Austin Academic Centre - Theses
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ItemAcute severe ulcerative colitis: clinical and translational studies( 2019)Acute Severe Ulcerative Colitis (ASUC) is a life-threatening condition that affects 20% of people with ulcerative colitis at some point in their life. Intravenous corticosteroids are first line therapy; however, approximately one-third do not respond, prompting the need for medical salvage treatment such as infliximab. Despite this, 20-30% of patients require life changing surgery to remove the large bowel with stoma formation within three months of presentation. Infliximab has been used as medical salvage therapy for over 15 years; however, the ideal dosing strategy is unknown. This thesis aims to identify the optimal infliximab induction strategy in ASUC; to improve clinical response rates to infliximab and reduce colectomy rates, and; to explore clinical and experimental predictors and mechanisms of treatment response. A systematic review and meta-analysis was undertaken to examine the efficacies of different infliximab induction strategies. A retrospective study was performed to assess biomarkers of response to infliximab. This thesis is built upon a clinical study which aims to determine the optimal infliximab induction strategy in ASUC by comparing high dose strategies to standard dose induction, in order to improve clinical outcomes in ASUC. Nested within this clinical trial are exploratory studies assessing biomarkers of steroid response. This study is also aligned with research examining the immunological processes driving ASUC in order to identify new mechanisms of disease and biomarkers of treatment response. In summary, this thesis describes the implementation of the largest randomised controlled trial currently being undertaken globally to identify the optimal use of infliximab salvage therapy in ASUC. Comprehensive and longitudinal data collection will allow for the investigation of novel clinical, biochemical and immunological predictors of response to therapy.
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ItemAn integrated eHealth strategy to optimise outpatient disease and psychological management in inflammatory bowel disease( 2019)The increasing incidence of inflammatory bowel disease (IBD) over the past decade has resulted in increased health care resource utilisation and longer specialist outpatient waiting lists. IBD is associated with an increased prevalence of psychological morbidity and adversely affects quality of life, societal interaction and functioning. Electronic-health or ‘eHealth’ technologies incorporating self-management strategies to manage patients remotely such as telemedicine, web-based interventions, and smart-phone applications may offer a solution to streamline outpatient management, by detecting earlier changes in patient well-being (disease activity, medication status and psychological health) and providing greater access to personalised care in real-time. However, whether eHealth technologies offer any significant benefit over traditional outpatient based IBD care remains to be proven. This thesis encompasses a framework and the design of a decision support tool which aims to improve the outpatient management of IBD patients by proving that eHealth monitoring of patients with mild-to-moderate ulcerative colitis, stratified for disease activity and psychological distress and treated according to a fixed regime of eHealth directed self-management, is an effective model of care compared with IBD clinic-led outpatient management. A colloquium was initially held to obtain key stakeholders’ perspectives on the role of an eHealth tool to facilitate decision support for IBD. Retrospective studies were then undertaken to establish the extent to which gastroenterologists adhere to evidence based international guidelines in clinical practice. A cost analysis study was conducted to describe the current cost of care and to compare the costs associated with treating active disease compared to disease in remission. A cross-sectional study was then undertaken to establish the relationship between patient-reported outcomes and disease activity. Patient perspectives regarding the potential value of an eHealth intervention for outpatient IBD management were then explored. Finally, clinical algorithms were developed for disease activity, psychological wellbeing and preventive care and incorporated into a decision support tool which was assessed for feasibility, usability and acceptability compared to standard IBD care. In summary, this is the first prospective study to demonstrate that an eHealth tool to facilitate decision support significantly improves the delivery of quality care and promotes shared decision-making in patients with mild-to-moderate ulcerative colitis.
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ItemLennox-Gastaut syndrome: a secondary network epilepsy( 2018)Lennox-Gastaut syndrome (LGS) is a severe epilepsy that usually begins in childhood. Diverse aetiologies can cause LGS, including structural and genetic abnormalities. However, the electroclinical phenotype that emerges from these aetiologies is remarkably consistent across patients and includes tonic seizures and generalised interictal epileptiform discharges on scalp electroencephalography (EEG). Frequent epileptic activity is thought to contribute to cognitive impairment in LGS (‘epileptic encephalopathy’). The mechanisms by which diverse aetiologies lead to LGS, and by which epileptic activity causes impaired cognition, are poorly understood. This thesis aimed to determine the brain regions underlying epileptic activity in LGS, and to assess how LGS may alter functional organisation of brain networks that support cognition. Simultaneous EEG with functional magnetic resonance imaging (EEG-fMRI) was performed in 38 patients, including 11 children with recent-onset LGS and 27 older patients with longstanding LGS. To limit motion during scanning, younger patients were anaesthetised with low-dose isoflurane and remifentanil. Data from the older patients, who tolerated scanning without anaesthesia, were compared to resting-state fMRI in 29 age-matched healthy controls. The primary hypothesis was that LGS reflects abnormal expression of a shared network that is ‘secondary’ to the specific aetiology of LGS. Five studies were performed. Study 1 examined technical feasibility of anaesthetised fMRI in children with LGS. Resting-state networks previously described in non-anaesthetised subjects were observable in the anaesthetised patients with LGS, demonstrating that isoflurane-remifentanil anaesthesia can extend the utility of fMRI to young and intellectually disabled patients while retaining interpretability of fMRI. Study 2 explored brain areas underlying interictal epileptiform discharges in LGS using EEG-fMRI. In both anaesthetised and non-anaesthetised patient groups, discharges recruited widespread areas of frontal, parietal, and temporal cortex, as well as the thalamus and brainstem. Activation was similar across individual patients with structural, genetic, and unknown aetiologies of LGS. Further analysis using dynamic causal modelling suggested a cortically driven process underlying discharges. Study 3 explored network mechanisms of impaired cognition in LGS by comparing resting-state functional connectivity between patients and healthy controls, focusing on corticocortical interactions. Patients showed abnormal integration and segregation of major cognition-related networks, including the executive-control and default-mode networks. Altered connectivity persisted during periods without epileptic activity on patients’ in-scanner EEG, potentially contributing to pervasively impaired cognition in LGS. Study 4 tested thalamocortical circuits and found abnormally enhanced connectivity in LGS, maximally involving mediodorsal and ventrolateral nuclei. Finally, study 5 examined neural changes accompanying successful treatment of LGS by re-scanning one patient who experienced seizure remission following resection of a cortical lesion. After surgery, the patient showed reversal of abnormal network patterns seen in non-operated patients, with improved network integration and segregation. This thesis provides a new way of conceptualising LGS as a ‘secondary network epilepsy’, where the syndrome’s characteristic epileptological and cognitive features reflect abnormal expression of a shared brain network, rather than the specific initiating aetiology. The epileptic process in LGS is cortically driven, affects specific thalamic subregions, and may be reversible with early surgical intervention.