ORCID Profile
0000-0001-7310-276X
Current Organisations
Royal Melbourne Hospital
,
Monash University
,
Alfred Health
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Publisher: Elsevier BV
Date: 10-2021
Publisher: Wiley
Date: 05-2009
DOI: 10.1111/J.1528-1167.2008.01938.X
Abstract: To determine the relative contributions of subjective anxiety, depression, sleep disturbance, and seizure-related variables to quality-of-life scores in adults with epilepsy, and the interrelationships among these factors. Consecutive adult patients with epilepsy attending neurology outpatient clinics were recruited. Patients completed the following scales: Hospital Anxiety and Depression Scale (HADS), Hamilton Anxiety Rating Scale, Medical Outcomes Study (MOS) Sleep Scale, Epworth Sleepiness Scale, and Quality of Life in Epilepsy Inventory-31 (QOLIE-31). Univariate and multivariate linear regression models were used to identify variables associated with QOLIE-31 overall score. Path analysis model was constructed to test for interrelations between the variables. Two hundred forty-seven patients completed the questionnaires. By multivariate analysis, in order of degree of contribution, HADS anxiety subscale score, MOS Sleep Scale Sleep Problems Index score, HADS depression subscale score, number of current antiepileptic drugs used, and seizure freedom in the past 4 weeks, significantly correlated with QOLIE-31 overall score, accounting for 65.2% of the variance. Complex interrelationships were present between these factors. A general linear model to predict QOLIE-31 overall score in the presence of these factors was constructed. Subjective anxiety, depression, and sleep disturbance exerted greater effect than short-term seizure control on quality of life scores of patients with epilepsy. These factors should be considered simultaneously when evaluating effects of treatment on quality of life.
Publisher: Wiley
Date: 18-02-2021
DOI: 10.1111/APT.16263
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 22-10-2014
Publisher: Elsevier BV
Date: 12-2000
DOI: 10.1016/S0920-1211(00)00180-7
Abstract: There have been anecdotal reports of raised glutamic acid decarboxylase (GAD) autoantibodies in patients with refractory epilepsy. We measured serum GAD autoantibodies in 105 patients with idiopathic or symptomatic epilepsy. There was no significant difference in the absolute titre of GAD autoantibody between patients with controlled and uncontrolled epilepsy. However, four female patients with uncontrolled epilepsy had levels that were over three times above the highest detected in the seizure-free group, three of whom also tested positive for pancreatic islet cell antibodies. Larger scale studies, perhaps comparing different epilepsy syndromes, are required to determine the exact clinical role of GAD autoantibodies in epilepsy.
Publisher: Wiley
Date: 24-08-2004
Publisher: BMJ
Date: 31-07-2012
Abstract: Phenobarbital is an effective treatment for epilepsy but concerns remain over its potential neurocognitive toxicity. This prospective study evaluated the effects of phenobarbital treatment on cognition and mood in people with epilepsy in rural China. We recruited 144 adults with convulsive seizures and 144 healthy controls from six sites in rural China. People with epilepsy were treated with phenobarbital monotherapy for 12 months. At baseline, and at 3, 6 and 12 months, cases and controls were evaluated with a battery of neuropsychological tests: the Mini-Mental State Examination, the Hamilton Depression Rating Scale, a digit span test, a verbal fluency test, an auditory verbal learning test and a digit cancellation test. Efficacy of phenobarbital treatment was evaluated at the end of follow-up for those with epilepsy. Cognitive test scores and mood ratings were available for 136 (94%) people with epilepsy and 137 (95%) controls at the 12 month follow-up. Both groups showed slightly improved performance on a number of neuropsychological measures. The people with epilepsy showed greater performance gains (p=0.012) in verbal fluency. Nine people with epilepsy complained of memory problems during the treatment period. In this study, phenobarbital was not found to have a major negative impact on cognitive function of people with convulsive seizures and some cognitive gains were observed, possibly due to improved seizure control.
Publisher: Elsevier BV
Date: 03-2003
DOI: 10.1016/S0304-3940(02)01453-2
Abstract: The multidrug resistance (mdr1) gene family encodes the efflux transporter P-glycoprotein (P-gp) which contributes to the functionality of the blood-brain barrier. We have characterised the regional expression of mdr1 genes in nai ve rat brain. Adult male Sprague-Dawley rats (n=6) were sacrificed and their brains rapidly removed. Seven distinct anatomical regions were isolated by microdissection and the expression of mdr1a and mdr1b determined by quantitative reverse-transcriptase polymerase chain reaction. The mdr1a isoform was expressed in all brain regions investigated, while mdr1b was expressed to a quantifiable degree in hippoc us alone. These findings reveal a differential expression of mdr1 genes in normal rodent brain tissue and suggest that P-gp may afford a broader protection of the hippoc us than other brain structures.
Publisher: Elsevier BV
Date: 10-2000
Publisher: Wiley
Date: 20-05-2013
DOI: 10.1111/EPI.12217
Abstract: HLA-B*15:02 screening is recommended before starting carbamazepine in Han Chinese and Southeast Asians because the allele is strongly predictive of Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) induced by the drug. We examined whether other HLA-B alleles are also involved and whether the association extends to other antiepileptic drugs (AEDs). Cases of SJS/TEN induced by any AEDs were recruited and matched (1:5) with AED-tolerant controls. Carrier rates of HLA-B alleles, determined by direct sequencing, were compared between cases and controls. Results were meta-analyzed with previous studies to examine the associations between HLA-B*15:02 and SJS/TEN induced by phenytoin and lamotrigine. A total of 55 cases (27 carbamazepine, 15 phenytoin, 6 lamotrigine, 7 other AEDs) and 275 controls were recruited. In drug-specific analysis, the carrier rate of HLA-B*15:02 was significantly higher in carbamazepine-SJS/TEN cases compared with carbamazepine-tolerant controls (92.3% vs. 11.9% p = 3.51 × 10(-18) odds ratio (OR) 89.25 95% confidence interval (CI) 19.25-413.83), and also in phenytoin-SJS/TEN cases compared with phenytoin-tolerant controls (46.7% vs. 20.0% p = 0.045 OR 3.50 95% CI 1.10-11.18). Meta-analyses showed a strong association of HLA-B*15:02 with phenytoin-SJS/TEN (p < 3 × 10(-4) OR 4.26 95% CI 1.93-9.39) and, to a lesser extent, lamotrigine-SJS/TEN (p = 0.03 OR 3.59 95% CI 1.15-11.22). Compared with drug-tolerant controls, the carrier rates of HLA-B*40:01 and HLA-B*58:01 were lower in cases of SJS/TEN induced by carbamazepine (p = 0.004) and other AEDs (p = 0.009), respectively. SJS/TEN induced by carbamazepine and phenytoin is strongly and moderately associated with HLA-B*15:02 in Han Chinese, respectively. Possible protective associations with HLA-B*40:01 and HLA-B*58:01 warrant further investigation.
Publisher: The Electrochemical Society
Date: 2022
Abstract: Identification of biomarkers in clinical applications for diagnostics at the point-of-care (POC) setting requires the development of industry viable biosensing platform. Herein, we report such development of biosensor architecture for the detection of pharmacogenetic biomarker HLA-B*15:02 gene. The biosensor architecture comprises of an oligonucleotide stem-loop probe modified with a methylene blue redox (MB) reporter, immobilized via a rapid “printing” method on the commercially available disposable screen-printed electrodes (SPE). The square wave voltammetric measurements on the DNA sensor showed a clear peak difference of ∼80 nA with a significant difference in peak height values of the faradaic current generated for the MB redox moiety between the positive control (biotin-modified 19 based oligonucleotides with the sequence mimicking the specific region of the HLA-B*15:02 allele and complementary to the probe sequence) and negative control s les (biotin-modified 19 based oligonucleotides with the sequence unrelated to the probe sequence and the HLA-B*15:02 allele). These initial proof of concept results provide support for the possibility of using this signal-off biosensor architecture in the intended pharmacogenetic biomarker testing.
Publisher: Elsevier BV
Date: 09-2022
DOI: 10.1016/J.BIOS.2022.114410
Abstract: Acute stroke is the third leading cause of mortality and disability worldwide. Administration of appropriate therapy for acute stroke is critically dependent on timely classification into either ischemic or hemorrhagic subtypes, which have ergent treatment pathways. The current classification method is based on neuroimaging, which generally requires the transport of the patient to a hospital-based facility unless a mobile stroke unit is available. Plasma glial fibrillary acidic protein (GFAP) level has been identified as a useful blood-based biomarker to differentiate stroke subtypes. However, its conventional immunoassay methods are laboratory-based and time-consuming. Novel approaches for rapid stroke classification near the patients are urgently needed. Here, we report the development and testing of a microfluidic-based magnetoimpedance biosensor platform for measuring GFAP levels. The platform consists of a microfluidic chip for GFAP extraction from a blood s le and a magnetoimpedance (MI) biosensor that employs Dynabeads as a magnetic label to capture the GFAP molecules. We demonstrated the detection of recombinant GFAP protein in phosphate-buffered saline (PBS) and in mouse blood s les (detection limit 0.01 ng/mL) and of physiological GFAP in blood and plasma s les (detection limit 1.0 ng/mL) obtained from acute stroke patients. This detection level is within the range of cut-off levels required for clinical stroke subtype differentiation. This platform has the potential to be incorporated into a small device with further development to assist in the classification of acute stroke patients and clinical decision-making at the point-of-care.
Publisher: Wiley
Date: 06-09-2023
DOI: 10.1002/EPI4.12822
Abstract: Differentiating status epilepticus (SE) from prolonged psychogenic non‐epileptic seizures (pPNES) can be difficult clinically. We aimed to define the utility of peripheral cell counts, cell ratios, and lactate levels in distinguishing SE from pPNES. Retrospective two‐centre study investigating the sensitivity and specificity of acute (≤12 hours of event offset) peripheral cell counts, cell ratios (neutrophil‐lymphocyte ratio, neutrophil‐monocyte ratio, monocyte‐lymphocyte ratio, platelet‐lymphocyte ratio, systemic immune inflammatory index [SII], systemic inflammatory response index [SIRI]), and lactate levels in differentiating SE from pPNES. Patients were identified from two tertiary hospitals, with one forming the development cohort and the other the validation cohort. Using generalised additive models to generate biomarker versus time curves, optimal blood collection times were defined for set parameters. Three diagnostic scores combining neutrophil count, SII or SIRI with lactate levels were developed and validated in separate cohorts. For the development cohort, 1262 seizure‐like events were reviewed and 79 SE and 44 pPNES events included. For the validation cohort, 241 events were reviewed and 20 SE and 11 pPNES events included. In idually, the biomarkers generally had low sensitivity and reasonable specificity for differentiating SE from pPNES, with neutrophil count, SIRI and SII performing best with sensitivities of 0.65‐0.84, specificities of 0.64‐0.89, and ROC AUCs of 0.78‐0.79. Lactate levels peaked at 60 minutes, while cell counts and ratios peaked after 240 minutes. Combining early peaking lactate levels and later peaking neutrophil count, SIRI or SII resulted in three scores that improved predictive potential with sensitivities of between 0.75‐0.79, specificities between 0.93‐1.00, and ROC AUCs of 0.89‐0.91. Lactate levels peak early post‐SE, whereas cell counts and ratios do so later. The differing post‐event time profiles of lactate levels versus neutrophil count, SIRI and SII allows incorporation into three separate scores which can assist in differentiating SE from pPNES.
Publisher: Elsevier BV
Date: 11-2005
DOI: 10.1016/J.JOCN.2004.11.011
Abstract: Simple partial status epilepticus (SPSE) is uncommon compared with generalized tonic-clonic status epilepticus. We evaluated the clinical profile and predictors of poor outcome in a group of Chinese patients with this condition. We identified 32 patients above the age of 14 years with SPSE from a large urban hospital over an eleven-year period. Factors for poor outcome, defined as death or morbidity, were analyzed. The most common underlying causes were due to cerebrovascular disease (46.9%), CNS infection (15.6%), metabolic derangement (12.5%) and tumor (12.5%). At 30 days from the onset of seizures, 13(40.5%) patients had recovered fully and seven (21.9%) had died. Poor outcome was associated with the presence of an acute symptomatic injury.
Publisher: Elsevier BV
Date: 04-2009
DOI: 10.1016/J.YEBEH.2009.01.010
Abstract: Cross-sectional studies have suggested that valproate treatment may be associated with hyperinsulinemia and hyperandrogenism in women. Few prospective data are available. We evaluated the reproductive endocrine and insulin-related metabolic parameters in men and women with untreated epilepsy randomized to valproate (n=44) or lamotrigine (n=37) monotherapy for 12 months. On treatment, there was no significant difference in fasting serum insulin concentrations between the two groups. In women (n=40), there was no significant difference between the two groups in change from baseline in serum total testosterone, dehydroepiandrosterone sulfate, luteinizing hormone, or follicle-stimulating hormone. In men (n=41), follicle-stimulating hormone concentration significantly decreased in patients taking valproate compared with those on lamotrigine as early as 3 months after treatment. Greater attention should be paid to investigate the potential impact of valproate on reproductive function in men.
Publisher: Springer Science and Business Media LLC
Date: 17-07-2023
DOI: 10.1007/S12264-023-01087-W
Abstract: Epilepsy is a common, chronic neurological disorder that has been associated with impaired neurodevelopment and immunity. The chemokine receptor CXCR5 is involved in seizures via an unknown mechanism. Here, we first determined the expression pattern and distribution of the CXCR5 gene in the mouse brain during different stages of development and the brain tissue of patients with epilepsy. Subsequently, we found that the knockdown of CXCR5 increased the susceptibility of mice to pentylenetetrazol- and kainic acid-induced seizures, whereas CXCR5 overexpression had the opposite effect. CXCR5 knockdown in mouse embryos via viral vector electrotransfer negatively influenced the motility and multipolar-to-bipolar transition of migratory neurons. Using a human-derived induced an in vitro multipotential stem cell neurodevelopmental model, we determined that CXCR5 regulates neuronal migration and polarization by stabilizing the actin cytoskeleton during various stages of neurodevelopment. Electrophysiological experiments demonstrated that the knockdown of CXCR5 induced neuronal hyperexcitability, resulting in an increased number of seizures. Finally, our results suggested that CXCR5 deficiency triggers seizure-related electrical activity through a previously unknown mechanism, namely, the disruption of neuronal polarity.
Publisher: Elsevier BV
Date: 06-2004
Publisher: Springer Science and Business Media LLC
Date: 13-12-2013
DOI: 10.1007/S00439-013-1405-1
Abstract: High-frequency action potentials are mediated by voltage-gated sodium channels, composed of one large α subunit and two small β subunits, encoded mainly by SCN1A, SCN2A, SCN3A, SCN1B, and SCN2B genes in the brain. These play a key role in epilepsy, with the most commonly mutated gene in epilepsy being SCN1A. We examined whether polymorphisms in the above genes affect epilepsy risk in 1,529 epilepsy patients and 1,935 controls from four ethnicities or locations: Malay, Indian, and Chinese, all from Malaysia, and Chinese from Hong Kong. Of patients, 19 % were idiopathic, 42 % symptomatic, and 40 % cryptogenic. We genotyped 43 polymorphisms: 27 in Hong Kong, 28 in Malaysia, and 12 in both locations. The strongest association with epilepsy was rs3812718, or SCN1A IVS5N+5G>A: odds ratio (OR) = 0.85 for allele G (p = 0.0009) and 0.73 for genotype GG versus AA (p = 0.003). The OR was between 0.76 and 0.87 for all ethnicities. Meta-analysis confirmed the association (OR = 0.81 and p = 0.002 for G, and OR = 0.67 and p = 0.007 for GG versus AA), which appeared particularly strong for Indians and for febrile seizures. Allele G affects splicing and speeds recovery from inactivation. Since SCN1A is preferentially expressed in inhibitory neurons, G may decrease epilepsy risk. SCN1A rs10188577 displayed OR = 1.20 for allele C (p = 0.003) SCN2A rs12467383 had OR = 1.16 for allele A (p = 0.01), and displayed linkage disequilibrium with rs2082366 (r (2) = 0.67), whose genotypes tended toward association with SCN2A brain expression (p = 0.10). SCN1A rs2298771 was associated in Indians (OR = 0.56, p = 0.005) and SCN2B rs602594 with idiopathic epilepsy (OR = 0.62, p = 0.002). Therefore, sodium channel polymorphisms are associated with epilepsy.
Publisher: Wiley
Date: 16-02-2023
DOI: 10.1002/EPI4.12704
Abstract: Electroencephalogram (EEG) datasets from epilepsy patients have been used to develop seizure detection and prediction algorithms using machine learning (ML) techniques with the aim of implementing the learned model in a device. However, the format and structure of publicly available datasets are different from each other, and there is a lack of guidelines on the use of these datasets. This impacts the generatability, generalizability, and reproducibility of the results and findings produced by the studies. In this narrative review, we compiled and compared the different characteristics of the publicly available EEG datasets that are commonly used to develop seizure detection and prediction algorithms. We investigated the advantages and limitations of the characteristics of the EEG datasets. Based on our study, we identified 17 characteristics that make the EEG datasets unique from each other. We also briefly looked into how certain characteristics of the publicly available datasets affect the performance and outcome of a study, as well as the influences it has on the choice of ML techniques and preprocessing steps required to develop seizure detection and prediction algorithms. In conclusion, this study provides a guideline on the choice of publicly available EEG datasets to both clinicians and scientists working to develop a reproducible, generalizable, and effective seizure detection and prediction algorithm.
Publisher: Elsevier BV
Date: 03-2002
Publisher: Wiley
Date: 07-2009
DOI: 10.1111/J.1528-1167.2009.02059.X
Abstract: The association between a specific polymorphism (3435C>T) in the ABCB1 gene, coding for the membrane drug transporter P-glycoprotein (PgP), and pharmacoresistance to seizure control is controversial. Studies have been limited by multiple drug use, chronic cohorts with varying definitions, and retrospective clinical data. Herein we examine the relationship of this polymorphism with seizure recurrence in three independent international cohorts of patients newly treated for epilepsy. Data were collected on demographics, medication details, and seizure control after 12 months of treatment. The distribution of ABCB1 3435C>T genotypes was compared between patients with and without recurrent unprovoked seizures. Five hundred forty-two newly treated patients were enrolled (212 from Australia, 285 from Scotland, and 45 from Hong Kong). A total of 38.4% had recurrent unprovoked seizures after starting antiepileptic drug (AED) treatment. Genotype frequencies and ethnicity did not differ between the Scottish and Australian cohorts, but both were significantly different in the Hong Kong cohort. There was no significant relationship between the ABCB1 3435C>T genotype and the rate of recurrence of unprovoked seizures in the three cohorts in idually or combined however the epilepsy syndrome and a greater number of seizures pretreatment was associated with an increased risk of seizure recurrence. The ABCB1 3435C>T genotype does not have a major role in determining the efficacy of seizure control with initial AED therapy. The study highlights issues that arise in combining pharmacogenetic datasets from different ethnic regions and health systems, an approach that is essential to advance this field.
Publisher: Elsevier BV
Date: 10-2013
DOI: 10.1016/J.YEBEH.2013.06.019
Abstract: A proportion of patients with seemingly "uncontrolled" epilepsy could still control their epilepsy with further pharmacological manipulations. It is possible that their epilepsy might not be truly "drug-resistant". We audited the patients with "uncontrolled epilepsy" using the recent ILAE definition of drug-resistant epilepsy. Patients with newly diagnosed epilepsy at Glasgow and patients with chronic epilepsy treated in Hong Kong were independently assessed at their last clinic visit. If the patient was not seizure-free, the epilepsy was considered "uncontrolled". In this latter situation, if the patient had adequate trials of two or more tolerated, appropriately chosen, and appropriately used AED schedules, the epilepsy was classified as "drug-resistant" in accordance with the ILAE definition. If not, the outcome was classified as "undefined", and the reason(s) for this was documented. In the newly diagnosed cohort with uncontrolled epilepsy (n=311), outcome was "undefined" in 175 (56%). The most common reasons were trying just one AED usually at the patient's behest (n=68 39%) intermittent compliance (60 34%) adverse effects at low dosage (51 29%) inadequate dosing (49 28%) social issues such as imprisonment, alcohol, and recreational drug use (34 19%) psychiatric problems affecting documentation, attendance, etc. (32 18%) patient choice accepting less than optimal control (14 8%) and seizure freedom of less than 12 months (12.7%). In the chronic cohort of 194 patients with uncontrolled epilepsy, drug responsiveness was "undefined" in just 79 (41%). The most common reasons were inadequate use of the AED(s) (35 44%), followed by a lack of information on treatment response in the medical records (18 23%) and failure of only one adequately used AED (11 14%). Uncontrolled epilepsy is not necessarily the same as drug-resistant epilepsy. Efforts should be made to understand why a patient is not seizure-free so that appropriate adjustment in AED regimen can be taken to enable the patient to attain long-term seizure freedom.
