No description available.

The pharmacokinetics of phenytoin is complicated by the nonlinearity of the dose-concentration relationship which is a consequence of capacity-limited metabolism. Individualized therapy with phenytoin is therefore optimally required. As no data are available on the population pharmacokinetics of phenytoin in the Western Cape, this study was undertaken to address this issue. This study was conducted prospectively primarily to: (1) investigate the influence of various patient variables on the population pharmacokinetic parameters of phenytoin, (2) assess whether the parallel Michaelis-Menten and first-order elimination model provides a better fit to the data than the Michaelis-Menten model, (3) determine population pharmacokinetic parameter estimates of phenytoin representative of the patient population, and (4) validate and compare the clinical applicability of the parameter estimates and the models. The study population comprised 332 black and coloured, adult, male and female epileptic patients residing in the Western Cape, South Africa. All patients were on phenytoin monotherapy for the management of their epilepsy and no drugs known to interfere with phenytoin pharmacokinetics were taken concurrently. Clinical pharmacokinetic dosing services were initiated at 9 clinics from which patients were selected for this study. The service entailed a patient interview, a chart review, drug analysis and provision of either a written or verbal consultation report. The data were analyzed using NONMEM (nonlinear mixed-effects modelling), a computer programme designed for population pharmacokinetic analysis that allows pooling of data from many individuals. The Michaelis-Menten and the parallel Michaelis-Menten and first-order elimination models were fitted to 853 steady-state dose: serum concentration pairs.

Viewing a seizure as a behavioral chain consisting of a precursor aura phase and a climactic phase has moved researchers to introduce behavioral techniques either singularly or in combination at aura to circumvent seizures. Many of the aura interruption techniques have been shown to be effective in reducing seizure rate, but a systematic examination and application of the technqiues and the additive effects of. combinations have not been explored . The present study examines by way of an A-B-A-B-BC-B-BC single subject design the singular and additive effects of three aura interruption techniques (i.e., startle, shake, and differential reinforcement of other behaviors). The study involved four developmentally disabled adults for which an aura was discerned by way of a self-report measure, and an observable behavior scale. Clients were randomly assigned to one of six aura interruption combination pairs designed to encompass all permutations of the three aura interruption techniques singularly and in combination. Observers (i.e., parents or care home operators) were trained by way of videotapes and role-playing situations on how to detect and record seizure occurrences as well as when and how to introduce the aura interruption technique(s). Results indicate that aura interruption techniques alone are effective in reducing seizure rates below baseline levels and that techniques in combination with others do not produce further reductions in seizure rates.

No description available.

Objectives: To validate the revised 12-item revised Neurological Disorders Depression Inventory-Epilepsy for Youth (NDDI-E-Y), a self-report screening tool for depressive symptoms tailored to youth ages 12–17 with epilepsy. Methods: Youth at two sites completed the NDDI-E-Y during a routine epilepsy visit. Youth at one site also completed the Children's Depression Inventory-2 (CDI-2). Seizure and demographic data were abstracted from the electronic medical record. Exploratory factor analyses were conducted. Internal consistency, area under the curve (AUC), and construct validity were assessed. Results: NDDI-E-Y questionnaires were analyzed for 143 youth. The coefficient for internal consistency for the NDDI-E-Y was 0.92. Factor analyses suggested a one-factor solution with all 12 items loading on the factor. The NDDI-E-Y was positively correlated with the CDI-2 (N = 99). Sensitivity and specificity of the NDDI-E-Y were high. Significance: Reliability and construct validity were established for the revised 12-item NDDI-E-Y. The NDDI-E-Y is a brief, free measure of depressive symptoms that can be administered during a routine epilepsy visit.

Purpose: To investigate reasons for patients not proceeding to resective epilepsy surgery after subdural grid evaluation (SDE). To correlate noninvasive investigation results with invasive EEG observations in a set of patients with nonlesional brain MRIs. Methods: Retrospective study of adult epilepsy patients undergoing SDE during an 8-year period at Cleveland Clinic. Construction of semiquantitative "scores" and Bayesian predictors summarizing the localizing value and concordance between noninvasive parameters in a subset with nonlesional MRIs. Results: One hundred forty patients underwent SDE, 25 of whom were subsequently denied resective surgery. In 10 of 25, this was caused by a nonlocalizing subdural ictal EEG onset. Eight of 10 such patients were nonlesional on MRI. Among all nonlesional patients (n = 34 of 140), n 1 = 10 of 34 patients had nonlocalizing and n2 = 24 of 34 had localizing, subdural ictal onsets. As groups, n1 and n 2 were statistically disjoint relative to their noninvasive scores. Bayesian measures predictive of focal invasive ictal EEG were highest for complete concordance of noninvasive parameters, decreasing with lesser degrees of concordance. A localizing scalp interictal EEG was a particularly good Bayesian prognosticator. Conclusions: A small but significant proportion of SDE patients are denied subsequent therapeutic resective surgery. This is due to several reasons, including a nonlocalizing intracranial ictal EEG. The majority of such patients have nonlesional MRIs. The noninvasive data may be summarized by a semiquantitative score, as well as Bayesian likelihood ratios, which correlate with subsequent invasive outcome. This approach may find use in the selection and counseling of potential surgical candidates offered SDE.

