IU Indianapolis ScholarWorks :: Browsing by Subject "epilepsy"

Browsing by Subject "epilepsy"

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Bioisosteres of ethyl 8-ethynyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo [1,5-a][1,4]diazepine-3-carboxylate (HZ-166) as novel alpha 2,3 selective potentiators of GABAA receptors: Improved bioavailability enhances anticonvulsant efficacy
(Elsevier, 2018-07) Witkin, Jeffrey M.; Smith, Jodi L.; Ping, X.; Gleason, S. D.; Poe, M. M.; Li, G.; Jin, X.; Hobbs, J.; Schkeryantz, J. M.; McDermott, J. S.; Alatorre, A. I.; Siemian, J. N.; Cramer, J. W.; Airey, D. C.; Methuku, K. R.; Tiruveedhula, V. V. N. P. B.; Jones, T. M.; Crawford, J.; Krambis, M. J.; Fisher, J. L.; Cook, J. M.; Cerne, R.; Neurological Surgery, School of Medicine
HZ-166 has previously been characterized as an α2,3-selective GABAA receptor modulator with anticonvulsant, anxiolytic, and anti-nociceptive properties but reduced motor effects. We discovered a series of ester bioisosteres with reduced metabolic liabilities, leading to improved efficacy as anxiolytic-like compounds in rats. In the present study, we evaluated the anticonvulsant effects KRM-II-81 across several rodent models. In some models we also evaluated key structural analogs. KRM-II-81 suppressed hyper-excitation in a network of cultured cortical neurons without affecting the basal neuronal activity. KRM-II-81 was active against electroshock-induced convulsions in mice, pentylenetetrazole (PTZ)-induced convulsions in rats, elevations in PTZ-seizure thresholds, and amygdala-kindled seizures in rats with efficacies greater than that of diazepam. KRM-II-81 was also active in the 6 Hz seizure model in mice. Structural analogs of KRM-II-81 but not the ester, HZ-166, were active in all models in which they were evaluated. We further evaluated KRM-II-81 in human cortical epileptic tissue where it was found to significantly-attenuate picrotoxin- and AP-4-induced increases in firing rate across an electrode array. These molecules generally had a wider margin of separation in potencies to produce anticonvulsant effects vs. motor impairment on an inverted screen test than did diazepam. Ester bioisosters of HZ-166 are thus presented as novel agents for the potential treatment of epilepsy acting via selective positive allosteric amplification of GABAA signaling through α2/α3-containing GABA receptors. The in vivo data from the present study can serve as a guide to dosing parameters that predict engagement of central GABAA receptors.
Burden of Seizure Clusters on Patients With Epilepsy and Caregivers: Survey of Patient, Caregiver, and Clinician Perspectives
(Lippincott, Williams & Wilkins, 2017-11) Penovich, Patricia E.; Buelow, Janice; Steinberg, Kathy; Sirven, Joseph; Wheless, James; School of Nursing
Objectives: To characterize the burden of seizure clusters (SC) on patients and caregivers, a large internet-based survey was conducted. Methods: The Seizure Cluster Burden of Illness US Survey was conducted online by Harris Poll on behalf of The Epilepsy Foundation in September 2014. Respondents included adult patients 18 years and above with epilepsy or a seizure disorder who had experienced SC in the past year (defined as ≥2 seizures within 24 h outside the patient’s typical seizure pattern), caregivers providing current care for a patient with SC (adult or child), and clinicians (neurologists, epileptologists) who treat adult or pediatric patients. Responses to a wide range of topics, including emotional well-being, daily function, productivity, and approach to clinical practice, were collected. Results: There were 861 respondents (259 adult SC patients, 263 caregivers, and 339 clinicians). A majority of all respondent groups felt SC have a moderate/major negative impact on patient and caregiver quality of life, including emotional, financial, and social components. Responses indicated possible overutilization of emergency room services and underutilization of rescue treatment. Only 30% of patients reported having a seizure emergency plan. Some responses showed discrepancies between clinicians and patients/caregivers in the perceived degree of negative impact of SC and management practices for SC. Conclusions: These results suggest the need for increased education on managing SC. Clinicians need to develop seizure emergency plans and discuss rescue therapies, whereas patients and caregivers need to ask for and utilize these management strategies.