Publisher: Elsevier BV
Date: 12-2004
Publisher: Elsevier BV
Date: 03-2014
DOI: 10.1016/J.EPLEPSYRES.2014.01.011
Abstract: Epilepsy is resistant to treatment with antiepileptic drugs (AEDs) in about one third of epilepsy patients. AED export by P-glycoprotein (Pgp) overexpressed in the blood-brain barrier may contribute to AED resistance. The Pgp transport status of many of the recently approved AEDs remains unknown. We investigated whether several new AEDs - zonisamide (ZNS), pregabalin (PGB), and rufinamide (RFM) - are human Pgp substrates. MDCKII and LLC-PK1 cells transfected with the human MDR1 gene, which encodes the Pgp protein, were used in concentration equilibrium transport assays (CETA) to determine the substrate status of ZNS, PGB, and RFM. For each drug, an equal concentration was added to apical and basal chambers, and the concentration in both chambers was measured up to 4h. RFM, ZNS, and PGB were not transported by MDR1-transfected cells from basolateral to apical sides in CETA. ZNS, RFM, and PGB are not substrates of human Pgp. These data suggest that resistance to these drugs may not be attributed to increased Pgp activity in resistant patients.
Publisher: WHO Press
Date: 12-2008
Publisher: Elsevier BV
Date: 03-2014
DOI: 10.1016/J.YEBEH.2013.12.004
Abstract: Growing evidence suggests a bidirectional interaction between epileptic seizures and psychological states, fuelling the interest in the development and application of psychobehavioral therapy for people with epilepsy (PWE). The objective of this article is to review the various psychobehavioral therapies in regard to their application, hypothesized mechanisms, and effectiveness. Most psychobehavioral therapy aims at improving psychological well-being and seizure control. Behavioral approaches, cognitive-behavioral therapy (CBT), and mind-body interventions are the most widely applied approaches for PWE. Cognitive-behavioral therapy, mind-body approaches, and multimodel educative interventions have consistently demonstrated positive effects on enhancing well-being. Nevertheless, the effects on seizure control remain inconsistent, partly attributable to small clinical trials and inadequate control groups. Assessor-blinded randomized controlled trials with sufficient power and carefully defined therapeutic components corresponding with objective and subjective outcome measures are recommended for future trial designs.
Publisher: The Electrochemical Society
Date: 30-05-2021
DOI: 10.1149/MA2021-01642078MTGABS
Abstract: Pharmacogenomics is one of the endeavours in the modern acute health care sector due to the complexity of the drug reactions associated with the patients' genetic markers[1]. Therefore, the availability of patient pharmacogenetic marker testing at the point-of-care (POC) setting will help the clinicians to prescribe and personalize the medication to ensure maximum efficiency with minimal adverse drug reactions (ADR). In this regard, we focused on developing a HLA-B*15:02 pharmacogenetic biomarker testing known to cause specific ADRs for Carbamazepine[2]. In this study, disposable screen-printed electrodes (SPE) as the planar sensor surfaces and a sequence-specific stem-loop probe modified with a methylene blue redox (MB) reporter was used to detect the targeted DNA sequence of HLA-B*15:02. The oligo probe with MB reporter at the 3′ end was designed to incorporate 25 nucleotides to detect the specific region. The disulphide-reducing reagent, Tris(2-carboxyethyl) phosphine hydrochloride was introduced to reduce the S-S bond of the oligo probe. The probe immobilization on the working electrode area was performed using the fully automated non-contact dispensing system sciFLEXARRAYER SX by dispensing an array of droplets of 50 µM probe mixture into accurate positioning of the gold working electrode area of SPEs (220AT DropSens). Around 20 SPEs were loaded, and probes were printed during a single batch processing task. Two printing runs were performed, and a total of N=30 biosensors were used in the experimental procedure. The electrochemical behaviour of the sensor was studied by performing the square wave voltammetry (SWV) measurements from -0.4 V to -0.1 V, with a modulation litude of 0.02 V and frequency of 25 Hz at a scan rate of 0.026 V/s (Autolab-PGSTAT204). The target hybridization time was fixed at 30 minutes. The p-values ≤ 0.05 was considered statistically significant. The SWV measurements on the sensors with 75 µl, 1X PBS solution (Baseline) showed a well-defined peak at -0.31 V with the standard deviation (SD) of 0.004 V (N total =30) which is consistent with the potential of the MB redox moiety. The statistical t-test has been shown that no statistical significance (p=0.1760) between the two printing runs with the peak heights of 640.5 nA ± 151.2 nA (SD). Upon target hybridization, measured peak heights showed that (a) 152.0 nA ± 23.3 nA for the 50 µM Positive control (oligo with the sequence complementary to the probe), (b) 231.8 nA ± 54.8 nA for the 50 µM Negative control (oligo with the non-complementary sequence to the probe), and (c) 226.2 nA ± 93.2 nA for the Blank-oligo free sensors. This shows ~34% signal suppression in Positive control hybridized sensors, whereas insignificance difference between the Negative and Blank s les hybridized sensors. Furthermore, statistical analysis (one-way ANOVA) show that a statistical significance (p=0.0250) for the Positive vs. Negative, a statistical significance (p=0.0388) for the Positive vs. Blank s le, and no statistical significance (p=0.9793) for the Negative vs. Blank s le. These results confirmed that a complementary target binding event in the stem-loop probe results in a significant signal decrease and the possibility of using this 'signal-off biosensor architecture in detecting HLA-B*15:02 pharmacogenetic biomarker testing platform. It was found that only 6 µl probe mixture was required to cover one sensor. Accordingly, the calculated probe surface density was equivalent to ~1.43×10 15 molecules/cm 2 , which will be 3 order of magnitudes higher than the typical probe surface density (~10 12 ) of biosensors[3]. This high level of probe surface density on the sensors was achieved by printing a high concentration of low volume of redox probes. This will not be possible in the typical wet bench probe immobilization methods. Also, it showed a significantly higher level of faradaic current generated in the biosensor and clear differentiation of the targets. Therefore, this work showcases encouraging results of biosensor architecture, rapid probe immobilization method, the possibility of using the ultra-low volume of probe reagents, and high-throughput productions. This suggested that further development of this pharmacogenetic biomarker testing platform will enhance the technical feasibility and enable the transition of this biosensor from the research to industry. Acknowledgements This work used the Melbourne Centre for Nanofabrication (MCN) in the Victorian Node of the NCRIS-enabled Australian National Fabrication Facility (ANFF). References FDA. Table of Pharmacogenomic Biomarkers in Drug Labeling . Available from: rugs/science-and-research-drugs/table-pharmacogenomic-biomarkers-drug-labeling . Soraya, G.V., et al., An interdigitated electrode biosensor platform for rapid HLA-B*15:02 genotyping for prevention of drug hypersensitivity. Biosens Bioelectron, 2018. 111 : p. 174-183. Ricci, F., et al., Effect of molecular crowding on the response of an electrochemical DNA sensor. Langmuir, 2007. 23 (12): p. 6827-6834.
Publisher: Wiley
Date: 30-09-2021
DOI: 10.1111/EPI.17086
Abstract: Cognitive impairment is common in patients with chronic drug‐resistant temporal lobe epilepsy (TLE). Hyperphosphorylated tau (pTau) and amyloid‐β (Aβ) plaques, pathological hallmarks of Alzheimer disease, have been hypothesized to play a mechanistic role. We investigated Aβ plaques and pTau prevalence in TLE patients who underwent resective surgery and correlated their presence with preoperative psychometric test scores and clinical factors. Patients were retrospectively selected from the epilepsy surgery register of the Royal Melbourne Hospital, Australia. Sections from the resected temporal lobe were immunostained for pTau and Aβ plaques (antibodies: AT8, 1E8). The presence and severity of pathology were correlated with clinical characteristics, and verbal and visual learning functions as measured by the Verbal Pair Associates (VPA) test and Rey Complex Figure Test. Fifty‐six patients (55% female) aged 20–68 years (median = 34 years) at surgery were included. Aβ plaques were detected in four patients (7%), all at the moderate level. There was no difference in duration, age at onset of epilepsy, or side of resection between patients with and without Aβ plaques. Sparse pTau was found in two patients (3.5%). Both had moderate Aβ plaques and were years of age. Patients with Aβ plaques had a lower median score for the VPA hard assessment compared to those without (0 vs. 4 p = .02). There was otherwise no correlation between pathology and psychometric test scores. Aβ plaques and pTau were uncommon in the resected brain tissue of patients who have undergone temporal lobectomy, and did not correlate with clinical characteristics or preoperative psychometric test scores, except for a lower VPA median score in patients with Aβ plaques. Therefore, considering the low prevalence of Aβ plaques and pTau herein observed, it is unlikely that cognitive impairment in TLE is driven by the same mechanisms as in Alzheimer disease.
Publisher: Wiley
Date: 29-10-2001
DOI: 10.1046/J.1528-1157.2001.04501.X
Abstract: To investigate the interaction among efficacy, tolerability, and overall effectiveness of the first antiepileptic drug (AED) in patients with newly diagnosed epilepsy. The 470 patients were diagnosed, treated and followed up from January 1984 at a single center. Outcome was classified as seizure freedom for at least the last year or failure of initial treatment because of inadequate seizure control, adverse events, or for other reasons. Overall, 47% of patients became seizure-free with the first prescribed AED. A higher proportion (p = 0.025) of patients with symptomatic or cryptogenic epilepsy changed treatment because of intolerable side effects (17%), and a lower proportion (p = 0.007) became seizure-free (43.5%) compared with those with idiopathic epilepsy (8.5% and 58%, respectively). Most patients (83%) received carbamazepine (CBZ n = 212), sodium valproate (VPA n = 101), or lamotrigine (LTG n = 78). The majority of seizure-free patients required only a moderate daily AED dose (93.1% with < or =800 mg CBZ, 91.3% with < or =1,500 mg VPA, 93.8% with 90% doing so at moderate or even modest dosing. Tolerability was as important as efficacy in determining overall effectiveness.
Publisher: Wiley
Date: 14-12-2020
DOI: 10.1111/EPI.16788
Abstract: Epilepsy is seen historically as a disease of aberrant neuronal signaling manifesting as seizures. With the discovery of numerous auto‐antibodies and the subsequent growth in understanding of autoimmune encephalitis, there has been an increasing emphasis on the contribution of the innate and adaptive immune system to ictogenesis and epileptogenesis. Pathogenic antibodies, complement activation, CD8+ cytotoxic T cells, and microglial activation are seen, to various degrees, in different seizure‐associated neuroinflammatory and autoimmune conditions. These aberrant immune responses are thought to cause disruptions in neuronal signaling, generation of acute symptomatic seizures, and, in some cases, the development of long‐term autoimmune epilepsy. Although early treatment with immunomodulatory therapies improves outcomes in autoimmune encephalitides and autoimmune epilepsies, patient identification and treatment selection are not always clear‐cut. This review examines the role of the different components of the immune system in various forms of seizure disorders including autoimmune encephalitis, autoimmune epilepsy, Rasmussen encephalitis, febrile infection–related epilepsy syndrome (FIRES), and new‐onset refractory status epilepticus (NORSE). In particular, the pathophysiology and unique cytokine profiles seen in these disorders and their links with diagnosis, prognosis, and treatment decision‐making are discussed.
Publisher: Elsevier BV
Date: 05-2010
DOI: 10.1016/J.YEBEH.2010.03.016
Abstract: This study evaluated the safety and efficacy of levetiracetam as adjunctive therapy for partial seizures in everyday clinical practice in Asian populations. Patients aged > or =16 years (N=251) with inadequately controlled partial epilepsy were recruited from 29 centers across Asia. Levetiracetam was added to existing antiepileptic medication for 16 weeks at a starting dose of 500 or 1000 mg/day and titrated to a maximum of 3000 mg/day according to clinical response. The study completion rate was 86.9%. Adverse events were reported by 73.3% of patients and were generally mild, leading to treatment withdrawal in only 7.2%. The most common adverse events were somnolence (30.3%) and dizziness (14.7%). Compared with pretreatment baseline, 44.0% of patients had a > or =50% reduction in seizure frequency, with a median reduction of 46.4%, and 17.7% became seizure free during the treatment period. Levetiracetam was well tolerated and efficacious as adjunctive therapy for partial epilepsy in clinical practice among Asian populations.
Publisher: Wiley
Date: 19-07-2023
DOI: 10.1002/EPI4.12795
Abstract: To determine predictors of successful ictal Single Photon Emission Computed Tomography (SPECT) injections during Epilepsy Monitoring Unit (EMU) admissions for patients undergoing presurgical evaluation for drug resistant focal epilepsy. In this retrospective study, consecutive EMU admissions were analysed at a single centre between 2019‐2021. All seizures that occurred during the admission were reviewed. ‘Injectable seizures’ occurred during hours when the radiotracer was available. EMU‐level data were analysed to identify factors predictive of an EMU admission with a successful SPECT injection (successful admission). Seizure‐level data were analysed to identify factors predictive of an ‘injectable seizure’ receiving a SPECT injection during the ictal phase (successful injection). A multivariate generalised linear model was used to identify predictive variables. 125 EMU admissions involving 103 patients (median 37 years, IQR27.0‐45.5) were analysed. 38.8% of seizures that were eligible for SPECT (n=134) were successfully injected this represented 17.4% of all seizures (n=298) that occurred during admission. Unsuccessful admissions were most commonly due to a lack of seizures during EMU‐SPECT (19.3%) or no 'injectable seizures’ (62.3%). Successful EMU‐SPECT was associated with baseline seizure frequency per week (95%CI 2.1‐3.0, p .001) and focal PET hypometabolism (95%CI 2.0‐3.7, p .001). On multivariate analysis, the only factor associated with successful injection was patients being able to indicate they were having a seizure to staff (95%CI 1.0‐4.4, p=0.038). Completing a successful ictal SPECT study remains challenging. Baseline seizure frequency of per‐week, a PET hypometabolic focus and a patient's ability to indicate seizure onset were identified as predictors of success. These findings may assist EMUs in optimising their SPECT protocols, patient selection, and resource allocation.
Publisher: JMIR Publications Inc.
Date: 10-08-2023
DOI: 10.2196/43612
Abstract: China is facing a rapidly expanding aging population. Insights into the health status of older adults are of great significance for health resource allocation and health care provision to this population. With the goal of providing a comprehensive understanding of the health status of older adults and to inform potential interventions, we investigated the level of disability and identified risk factors associated with disability among the older population (aged ≥60 years) living in China. A total of 8467 older adults living in the Chinese city of Shenzhen were enrolled in this cross-sectional study. We used a multidimensional ability assessment survey, which assessed their activities of daily living (ADL including eating, bathing, grooming, dressing, defecation control, urination control, using a toilet unaided, transfer, flat-ground walking, stair activity), mental status (including cognitive function, aggressive behavior, depression symptoms), sensory and communication (including consciousness level, vision, hearing, communication), and social participation (including living, working, time/space orientation, distinguish persons, social communication) abilities. The impact of demographic risk factors on ability levels was analyzed using ordinal logistic regression. The correlations between the four dimensions of ability mentioned above were analyzed using Spearman correlation analysis. A total of 7766 participants were effectively assessed. The participants’ average age was 70.64 (SD 8.46) years comprising 56.53% females. The overall ability level was classified as mildly, moderately, and severely impaired for 27.57% (n=2141), 2.83% (n=220), and 4.28% (n=332) of the 7766 participants, respectively. With increasing age, the proportion of impaired participants increased from 17.62% (365/2071) in the age group 60-64 years to 91.3% (253/277) in the age group above 90 years (P .001), corresponding to an approximate 10% rise for every 5-year age increment. The odds of having more severe overall ability impairment in females was 1.15 times that in males (odds ratio [OR] 1.15, 95% CI 1.04-1.28). Participants who were orced or widowed had a higher risk of more severe overall ability impairment than those currently married (OR 1.98, 95% CI 1.68-2.33). Participants living with nonrelatives had an increased risk of more severe overall ability impairment than those living alone (OR 2.38, 95% CI 1.46-3.91). Higher education level was a protective factor of overall ability impairment (college degree or above: OR 0.32, 95% CI 0.24-0.42). The four dimensions of ability assessed were significantly correlated a low score for ADL was significantly correlated with poorer mental status, sensory and communication, and social participation (all P .001). The proportion of disability among Chinese older adults increases with age, being female, having lower education levels, being orced or widowed, and living with nonrelatives. Impairment in ADL ability is significantly correlated with poor mental status, social participation, and sensory and communication abilities. A holistic approach to improving the health of the older population is recommended in China.
Publisher: Wiley
Date: 14-02-2011
DOI: 10.1111/J.1528-1167.2010.02960.X
Abstract: To assess the efficacy, safety, and tolerability of adjunctive carisbamate treatment at 800 mg/day and 1,200 mg/day in patients with partial-onset seizures (POS). Patients ≥ 16 years of age with an established diagnosis of POS for ≥ 1 year and uncontrolled on one to three antiepileptic drugs were enrolled. Eligible patients remained on stable doses of prescribed antiepileptic drugs for an 8-week pretreatment baseline phase and were then randomized (1:1:1) to receive carisbamate (800 mg/day or 1,200 mg/day), or placebo, for a 14-week double-blind phase. Primary efficacy endpoints were percentage reduction in POS frequency and responder rate (patients with ≥ 50% reduction in POS frequency) during the double-blind versus baseline phase. Five hundred forty-seven patients were randomized 540 composed the intent-to-treat (ITT) analysis. Four hundred thirty-four patients (79%) completed the study. The median percent reduction from baseline to treatment phase in POS frequency was: 21% (placebo) 30% (carisbamate 800 mg) 36% (carisbamate 1,200 mg), and 32% (combined carisbamate doses). The combined carisbamate dose group was not significantly different from placebo for the median percent reduction of POS frequency (p = 0.20) or responder rate (p = 0.18). Therefore, the difference from placebo for the in idual carisbamate dose groups was also considered nonsignificant, based on a prespecified step-down analysis. Dizziness was the most common treatment-emergent adverse event, with a higher incidence (≥ 5% difference) in the combined carisbamate group (31%) than placebo (9%) the incidence was higher with carisbamate 1,200 mg (32%, n = 58) than with carisbamate 800 mg (30%, n = 53). Adjunctive carisbamate therapy in patients with POS did not demonstrate efficacy across the dose range assessed versus placebo. No new safety findings were observed.
Publisher: Wiley
Date: 27-01-2022
DOI: 10.1111/EPI.17172
Abstract: An important but understudied benefit of resective epilepsy surgery is improvement in productivity that is, people's ability to contribute to society through participation in the workforce and in unpaid roles such as carer duties. Here, we aimed to evaluate productivity in adults with drug‐resistant epilepsy (DRE) pre‐ and post‐resective epilepsy surgery, and to explore the factors that positively influence productivity outcomes. We conducted a systematic review and meta‐analysis using four electronic databases: Medline (Ovid), EMBASE (Ovid), EBM Reviews ‐ Cochrane Central Register of Controlled Trials (CENTRAL), and Cochrane Library. All studies over the past 30 years reporting on pre‐ and post‐resective epilepsy surgical outcomes in adults with DRE were eligible for inclusion. Meta‐analysis was performed to assess the post‐surgery change in employment outcomes. A total of 1005 titles and abstracts were reviewed. Seventeen studies, comprising 2056 unique patients, were suitable for the final quantitative synthesis and meta‐analysis. Resective epilepsy surgery resulted in a 22% improvement in overall productivity (95% confidence interval [CI]: 1.07–1.40). The factors associated with increased post‐surgery employment risk ratios were lower pre‐surgical employment in the workforce (relative risk ratio [RRR] =0.34 95% CI: 0.15–0.74), shorter follow‐up duration (RRR = 0.95 95% CI: 0.90–0.99), and lower mean age at time of surgery (RRR= 0.97 95% CI: 0.94–0.99). The risk of bias of the included studies was assessed using Risk Of Bias In Non‐randomised Studies ‐ of Interventions and was low for most variables except ”measurement of exposure.” There is clear evidence that resective surgery in eligible surgical DRE patients results in improved productivity. Future work may include implementing a standardized method for collecting and reporting productivity in epilepsy cohorts and focusing on ways to reprioritize health care resource allocation to allow suitable candidates to access surgery earlier. This will ultimately benefit in iduals with DRE, their families, our communities, and the wider health care system.