Dravet syndrome (DS) is a severe form of pediatric epilepsy with characterizations of pharmacoresistant seizures and developmental delay. A rarer variant of the DS model is caused by heterozygous loss-of-function mutations in SCN1B, which is essential in regulating sodium channel gating, expression, localization, and the firing of action potentials. Mutations in SCN1B result in severe seizures as well as a higher risk of Sudden Unexpected Death in EPilepsy (SUDEP). Factors underlying SUDEP are poorly understood, although cardiac arrythmias have been implicated. Acebutolol (ACE) is a common beta-blocker used in the treatment of arrhythmias and hypertension. We hypothesized that treating mice with ACE will decrease cardiac arrhythmias and the incidence of SUDEP, prolonging lifespan of Scn1b null mice. Wild-type (WT) and null (KO) mice were given daily injections of 10 mg/kg ACE or saline starting at postnatal day 15 (after typical seizure onset) either during the day (09:00) or at night (21:00). ECG was recorded daily including a baseline and a 20-minute post injection measurement to analyze the long-term and acute effects of treatment. 20 minutes following ACE injection, KO mice displayed a significant reduction in heart rate compared to WT (38% vs. 11%). Interestingly, HR the day prior to death consistently dropped ~50% (average 414 bpm to 193 bpm) in our saline group; this was prevented in KO animals treated with ACE (421 bpm). A modest, but significant, increase in survival curves in our KO animals was observed compared to saline treated mice for those given injections during the day (a 2 day increase in median survival). In addition, in this group, the onset of animal death was delayed. Surprisingly, in the mice injected during the night hours, there was a trend towards a decrease in lifespan. From these findings there is a notable hypersensitivity to ACE in this DS model. Leading up to death, we believe it is possible ACE assisted in decreased cardiovascular deficits that could lead to SUDEP and contributed to the modest increased lifespan. While we are still seeing death in the ACE treated group because of unnoticed, prolonged seizures, or other mechanisms of SUDEP. In addition, our results demonstrate the importance of timing in delivery of drugs targeted at SUDEP. Further work includes testing this hypothesis by adding 24 hour drug delivery or an anti-epileptic drug to see if lifespan is further affected is warranted.

Part I. Development of an isoxylitone analog as an antiepileptic drug candidate. Delphinium denudatum is a medicinal plant traditionally used to treat a variety of conditions in Central Asia. Its interesting anticonvulsant effects were determined to be a property of the compound isoxylitone. Prior work from our group in collaboration with the Poulter group from Western University investigated this compound and generated a large number of isoxylitone analogs in order to optimize its antiepileptic activity. This led to the discovery of the prodrug 13 and the active form 15 shown below, which emerged as the most potent. In this work, the library of analogs was further expanded with 22 new compounds with several which matched the activity of 13 and 15, such as compounds 22 and 37, which led to valuable new insights on the activity of these analogs, and suggested other possible future improvements. In addition, efforts were continued regarding developing compound 15 as a clinical trial candidate. Optimization of the synthesis was performed to drastically reduce costs and waste of chemicals, as well as accelerating the duration of the synthesis. The purification of the final product was also greatly facilitated by the direct synthesis of 15, compared to the prior process of first preparing 13 and hydrolyzing the ester. Efforts were exerted to gather additional knowledge on the characteristics of the compound, with structural and conformational analysis via X-ray crystallography and NOE NMR as well as accelerated stability studies to test the viability of 15 in long-term storage under various conditions. All the information gathered throughout this work supported 15 and its sodium salt as excellent clinical trial candidates as treatments for epilepsy. Part II. Synthesis of SOX9 inhibitors as promoters of recovery from spinal cord injury. According to the World Health Organization, 250 to 500 thousand people develop a spinal cord injury each year with a large portion resulting in tetraplegia. A common misconception is that this is permanent because the damaged nerves cannot be repaired. In fact, nerves can and do regrow after being damaged, but cannot do so after spinal cord injuries due to formation of scar tissues which physically and chemically prevents the healing. The Brown group at Western University identified the SOX9 transcription factor as an important promoter of the formation of this scar and showed that SOX9 inhibitors could improve recovery and mobility in mice affected by spinal cord injuries. In collaboration with their group, previous work in our lab performed and SAR study on the lead compounds ZO2(1) and STL26 (2), shown below. The different sections of the molecule have been designated units A to D, to simplify discussion. Initial work by our group established an efficient method to prepare a library of analogs of the lead compounds. A number of compounds were prepared, which primarily investigated small amines as unit A and phenols with small aliphatic substituents as unit D. The initial SAR data confirmed the validity of STL26 as lead compound, as most alterations to the structure were detrimental to the SOX9 inhibitory activity. The objective of this work was to build on these preliminary SAR results, and expand the library of analogs. Larger substituents were introduced in unit A and D and showed that any group larger or smaller than diethylamide in unit A was detrimental to the activity, but that there seemed to be ample space to increase the size of the unit D isopropyl group. Analogs investigating unit B showed that adding substituents at most of the positions was detrimental, as well as changing the relative positions of unit A and B to be ortho or para to each other. However, the C4 on ring B seemed to be very tolerant to various electron donating or withdrawing functional groups. During this SAR study, a recurring theme was the awful solubility of the compounds in water, which heavily complicated their administration to mice during the bioassays. While none of the analogs tested proved superior to 2, the knowledge accrued during this work painted a clear path forward on which areas of the structure could be safely altered to improve solubility without negative impacts on SOX9 inhibition. Some additional efforts were put into obtaining an accurate three-dimensional structure of an active STL26 (2) analog, and information on the primary conformation in solution. Achieving these goals required the use of NOE NMR experiments and X-ray crystallography. One conformation was discovered to be strongly favoured as a result of an intramolecular hydrogen bond even in protic solvents. Subsequently, a small number of additional analogs were prepared containing modifications that would strongly favor or hinder the preferred conformation, in order to better understand its role in the inhibitory activity. The presence of this hydrogen bond appeared to be key to the activity of the compounds.