Chronic Low-Level Vagus Nerve Stimulation Reduces Stellate Ganglion Nerve Activity and Paroxysmal Atrial Tachyarrhythmias in Ambulatory Canines
(Office of the Vice Chancellor for Research, 2011-04-08) Shen, Mark J.; Shinohara, Tetsuji; Park, Hyung-Wook; Frick, Kyle; Ice, Daniel S.; Choi, Eue-Keun; Han, Seongwook; Sharma, Rahul; Shen, Changyu; Fishbein, Michael C.; Chen, Lan S.; Lopshire, John C.; Zipes, Douglas P.; Lin, Shien-Fong; Chen, Peng-Sheng
Introduction: Left sided low-level vagus nerve stimulation (LL-VNS) is used clinically for epilepsy and depression. We hypothesize that LL-VNS can suppress sympathetic outflow and reduce atrial tachyarrhythmias in ambulatory dogs. Methods: We implanted in 12 dogs a neurostimulator in left cervical vagus nerve and a radiotransmitter for continuous recording of left stellate ganglion nerve activities (SGNA), left thoracic vagal nerve activities (VNA) and electrocardiograms. The first 6 dogs (Group 1) underwent 1 week continuous LL-VNS. Another 6 dogs (Group 2) underwent intermittent rapid atrial pacing followed by active or sham LL-VNS on alternate weeks. Results: Integrated SGNA was significantly reduced during LL-VNS (7.8±0.9 mV-s vs. 9.4±0.9 mVs at baseline, P<0.05) in Group 1.The reduction was most apparent from 7 to 9 AM, (31% reduction, 10.8±2.5 mV-s versus 15.6±2.9 mV-s at baseline, P<0.01), along with a significantly reduced heart rate (P<0.05). SGNA-induced heart rate acceleration averaged 107.9±9.0 bpm during LL-VNS and 129.2±9.3 bpm at baseline (P<0.05). LL-VNS did not change VNA. The tyrosine hydroxylase-positive nerve structures in the left stellate ganglion were 99,684±22,257 µm2/mm2 in LL-VNS dogs and 186,561±11,383 µm2/mm2 (P<0.01) in normal control dogs. In Group 2, the frequencies of paroxysmal atrial fibrillation and atrial tachycardia during active LLVNS were 1.4±2.5/d and 8.0±5.8/d, respectively, significantly lower than during sham stimulation (9.2±6.2/d, P<0.01 and 22.0±4.4/d, P<0.001, respectively). Conclusion: LL-VNS suppresses SGNA and reduces the incidences of paroxysmal atrial tachyarrhythmias in ambulatory dogs. Significant neural remodeling of the left stellate ganglion is evident one week after cessation of chronic LL-VNS.
Comorbidity of attention deficit hyperactivity disorder in a patient with epilepsy: Staring down the challenge of inattention versus nonconvulsive seizures
(Elsevier, 2024) Miller, Derryl J.; Komanapalli, Hannah; Dunn, David W.; Neurology, School of Medicine
Epilepsy is a heterogeneous disorder of recurrent seizures which often is comorbid with anxiety, depression, attention deficit hyperactivity disorder (ADHD), intellectual disability (ID), and other psychiatric manifestations. Treating both epilepsy and behavioral symptoms from psychiatric disorders can result in polypharmacy with interactions of medications leading to both worsened efficacy of antiseizure medications due to psychotropic effects and worsening of psychiatric symptoms due to antiseizure medication side effects. We aim to suggest pragmatic strategies for the neurologist in the diagnosis and management of comorbid ADHD in patients with epilepsy based on the International League Against Epilepsy (ILAE) Pediatric Commission guidelines and additional literature review. The screening tool of choice for the symptoms of ADHD is validated in the country of practice and written in the language of the family, though various screening tools and advantages and disadvantages of each will be discussed. Once ADHD is diagnosed, recent safety data suggest that Methylphenidate, Amphetamine, and Atomoxetine are generally safe for patients with epilepsy. We present a case of a child with epilepsy and ADHD and discuss the clinical signs, symptoms, and strategies for treatment as well as when to refer to child psychiatry.
Delay Differential Analysis of Seizures in Multichannel Electrocorticography Data
(MIT, 2017-12) Lainscsek, Claudia; Weyhenmeyer, Jonathan; Cash, Sydney S.; Sejnowski, Terrence J.; Neurological Surgery, School of Medicine
High-density electrocorticogram (ECoG) electrodes are capable of recording neurophysiological data with high temporal resolution with wide spatial coverage. These recordings are a window to understanding how the human brain processes information and subsequently behaves in healthy and pathologic states. Here, we describe and implement delay differential analysis (DDA) for the characterization of ECoG data obtained from human patients with intractable epilepsy. DDA is a time-domain analysis framework based on embedding theory in nonlinear dynamics that reveals the nonlinear invariant properties of an unknown dynamical system. The DDA embedding serves as a low-dimensional nonlinear dynamical basis onto which the data are mapped. This greatly reduces the risk of overfitting and improves the method's ability to fit classes of data. Since the basis is built on the dynamical structure of the data, preprocessing of the data (e.g., filtering) is not necessary. We performed a large-scale search for a DDA model that best fit ECoG recordings using a genetic algorithm to qualitatively discriminate between different cortical states and epileptic events for a set of 13 patients. A single DDA model with only three polynomial terms was identified. Singular value decomposition across the feature space of the model revealed both global and local dynamics that could differentiate electrographic and electroclinical seizures and provided insights into highly localized seizure onsets and diffuse seizure terminations. Other common ECoG features such as interictal periods, artifacts, and exogenous stimuli were also analyzed with DDA. This novel framework for signal processing of seizure information demonstrates an ability to reveal unique characteristics of the underlying dynamics of the seizure and may be useful in better understanding, detecting, and maybe even predicting seizures.
