Common Antiepileptic Drugs Research Articles

Abstract #110: Ephaptic coupling, a mechanism for spontaneous neural propagation in the brain

It is well documented that synapses play a significant role in the transmission of information between neurons in the brain. However, in the absence of synaptic transmission, neural activity has been observed to continue to propagate. Several experimental results have shown that propagation of epileptiform activity in rodent hippocampi propagates at a speed of ∼0.1 m/s. This observed activity in the 4-AP model propagates independently of synaptic transmission and gap junctions, and is outside the range of ionic diffusion and axonal conduction speeds. Compartment modeling of pyramidal neurons indicate that ephaptic coupling, or endogenous electric fields, could be responsible for this propagation of neural activity in pathological conditions such as epilepsy. Recent studies suggest electric fields can activate neighboring neurons, thereby generating a self-propagating wave. However, there is no experimental data suggesting ephaptic coupling is necessary and sufficient for spontaneous, self-regenerating propagation of neural activity. Using in vitro and in vivo electrophysiology in combination with imaging of trans-membrane voltages using genetically encoded voltage indicators, we test the hypothesis that ephaptic coupling is a critical mechanism for non-synaptic neural propagation. We have developed a novel extracellular electric field clamp capable of measuring the endogenous field and generate an "anti" field to block non-synaptic spontaneous propagation in the rodent hippocampus (Figure 1A). By blocking propagation, we are able to show that ephaptic coupling is a necessary mechanism for propagation of spontaneous activity. Finally, since electric fields propagate as volume conductors, we test if activity can propagate through a complete physical cut of the tissue, thereby eliminating all other forms of close cell-to-cell communication and showing that electric fields alone are sufficient to mediate non-synaptic propagation. Preliminary results suggest that spontaneous epileptiform activity propagates by triggering the activity on the other side across the cut with ephaptic coupling without changing the speed (Figure 1B). Our findings suggest that ephaptic coupling is necessary and sufficient to mediate non-synaptic neural propagation. Further investigation of this mechanism could explain how focal seizures appear to start abruptly and unpredictably, and how the rare micro-seizures of human partial epilepsy (seizure-like events that are not clinically detectable and are resistant to most common antiepileptic drugs) propagate through the hippocampus and cortex. Furthermore, endogenous electric fields could play an important role in brain function and could provide an explanation for unresolved mechanisms of deep brain stimulation or transcranial direct current stimulation (tDCS).

Pharmacoeconomic aspects of monotherapy of focal epilepsy

To perform a clinical/economic comparison of monotherapy with antiepileptic drugs (AED) in patients with newly diagnosed focal epilepsy (FE) based on the results of previous studies. The most common AEDs (carbamazepine (CBZ), oxcarbazepine (OXZ), lamotrigine (LTG), lacosamide (LCM)) were compared in patients, aged 16 years and over, with illness duration of five years. CBZ, OXZ and LCM can be used as monotherapy in patients with newly diagnosed FE. Monotherapy with LCM is associated with lowest costs for stopping focal seizures and the highest percentage of seizure-free patients. CBZ remains the most economical AED: the cost-effectiveness is minimal compared to all other AEDs used in the study. However, monotherapy with LCM is advisable if it is necessary to minimize side-effects in patients with newly diagnosed FE.

Metabolic Evaluation of Epilepsy: A Diagnostic Algorithm With Focus on Treatable Conditions.

Although inborn errors of metabolism do not represent the most common cause of seizures, their early identification is of utmost importance, since many will require therapeutic measures beyond that of common anti-epileptic drugs, either in order to control seizures, or to decrease the risk of neurodegeneration. We translate the currently-known literature on metabolic etiologies of epilepsy (268 inborn errors of metabolism belonging to 21 categories, with 74 treatable errors), into a 2-tiered diagnostic algorithm, with the first-tier comprising accessible, affordable, and less invasive screening tests in urine and blood, with the potential to identify the majority of treatable conditions, while the second-tier tests are ordered based on individual clinical signs and symptoms. This resource aims to support the pediatrician, neurologist, biochemical, and clinical geneticists in early identification of treatable inborn errors of metabolism in a child with seizures, allowing for timely initiation of targeted therapy with the potential to improve outcomes.

