The human neocortex is a highly sophisticated and organized brain structure that is thought to mediate some of the most complex cognitive functions in humans including language and abstract thought. As such, environmental and genetic insults to its normal structure or function can result in devastating neurological conditions including severe epilepsy and intellectual disability. Malformations of cortical development are an increasing collection of disorders that cause neocortical abnormalities due to impaired developmental processes. One recently identified disorder in this class is a thin lissencephaly variant (TLIS) associated with several mutations in the C-terminus death domain of the caspase-2 activation adaptor CRADD (also known as RAIDD). Beyond this, little is known about the mechanism underlying TLIS pathophysiology despite an increasing number of identified individuals suffering from it. In order to better understand this disorder, as well as the normal developmental mechanisms that are impaired in its pathogenesis, I have developed and characterized three murine models by introducing one of a number of different genetic perturbations associated with TLIS. These animal models show behavioral and biochemical abnormalities similar to those seen in human TLIS subjects. Focusing future studies on the developmental processes that underlie differences seen in these mouse models could greatly inform understanding of disease mechanism in humans and assist in the development in therapeutic interventions. My work presented in this dissertation thus effectively establishes a translationally relevant animal model of TLIS.

BACKGROUND: Epilepsy monitoring units (EMUs) provide a safe environment for forming a more illustrative understanding of the patient’s seizure disorder. Patients are admitted to EMUs usually for several days at a time. Upon admission, electroencephalogram (EEG) electrodes are placed and patients are continuously watched via EEG, video, and audio means. By weaning patients off anti-epileptic medications and monitoring brain activity with EEGs, the data will typically allow for a stronger appreciation of the seizure activity. Therefore, it will provide information to develop a more targeted clinical approach for the patient. OBJECTIVE: The purpose of the study is to gain a better understanding of patients’ expectations and experiences with being monitored for seizure activity in an EMU, especially during the Coronavirus Disease 2019 (COVID-19) pandemic METHODS: Patients were interviewed with regards to their inpatient EMU admission for continuous EEG monitoring at Beth Israel Deaconess Medical Center (BIDMC). Phone interviews were conducted both before and after the EMU admission for each patient, using a structured questionnaire that focused on topics such as proclaimed knowledge of personal seizure disorder, quality of life, EMU experience, and hospital admission during the COVID-19 pandemic. Patient responses were documented and analyzed in an exploratory manner to identify relevant themes. The study was conducted according to a protocol approved by the BIDMC Committee on Clinical Investigations. RESULTS: From September 2020 through December 2020, 15 patients were enrolled and interviewed (11 female; age range 26-68 years [median 48]; length of stay range 2-12 days [median 5]). The majority of the population was admitted for event capture or seizure characterization (13/15) and had a history of seizure activity (14/15). The majority of patients had a history of focal seizures (12). Only 4/15 patients had a family history of seizures. Overall, patients felt extremely comfortable speaking with providers. A third (4/12) did not have any notable negative experiences. There were no overarching patterns to the negative experiences that were reported; most responses were specific to the individual. The vast majority (83.3%) applauded providers and staff involved in their EMU admission. CONCLUSIONS: Despite the COVID-19 pandemic, epilepsy patients had mostly positive experiences with their EMU hospitalization at BIDMC. Continuous EEG monitoring remains an important aspect of clinical epilepsy evaluation for some patients, and was a feasible and well-tolerated procedure even during pandemic-altered circumstances.