Epilepsy and attention-deficit hyperactivity disorder: links, risks, and challenges.
(Dove, 2016) Williams, Amy E.; Giust, Julianne M.; Kronenberger, William G.; Dunn, David W.; Department of Psychiatry, IU School of Medicine
Attention-deficit hyperactivity disorder (ADHD) has a prevalence rate of 7%–9% in the general population of children. However, in children with epilepsy, ADHD has been found to be present in 20%–50% of patients. This paper provides a review of ADHD prevalence in pediatric epilepsy populations and reviews data on specific symptom presentation and attention deficits in patients with epilepsy. This paper also reviews evidence-based treatments for ADHD and specifically the treatment of ADHD as a comorbid condition in children with epilepsy.
Epilepsy Mutations in Different Regions of the Nav1.2 Channel Cause Distinct Biophysical Effects
(2020-06) Mason, Emily R.; Cummins, Theodore; Sullivan, William J., Jr.; Brustovetsky, Nickolay; Sheets, Patrick; Hashino, Eri
While most cases of epilepsy respond well to common antiepileptic drugs, many genetically-driven epilepsies are refractory to conventional antiepileptic drugs. Over 250 mutations in the Nav1.2 gene (SCN2A) have been implicated in otherwise idiopathic cases of epilepsy, many of which are refractory to traditional antiepileptic drugs. Few of these mutations have been studied in vitro to determine their biophysical effects on the channels, which could reveal why the effects of some are refractory to traditional antiepileptic drugs. The goal of this dissertation was to characterize multiple epilepsy mutations in the SCN2A gene, which I hypothesized would have distinct biophysical effects on the channel’s function. I used patch-clamp electrophysiology to determine the biophysical effects of three SCN2A epilepsy mutations (R1882Q, R853Q, and L835F). Wild-type (WT) or mutant human SCN2A cDNAs were expressed in human embryonic kidney (HEK) cells and subjected to a panel of electrophysiological assays. I predicted that the net effect of each of these mutations was enhancement of channel function; my results regarding the L835F and R1882Q mutations supported this hypothesis. Both mutations enhance persistent current, and R1882Q also impairs fast inactivation. However, examination of the same parameters for the R853Q mutation suggested a decrease of channel function. I hypothesized that the R853Q mutation creates a gating pore in the channel structure through which sodium leaks into the cell when the channel is in its resting conformation. This hypothesis was supported by electrophysiological data from Xenopus oocytes, which showed a significant voltage-dependent leak current at negative potentials when they expressed the R853Q mutant channels. This was absent in oocytes expressing WT channels. Overall, these results suggest that individual mutations in the SCN2A gene generate epilepsy via distinct biophysical effects that may require novel and/or tailored pharmacotherapies for effective management.
The Everyday Lives of Adolescent Girls with Epilepsy: A Qualitative Description
(2009-11-04T18:21:53Z) MacLeod, Jessica S.; Swenson, Melinda M.; Foote, Carrie; Austin, Joan Kessner; Sims, Sharon L.
This study is a qualitative description of the everyday lives of adolescent girls with epilepsy. The primary purpose of the research was to determine whether or not elements of stigma were present in narratives about participants’ day-to-day living. The researcher used open-ended and semi-structured interview techniques in a series of interviews with four adolescent girls with epilepsy. Elements of stigma were present in some of the constructed themes; however, the researcher also uncovered other unexpected themes. Themes constructed by the researcher included: 1) I Am Like Everyone Else (Except for my Seizures); 2) There are Worse Things than Epilepsy; 3) My Parents Trust Me; 4) Am I Having a Seizure?; 5) Bullying Because of Seizures; 6) Bullying Because of Something other than Seizures; 7) Coping with Bullying; 8) Academic Difficulties;9) Disclosure Management; 10) Seizures are Scary to Have and to See; and 11)If I have a Seizure, Don’t Attract Attention to Me! The researcher considers topics thought to be important to adolescents with epilepsy about which the participants kept silent. The researcher makes suggestions about how the research can be used to improve health care practice and guide educational policies for adolescent students with epilepsy. Based on the findings, the researcher suggests areas for future research in nursing and educational policy.
