Medicine (RMH) - Theses
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ItemTranslational investigations of the intersection between Alzheimer’s disease and epilepsy: mechanistic insights and treatment opportunities( 2019)Alzheimer’s disease (AD) is a neurodegenerative disease characterized by progressive cognitive deficits compromising patients’ execution of daily activities. The incidence of unprovoked seizures has been reported to be higher in AD compared to healthy age matched population and is considered a risk factor for the development of acquired epilepsy. Abnormal electrical activity has also been correlated with increased cognitive decline in these patients and may be associated with a faster progression of AD symptoms. Thus, understanding how seizures develop in AD and how to treat them would be of extreme relevance for developing more effective therapies. The work presented in this thesis used a bidirectional approach to investigate the relationship between epilepsy and AD and potential treatment options. First, three antiepileptic drugs were assessed in their ability to delay the development of acquired epileptogenesis in the Tg2576 mice. These widely studied AD mice overexpress the human form of the amyloid precursor protein (APP) with a mutation that results in increased deposition of amyloid plaques with age. The amygdala kindling model was used to induce epileptogenesis and previous studies have shown that these mice have increased susceptibility to kindling induced seizures. The antiepileptic drugs brivaracetam (BRV), levetiracetam (LEV) and lacosamide (LAC) were administered via subcutaneously implanted osmotic pumps. BRV and LEV act through ligand binding to the SV2A synaptic vesicle protein and LAC through Na+ channels. After 28 days of continuous treatment with either one of the drugs or vehicle (VEH) animals were submitted to daily electrical stimulations, also under treatment, and the only drug able to slow down the epileptogenic process was BRV. Therefore, in the second study, the effect of BRV was further investigated. Mice were then pre-treated for 28 days, but pumps were removed, and drug allowed to wash-out for one week before kindling. BRV demonstrated a long-lasting effect and treated Tg2576 mice required significantly more stimulations to experience the first class 5 seizure. Investigations of the potential mechanisms underlying this effect revealed that BRV is not acting through changes in the expression levels of APP protein or SV2 mRNA. Lastly, with an approach in the opposite direction, a histopathological evaluation of resected tissue from patients with temporal lobe epilepsy (TLE) aimed at correlating the cognitive deficits often found in these patients with the presence of AD lesion hallmarks (tau and amyloid pathology). However, no significant tau deposition was found and although amyloid plaques were present in a higher proportion of patients compared to other similar studies, there was no strong evidence to suggest it is the mechanism responsible for cognitive impairments. In conclusion, network treatment strategies, such as antiepileptic drugs, could be useful in the treatment of seizures in AD, and in this study a potential antiepileptogenic effect was demonstrated for BRV in an AD-acquired epilepsy model. We have also shown that amyloid and tau pathology may not be the main underlying cause of cognitive deficits in TLE, but understanding these mechanisms might also advance our understanding of cognitive decline in AD.
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ItemAntiepileptic drug teratogenicity: a human and laboratory translational study( 2018)Antiepileptic drug (AED) associated teratogenicity has been well documented in the literature. The risk of physical birth defects during the first trimester of pregnancy is increased threefold for most AEDs and over ten-fold for the most teratogenic AED, valproate. Despite this risk, women require long term treatment to stop or reduce the occurrence of seizures and the consequent harm to both mother and foetus, including the possibility of sudden unexpected death in epilepsy. The mechanism resulting in this teratogenicity, and in particular why some women are more susceptible to have children with AED induced birth defects is incompletely elucidated. In recent years there has been emerging evidence that AEDs may be interacting with genomic factors to result in birth defects. These genomic factors may be susceptibility alleles in the mother or father, de novo mutations in the child or epigenetic factors such as alterations in DNA methylation in the mother or child. The studies reported in this thesis aim to a) develop an animal model of valproate induced defects that closely mimics a human clinical setting and can be used to better understand the pathogenesis of AED induced defects, and b) identify genomic markers of AED induced defects using whole genome analysis of human samples and determining if having epilepsy is a contributing factor to the onset of these defects. For aim a) the development of the animal model entailed using an epileptic strain of rats, Genetic Absence Epilepsy Rats from Strasbourg, determining a dose at which dietary valproate is therapeutic, mating the rats and conducting a morphological assessment of both internal and external defects. For aim b) human samples were collected and subjected to whole genome analysis, including whole exome sequencing and DNA methylation scans. Additionally, birth defect rates for non-epileptic women in the Australian Pregnancy Register were also separately quantified. The human samples for investigations were collected from participants and their families enrolled in the Register. Using both human and animal models this study aimed to generate new knowledge, which could ultimately lead to a pharmacogenomic approach to the selection of AEDs for women who wish to become pregnant. This would allow women to make more informed decisions, reduce the risk of having a baby with a birth defect and potentially assist in the formation of new AEDs with lower teratogenic risk.
