Outcome after aneurysmal subarachnoid haemorrhage

Abstract

Aneurysmal subarachnoid haemorrhage (aSAH) is a devastating form of stroke associated with significant morbidity and mortality. It affects younger people than other stroke types and consequently has a disproportionately high socio-economic impact. Survivors often suffer a range of disabling symptoms including physical and cognitive deficits. These deficits lead to a reduced quality of life and impair ability to return to work following aSAH. In order to develop treatments to improve outcome after aSAH we need to better understand the mechanisms that underlie neurological injury. At present the calcium channel blocker, nimodipine which was developed in the 1980s, is the only licensed treatment to improve outcome following aSAH. Despite multiple trials there have been no major developments to improve outcome following haemorrhage for over 30 years and it is our lack of understanding of the pathophysiology of neurological injury that, at least in part, explains this lack of therapeutic innovation. This thesis focusses on understanding outcome after aSAH and has three main aims. First, to explore the burden of hidden disability by studying cognitive, auditory, headache and fatigue outcomes in the long-term following aSAH including the implications for quality of life and employment. Second, to improve outcome prediction following aSAH by including additional variables and advanced statistical learning methods. Third, to use a genetic approach to provide insight into the mechanisms underlying neurological injury following aSAH. The results reported in this thesis are that cognitive and auditory deficits, in addition to persistent headache and fatigue, are significantly more common in aSAH survivors compared to a control population. Auditory deficits are most in keeping with a central auditory processing disorder rather than a peripheral deficit and are closely linked to impaired cognition following aSAH. Cognitive deficits, persistent headache and fatigue all significantly contribute to unemployment following aSAH. In addition to the well-known clinical variables that predict outcome after aSAH, C-reactive protein (CRP) is an independent predictor of outcome following aSAH. The incorporation of CRP and the use of advanced predictive modelling methodology such as support vector machines improves outcome prediction following aSAH. Despite a statistical improvement these new models are unlikely to have major clinical impact and require validation in an external cohort. To identify genetic contribution to outcome after SAH, first a candidate gene approach was used. This identified that haptoglobin, a haemoglobin scavenging molecule, is implicated in outcome after aSAH, although the evidence is not conclusive. Genetic variation in NRF2, a transcription factor regulating haemoglobin scavenging, inflammation and oxidative injury, is also associated with outcome after aSAH. These findings provide insight into the pathophysiology of neurological injury following aSAH but are limited by the candidate nature of the analyses. A subsequent unbiased genome-wide analysis provides novel evidence for a role of the sphingosine1-phosphate signalling pathway in neurological injury and outcome following aSAH. This thesis concludes that aSAH leads to widespread long-term neurological symptoms which impact quality of life and employment. The inclusion of additional clinically available predictors and use of advanced statistical learning methods can improve outcome prediction following aSAH. However, the improvements are small and unlikely to influence clinical practice. Ultimately to improve outcome we need to better understand the mechanisms which drive neurological injury. Using both candidate and genome-wide analysis a number of mechanisms including haemoglobin scavenging, inflammation, oxidative injury and sphingolipid signalling have been implicated in outcome. These pathways may act as therapeutic targets to improve outcome after aSAH and warrant further study.

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ORCID for Ian Galea: orcid.org/0000-0002-1268-5102

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