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

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Intracranial Aneurysm Classifier Using Phenotypic Factors: An International Pooled Analysis

Intracranial aneurysms (IAs) are usually asymptomatic with a low risk of rupture, but consequences of aneurysmal subarachnoid hemorrhage (aSAH) are severe. Identifying IAs at risk of rupture has important clinical and socio-economic consequences. The goal of this study was to assess the effect of patient and IA characteristics on the likelihood of IA being diagnosed incidentally versus ruptured. Patients were recruited at 21 international centers. Seven phenotypic patient characteristics and three IA characteristics were recorded. The analyzed cohort included 7992 patients. Multivariate analysis demonstrated that: (1) IA location is the strongest factor associated with IA rupture status at diagnosis; (2) Risk factor awareness (hypertension, smoking) increases the likelihood of being diagnosed with unruptured IA; (3) Patients with ruptured IAs in high-risk locations tend to be older, and their IAs are smaller; (4) Smokers with ruptured IAs tend to be younger, and their IAs are larger; (5) Female patients with ruptured IAs tend to be older, and their IAs are smaller; (6) IA size and age at rupture correlate. The assessment of associations regarding patient and IA characteristics with IA rupture allows us to refine IA disease models and provide data to develop risk instruments for clinicians to support personalized decision-making

The genetic basis of endometriosis and comorbidity with other pain and inflammatory conditions

Endometriosis is a common condition associated with debilitating pelvic pain and infertility. A genome-wide association study meta-analysis, including 60,674 cases and 701,926 controls of European and East Asian descent, identified 42 genome-wide significant loci comprising 49 distinct association signals. Effect sizes were largest for stage 3/4 disease, driven by ovarian endometriosis. Identified signals explained up to 5.01% of disease variance and regulated expression or methylation of genes in endometrium and blood, many of which were associated with pain perception/maintenance (SRP14/BMF, GDAP1, MLLT10, BSN and NGF). We observed significant genetic correlations between endometriosis and 11 pain conditions, including migraine, back and multisite chronic pain (MCP), as well as inflammatory conditions, including asthma and osteoarthritis. Multitrait genetic analyses identified substantial sharing of variants associated with endometriosis and MCP/migraine. Targeted investigations of genetically regulated mechanisms shared between endometriosis and other pain conditions are needed to aid the development of new treatments and facilitate early symptomatic intervention

The genetic basis of endometriosis and comorbidity with other pain and inflammatory conditions

Endometriosis is a common condition associated with debilitating pelvic pain and infertility. A genome-wide association study meta-analysis, including 60,674 cases and 701,926 controls of European and East Asian descent, identified 42 genome-wide significant loci comprising 49 distinct association signals. Effect sizes were largest for stage 3/4 disease, driven by ovarian endometriosis. Identified signals explained up to 5.01% of disease variance and regulated expression or methylation of genes in endometrium and blood, many of which were associated with pain perception/maintenance (SRP14/BMF, GDAP1, MLLT10, BSN and NGF). We observed significant genetic correlations between endometriosis and 11 pain conditions, including migraine, back and multisite chronic pain (MCP), as well as inflammatory conditions, including asthma and osteoarthritis. Multitrait genetic analyses identified substantial sharing of variants associated with endometriosis and MCP/migraine. Targeted investigations of genetically regulated mechanisms shared between endometriosis and other pain conditions are needed to aid the development of new treatments and facilitate early symptomatic intervention

Association of common genetic variants with brain microbleeds

OBJECTIVE: To identify common genetic variants associated with the presence of brain microbleeds (BMBs). METHODS: We performed geno

The influence of intraoperative resection control modalities on survival following gross total resection of glioblastoma

The purpose of the present study is to analyze the impact of intraoperative resection control modalities on overall survival (OS) and progression-free survival (PFS) following gross total resection (GTR) of glioblastoma. We analyzed data of 76 glioblastoma patients (30f, mean age 57.4 ± 11.6 years) operated at our institution between 2009 and 2012. Patients were only included if GTR was achieved as judged by early postoperative high-field MRI. Intraoperative technical resection control modalities comprised intraoperative ultrasound (ioUS, n = 48), intraoperative low-field MRI (ioMRI, n = 22), and a control group without either modality (n = 11). The primary endpoint of our study was OS, and the secondary endpoint was PFS-both analyzed in Kaplan-Meier plots and Cox proportional hazards models. Median OS in all 76 glioblastoma patients after GTR was 20.4 months (95 % confidence interval (CI) 18.5-29.0)-median OS in patients where GTR was achieved using ioUS was prolonged (21.9 months) compared to those without ioUS usage (18.8 months). A multiple Cox model adjusting for age, preop Karnofsky performance status, tumor volume, and the use of 5-aminolevulinic acid showed a beneficial effect of ioUS use, and the estimated hazard ratio was 0.63 (95 % CI 0.31-1.2, p = 0.18) in favor of ioUS, however not reaching statistical significance. A similar effect was found for PFS (hazard ratio 0.59, p = 0.072). GTR of glioblastoma performed with ioUS guidance was associated with prolonged OS and PFS. IoUS should be compared to other resection control devices in larger patient cohorts

Genetic variation in NFE2L2 is associated with outcome following aneurysmal subarachnoid haemorrhage