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ItemThe association of antiepileptic drugs (AEDs) with bone disease, balance function, falls and fractures: studies of the risk( 2012)Aims: Patients with epilepsy taking long-term anti-epileptic drug (AED) therapy have been reported to have an elevated risk of fractures, falls, balance impairment and bone disease. In the work for this thesis, four studies were undertaken which were designed to investigate the associations of AED therapy with the prevalence of falls and fractures in patients taking AEDs compared to non-AED users; to assess the level of patient awareness regarding AED-related bone health, falls and fracture risk; to examine potential associations of AED therapy, both recent and long-term, on bone measures; and to evaluate any association of chronic therapy on balance function. Included in the evaluation were risk factors including age, AED polytherapy, therapy length, gender and types of AED (enzyme-inducing vs. non-enzyme inducing). Methods: Data on falls, fracture history and associated risks were collected in 150 epilepsy outpatients taking AEDs and 506 controls, and analysed cross-sectionally by univariate and multivariate methods to assess the prevalence of falls and fractures, and associated factors. Baseline and follow-up bone assessments (separated by at least two years) were performed in two cohorts, including: i) 54 twin and sibling pairs discordant for chronic therapy, and ii) 57 newly-diagnosed epilepsy patients recently started on therapy and 54 controls, using dual energy X-ray absorptiometry, and peripheral quantitative computed tomography. Balance examinations were performed for 26 AED-discordant twin and sibling pairs, with re-assessment at least one year later. The annual rate of change of bone and balance measures were calculated. Cross-sectional and longitudinal data were analyzed by univariate and multivariate analyses. Results: Compared to controls, epilepsy outpatients had a higher risk of fractures at vertebrae (p = 0.037), clavicle (p = 0.019) and ankle sites (p = 0.048), and multiple fracture episodes (p = 0.008). Female users had more non-seizure falls (31% vs. 17%, p = 0.027) and multiple falls (18% vs. 5%, p = 0.028) compared to female non-users. Less than 30% of patients knew of the association of AED use with increased risk for fractures, reduced bone mineral density (BMD) or falls. Prolonged AED therapy (> 20 years) significantly predicted an increased rate of bone loss for forearm BMD (-0.53%/yr; p = 0.040) and whole-body BMD (-0.37%/yr; p = 0.043). AED therapy was a significant predictor of increased bone loss at whole-body BMC (-0.26%/year; p = 0.041). Use of enzyme-inducing AEDs was associated with increased bone loss at the total hip (-1.65%/yr; p = 0.013) and whole-body BMD (-1.41%/yr; p = 0.019). In the initial years of AED therapy carbamazepine monotherapy (an enzyme-inducer) was associated with increased bone loss at the total hip (p = 0.034) and inter-trochanteric regions (p = 0.035). Postural sway deterioration was greater in AED users than non-users, with anterior-posterior (A-P) tilting and a concurrent distraction task (p = 0.016), and medial-lateral tilting without distraction (p = 0.027). In females (but not in the small male subsample), sway deterioration was greater in users with the A-P tilting platform and a concurrent distraction task (p = 0.035). Lower limb muscle strength and gait did not deteriorate over time. Conclusions: AED users demonstrated a higher risk of fractures, particularly with prolonged therapy. Female users were at increased risk of falls than female non-users. Greater BMD loss was associated with prolonged therapy and enzyme-inducing AEDs. Carbamazepine use in early therapy predicted increased hip region bone loss. Postural stability deteriorated over time in AED users compared to non-users. Awareness amongst epilepsy patients of AED-related effects was low. Findings suggests an association between chronic therapy and progressive underlying pathophysiology, adversely affecting bone measures and balance, both risk factors for fractures. Patients may benefit from taking NEIAEDs, rather than EIAEDs, to reduce associated long-term risks of bone fragility. These risks need consideration when managing patients taking AEDs.