Clinical and genetic studies on the causes and prognosis of intracranial haemorrhage

Introduction: Intracranial haemorrhage occurs within the compartments of the intracranial vault (skull). Spontaneous (non-traumatic) intracerebral haemorrhage (ICH) and aneurysmal subarachnoid haemorrhage (aSAH) have a high mortality and morbidity rate, while convexity subarachnoid haemorrhage (cSAH) in older people is associated with a high risk of future intracranial bleeding. In this thesis I present several studies investigating factors associated with the development and prognosis of ICH, aSAH cSAH. Methods: I evaluated patients recruited to the Genetics and Observational Subarachnoid Haemorrhage (GOSH) study with aSAH or unruptured intracranial aneurysm as well as patients with ICH recruited to the Clinical Relevance Of Cerebral Microbleeds In Stroke (CROMIS-2) study, both multicentre observational studies recruiting patients from the UK. Individual patient data was also collected for meta-analysis of published studies. Main findings: 1) We found a different risk factor profile in patients with aSAH compared to patients with unruptured intracranial aneurysms and continued our research by validating a prediction model for the prediction of long-term functional outcome after aSAH; 2) in our cohort of patients with convexity SAH we found that it is associated with a higher rate of symptomatic ICH in patients with probable cerebral amyloid angiopathy (CAA); 3) our genetic association analysis showed that Haptoglobin might be associated with mortality after ICH. Additionally, Apolipoprotein E is associated with novel neuroimaging markers of CAA. In our genome-wide association analysis we found new loci (rs4675692) associated with ICH status in a genome-wide association study (but did not find a repeat expansion for C9orf72) and finally found previously reported and novel genetic variants in familial aSAH. Conclusion: These findings, in diverse cohorts, confirm the importance of clinical, radiological and genetic factors for disease expression and prognosis in different forms of intracranial haemorrhage