Medicine (RMH) - Theses
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ItemDiagnostic and treatment strategies for the management of acute stroke with special reference to clot retrieval( 2017)This body of work comprises contributions to human cerebrovascular disease as performed over a period of 12 years (from year 2005 to 2017) as a specialist at major university teaching hospital in Melbourne in collaboration with the most prominent colleagues recognized internationally in this field. The body of work is divided into 2 parts. The first part comprises of 41 peer-reviewed papers submitted in full in hard copy representing the most pivotal and highly cited papers in major specialist journals where I have been either senior and corresponding author, lead author or a major contributor. This body of work is divided into essentially 6 sections based on prognosis, diagnostic factors, pharmacogenetics, aging, relation to epilepsy and other diseases and my own specialty of therapeutics including endovascular clot retrieval. The second part submitted for completion includes the total 114 peer-reviewed papers representing my contribution, less pivotal to the central themes, to the medical literature. It includes for particular interest my collaboration with engineers in the development of endovascular devices for the performance of therapeutic manoeuvres. Each section is preceded by a brief introductory overview to facilitate assessment.
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ItemMedical rehabilitation in natural disasters( 2017)The number of severe natural disasters (such as earthquakes, storms, draught, floods etc.) has escalated in recent years. Natural disasters often occur unexpectedly, precipitously and with great magnitude of destruction, resulting in significant loss of life and long-term disability from severe injuries including spinal cord injury, traumatic brain injury, limb amputation, fracture, peripheral nerve injury, crush injury and psychological impairment. In the last two decades, advances in disaster response/rescue and field management, have improved the survival rates of disaster victims significantly worldwide. Current data shows a significant increase in the number of injuries sustained relative to mortality, indicating medical rehabilitation is integral to comprehensive disaster management. Empirical evidence on medical rehabilitation following natural disasters is increasing and various studies have reported effectiveness of rehabilitation in survivors. Evidence suggests early provision of rehabilitation programs reduce disability, leading to better clinical outcomes, and improves participation and quality of life of disaster victims. The World Health Organization (WHO) rehabilitation guidelines recommend implementation and access to rehabilitation during all phases of the disaster response. In line with this, there is strong consensus amongst global health authorities that medical rehabilitation should be initiated in the immediate emergency response phase, and should be continued in the community over a longer-term until treatment goals are achieved and survivors are successfully reintegrated into society. Many countries now recognize the importance of disaster planning, preparedness and management initiatives, and their disaster management capacity and collaboration has improved. Unfortunately, major disparities and gaps amongst countries exist, and those with a high disaster risk tend to have a low coping capacity, with inadequate disaster response/management plans. Many countries have limited or lack of access to appropriate services such as rehabilitation, where fragmented healthcare systems are compromised by lack of financial and political support. Rehabilitation-inclusive disaster management strategies/plans are yet to be developed in many countries, particularly in the Asia-Pacific region (where the majority of natural disasters occur). There is a concern in regards to the inadequacy of global organizational capacities and capabilities and matching of resources across the disaster cycle. In past large-scale disasters, it was beyond the capacity of many countries to have optimal disaster management and many were dependent on global humanitarian and medical assistance. This is reflected by the growing number of emergency medical teams (EMTs) responding to disasters worldwide. However, the influx of EMTs during past disasters presented immense challenges regarding response coordination and management. There was lack of standardized protocols/guidelines, coordination and evaluation mechanisms in place. This resulted in inadequate care delivery, particularly rehabilitation, with often devastating consequences for the affected individuals, families and communities. Although there have been improvements in the organization of emergency responses, care and services, this has often not extended to include rehabilitation services. Currently, there is increased scrutiny of the humanitarian response sector driven towards professionalism and accountability, to provide effective and appropriate interventions in different disaster settings. Further, there have been significant developments in international, regional and national collaboration and management capacities in disaster management, including implementation of disaster-risk reduction frameworks, quality and coordination mechanism of EMTs. One of the noteworthy developments is the establishment of the WHO-EMT Initiative and launch of EMT guidelines, including the ‘Minimum technical standards and ecommendations for