Thesis ((M. Pharm. (Pharmaceutics)) -- University of Limpopo, 2019 / Epilepsy is the fourth most common neurological disorder after migraine, stroke and Alzheimer’s disease and it affects about fifty million people worldwide. Careful consideration should be taken when deciding to initiate treatment in epilepsy as it should consider the balance between the possibility of further seizures and their associated risks, including the possible risk of sudden expected death, inconvenience and the risks of taking regular medication for each individual. In the early 1980’s, the first-line treatment for epilepsy was polytherapy. This was due to findings that smaller doses of two drugs rather than larger doses of one drug can achieve synergistic effects or less drug toxicity. However, following more trials on the treatment of epilepsy, this was later changed to monotherapy as first-line treatment. Despite the change, patients remain uncontrolled on a single anti-epileptic drug, thus they are initiated on polytherapy, one such combination being carbamazepine in combination with sodium valproate. The use of these in combination has pharmacological threats such as compliance, the control of side effects and the achievement of synergistic effects. The development of a Fixed Dose Combination (FDC) has often been used to resolve pharmacological threats, and this study aims to develop a fixed dose combination tablet of carbamazepine and sodium valproate to resolve the pharmacological threats in epilepsy. Samples of carbamazepine and sodium valproate and a physical mixture (1:1 w/w) of both drugs and excipients were prepared for compatibility with thermal analysis and spectroscopy techniques. Data was analysed by comparing the DSC curves, FTIR spectra, XRPD peaks and TAM analysis of carbamazepine and sodium valproate alone and in their physical mixture (1:1 w/w) and with excipients. Both carbamazepine and sodium valproate were evaluated for flowability using angle of repose, tapped and bulk density, compressibility index and particle size distribution. To formulate the proposed FDC tablet of carbamazepine and sodium valproate, direct compression and wet granulation methods were employed. The tablets were then evaluated for official and non-official post formulation parameters (weight variation, crushing strength, friability, diameter and thickness, and disintegration) according to BP and USP standards. A standardised HPLC method was developed and validated for analytical procedures. Dissolution studies were conducted xiii according to USP methods to verify and quantify the release of the APIs from the FDC tablet. Carbamazepine and sodium valproate were tested for compatibility with excipients using DSC, FTIR, XRPD and TAM analysis. The overall results confirmed that carbamazepine and sodium valproate are compatible, with each other and the excipients used in the study. Powder flow of carbamazepine and sodium valproate was poor, hence they were subjected to granulation prior to compression to improve flowability. The specifications of the fixed-dose combination were developed in accordance with the FDA’s quality by design concept and WHO recommendations. The tablets were subjected to non-official and official pharmacopoeial tests, and passed all the tests. Dissolution studies according to a USP method were conducted to verify and quantify the release of the APIs in the fixed-dose combination. The initial dissolution rate (DRi) of carbamazepine and sodium valproate in the SLS dissolution medium was rapid as required for an immediate release formulation. The study aimed at developing a fixed dose combination of carbamazepine and sodium valproate to try to reduce the burden of taking more than one tablet for epilepsy. Based on the results obtained from preformulation studies to assay of the final product, the study was successful. / Chieta bursary and HWseta

Indiana University-Purdue University Indianapolis (IUPUI) / Epilepsy is the most common chronic neurological condition in the United States, and it is incurable. Those who suffer from it must engage in both collaborative and independent management of their condition for the remainder of their lives. The treatment and care of those with epilepsy must therefore include not only medical interventions, which alone cannot cure the disorder or prevent the disability associated with it, but must also prepare persons for and facilitate their independent management—self-management—of the disorder. Self-management is a process that affects important outcomes including resource utilization, mortality, and quality of life. In the United States, those age 60 years and older have the highest incidence of new-onset epilepsy. Despite the high incidence of epilepsy in this population, coupled with the knowledge that self-management affects important outcomes, a thorough search of the literature suggests that self-management experiences of older adults diagnosed with epilepsy late in life have not been investigated. The purpose of the study was to examine, using a qualitative descriptive design, the self-management experiences of older adults diagnosed with epilepsy at or after age 60. Semi-structured interviews were used to generate data. A total of 20 older adults participated. Major findings indicate that older adults in the sample, and particularly the women, experienced a delay in receiving an epilepsy diagnosis. These older adults experienced multiple problems and life changes since diagnosis—some of which are unique to this population and many of which are amenable to intervention. These older adults devise and execute a variety of management strategies, within a system, that are classified as disease/treatment-focused and problem/life changes-focused. These strategies further are categorized as proactive or reactive, with proactive strategies being pre-planned and effective, and reactive strategies being unplanned and less effective. Knowledge generated from this study reveals the problems experienced by older adults with epilepsy, as well as their management needs. These findings will inform future studies, the aim of which will be to investigate more thoroughly these problems and needs and, ultimately, to inform interventions aimed at resolving this population’s problems and concerns while also improving outcomes.

