Paediatrics (RCH) - Theses
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ItemNo Preview AvailableBottom-of-sulcus dysplasia (BOSD): nidus or network?( 2023-12)Bottom-of-sulcus dysplasia (BOSD) is a subtype of focal cortical dysplasia (FCD) type II where imaging, genetic and histopathological abnormalities are maximal at the bottom of a single sulcus. BOSDs are highly epileptogenic but due to their small size and complex seizure manifestations, are challenging to diagnose, and treat. Patients with BOSD often experience diagnostic delays, are thought to be poor surgical candidates, or have larger than necessary resections. This hypothesis tested in this thesis was that the electroclinical and cognitive manifestations of BOSD relate to their connectivity (network) while epileptogenicity and the surgical target are localised to MRI-positive lesion (nidus). Chapters 1-3 review BOSD and FCD literature, and outline thesis aims and methodologies. Chapter 4 describes the clinical, imaging, histopathology, and genetic features of patients with BOSD. BOSDs present with a recognisable clinical syndrome with rapidly-escalating, stereotyped, focal seizures, almost universally becoming drug-resistant and requiring epilepsy surgery. BOSDs were missed on initial MRI in the majority (68%), with diagnosis being aided by 18F-FDG-PET. Genetic testing confirmed BOSD are an “mTORopathy” with pathogenic variants found in 63%. Delay to diagnosis and surgery was important, with low intellect being associated with longer epilepsy duration (network). Chapter 5 examines whether single-stage, limited-resection, epilepsy surgery is effective in BOSD-related epilepsy. All patients had surgery without intracranial EEG monitoring, despite BOSDs frequently involving eloquent cortex (40%). Most patients (68%) had resection of the dysplastic sulcus only; 16% were reoperated for recurrent seizures. At median 6.3 years follow-up 87% of patients were seizure-free. These findings support corticectomy limited to the MRI-positive BOSD (nidus). Chapter 6 seeks to understand the neurobiological basis for the observations made in Chapter 5. Group-level analyses showed that markers of epileptogenicity and dysplasia are mostly confined to the dysplastic sulcus with ECoG and 18F-FDG-PET abnormalities over the gyral crown and adjacent gyri being less and reducing following resection of the dysplastic sulcus only. These findings suggest that intrinsic epileptogenicity is limited to the dysplastic sulcus (nidus), and support limited-resection surgery. Chapter 7 examines the determinants of age at seizure onset in BOSD. Larger BOSD volume, germline mTOR pathway variants, and location within, and increased connectivity to, the default mode network were associated with younger seizure onset. These findings de-emphasise the contribution of postnatal cerebral maturation, for example myelination, to seizure onset age and reveal novel contributions of default mode network connectivity and genetic aetiology. Chapter 8 explores the contribution of 18F-FDG-PET to automated detection of BOSD. This study validated the Multi-centre Epilepsy Lesion Detection group’s machine- learning method in BOSD with the addition of 18F-FDG-PET. Of all surface-based features, cortical and subcortical hypometabolism discriminated BOSD from non-BOSD regions with highest sensitivity. Furthermore, addition of 18F-FDG-PET to the machine- learning method increased automated BOSD detection beyond use of MRI-only. BOSD are a discrete epileptogenic and dysplastic nidus with network-driven electroclinical and cognitive manifestations. Despite growing awareness, BOSD are still frequently missed in clinical practice. Efforts to suspect, detect and effectively treat BOSD are warranted, given their excellent response to surgery.
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ItemUrinary tract infection in children – changing the management paradigm so more children can be treated at home( 2023-07)Urinary tract infections (UTI) are a common reason for paediatric emergency department (ED) presentations. Although most children are successfully treated with oral antibiotics, approximately one-third receive intravenous (IV) antibiotics and hospital admission. However, there is limited evidence supporting these decisions, and consequently an opportunity to approach antibiotic use differently to potentially treat more children out of hospital. Guidelines recommend most patients can be treated with oral antibiotics, but the studies used to support these guidelines excluded several cohorts. The aims of this thesis were to investigate current UTI management, particularly use of antibiotics and Hospital-in-the-Home (HITH), to define which children actually need IV antibiotics, and to explore the feasibility of using shorter IV antibiotic durations. The initial study focused on use of HITH for IV antibiotics for UTI. The study found that 90% of patients successfully completed treatment without readmission to hospital, and none became severely unwell at home. However, HITH was underused, with only 8% of patients on IV antibiotics using this model. The study supports home IV antibiotics for selected UTI management. The next study used a wider lens, examining all current UTI management in ED and found little variation in antibiotic route, choice, and duration for lower UTIs and uncomplicated upper UTIs. However, complicated upper UTIs, where there is less evidence, showed more variation. No single feature reliably predicted use of IV antibiotics, but multiple complicating factors were associated with their initiation, suggesting they represent ‘red flags’ for clinicians. In the following study, clinicians were asked why they used IV antibiotics for UTI and admitted children to hospital. Although they had defined reasons for using IV, objective clinical evidence did not always support their reasons. The study hypothesised that multiple features lead to the decision to prescribe IV antibiotics and that these features may group together. Given the finding that multiple but not always the same features led to IV antibiotic initiation, the next study aimed to develop a clinical score to determine which children need IV antibiotics. The Melbourne RUPERT score was successfully developed and tested on patients with confirmed and probable UTI. Using six clinical features, the score is straightforward, easily attainable, reproducible and aids consistent stratification of patients to determine route of initial antibiotic treatment. Finally, using outcomes and learnings from the preceding studies, a randomised control trial protocol was developed. This trial aims to investigate whether an ultra-short IV duration (1 day) is non-inferior to the standard duration for children requiring IV antibiotics. If a single daily dose of IV antibiotics followed by oral antibiotics proves sufficient, patients could be discharged home from the ED on oral antibiotics, eliminating the need for hospital admission. In questioning whether more children with UTI could be treated out of hospital, this thesis found that indeed they can, through delivering IV antibiotics at home, treating more children with oral antibiotics, and investigating an identified practice of earlier switch from IV to oral. This has the potential for major impacts on patient care and hospital sustainability.
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ItemUtilising high resolution impedance manometry to diagnose and manage oesophageal dysfunction in children with oesophageal atresia( 2022)Oesophageal atresia is the most common congenital oesophageal abnormality and requires life-saving surgery in the neonatal period. Despite successful surgery, most patients will have ongoing oesophageal dysmotility. Dysmotility in oesophageal atresia is a life-long risk. Dysmotility results in chronic swallowing dysfunction into adulthood – leading to poor food bolus transport, choking, and even death. We are currently unable to reliably predict which patients will develop dysmotility and require oesophageal dilatations. Therefore, clinical management is reactive, rather than proactive. This research seeks to understand the motility patterns in oesophageal atresia, as well as the dilatation burden and late mortality risk. This research utilises high resolution impedance manometry, which provides accurate and reliable measurements of oesophageal wall compliance, to develop an understanding of how compliance relates to food bolus transport. This will allow for objective characterisation of oesophageal contraction in patients with oesophageal atresia. Simultaneously, patient and carer quality of life will also be assessed. With the largest cohort of patients with oesophageal atresia undergoing high resolution impedance manometry internationally, this research demonstrates that the distinct motility patterns of these patients remain consistent over time. This informs patient management and parental counselling, as well as the development of a strategy for predicting and preventing morbidity and mortality in oesophageal atresia.