Background and purposeNuclear factor erythroid 2-related factor 2 (NRF2; encoded by the NFE2L2 gene) has been implicated in outcome following aneurysmal subarachnoid haemorrhage (aSAH) through its activity as a regulator of inflammation, oxidative injury and blood breakdown product clearance. The aim of this study was to identify whether genetic variation in NFE2L2 is associated with clinical outcome following aSAH.MethodsTen tagging single nucleotide polymorphisms (SNPs) in NFE2L2 were genotyped and tested for association with dichotomized clinical outcome, assessed by the modified Rankin scale, in both a discovery and a validation cohort. In silico functional analysis was performed using a range of bioinformatic tools.ResultsOne SNP, rs10183914, was significantly associated with outcome following aSAH in both the discovery (n = 1007) and validation cohorts (n = 466). The risk of poor outcome was estimated to be 1.33-fold (95% confidence interval 1.12–1.58) higher in individuals with the T allele of rs10183914 (pmeta-analysis = 0.001). In silico functional analysis identified rs10183914 as a potentially regulatory variant with effects on transcription factor binding in addition to alternative splicing with the T allele, associated with a significant reduction in the NFE2L2 intron excision ratio (psQTL = 1.3 × 10−7).ConclusionsThe NFE2L2 SNP, rs10183914, is significantly associated with outcome following aSAH. This is consistent with a clinically relevant pathophysiological role for oxidative and inflammatory brain injury due to blood and its breakdown products in aSAH. Furthermore, our findings support NRF2 as a potential therapeutic target following aSAH and other forms of intracranial haemorrhage.<br/

Clinical studies and pre-clinical animal models on facial nerve preservation, reconstruction, and regeneration following cerebellopontine angle tumor surgery-A systematic review and future perspectives

Background and purpose: Tumorous lesions developing in the cerebellopontine angle (CPA) get into close contact with the 1st (cisternal) and 2nd (meatal) intra-arachnoidal portion of the facial nerve (FN). When surgical damage occurs, commonly known reconstruction strategies are often associated with poor functional recovery. This article aims to provide a systematic overview for translational research by establishing the current evidence on available clinical studies and experimental models reporting on intracranial FN injury. Methods: A systematic literature search of several databases (PubMed, EMBASE, Medline) was performed prior to July 2020. Suitable articles were selected based on predefined eligibility criteria following the Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA) guidelines. Included clinical studies were reviewed and categorized according to the pathology and surgical resection strategy, and experimental studies according to the animal. For anatomical study purposes, perfusion-fixed adult New Zealand white rabbits were used for radiological high-resolution imaging and anatomical dissection of the CPA and periotic skull base. Results: One hundred forty four out of 166 included publications were clinical studies reporting on FN outcomes after CPA-tumor surgery in 19,136 patients. During CPA-tumor surgery, the specific vulnerability of the intracranial FN to stretching and compression more likely leads to neurapraxia or axonotmesis than neurotmesis. Severe FN palsy was reported in 7 to 15 % after vestibular schwannoma surgery, and 6% following the resection of CPA-meningioma. Twenty-two papers reported on experimental studies, out of which only 6 specifically used intracranial FN injury in a rodent (n = 4) or non-rodent model (n = 2). Rats and rabbits offer a feasible model for manipulation of the FN in the CPA, the latter was further confirmed in our study covering the radiological and anatomical analysis of perfusion fixed periotic bones. Conclusion: The particular anatomical and physiological features of the intracranial FN warrant a distinguishment of experimental models for intracranial FN injuries. New Zealand White rabbits might be a very cost-effective and valuable option to test new experimental approaches for intracranial FN regeneration. Flexible and bioactive biomaterials, commonly used in skull base surgery, endowed with trophic and topographical functions, should address the specific needs of intracranial FN injuries

Associations of renal function with cerebral small vessel disease and functional outcome in acute intracerebral haemorrhage: A hospital-based prospective cohort study.

BACKGROUND Intracerebral haemorrhage (ICH) is a severe clinical consequence of cerebral small vessel disease (SVD), but associations between renal impairment and SVD in patients with ICH have not been fully characterised. METHODS Using data from the CROMIS-2 ICH observational study, we compared SVD neuroimaging markers and total burden (score 0-3) identified using CT brain imaging in patients with and without renal impairment (estimated glomerular filtration rate, eGFR<60). We assessed functional outcome at 6-month follow-up using the modified Rankin scale. RESULTS 1027 participants were included (mean age 72.8, 57.1% male); 274 with and 753 without renal impairment. 18.7% of the eGFR60 (p = 0.039). SVD burden was associated with renal impairment after adjusting for hypertension (OR 1.36, 95% CI 1.04-1.77, p = 0.023), but not after adjusting for age. Cerebral atrophy was more prevalent in patients with eGFR<60 (81.2% vs. 72.0%, p = 0.002), as were WMH (45.6% vs. 36.6%, p = 0.026). Neither was associated with renal function after adjusting for age and vascular risk factors. Renal impairment was associated with functional outcome (OR 0.65, 95% CI 0.47-0.89, p = 0.007), but not after adjusting for age, pre-morbid function and comorbidities (OR 0.95, 95% CI 0.65-1.38, p = 0.774). CONCLUSION In acute ICH, renal impairment is associated with a higher cerebral SVD burden independent of hypertension, but not age. Reduced eGFR is associated with worse functional outcome, but not independent of age and comorbidities. Since CT has limited sensitivity to detect SVD severity and distribution, further studies including MRI are needed