rehabilitation in sudden onset disasters’. These guidelines not only classify medical response teams per their capability, but also set out the core standards for medical care of disaster victims. The WHO rehabilitation guideline provides standardized protocols for rehabilitation in future emergencies, acknowledging variations in type and patterns of injury, disease and subsequent long-term disability. It provides much needed direction for preparedness for rapid, professional, coordinated medical responses by both national and international response teams. It also provides guidance on building or strengthening the capacity of local and international EMTs within defined coordination mechanisms. A WHO registration system for all EMTs was initiated in July 2015, which enables establishment of a global registry of emergency medical response teams for deployment in future calamities. There are still immense challenges in putting these standards into practice in disaster settings. The successful implementation of these frameworks will require increased resilience of the rehabilitation community with multi-stakeholder partnerships. There is still much progress to be made on tackling the underlying drivers of disaster risk, such as poverty, climate change, rapid urbanization, and factors such as environmental degradation, poor local governance, population growth, economic development patterns, to establish a rehabilitation-inclusive disaster management model for future catastrophes. The aim is to strengthen national capacity, foster an environment of self-empowerment of EMTs and local health services, and work in rehabilitation within defined coordination mechanisms in disaster-affected area. This thesis explores the medical rehabilitation management of disaster survivors, following natural disasters. The aim was to provide evidence and systematic analyses of various rehabilitation interventions trialled in disaster survivors, in terms of their effectiveness, safety and cost-efficiency. Rehabilitation professionals’ role and gaps in evidence for medical rehabilitation in disaster management and Australian perspective were explored, specifically in the Asia-Pacific region. Further, a brief overview of current developments, challenges, and gaps in the rehabilitation-inclusive disaster management plan, including implementation of WHO guidelines, is discussed to improve care for victims of future calamities.
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ItemMycobacterium ulcerans on the Bellarine Peninsula: turning observations into science( 2015)The Bellarine Peninsula in south-eastern Australia has been experiencing an epidemic of M. ulcerans since 1998.[1] It affects local residents, but also visitors from outside the endemic region, with more than 50% of cases managed at the local referral health service, Barwon Health. Since 1998 an electronic database (Epi info 6, Centers for Disease Control and Prevention, Atlanta, Ga, USA), designed and implemented by the author and approved by the Barwon Health Ethics Committee, has been established that prospectively records clinical, epidemiological and treatment information on all cases of M. ulcerans managed by staff of Barwon Health. All data has been collected and entered into the database by the author. During the period 1998 until 2014 the management of M. ulcerans in Barwon Health gradually evolved, largely based on observations obtained by clinicians in Barwon Health during their management of patients with M. ulcerans. The analysis of the data collected has been used to confirm and document these observations on a scientific level and to influence the ongoing evolution of clinical practice. These finding have been further disseminated, helping to influence a change of clinical practice in the management of M. ulcerans both throughout Australia and internationally. The results of this research (turning observations into science) are presented in this thesis and include the following important components: 1. The determination that antibiotics are effective in the treatment of M. ulcerans in Australian patients. This has resulted in nearly universal cures achieved with antibiotic treatment of the disease, the performance of more conservative and less reconstructive surgery, less hospitalizations, lower long-term morbidity and reduced cost of care. (Chapters 1, 2 and 3) 2. The demonstration that all oral antibiotic combinations are effective, better tolerated and less toxic than previously administered injectable antibiotics. This also allowed treatment to be given from home and avoided hospitalization. (Chapters 1, 2 and 3) 3. The first demonstration that fluoroquinolone antibiotics are an effective and safe antibiotic that can be used in combination with other known effective antibiotics in M. ulcerans treatment in humans. This has increased the options for safe and effective oral antibiotic treatment. (Chapters 1, 2 and 3) 4. The first study to describe successful outcomes in the treatment of M. ulcerans in selected patients with antibiotic treatment durations shorter than the current WHO and Australian recommended 8 weeks. This has offered significant benefits in terms of reducing toxicity and improving adherence associated with M. ulcerans antibiotic treatment. (Chapter 4) 5. The first clinical reports of the occurrence of paradoxical reactions resulting from the antibiotic treatment of M. ulcerans. This lead to the realization that previously perceived treatment failures were incorrect and instead were occurring as a result of the effectiveness of antibiotic