Familial Liability to Epilepsy and Attention-Deficit/Hyperactivity Disorder: A Nationwide Cohort Study
(Elsevier, 2017) Brikell, Isabell; Ghirardi, Laura; D'Onofrio, Brian M.; Dunn, David W.; Almqvist, Catarina; Dalsgaard, Søren; Kuja-Halkola, Ralf; Larsson, Henrik; Department of Psychiatry, School of Medicine
Background Epilepsy and attention-deficit/hyperactivity disorder (ADHD) are strongly associated; however, the underlying factors contributing to their co-occurrence remain unclear. A shared genetic liability has been proposed as one possible mechanism. Therefore, our goal in this study was to investigate the familial coaggregation of epilepsy and ADHD and to estimate the contribution of genetic and environmental risk factors to their co-occurrence. Methods We identified 1,899,654 individuals born between 1987 and 2006 via national Swedish registers and linked each individual to his or her biological relatives. We used logistic regression to estimate the association between epilepsy and ADHD within individual and across relatives. Quantitative genetic modeling was used to decompose the cross-disorder covariance into genetic and environmental factors. Results Individuals with epilepsy had a statistically significant increased risk of ADHD (odds ratio [OR] = 3.47, 95% confidence interval [CI] = 3.33–3.62). This risk increase extended to children whose mothers had epilepsy (OR = 1.85, 95% CI = 1.75–1.96), children whose fathers had epilepsy (OR = 1.64, 95% CI = 1.54–1.74), full siblings (OR = 1.56, 95% CI = 1.46–1.67), maternal half siblings (OR = 1.28, 95% CI = 1.14–1.43), paternal half siblings (OR = 1.10, 95% CI = 0.96–1.25), and cousins (OR = 1.15, 95% CI = 1.10–1.20). The genetic correlation was 0.21 (95% CI = 0.02–0.40) and explained 40% of the phenotypic correlation between epilepsy and ADHD, with the remaining variance largely explained by nonshared environmental factors (49%, nonshared environmental correlation = 0.36, 95% CI = 0.23–0.49). The contribution of shared environmental factors to the cross-disorder overlap was not statistically significant (11%, shared environmental correlation = 0.32, 95% CI = −0.16–0.79). Conclusions This study demonstrates a strong and etiologically complex association between epilepsy and ADHD, with shared familial factors and risk factors unique to the individual contributing to co-occurrence of the disorders. Our findings suggest that epilepsy and ADHD may share less genetic risk as compared with other neurodevelopmental disorders.
Goal Development in Parents of Children with Epilepsy and Learning Disorders
(Office of the Vice Chancellor for Research, 2014-04-11) Keener, Lindsey; Miller, Wendy; Buelow, Janice M.
Epilepsy is the most common, chronic neurological condition in children, impacting 2.4 children per 1,000. Caregivers of children with epilepsy and learning disorders are affected by many confounding factors including complex drug regimens, navigating a complex healthcare system, the uncertainty of their child’s future and the challenge of creating an effective educational program in conjunction with their child’s school. Parents of children with epilepsy and learning disorders participated in the Creating Avenues for Parent Partnerships (CAPP) program. The original study was an experimental design in which parents were randomly placed in an intervention group or a wait list control group. Each group consisted of 25 parents, with a total of 50 parents participating in the pilot test of CAPP. One of the instruments that the parents completed throughout the duration of this interventional program was the Goal Attainment Scale (GAS). In the GAS, parents described their goals related to their child’s condition and care. Using a qualitative and systematic coding system the parent’s goals were categorized based on content and outcomes related to their child. The goals created by parents in this population subset fell into eight distinct categories. The categories discerned during analysis were future oriented, internal/perspective adjustment, interpersonal, maintaining normalcy, education/coordination with schools, interaction with health care professionals, physical fitness, and acknowledgement/fostering independence.. Based on analysis of the goals that parents created within the GAS, parents of children with epilepsy are particularly concerned with the security of their child’s future (both residentially and vocationally), educational advancement in partnership with schools, and improving health status through interaction with health care professionals. For the nurse interacting with patients and their caregiver in this specialized population it is critical to understand the goals that caregivers create in relation to the problems that they perceive as the most significant in their lives. Then the nurse will be able to enable caregivers to meet their goals and improve the health outcomes and overall quality of life in children with epilepsy and learning disorders.

Browsing by Subject "epilepsy"

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