Cerebral Cavernous Malformations (CCM) and Intracranial Aneurysms (IA) are cerebrovascular disorders that can lead to a hemorrhagic stroke and other neurological problems. CCMs are characterized by abnormally enlarged capillary cavities while IAs are saccular outpouchings of intracranial arteries. CCM is found in approximately 0.4% to 0.9% of the population, while IA is more common (3-6%). / This dissertation aimed to add to the body of research for CCM and IA and was divided into two parts. Initial work focused on the characterization and identification of the genes involved in CCM; the second phase focused on the identification of a susceptibility gene for IA. / In the first phase, the CCM1, CCM2 and CCM3 genes were characterized in families and in sporadic cases of CCM. In both cohorts, a causative mutation was identified in 71% of the cases. Subsequent MLPA analysis of subjects with no CCM mutations revealed that large genomic deletions and duplications are a common cause of CCM. In addition, investigation of CCM1 point mutations revealed that these were not simple missense mutations but that they rather activated cryptic splice-donor sites and caused aberrant splicing. Furthermore, the genetic predisposition to CCM in sporadic cases with a single lesion was determined to be different from sporadic cases with multiple malformations. Investigation into the loss of heterozygosity demonstrated a plausible mechanism for CCM pathogenesis involving a second somatic hit at the site of the lesion, suggesting that CCM may be caused by a complete loss of CCM protein function. / In the second phase, a genome-wide scan of a large family and subsequent linkage analysis using a monogenic approach identified a susceptibility locus for IA (ANIB4). / As a result of this research, we have greatly contributed to the field of CCM, most specifically to its clinical diagnosis. A greater understanding of the genetics involved in CCM will facilitate and permit better management care for patients. Furthermore, the possibility of identification of a gene with a major effect for IA will give us more insight into which pathways are involved in IA formation.

Thesis (M.S.)--School of Materials Science and Engineering, Georgia Institute of Technology, 2005. Directed by Janet Hampikian. / Zhuqing Zhang, Committee Member ; Roger Narayan, Committee Member ; Brent Carter, Committee Member ; Janet Hampikian, Committee Chair. Includes bibliographical references.

Thesis (Ph. D.)--University of Washington, 2005. / Vita. Includes bibliographical references (leaves 97-111).

No description available.

published_or_final_version / Surgery / Master / Master of Medical Sciences

No description available.

MMed, Ophthalmology, Faculty of Health Sciences, University of the Witwatersrand / Aim To determine and document the demographic profile, clinical features, associations and clinical and visual outcomes in black African patients with idiopathic intracranial hypertension (IIH) attending St John Eye Hospital during 2006 and 2007. Method A retrospective descriptive study was conducted on black African IIH patients. Patient files and data of 21 of 32 IIH patients, seen in the Neuro-ophthalmology clinic at St John Eye Hospital over a two year period (2006 and 2007), were available and this study is based on these 21 patients. All 21 patients fulfilled the modified Dandy criteria for the diagnosis of IIH. Information obtained from files of the 21 patients were recorded on a data capture sheet. The demographics, initial (presenting) and final visual acuities and visual fields, initial and final clinical symptoms and signs, associations and treatment modalities were recorded on the data capture sheet. Visual and clinical outcomes were determined by comparing the final with the initial (presenting) symptoms and signs. The minimum follow-up period between the initial and the final visit was two months. Patients were regarded as legally blind if they had severe to profound visual acuity and/or visual field loss. Results All 21 patients were female and black African. Mean age was 31.2 ± 8.9 years (range 16 – 50 years). Mean period of follow up was 19.9 ± 20.1 months (range 2 – 77 months). 71.4% were obese. All patients presented with symptoms. The commonest presenting symptom was headache (90%) followed by visual loss (67%), transient visual obscurations (38%) and diplopia (29%). The results of the presenting signs were as follows: Seven eyes (17%) had visual acuity loss (most of which were mild [9.5%]), seven patients (33%) had abduction deficits, four patients (9.5%) had unilateral abnormal pupil reactions and all patients had papilloedema. Of the recorded associations seven patients (33%) were hypertensive, six (29%) were on contraception (two [9.5%] were on oral contraception) and two (9.5%) were taking prednisone prior to presentation. After the initial visit, all 21 vi IIH patients were treated with acetazolamide (Diamox) and weight loss was recorded in three patients (14%). Two patients (9.5%) had optic nerve sheath fenestrations (ONSF), two (9.5%) had lumbar-peritoneal shunts (LPS) and six (28.6%) had multiple lumbar punctures (LP’s). The outcome analysis was as follows: Symptoms in 19 patients (90%) improved but 16 patients (76%) still had papilloedema. Two patients (9.5%) had abduction deficits at the final visit. Visual acuity loss occurred in five eyes (12%) at the final visit compared to seven eyes (17%) at the initial visit (presentation). From the initial visit (presentation) to the final visit, visual acuity in seven eyes (16%) improved, 31 eyes (74%) remained stable and four eyes (10%) worsened. Although visual fields in 33 eyes (79%) improved from the initial to the final visit, 36 eyes (86%) still had visual field loss at the final visit. 26% of eyes had severe to profound visual impairment i.e. were legally blind, at the final visit. Conclusion The results of 21 black African IIH patients reported in this study were similar to some other studies with regards to demographics, clinical features and clinical and visual outcomes. An association between IIH and oral contraceptives, steroids and hypertension could not be established. Although symptoms resolved in most patients, a significant number of patients still had papilloedema and visual field loss following treatment. Despite treatment, a quarter of the patients were legally blind at the final visit, indicating that this condition is not benign.