Modern approaches in the treatment of Lennox–gastaut syndrome (a review of literature)

Lennox–Gastaut syndrome (LGS) is a childhood epileptic encephalopathy characterized by frequent polymorphic seizures (including tonic axial seizures), pronounced cognitive impairment, typical changes in the electroencephalogram and drug resistance. Frequency of LGS accounts for approximately 4–10 % of all childhood epilepsy. The difficulties in the diagnosis and treatment of LGS are associated with the presence of various seizures that are frequently resistant to multiple antiepileptic drugs as well as with the disease evolution with age. This review covers the main principles of LGS therapy, analyzes the most common antiepileptic drugs used in LGS, and describes clinical trials evaluating the efficacy and tolerability of antiepileptic drugs in LGS. The article contains a detailed algorithm for the treatment of LGS, based on international guidelines and expert opinions.

Treating People With Epilepsy in Rural Low-Income Countries Is Feasible. Observations and Reflections From a "Real Life Experience" After a Long Lasting Intervention in the Rural Chaco.

Introduction: Epilepsy represents an important public health issue, in particular in low and middle-income countries where significant disparities are present in the care available for patients with epilepsy. Treatment cost and unavailability of drugs represent important barriers in treating people with epilepsy especially in rural setting. Aim of the study was to evaluate, by means of routine data, the current real-life clinical practice in epilepsy in the rural communities of the Plurinational State of Bolivia. Treatment activity followed educational campaigns and an anthropological fieldwork over more than 20 years.Material and Methods: Medical records of people with epilepsy (PWE) living in the rural communities of the Bolivian Chaco who received antiepileptic drugs (AEDs), from 2012 to 2016, and were followed-up for at least 1 year were analyzed. Treatment delivery and follow up visits were managed by a neurologist with the support of rural health care workers.Results: From 2012 to 2016, 157 PWE (76 men with a mean age of 24.2 ± 15.7) have been included in the study. Structural epilepsy was the most common type, recorded in 54 cases (34.4%) and the most common reported causes were perinatal factors, present in 11 subjects (20.0%). Almost all patients presented epilepsy with generalized tonic-clonic seizures (91.4%). The most common AED prescribed was phenobarbital followed by carbamazepine. During the follow-up, a dramatic seizures reduction was observed, with 31 subjects (19.7%) being seizures-free at the last follow-up. However, 48 subjects (30.6%) did not assume the medication regularly and 10 interrupted the drug intake. More than 20% of PWE did not receive any financial supports for AEDs. During the follow-up period 10 patients died but only in one case the death was probably caused by epilepsy.Conclusion: Our study demonstrated that PWE in rural areas of the Bolivian Chaco are willing to seek medical attention and to receive antiepileptic treatment. However, improvement in care is needed to assure compliance to AED treatment, including activity to increase awareness toward epilepsy among community members and health staff of the rural communities and to guarantee the coverage of treatment costs and drug supply.

055 Effect of common concomitant antiepileptic drugs during adjunctive treatment with perampanel: post hoc analysis from the open-label extension of a phase III study in patients with idiopathic generalised epilepsy

IntroductionPerampanel is approved for adjunctive treatment of partial seizures, with or without secondarily generalised seizures, and primary generalised tonic-clonic (PGTC) seizures in epilepsy patients aged ≥12 years. Perampanel is also approved for monotherapy use for partial seizures in the US. This post hoc analysis assessed the effects of the most common concomitant Baseline antiepileptic drugs (AEDs) on discontinuation rates and treatment-emergent adverse event (TEAE) incidence during adjunctive treatment with perampanel in patients (aged ≥12 years) with idiopathic generalised epilepsy (IGE) and PGTC seizures in the open-label extension (OLEx) Phase of Study 332 (NCT02307578).MethodsPatients completing the double-blind study could receive perampanel (≤12 mg/day) during the OLEx (6 week blinded Conversion Period;≤136 weeks’ Maintenance). Here, we report results for perampanel >4–8 mg/day and >8–12 mg/day.ResultsMost common concomitant Baseline AEDs were valproic acid (n=55), lamotrigine (n=53), levetiracetam (n=37), topiramate (n=21) and zonisamide (n=12); patients may have received >1 of these Baseline AEDs. The most common reasons for discontinuing were adverse event(s) (AE), ‘other’ and patient choice. Lamotrigine: patient choice, n=6/34 (>4–8 mg/day); AE/‘other’, both n=3/19 (>8–12 mg/day). Levetiracetam: patient choice, n=5/27 (>4–8 mg/day); AE, n=2/10 (>8–12 mg/day). Topiramate: ‘other’, n=3/15 (>4–8 mg/day); AE/‘other’, both n=1/6 (>8–12 mg/day). Valproic acid: patient choice, n=6/38 (>4–8 mg/day); ‘other’, n=4/17 (>8–12 mg/day). Zonisamide: patient choice/‘other’, both n=2/10 (>4–8 mg/day); no discontinuations (>8–12 mg/day). Patient-reported TEAEs ranged from: 88.2% (lamotrigine) to 93.3% (topiramate) for perampanel >4–8 mg/day, and 70.6% (valproic acid) to 100.0% (topiramate and zonisamide) for perampanel >8–12 mg/day. The most common TEAE was dizziness.ConclusionIn this post hoc analysis, primary reasons for discontinuation and TEAE incidence differed between the most common Baseline AED subgroups and perampanel dose range, although TEAE types were similar. These data provide additional information on the safety of adjunctive perampanel in patients with IGE.Study supportEisai Inc.

