Epidemiology and management of epilepsy in Hong Kong: an overview

AbstractOver half of the estimated 50 million people with epilepsy live in Asia, but there has been limited information on the epidemiology, aetiology and management of epilepsy from this region. In this article, we summarise some of the main problems faced by patients and the current treatment options available in an urban area of China

Evaluation of perampanel as monotherapy for focal seizures: Experience from open-label extension studies

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. © 2017 The Author

The Concept of Drug-Resistant Epileptogenic Zone

Resective surgery is the most effective way to treat drug-resistant epilepsy. Despite extensive pre-surgical evaluation, only 30–70% patients would become seizure-free after surgery. New approaches and strategies are needed to improve the outcome of epilepsy surgery. It is commonly observed in clinical practice that antiepileptic drugs (AEDs) could maintain seizure freedom in a large proportion of patients after surgery, who were uncontrolled before the operation. In some patients cessation of AEDs leads to seizure recurrence which, in most cases, can be controlled by resuming AEDs. These observations suggest that the surgery has converted the epilepsy from drug-resistant to drug-responsive, implying that the operation has removed the brain tissue accounting for pharmacoresistance, rather than the pathological substrate of epilepsy (at least not completely). Based on these observations, it is hypothesized that there is a drug-resistant epileptogenic zone (DREZ) which overlaps with the epileptogenic zone (EZ), and has both epileptogenic and drug-resistant properties. DREZ is necessary and sufficient to cause drug-resistant epilepsy, and its remove would render the epilepsy drug-responsive. Testing the hypothesis requires the development of new methods to define the DREZ, which may be used to guide surgical planning when the epileptogenic zone cannot be completely excised. This concept can also help understand the mechanisms of drug-resistant epilepsy, leading to new therapeutic strategies

Efficacy and safety of retigabine/ezogabine as adjunctive therapy in adult Asian patients with drug-resistant partial-onset seizures: A randomized, placebo-controlled Phase III study

AbstractPurposeThe purpose of this study was to evaluate the efficacy and safety of adjunctive retigabine/ezogabine (RTG/EZG) therapy in Asian adults with partial-onset seizures.MethodsA Phase III, randomized, double-blind, placebo-controlled, parallel-group study was conducted at 26 centers in Asia. Eligible patients were randomized in a 1:1:1 ratio to receive RTG/EZG 600mg/day (200mg 3 times daily), RTG/EZG 900mg/day (300mg 3 times daily), or placebo. The study consisted of an 8-week screening/baseline phase, followed by a 16-week treatment phase (4-week titration phase and 12-week maintenance phase).ResultsThe study was terminated early because of emerging safety information on RTG/EZG (i.e., retinal pigmentation and skin/mucosal discoloration) from long-term trials. Of 132 patients screened and 76 randomized, 75 (placebo, n=25; RTG/EZG 600mg/day, n=26; RTG/EZG 900mg/day, n=24) received at least 1 dose of the study drug and were included in the safety and intent-to-treat populations. The responder rate (≥50% reduction in 28-day total partial-onset seizure frequency) was 31% with RTG/EZG 600mg/day and 17% with RTG/EZG 900mg/day versus 0% with placebo. Median percent change from baseline in 28-day total partial-onset seizure frequency during the maintenance phase was −33.90% and −22.46% with RTG/EZG 600 and 900mg/day, respectively, versus −22.21% with placebo. No new safety concerns were identified.ConclusionsInsufficient data were obtained to permit definitive conclusions. However, the results appear to be broadly in line with those from previous studies that included primarily Caucasian patients

Experimental investigations on the load bearing behaviour of an innovative prestressed composite floor system in fire

[EN] In Germany, regulations for hollow spaces in slab systems require 30 minutes standard fire resistance of the load-bearing steel construction. Within a current national research project a natural fire scenario for the hollow space was developed based on realistic fire loads and ventilation conditions in the hollow space. Assuming this realistic fire scenario in the hollow space, two large scale tests on an innovative composite floor system were performed to evaluate the influence on the load bearing behaviour of the floor system. The integrated and sustainable composite floor system consists of a prestressed concrete slab, an unprotected, bisected hot rolled I-profile with composite dowels either in puzzle or clothoidal shape, and removable floor panels on the top of the I-profile. This floor system ensures the opportunity to adjust the technical building installations in accordance with the use of the building. This integrated and sustainable composite floor system was developed in several research projects. The standard fire resistance R90 for the fire scenario below the slab system has already been proven successfully. In this paper, experimental investigations regarding the heating and load bearing behaviour of the innovative composite floor system under the newly developed natural fire scenario of hollow spaces are presented. In doing so, the special test set-up to realise the fire tests for the fire scenario hollow space will be described in detail. After the fire scenario for the hollow space, the specimen was subjected to the ISO standard fire curve to establish the failure temperature of the unprotected I-profile. In addition to the temperature development and the load bearing behaviour inside the innovative floor during the heating phase, the cooling phase and the influence of a web opening on the load bearing behaviour will be discussed.This IGF project (IGF-Nr. 18894N) of the FOSTA is supported via AiF within the programme for promoting the Industrial Collective Research (IGF) of the German Ministry of Economic Affairs and Energy (BMWi), based on a resolution of the German Parliament.Schaumann, P.; Meyer, P.; Mensinger, M.; Koh, SK. (2018). Experimental investigations on the load bearing behaviour of an innovative prestressed composite floor system in fire. En Proceedings of the 12th International Conference on Advances in Steel-Concrete Composite Structures. ASCCS 2018. Editorial Universitat Politècnica de València. 811-818. https://doi.org/10.4995/ASCCS2018.2018.7020OCS81181