treatment. This has lead to a dramatic change in management of M. ulcerans leading to a reduction in the need for further surgery, reconstructive surgery and the need to change or prolong M. ulcerans antibiotic treatment regimens. (Chapter 5) 6. A comprehensive description of the incidence, clinical spectrum, diagnostic features and treatment of paradoxical reactions associated with the antibiotic treatment of M. ulcerans. This provided information that will aid clinicians in recognizing, diagnosing and managing paradoxical reactions when treating patients with M. ulcerans. (Chapter 6) 7. The determination of risk factors for the development of paradoxical reactions that may minimize the occurrence and impact of paradoxical reactions during M. ulcerans treatment. It also provides important prognostic information for clinicians managing M. ulcerans. (Chapter 6) 8. The first described use of corticosteroids to treat severe paradoxical reactions occurring during the antibiotic treatment of M. ulcerans. This has lead to a reduced need for further surgery and reconstructive surgery as well as minimizing long-term morbidity from the disease. (Chapter 7) This research has been extended to Africa and to HIV coinfected patients where the first reported safe and effective use of prednisolone to manage a severe paradoxical reaction in an HIV-infected patient was described. (Chapter 14) 9. The determination of risk factors for treatment failure if surgery without antibiotics is used for treatment of M. ulcerans. This allows an improved selection of patients if surgery alone is considered in the treatment of M. ulcerans, but also provides important prognostic information for clinicians managing M. ulcerans. (Chapter 8) 10. A comprehensive description of the clinical features and diagnosis of M. ulcerans in an Australian population. This provided important information to aid health practitioners identify, diagnose and treat M. ulcerans. (Chapter 9) 11. A comprehensive description of the clinical features, diagnosis and risk factors of the severe oedematous form of M. ulcerans. This provided important information that will increase the awareness of odematous M. ulcerans disease, and improve the understanding of its clinical presentation and risk factors. This should allow clinicians to diagnose and treat early oedematous forms of M. ulcerans which will have a major impact on the morbidity and cost of this form of disease. (Chapter 10) 12. The use of available evidence, best practice and expert opinion to develop the first guidelines for the management of M. ulcerans/HIV co-infection. These will be an important aid in managing the complex issues relating to the clinical care of patients in endemic areas where these infections are increasingly found to co-exist. (Chapter 12) 13. The use of field experience, best practice and available evidence to propose a research agenda to improve the effectiveness, accessibility, acceptability and feasibility of care for M. ulcerans in Africa, including in those populations co-infected with tuberculosis or HIV. (Chapters 13 and 15)
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ItemUnderstanding the role of infections in the pathogenesis of inflammatory bowel disease, and improving the quality and safety of treatment( 2014)Inflammatory bowel disease (IBD), comprising Crohn’s disease and ulcerative colitis are chronic inflammatory diseases of the gastrointestinal tract. These conditions cause significant morbidity and reduced quality of life in patients who are often young. The pathogenesis of IBD is uncertain, however the current paradigm is that mucosal inflammation is caused by a dysfunctional interaction between the innate immune system and the bacterial microbiota within the gastrointestinal tract. Single nucleotide polymorphisms (SNPs) of genes related to innate immunity such as pattern recognition receptors, mucosal barrier and autophagy are likely to play an important role. Despite the potential role of altered innate immunity, the mainstay of treatment of inflammatory bowel disease is immunosuppressive medications. This includes thiopurine drugs, which affect lymphocyte function, and monoclonal antibody therapy based on inhibition of tumour necrosis factor α. Although often effective, these medications have the potential to increase the risk of infections and malignancy. This thesis examines the role of infections in inflammatory bowel disease, initially assessing the role of the bacterial microbiota through analysis for the putative pathogen Mycobacterium avium subspp. paratuberculosis, and attempts to correlate these findings with a multiplex analysis of SNPs previously associated with IBD. The microbiota is then analysed more broadly using a metagenomic type approach with a custom phylogenetic oligonucleotide microarray based on 16s ribosomal RNA probes. Approaches to improving quality and safety in IBD are then examined. A survey of Australian gastroenterologists in relation to screening for latent infections and vaccination, with respect to immunomodulators and monoclonal antibody therapies was carried out and discussed. A comprehensive audit of the use of infliximab, an anti-TNF α agent at a tertiary metropolitan hospital was undertaken. A novel electronic clinical decision support system was designed with the aim of improving the clinical governance related to these agents, and the impact of this system was examined. A study to assess the use of pharmacogenetics and measurement of thiopurine metabolites to improve the safety of thiopurine use was conducted in addition.