Prescription trends and psychiatric symptoms following first receipt of one of seven common antiepileptic drugs in general practice

We sought to examine the risk of psychiatric symptoms associated with a first prescription for specific antiepileptic drugs (AEDs) used in monotherapy in a general cohort of patients with epilepsy. We used The Health Improvement Network database (comprising the years 2000–2012) to identify incident patients with epilepsy. The index date was that on which they met the case definition for epilepsy, and analyses only included patients who remained on monotherapy or received no AED therapy following diagnosis to avoid confounding by polytherapy. Psychiatric symptoms were defined using mental health clinical or treatment (medical or therapeutic) code. We analyzed the AED of interest as a time-varying covariate in multivariate Cox proportional hazard regression models controlling for confounding factors. We identified 9595 patients with incident epilepsy, 7400 of whom (77%) received a first-recorded AED prescription. Prescriptions for newer generation AEDs (lamotrigine and levetiracetam) steadily increased (constituting over 30% of all AED prescriptions by 2012) while valproate use significantly declined in females (~40% in 2002 to just over 20% by 2012). A total of 2190 patients were first exposed to carbamazepine (29.3%) and 222 to lamotrigine (3%), both of which were associated with a lower hazard of any coded psychiatric symptom or disorder in multivariate analyses (hazard ratio [HR]: 0.84, 95% confidence interval [95% CI]: 0.73–0.97; p = 0.02 and HR: 0.83, 95% CI: 0.70–0.99; p = 0.03, respectively, for carbamazepine and lamotrigine). Carbamazepine was also associated with a lower hazard for depression (HR: 0.81; 95% CI: 0.69–0.96; p = 0.013) and anxiety (HR: 0.77; 95% CI: 0.63–0.95; p = 0.013) in secondary analyses. This study provides evidence that carbamazepine and lamotrigine are associated with lower hazards for psychiatric symptoms following a diagnosis of epilepsy. These estimates can be used in clinical settings, and the precision should improve with more contemporary data that include larger proportions of newer generation AEDs.

Changes in antiepileptic drug-prescribing patterns in pregnant women with epilepsy

ObjectiveWe analyzed current prescribing patterns for antiepileptic drugs (AEDs) in pregnant women with epilepsy (PWWE) at 20 USA tertiary epilepsy centers. MethodsThe Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study is an NIH-funded, prospective, observational, multicenter investigation of pregnancy outcomes for both mother and child, which enrolled women from December 2012 to January 2016. Inclusion criteria for PWWE included ages 14–45 years and up to 20 weeks gestational age. Exclusion criteria included history of psychogenic nonepileptic spells, expected intelligence quotient (IQ) <70, other major medical illness, progressive cerebral disease, and switching AEDs in pregnancy prior to enrollment. ResultsThree hundred fifty-one PWWE were enrolled in the MONEAD study, which included 259 (73.8%) on monotherapy, 77 (21.9%) on polytherapy, and 15 (4.3%) on no AEDs. The most common AED monotherapy regimens were lamotrigine (42.1% of monotherapies), levetiracetam (37.5%), carbamazepine (5.4%), zonisamide (5.0%), oxcarbazepine (4.6%), and topiramate (3.1%). All other individual monotherapies were each <1%. The most common AED polytherapy combination was lamotrigine + levetiracetam (42.9% of polytherapies), followed by lacosamide + levetiracetam (6.5%), lamotrigine + zonisamide (5.2%), and all other remaining combinations (each <4%); only 5.2% of polytherapy subjects were on ≥3 AEDs (1.1% of total PWWE). Only four subjects (1.1%) were on valproate (1 monotherapy, 3 polytherapy). ConclusionsThe distribution of AED use likely reflects current prescribing patterns for PWWE cared for in USA tertiary epilepsy centers. This distribution has changed markedly since the turn of the century, but changes in the general population remain uncertain.