Zhu Xian Lun. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1991. / Includes bibliographical references (leaves 83-103). / ACKNOWLEDGEMENT --- p.1 / ABSTRACT --- p.2 / Chapter CHAPTER 1 --- INTRODUCTION --- p.4 / Chapter CHAPTER 2 --- TREATMENT METHODS OF INTRACRANIAL ANEURYSMS OTHER THAN CLIPPING --- p.6 / Chapter CHAPTER 3 --- EXPERIMENTAL ANEURYSM MODELS --- p.24 / Chapter CHAPTER 4 --- A SUITABLE ANEURYSM MODEL FOR THE STUDY --- p.30 / Introduction / Materials and methods --- p.31 / Results --- p.37 / Discussion --- p.46 / Conclusion --- p.56 / Chapter CHAPTER 5 --- REINFORCEMENT AND FILLING TREATMENT IN EXPERIMENTAL ANEURYSMS --- p.57 / Introduction / Materials and methods --- p.58 / Results --- p.63 / Discussion --- p.71 / Conclusion --- p.77 / Chapter CHARTER 6 --- SUMMARY --- p.79 / Chapter APPENDIX I --- REFERENCES --- p.83 / Chapter APPENDIX II --- TABLES --- p.104 / Chapter APPENDX III --- FIGURES --- p.115

Stroke is the third leading cause of death and the most common cause of disability in the world. To relieve the heavy burden of stroke, we need to understand the mechanisms that will form the basis of improved prevention and treatment. Epidemiological studies have found evidence for a genetic influence on the common form of stroke. However the genetic of stroke is still in its infancy. Subclinical intracranial atherosclerosis is sometime a predisposing factor for ischemic stroke (IS). This study was carried out to elucidate genetic factors influencing the complex phenotype of IS and subclinical intracranial atherosclerosis. In the Belgium Stroke Study (BSS), we collected 237 middle-aged (45-60 yrs) patients with small vessel occlusion (SVO) or large vessel atherosclerosis (LVA) IS, according to the Acute Stroke Treatment (TOAST) criteria, 326 ethnicity and gender matched subjects were used as controls. We tested variants in cholesterol-related candidate genes (sterol regulatory element binding protein, SREBP, SREBP-cleavage activating protein, SCAP, Apolipoprotein E, APOE, and Proprotein convertase subtilisin/kexin type 9, PCSKA) for association with IS. Significant gene-IS associations were further tested in a Finnish autopsy collection of 1004 cases with a quantitative assessment of atherosclerosis in the circle of Willis. While we could not detect any significant association between polymorphisms in the SREBP and SCAP genes and IS, we found evidence for association at the APOE and PCSK9 loci. The APOE ε4+ genotype was related to a more severe intracranial atherosclerosis score in men, and within the most common APOE ε3/ε3 genotype group a higher risk of IS was associated with the G-allele at the -219G/T promoter polymorphisms. At PCSK9, the minor allele (G) of the tagging E670G polymorphism appeared as a significant predictor of LVA (OR = 3.52, 95% CI 1.25-9.85; p = 0.017). Accordingly, in the Finnish autopsy series, G-allele carriers tended to have more severe allele copy number-dependent (p=0.095) atherosclerosis in the circle of Willis and in its branches. Our findings in this unique combination of clinical and autopsy data suggest a multifaceted role of apoE on the risk of cerebrovascular diseases. The APOE ε4+ genotype did not predict the risk of IS, but was associated with severity of subclinical intracranial atherosclerosis in men. In contrast, the promoter variants affecting apoE expression were significant predictors of IS, suggesting that quantitative rather than qualitative variation of apoE is related to IS independently of subclinical intracranial atherosclerosis. Furthermore, we demonstrated that PCSK9 associates with the risk of LVA stroke subtype, and suggest that the risk is related to the severity of the underlying intracranial atherosclerosis. Atherogenesis is considered as an active, inflammatory process, interleukin (IL)-18 a proinflammatory cytokine, is thought to play a central role in the development of atherosclerosis and more specifically in plaque rupture. We genotyped four haplotype tagging polymorphisms at the IL18 gene in the BSS and the Finnish autopsy series. The minor alleles of the IL18 -607 and +127 polymorphisms, as well as the haplotype carrying both minor alleles, associated with IS after adjustment for all cardiovascular risk factors. No association was seen with the development of subclinical intracranial atherosclerosis. Our findings suggest that variation in the IL18 gene influences the acute atherosclerotic IS event, but not the previous development of subclinical intracranial atherosclerosis, suggesting a causal role of IL18 in the vulnerability of cerebral arterial atherosclerotic plaques to acute rupture and subsequent thrombosis.

Thesis (M. Med. Sc.)--University of Hong Kong, 2009. / Includes bibliographical references (p. 30-34).