Publisher: Wiley
Date: 03-2010
DOI: 10.1111/J.1528-1167.2009.02318.X
Abstract: To assess the efficacy, safety, and tolerability of the investigational drug carisbamate as adjunctive treatment for partial-onset seizures (POS). Two identical, randomized, placebo-controlled, double-blind studies were conducted in adults with POS uncontrolled for >or=1 year. Therapy-refractory epilepsy patients (>or=16 years) remained on stable doses of prescribed antiepileptic drugs ( or=50% reduction in POS frequency) during the double-blind phase compared with the prospective baseline phase. Of the 565 patients randomized in study 1, 93% completed the study of the 562 randomized in study 2, 94% completed the study. Patient characteristics were similar across both studies and treatment arms: mean age, 35 years (study 1, range 16-75 years) and 36 years (study 2, range 16-74 years) approximately 50% were men. Treatment with carisbamate 400 mg/day resulted in significant improvement (p or=5% in any group), those with an incidence exceeding placebo (>or=3%) were dizziness (400 mg/day group) and somnolence. Carisbamate 400 mg/day was effective in patients with refractory partial-onset seizures in one of these global studies. More than 200 mg/day of carisbamate is required for efficacy. Carisbamate was well-tolerated in both studies.
Publisher: Elsevier BV
Date: 04-2021
Publisher: Oxford University Press (OUP)
Date: 08-2009
DOI: 10.1373/CLINCHEM.2009.127894
Abstract: Background: Severe and potentially fatal hypersensitivity reactions to drugs, particularly antiepileptics, are clinically unpredictable. Recent evidence has revealed a strong and specific association between the implicated drug, the type of adverse reaction, and the particular HLA genotype. An urgent need exists for rapid diagnosis of HLA status to guide drug prescription however, traditional HLA genotyping has a long turnaround time, is expensive, and is available only in specialized centers. We tested the feasibility of the loop-mediated isothermal lification (LAMP)-based approach to detect a specific HLA genotype. As an ex le, we used B*1502, an HLA allele strongly associated with carbamazepine-induced Stevens–Johnson syndrome/toxic epidermal necrolysis, and validated the assay’s application as a simple, accurate, rapid, and low-cost blood test for use in both clinical and bedside settings. Methods: We evaluated B*1502 status with the new LAMP method and compared the results with those obtained by sequence-based typing (SBT) (n = 250) and by sequence-specific primer PCR (SSP-PCR) (n = 200) for 450 s les of DNA (n = 50) and blood (n = 400) from a hematology laboratory. Results: LAMP results showed 100% concordance with both SBT and SSP-PCR results, confirming that LAMP detection of a specific HLA genotype (B*1502 in this case) is an accurate method. All results were available within 1 h. Conclusions: Our study confirmed that the new LAMP method for detecting a specific HLA genotype is simple, inexpensive, accurate, and rapid, and may be of help in overcoming barriers in effective clinical practice.
Publisher: Public Library of Science (PLoS)
Date: 09-09-2008
Publisher: Informa UK Limited
Date: 03-2006
Abstract: Pharmacoresistance remains a major challenge in epilepsy management. The availability of ten new antiepileptic drugs since the late 1980s has not dramatically improved the outcome of refractory epilepsy. This article provides an overview of the contemporary understanding of epilepsy and the limitation of current treatment modalities, discusses putative biological mechanisms of medical intractability and reviews some of the novel strategies under investigation to overcome the challenge of pharmacoresistance.
Publisher: Wiley
Date: 28-05-2022
DOI: 10.1111/EPI.17297
Abstract: This study was undertaken to review the reported performance of noninvasive wearable devices in detecting epileptic seizures and psychogenic nonepileptic seizures (PNES). We conducted a systematic review and meta‐analysis of studies reported up to November 15, 2021. We included studies that used video‐electroencephalographic (EEG) monitoring as the gold standard to determine the sensitivity and false alarm rate (FAR) of noninvasive wearables for automated seizure detection. Twenty‐eight studies met the criteria for the systematic review, of which 23 were eligible for meta‐analysis. These studies (1269 patients in total, median recording time = 52.9 h per patient) investigated devices for tonic–clonic seizures using wrist‐worn and/or ankle‐worn devices to measure three‐dimensional accelerometry (15 studies), and/or wearable surface devices to measure electromyography (eight studies). The mean sensitivity for detecting tonic–clonic seizures was .91 (95% confidence interval [CI] = .85–.96, I 2 = 83.8%) sensitivity was similar between the wrist‐worn (.93) and surface devices (.90). The overall FAR was 2.1/24 h (95% CI = 1.7–2.6, I 2 = 99.7%) FAR was higher in wrist‐worn (2.5/24 h) than in wearable surface devices (.96/24 h). Three of the 23 studies also detected PNES the mean sensitivity and FAR from these studies were 62.9% and .79/24 h, respectively. Four studies detected both focal and tonic–clonic seizures, and one study detected focal seizures only the sensitivities ranged from 31.1% to 93.1% in these studies. Reported noninvasive wearable devices had high sensitivity but relatively high FARs in detecting tonic–clonic seizures during limited recording time in a video‐EEG setting. Future studies should focus on reducing FAR, detection of other seizure types and PNES, and longer recording in the community.
Publisher: Wiley
Date: 04-2007
DOI: 10.1111/J.1526-4610.2007.00763_3.X
Abstract: We evaluated the efficacy and safety of topiramate for migraine prophylaxis among Chinese patients in a multicenter prospective observational study. We found that topiramate at low doses was effective in preventing migraine headache in Chinese patients and was generally well tolerated. There was no difference in baseline headache frequency or intensity between responders and nonresponders.
Publisher: Elsevier BV
Date: 04-2001
DOI: 10.1016/S0163-7258(01)00122-X
Abstract: In the past decade, nine new drugs have been licensed for the treatment of epilepsy. With limited clinical experience of these agents, the mechanisms of action of antiepileptic drugs may be an important criterion in the selection of the most suitable treatment regimens for in idual patients. At the cellular level, three basic mechanisms are recognised: modulation of voltage-dependent ion channels, enhancement of inhibitory neurotransmission, and attenuation of excitatory transmission. In this review, we will attempt to introduce the concepts of ion channel and neurotransmitter modulation and, thereafter, group currently used antiepileptic drugs according to their principal mechanisms of action.
Publisher: Wiley
Date: 21-03-2023
DOI: 10.1111/EPI.17573
Abstract: To assess the temporal trends in the use of second antiseizure (ASM) regimens and compare the efficacy of substitution monotherapy and combination therapy after failure of initial monotherapy in people with epilepsy. This was a longitudinal observational cohort study conducted at the Epilepsy Unit of the Western Infirmary in Glasgow, Scotland. We included patients who were newly treated for epilepsy with ASMs between July 1982, and October 2012. All patients were followed up for a minimum of 2 years. Seizure freedom was defined as no seizure for at least 1 year on unchanged medication at the last follow up. During the study period, 498 patients were treated with a second ASM regimen after failure of the initial ASM monotherapy, of whom 346 (69%) were prescribed combination therapy and 152 (31%) were given substitution monotherapy. The proportion of patients receiving second regimen as combination therapy increased during the study period from 46% in first epoch (1985–1994) to 78% in the last (2005–2015) (RR = 1.66, 95% CI: 1.17–2.36, corrected‐ p = .010). Overall, 21% (104/498) of the patients achieved seizure freedom on the second ASM regimen, which was less than half of the seizure‐free rate on the initial ASM monotherapy (45%, p .001). Patients who received substitution monotherapy had similar seizure‐free rate compared with those who received combination therapy (RR = 1.17, 95% CI: 0.81–1.69, p = .41). In idual ASMs used, either alone or in combination, had similar efficacy. However, the subgroup analysis was limited by small s le sizes. The choice of second regimen used based on clinical judgment was not associated with treatment outcome in patients whose initial monotherapy failed due to poor seizure control. Alternative approaches such as machine learning should be explored to aid in idualized selection of the second ASM regimen.
Publisher: Elsevier BV
Date: 07-2012
DOI: 10.1016/J.ADDR.2011.12.003
Abstract: Epilepsy is the most common serious chronic neurological disorder. Current data show that one-third of patients do not respond to anti-epileptic drugs (AEDs). Most non-responsive epilepsy patients are resistant to several, often all, AEDs, even though the drugs differ from each other in pharmacokinetics, mechanisms of action, and interaction potential. The mechanisms underlying drug resistance of epilepsy patients are still not clear. In recent years, one of the potential mechanisms interesting researchers is over-expression of P-glycoprotein (P-gp, also known as ABCB1 or MDR1) in endothelial cells of the blood-brain barrier (BBB) in epilepsy patients. P-gp plays a central role in drug absorption and distribution in many organisms. The expression of P-gp is greater in drug-resistant than in drug-responsive patients. Some studies also indicate that several AEDs are substrates or inhibitors of P-gp, implying that P-gp may play an important role in drug resistance in refractory epilepsy. In this article, we review the clinical and laboratory evidence that P-gp expression is increased in epileptic brain tissues and that AEDs are substrates of P-gp in vitro and in vivo. We discuss criteria for identifying the substrate status of AEDs and use structure-activity relationship (SAR) models to predict which AEDs act as P-gp substrates.
Publisher: Elsevier BV
Date: 08-2013
DOI: 10.1016/J.EPLEPSYRES.2013.02.015
Abstract: Up to 13% of patients with epilepsy have moderate or severe sleep-disordered breathing, in particular obstructive sleep apnea (OSA), a disorder associated with reduced quality of life, worsened seizure control, and increased cardiovascular morbidity and mortality. Combining video-EEG monitoring with polysomnography (VPSG) provides the opportunity to diagnose clinically significant OSA as well as relate the occurrence of seizures and the epilepsy diagnosis to the presence and severity of sleep-disordered breathing. We have established routine VPSG in our inpatient video-EEG monitoring unit and present our findings in 87 patients. Clinically significant sleep-disordered breathing was diagnosed in 19 of 87 (22%) patients. Patients with psychogenic non-epileptic seizures (PNES) had poorer sleep quality compared to patients with epilepsy and those with neither diagnosis, whereas the prevalence of clinically significant sleep-disordered breathing in patients with PNES (29%) did not differ significantly compared to patients with epilepsy (21%) and those with neither diagnosis (22%). The differences in sleep quality are not explained by differences in body mass index (BMI) or anti-epileptic drug (AED) effects.
Publisher: Cold Spring Harbor Laboratory
Date: 05-03-2019
DOI: 10.1101/561308
Abstract: Human Leukocyte Antigen (HLA) testing is useful in the clinical work-up of coeliac disease (CD), with high negative but low positive predictive value. We construct a genomic risk score (GRS) using HLA risk loci to improve CD prediction and guide exclusion criteria. Imputed HLA genotypes for five European CD case-control GWAS (n ,000) were used to construct and validate an HLA based risk models ( HDQ 15 ). Conditioning on this score, we identified novel HLA interactions which modified CD risk, and integrated these novel alleles into a new risk score ( HDQ 17 ). A GRS from HLA risk allele genotypes yields performance equivalent to a state-of-the-art GRS (GRS 228 ) using 228 single nucleotide polymorphisms (SNPs) and significantly improves upon all previous HLA based risk models. Conditioning on this model, we find two novel associations, HLA-DQ6.2 and HLA-DQ7.3, that interact significantly with HLA-DQ2.5 (p = 2.51 × 10 −9 , 1.99 × 10 −7 for DQ6.2 and DQ7.3 respectively). These epistatic interactions yield the best performing risk score ( HDQ 17 ) which retains performance when implemented using 6 tag SNPs. Using the HDQ 17 model, the positive predictive value of CD testing in high risk populations increases from 17.5% to 27.1% while maintaining a negative predictive value above 99%. Our proposed HLA-based GRS achieves state-of-the-art risk prediction, helps elucidate further risk factors and improves HLA typing exclusionary criteria, which may reduce the number of patients requiring unnecessary endoscopies.
Publisher: Wiley
Date: 07-11-2023
DOI: 10.1111/EPI.17449
Abstract: Childhood trauma has been implicated as a risk factor for the etiology of psychogenic nonepileptic seizures (PNES). Relatively little attention has been paid to whether profiles of specific trauma types differ between patients with epilepsy and PNES. Investigating childhood trauma profiles in these patient groups may identify psychological vulnerabilities that predispose to developing PNES, and aid early diagnoses, prevention, and treatment. Data were collected from two cohorts ( n Retrospective = 203 n Prospective = 209) admitted to video–electroencephalography (EEG) monitoring units in Melbourne Australia. The differences in Childhood Trauma Questionnaire domain score between patient groups were investigated using standardized effect sizes and general linear mixed‐effects models (GLMMs). Receiver‐operating characteristic curves were used to investigate classification accuracy. In the retrospective cohort, patients diagnosed with PNES reported greater childhood emotional abuse, emotional neglect, physical abuse, sexual abuse, and physical neglect relative to patients with epilepsy. These differences were replicated in the prospective cohort, except for physical abuse. GLMMs revealed significant main effects for group in both cohorts, but no evidence for any group by domain interactions. Reported sexual abuse showed the best screening performance of PNES, although no psychometric scores were adequate as isolated measures. Patients with PNES report a greater frequency of childhood trauma than patients with epilepsy. This effect appears to hold across all trauma types, with no strong evidence emerging for a particular trauma type that is more prevalent in PNES. From a practical perspective, inquiry regarding a history of sexual abuse shows the most promise as a screening measure.
Publisher: Wiley
Date: 29-03-2013
DOI: 10.1111/EPI.12158
Abstract: Antiepileptic drugs (AEDs) do not effectively treat 30-40% of patients with epilepsy. Export of AEDs by P-glycoprotein (Pgp, ABCB1, or MDR1), which is overexpressed in the blood-brain barrier in drug-resistant patients, may be a mechanism for resistance to AEDs. For most recently approved AEDs, whether they are transported by Pgp is unknown. We investigated whether a new AED, lacosamide (LCM), is a substrate of human Pgp. LLC-PK1 and MDCKII cells transfected with the human MDR1 gene were used to determine the substrate status of LCM in concentration equilibrium transport assays (CETAs). An equal concentration of drug was initially loaded in both the apical and basal chambers, and the concentration in both chambers was measured up to 4 h. The experiments were repeated in the presence of the Pgp inhibitors verapamil and tariquidar. Caco-2 assays were used to determine the intrinsic permeability and efflux ratio of LCM as well as its potential to inhibit digoxin, a Pgp substrate. Lacosamide was transported by MDR1-transfected cells from basolateral to apical sides. The efflux of LCM could be completely blocked by verapamil or tariquidar. In Caco-2 assays, LCM showed high permeability without a significant efflux ratio it did not inhibit digoxin, a Pgp substrate. Although LCM is a substrate of Pgp in CETA, Caco-2 data demonstrated that passive diffusion should play a major role in the overall disposition of LCM. The critical role of Pgp should be addressed in vivo.
Publisher: Springer Science and Business Media LLC
Date: 21-12-2023
Publisher: Elsevier BV
Date: 07-2008
DOI: 10.1016/J.SEIZURE.2007.12.005
Abstract: Several specialist clinic-based epidemiology studies suggested low prevalence in Hong Kong Special Administrative Region (HKSAR) of China. Population-based epidemiological data for epilepsy is not available. We performed the first population-based epidemiological survey of epilepsy in this locality. We conducted a territory-wide survey. We randomly selected 9547 households from fixed-line telephone directory. We successfully surveyed 17,783 persons of 5178 households by telephone interview. All positive respondents 685 (3.85%) were invited for clinical validation. 127 subjects were validated by board-certified neurologists. Seizure disorders were confirmed in 28 subjects. The crude prevalence of active epilepsy and seizure disorder were estimated to be 3.94/1000 (95% confidence interval (CI): 2.10-6.74/1000) and 8.49/1000 (95% CI: 5.64-12.27/1000), respectively. The prevalence of epilepsy in HKSAR is more common than previously thought. The data retrieved is useful for planning and allocation of health resources for patients with seizure disorders.
Publisher: Elsevier BV
Date: 2001
Publisher: Elsevier BV
Date: 11-2013
DOI: 10.1016/J.YEBEH.2013.07.027
Abstract: Cognitive deficits and psychological impairments are often associated with seizures. In order to describe the neuropsychological profiles of adult patients with epilepsy (PWEs) in Hong Kong China, a total of 186 PWEs were recruited with 102 being drug-responsive and 84 being drug-resistant. Symptoms of depression, anxiety, and epilepsy-specific quality of life (QOL) were measured. Cognitive assessments consisted of intelligence, memory, verbal and visual abilities, and executive function. Neurocognitive impairments were prevalent among PWEs, and patients with drug-resistant epilepsy had significantly more impaired psychological and cognitive profiles. Thirty-nine percent and 30% of patients with drug-resistant epilepsy reported moderate to severe levels of anxiety and depression, respectively, versus 16% and 7% of patients with drug-responsive epilepsy. The most commonly occurring cognitive deficit was memory. Thirty-five percent to 47% of patients with drug-resistant epilepsy and 26% to 35% of patients with drug-responsive epilepsy were compromised in verbal recall memory. Our findings also suggested significant correlations between psychological well-being and cognitive performance. Patients who reported more psychological symptoms tended to perform worse in neurocognitive tests. Identification and management of neuropsychological difficulties in PWEs are important and should be included in primary epilepsy care.
Publisher: Wiley
Date: 10-05-2021
DOI: 10.1111/EPI.16918
Abstract: Alzheimer's disease (AD) can increase the risk of epilepsy by up to 10‐fold compared to healthy age‐matched controls. However, the pathological mechanisms that underlie this increased risk are poorly understood. Because disruption in brain glutamate homeostasis has been implicated in both AD and epilepsy, this might play a mechanistic role in the pathogenesis of epilepsy in AD. Prior to the formation of amyloid beta (Aβ) plaques, the brain can undergo pathological changes as a result of increased production of amyloid precursor protein (APP) and Aβ oligomers. Impairments in the glutamate uptake ability of astrocytes due to astrogliosis are hypothesized to be an early event occurring before Aβ plaque formation. Astrogliosis may increase the susceptibility to epileptogenesis of the brain via accumulation of extracellular glutamate and resulting excitotoxicity. Here we hypothesize that Aβ oligomers and proinflammatory cytokines can cause astrogliosis and accumulation of extracellular glutamate, which then contribute to the pathogenesis of epilepsy in AD. In this review article, we consider the evidence supporting a potential role of dysfunction of the glutamate‐glutamine cycle and the astrocyte in the pathogenesis of epilepsy in AD.
Publisher: Wiley
Date: 06-06-2023
DOI: 10.1002/EPI4.12766
Abstract: Anxiety and depression are common comorbidities in people living with epilepsy. Emerging research suggests that these conditions may even predate epilepsy onset. This review aimed to summarize the prevalence of clinically significant anxiety and depressive symptoms in people with first seizures and newly diagnosed epilepsy, as well as clinicodemographic factors associated with these symptoms. A scoping literature review was performed. OVID Medline and Embase were searched from January 1, 2000, through May 1, 2022. Articles of interest were selected based on predetermined inclusion and exclusion criteria. From 1836 studies identified on screening, 16 met eligibility criteria and were included in the review. Clinically significant anxiety and depressive symptoms, as determined by validated cutoff scores for anxiety and depression screening instruments, were common in people with first seizures (range 13–28%) and newly diagnosed epilepsy (range 11–45%). They were associated with a range of clinicodemographic factors including past psychiatric history and trauma, personality traits, self‐esteem, and stigma profiles. There is substantial evidence that clinically significant anxiety and depressive symptoms are often present at the time and shortly following the first seizure or epilepsy diagnosis. Future research is needed to better understand the complex interactions between these common psychiatric comorbidities, new‐onset seizure disorders, and certain clinicodemographic characteristics. This knowledge may inform targeted and holistic treatment approaches.
