Background A cerebral cavernous malformation (CCM) is a small cluster of thin-walled, dilated blood vessels within the brain which is prone to bleed. Although the quantity of blood leaking tends to be small, even a small intracranial haemorrhage (ICH) can result in a clinically significant neurological deficit. Because some focal neurological deficits (FND) may in fact be haemorrhages that were undetected by imaging, FND were also included in the analysis wherever possible. In Scotland, between 2006 and 2010, the annual CCM detection rate was 0.8 per 100,000 people. Since estimates of prognosis inform decisions about whether to treat CCM, it is crucial that the untreated clinical course of the disease is fully understood. Aim The aims of this thesis are (i) to quantify the risk of ICH (or ICH or FND, referred to as ‘clinical event’) for an untreated adult within five years of CCM diagnosis, (ii) to identify prognostic factors for ICH (clinical event), and (iii) to create a model to predict, at the time of diagnosis, an individual’s risk of a subsequent ICH (clinical event). Methods Initially, a literature review was undertaken. Then data from adults diagnosed with CCM in the Scottish Intracranial Vascular Malformation Study (SIVMS) were analysed. SIVMS is a prospective, population-based cohort study: it includes all adults resident in Scotland at the time of diagnosis of a first-ever intracranial vascular malformation during the two five-year periods 1999–2003 and 2006–2010. Time-to-event methods were employed to compare the estimated risk of ICH (clinical event) for those who experienced a first ICH (clinical event) during untreated five-year follow-up with those who experienced a second ICH (clinical event). A statistical challenge when analysing clinical outcomes from patients with CCM is that the outcome event of ICH or FND is comparatively rare; therefore a larger cohort of CCM patients was required to identify more robustly potential predictors of ICH (clinical event) and to create a prognostic model to predict, at the time of diagnosis, an individual’s risk of a subsequent ICH (clinical event). Three research groups agreed to contribute their data to enable an individual patient data meta-analysis (IPDMA) to be undertaken. Results In the two SIVMS cohorts, 136 (1999–2003) and 165 adults (2006–2010) were diagnosed with CCM. In the earlier cohort, the estimated risk of a first ICH within five years of presentation (2.4%, 95% CI 0.0% to 5.7%) was significantly lower (p < 0.0001) than the risk of a recurrent ICH (31.9%, 95% CI 4.5% to 59.3%), but the annual risk of a recurrence declined over the five-year period. In the same cohort, women had an increased risk of a second clinical event (log-rank χ2(1) = 6.2, p = 0.01). The IPDMA was based on 988 adults, 62 of whom suffered a first ICH within five years of CCM diagnosis. When the data were pooled, the estimated adjusted hazard ratio for first ICH for clinical presentation (ICH/FND vs other presentation) was 4.5 (95% CI 1.5 to 13.4) and for brainstem location (brainstem vs other location) the adjusted hazard ratio was 3.3 (95% CI 1.5 to 7.2); age, sex and CCM multiplicity did not add any additional prognostic information. Conclusion In this thesis two risk factors have been identified that are independently associated with increased likelihood of experiencing an ICH (or clinical event) within five years of diagnosis. A prognostic model has been built and evaluated, based on these factors. Other areas to be explored in the future include external validation of the model and investigating the effects of (i) antithrombotic therapy and (ii) pregnancy on the progression of the disease.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第21261号 / 医博第4379号 / 新制||医||1029(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 山下 潤, 教授 湊谷 謙司, 教授 羽賀 博典 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM