This thesis describes the process of synthesizing 5-substituted-mercapto derivatives of hydantoin in which the sulfur of the side chain is attached directly to the hydantoin nucleus.

The purpose of the study was to investigate whether interictal stereotactic EEG data recorded during surgical implantation of depth electrodes can be used to predict the seizure focus in patients with epilepsy. We retrospectively studied 21 patients who underwent invasive stereotactic EEG monitoring and surgical treatment at Boston Children’s Hospital. Interictal data were analyzed using the method of Granger Causality (GC) statistics to calculate causal interactions between brain regions. In 10 cases, intraoperative GC analysis accurately identified the seizure focus, as supported by their statistically significant rank order sum P values. The remaining 11 cases failed to achieve statistical significance for intraoperative GC analysis. When we examined the visual representations of the causality network described by GC, we observed that despite insignificant rank order P values, GC analysis could still be valuable in revealing the seizure network. It is apparent that there needs to be additional, more in-depth investigations regarding the value of using intraoperative interictal EEG data for defining the seizure focus. Future studies should focus on identifying clinical factors that may affect the utility of intraoperative GC analysis and also on experimenting how GC analysis could aid in decision-making during electrode implantation. / 2022-06-05T00:00:00Z

Epilepsy is one of the most common neurological conditions affecting children and adolescence. Youth with epilepsy (YWE) are at greater risk for emotional, behavioral, and academic concern when compared with both healthy controls and youth with other chronic medical conditions. In addition, rates of nonadherence to antiepileptic medications are quite high, leading to less than optimal seizure control and negative impact on quality of life. Despite well documented need for behavioral health intervention, epilepsy has been underserved by pediatric psychologists in both clinical and research endeavors. This commentary posits that pediatric psychologists are uniquely qualified to join epilepsy treatment teams and contribute to scholarly activities related to YWE. Current research and clinical activities of pediatric psychologists within the epilepsy population are explored. We conclude with a call for increased training opportunities within the epilepsy population so that pediatric psychologists can impact the management of behavioral health needs with in this population.

Carbamazepine is a drug which is now widely used for the treatment of both generalised epilepsy (tonic-clonic seizures) and partial epilepsy (with simple or complex symptomatology). This study was undertaken in an attempt to assess the role of the metabolites of carbamazepine, viz. 10, 11-epoxy-carbamazepine and 10, 11-dihydro-10,11-dihydroxy-carbamazepine, with regard to their therapeutic efficacy and the occurrence of side effects of the parent drug. It was also designed to seek a possible explanation as to why certain patients with optimal levels of carbamazepine in plasma fail to respond to therapy. A total of 23 epileptic patients (11 females and 12 males) suffering from either generalised (tonic-clonic) seizures or partial complex seizures took part in the study. The patients were divided into two groups according to their seizure frequency: Responders - those patients who had no seizures in the month prior to entry into the study (12 patients). Non-Responders - those patients who had a minimum of one seizure a week in the month prior to entry into the study (11 patients). Carbamazepine and its metabolites were monitored between 8 a.m. and 6 p.m. by taking blood samples at two hourly intervals. Cerebrospinal fluid (CSF) was also obtained from seven patients in the non-responder group. The drug and its metabolites were assayed simultaneously by the thin-layer chromatographic (TLC) method of Hundt and Clark (1975). Six of the 23 epileptic patients complained of side effects: nausea and headaches were the most frequently mentioned complaint. Statistical analysis showed, however, that there was no significant difference in the peak levels of carbamazepine and metabolites in patients both with or without side effects. Therefore, it was not possible to define a threshold level of the drug above which side effects were likely to occur. Also, no definite conclusion could be reached as to whether the metabolites play a role in the manifestation of side effects. The area under the curve (AUC) is a measure of the overall plasma concentration of carbamazepine and metabolites (present between 8 a.m. and 6 p.m.) in the individual patients of the two groups. There was no significant difference in the AUC of carbamazepine between responders and non-responders. However, the AUC of the dihydroxy and epoxy metabolites was significantly higher in the non-responders (P<-0.002 and P < 0.02 respectively). Moreover, in the CSF samples of the non-responders, the mean (±SD) ratio of the dihydroxy metabolite to the parent drug was as high as 1.17 (±0,36). The results show a clear association between high levels of metabolites and poor response to carbamazepine therapy. Furthermore, it would seem that either both metabolites are inactive or that if the epoxy metabolite is active as in the rat (Frigerio and Morselli 1975), any likely therapeutic effect is counter-acted by the relatively large concentration of inactive dihydroxy metabolite (Schmutz et al 1979). Moreover, it may follow that non-response to carbamazepine - despite optimal levels of the drug in plasma - may be due to competition by inactive dihydroxy metabolite for the site (s) of action of the parent drug in the brain. Research strategies which might be used to test this hypothesis have been proposed.