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ItemImproving the outcome of patients with lymphoproliferative disorders( 2014)Lymphoproliferative disorders (LPD) collectively form the commonest category of haematologic malignancy in Australia. Most patients are not cured and improvements in treatments are urgently needed. Within this thesis I have taken two broad approaches to this problem. Optimising standard therapies 1. Using PET-CT in identify patients at risk of early disease relapse The identification of patients at highest risk of failing existing therapies is a rational starting point to improve outcomes. Using clinical datasets from Peter MacCallum Cancer Centre, I studied the ability of PET-CT to identify patients at risk of disease relapse. Theoretically, early detection of relapse when tumour burden may increase the probability of successful salvage therapy and ultimate cure. Therefore I reviewed the outcomes and method of detecting relapse patterns in patients with de novo DLBCL and transformed indolent lymphoma. No clear benefit from a surveillance strategy was demonstrated, meaning that patients can be spared the anxiety and radiation of scanning. I also explored the role of PET-CT in primary mediastinal B-cell lymphoma and found negative end of treatment PET-CT was predictive of excellent progression-free survival, but positive scans require histologic confirmation prior to escalation of therapy. 2. Central nervous system (CNS) relapse in aggressive NHL This complication is typically rapidly fatal and identifying patients at increased risk In the first study I analysed a group of high-risk patients with DLBCL and found that the addition of high dose systemic methotrexate and/or cytarabine was associated with lower rates of CNS relapse compared with intrathecal prophylaxis alone. This finding highlights the benefits obtaining when a customised therapeutic approach is used. In a second study, by collaborating through a large, international multicentre network I collated a large series of patients with mantle cell lymphoma who developed CNS relapse. Within this, I identified blastoid histology, high mantle cell lymphoma international prognostic index, raised serum lactate dehydrogenase and poor performance status as risk factors for CNS involvement. Developing new therapies The second half of this thesis focuses on the development of novel therapeutic strategies. 3. NMP and anti-CD20 monoclonal antibodies in lymphoma N-methyl-2-pyrrolidone (NMP) shares biologic properties with the established anti-cancer immune modulating drug lenalidomide, which is active with rituximab in lymphoma. I have shown that NMP has in vitro enhancement of rituximab-mediated induction of antibody dependent cellular cytotoxicity on lymphoma cell lines. The promising pre-clinical activity of this combination will be assessed in future clinical trials. 4. Rational clinical trial design using immunotherapies Finally, I designed three early phase clinical trial protocols using immunotherapies: 1) oral NMP in myeloma, 2) intra-tumoral αgalactoceramide and CpG and 3) ISCOMAB and rituximab, in indolent B-cell lymphoma. These clinical trial protocols combine correlative scientific with clinical endpoints and are now ready for activation.