Prescribing antiepileptic drugs to women of reproductive age

The notion that use of antiepileptic drugs by pregnant women increases the risk for major congenital malformations is not new, but the oversimplification of grouping all antiepileptic drugs together into the same risk category is outdated. Data have accumulated to show the differential risks for major congenital malformations, with the highest risk consistently associated with in-utero valproate exposure. 1 Hernandez-Diaz S Smith CR Shen A et al. Comparative safety of antiepileptic drugs during pregnancy. Neurology. 2012; 78: 1692-1699 Crossref PubMed Scopus (399) Google Scholar The Neurodevelopmental Effects of Antiepileptic Drugs study also concluded that the highest risk for impaired cognitive function at 6 years of age occurs in the children of women who took valproate during pregnancy compared with other antiepileptic drug monotherapies. 2 Meador KJ Baker GA Browning N et al. Fetal antiepileptic drug exposure and cognitive outcomes at age 6 years (NEAD study): a prospective observational study. Lancet Neurol. 2013; 12: 244-252 Summary Full Text Full Text PDF PubMed Scopus (526) Google Scholar Reports from pregnancy registries have also revealed that the teratogenic risk for valproate is dose dependent, 3 Harden CL Meador KJ Pennell PB et al. Practice parameter update: management issues for women with epilepsy—focus on pregnancy (an evidence-based review): teratogenesis and perinatal outcomes: report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and American Epilepsy Society. Neurology. 2009; 73: 133-141 Crossref PubMed Scopus (274) Google Scholar and it was tempting for physicians to not worry about the level of the so-called safe antiepileptic drugs, such as lamotrigine. However, a landmark paper in 2011 by the investigators of the EURAP international registry, 4 Tomson T Battino D Bonizzoni E et al. Dose-dependent risk of malformations with antiepileptic drugs: an analysis of data from the EURAP epilepsy and pregnancy registry. Lancet Neurol. 2011; 10: 609-617 Summary Full Text Full Text PDF PubMed Scopus (549) Google Scholar reporting on 3909 pregnancies exposed to the four most common antiepileptic drug monotherapies (carbamazepine, valproate, lamotrigine, and phenobarbital), showed that not only did the antiepileptic drug choice matter in determining the relative risk of major congenital malformations, but also the dose at conception, even for lamotrigine despite having the lowest risk. Comparative risk of major congenital malformations with eight different antiepileptic drugs: a prospective cohort study of the EURAP registryDifferent antiepileptic drugs and dosages have different teratogenic risks. Risks of major congenital malformation associated with lamotrigine, levetiracetam, and oxcarbazepine were within the range reported in the literature for offspring unexposed to antiepileptic drugs. These findings facilitate rational selection of these drugs, taking into account comparative risks associated with treatment alternatives. Data for topiramate and phenytoin should be interpreted cautiously because of the small number of exposures in this study. Full-Text PDF

Acute Kidney Injury and Creatine Kinase Elevation After Beginning Treatment with Levetiracetam

Levetiracetam (LEV) is one of the most common anti-epileptic drugs available. In general, it is tolerated relatively well; the majority of adverse effects are moderate and normally occur during the initial titration. We present a patient who developed two moderately serious adverse effects after an initial LEV dose: a 28-year-old male was admitted to intensive care unit after suffering two generalised seizures, and was given 1000 mg of LEV. Twenty-four hours after admittance, the laboratory tests showed a serum creatinine of 2.84 mg/dL and creatine kinase (CK) of 421 U/L (normal, 0–171 U/L). At all times the diuresis was normal, with a maximum value of creatinine of 4.67 mg/dL 48 hours following admittance, and the CK values ranged between 421–681 U/L with proteinuria of 840 mg/day. On the seventh day, blood tests showed a CK of 1,559 U/L and a creatinine of 1.55 mg/dL. LEV was progressively substituted for lacosamide, after which creatinine, CK and albumin excretion rate were normalised. Thus, CK and renal function during treatment with LEV should be monitored, and acute kidney injury due to LEV should be considered in the differential diagnosis for any unexplained acute renal failure.