Publisher: Public Library of Science (PLoS)
Date: 07-05-2014
Publisher: Wiley
Date: 16-02-2022
DOI: 10.1111/EPI.17182
Abstract: Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe cutaneous adverse drug reactions. Antiseizure medications (ASMs) with aromatic ring structure, including carbamazepine, are among the most common culprits. Screening for human leukocyte antigen ( HLA ) allele HLA ‐ B*15 : 02 is recommended prior to initiating treatment with carbamazepine in Asians, but this allele has low positive predictive value. We performed whole genome sequencing and analyzed 6 199 696 common variants among 113 aromatic ASM‐induced SJS/TEN cases and 84 tolerant controls of Han Chinese ethnicity. In the primary analysis, nine variants reached genome‐wide significance ( p 5e‐08), one in the carbamazepine subanalysis (85 cases vs. 77 controls) and a further eight identified in HLA ‐ B*15 : 02 ‐negative subanalysis (35 cases and 53 controls). Interaction analysis between each novel variant from the primary analysis found that five increased risk irrespective of HLA ‐ B*15 : 02 status or zygosity. HLA ‐ B*15 : 02 ‐positive in iduals were found to have reduced risk if they also carried a chromosome 12 variant, chr12.9426934 (heterozygotes: relative risk = .71, p = .001 homozygotes: relative risk = .23, p .001). All significant variants lie within intronic or intergenic regions with poorly understood functional consequence. In silico functional analysis of suggestive variants ( p 5e‐6) identified through the primary and subanalyses (stratified by HLA ‐ B*15 : 02 status and drug exposure) suggests that genetic variation within regulatory DNA may contribute to risk indirectly by disrupting the regulation of pathology‐related genes. The genes implicated were specific either to the primary analysis ( CD9 ), HLA ‐ B*15 : 02 carriers ( DOCK10 ), noncarriers ( ABCA1 ), carbamazepine exposure ( HLA ‐ E ), or phenytoin exposure ( CD24 ). We identified variants that could explain why some carriers of HLA ‐ B*15 : 02 tolerate treatment, and why some noncarriers develop ASM‐induced SJS/TEN. Additionally, this analysis suggests that the mixing of HLA ‐ B*15 : 02 carrier status in previous studies might have masked variants contributing to susceptibility, and that inheritance of risk for ASM‐induced SJS/TEN is complex, likely involving multiple risk variants.
Publisher: Elsevier BV
Date: 11-2013
DOI: 10.1016/J.NEULET.2013.10.020
Abstract: In a recent genome-wide association study (GWAS) of symptomatic epilepsy in the Chinese population, the most significant single nucleotide polymorphism (SNP) allele was rs2292096 [G] (P=1.0×10(-8), odds ratio [OR]=0.63), in the CAMSAP1L1 gene (also known as CAMSAP2). Here, we report that rs2292096 genotypes tended to associate with expression of CAMSAP1L1 RNA in the temporal lobe (p=0.054) and hippoc us (p=0.20) of epilepsy surgery patients, with expression tending to increase with the G allele. CAMSAP1L1 and β-tubulin double immunofluorescence exhibited partial overlap. CAMSAP1L1 siRNA transfection of human SH-SY5Y neuroblastoma cells treated with or without retinoic acid reduced the CAMSAP1L1 protein level nearly 60% and stimulated neurite outgrowth, as measured by total length, number of processes and number of branches. Therefore, the rs2292096 G allele of CAMSAP1L1, which was associated with reduced risk of symptomatic epilepsy, tended to associate with increased expression of CAMSAP1L1, which represses neurite outgrowth. Greater neurite growth in response to brain insults might increase formation of ectopic neural circuits and thus the risk of epileptogenesis.
Publisher: Elsevier BV
Date: 11-2010
DOI: 10.1016/J.YEBEH.2010.08.007
Abstract: The aim of this study was to investigate the association between carbamazepine (CBZ)-induced cutaneous adverse drug reactions (cADRs) and the HLA-B*1502 allele among patients from central China. Eight patients with Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN), 28 with mild maculopapular eruptions (MPEs), 50 CBZ-tolerant controls, and 71 healthy volunteers were recruited. HLA genotyping was performed using the polymerase chain reaction sequence-based typing (SBT) method. As a result, the HLA-B*1502 allele was observed at the following rates: (1) 100% (8/8) among those with CBZ-induced SJS/TEN, (2) 10.7% (3/28) among those with CBZ-induced MPEs (3) 8.0% (4/50) among CBZ-tolerant controls (4) 8.5% (6/71) among healthy volunteers. The eight patients with SJS/TEN positive for the HLA-B*1502 allele had an odds ratio (OR) of 184 compared with CBZ-tolerant controls. There was no significant difference in frequency between patients with MPEs and CBZ-tolerant controls (P>0.05). Thus, CBZ-induced SJS/TEN, but not MPEs, is strongly associated with HLA-B*1502. Testing for HLA-B*1502 should be recommended for patients from central China prior to initial CBZ treatment.
Publisher: Massachusetts Medical Society
Date: 03-02-2000
Publisher: Massachusetts Medical Society
Date: 08-09-2011
Publisher: Elsevier BV
Date: 10-2011
DOI: 10.1016/J.YEBEH.2011.06.035
Abstract: We evaluated the interrater reliability of the consensus definition of drug-resistant epilepsy proposed by the International League Against Epilepsy. According to the definition framework, outcome of each antiepileptic drug (AED) trial was categorized as "seizure freedom" or "treatment failure." This level 1 assessment was used to determine the level 2 classification, which defined drug-resistant epilepsy as the failure of adequate trials of two or more AED schedules to achieve sustained seizure freedom. Two raters classified treatment outcomes of 150 patients independently. The patients had received a total of 428 trials of AEDs. Categorization of level 1 outcome to in idual AED trials by the raters was consistent in 413 (96.5%). For the level 2 classification of drug-resistant or drug-responsive epilepsy, there was absolute agreement between the raters in 141 patients (94%), with a κ index of 0.91 (P<0.001). The definition appeared to have a high degree of interrater reliability in this setting.
Publisher: Future Medicine Ltd
Date: 10-2012
DOI: 10.2217/PGS.12.127
Abstract: Aim: Approximately 30% of epilepsy patients do not response to antiepileptic drugs (AEDs). The functional SCN1A IVS5N+5 polymorphism may play a role in response to some AEDs. The purpose of this study was to examine this hypothesis in a cohort study of Malaysian and Hong Kong Chinese epilepsy patients on sodium valproate (VPA) monotherapy and in a meta-analysis. Patients & methods: The SCN1A IVS5N+5 polymorphism was genotyped in 583 Malaysian (84%) and Hong Kong Chinese (16%) epilepsy patients receiving VPA monotherapy. The related association studies, including the current study, were meta-analyzed by using fixed- and random-effects models under various genetic models. Results: A total of 277 (47.5%) and 306 (52.5%) patients were VPA nonresponsive and responsive, respectively. Unlike Chinese and Indian patients, Malay nonresponsive patients with idiopathic generalized epilepsy showed significant association, probably caused by the small s le size. Conclusion: The cohort study and meta-analysis did not demonstrate an association between AED responsiveness and this polymorphism. Future studies with a larger s le size of Malays with idiopathic generalized epilepsy are suggested. Original submitted 15 June 2012 Revision submitted 23 July 2012
Publisher: Oxford University Press (OUP)
Date: 29-10-2012
DOI: 10.1093/HMG/DDS451
Abstract: Anorectal malformations (ARMs, congenital obstruction of the anal opening) are among the most common birth defects requiring surgical treatment (2-5/10 000 live-births) and carry significant chronic morbidity. ARMs present either as isolated or as part of the phenotypic spectrum of some chromosomal abnormalities or monogenic syndromes. The etiology is unknown. To assess the genetic contribution to ARMs, we investigated single-nucleotide polymorphisms and copy number variations (CNVs) at genome-wide scale. A total of 363 Han Chinese sporadic ARM patients and 4006 Han Chinese controls were included. Overall, we detected a 1.3-fold significant excess of rare CNVs in patients. Stratification of patients by presence/absence of other congenital anomalies showed that while syndromic ARM patients carried significantly longer rare duplications than controls (P = 0.049), non-syndromic patients were enriched with both rare deletions and duplications when compared with controls (P = 0.00031). Twelve chromosomal aberrations and 114 rare CNVs were observed in patients but not in 868 controls nor 11 943 healthy in iduals from the Database of Genomic Variants. Importantly, these aberrations were observed in isolated ARM patients. Gene-based analysis revealed 79 genes interfered by CNVs in patients only. In particular, we identified a de novo DKK4 duplication. DKK4 is a member of the WNT signaling pathway which is involved in the development of the anorectal region. In mice, Wnt disruption results in ARMs. Our data suggest a role for rare CNVs not only in syndromic but also in isolated ARM patients and provide a list of plausible candidate genes for the disorder.
Publisher: Cold Spring Harbor Laboratory
Date: 20-07-2019
DOI: 10.1101/19002717
Abstract: The primary aim of the study was to determine whether patients with psychogenic non-epileptic seizures (PNES) have different personality profiles compared to patients with epileptic seizures (ES). The secondary aim was to determine whether any such personality differences could be used to efficiently screen for PNES in clinical settings. PNES and ES are often difficult to differentiate, leading to incorrect or delayed diagnosis. While the current gold-standard investigation is video-EEG monitoring (VEM), it is resource intensive and not universally available. Although some research has investigated the differential psychological profiles of PNES and ES patients, most studies have focused on symptoms of psychopathology. The lack of research using modern personality models in PNES and ES presents a gap in knowledge that this study aimed to address. A retrospective collection of data was conducted on patients who completed the NEO-Five Factor Inventory questionnaire during a VEM admission to the Royal Melbourne Hospital between 2002-2017. Patients were classified as either ES or PNES based on clinical consensus diagnosis. For patients with ES, type of epilepsy and laterality of seizure focus were also recorded. Personality differences were investigated using Bayesian linear mixed effects models. Receiver operating characteristic curve analysis was also performed to generate sensitivities and specificities of in idual personality scores. 305 patients were included in the study. The ‘openness to experience’ domain was the only personality factor demonstrating strong evidence for a group difference (BF 10 = 21.55, d = −0.43 [95% CI −0.71, −0.17]), with patients in the PNES group having higher scores compared to the ES group. Within the openness to experience domain, only the ‘aesthetic interest’ facet showed evidence for a group difference (BF 10 = 7.98, d = −0.39 [95% CI −0.66, −0.12]). ES patients had lower scores on these measures compared to the normal population, while PNES patients did not. Both openness to experience and aesthetic interest, however, showed poor sensitivities (53%, 46% respectively) and specificities (69%, 46% respectively) for classifying PNES and ES patients. There were no differences between personality profiles in Temporal Lobe Epilepsy (TLE) and non-TLE patients, or in laterality in TLE. Patients with ES exhibit lower openness to experience and aesthetic interest compared to patients with PNES and compared to the general population. Despite these differences, the relatively low sensitivity and specificity of these instruments suggests their use is limited in a clinical setting. Nevertheless, these findings open up new avenues of research using modern personality models to further understand patients with epilepsy and related presentations.
Publisher: Wiley
Date: 25-03-2022
DOI: 10.1111/EPI.17217
Abstract: Around 30% of patients undergoing surgical resection for drug‐resistant mesial temporal lobe epilepsy (MTLE) do not obtain seizure freedom. Success of anterior temporal lobe resection (ATLR) critically depends on the careful selection of surgical candidates, aiming at optimizing seizure freedom while minimizing postoperative morbidity. Structural MRI and FDG‐PET neuroimaging are routinely used in presurgical assessment and guide the decision to proceed to surgery. In this study, we evaluate the potential of machine learning techniques applied to standard presurgical MRI and PET imaging features to provide enhanced prognostic value relative to current practice. Eighty two patients with drug resistant MTLE were scanned with FDG‐PET pre‐surgery and T1‐weighted MRI pre‐ and postsurgery. From these images the following features of interest were derived: volume of temporal lobe (TL) hypometabolism, % of extratemporal hypometabolism, presence of contralateral TL hypometabolism, presence of hippoc al sclerosis, laterality of seizure onset volume of tissue resected and % of temporal lobe hypometabolism resected. These measures were used as predictor variables in logistic regression, support vector machines, random forests and artificial neural networks. In the study cohort, 24 of 82 (28.3%) who underwent an ATLR for drug‐resistant MTLE did not achieve Engel Class I (i.e., free of disabling seizures) outcome at a minimum of 2 years of postoperative follow‐up. We found that machine learning approaches were able to predict up to 73% of the 24 ATLR surgical patients who did not achieve a Class I outcome, at the expense of incorrect prediction for up to 31% of patients who did achieve a Class I outcome. Overall accuracies ranged from 70% to 80%, with an area under the receiver operating characteristic curve (AUC) of .75–.81. We additionally found that information regarding overall extent of both total and significantly hypometabolic tissue resected was crucial to predictive performance, with AUC dropping to .59–.62 using presurgical information alone. Incorporating the laterality of seizure onset and the choice of machine learning algorithm did not significantly change predictive performance. Collectively, these results indicate that "acceptable" to "good" patient‐specific prognostication for drug‐resistant MTLE surgery is feasible with machine learning approaches utilizing commonly collected imaging modalities, but that information on the surgical resection region is critical for optimal prognostication.
Publisher: Wiley
Date: 11-08-2023
DOI: 10.1111/EPI.17735
Abstract: More than one third of mesial temporal lobe epilepsy (MTLE) patients are resistant to current antiseizure medications (ASMs), and half experience mild‐to‐moderate adverse effects of ASMs. There is therefore a strong need to develop and test novel ASMs. The objective of this work is to evaluate the pharmacokinetics and neurological toxicity of E2730, a novel uncompetitive inhibitor of γ‐aminobutyric acid transporter‐1, and to test its seizure suppression effects in a rat model of chronic MTLE. We first examined plasma levels and adverse neurological effects of E2730 in healthy Wistar rats. Adult male rats were implanted with osmotic pumps delivering either 10, 20, or 100 mg/kg/day of E2730 subcutaneously for 1 week. Blood s ling and behavioral assessments were performed at several timepoints. We next examined whether E2730 suppressed seizures in rats with chronic MTLE. These rats were exposed to kainic acid‐induced status epilepticus, and 9 weeks later, when chronic epilepsy was established, were assigned to receive one of the three doses of E2730 or vehicle for 1 week in a randomized crossover design. Continuous video‐electroencephalographic monitoring was acquired during the treatment period to evaluate epileptic seizures. Plasma levels following continuous infusion of E2730 showed a clear dose‐related increase in concentration. The drug was well tolerated at all doses, and any sedation or neuromotor impairment was mild and transient, resolving within 48 h of treatment initiation. Remarkably, E2730 treatment in chronically epileptic rats led to seizure suppression in a dose‐dependent manner, with 65% of rats becoming seizure‐free at the highest dose tested. Mean seizure class did not differ between the treatment groups. This study shows that continuous subcutaneous infusion of E2730 over 7 days results in a marked, dose‐dependent suppression of spontaneous recurrent seizures, with minimal adverse neurological effects, in a rat model of chronic MTLE. E2730 shows strong promise as an effective new ASM to be translated into clinical trials.
Publisher: Wiley
Date: 06-12-2012
DOI: 10.1111/EPI.12048
Abstract: Detailed data on the mortality of epilepsy are still lacking from resource-poor settings. We conducted a long-term follow-up survey in a cohort of people with convulsive epilepsy in rural areas of China. In this longitudinal prospective study we investigated the causes of death and premature mortality risk among people with epilepsy. We attempted to trace all 2,455 people who had previously participated in a pragmatic assessment of epilepsy management at the primary health level. Putative causes of death were recorded for those who died, according to the International Classification of Diseases. We estimated proportional mortality ratios (PMRs) for each cause, and standardized mortality ratios (SMRs) for each age-group and cause. Survival analysis was used to detect risk factors associated with increased mortality. During 6.1 years of follow-up there were 206 reported deaths among the 1,986 people with epilepsy who were located. The highest PMRs were for cerebrovascular disease (15%), drowning (14%), self-inflicted injury (13%), and status epilepticus (6%), with probable sudden unexpected death in epilepsy (SUDEP) in 1%. The risk of premature death was 2.9 times greater in people with epilepsy than in the general population. A much higher risk (SMRs 28-37) was found in young people. Duration of epilepsy and living in a waterside area were independent predictors for drowning. Drowning and status epilepticus were important, possibly preventable, causes of death. Predictors of increasing mortality suggest interventions with efficient treatment and education to prevent premature mortality among people with epilepsy in resource-poor settings.
Publisher: Elsevier BV
Date: 03-2013
DOI: 10.1016/J.YEBEH.2012.09.007
Abstract: With no known intervention to prevent or cure epilepsy, treatment is primarily symptomatic and requires long-term administration of medications to suppress seizure occurrence. Current antiepileptic drugs (AEDs) are ineffective in one-third of patients (Kwan and Brodie, 2000). Such therapeutic inadequacy is largely due to our insufficient understanding of the basic molecular pathophysiological processes that underlie epileptogenesis. Breakthroughs are needed in the identification of new molecular targets that will translate to novel intervention approaches. Discovering genetic variants that increase the susceptibility to disease is a promising avenue to identifying such targets. However, early candidate gene-based studies in epilepsy proved ineffective in identifying genetic risk factors for the non-Mendelian, complex epilepsies, which represent >95% of clinically encountered epilepsy. Furthermore, genome-wide association studies (GWAS) of epilepsy patients have been largely negative, with the exception of several putative susceptibility loci discovered in Han Chinese focal epilepsy and European Caucasian GGE patients (Kasperaviciute et al., 2010 Guo et al., 2012 Consortium et al., 2012). Results of these GWAS suggest that, similar to other common diseases, associations with common single nucleotide variants (SNV) appear likely to account for a small fraction of the heritability of epilepsy, thus fuelling the effort to also search for alternative genetic contributors, with a recent increased emphasis on rare variants with larger effects (Manolio et al., 2009). It is possible that both common and rare variants contribute to an increased susceptibility to common epilepsy syndromes (Mulley et al., 2005). We review the approaches that have been taken to identify genetic risk markers of the common epilepsy syndromes, the experimental platforms, and their caveats. We discuss current technologies and analytical frameworks that might expedite the discovery of these variants by leveraging advances in microarray-based, high-throughput, genotyping technology, and complementary interdisciplinary expertise of study teams including the need for meta-analyses under global collaborative frameworks. We briefly discuss the analytical options made available through rapid advances in sequencing and other genomic technologies.
Publisher: Wiley
Date: 25-10-2012
DOI: 10.1111/J.1528-1167.2012.03722.X
Abstract: The recent definition of drug-resistant epilepsy proposed by the International League Against Epilepsy (ILAE) stipulated failure of an adequate trial of two tolerated, appropriately chosen and used antiepileptic drug (AED) schedules to achieve seizure freedom. Doses failed were not specifically discussed. We explored the effect of the doses at which the first and second AED regimens failed on subsequent outcomes in a population of adults with newly diagnosed epilepsy followed for up to 20 years. Patients in whom epilepsy was diagnosed and the first AED prescribed between July 1, 1982 and April 1, 2006, were followed until March 31, 2008. Dosage at which an AED failed was categorized according to the World Health Organization's defined daily dose (DDD) for each drug. Cumulative incidence curves for time to final seizure freedom (no seizure for at least 1 year on unchanged dosage at last follow up) were stratified by whether the first regimen was failed at doses above or below the 25%, 50%, or 75% cutoffs for the DDD of each AED. Among patients who had taken a second regimen (n = 327), those in whom the first AED failed at doses above the various cutoffs (particularly 50% and 75% DDD) had lower probability of becoming seizure-free at last follow-up (p = 0.06 for 25% DDD, p < 0.001 for both 50% and 75% DDD). The same difference was observed for patients who had taken a third regimen (n = 141 p = 0.23 for 25% DDD, p < 0.01 for 50% DDD and p = 0.002 for 75% DDD). A trend to higher seizure-free rate was observed in patients who had taken the third regimen when both the first and second regimens failed at <75% DDD. The difference remained significant after adjusting for covariates when using 50% DDD as the cutoff for patients who took a second regimen (hazard ratio 1.60, 95% confidence interval 1.08-2.37). Higher failure dosage of the first AED predicts poorer subsequent outcome. This methodology could be used to refine further the ILAE definition of drug-resistant epilepsy by exploring the doses need to fail to provide an adequate AED trial.