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ItemBiliary tract injury( 2012)Aim - The aim of the thesis was to examine the causes, mechanisms, recognition and treatment of biliary injury. The hypothesis was that the management principles for biliary injury were similar regardless of the cause. Methods - Biliary injuries secondary to operative damage (iatrogenic), following transplantation or as a result of blunt or penetrating (traumatic) trauma were examined. The following databases were analyzed; A prospective database of biliary injuries in Victoria from 1997 - 1999, a database of iatrogenic biliary injuries from the Royal Infirmary of Edinburgh from 1984 - 2003, a prospective database for all liver transplants performed by the Scottish Liver Transplant Unit (SLTU) until September 2001 and the prospectively gathered trauma registry at The Royal Melbourne Hospital from 1999 - 2011. Retrospective case note review was performed for further data collection. Patient data was entered onto a Microsoft Access database and statistical analysis performed with SSPS versions using Cox regression for multivariate analysis, the Mann Whitney U test for independent variables and the Log rank test when appropriate. Not all data sets were of sufficient size to allow statistical analysis. Management of biliary injury included non-operative, percutaneous, endoscopic and surgical options. Results - Iatrogenic injuries were recorded in 33 patients from the Victorian audit and 123 patients from the Royal Infirmary of Edinburgh. Fifty five (14.6%) of 379 consecutive orthotopic liver transplants at the SLTU had biliary complications. Thirty three patients (0.1%) of 26,014 blunt and penetrating trauma patients had injuries to the biliary tree and gallbladder. Of the 123 iatrogenic injuries from the Royal Infirmary of Edinburgh, 55 (44.7%) had an attempted repair prior to referral, 59 (47.9%) were repaired after referral and 9 (7.3%) were managed without surgery. For the 59 patients repaired after referral a successful repair was possible in 22 (88%) of 25 patients repaired within the first two weeks compared with 20 (91%) of 22 repaired after 6 weeks (p=0.615). Nine patients were considered for hepatic resection. Five patients developed hepatic failure and were considered for liver transplantation with only two reaching transplantation. Of the 55 grafts from the SLTU with biliary complications, 28 biliary leaks occurred with 17 anastomotic leaks successfully treated non-operatively. Of the thirty anastomotic strictures, six (38%) of the 16 early anastomotic strictures required surgery for complete resolution, compared with 12 (86%) of the 14 late anastomotic strictures (p=0.0106). Of the blunt and penetrating biliary injuries there were 10 gallbladder and 23 biliary tree injuries. Fourteen patients had injuries to the intra-hepatic biliary tree and nine to the extra-hepatic biliary tree. Delay in the recognition of biliary injury following iatrogenic injury continues to be prevalent, with the delay often associated with sepsis, jaundice and peritonitis. Injury following liver transplantation is complicated by the association of hepatic arterial thrombosis and immunosuppression, whilst traumatic injury is frequently associated with intra-abdominal organ injury. The timing of repair and utilization of temporizing measures such as biliary drainage depends upon the associated injuries and presence of sepsis or jaundice. For all types of biliary injury, surgical reconstruction with Roux-en-Y hepaticojejunostomy remains the gold standard for repair. Successful long lasting repair is possible in the majority when managed by a specialist hepatobiliary team. Conclusion - The management of biliary injuries is multi-factorial and requires tailoring according to patient variables. However, common management pathways exist regardless of the cause.
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ItemThe effect of patient factors and clinician choices on management of colorectal cancer and other malignancies( 2011)Cancer is one of the leading causes of morbidity and mortality world-wide, and colorectal cancer is one of the most common malignancies in the developed world. Being able to predict the most appropriate strategies for diagnosis, treatment and monitoring for any malignancy, both in the adjuvant and metastatic disease settings, is crucial as more management options come into play. In particular, the choices surrounding chemotherapy dosing can depend on many factors, and increasing interest is developing regarding optimization and individualization of treatment strategies for cancer based on these factors. Modern oncology is currently focused on biomarker-based research and translation to care. Although this thesis does not incorporate any pre-clinical biomarker-based research, patient variables (such as age and comorbidities) can be regarded as a type of clinical ‘biomarker’ – for example, age is a very strong prognostic factor for a number of malignancies, perhaps even more important than particular laboratory-based biomarkers in many circumstances. This research will focus on key aspects of patient care, from surgery to chemotherapy, radiation therapy and disease monitoring, which may be potentially regarded as ‘biomarkers’ - stratifying patients into those who may benefit the most, and least, from various treatment modalities and strategies. This body of work focuses primarily on colorectal cancer. The thesis provides a comprehensive ‘snapshot’ of current management strategies in Australia for colorectal cancer – from diagnosis through to surgical and oncological management – and each paper compares the findings with what is currently regarded as ‘gold-standard’ practice. It is well known that patients on clinical trials are mostly younger and fitter than those seen in routine practice, and treating physicians cannot always apply the findings from randomized controlled studies to the individual cancer patient. It is useful to understand in parallel with the evidence gained from clinical trials, its applicability and modifications employed in routine practice and as such, this research has been largely conducted using a prospectively collected comprehensive cancer database; together with surveys of Australian oncologists and review of available literature. Many issues requiring treatment decisions for colorectal cancer are also applicable to many malignancies, and the thesis also includes some papers which relate to cancer management in general – in particular, the impact of patient age and comorbidity on treatment decisions, and the effect of liver dysfunction on chemotherapy choices for cancer patients.