Trkb-IP3 Pathway Mediating Neuroprotection in Rat Hippocampal Neuronal Cell Culture Following Induction of Kainic Acid.

BackgroundFollowing brain injury, development of hippocampal sclerosis often led to the temporal lobe epilepsy which is sometimes resistant to common anti-epileptic drugs. Cellular and molecular changes underlying epileptogenesis in animal models were studied, however, the underlying mechanisms of kainic acid (KA) mediated neuronal damage in rat hippocampal neuron cell culture alone has not been elucidated yet.MethodsEmbryonic day 18 (E-18) rat hippocampus neurons were cultured with poly-L-lysine coated glass coverslips. Following optimisation, KA (0.5 μM), a chemoconvulsant agent, was administered at three different time-points (30, 60 and 90 min) to induce seizure in rat hippocampal neuronal cell culture. We examined cell viability, neurite outgrowth density and immunoreactivity of the hippocampus neuron culture by measuring brain derived neurotrophic factor (BDNF), γ-amino butyric acid A (GABAA) subunit α-1 (GABRA1), tyrosine receptor kinase B (TrkB), and inositol trisphosphate receptor (IP3R/IP3) levels.ResultsThe results revealed significantly decreased and increased immunoreactivity changes in TrkB (a BDNF receptor) and IP3R, respectively, at 60 min time point.ConclusionThe current findings suggest that TrkB and IP3 could have a neuroprotective role which could be a potential pharmacological target for anti-epilepsy drugs.

VPA Inhibits P19 Neural Differentiation through Redox Dysregulation and Oxidative Stress

Valproic acid (VPA), a common anti-epileptic drug and migraine reducer, causes deficiencies in developing nervous systems and can be manifested as neural tube defects (NTDs). The appearance of these defects is believed to be due to the disruption of the redox state of differentiating cells. P19 cells are embryo carcinoma cells and are an established model for neurogenesis. Preliminary work in P19 cells shows that during neural differentiation, the glutathione (GSH) redox potential (Eh) shifts from a reducing state to a more oxidizing one. The effects of VPA exposure during distinct stages of neural differentiation are unknown. The purpose of this study was to determine if specific states of neural differentiation are more susceptible to redox disruption. In undifferentiated cells, GSH Eh were much more easily disrupted with VPA treatment than differentiated cells, suggesting earlier periods of development are more susceptible to redox dysregulation. Cellular proteins in undifferentiated P19 cells also demonstrate a greater degree of redox dysregulation, where VPA altered protein redox states to a greater extent in undifferentiated cells. Furthermore, P19 cells treated early in pro-differentiation conditions with VPA decreased the expression of neurogenic terminal differentiation markers (B III tubulin) compared to control, untreated cultures. Interestingly, pretreatment with D3T, a Nrf2 inducer, prior to VPA exposure, diminished GSH Eh oxidative shifts, increased differentiation and reduced alterations to protein redox states. Together, these data suggest that VPA-induced oxidative stress is a critical factor regulating P19 neurogenesis and may serve as an important mediator in VPA-induced NTDs. Clearly, VPA-induced oxidative stress in the embryo elicits further study.

P 134 Photic driving response in epileptic and non-epileptic patients

Objective To determine the prevalence of photic driving - a physiologic response to photic stimulation in the occipital cortex – at different frequencies and in different populations and to evaluate the role of the individual alpha-frequency on the reaction to photic driving. Methods We retrospectively searched our medical database for patients who have had an EEG with photic stimulation in the year 2016 and retrieved 20 EEGs of patients who finally turned out to have non-epileptic events (syncopies, migraine, non-epileptic seizures) (age 38.2 ± 12.1, 10 female) and 20 patients with focal epilepsy on a monotherapy with valproate, lamotrigine or levetiracetam (33.2 ± 12.5, 12 female) excluding those with occipital lesions or mental retardation. In all individuals photic stimulation was applied at 3, 6, 9, 12, 15, 20 and 30 Hz for 20 s (XLTEK XLPS-1F®) each with stimulation-free intervals of 10 s. Each 18 s of the stimulation sequence as well as 9 s of the interstimulus intervals were analyzed. The peak amplitude at each stimulation frequency as well as at first and second harmonic frequencies ±0.1 Hz were calculated in a fast Fourier transformation in the frequency domain. Similarly, the mean alpha-frequency and its amplitude of each subject were calculated as an average of the calculated alpha-frequency of each interstimulation interval. Results No significant differences were found between the amplitude of the photic driving response to the photic stimulation between the control group and the group with focal epilepsy at any basic stimulation frequency ( Fig. 1 ) as well as for its harmonics. Additionally, the alpha frequencies did neither differ between the groups nor did they change in the course of the photic stimulation. We also could not establish a relationship between the individual alpha-frequency and the individual propensity to react to a photic stimulation in the alpha-frequency-range (9 and 12 Hz in our laboratory) ( Fig. 2) . Conclusion The fundamental response to photic driving is not significantly influenced by focal epilepsy as well as a range of common antiepileptic drugs and may thus demonstrate a conservative response of the brain. While the photic driving response is maximal at the alpha-frequency range the individual alpha-frequency apparently does not significantly influence this response and thus both may be triggered by different generators.

