs, especially phenytoin, are closely related to the development of hyperammonemia. This study demonstrated that introduction of new AEDs changed the co-prescribing pattern in patients receiving valproic acid, resulting in a marked decrease of hyperammonemia. Although their higher cost may be problematic, new AEDs are beneficial for reducing the risk of drug interactions.

Analysis of pooled phase III trials of adjunctive perampanel for epilepsy: Impact of mechanism of action and pharmacokinetics on clinical outcomes

AimTo further explore the impact of concomitant antiepileptic drugs (AEDs) on the efficacy and tolerability of adjunctive perampanel for focal epilepsy. MethodsData were pooled from three phase III trials of adjunctive perampanel in patients (≥12 years of age) with refractory partial-onset seizures. Concomitant AEDs were categorized according to whether or not they were enzyme-inducing AEDs (EIAEDs; known to reduce perampanel plasma concentrations) or sodium channel blockers (SCBs). Post hoc analyses assessed the impact of co-administration of non-EIAED SCBs and the overall number of concomitant AEDs on changes in seizure frequency, 50% responder rates, rates of treatment-emergent adverse events (TEAEs), and rates of discontinuation due to TEAEs, in patients randomized to receive daily placebo or perampanel 2, 4, 8, or 12mg. ResultsAmongst 1480 randomized and treated patients, most were receiving two or more concomitant AEDs (n=1273, 86.0%), one or more EIAEDs (n=1083, 73.2%), and/or one or more SCBs (n=1203, 81.3%) at Baseline. The magnitude of seizure reduction appeared unaffected by the presence of non-EIAED SCBs, but lower in the presence of multiple AEDs. Frequency of TEAEs did not appear to be affected by the presence of non-EIAED SCBs or multiple AEDs. ConclusionBeyond the known interactions between perampanel and EIAEDs, perampanel efficacy appears to be unaffected by the use of concomitant non-EIAED SCBs, but may be reduced in the presence of multiple concomitant AEDs (possibly indicative of the presence of more refractory epilepsy). Nonetheless, with careful titration to balance efficacy and tolerability, perampanel may be combined with a range of AEDs, facilitating integration into treatment plans.

Antiepileptic drugs and the risk of ischaemic stroke and myocardial infarction: a population-based cohort study

ObjectivesHepatic enzyme-inducing antiepileptic drugs (AEDs) increase serum lipid levels and other atherogenic markers via the induction of cytochrome P450 and may therefore increase the risk of vascular events. We sought...

Enzyme-Inducing Anticonvulsants Increase Plasma Clearance of Dexmedetomidine

Background:Dexmedetomidine is useful during mapping of epileptic foci as it facilitates electrocorticography unlike most other anesthetic agents. Patients with seizure disorders taking enzyme-inducing anticonvulsants appear to be resistant to its sedative effects. The objective of the study was to c

First Analysis of the Association Between CYP3A4/5, ABCB1 Genetic Polymorphisms and Oxcarbazepine Metabolism and Transport in Chinese Epileptic Patients with Oxcarbazepine Monotherapy and Bitherapy

Oxcarbazepine (OXC) is widely used in anti-epileptic treatment. Cytochrome P450 3A4 (CYP3A4), cytochrome P450 3A5(CYP3A5), and ATP-binding cassette sub-family B member 1 (ABCB1) are potential genes involved in OXC metabolisms and transport in vivo. This study aims to examine the genetic effects of CYP3A4, CYP3A5, and ABCB1 on OXC metabolism and transport in Chinese epileptic patients using OXC as monotherapy and bitherapy with lamotrigine (LTG), levetiracetam (LEV), or valproic acid (VPA). Sixty-six Chinese epileptic patients were recruited from Xiangya Hospital Central South University, of whom 40 patients were receiving OXC monotherapy, 11 patients were placed in the OXC bitherapy group combined with one enzyme-inducing anti-epileptic drugs (LTG or LEV), and 15 patients were placed in the OXC bitherapy group combined with VPA. Oxcarbazepine and its main metabolite 10-hydrocarbazepine (MHD) plasma concentrations were measured using high performance liquid chromatography (HPLC)-UV method. In addition, eight single nucleotide polymorphisms (SNPs) in CYP3A4, CYP3A5, ABCB1 gene were genotyped by polymerase chain reaction-improved multiple ligase detection reaction (PCR-iMLDR). In the OXC+VPA group, ABCB1 rs2032582 and rs2032582-rs10234411-rs1045642 TAG haplotype were associated with MHD and MHD+OXC plasma concentration before permutation test. In OXC monotherapy and OXC+ LTG/LEV groups, no significant association between genetic polymorphisms in CYP3A4/5, ABCB1 gene and OXC plasma concentration parameters were observed. CYP3A4/5 and ABCB1 genetic variants might not take part in the metabolism and transport of MHD and OXC among epileptic patients using OXC monotherapy and bitherapy in combination with LEV, LTG or VPA.

Enzyme-inducing antiepileptic drugs and fractures in people with epilepsy: A systematic review

ObjectivePeople with epilepsy (PWE) have an increased fracture risk, independent of seizures. Antiepileptic drugs are thought to increase this risk, particularly those that induce the hepatic cytochrome P450 enzyme system. We aimed to determine whether PWE treated with enzyme-inducing antiepileptic drugs (EIAEDs) have decreased bone mineral density (BMD), or increased fracture incidence, versus those treated with non-EIAEDs. MethodsWe searched MedLine, EMBase, CENTRAL, and CINAHL prior to November 2014 for all studies comparing fracture risk, or BMD change, in PWE treated for ≥1 year with EIAEDs versus non-EIAEDs. ResultsThirteen observational studies met eligibility criteria. These studies, representing 68,973 adult PWE, were significantly heterogeneous, making meta-analysis impossible. Study results were split, with 5 studies showing decreased BMD in EIAED users, 5 studies showing no effect of EIAED on BMD, 2 studies showing increased fracture incidence in EIAED users, and 1 study showing no difference in fracture risk. The largest study (n=63,259), which was also the most methodologically rigorous, showed an increased hazard ratio of 9–22% for any fracture, and 49–53% for hip fracture, in EIAED users. SignificanceThe literature is divided regarding the bone effects of EIAEDs; however, current best evidence supports an increased fracture risk in PWE treated with an EIAED compared to those treated with non-EIAEDs. A single article dominated our review, and other large methodologically rigorous studies are needed to confirm or refute its results. Further small studies, with limited power to control for multiple potentially confounding variables, are not likely to help.

Spotlight on the May 12 Issue

#### Notable in Neurology This issue features an article on the effect of white matter lesions on manual dexterity in healthy middle-aged persons and another describing that the lower the hippocampus global connectivity, the higher its local metabolism in Alzheimer disease. Another featured article focuses on perampanel efficacy and tolerability with enzyme-inducing antiepileptic drugs in patients with epilepsy. ### HIV status and the risk of ischemic stroke among men The authors analyzed data on 76,835 participants free of baseline cardiovascular disease, assessing demographics, stroke risk factors, comorbid diseases, substance use, HIV biomarkers, and incidence of ischemic stroke. HIV infection was associated with an increased ischemic stroke risk …