Publisher: Wiley
Date: 12-06-2023
DOI: 10.1002/EPI4.12772
Abstract: This study evaluated sleep and respiratory abnormalities, and their relationship with seizures, in adults with developmental and epileptic encephalopathies (DEEs). We studied consecutive adults with DEEs undergoing inpatient video‐EEG monitoring and concurrent polysomnography between December 2011 and July 2022. Thirteen patients with DEEs were included (median age: 31 years, range: 20–50 69.2% female): Lennox–Gastaut syndrome ( n = 6), Lennox–Gastaut syndrome‐like phenotype ( n = 2), Landau–Kleffner syndrome ( n = 1), epilepsy with myoclonic‐atonic seizures ( n = 1), and unclassified DEEs ( n = 3). Sleep architecture was often fragmented by epileptiform discharges and seizures resulting in arousals (median arousal index: 29.0 per h, range: 5.1–65.3). Moderate‐to‐severe obstructive sleep apnea (OSA) was observed in seven patients (53.8%). Three patients (23.1%) had tonic seizures that frequently occurred with central apnea one met criteria for mild central sleep apnea. Of the patients with tonic seizures, two had other identifiable seizure manifestations, but in one patient, central apnea was commonly the only discernable seizure manifestation. Polysomnography during video‐EEG is an effective diagnostic tool in detecting sleep and seizure‐related respiratory abnormalities. Clinically significant OSA may increase the risk of comorbid cardiovascular disease and premature mortality. Treatment of epilepsy may improve sleep quality, and conversely, improved sleep, may decrease seizure burden.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-05-2012
Publisher: Wiley
Date: 27-12-2021
DOI: 10.1111/EPI.17150
Abstract: To evaluate the long‐term safety and efficacy of add‐on cannabidiol (CBD) in patients with seizures associated with tuberous sclerosis complex (TSC) in the open‐label extension (OLE) of the randomized, placebo‐controlled phase 3 trial GWPCARE6 (NCT02544763). Results of an interim (February 2019 data cut) analysis are reported. Patients who completed the randomized trial enrolled to receive CBD (Epidiolex ® in the United States Epidyolex ® in the EU 100 mg/mL oral solution). The initial target dose was 25 mg/kg/day, which, based on response and tolerability, could be decreased or increased up to 50 mg/kg/day. The primary end point was safety. Key secondary end points included percentage reduction in TSC‐associated (countable focal and generalized) seizures, responder rates, and Subject/Caregiver Global Impression of Change (S/CGIC). Of 201 patients who completed the randomized phase, 199 (99%) entered the OLE. Mean age was 13 years (range, 1–57). At the time of analysis, 5% of patients had completed treatment, 20% had withdrawn, and 75% were ongoing. One‐year retention rate was 79%. Median treatment time was 267 days (range, 18–910) at a 27 mg/kg/day mean modal dose. Most patients (92%) had an adverse event (AE). Most common AEs were diarrhea (42%), seizure (22%), and decreased appetite (20%). AEs led to permanent discontinuation in 6% of patients. There was one death that was deemed treatment unrelated by the investigator. Elevated liver transaminases occurred in 17 patients (9%) patients 12 were taking valproate. Median percentage reductions in seizure frequency (12‐week windows across 48 weeks) were 54%–68%. Seizure responder rates (≥50%, ≥75%, 100% reduction) were 53%–61%, 29%–45%, and 6%–11% across 12‐week windows for 48 weeks. Improvement on the S/CGIC scale was reported by 87% of patients/caregivers at 26 weeks. In patients with TSC, long‐term add‐on CBD treatment was well tolerated and sustainably reduced seizures through 48 weeks, with most patients/caregivers reporting global improvement.
Publisher: SAGE Publications
Date: 09-2013
Publisher: Oxford University Press (OUP)
Date: 18-06-2014
DOI: 10.1111/BJD.12897
Abstract: The human leucocyte antigen (HLA) allele, HLA-A*31:01, is a biomarker for adverse cutaneous reactions to carbamazepine, a first-line antiepileptic drug. To develop a platform that can rapidly detect the HLA-A*31:01 allele in blood s les to facilitate pretreatment screening. A novel protocol based on loop-mediated isothermal lification (LAMP) was designed and optimized. It was applied to purified genomic DNA s les derived from B-cell lines with known HLA genotypes, and to DNA and whole blood s les collected from patients with epilepsy, in whom HLA-A genotypes were determined by sequence-based typing. The turnaround time for the LAMP-based protocol was < 45 min. In the DNA s les derived from B-cell lines (n = 66), the sensitivity, specificity, positive predictive value and negative predictive value of the LAMP-based protocol for detecting HLA-A*31:01 were 1·00 [95% confidence interval (CI) 0·88-1·00], 0·95 (95% CI 0·82-0·99), 0·94 and 1·00, respectively. The LAMP-based protocol produced the same results in the DNA and whole blood s les collected from patients (n = 34). Its sensitivity, specificity, positive predictive value and negative predictive value in detecting HLA-A*31:01 in the patient s les were 1·00 (95% CI 0·57-1·00), 0·97 (95% CI 0·83-0·99), 0·83 and 1·00, respectively. The findings demonstrated the feasibility of accurately detecting HLA-A*31:01 in DNA and whole blood s les using a LAMP-based protocol. Given its rapid turnaround time, this novel platform has the potential to be adapted into a point-of-care screening test.
Publisher: Springer Science and Business Media LLC
Date: 27-03-2013
Publisher: Future Medicine Ltd
Date: 03-2014
DOI: 10.2217/PGS.13.239
Abstract: Aim: To examine the relevance of ABCC2 polymorphisms to drug responsiveness in epilepsy cohorts from the Asia Pacific region. Materials & methods: The rs2273697 and rs3740066 polymorphisms were genotyped in 2056 Malaysian (55%), Hong Kong (32%) and Japanese (13%) epilepsy patients. Results: Significant allele association of rs2273697 was observed in Chinese females with epilepsy, Malaysian Chinese patients with generalized seizure and Japanese patients with partial seizure for the AA versus GG genotype model and Malaysian Chinese patients with generalized seizure for the GA versus GG and autosomal dominant models. Significant association of the rs3740066 allele was observed in Malaysian females of Malay origin with cryptogenic epilepsy and Chinese patients with partial seizure and for genotypes in Malay patients with cryptogenic epilepsy for the CT versus CC and autosomal dominant genotype models. Significant results were observed for all haplotypes, but following Bonferroni correction, only the GT haplotype in Chinese patients remained significant. Conclusion: This study suggests that the GT haplotype might be a risk factor for resistance to medication in Chinese patients. Original submitted 14 August 2013 Revision submitted 25 November 2013
Publisher: Wiley
Date: 13-11-2012
DOI: 10.1111/EPI.12022
Abstract: To evaluate the long-term outcome of phenobarbital treatment for convulsive epilepsy in rural China, and to explore factors associated with overall seizure outcomes. We carried out follow-up assessments of people who took part in an epilepsy community management program conducted in rural counties of six provinces in China. People with convulsive epilepsy who were previously untreated (or on irregular treatment) were commenced on regular treatment with phenobarbital. Information was collected using a standardized questionnaire by face-to-face interviews of the in iduals (and their families where necessary). Information collected included treatment status, medication change, seizure frequency, and mortality. Among the 2,455 people who participated in the original program, outcomes were successfully ascertained during the follow-up assessment in 1986. Among them, 206 had died. Information on treatment response was obtained in 1,780 (56% male mean age 33.9 years, range 3-84 mean duration of follow-up 6.4 years). Among them, 939 (53%) were still taking phenobarbital. The most common reasons for stopping phenobarbital were seizure freedom or substantial seizure reduction, socioeconomic reasons, and personal preference. Four hundred fifty-three in iduals (25%) became seizure-free for at least 1 year while taking phenobarbital, 88% of whom did so at daily doses of 120 mg or below. Four hundred six (23%) reported adverse events, which led to withdrawal of phenobarbital in <1%. The most common adverse effects were malaise/somnolence (7.4%), dizziness (3%), and lethargy (2.6%). At the follow-up assessment, 688 (39%) in iduals had been seizure free for at least the previous year. People with persistent seizures had significantly longer duration of epilepsy and higher number of seizures in the 12 months before treatment. People who were taking AED treatment irregularly at recruitment were less likely to become seizure-free. We observed long-term benefits of regular treatment with phenobarbital for convulsive epilepsy in rural China. One hundred years after the discovery of its antiepileptic effect, phenobarbital is still playing an important role in the management of epilepsy.
Publisher: SAGE Publications
Date: 17-10-2011
Abstract: Objective: Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease with complex genetic inheritance. CD247 (CD3Z, TCRZ) plays a vital role in antigen recognition and signal transduction in antigen-specific immune responses, and is known to be involved in SLE pathogenesis. Weak disease association was reported for genetic variants in this gene in Caucasian studies for SLE, Crohn's disease and systemic sclerosis, but its role as a genetic risk factor was never firmly established. Methods: In this study, using a collection of 612 SLE patients and 2193 controls of Chinese ethnicity living in Hong Kong in a genome-wide study, single nucleotide polymorphisms (SNPs) in and around CD247 were identified as being associated with SLE. The two most significant SNPs in this locus were selected for further replication using TaqMan genotyping assay in 3339 Asian patients from Hong Kong, Mainland China, and Thailand, as well as 4737 ethnically and geographically matched controls. Results: The association of CD247 with SLE in Asian populations was confirmed (rs704853: odds ratio [OR] = 0. 81, p = 2.47 × 10 −7 rs858543: OR = 1.10, p = 0.0048). Patient-only analysis suggested that rs704853 is also linked to oral ulcers, hematologic disorders and anti-double-stranded DNA (dsDNA) antibody production. Conclusion: A significant association between variants in CD247 and SLE was demonstrated in Asian populations. Understanding the involvement of CD247 in SLE may shed new light on disease mechanisms and development of new treatment paradigms.
Publisher: Elsevier BV
Date: 06-2010
DOI: 10.1016/J.LFS.2010.04.008
Abstract: One possible mechanism for epilepsy drug resistance is overexpression of P-glycoprotein in the blood-brain barrier, but whether (or which) antiepileptic drugs (AEDs) are transported by P-gp remains unclear. We evaluated AEDs as P-gp substrates using cell monolayers. Bi-directional transport assays and concentration equilibrium transport assays (CETAs) were performed for phenytoin (PHT), phenobarbital (PB), and ethosuximide (ESM) using wildtype Madin-Darby Canine Kidney II cell line MDCKII and porcine renal endothelial cell line LLC-PK1 cells and these cells transfected with human MDR1 cDNA to express P-gp. Wildtype cells demonstrated no efflux transport of PHT, PB, or ESM. In CETAs, both MDR1-transfected cell lines transported PHT from basolateral to apical when PHT loading concentrations were 5 or 10, but not 20microg/ml. MDCK-MDR1 cells transported PB when initial concentrations were 10 or 20, but not 5microg/ml. LLC-MDR1 did not transport PB. P-gp inhibitor verapamil blocked efflux transport. MDR1-transfected cells did not transport ESM at 5.6 or 56microg/ml. Bi-directional transport assays demonstrated weak transport for PHT but not PB or ESM. Human P-gp transports PHT and PB, but not ESM, in a concentration dependent manner. CETA may be more sensitive than bi-directional assays to detect transport of drugs with high passive diffusion. Potential P-gp substrates should be tested at clinically relevant concentration ranges.
Publisher: Oxford University Press (OUP)
Date: 14-08-2013
DOI: 10.1093/HMG/DDT399
Abstract: Although over 60 loci for type 2 diabetes (T2D) have been identified, there still remains a large genetic component to be clarified. To explore unidentified loci for T2D, we performed a genome-wide association study (GWAS) of 6 209 637 single-nucleotide polymorphisms (SNPs), which were directly genotyped or imputed using East Asian references from the 1000 Genomes Project (June 2011 release) in 5976 Japanese patients with T2D and 20 829 nondiabetic in iduals. Nineteen unreported loci were selected and taken forward to follow-up analyses. Combined discovery and follow-up analyses (30 392 cases and 34 814 controls) identified three new loci with genome-wide significance, which were MIR129-LEP [rs791595 risk allele = A risk allele frequency (RAF) = 0.080 P = 2.55 × 10(-13) odds ratio (OR) = 1.17], GPSM1 [rs11787792 risk allele = A RAF = 0.874 P = 1.74 × 10(-10) OR = 1.15] and SLC16A13 (rs312457 risk allele = G RAF = 0.078 P = 7.69 × 10(-13) OR = 1.20). This study demonstrates that GWASs based on the imputation of genotypes using modern reference haplotypes such as that from the 1000 Genomes Project data can assist in identification of new loci for common diseases.
Publisher: Wiley
Date: 14-06-2018
DOI: 10.1111/EPI.14436
Abstract: There is little detailed phenotypic characterization of bilateral hippoc al sclerosis (HS). We therefore conducted a multicenter review of people with pharmacoresistant epilepsy and bilateral HS to better determine their clinical characteristics. Databases from 11 EPIGEN centers were searched. For identified cases, clinicians reviewed the medical notes, imaging, and electroencephalographic (EEG), video-EEG, and neuropsychometric data. Data were irretrievably anonymized, and a single database was populated to capture all phenotypic information. These data were compared with phenotyped cases of unilateral HS from the same centers. In total, 96 patients with pharmacoresistant epilepsy and bilateral HS were identified (43 female, 53 male age range = 8-80 years). Twenty-five percent had experienced febrile convulsions, and 27% of patients had experienced status epilepticus. The mean number of previously tried antiepileptic drugs was 5.32, and the average number of currently prescribed medications was 2.99 44.8% of patients had cognitive difficulties, and 47.9% had psychiatric comorbidity 35.4% (34/96) of patients continued with long-term medical therapy alone, another 4 being seizure-free on medication. Sixteen patients proceeded to, or were awaiting, neurostimulation, and 11 underwent surgical resection. One patient was rendered seizure-free postresection, with an improvement in seizures for 3 other cases. By comparison, of 201 patients with unilateral HS, a significantly higher number (44.3%) had febrile convulsions and only 11.4% had experienced status epilepticus. Importantly, 41.8% (84/201) of patients with unilateral HS had focal aware seizures, whereas such seizures were less frequently observed in people with bilateral HS, and were never observed exclusively (P = .002 Fisher's exact test). The current work describes the phenotypic spectrum of people with pharmacoresistant epilepsy and bilateral HS, highlights salient clinical differences from patients with unilateral HS, and provides a large platform from which to develop further studies, both epidemiological and genomic, to better understand etiopathogenesis and optimal treatment regimes in this condition.
Publisher: Wiley
Date: 06-2010
DOI: 10.1111/J.1528-1167.2009.02397.X
Abstract: To improve patient care and facilitate clinical research, the International League Against Epilepsy (ILAE) appointed a Task Force to formulate a consensus definition of drug resistant epilepsy. The overall framework of the definition has two "hierarchical" levels: Level 1 provides a general scheme to categorize response to each therapeutic intervention, including a minimum dataset of knowledge about the intervention that would be needed Level 2 provides a core definition of drug resistant epilepsy using a set of essential criteria based on the categorization of response (from Level 1) to trials of antiepileptic drugs. It is proposed as a testable hypothesis that drug resistant epilepsy is defined as failure of adequate trials of two tolerated, appropriately chosen and used antiepileptic drug schedules (whether as monotherapies or in combination) to achieve sustained seizure freedom. This definition can be further refined when new evidence emerges. The rationale behind the definition and the principles governing its proper use are discussed, and ex les to illustrate its application in clinical practice are provided.
Publisher: Wiley
Date: 20-10-2022
DOI: 10.1111/EPI.17426
Abstract: Older adults represent a highly heterogeneous population, with multiple erse subgroups. Therefore, an in idualized approach to treatment is essential to meet the needs of each unique subgroup. Most comparative studies focusing on treatment of epilepsy in older adults have found that levetiracetam has the best chance of long-term seizure freedom. However, there is a lack of studies investigating other newer generation antiseizure medications (ASMs). Although a number of randomized clinical trials have been performed on older adults with epilepsy, the number of participants studied was generally small, and they only investigated short-term efficacy and tolerability. Quality of life as an outcome is often missing but is necessary to understand the effectiveness and possible side effects of treatment. Prognosis needs to move beyond the focus on seizure control to long-term patient-centered outcomes. Dosing studies with newer generation ASMs are needed to understand which treatments are the best in the older adults with different comorbidities. In particular, more high-level evidence is required for older adults with Alzheimer's disease with epilepsy and status epilepticus. Future treatment studies should use greater homogeneity in the inclusion criteria to allow for clearer findings that can be comparable with other studies to build the existing treatment evidence base.
Publisher: Wiley
Date: 13-01-2021
DOI: 10.1002/EPI4.12460
Abstract: ‘First seizure’ clinics (FSCs) aim to achieve early expert assessment for in iduals with possible new‐onset epilepsy. These clinics also have substantial potential for research into epilepsy evolution, outcomes, and costs. However, a paucity of FSCs details has implications for interpretation and utilization of this research. We reviewed investigation findings over 11 years (2000‐2010) from two established independent FSCs at Austin Health (AH) and Royal Melbourne Hospital (RMH), Australia. These adult clinics are in major public hospitals and operate with similar levels of expertise. Organizational differences include screening and dedicated administration at AH. Included were N = 1555 patients diagnosed with new‐onset unprovoked seizures/epilepsy (AH n = 901, RMH n = 654). Protocol‐driven interviews and investigations had been recorded prospectively and were extracted from medical records for study. Median patient age was 37 (IQR 26‐52, range 18‐94) years (AH 34 vs RMH 42 years P .001). Eighty‐six percent of patients attended FSC within three weeks postindex seizure (median AH 12 vs RMH 25 days P .01). By their first appointment, 42% had experienced ≥2 seizures. An EEG was obtained within three weeks postindex seizure in 73% of patients, demonstrating epileptiform discharges in 25% (AH 33% vs RMH 15%). Seventy‐six percent of patients had an MRI within 6 weeks. Of those with imaging (n = 1500), 19% had potentially epileptogenic abnormalities (RMH 28% vs AH 12% P .01). At both sites, changes due to previous stroke/hemorrhage were the commonest lesions, followed by traumatic brain injury. ≥WHO level 1 brain tumors diagnosed at presentation comprised a very small proportion ( %) at each clinic. At both sites, epilepsy type could be determined in 60% of patients RMH had more focal and AH more generalized epilepsy diagnoses. Differences between the clinics’ administrative and screening practices may contribute to differences in investigation findings. Insight into these differences will facilitate interpretation and utilization, and planning of future research.
Publisher: Wiley
Date: 24-01-2005
DOI: 10.1111/J.0013-9580.2005.31904.X
Abstract: The pathogenesis underlying pharmacoresistance in epilepsy is unclear. One of the candidate mechanisms that has attracted growing interest is the limitation of antiepileptic drug (AED) access to the seizure focus by a range of efflux transporters, the prototype of which is P-glycoprotein (P-gp). P-gp is encoded by the multidrug resistance (MDR1 or ABCB1) gene. Predominantly expressed in organs with excretory functions and at blood-tissue barriers, P-gp is thought to act as a physiologic defense by extruding xenobiotics from mammalian cells and affording protection of sensitive organs. The high level of P-gp in the cerebrovascular endothelium is believed to contribute to the functionality of the blood-brain barrier. Overexpression of P-gp causes multidrug resistance in certain cancers. It has been hypothesized that overexpression of P-gp and other efflux transporters in the cerebrovascular endothelium, in the region of the epileptic focus, also may lead to drug resistance in epilepsy. This hypothesis is supported by the findings of elevated expression of efflux transporters in epileptic foci in patients with drug-resistant epilepsy, induction of expression by seizures in animal models, and experimental evidence that some commonly used AEDs are substrates. Conflicting reports suggest a possible association between variants of the MDR1 gene and medical intractability in epilepsy. Further studies to delineate the exact role, if any, of P-gp and other efflux transporters in drug-resistant epilepsy are warranted.