Evaluation of the Effects of Extracorporeal Membrane Oxygenation on Antiepileptic Drug Serum Concentrations in Pediatric Patients.

Patients supported on extracorporeal membrane oxygenation (ECMO) have an increased incidence of seizures. Phenobarbital (PB) and fosphenytoin (fos-PHT) are common antiepileptic drugs (AEDs) used to manage seizures in the pediatric population; however, it is unknown what effect ECMO has on the serum concentrations of AEDs. The purpose of this study is to evaluate the effect of ECMO on AED serum concentrations. A retrospective, matched-cohort study was performed in patients younger than 18 years who received ECMO and were treated with intravenous (IV) PB or fos-PHT at Texas Children's Hospital between 2004 and 2014. Patients receiving IV AED therapy and ECMO were matched, based on age, sex, and weight, with patients receiving IV AED therapy without ECMO. The 24-hour cumulative AED dose, serum concentrations, number of doses per serum concentration drawn ratio, volume of distribution, therapeutic serum concentrations, and time to therapeutic serum concentration were compared between both groups. The fos-PHT and PB groups were analyzed in all patients and in neonates only. Fourteen patients met inclusion criteria. The fos-PHT neonatal (20.1 vs 11.3 mg/kg/day, p = 0.044), PB composite (33.9 vs 21.6 mg/kg/day, p = 0.012), and PB neonatal (40.3 vs 20 mg/kg/day, p = 0.04) had larger 24-hour cumulative doses compared with non-ECMO patients. Lower serum concentrations were observed in the PB composite ECMO group (19.1 vs 35.4 mg/L, p < 0.001) and the PB neonatal ECMO group (20.5 vs 27.8 mg/L, p = 0.01) compared with non-ECMO patients. Pediatric patients receiving PB on ECMO and neonatal patients receiving fos-PHT on ECMO required larger doses, and in pediatric patients achieved lower serum concentrations, suggesting the necessity for alternative dosing strategies in these populations.

Evaluation of Safety in Exceeding Maximum Adult Doses of Commonly Used Second-Generation Antiepileptic Drugs in Pediatric Patients.

Pediatric patients often require larger doses of antiepileptic drug (AED) than adults in order to attain therapeutic serum concentrations and/or achieve seizure control. Safety and efficacy data are often extrapolated from adult literature; hence, optimal dosage may only be determined anecdotally or based on expert opinion. With limited pediatric dosing guidelines, milligrams per day that are based on weight may exceed the maximum adult dose. The primary objective of this study is to evaluate the safety of exceeding maximum doses as specified by the US Food and Drug Administration or manufacturers of commonly used AEDs in pediatric patients. This study is a single-center, retrospective analysis of all pediatric patients seen in the outpatient clinic between October 2010 and October 2014 who were prescribed a dose that exceeds the maximum approved dose of oxcarbazepine, zonisamide, topiramate, levetiracetam, lamotrigine, or clobazam. Baseline demographics (ie, sex, age, race/ethnicity, weight, height, diagnosis), serum drug concentrations, and appropriate laboratory tests were collected. Side effects were reviewed. During the 4-year study period, 41,137 prescriptions were included. A total of 2% of prescriptions exceeded the maximum dose of 1 of the included AEDs. The most common AED prescribed above the maximum dose was levetiracetam (53%), whereas lamotrigine was the least common (6%). The largest doses prescribed exceeded the maximum by 3-fold (i.e., levetiracetam dose of 9000 mg/day). It appears safe to use doses exceeding the maximum approved dose of the evaluated AEDs in pediatric patients, with appropriate counseling and monitoring for adverse effects.