Indiana University-Purdue University Indianapolis (IUPUI) / Voltage-‐gated sodium channels (VGSCs) are critical for the initiation and propagation of electrical signals in neurons; consequently they are significant regulators of neuronal excitability. They are exquisitely tuned and aberrations in their activity can lead to pathophysiological conditions. This dissertation highlights the roles of two prominent brain isoforms of VGSCs, Nav1.1 and Nav1.6. These isoforms have distinct localization in the brain. Specifically, Nav1.1 is predominantly expressed in the soma and proximal axon initial segment (AIS) of GABAergic neurons, while Nav1.6 is found at the distal AIS and nodes of Ranvier of both GABAergic and excitatory neurons. Several mutations have been identified in Nav1.1 and recently mutations in Nav1.6 have been discovered in patients with distinct epileptic phenotypes that respond poorly to current anti-epileptics. There is a need to better understand mechanistically how mutations in these channel isoforms lead to epilepsy in order to identify more efficacious treatment strategies. Therefore, the aims of this dissertation were to 1) examine the differential biophysical properties of Nav1.1 and Nav1.6, 2) determine the biophysical consequences of epilepsy-­associated mutations in Nav1.1 and Nav1.6 and examine the effects of cannabinoids on wildtype and mutant channel activity and 3) test the effects of selective inhibition of Nav1.1 versus Nav1.6 on epileptiform activity. To address these aims, whole­‐cell electrophysiology and mutlielectrode array recordings were used. The results demonstrate that 1) Nav1.1 and Nav1.6 have important differences in their biophysical properties that may be important in the fine­‐tuning of neuronal excitability, 2) epilepsy-­‐associated mutations in Nav1.1 and Nav1.6 alter several biophysical properties of the channels but have differential effects on resurgent current generation suggesting a divergence in the mechanism by which they induce epileptogenesis and cannabidiol can inhibit aberrant channel activity and reduce neuronal excitability and 3) pharmacological inhibition of Nav1.6, but not Nav1.1, abolishes epileptiform activity. Overall, this dissertation provides insight into the distinct contributions of Nav1.1 and Nav1.6 to physiological and pathophysiological firing activity and their ability to be targeted for therapeutic purposes. This knowledge is critical for understanding the potential role of VGSCs in epilepsy syndromes and identifying possible drug targets for more efficacious treatment strategies.

No description available.

Indiana University-Purdue University Indianapolis (IUPUI) / At the turn of the twentieth century, the movement to improve care of those afflicted with epilepsy reached Indiana. In 1905, the Indiana legislature passed an act creating the Indiana Village for Epileptics, thus beginning the segregation of epileptics from the rest of the state's population. Placing epileptics in colonies was considered a progressive solution to a centuries old medical ailment. This thesis will examine the Indiana Village for Epileptics from its inception until the retirement of the first superintendent, Dr. Walter C. Van Nuys. Van Nuys' tenure was so long-he stepped down in 1952-that the Village had become an outdated and unnecessary institution because of advances in medical treatments for the disease. The age of segregation had ended and epileptics were no longer seen as a menace to society.

Indiana University-Purdue University Indianapolis (IUPUI) / 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.

Purpose While epilepsy surgery has been shown to reduce seizure frequency and severity and even cures seizures in children with drug-resistant epilepsy, data from middle-income countries (MIC) are lacking. Method This study is a retrospective review of children with drug-resistant epilepsy who underwent surgical treatment at Red Cross War Memorial Children's Hospital (RCWMCH) between 1 January 2000 and 31 December 2021 (HREC: 140/2020). Results During the 21-year study period, 60 patients underwent epilepsy surgery for drugresistant epilepsy. The median age of the children was seven years (IQR 4.81-10.27years) at the time of surgery, with a male predominance of 33 patients. The most common surgical procedure performed was an anterior temporal lobectomy for temporal lobe epilepsy in 19 cases (31.7%), followed by peri-insular hemispherotomy in 9 cases (15.0%) and frontal lobectomy in 8 cases (13.3%). Of the 60 patients, complete records were available for 55 patients noting complications in 11 (20.0%), of which 4 cases (7.3%) had major complications. Notably, 2 patients (3.6%) had new-onset psychiatric symptoms. The long term outcomes after surgery showed 1-year seizure freedom in 32 patients (58.2%); among these, 21 patients (38.2%) could stop ASM one year after surgery, 17 patients (30.9%) had a recurrence of their seizures, and three had to restart ASM after 2-3 years. Eight patients (14.5%) required repeat surgery. The one-year-Modified Engel scoring for the study population was: 1-A in 52.7%, I-B in 3.6%, I-C in 1.8%, II-A in 15.8%, III-A in 10.9%, IV-A in 3.6% and IV-B in 10.9%. The most common histological finding in anterior temporal lobectomy (ATL) was focal cortical dysplasia (FCD), found in 11 patients (57.9%). The periinsular hemispherotomy (PIH) cases had equal numbers of FCD and Rasmussen's encephalitis in 4 patients (44.4%). The number of FCD in this series is much higher than in international data. Conclusion Epilepsy surgery is an effective and attainable intervention for drug-resistant epilepsy in the paediatric population despite limited resources and challenging aetiological profiles. Low complication rates were comparable to international data, with good seizure freedom outcomes.

No description available.