Attention-deficit/hyperactivity disorder medication and seizures

OBJECTIVE: Individuals with attention-deficit/hyperactivity disorder (ADHD) are at increased risk of seizures, but there is uncertainty about whether ADHD medication treatment increases risk among patients with and without preexisting seizures. METHODS: We followed a sample of 801,838 patients with ADHD who had prescribed drug claims from the Truven Health MarketScan Commercial Claims and Encounters databases to examine whether ADHD medication increases the likelihood of seizures among ADHD patients with and without a history of seizures. First, we assessed overall risk of seizures among patients with ADHD. Second, within-individual concurrent analyses assessed odds of seizure events during months when a patient with ADHD received ADHD medication compared with when the same individual did not, while adjusting for antiepileptic medications. Third, within-individual long-term analyses examined odds of seizure events in relation to the duration of months over the previous 2 years patients received medication. RESULTS: Patients with ADHD were at higher odds for any seizure compared with non-ADHD controls (odds ratio [OR] = 2.33, 95% confidence interval [CI] = 2.24-2.42 males; OR = 2.31, 95% CI = 2.22-2.42 females). In adjusted within-individual comparisons, ADHD medication was associated with lower odds of seizures among patients with (OR = 0.71, 95% CI = 0.60-0.85) and without (OR = 0.71, 95% CI = 0.62-0.82) prior seizures. Long-term within-individual comparisons suggested no evidence of an association between medication use and seizures among individuals with (OR = 0.87, 95% CI = 0.59-1.30) and without (OR = 1.01, 95% CI = 0.80-1.28) a seizure history. CONCLUSIONS: Results reaffirm that patients with ADHD are at higher risk of seizures. However, ADHD medication was associated with lower risk of seizures within individuals while they were dispensed medication, which is not consistent with the hypothesis that ADHD medication increases risk of seizures