Publisher: Future Medicine Ltd
Date: 07-2013
DOI: 10.2217/PGS.13.104
Abstract: Aim: Approximately a third of newly diagnosed epilepsy patients do not respond to antiepileptic drugs (AEDs). Evidence suggests that low penetrance variants in the genes of drug targets such as voltage-gated sodium channels may be involved in drug responsiveness. To examine this hypothesis, we compared data from two epilepsy cohorts from Malaysia and Hong Kong, as well as a meta-analysis from published data. Materials & methods: Genotype analysis of 39 polymorphisms located in the SCN1A, SCN2A and SCN3A genes was performed on 1504 epilepsy patients from Malaysia and Hong Kong who were receiving AEDs. Meta-analysis was performed for pooled data of SCN1A rs3812718 and rs2298771, and SCN2A rs17183814 polymorphisms. Results: Our data from the Hong Kong and Malaysia cohorts showed no significant allele, genotype and haplotype association of polymorphisms in the SCN1A, SCN2A, and SCN3A genes with drug responsiveness in epilepsy. This finding was supported by a meta-analysis for SCN1A rs3812718 and rs2298771, and for SCN2A rs17183814 polymorphisms. Conclusion: Our comprehensive study suggests that common polymorphisms in SCN1A, SCN2A and SCN3A do not play major roles in influencing response to AEDs. Original submitted 11 March 2013 Revision submitted 31 May 2013
Publisher: Informa Healthcare
Date: 09-2007
DOI: 10.1517/14728214.12.3.407
Abstract: Epilepsy affects < or = 1% of the world's population. Antiepileptic drugs (AEDs) are the mainstay of treatment, although more than a third of patients are not rendered seizure free with existing medications. Uncontrolled epilepsy is associated with increased mortality and physical injuries, and a range of psychosocial morbidities, posing a substantial economic burden on in iduals and society. Limitations of the present AEDs include suboptimal efficacy and their association with a host of adverse reactions. Continued efforts are being made in drug development to overcome these shortcomings employing a range of strategies, including modification of the structure of existing drugs, targeting novel molecular substrates and non-mechanism-based drug screening of compounds in traditional and newer animal models. This article reviews the need for new treatments and discusses some of the emerging compounds that have entered clinical development. The ultimate goal is to develop novel agents that can prevent the occurrence of seizures and the progression of epilepsy in at risk in iduals.
Publisher: Wiley
Date: 18-03-2021
DOI: 10.1111/EPI.16871
Abstract: This study was undertaken to identify factors that predict discordance between the screening instruments Neurological Disorders Depression Inventory for Epilepsy (NDDI‐E) and Generalized Anxiety Disorder scale (GAD‐7), and diagnoses made by qualified psychiatrists among patients with seizure disorders. Importantly, this is not a validation study rather, it investigates clinicodemographic predictors of discordance between screening tests and psychiatric assessment. Adult patients admitted for inpatient video‐electroencephalographic monitoring completed eight psychometric instruments, including the NDDI‐E and GAD‐7, and psychiatric assessment. Patients were grouped according to agreement between the screening instrument and psychiatrists’ diagnoses. Screening was "discordant" if the outcome differed from the psychiatrist's diagnosis, including both false positive and false negative results. Bayesian statistical analyses were used to identify factors associated with discordance. A total of 411 patients met inclusion criteria mean age was 39.6 years, and 55.5% ( n = 228) were female. Depression screening was discordant in 33% of cases ( n = 136/411), driven by false positives ( n = 76/136, 56%) rather than false negatives ( n = 60/136, 44%). Likewise, anxiety screening was discordant in one third of cases ( n = 121/411, 29%) due to false positives ( n = 60/121, 50%) and false negatives ( n = 61/121, 50%). Seven clinical factors were predictive of discordant screening for both depression and anxiety: greater dissociative symptoms, greater patient‐reported adverse events, subjective cognitive impairment, negative affect, detachment, disinhibition, and psychoticism. When the analyses were restricted to only patients with psychogenic nonepileptic seizures (PNES) or epilepsy, the rate of discordant depression screening was higher in the PNES group ( n = 29, 47%) compared to the epilepsy group ( n = 70, 30%, Bayes factor for the alternative hypothesis = 4.65). Patients with seizure disorders who self‐report a variety of psychiatric and other symptoms should be evaluated more thoroughly for depression and anxiety, regardless of screening test results, especially if they have PNES and not epilepsy. Clinical assessment by a qualified psychiatrist remains essential in diagnosing depressive and anxiety disorders among such patients.
Publisher: Elsevier BV
Date: 08-2007
DOI: 10.1016/J.YEBEH.2007.04.013
Abstract: There is accumulating evidence to suggest that overexpression of efflux drug transporters at the blood-brain barrier, by reducing antiepileptic drug (AED) accumulation in the seizure foci, contributes to drug resistance in epilepsy. P-glycoprotein, encoded by the ABCB1 gene, is the most studied drug transporter. There are conflicting data as to whether the CC genotype of the ABCB1 3435C>T polymorphism is associated with drug resistance in Caucasian patients with epilepsy. We investigated this association in ethnic Chinese. ABCB1 3435C>T was genotyped in 746 Han Chinese patients with epilepsy and 179 controls. Patients with drug-resistant epilepsy were more likely to have the TT genotype compared with those with drug-responsive epilepsy (16.7% vs 7.4%, odds ratio=2.5, 95% confidence interval=1.4-4.6, P=0.0009). Our results contrast with those of studies of Caucasians, and highlight the complexity of the possible role of this polymorphism in AED response in different ethnic populations.
Publisher: Wiley
Date: 03-10-2013
DOI: 10.1111/EPI.12391
Abstract: To evaluate the safety and tolerability of adjunctive brivaracetam (BRV), a high-affinity synaptic vesicle protein 2A (SV2A) ligand, in adults with uncontrolled epilepsy. Efficacy was also assessed in patients with focal seizures as a secondary objective, and explored by descriptive analysis in patients with generalized seizures. This was a phase III, randomized, double-blind, placebo (PBO)-controlled flexible dose trial (N01254/NCT00504881) in adults (16-70 years) with uncontrolled epilepsy (up to 20% could be patients with generalized epilepsy). After a prospective 4-week baseline, patients were randomized (3:1) to b.i.d. BRV or PBO, initiated at 20 mg/day and increased, as needed, to 150 mg/day during an 8-week dose-finding period. This was followed by an 8-week stable-dose maintenance period. The treatment period comprised the dose-finding period plus the maintenance period (16 weeks). A total of 480 patients were randomized (BRV 359, PBO 121) of these, 431 had focal epilepsy and 49 had generalized epilepsy. Ninety percent BRV- and 91.7% PBO-treated patients completed the study. Similar proportions of patients (BRV 66.0%, PBO 65.3%) reported adverse events (AEs) during the treatment period. AEs led to treatment discontinuation in 6.1% and 5.0% of BRV- and PBO-treated patients, respectively. The incidence of AEs declined from the dose-finding (BRV 56.0%, PBO 55.4%) to the maintenance (BRV 36.8%, PBO 40.9%) period. The most frequent AEs during the treatment period were headache (BRV 14.2% vs. PBO 19.8%), somnolence (BRV 11.1% vs. PBO 4.1%), and dizziness (BRV 8.6% vs. PBO 5.8%). The incidence of psychiatric AEs was similar for BRV and PBO (BRV 12.3%, PBO 11.6%). In patients with focal seizures, the baseline-adjusted percent reduction in seizure frequency/week in the BRV group (n = 323) over PBO (n = 108) was 7.3% (p = 0.125) during the treatment period. The median percent reduction in baseline-adjusted seizure frequency/week was 26.9% BRV versus 18.9% PBO (p = 0.070), and the ≥50% responder rate was 30.3% BRV versus 16.7% PBO (p = 0.006). In patients with generalized seizures only, the number of seizure days/week decreased from 1.42 at baseline to 0.63 during the treatment period in BRV-treated patients (n = 36), and from 1.47 at baseline to 1.26 during the treatment period in PBO-treated patients (n = 13). The median percent reduction from baseline in generalized seizure days/week was 42.6% versus 20.7%, and the ≥50% responder rate was 44.4% versus 15.4% in BRV-treated and PBO-treated patients, respectively. Adjunctive BRV given at in idualized tailored doses (20-150 mg/day) was well tolerated in adults with uncontrolled epilepsy, and our results provided support for further evaluation of efficacy in reducing focal and generalized seizures.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2009
Publisher: Wiley
Date: 09-03-2001
DOI: 10.1046/J.1528-1157.2001.29000.X
Abstract: We investigated the response to antiepileptic drug (AED) therapy in patients with localisation-related epilepsy associated with different underlying causes. Five hundred and fifty adolescent and adult patients who had partial epilepsy treated with AEDs and who had undergone magnetic resonance imaging of brain were followed up prospectively from 1984 at a single centre. More than 70% were newly diagnosed. None had had epilepsy surgery. Three hundred and twelve (57%) patients had been seizure free at their last clinic visit for at least a year. Patients with mesial temporal sclerosis (MTS n = 73, 42% seizure free) were less likely to be controlled (p < 0.01) than were those with arteriovenous malformation (AVM n = 14, 78%), cerebral infarction (n = 46, 67%), primary tumour (n = 35, 63%), cortical gliosis (n = 81, 57%), cerebral atrophy (n = 49, 55%), and cortical dysplasia (CD n = 63, 54%). Among the seizure-free patients, those with MTS were more likely to require more than one AED compared with those with other aetiologies (48 vs. 35% p < 0.05). There was no difference in outcome between patients with symptomatic and cryptogenic epilepsy (n = 361, 58% vs. n = 189, 56% seizure free, respectively). Patients with MTS, CD, and cryptogenic epilepsy were more likely (p = 0.02) to have a family history of epilepsy than were the other groups. MTS patients also had a higher incidence of febrile convulsions (p < 0.001). The majority of patients with focal-onset epilepsy became seizure free on AED treatment. MTS-related seizures had the worst prognosis. Although many patients with this pathology may benefit from epilepsy surgery, a considerable number will be controlled with AED therapy.
Publisher: JMIR Publications Inc.
Date: 18-10-2022
Abstract: hina is facing a rapidly expanding aging population. Insights into the health status of older adults are of great significance for health resource allocation and health care provision to this population. ith the goal of providing a comprehensive understanding of the health status of older adults and to inform potential interventions, we investigated the level of disability and identified risk factors associated with disability among the older population (aged ≥60 years) living in China. total of 8467 older adults living in the Chinese city of Shenzhen were enrolled in this cross-sectional study. We used a multidimensional ability assessment survey, which assessed their activities of daily living (ADL including eating, bathing, grooming, dressing, defecation control, urination control, using a toilet unaided, transfer, flat-ground walking, stair activity), mental status (including cognitive function, aggressive behavior, depression symptoms), sensory and communication (including consciousness level, vision, hearing, communication), and social participation (including living, working, time/space orientation, distinguish persons, social communication) abilities. The impact of demographic risk factors on ability levels was analyzed using ordinal logistic regression. The correlations between the four dimensions of ability mentioned above were analyzed using Spearman correlation analysis. total of 7766 participants were effectively assessed. The participants’ average age was 70.64 (SD 8.46) years comprising 56.53% females. The overall ability level was classified as mildly, moderately, and severely impaired for 27.57% (n=2141), 2.83% (n=220), and 4.28% (n=332) of the 7766 participants, respectively. With increasing age, the proportion of impaired participants increased from 17.62% (365/2071) in the age group 60-64 years to 91.3% (253/277) in the age group above 90 years ( i P /i & .001), corresponding to an approximate 10% rise for every 5-year age increment. The odds of having more severe overall ability impairment in females was 1.15 times that in males (odds ratio [OR] 1.15, 95% CI 1.04-1.28). Participants who were orced or widowed had a higher risk of more severe overall ability impairment than those currently married (OR 1.98, 95% CI 1.68-2.33). Participants living with nonrelatives had an increased risk of more severe overall ability impairment than those living alone (OR 2.38, 95% CI 1.46-3.91). Higher education level was a protective factor of overall ability impairment (college degree or above: OR 0.32, 95% CI 0.24-0.42). The four dimensions of ability assessed were significantly correlated a low score for ADL was significantly correlated with poorer mental status, sensory and communication, and social participation (all i P /i & .001). he proportion of disability among Chinese older adults increases with age, being female, having lower education levels, being orced or widowed, and living with nonrelatives. Impairment in ADL ability is significantly correlated with poor mental status, social participation, and sensory and communication abilities. A holistic approach to improving the health of the older population is recommended in China.
Publisher: Wiley
Date: 20-08-2012
DOI: 10.1111/J.1528-1167.2012.03648.X
Abstract: To evaluate safety, tolerability, and seizure outcome data during long-term treatment with once-daily adjunctive per anel (up to 12 mg/day) in patients with refractory partial-onset seizures. Study 307 was an extension study for patients completing the double-blind phase of three pivotal phase III trials (studies 304, 305, and 306). The study consisted of two phases: an open-label treatment phase (including a 16-week blinded conversion period and a planned 256-week maintenance period) and a 4-week follow-up phase. Patients were blindly titrated during the conversion period to their in idual maximum tolerated dose (maximum 12 mg/day). Adverse events (AEs) were monitored throughout the study and seizure frequency recorded. The interim data cutoff date for analyses was December 1, 2010. In total, 1,218 patients were enrolled in the study. At the interim cutoff date, 1,186 patients were in the safety analysis set 1,089 (91.8%) patients had >16 weeks of exposure to per anel, 580 (48.9%) patients had >1 year of exposure, and 19 (1.6%) patients had >2 years of exposure. At the interim analysis, 840 (70.8%) patients remained on per anel treatment. The large majority of patients (n = 1,084 [91%]) were titrated to 10 mg or 12 mg/day. Median (range) duration of exposure was 51.4 (1.1-128.1) weeks. Treatment-emergent AEs were reported in 87.4% of patients. The most frequent were dizziness (43.9%), somnolence (20.2%), headache (16.7%), and fatigue (12.1%). Serious AEs were reported in 13.2% of patients. In the intent-to-treat analysis set (n = 1,207), the frequency of all seizures decreased over the first 26 weeks of per anel treatment in patients with at least 26 weeks of exposure to per anel (n = 1,006 [83.3%]) this reduction was maintained in patients with at least 1 year of exposure (n = 588 [48.7%]). The overall median percent changes in seizure frequency in patients included in each 13-week interval of per anel treatment were -39.2% for weeks 14-26 (n = 1,114), -46.5% for weeks 40-52 (n = 731), and -58.1% for weeks 92-104 (n = 59). Overall responder rates in patients included in each 13-week interval of per anel treatment were 41.4% for weeks 14-26 (n = 1,114), 46.9% for weeks 40-52 (n = 731), and 62.7% for weeks 92-104 (n = 59). During the blinded conversion period, the reduction in seizure frequency in patients previously randomized to placebo (-42.4%, n = 369) was similar to that in patients previously randomized to per anel (-41.5%, n = 817). Consistent with pivotal phase III trials, these interim results demonstrated that per anel had a favorable tolerability profile in patients with refractory partial-onset seizures over the longer term. The decrease in seizure frequency was consistent and maintained in those patients over at least 1 year of per anel exposure.
Publisher: Wiley
Date: 16-01-2014
Abstract: This pictorial essay highlights the role of the radiologist as a member of the adult epilepsy multidisciplinary team, and gives an overview of MRI-evident epileptogenic lesions.
Publisher: Springer Science and Business Media LLC
Date: 19-04-2021
DOI: 10.1007/S11306-021-01793-4
Abstract: The mechanistic role of amyloid precursor protein (APP) in Alzheimer's disease (AD) remains unclear. Here, we aimed to identify alterations in cerebral metabolites and metabolic pathways in cortex, hippoc us and serum s les from Tg2576 mice, a widely used mouse model of AD. Metabolomic profilings using liquid chromatography-mass spectrometry were performed and analysed with MetaboAnalyst and weighted correlation network analysis (WGCNA). Expressions of 11 metabolites in cortex, including hydroxyphenyllactate-linked to oxidative stress-and phosphatidylserine-lipid metabolism-were significantly different between Tg2576 and WT mice (false discovery rate < 0.05). Four metabolic pathways from cortex, including glycerophospholipid metabolism and pyrimidine metabolism, and one pathway (sulphur metabolism) from hippoc us, were significantly enriched in Tg2576 mice. Network analysis identified five pathways, including alanine, aspartate and glutamate metabolism, and mitochondria electron transport chain, that were significantly correlated with AD genotype. Changes in metabolite concentrations and metabolic pathways are present in the early stage of APP pathology, and may be important for AD development and progression.
Publisher: Springer Science and Business Media LLC
Date: 2005
DOI: 10.2165/00023210-200519110-00001
Abstract: In pharmacotherapy, overtreatment may be defined as an excessive drug load (that is, excessive drug dosages or unnecessary polypharmacy) leading to a suboptimal risk-to-benefit ratio. The risk of overtreatment in the pharmacological management of epilepsy is substantial and may have serious consequences in terms of a greater incidence and severity of adverse effects. These effects can range from subtle CNS impairment to overt toxic effects, including teratogenicity. Overtreatment also causes increased treatment costs and may even lead to a paradoxical deterioration in seizure control. The prevention and correction of overtreatment requires a thorough understanding of the situations and mechanisms that lead to inappropriate prescribing of antiepileptic drugs. These include initiating treatment in conditions where it is not indicated (for ex le, long-term prophylaxis after head trauma or supratentorial surgery in seizure-free patients), use of excessively fast titration rates, prescription of excessively high initial target dosages, failure to consider conditions associated with reduced dosage requirements (for ex le, old age or comorbidities associated with impaired drug clearance), and failure to consider the dose-response characteristics of the selected drug. Many patients whose seizures do not respond to the initially prescribed medication can be optimally managed by switching to monotherapy with an alternative agent premature use of combination therapy represents another common form of overtreatment. Overtreatment may also result from a failure to adjust the dosage to prevent or compensate for adverse pharmacokinetic or pharmacodynamic drug interactions, and from a failure to reduce drug load in patients who have not benefited from high dosages or polypharmacy. While the measurement of drug concentrations can aid in minimising adverse effects, there is also a danger of overtreatment resulting from inappropriate interpretation of drug concentration data. Continuation of drug therapy in seizure-free patients in whom the risk-benefit ratio is in favour of gradual withdrawal may also be regarded as overtreatment. Tailoring therapy to the needs of the in idual patient is the key to the successful management of epilepsy. Even though the importance of complete seizure control cannot be overemphasised, no patient should be made to suffer more from the adverse effects of treatment than from the manifestations of the seizure disorder.
Publisher: Elsevier BV
Date: 07-2012
Publisher: BMJ
Date: 10-2004
Publisher: Elsevier BV
Date: 2017
DOI: 10.1016/J.SEIZURE.2016.11.022
Abstract: Despite the exponential growth of approved antiepileptic drugs (AEDs) over the past 25 years, epilepsy remains uncontrolled in approximately a third of patients. This article summarises the clinical trials and properties of the AEDs developed over this period, and reviews the pre-clinical and clinical development paradigms of modern AEDs. We discuss possible reasons for the apparent failure to develop more efficacious compounds. We also review the current regulatory frameworks for drug approval in the United States and Europe, and the changes on the horizon. Encouragingly, better elucidation of the pathophysiological mechanisms underpinning pharmacoresistance and the epilepsies by recent research has enabled a revised approach to the development of more promising therapies. A new era of pharmacological treatment for epilepsy appears imminent. Future research in pharmacotherapy for drug-resistant epilepsy will be advanced through concerted effort between scientists, clinicians, and the industry.