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ItemMolecular prognostic and predictive biomarkers in colorectal cancer( 2012)Increasing knowledge of the underlying signalling pathways and molecular defects involved in colorectal cancer (CRC) growth/progression has led to the development of several novel target-based therapeutics along with the discovery of various prognostic and predictive biomarkers. The mitogen-activated protein kinase (MAPK) signalling pathway plays a critical role in colorectal cancer progression. Mutations in BRAF, a principal effector of Ras in this signaling cascade, are found in 10% of CRC. The low frequency of this mutation makes it a challenging target for drug development, unless subsets of patients with higher rates of BRAFV600E can be defined. This thesis first investigates the potential of enriching a CRC patient population for BRAFV600E mutations based on clinical features and KRAS status. The mutational concordance between primary-metastasis pairs, and the impact of BRAFV600E and other molecular changes on patient outcome were also evaluated. This was achieved by analyzing primary CRC from 525 patients evenly matched for age, gender and tumour location, and 81 primary-metastasis pairs. BRAFV600E, KRAS, PIK3CA, NRAS mutations, microsatellite instability (MSI) and loss of heterozygosity (LOH) were determined and correlated with clinical features and patient outcomes. The prevalence of BRAFV600E was found to be considerably higher in older females with KRAS wild-type right-sided colon cancers (50%) compared to the unselected cohort (10%). BRAFV600E was associated with inferior overall survival in metastatic CRC and is independent of MSI status. The previous study suggested that BRAF mutant cancers represent a discrete subset of metastatic CRC defined by poorer survival, right-side tumour location and association with MSI. Whether BRAF mutant CRC is further defined by a distinct pattern of metastatic spread was investigated by using prospective clinical data and molecular analyses from 2 major centers (Royal Melbourne Hospital and The University of Texas MD Anderson Cancer Center). Patients with known BRAF mutation status were analysed for clinical characteristics, survival, and metastatic sites. A distinct pattern of metastatic spread was observed in BRAF mutant tumours, namely higher rates of peritoneal metastases (46% vs 24%, P=0.001), distant lymph node metastases (53% vs 38%, P=0.008), and lower rates of lung metastases (35% vs 49%, P=0.049). To further develop the concept of cancer gene mutations as predictors of site of relapse, CRC metastases from different sites were then examined for oncogene mutation profiles. One-hundred CRC metastases were screened for mutations in 19 oncogenes, and further 61 metastases and 87 matched primary cancers were analysed for genes with identified mutations. Mutation prevalence was compared between metastases from liver, lung and brain. Differential mutations between metastasis sites were evaluated as predictors for site of relapse in patients from the VICTOR trial. KRAS mutation prevalence differed between metastasis sites, being more common in lung (62.0%) and brain (56.5%) than in liver metastases (32.3%; P=0.003). Mutation status was highly concordant between primary cancer and metastasis from the same individual. KRAS mutation was found to be predictive of lung relapse but not liver relapse in patients from the VICTOR trial.