Refractory Epilepsy: Natural History and Pathogenesis

Despite antiepileptic drug (AED) treatment, up to one third of patients continue to have seizures. Refractory epilepsy is a poorly understood subject, both in terms of its development and pathogenesis. Outcome studies have focused on terminal remission, but little is known about the natural history of epilepsy in terms of its progression to eventual remission or persistent refractoriness. Such an understanding is essential to the formulation of a rational management approach. Natural history of treated epilepsy Long-term outcome of newly diagnosed patients was investigated longitudinally for up to 15 years. Response to the first drug and successive substitution monotherapy or polytherapy was analysed. Outcome among patients with different neuropathologies was compared in a separate study. Among 470 newly diagnosed patients, 64% became seizure-free for at least a year. Patients with high numbers of pre-treatment seizures were less likely to become seizure- free. Epilepsy was controlled by the first AED in 47% of patients. Patients with symptomatic or cryptogenic epilepsy were less likely to become seizure-free on the first AED, partly because they were more likely to develop intolerable side-effects compared to those with idiopathic epilepsy. The majority of such withdrawals occurred at low doses of the three most commonly prescribed AEDs, carbamazepine (CBZ), sodium valproate (VPA) and lamotrigine (LTG). Over 90% of seizure-free patients also required only a moderate daily dose (up to 800mg CBZ, ISOOmg VPA, 300mg LTG). The probability of attaining seizure-freedom declined progressively with successive AED regimens. While 47% became seizure-free on the first drug, only 10% did so on the second drug and 1% on the third monotherapy. Three percent became seizure-free on a combination of two AEDs. The subsequent seizure-free rate was 41% among those failing the first drug due to intolerable side effects, but only 11% among those in whom the first AED was well tolerated but did not control the seizures completely. Among patients with inadequate seizure control on the first well tolerated AED, those who received substituted monotherapy and those who received add-on treatment had similar seizure-free rates and incidence of intolerable side effects. More patients became seizure- free on combinations involving an AED that blocked sodium channels and one with multiple mechanisms of action than on other combinations. Combination treatment was more effective when prescribed immediately after the first drug failed due to inadequate seizure control than w'hen it was delayed until a substitution also proved unsuccessful. In a separate study, compared with other pathologies identified on magnetic resonance imaging, mesial temporal sclerosis (MTS) was associated with the worst prognosis, although 42% did become seizure-free on AED treatment. Pathogenesis of refractory epilepsy Two candidate biological mechanisms in the pathogenesis of refractory epilepsy were studied. Glutamic acid decarboxylase (GAD) autoantibody titres were compared between patients with controlled and uncontrolled epilepsy. GAD catalyses the conversion of glutamate to y-aminobutyric acid, the major inhibitory neurotransmitter. Autoantibodies against GAD are prevalent in insulin dependent diabetes mellitus, and have been documented in anecdotal cases of refractory epilepsy. The drug transporter P-glycoprotein (P-gp) was investigated in a series of laboratory-based pilot experiments. Encoded by the multidrug resistance gene family (MDRl in man and mdrla and lb in rodents), P-gp actively extrudes a wide range of xenobiotics out of cells. Its over-expression is thought to underlie the resistance of some cancers to multiple chemotherapeutics. P-gp is physiologically expressed at high level in the cerebral capillary endothelium where it contributes to the integrity of the blood-brain barrier. Overexpression of P-gp in brain tissues resected from patients with refractory epilepsy has been reported in surgical case series. Mdrla(-/-) mice devoid of cerebral P-gp were used to determine whether AEDs were substrates of the drug transporter. The pharmacokinetic profiles of four established and four new AEDs in mdrla(-/-) mice and wild-type mice were compared. The technique of quantitative reverse transcriptase-polymerase chain reaction was developed and validated to determine tissue concentration of mdrl mRNA as an indicator of gene expression. Expression was determined in different regions of the normal rat brain, and in brains of genetically epilepsy-prone rats (GEPRs) subject to a single audiogenic seizure. To explore the effect of tissue damage, a laser beam was impinged upon the cerebral cortex of rats. Mdrl expression was measured in tissues surrounding the focal necrosis. Human brain tissues resected during epilepsy surgery were also analysed for MDRl gene expression. There was no difference in GAD autoantibody titres between patients with controlled and uncontrolled epilepsy. (Abstract shortened by ProQuest.)

Antiepileptic drug research in Asia: Where do we go from here?

Abstract Efforts in clinical research of antiepileptic drug therapy in Asia have traditionally biased towards postmarketing surveillance studies

Onset voltage shift due to non-zero Landau ground state level in coherent magnetotransport

Coherent electron transport in double-barrier heterostructures with parallel electric and magnetic fields is analyzed theoretically and with the aid of a quantum simulator accounting for 3-dimensional transport effects. The onset-voltage shift induced by the magnetic field in resonant tunneling diodes, which was previously attributed to the cyclotron frequency $w_c$ inside the well is found to arise from an upward shift of the non-zero ground (lowest) Landau state energy in the entire quantum region where coherent transport takes place. The spatial dependence of the cyclotron frequency is accounted for and verified to have a negligible impact on resonant tunneling for the device and magnetic field strength considered. A correction term for the onset-voltage shift arising from the magnetic field dependence of the chemical potential is also derived. The Landau ground state with its nonvanishing finite harmonic oscillator energy $\hbar w_c /2$ is verified however to be the principal contributor to the onset voltage shift at low temperatures.Comment: 13 pages, and 3 figures. Accepted for publication in Phys. Rev.

Supersymmetry on the honeycomb lattice: resonating charge stripes, superfrustration, and domain walls

We study a model of spinless fermions on the honeycomb lattice with nearest-neighbor exclusion and extended repulsive interactions that exhibits `lattice supersymmetry' [P. Fendley, K. Schoutens, and J. de Boer, Phys. Rev. Lett. 90, 120402 (2003)]. Using a combination of exact diagonalization of large ($N\leq56$ site) systems, mean-field numerics, and symmetry analysis, we establish a rich phase structure as a function of fermion density, that includes non-Fermi liquid behavior, resonating charge stripes, domain-wall and bubble physics, and identify a finite range of fillings with extensive ground state degeneracy and both gapped and gapless spectra. We comment on the stability of our results to relaxing the stringent requirements for supersymmetry, and on their possible broader relevance to systems of strongly-correlated electrons with extended repulsive interactions.Comment: 15 pages, 12 figures, 1 tabl