Publisher: Wiley
Date: 12-08-2009
DOI: 10.1111/J.1528-1167.2009.02237.X
Abstract: The goal of antiepileptic therapy is to achieve long-term seizure freedom with minimal or no adverse effects. Current evidence suggests that in many patients who have failed two appropriate antiepileptic drugs (AEDs) because of lack of efficacy, the chance of subsequent seizure freedom with further drug manipulation is low (reports ranging from as little as a few percent to nearly one-fourth of patients). Achieving this may require repeated drug manipulations. Surgery, in appropriately selected candidates, may render up to 70% of patients seizure-free when temporal resection is done, although frontal resection may have only a 25% yield. Both courses of actions (further drug trials and surgery) are associated with a plethora of potential adverse outcomes. Therefore, it is recommended that such patients be promptly referred to an epilepsy center for a comprehensive review of the diagnosis and management, which may include initial evaluation for surgery. Because presurgical evaluation and surgery itself may entail discomfort and risk, the decision to offer surgical treatment requires in idual risk-benefit analysis that includes an assessment of possible success with additional trials of medication.
Publisher: Wiley
Date: 10-01-2023
DOI: 10.1111/EPI.17494
Abstract: In an aging world, it is important to know the burden of epilepsy affecting populations of older persons. We performed a selective review of epidemiological studies that we considered to be most informative, trying to include data from all parts of the world. We emphasized primary reports rather than review articles. We reviewed studies reporting the incidence and prevalence of epilepsy that focused on an older population as well as studies that included a wider age range if older persons were tabulated as a subgroup. There is strong evidence that persons older than approximately 60 years incur an increasing risk of both acute symptomatic seizures and epilepsy. In wealthier countries, the incidence of epilepsy increases sharply after age 60 or 65 years. This phenomenon was not always observed among reports from populations with lower socioeconomic status. This discrepancy may reflect differences in etiologies, methods of ascertainment, or distribution of ages this is an area for more research. We identified other areas for which there are inadequate data. Incidence data are scarcer than prevalence data and are missing for large areas of the world. Prevalence is lower than would be expected from cumulative incidence, possibly because of remissions, excess mortality, or misdiagnosis of acute symptomatic seizures as epilepsy. Segmentation by age, frailty, and comorbidities is desirable, because “epilepsy in the elderly” is otherwise too broad a concept. Data are needed on rates of status epilepticus and drug‐resistant epilepsy using the newer definitions. Many more data are needed from low‐income populations and from developing countries. Greater awareness of the high rates of seizures among older adults should lead to more focused diagnostic efforts for in iduals. Accurate data on epilepsy among older adults should drive proper allocation of treatments for in iduals and resources for societies.
Publisher: Wiley
Date: 07-04-2022
DOI: 10.1002/JPEN.2373
Abstract: Induction of ketosis by manipulation of nutrition intake has been proposed as an adjunctive treatment for super‐refractory status epilepticus (SRSE). However, the classical 4:1 ketogenic ratio may not meet the nutrition needs, specifically protein for critically ill adults. The aim of this study was to analyze the outcomes of adults with SRSE who received a lower ketogenic ratio of 2:1 grams of fat to non‐fat grams, including 20%–30% of energy from medium chain triglycerides. We reviewed patients aged ≥18 years with SRSE treated with ketogenic therapy between July 2015 and December 2020 at two quaternary teaching hospitals in Melbourne, Australia. Data collected from medical records included patient demographics, nutrition prescription, clinical outcomes, and ketogenic therapy‐related complications. The primary outcome of the study was to assess tolerability of ketogenic therapy. Twelve patients (female = 7) were treated with ketogenic therapy for SRSE. Patients received between 4 and 8 antiseizure medications and 1–5 anesthetic agents prior to commencement of ketogenic therapy. Blood beta‐hydroxybutyrate concentrations were variable (median = 0.5 mmol/L, range: 0.0–6.1 mmol/L). SRSE resolved in 10 cases (83%) after a median of 9 days (range: 2–21 days) following commencement of ketogenic therapy. Ketogenic therapy–associated complications were reported in five patients, leading to cessation in two patients. Despite the challenge in maintaining ketosis during critical illness, low ratio 2:1 ketogenic therapy incorporating medium chain triglycerides is tolerable for adults with SRSE. Further studies are required to determine the optimal timing, nutrition prescription and duration of ketogenic therapy for SRSE treatment.
Publisher: Elsevier BV
Date: 05-2022
DOI: 10.1016/J.JMGM.2021.108116
Abstract: Oxidative stress is one of the pathophysiological mechanisms implicated in drug-resistant epilepsy. Recurrent seizures and prolonged treatment with anti-seizure medicines (ASMs) can produce reactive oxygen species (ROS) resulting in neuronal cell damage, cell toxicity, and cell death. This damage may contribute to the loss of efficacy of anti-seizure medicines. Add-on therapy with antioxidants, neuroimmunophilins, and polyphenols may thus be beneficial in drug-resistant epilepsy. In vitro and in vivo studies have shown a significant improvement in drug efficacy and seizure suppression using co-treatment of anti-seizure medication with naturally available antioxidants including alpha-lipoic acid (α-lipoic acid) from walnut however, the underlying mechanisms of action remain to be fully understood. We undertook molecular docking and molecular dynamics simulations to determine whether alpha-lipoic acid and related analogues interacted with the human manganese superoxide dismutase (MnSOD) protein, a member of the oxidative metabolic pathway. The 3D structure of the compounds and the protein were retrieved from protein and chemical databases, binding sites were identified and ligand-protein interactions were performed. Alpha-lipoic acid and various analogues docked within a human MnSOD binding region. Docking results were validated by molecular dynamic simulation. The CMX-2043 analogue showed strong binding with MnSOD compared to alpha-lipoic acid and other analogues. Our findings provide new insights into additional mechanisms of action, which may in part, account for the antioxidant properties associated with alpha-lipoic acid and related analogues. The results support further in vitro and in vivo evaluation of these compounds to better understand their potential as add-on therapy for ASM treatment in epilepsy.
Publisher: Cold Spring Harbor Laboratory
Date: 20-12-2019
DOI: 10.1101/2019.12.19.883405
Abstract: The epilepsies are commonly accompanied by widespread abnormalities in cerebral white matter. ENIGMA-Epilepsy is a large quantitative brain imaging consortium, aggregating data to investigate patterns of neuroimaging abnormalities in common epilepsy syndromes, including temporal lobe epilepsy, extratemporal epilepsy, and genetic generalized epilepsy. Our goal was to rank the most robust white matter microstructural differences across and within syndromes in a multicentre s le of adult epilepsy patients. Diffusion-weighted MRI data were analyzed from 1,069 non-epileptic controls and 1,249 patients: temporal lobe epilepsy with hippoc al sclerosis (N=599), temporal lobe epilepsy with normal MRI (N=275), genetic generalized epilepsy (N=182) and nonlesional extratemporal epilepsy (N=193). A harmonized protocol using tract-based spatial statistics was used to derive skeletonized maps of fractional anisotropy and mean diffusivity for each participant, and fiber tracts were segmented using a diffusion MRI atlas. Data were harmonized to correct for scanner-specific variations in diffusion measures using a batch-effect correction tool (ComBat). Analyses of covariance, adjusting for age and sex, examined differences between each epilepsy syndrome and controls for each white matter tract (Bonferroni corrected at p .001). Across “all epilepsies” lower fractional anisotropy was observed in most fiber tracts with small to medium effect sizes, especially in the corpus callosum, cingulum and external capsule. Less robust effects were seen with mean diffusivity. Syndrome-specific fractional anisotropy and mean diffusivity differences were most pronounced in patients with hippoc al sclerosis in the ipsilateral parahippoc al cingulum and external capsule, with smaller effects across most other tracts. Those with temporal lobe epilepsy and normal MRI showed a similar pattern of greater ipsilateral than contralateral abnormalities, but less marked than those in patients with hippoc al sclerosis. Patients with generalized and extratemporal epilepsies had pronounced differences in fractional anisotropy in the corpus callosum, corona radiata and external capsule, and in mean diffusivity of the anterior corona radiata . Earlier age of seizure onset and longer disease duration were associated with a greater extent of microstructural abnormalities in patients with hippoc al sclerosis. We demonstrate microstructural abnormalities across major association, commissural, and projection fibers in a large multicentre study of epilepsy. Overall, epilepsy patients showed white matter abnormalities in the corpus callosum, cingulum and external capsule, with differing severity across epilepsy syndromes. These data further define the spectrum of white matter abnormalities in common epilepsy syndromes, yielding new insights into pathological substrates that may be used to guide future therapeutic and genetic studies.
Publisher: Wiley
Date: 11-2002
DOI: 10.1046/J.1528-1157.2002.156702.X
Abstract: The multidrug resistance (mdr) gene family encodes the drug transport macromolecule P-glycoprotein (P-gp), which contributes to the functionality of the blood-brain barrier. Recent evidence suggests that P-gp-mediated drug extrusion may play a facilitatory role in refractory epilepsy. We investigated the regional expression of mdr genes in genetically epilepsy-prone rat (GEPR) brain after a single audiogenic seizure. Three groups of adult male GEPRs (n = 5/group) were exposed to a seizure-inducing audiogenic stimulus and killed at 4 h, 24 h, and 7 days thereafter. A further group (n = 5) served as a stimulus-naïve control. Expression of mdr1a and mdr1b in distinct anatomic brain regions (cortex, midbrain, pons/medulla, hippoc us) was determined by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) in the presence of competitive internal standards. When compared with control, mdr1a expression in cortex and midbrain was significantly (p < 0.05) increased at 24 h after a single audiogenic seizure. Cortical mdr1a expression remained elevated at 7 days after stimulus. In contrast, mdr1a expression in pons/medulla and hippoc us was unchanged. The mdr1b isoform was quantifiable in hippoc us alone and not influenced by seizure activity. These findings suggest that acute seizures in the GEPR can induce the expression of mdr genes. The pattern of increased expression appears to follow the anatomic pathway of audiogenic seizures in these animals, with initiation in the midbrain and propagation to the cortex. Further studies are required to investigate the effects of recurrent seizure activity and to characterise mdr expression in other experimental seizure models.
Publisher: Oxford University Press (OUP)
Date: 24-11-2011
DOI: 10.1093/HMG/DDR550
Abstract: In the majority of patients, epilepsy is a complex disorder with multiple susceptibility genes interacting with environmental factors. However, we understand little about its genetic risks. Here, we report the first genome-wide association study (GWAS) to identify common susceptibility variants of epilepsy in Chinese. This two-stage GWAS included a total of 1087 patients and 3444 matched controls. In the combined analysis of the two stages, the strongest signals were observed with two highly correlated variants, rs2292096 [G] [P= 1.0 × 10(-8), odds ratio (OR) = 0.63] and rs6660197 [T] (P= 9.9 × 10(-7), OR = 0.69), with the former reaching genome-wide significance, on 1q32.1 in the CAMSAP1L1 gene, which encodes a cytoskeletal protein. We also refined a previously reported association with rs9390754 (P= 1.7 × 10(-5)) on 6q21 in the GRIK2 gene, which encodes a glutamate receptor, and identified several other loci in genes involved in neurotransmission or neuronal networking that warrant further investigation. Our results suggest that common genetic variants may increase the susceptibility to epilepsy in Chinese.
Publisher: Elsevier BV
Date: 2010
Publisher: Springer Science and Business Media LLC
Date: 2018
DOI: 10.2165/00003495-200666140-00004
Abstract: After being regarded as a last resort for over two decades, the role of combination therapy as a treatment strategy for epilepsy is undergoing re-evaluation. This is a result of the growing appreciation that all seizures cannot be controlled by monotherapy in a substantial proportion of patients, and of the development of a range of modern antiepileptic drugs (AEDs), some of which are better tolerated and less prone to complex pharmacokinetic drug interactions than their older counterparts.Robust evidence to guide clinicians on when and how to combine AEDs is lacking, and current practice recommendations are largely empirical. Monotherapy should remain the treatment of choice for newly diagnosed epilepsy. A combination of two AEDs can be considered after failure, resulting from lack of efficacy, of one or two different monotherapy regimens. A few patients will become seizure-free with a combination of three AEDs, but treatment with a combination of four or more is unlikely to be successful. There is some evidence to support a pharmacomechanistic approach to AED combination. Care should be taken to avoid excessive drug load, which is associated with increased toxicity. Bigger and better randomised, controlled studies are needed to determine the optimal time and way to combine AEDs.
Publisher: Wiley
Date: 27-05-2023
DOI: 10.1111/EPI.17644
Abstract: Improved quality of life (QoL) is an important outcome goal following epilepsy surgery. This study aims to quantify change in QoL for adults with drug‐resistant epilepsy (DRE) who undergo epilepsy surgery, and to explore clinicodemographic factors associated with these changes. We conducted a systematic review and meta‐analysis using Medline, Embase, and Cochrane Central Register of Controlled Trials. All studies reporting pre‐ and post‐epilepsy surgery QoL scores in adults with DRE via validated instruments were included. Meta‐analysis assessed the postsurgery change in QoL. Meta‐regression assessed the effect of postoperative seizure outcomes on postoperative QoL as well as change in pre‐ and postoperative QoL scores. A total of 3774 titles and abstracts were reviewed, and ultimately 16 studies, comprising 1182 unique patients, were included. Quality of Life in Epilepsy Inventory–31 item (QOLIE‐31) meta‐analysis included six studies, and QOLIE‐89 meta‐analysis included four studies. Postoperative change in raw score was 20.5 for QOLIE‐31 (95% confidence interval [CI] = 10.9–30.1, I 2 = 95.5) and 12.1 for QOLIE‐89 (95% CI = 8.0–16.1, I 2 = 55.0%). This corresponds to clinically meaningful QOL improvements. Meta‐regression demonstrated a higher postoperative QOLIE‐31 score as well as change in pre‐ and postoperative QOLIE‐31 score among studies of cohorts with higher proportions of patients with favorable seizure outcomes. At an in idual study level, preoperative absence of mood disorders, better preoperative cognition, fewer trials of antiseizure medications before surgery, high levels of conscientiousness and openness to experience at the baseline, engagement in paid employment before and after surgery, and not being on antidepressants following surgery were associated with improved postoperative QoL. This study demonstrates the potential for epilepsy surgery to provide clinically meaningful improvements in QoL, as well as identifies clinicodemographic factors associated with this outcome. Limitations include substantial heterogeneity between in idual studies and high risk of bias.
Publisher: Wiley
Date: 05-2007
DOI: 10.1111/J.1528-1167.2007.01022.X
Abstract: A previous study conducted in Taiwan found a 100% association between HLA-B*1502 allele and carbamazepine-induced Stevens-Johnson syndrome (SJS) in Han Chinese subjects, with an extremely high odds ratio compared with carbamazepine-tolerant subjects (odds ratio = 2,504). We examined this association in 24 Hong Kong Han Chinese subjects who had cutaneous adverse reactions induced by different antiepileptic drugs (AEDs). They were matched with 48 AED-tolerant controls. HLA-B*1502 was associated with severe cutaneous reactions (SCR) induced by AEDs, which included carbamazepine, phenytoin, and lamotrigine (p = 0.001, odds ratio = 17.6), but was not associated with maculopapular exanthema (MPE) (p = 0.32). Further studies in larger s les of ethnically matched subjects should be conducted to confirm the findings. Identification of genetic polymorphisms predisposing to development of AED-induced SCR offers the possibility of avoiding these high-risk drugs in genetically susceptible in iduals.
Publisher: Elsevier BV
Date: 10-2002
DOI: 10.1016/S1525-5050(02)00511-5
Abstract: Evidence suggests that the efflux transporter P-glycoprotein (P-gp) may play a facilitatory role in refractory epilepsy by limiting the brain access of antiepileptic drugs (AEDs). We have conducted a preliminary pharmacokinetic study of seven commonly used AEDs in mdr1a knockout mice, devoid of P-gp at the blood-brain barrier. A parallel group of matched wild-type mice served as controls. AEDs were administered by subcutaneous injection and serum and brain drug concentrations determined at 30, 60, and 240min post-dosing. The brain-serum concentration ratio for topiramate was higher in mdr1a(-/-) mice than in wild-type controls at all time points investigated. No consistent effects were observed with any other AED investigated. These findings suggest that topiramate may be a substrate for P-gp-mediated transport. Further studies employing a range of model systems are required to substantiate this observation and to address the potential role of drug transporters in refractory epilepsy.
Publisher: Wiley
Date: 21-06-2011
DOI: 10.1111/J.1528-1167.2011.03140.X
Abstract: Antiepileptic drugs (AEDs) are widely used not only in the treatment of epilepsy but also as treatments for psychiatric disorders. Pharmacoresistance of AEDs in the treatment of epilepsy and psychiatric disorders is a serious problem. Transport of antiepileptic drugs by P-glycoprotein (Pgp, ABCB1, or MDR1), which is overexpressed in the blood-brain barrier, may be a mechanism for resistance of AEDs. For most AEDs, conflicting evidence precludes consensus on whether they are substrates of Pgp. The objective of this study was to evaluate whether analogs and metabolites of the AED carbamazepine are substrates of human Pgp. Polarized cell lines MDCKII and LLC transfected with the human MDR1 gene were used in the bidirectional transport assay and concentration equilibrium transport assay. The expression of Pgp was detected by real-time polymerase chain reaction (PCR) and immunofluorescent staining. Rhodamine-123 uptake was also determined. Pgp did not transport carbamazepine, but it did transport its active metabolite carbamazepine-10,11-epoxide. Pgp also pumped eslicarbazepine acetate and oxcarbazepine, as well as their active metabolite (S)-licarbazepine. Transport of the drugs was in the order of ESL>OXC>S-LC>CBZ-E in concentration equilibrium conditions. The transport of these drugs was blocked by Pgp inhibitors tariquidar and verapamil. All carbamazepine analogs or metabolites tested are Pgp substrates, except for carbamazepine. These data suggest that resistance to carbamazepine, oxcarbazepine, or eslicarbazepine acetate may be attributed to increased efflux function of Pgp because they or their active metabolites are Pgp substrates.
Publisher: Elsevier BV
Date: 10-2011
Publisher: BMJ
Date: 26-01-2012
DOI: 10.1136/BMJ.E345
Publisher: Wiley
Date: 22-07-2009
Publisher: Elsevier BV
Date: 02-2021
Publisher: Wiley
Date: 22-08-2001
DOI: 10.1046/J.1528-1157.2001.0420081002.X
Abstract: Treatment with sodium valproate (VPA) may be associated with polycystic ovarian syndrome (PCOS) in some women with epilepsy. By comparing hormone profiles in young adults taking VPA or lamotrigine (LTG) as monotherapy, this study aimed to explore whether a pharmacologic effect of VPA could be responsible for this observation. Hormone profiles in men and women taking VPA (n = 40) or LTG (n = 36) monotherapy for epilepsy were compared. None of the women were receiving hormonal contraception or replacement. Patients gave details of seizure type and frequency, menstrual cycle, and medical and drug history. Body mass index was calculated, and fasting insulin, glucose, cholesterol, triglycerides (TG), high- and low-density lipoproteins, testosterone, dihydroepiandosterone (DHEA), androstenedione, sex hormone-binding globulin (SHBG), free androgen index (FAI), luteinising hormone (LH), follicle-stimulating hormone (FSH), and antiepileptic drug (AED) concentrations were measured. There were no differences between treatment groups for both sexes in age and seizure control. Only four obese VPA-treated women were hyperinsulinaemic (p = 0.05) three with abnormal menstrual cycles one with raised testosterone. Testosterone (p = 0.02), FAI (p = 0.03), and TG (p = 0.02) levels were higher, however, in women taking the drug. Obese patients of both sexes (p = 0.01) and VPA-treated men (p = 0.03) had higher insulin concentrations. VPA therapy may be associated with subclinical elevation in fasting insulin levels. Testosterone and TG levels were higher in VPA-treated women compared with the levels in those taking LTG. However, only a minority of obese females exhibited biochemical characteristics suggestive of PCOS. Biochemical screening may allow women at risk of developing PCOS to avoid VPA.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 20-07-2020
DOI: 10.1212/WNL.0000000000009855
Abstract: To investigate the hypothesis that patients diagnosed with psychogenic nonepileptic seizures (PNES) on video-EEG monitoring (VEM) have increased mortality by comparison to the general population. This retrospective cohort study included patients evaluated in VEM units of 3 tertiary hospitals in Melbourne, Australia, between January 1, 1995, and December 31, 2015. Diagnosis was based on consensus opinion of experienced epileptologists and neuropsychiatrists at each hospital. Mortality was determined in patients diagnosed with PNES, epilepsy, or both conditions by linkage to the Australian National Death Index. Lifetime history of psychiatric disorders in PNES was determined from formal neuropsychiatric reports. A total of 5,508 patients underwent VEM. A total of 674 (12.2%) were diagnosed with PNES, 3064 (55.6%) with epilepsy, 175 (3.2%) with both conditions, and 1,595 (29.0%) received other diagnoses or had no diagnosis made. The standardized mortality ratio (SMR) of patients diagnosed with PNES was 2.5 (95% confidence interval [CI] 2.0–3.3). Those younger than 30 had an 8-fold higher risk of death (95% CI 3.4–19.8). Direct comparison revealed no significant difference in mortality rate between diagnostic groups. Among deaths in patients diagnosed with PNES (n = 55), external causes contributed 18%, with 20% of deaths in those younger than 50 years attributed to suicide, and “epilepsy” was recorded as the cause of death in 24%. Patients diagnosed with PNES have a SMR 2.5 times above the general population, dying at a rate comparable to those with drug-resistant epilepsy. This emphasizes the importance of prompt diagnosis, identification of risk factors, and implementation of appropriate strategies to prevent potential avoidable deaths.