Low risk of seizures with slow flumazenil infusion and routine anticonvulsant prophylaxis for high-dose benzodiazepine dependence.

High-dose benzodiazepine (BZD) dependence represents an emerging and under-reported addiction phenomenon and is associated with reduced quality of life. To date there are no guidelines for the treatment of high-dose BZD withdrawal. Low-dose slow flumazenil infusion was reported to be effective for high-dose BZD detoxification, but there is concern about the risk of convulsions during this treatment. We evaluated the occurrence of seizures in 450 consecutive high-dose BZD dependence patients admitted to our unit from April 2012 to April 2016 for detoxification with low-dose slow subcutaneous infusion of flumazenil associated with routine anticonvulsant prophylaxis. In our sample, 22 patients (4.9%) reported history of convulsions when previously attempting BZD withdrawal. Only four patients (0.9%) had seizures during ( n = 2) or immediately after ( n = 2) flumazenil infusion. The two patients with seizures during flumazenil infusion were poly-drug misusers. The most common antiepileptic drugs (AEDs) used for anticonvulsant prophylaxis were either valproate 1000 mg or levetiracetam 1000 mg. Our data indicate that, when routinely associated with AEDs prophylaxis, low-dose slow subcutaneous flumazenil infusion represents a safe procedure, with low risk of seizure occurrence.

An investigation of the characteristics of outpatients with epilepsy and antiepileptic drug utilization in a multicenter cross-sectional study in China.

This study aimed to describe the distribution of seizure types, clinical characteristics, and antiepileptic drug (AED) utilization in patients with epilepsy visiting tertiary hospitals in China. This was an observational, cross-sectional epidemiology study conducted at 11 tertiary hospitals across China from May 2014 to November 2014. A total of 1603 patients, of either sex or any age with confirmed diagnosis of epilepsy, visiting outpatient clinics at tertiary hospitals were screened and enrolled. Demographics, seizure types, frequency, etiologies, comorbidities, and current AED therapy were analyzed using descriptive statistics. Overall, the majority (n=1201; 74.9%) of patients were adults (16-59years of age), and the mean (SD) age was 27.5 (15.9) years. A total of 989 (61.7%) patients had partial seizures, and 653 (40.7%) had generalized seizures. The majority experienced monthly (n=663) or yearly (n=625) seizures, with 2.7seizures/month or 2.9seizures/year, respectively. The most commonly reported symptomatic etiologies were traumatic brain injury, encephalitis, and stroke, whereas the most common comorbidities were sleep disorder, headache, anxiety, and depression. Overall, monotherapy was used in 54.1% of patients, while 30.6% of patients used dual therapy. The most commonly prescribed monotherapy for patients with partial seizures was oxcarbazepine (25.9%), while that for patients with generalized seizures was valproic acid (38.9%), and the most common AED combination was valproic acid and lamotrigine. Overall, valproic acid was the most commonly prescribed AED as monotherapy and combination therapy. Findings from this study provide extensive information on clinical characteristics and utilization of AEDs in Chinese patients with epilepsy which may help physicians make well-informed clinical decisions.

Standard approach to antiepileptic drug therapy in focal epilepsy at a tertiary care hospital in Bengaluru: A retrospective cohort study