A dissertation submitted to the Faculty of Arts or partial fulfilment of the requirements for the degree of Master of Psychology at the University of Zululand, 2003 / There has been an increasing recognition on the part of physicians and others involved in the welfare of individuals with epilepsy, that seizers may be less disabling than their psychosocial correlates. There exists a lay propensity to discriminate against people with epilepsy, which, in turn, is the paramount source of the psychological and social burden that individuals with epilepsy have to endure. The objective of this study is to ascetain the psychosocial perceptions of epiletics towards their affliction. In essence, it is a study on the impact of epilepsy as astigmatizing condition. The present investigation study on the impact of epilepsy as astigmatizing condition. The present investigation consists of four objectives.

Epilepsy is a neurological disorder that presents a significant public health burden, with an estimated five million people being newly diagnosed each year. However, current therapeutics designed to modify neuronal processes, provide no relief to 1-in-3 epileptic patients. Additionally, no disease modifying therapies currently exist to treat the underlying pathological processes involved in epileptogenesis. The overarching goal of this project is to further characterize the role astrocytes play in epileptogenesis, in hopes of revealing novel therapeutic targets to benefit patients who otherwise have no effective treatment options. System xc- (SXC), a cystine/glutamate antiporter expressed in astrocytes, is one such target that has been shown to play a critical role in establishing ambient extracellular glutamate levels in both health and disease. SXC has been shown to play a major role in setting ambient glutamatergic tone in the central nervous system (CNS) as pharmacological inhibition of SXC, using (S)-4-carboxyphenylglycine (S-4-CPG) or antisense xCT, resulted in a 60% reduction in extrasynaptic glutamate in the nucleus accumbens. Additionally, investigations in tumor-associated epilepsy revealed that overexpression of SXC seen in glioblastomas lead to higher levels of peritumoral glutamate, neuronal excitotoxicity, and ultimately seizures. These studies also found that SXC inhibition with sulfasalazine (SAS), an FDA approved drug and potent inhibitor of SXC, can ameliorate seizure burden in a glioblastoma mouse model. Therefore, the principal objective of this study is to further investigate the role of astrocytic SXC activity in epileptogenesis and seizure generation. In doing so, we also evaluated the efficacy of SAS in reducing seizure burden in vivo using an astrogliosis-mediated epilepsy mouse model. In this dissertation we show that (1) SXC inhibition, using SAS, is able to decrease induced epileptiform activity in multiple models of chemically induced hyperexcitability (2) this is due to a preferential decrease of NMDAR-mediated currents and (3) SXC inhibition, via SAS, decreases seizure burden in vivo in an astrogliosis-mediated epilepsy model. / Doctor of Philosophy / Epilepsy, characterized by unpredictable seizures, affects approximately 2.2 million Americans, with 150,000 new cases being diagnosed each year. Seizures typically occur when there is an imbalance between the excitatory and inhibitory processes in the brain. Because neurons are the primary cell in the brain that carry out these processes, clinically used anti-epileptic drugs (AEDs) work by either decreasing neuronal excitation or increasing neuronal inhibition. Despite success with managing seizures, up to 1-in-3 patients with epilepsy do not find any relief with existing AEDs. A statistic that has not changed in over 50 years of drug development. With this in mind, the overarching goal of this dissertation is to explore the efficacy of targeting non-neuronal processes to treat epilepsy and broaden the search for new AED targets by further characterizing a unique mouse model of epilepsy. One such target studied in our lab is system xc- (SXC), a glutamate/cystine antiporter present on astrocytes, a non-neuronal cell that provides maintenance, support and protection for neurons. Investigations in tumor-associated epilepsy from our lab revealed that hyperactivity of SXC in tumor cells was directly related to the development of tumor-associated epilepsy. These studies also revealed that SXC inhibition using sulfasalazine (SAS), an FDA approved drug, can decrease seizure burden in a tumor mouse model. Therefore, the principal objective of this study is to further investigate the role of astrocytic SXC activity in the development of epilepsy and seizure generation. In this dissertation we show that SXC inhibition, using SAS, is able to decrease neuronal hyperactivity and decreases seizure burden in an astrogliosis-mediated epilepsy model.