Publisher: Elsevier BV
Date: 11-2009
Publisher: Wiley
Date: 28-07-2018
DOI: 10.1111/BCP.13653
Publisher: Wiley
Date: 27-05-2014
DOI: 10.1111/EPI.12643
Publisher: Elsevier BV
Date: 09-2011
DOI: 10.1016/J.YEBEH.2011.02.012
Abstract: Pharmacogenomics holds the promise of selecting the right drug at the right dose for the right person. Its research and application in epilepsy are in their infancy. Although advances have been made in identifying genetic markers of adverse effects in terms of severe cutaneous reactions, there has been little progress in predicting efficacy. Most studies have been retrospective and case-control in design, despite the associated problems of recall bias and a usually undefined relationship between genotype and outcome. We describe the epidemiological framework necessary to detect genetic influences on antiepileptic drug response, and propose an ambitious prospective outcome study of newly diagnosed epilepsy across all age ranges, countries, and continents, which would provide the template for a global pharmacogenomic project. Other epidemiological considerations and statistical constraints and issues related to study design, databases, and ethics that are critical for advancement in the field are also discussed.
Publisher: Wiley
Date: 15-02-2023
DOI: 10.1002/EPI4.12693
Abstract: In vitro data prompted U.S Food and Drug Administration warnings that lamotrigine, a common sodium channel modulating anti‐seizure medication (NaM‐ASM), could increase the risk of sudden death in patients with structural or ischaemic cardiac disease, however, its implications for Sudden Unexpected Death in Epilepsy (SUDEP) are unclear. This retrospective, nested case–control study identified 101 sudden unexpected death in epilepsy (SUDEP) cases and 199 living epilepsy controls from Epilepsy Monitoring Units (EMUs) in Australia and the USA. Differences in proportions of lamotrigine and NaM‐ASM use were compared between cases and controls at the time of admission, and survival analyses from the time of admission up to 16 years were conducted. Multivariable logistic regression and survival analyses compared each ASM subgroup adjusting for SUDEP risk factors. Proportions of cases and controls prescribed lamotrigine ( P = 0.166), one NaM‐ASM ( P = 0.80), or ≥2NaM‐ASMs ( P = 0.447) at EMU admission were not significantly different. Patients taking lamotrigine (adjusted hazard ratio [aHR] = 0.56 P = 0.054), one NaM‐ASM (aHR = 0.8 P = 0.588) or ≥2 NaM‐ASMs (aHR = 0.49 P = 0.139) at EMU admission were not at increased SUDEP risk up to 16 years following admission. Active tonic–clonic seizures at EMU admission associated with ‐fold SUDEP risk, irrespective of lamotrigine (aHR = 2.24 P = 0.031) or NaM‐ASM use (aHR = 2.25 P = 0.029). Sensitivity analyses accounting for incomplete ASM data at follow‐up suggest undetected changes to ASM use are unlikely to alter our results. This study provides additional evidence that lamotrigine and other NaM‐ASMs are unlikely to be associated with an increased long‐term risk of SUDEP, up to 16 years post‐EMU admission.
Publisher: SAGE Publications
Date: 07-2012
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-01-2014
Publisher: Oxford University Press (OUP)
Date: 02-11-2010
DOI: 10.1093/HMG/DDQ474
Abstract: Systemic lupus erythematosus (SLE) is an autoimmune disease with a strong genetic involvement. The susceptibility genes identified so far can only explain a small proportion of disease heritability. Through a genome-wide association in a Hong Kong Chinese cohort and subsequent replication in two other Asian populations, with a total of 3164 patients and 4482 matched controls, we identified association of ELF1 (E74-like factor 1) with SLE (rs7329174, OR = 1.26, joint P= 1.47 × 10(-8)). ELF1 belongs to the ETS family of transcription factors and is known to be involved in T cell development and function. Database analysis revealed transcripts making use of three alternative exon1s for this gene. Near equivalent expression levels of distinct transcripts initiated from alternative exon1s were detected in peripheral blood mononuclear cells from both SLE patients and healthy controls. Although a direct association of rs7329174 with the three forms of transcripts for this gene was not detected, these findings support an important role of ELF1 in SLE susceptibility and suggest a potentially tight regulation for the expression of this gene.
Publisher: Wiley
Date: 23-10-2020
DOI: 10.1111/EPI.16721
Publisher: Wiley
Date: 31-01-2023
DOI: 10.1002/EPI4.12692
Abstract: Epilepsy is associated with an increased risk of cardiovascular disease and mortality. Whether cardiac structure and function are altered in epilepsy remains unclear. To address this, we conducted a systematic review and meta‐analysis of studies evaluating cardiac structure and function in patients with epilepsy. We searched the electronic databases MEDLINE, PubMed, COCHRANE, and Web of Science from inception to 31 December 2021. Primary outcomes of interest included left ventricular ejection fraction (LVEF) for studies reporting echocardiogram findings and cardiac weight and fibrosis for postmortem investigations. Study quality was assessed using the National Heart, Lung, and Blood Institute (NHLBI) assessment tools. Among the 10 case‐control studies with epilepsy patients (n = 515) and healthy controls (n = 445), LVEF was significantly decreased in epilepsy group compared with controls (MD: −1.80 95% confidence interval [CI]: −3.56 to −0.04 P = 0.045), whereas A‐wave velocity (MD: 4.73 95% CI: 1.87‐7.60 P = 0.001), E/e' ratio (MD: 0.39 95% CI: 0.06‐0.71 P = 0.019), and isovolumic relaxation time (MD: 10.18 95% CI: 2.05‐18.32 P = 0.014) were increased in epilepsy, compared with controls. A pooled analysis was performed in sudden unexpected death in epilepsy (SUDEP) cases with autopsy data (n = 714). Among SUDEP cases, the prevalence of cardiac hypertrophy was 16% (95% CI: 9%–23%) cardiac fibrosis was 20% (95% CI: 15%–26%). We found no marked differences in cardiac hypertrophy, heart weight, or cardiac fibrosis between SUDEP cases and epilepsy controls. Our findings suggest that epilepsy is associated with altered diastolic and systolic echocardiogram parameters compared with healthy controls. Notably, SUDEP does not appear to be associated with a higher incidence of structural cardiac abnormalities, compared with non‐SUDEP epilepsy controls. Longitudinal studies are needed to understand the prognostic significance of such changes. Echocardiography may be a useful noninvasive diagnostic test in epilepsy population.
Publisher: Wiley
Date: 20-12-2021
DOI: 10.1002/EPI4.12571
Abstract: New‐onset seizures affect up to 10% of people over their lifetime, however, their health economic impact has not been well‐studied. This prospective multicenter study will collect patient‐reported outcome measures (PROMs) from adults with new‐onset seizures seen in six Seizure Clinics across Melbourne, Australia and The University of Colorado, USA. Approximately 450 eligible patients will be enrolled in the study at or following their initial attendance to Seizure Clinics at the study hospitals. Inclusion criteria for the study group are those with new‐onset acute symptomatic seizures, new‐onset unprovoked seizures, and new‐onset epilepsy. Inclusion criteria for the three comparator groups are those with noncardiac syncope, those with psychogenic nonepileptic seizures, as well as published PROMs data from the Australian general population. Exclusion criteria are those aged less than 18 years, those with a preexisting epilepsy diagnosis, and those with intellectual disabilities or other impairments which would preclude them from comprehending and completing the questionnaires. Patients will complete eight online questionnaires regarding the effect that their seizures (or seizure mimics) have had on various aspects of their life. These questionnaires will be readministered at 6 and 12 months. Patients with new‐diagnosis epilepsy will also be asked to share the reasons why they have accepted or declined antiseizure medications. Primary outcome measures will be quality of life, work productivity, informal care needs, and mood, at baseline compared to 6 and 12 months later for those with new‐onset seizures and comparing these outcomes to those in the three comparator groups. Secondary outcomes include mapping of QoLIE‐31 to the EQ‐5D‐5L in epilepsy, modelling indirect costs of new‐onset seizures, and exploring why patients may or may not wish to take antiseizure medications. These data will form an evidence‐base for future studies that examine the effectiveness of various healthcare interventions for new‐onset seizure patients. This study is approved by the Alfred Health Human Research Ethics Committee (SERP: 52 538, Alfred HREC: 307/19), the Austin Health Human Research Ethics Committee (HREC/59148/Austin‐2019), and the Colorado Multiple Institutional Review Board (COMIRB) (COMIRB #20‐3028). ACTRN12621000908831.
Publisher: Elsevier BV
Date: 08-2006
DOI: 10.1016/J.YEBEH.2006.05.009
Abstract: Basic science studies of the human brain have supported the cortical representation of cardiovascular responses, including heart rate variability. Clinical observations of ictal bradyarrhythmia may be mechanistically explained by the influence of the central autonomic network, although the localization and lateralization issues need to be considered in the light of patterns of seizure spread, hand dominance, and presence of lesions. Ictal bradyarrhythmia also offers a mechanistic explanation of sudden unexpected death in epilepsy (SUDEP), though it may explain only some but not all cases of SUDEP. The missing links are (1) clinical evidence of common factors shared by patients with ictal bradyarrhythmia and patients who die from SUDEP, (2) evidence of arrhythmia as a risk factor for SUDEP from epidemiological studies, and, (3) determination of the importance of ictal bradyarrhythmia in SUDEP with respect to other proposed mechanisms including apnea and intrinsic cardiac abnormalities. There remains a need to review the seizure mechanisms in cases of SUDEP and to step up the amount of concurrent ECG/intracranial EEG analysis in both ictal bradyarrhythmia and SUDEP cases.
Publisher: Georg Thieme Verlag KG
Date: 10-2010
Publisher: Springer Science and Business Media LLC
Date: 30-07-2007
Abstract: The Health and Health Services Research Fund (HHSRF) is dedicated to support research related to all aspects of health and health services in Hong Kong. We evaluated the fund's outcomes and explored factors associated with the translation of research findings to changes in health policy and provider behaviour. A locally suitable questionnaire was developed based on the "payback" evaluation framework and was sent to principal investigators of the completed research projects supported by the fund since 1993. Research "payback" in six outcome areas was surveyed, namely knowledge production, use of research in the research system, use of research project findings in health system policy/decision making, application of the research findings through changed behaviour, factors influencing the utilization of research, and health/health service/economic benefits. Principal investigators of 178 of 205 (87%) completed research projects returned the questionnaire. Investigators reported research publications in 86.5% (mean = 5.4 publications per project), career advancement 34.3%, acquisition of higher qualifications 38.2%, use of results in policy making 35.4%, changed behaviour in light of findings 49.4%, evidence of health service benefit 42.1% and generated subsequent research in 44.9% of the projects. Payback outcomes were positively associated with the amount of funding awarded. Multivariate analysis found participation of investigators in policy committees and liaison with potential users were significantly associated with reported health service benefit (odds ratio [OR] participation = 2.86, 95% confidence interval [CI] 1.28–6.40 OR liaison = 2.03, 95% CI 1.05–3.91), policy and decision-making (OR participation = 10.53, 95% CI 4.13–26.81 OR liaison = 2.52, 95% CI 1.20–5.28), and change in behavior (OR participation = 3.67, 95% CI 1.53–8.81). The HHSRF has produced substantial outcomes and compared favourably with similar health research funds in other developed economies. Further studies are needed to better understand the factors and pathways associated with the translation of research findings into practice.
Publisher: Wiley
Date: 03-2014
DOI: 10.1111/EPI.12527
Abstract: To better understand the relationship between efficacy and per anel dose, integrated actual (last) dose data from three phase III trials and an extension study (blinded Conversion Period open-label Maintenance Period) were analyzed. Seizure frequency data were analyzed in patients who were randomized to and completed the 13-week Maintenance Period of the phase III studies on per anel 8 mg, and who received an actual (last) dose of 12 mg during (1) the extension 16-week blinded Conversion Period or (2) weeks 1-13 of the extension Maintenance Period. Due to a treatment-by-region interaction (p = 0.042), analyses excluded patients from the Latin America region (n = 162/1,480 10.9% of the treated cohort). Of 372 patients randomized to 8 mg in the phase III studies, 273 completed the Maintenance Period at 8 mg and 267 entered the extension study. In patients who then had an actual (last) dose of 12 mg during the extension blinded Conversion Period (n = 217), median percent change in seizure frequency per 28 days improved from -32.4% (8 mg, phase III Maintenance Period) to -44.2% (12 mg, extension blinded Conversion Period) 50% responder rates increased slightly from 37.3% to 42.9%. In patients who completed the phase III studies on 8 mg and had an actual (last) dose of 12 mg during weeks 1-13 of the extension Maintenance Period (n = 181), median percent change in seizure frequency per 28 days improved from -34.1% (phase III Maintenance Period) to -46.0% (weeks 1-13 extension Maintenance Period) 50% responder rates were 39.2% and 46.4%. Seizure control remained substantially unchanged in patients who completed the phase III studies at 12 mg and continued on that dose during the extension. Increasing per anel dose from 8 to 12 mg can produce additional benefits in seizure control in at least some patients who tolerate the higher dose.
Publisher: Hindawi Limited
Date: 08-08-2012
DOI: 10.1111/J.1600-0404.2012.01711.X
Abstract: The objective of this study was to investigate the timing of therapy initiation and other clinical factors as potential predictors for relapse and prognosis of epilepsy, based on hospital-based prospective observational data in China. One hundred and seventy-one newly diagnosed patients with one or more seizures were recruited and followed for at least 2 years. Kaplan-Meier survival analysis was used for calculating recurrence and remission rates. Univariate and multivariate analyses for risk factors were performed using Cox proportional hazards model. Among the 171 patients analyzed, more patients had partial (54.4%) than generalized seizures (45.6%). The range of patients' age was 6-70 years, but 70% were under 16 years of age. Multiple seizure types (HR = 2.01 95% CI, 1.31-3.10), epileptiform electroencephalogram (EEG) abnormality (HR = 1.95 95% CI, 1.09-3.49), and >1 seizure monthly before treatment (HR = 2.74 95% CI, 1.69-4.51) were predictors of seizure recurrence. The best negative predictors of remission were as follows: relapse (HR = 0.13 95% CI, 0.07-0.23) and epileptiform EEG within 1 year of treatment (HR = 0.61 95% CI, 0.39-0.97). Delayed treatment after three or more seizures did not significantly increase the risk of recurrence (P = 0.70) or remission (P = 0.31) compared with early treatment after one or two seizures. Multiple seizure types, epileptiform EEG abnormality, and >1 seizure monthly before treatment predict seizure recurrence. Relapse and epileptiform EEG within 1 year of treatment predict adverse seizure outcome. Early treatment does not affect relapse or prognosis.
Publisher: The Electrochemical Society
Date: 30-05-2021
DOI: 10.1149/MA2021-01362067MTGABS
Abstract: Pharmacogenomics is one of the endeavours in the modern acute health care sector due to the complexity of the drug reactions associated with the patients' genetic markers[1]. Therefore, the availability of patient pharmacogenetic marker testing at the point-of-care (POC) setting will help the clinicians to prescribe and personalize the medication to ensure maximum efficiency with minimal adverse drug reactions (ADR). In this regard, we focused on developing a HLA-B*15:02 pharmacogenetic biomarker testing known to cause specific ADRs for Carbamazepine[2]. In this study, disposable screen-printed electrodes (SPE) as the planar sensor surfaces and a sequence-specific stem-loop probe modified with a methylene blue redox (MB) reporter was used to detect the targeted DNA sequence of HLA-B*15:02. The oligo probe with MB reporter at the 3′ end was designed to incorporate 25 nucleotides to detect the specific region. The disulphide-reducing reagent, Tris(2-carboxyethyl) phosphine hydrochloride was introduced to reduce the S-S bond of the oligo probe. The probe immobilization on the working electrode area was performed using the fully automated non-contact dispensing system sciFLEXARRAYER SX by dispensing an array of droplets of 50 µM probe mixture into accurate positioning of the gold working electrode area of SPEs (220AT DropSens). Around 20 SPEs were loaded, and probes were printed during a single batch processing task. Two printing runs were performed, and a total of N=30 biosensors were used in the experimental procedure. The electrochemical behaviour of the sensor was studied by performing the square wave voltammetry (SWV) measurements from -0.4 V to -0.1 V, with a modulation litude of 0.02 V and frequency of 25 Hz at a scan rate of 0.026 V/s (Autolab-PGSTAT204). The target hybridization time was fixed at 30 minutes. The p-values ≤ 0.05 was considered statistically significant. The SWV measurements on the sensors with 75 µl, 1X PBS solution (Baseline) showed a well-defined peak at -0.31 V with the standard deviation (SD) of 0.004 V (N total =30) which is consistent with the potential of the MB redox moiety. The statistical t-test has been shown that no statistical significance (p=0.1760) between the two printing runs with the peak heights of 640.5 nA ± 151.2 nA (SD). Upon target hybridization, measured peak heights showed that (a) 152.0 nA ± 23.3 nA for the 50 µM Positive control (oligo with the sequence complementary to the probe), (b) 231.8 nA ± 54.8 nA for the 50 µM Negative control (oligo with the non-complementary sequence to the probe), and (c) 226.2 nA ± 93.2 nA for the Blank-oligo free sensors. This shows ~34% signal suppression in Positive control hybridized sensors, whereas insignificance difference between the Negative and Blank s les hybridized sensors. Furthermore, statistical analysis (one-way ANOVA) show that a statistical significance (p=0.0250) for the Positive vs. Negative, a statistical significance (p=0.0388) for the Positive vs. Blank s le, and no statistical significance (p=0.9793) for the Negative vs. Blank s le. These results confirmed that a complementary target binding event in the stem-loop probe results in a significant signal decrease and the possibility of using this 'signal-off biosensor architecture in detecting HLA-B*15:02 pharmacogenetic biomarker testing platform. It was found that only 6 µl probe mixture was required to cover one sensor. Accordingly, the calculated probe surface density was equivalent to ~1.43×10 15 molecules/cm 2 , which will be 3 order of magnitudes higher than the typical probe surface density (~10 12 ) of biosensors[3]. This high level of probe surface density on the sensors was achieved by printing a high concentration of low volume of redox probes. This will not be possible in the typical wet bench probe immobilization methods. Also, it showed a significantly higher level of faradaic current generated in the biosensor and clear differentiation of the targets. Therefore, this work showcases encouraging results of biosensor architecture, rapid probe immobilization method, the possibility of using the ultra-low volume of probe reagents, and high-throughput productions. This suggested that further development of this pharmacogenetic biomarker testing platform will enhance the technical feasibility and enable the transition of this biosensor from the research to industry. Acknowledgements This work used the Melbourne Centre for Nanofabrication (MCN) in the Victorian Node of the NCRIS-enabled Australian National Fabrication Facility (ANFF). References FDA. Table of Pharmacogenomic Biomarkers in Drug Labeling . Available from: rugs/science-and-research-drugs/table-pharmacogenomic-biomarkers-drug-labeling . Soraya, G.V., et al., An interdigitated electrode biosensor platform for rapid HLA-B*15:02 genotyping for prevention of drug hypersensitivity. Biosens Bioelectron, 2018. 111 : p. 174-183. Ricci, F., et al., Effect of molecular crowding on the response of an electrochemical DNA sensor. Langmuir, 2007. 23 (12): p. 6827-6834.
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Patrick Kwan.