Background: Epilepsy is a common neurological disorder which demands long-term therapy and thereby carries a huge medical, social, psychological, and economic impact on a developing country. In India, it is estimated that 6-10 million people suffer from epilepsy which accounts for 1/5th of the global epilepsy burden. About 2/3rd of the newly diagnosed epilepsies are focal. The overall aim of treating epilepsy should be complete control of seizures, without causing any untoward reaction due to the antiepileptic therapy. Aims and Objectives: The primary objectives are to analyze the pattern of antiepileptic drugs (AEDs) used in focal epilepsy and to assess the retention rate (success rate) at 1-year follow-up. The secondary objectives are to evaluate the effectiveness of substitution versus add-on in treatment failure cases and to assess the profile of adverse drug reactions (ADRs) reported. Materials and Methods: This is a retrospective cohort study spanning from January 2009 to January 2014. Patients diagnosed as focal epilepsy attending Neurology outpatient department attached to BMCRI were included in the study. Data were collected through the integration of case records to retrieve the information regarding the demographic and clinical details, AEDs, and ADRs. Retention rate with initial AED was determined at the end of 1-year follow-up. Efficacy was assessed in terms of adequate seizure control between substitution and add-on therapies in all treatment failure cases. The results were analyzed by descriptive statistics, Chi-square, and Fisher’s exact tests. Results: Out of 134 patients, 57% were males and 43% were females. The age ranged from 14 to 82 years. Monotherapy accounted for 67% of the total epileptic patients, in which 42% continued with initial, 25% substituted to alternative AED, and 33% of them required add-on therapy. The most common AEDs prescribed as monotherapy were carbamazepine (35.07%) and phenytoin (11.94%) and as add-on were carbamazepine with valproate (4.47%) and carbamazepine with phenytoin (4.47%). Carbamazepine showed higher retention rate among all initial AEDs at the end of 1-year follow-up (odds ratio: 2.1, 95% confidence interval: 1.03-4.24). On Fisher’s exact test, substitution therapy was better than add-on in adequate seizure control (P = 0.026). The overall incidence of ADRs was 21.6%. Drowsiness and agitation and tiredness were the common ADRs reported. Conclusion: Despite the availability of newer AEDs, the domain of pharmacotherapy in focal epilepsy is still dominated by conventional AEDs. Carbamazepine has showed better retention rate at 1-year follow-up. Our study suggests that substitution therapy is a better alternative than add-on therapy in all treatment failure cases with initial AEDs.

First patient in Serbia with biochemically and genetically diagnosed pyridoxine-dependent epilepsy

Introduction. Pyridoxine-dependent epilepsy (PDE) is a rare autosomal recessive inborn error of metabolism present with early-onset seizures resistant to common anticonvulsants. PDE has been shown to be caused by a defect of a ?-aminoadipic semialdehyde dehydrogenase (also known as ALDH7A1 or antiquitin) in the cerebral lysine degradation pathway. Its deficiency results in accumulation of ?-aminoadipic semialdehyde (?-AASA), piperideine -6-carboxylate and pipecolic acid, which serve as diagnostic markers in urine, plasma and cerebrospinal fluid of the disease. ?-Aminoadipic semialdehyde dehydrogenase is encoded by the ALDH7A1 or antiquitin gene and definite confirmation of diagnosis of PDE is made by genetic analysis. Case report. We present a first patient in Serbia who was diagnosed clinically, biochemically and genetically. We suspected PDE due to drug-resistant seizures in the seventh day of life when we attempted with pyridoxine. Since that time the patient has taken pyridoxine and the seizures have not recured. Our patient had markedly elevated ?- AASA in urine while on treatment with individual dosages of pyridoxine. Molecular-genetical analysis identified mutations of the ALDH7A1 (antiquitin) gene. Conclusion. ?-AASA is reliable marker to select PDF patient for molecular analysis of the ALDH7A1(antiquitin) gene. Diagnosis is confirmed by molecular- genetical analysis and pyridoxine withdrawal is no longer needed to establish the diagnosis of ?definite? PDE.

The ATP-sensitive K channel is seizure protective and required for effective dietary therapy in a model of mitochondrial encephalomyopathy

Effective therapies are lacking for mitochondrial encephalomyopathies (MEs). MEs are devastating diseases that predominantly affect the energy-demanding tissues of the nervous system and muscle, causing symptoms such as seizures, cardiomyopathy, and neuro- and muscular degeneration. Even common anti-epileptic drugs which are frequently successful in ameliorating seizures in other diseases tend to have a lower success rate in ME, highlighting the need for novel drug targets, especially those that may couple metabolic sensitivity to neuronal excitability. Furthermore, alternative epilepsy therapies such as dietary modification are gaining in clinical popularity but have not been thoroughly studied in ME. Using the Drosophila ATP61 model of ME, we have studied dietary therapy throughout disease progression and found that it is highly effective against the seizures of ME, especially a high fat/ketogenic diet, and that the benefits are dependent upon a functional KATP channel complex. Further experiments with KATP show that it is seizure-protective in this model, and that pharmacological promotion of its open state also ameliorates seizures. These studies represent important steps forward in the development of novel therapies for a class of diseases that is notoriously difficult to treat, and lay the foundation for mechanistic studies of currently existing therapies in the context of metabolic disease.