Epilepsy, a disease characterized by recurring spontaneous seizures, affects over 65 million people, 2% of the world’s population. Over 30% of patients are refractory to all current medical therapy, and for those that can be treated, many suffer from severe drug side-effects. Understanding the molecular basis of epilepsy is vital to the advancement of better therapeutic options and an eventual cure. Upregulation of brain-derived neurotrophic factor (BDNF) is highly associated with epileptogenesis in human patients, as well as animal models. Our laboratory discovered that BDNF induces the Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) pathway in neurons and that inhibition attenuates spontaneous seizures in a temporal lobe epilepsy model. The mechanism behind JAK/STAT signaling in neurons and its relationship to epilepsy still remains to be elucidated and is the subject of my thesis. Surprisingly, even though BDNF is such a major signaling molecule, its full genomic impact has never been assessed. We conducted a high-density RNA-sequencing analysis of the BDNF transcriptome in cortical neurons and probed such regulation with selective JAK inhibitors. Results suggest that 68% of BDNF-induced changes in gene expression implicated in epilepsy are regulated by JAK/STAT signaling. Eighty percent of BDNF-induced changes coding for proteins involved in synaptic neurotransmission (receptor subunits and ion channels) involve JAK/STATs. Additionally, these datasets include genes that have never been associated with BDNF regulation (such as Dopamine Receptor D5 and Galanin Receptor 1). Most interestingly, the datasets reveal that BDNF-induced JAK/STAT signaling in neurons is non-canonical, as STAT3 phosphorylation at tyrosine 705 is not required for action. To directly examine STAT3’s role in epileptogenesis, we studied the transcriptome of transgenic mice that express lower levels of STAT3 specifically in neurons. Using the intrahippocampal kainic-acid (KA) model of epilepsy, our datasets suggest that STAT3 knockdown in vivo, and selectively in neurons, protects mice from KA-induced dysregulation of the sphingolipid metabolism pathway that is associated with the trafficking, sorting, and stability of membrane-bound proteins, including neurotransmitter receptors and ion channels. Finally, we discuss a model for JAK/STAT signaling in neurons that includes structural aspects of an intracellular BDNF receptor (p75NTR) associated with JAK2. / 2021-06-14T00:00:00Z

Objective: Telementoring programs like Project ECHO® (Extension for Community Healthcare Outcomes) employ didactics, case-based learning and an “all teach-all learn”approach to increase PCP knowledge/confidence in managing chronic health conditions. The AAP Epilepsy and Comorbidities ECHO aimed to incorporate Quality Improvement (QI) methodology to create sustainable practice change, while increasing PCP knowledge/confidence/self-efficacy in epilepsy management using the ECHO model. Methods: ECHO sessions occurred monthly (5/2018-12/2018). Sessions included lectures, case presentations/discussion and QI review. Practices, recruited through the AAP, implementedmonthly PDSA cycles using team huddles, chart reviews, QI coaching calls and discussion. Measures for improvement were selected from the American Academy of Neurology Epilepsy Measures set. The AAP Quality Improvement Data Aggregator was used for data entry, run chart development, tracking outcomes. Participants completed pre and post-surveys and received Maintenance of Certification Part 4 credits. Results: Average session attendance was 14 (13-17), across 7 practices in 5 states. QI coaching facilitated practice change and development of resource toolkits with documentation templates, safety handouts, medication side effects sheets. Individual and aggregate run charts with data analysis augmented workflow changes. 479 chart reviews demonstrated improvement in 6/7 measures (Table1): documenting seizure frequency (7.1% increase), anti-seizure therapy side effects (23%), safety education(41.6%, p=0.036); Mental/behavioral health screening(32.2% p=0.027); Tertiary Center referral(26.7%); Health Care transition(45.3%, p=0.005). Counseling for women of childbearing age decreased by 7.8%. Participants reported gains in knowledge/confidence/self-efficacy regarding epilepsy management (p< 0.02). Conclusions: This project demonstrated that integrating QI into an ECHO model results in sustainable practice change and increases PCP knowledge/confidence/self-efficacy in managing epilepsy.