The purpose of this study was to investigate the neuropsychological outcomes of pediatric subjects undergoing temporal lobe surgery, and then compare the outcomes between subjects in the iMRI and the standard operating suites. This study involved 77 children ages one to 21 years (M = 11.98) at time of surgery for intractable epilepsy. Forty-seven returned for repeat neuropsychological assessment. At baseline, subjects with early onset of epilepsy (≤ 7 years) scored worse on a measure of attention (p = .02), FSIQ (p < .01), perceptual reasoning (p < .01), and processing speed (p = .06). At one-year follow-up, interactions were observed for the response style domain of the attention measure (p = .03), FSIQ (p = .06) and working memory (p = .08). Follow-up at one year, for the group as a whole, revealed decline in verbal memory (p = .04) and reading comprehension (p = .02); and improvement for word reading (p = .05). No significant differences were observed between the iMRI and standard operating suite. Though, hemisphere, duration of epilepsy, preoperative seizure frequency, lesional disease, seizure type, presence of epileptogenic focus, and number of lobes involved accounted for variance in neuropsychological outcomes. These results provide further support for that certain preoperative individual, disease, and therapeutic variables are predictive of neurocognitive outcome following surgery for temporal lobe epilepsy. Additionally, the results demonstrated that surgery may also impact attention.

Indiana University-Purdue University Indianapolis (IUPUI) / Approximately 30% of patients with epilepsy do not achieve adequate seizure control through current anti-seizure drugs (ASD) and treatment methods. Therefore, a critical need exists to efficiently screen ASDs to enhance our ability to tailor treatment protocols and improve patient outcomes. The zebrafish pentylenetetrazol (PTZ) seizure model has become an increasingly popular screening paradigm for novel ASDs. Here, we present an optimized PTZ assay to improve reliability and reproducibility based on work in our laboratory. This optimized assay improves robustness in our screening of anti-seizure drugs (topiramate, lamotrigine, carbamazepine and GS967). These findings show that electroencephalogram (EEG) and calcium sensitive GFP from fusion protein (GCaMP) assays largely correlate with the behavioral findings, helping us connect physiological and behavioral responses to ASDs. Genetic epilepsy syndromes, like voltage gated sodium channel SCN2A and SCN8A pathogenic variants, are often poorly controlled by current medications. Our optimized assay relied on a fast and precise zebrafish seizure model using mRNA overexpression of hSCN2A and hSCN8A variants including: hSCN2A R1882Q and R853Q and hSCN8A R1872Q. All three pathogenic variants increased seizure activity, and the ASDs significantly decreased this seizure activity. This mRNA overexpression assay can be used to quickly evaluate seizure activity induced by pathogenic variants in voltage gated sodium channel genes and test ASDs to determine efficacy. In a separate study, we tested if the addition of the human SCN2A sodium channel could potentially rescue the loss of the zebrafish scn1Lab gene. Our GCaMP assay data indicates that this loss was successfully rescued. Cumulatively, these findings can be used to improve the screening of novel ASDs and treatments for patients with refractory epilepsy.

Epilepsy is one of the most common neurological disorders in the world, involving recurrent and spontaneous seizures which can have devastating effects on individual health and quality of life, as well as on the economic health of nations. While currently available anti-seizure drugs can control the symptoms of epilepsy, these drugs do not work in one-third of patients. Drug-resistant epilepsy is a serious concern. Even in patients responding to anti-seizure drugs, these treatments are not curative – they must be taken chronically and have limited to no ability to reverse or prevent the course of epilepsy development, called epileptogenesis. Epileptogenesis is a dynamic process involving underlying changes in the development of epilepsy, including changes in network excitability and organization, cellular plasticity, and inflammation. As epilepsy research has refocused on finding anti-epileptogenic agents to meet the unmet need of patients with drug-resistant epilepsy, dysregulated metabolism has come to light as a new area of research – along with a revisiting of previously tried metabolic treatments for epilepsy such as the ketogenic diet.

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