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ItemThe management of colorectal cancer in Australia: heterogeneity of care and the need for increased data collection( 2011)Australia has one of the highest world-wide incidence rates of colorectal cancer, affecting one person in 20. It is the second most commonly diagnosed invasive malignancy. Each year, approximately 14,200 cases are diagnosed representing 13.1% of all incident cancer diagnoses. Of those diagnosed, about 50% will ultimately die from metastatic disease. After lung cancer, it is the second leading cause of cancer death in our country, resulting in around 80 deaths each week. Multiple factors impact on peoples’ outcomes, with stage at diagnosis being the most significant factor. Despite the commonness of this condition in our community, there are a number of areas where data are lacking, resulting in treatment uncertainty. These areas include the medical management (chemotherapy dosing, selection of appropriate candidates for adjuvant and metastatic therapy) and staging and surveillance strategies (optimal imaging modalities) for those diagnosed with this condition. The publications comprising this thesis examine these various aspects of colorectal cancer management in Australia. A recurrent finding arising from the research is the distinct heterogeneity of care, with no adopted standard. This emphasises the need for ongoing data collection in this area and proposed methods to address this issue are discussed in the later part of the thesis. The thesis comprises of four chapters, each focussing on a specific area of colorectal cancer management in Australia. A review of the current literature and discussion of the common themes precedes each set of associated publications. (Part Thesis Overview and Introduction only)
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ItemThe use of International Classification of Functioning, Disability and Health in motor neurone disease rehabilitation( 2011)Motor Neurone Disease (MND) is a relatively rare but fatal progressive neurodegenerative disorder of the motor system in adults. It causes diverse and challenging symptoms and disability. Given the broad spectrum of needs, current “gold-standard” management is ‘‘multidisciplinary care’‘ which includes neurological, rehabilitative and palliative care. This thesis focuses on the rehabilitation phases of multidisciplinary care through investigation of disability from the perspective of persons with MND and their caregivers using cross sectional and predominantly qualitative methodology. Six linked studies address current gaps in evidence-based practice and in services in MND rehabilitation. The studies review existing evidence for multidisciplinary care in MND, and explore the perspectives of MND patients and their caregivers on disability and service gaps. They further describe the disability impact of MND using a standardised framework endorsed by the World Health Organisation – the International Classification Functioning, Health and Disability (ICF) and finally, investigate the effectiveness of a peer support program, which complements rehabilitation in people with MND. Participants with a diagnosis of MND (n=44) were recruited from a tertiary MND clinic. This work was predominantly designed to test the hypothesis that issues relevant to multidisciplinary rehabilitation care from the perspective of the patient and caregiver can be addressed utilising the ICF framework. Gaps in evidence and service provision can then be identified to optimise clinical care in both clinical and research settings. Study 1 presented a systematic review of the effectiveness of multidisciplinary rehabilitation and care for MND. Despite some suggestion that multidisciplinary care improves quality of life and reduces hospitalisation and disability; findings were inconclusive as quality of evidence was poor. This study highlighted gaps in current research relating to methodological rigour and appropriate study designs and appropriate outcome measures. Studies 2 and 4 described the patient and caregiver’s perspective of MND-related disability and highlighted gaps in service and also the impact of MND on caregivers, thus allowing recommendations to be made for optimisation of clinical care and further development of service provision and health policies for people with MND and their caregivers. In particular, the need for coordinated care by neurology, rehabilitation and palliative care services (“neuropalliative rehabilitation” model) was highlighted. Studies 3, 4 and 5 moved a step towards addressing the current lack of a standardised language and consensus for the care for people with MND and their caregivers by mapping their disability experience and relevant environmental factors onto the ICF framework. Study 5 in particular explored relevant personal factors which have been identified as important but not yet been classified within the ICF. Study 6 was a small interventional study (n=7) that explored the value of a peer support program in persons with MND. Whilst the numbers were too small to make conclusive findings, it demonstrated the feasibility of such programs in persons with MND. In conclusion, the gaps in MND care identified should be prioritised for future service development using the “neuropalliative rehabilitation” model of care. For improved consensus of care and communication amongst treating clinicians, the framework of International Classification of Functioning, Disability and Health should be further explored in this population through development of a “core set”.