Scottish Intracranial Vascular Malformation Study was the first prospective, population-based study of the major types of intracranial vascular malformations; arteriovenous, cavernous and venous malformations including dural fistulae and carotid-cavernous fistulae. It was based in Scotland and designed in 1998 by my supervisor Professor Charles Warlow and the first Research Fellow Dr Rustam Al-Shahi supported by the SIVMS steering committee (www.saivms.scot.nhs.uk). Recruitment and follow-up began in January 1999. Recruitment and follow-up of all vascular malformation types was done by Dr Al-Shahi until March 2002 and this role then transferred to me in April 2002 until I left in August 2004. The main duties of the Research Fellow were to collect and review all the clinical material of cases notified to SIVMS and arbitrate with the relevant expertise where there was doubt whether the case met the criteria for inclusion in SIVMS. Apart from my clinical responsibilities in recruitment and follow-up, the post also involved supervision of the part-time study administrator and also weekly meetings with the study programmer. I was also responsible for convening and presenting updates of the study progress weekly to my supervisor Professor Charles Warlow, biannually to the Study steering committee meetings, and annually to my funding body, the Stroke Association. This Research Fellowship also allowed me to gain an appreciation of the efforts needed to sustain collaborators’ interest in a long running study and I made presentations to improve the profile of the study on the national and international stage. For my duration as the SIVMS Research Fellow, I recruited and followed-up all types of newly diagnosed intracranial vascular malformations (IVMs). This thesis, however, is based solely on the incident intracranial cavernous malformations (ICMs) recruited to the study by both Dr Al-Shahi and myself between January 1999 and December 2003. The follow-up data in this thesis were that available to me on August 31st 2004. The data cleaning and the analysis for this thesis has been performed by me alone under the supervision of Professor Warlow. Although the core study design was well-established and tested prior to my involvement with SIVMS, I did divise new studies such as the Sensitivity and Specificity of MRI in the diagnosis of intracranial CMs. This cavernoma imaging study was a separate study designed, executed and analysed by myself, a medical student Sue Liong, the Cavernoma Imaging Study Group [appendix 1] with guidance from Professor Warlow, Dr Al-Shahi, Dr Andrew Farrall (consultant neuroradiologist) and Dr Steff Lewis (Medical Statistician). Computing support was provided by Aidan Hutchison (SIVMS programmer).

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Introduction : l’innervation et la vascularisation des corps caverneux du pénis sont très difficilement explorables par les techniques de dissection anatomiques classiques. De ce fait, elles demeurent pas très bien connues. La dissection anatomique assistée par ordinateur (CAAD), combinant méthodes immuno-histochimiques et reconstruction tridimensionnelle représente un outil original permettant l’analyse microscopique des artères et des nerfs au sein des corps caverneux. Les objectifs de ce travail étaient donc d’étudier l’innervation et la vascularisation microscopique des corps caverneux par dissection anatomique assistée par ordinateur (CAAD).Matériel et méthodes : Des coupes histologiques sériées de pénis ont été réalisées chez huit cadavres adultes masculins et sur des pièces issues de pénnectomie pour cancer à l’hôpital du kremlin-Bicêtre. Les coupes ont été traitées par des méthodes histologiques (Hématoxyline-Eosine et trichrome de Masson) et immuno-histochimiques pour détecter les fibres nerveuses (anti-S100), les fibres somatiques (anti-PMP22), les fibres adrénergiques (anti-TH), cholinergiques (anti-VAChT) et nitrergiques (anti-nNOS). Les lames ont ensuite été numérisées par un scanner de haute résolution optique et les images bidimensionnelles ont été reconstruites en trois dimensions grâce au logiciel WinSurf. Résultats: La reconstruction tridimensionnelle des coupes histologiques immuno-marquées a permis de décrire l’innervation et la vascularisation des corps caverneux du pénis. Les artères et les nerfs du pénis sont très largement anastomosés entre eux.Les anastomoses entre les artères caverneuses et les artères urétrales se font en dehors de l’albuginée du corps spongieux d’où le terme de « shunts caverno-urétraux » utilisé dans ce travail pour qualifier ces vaisseaux anastomotiques.La vascularisation et l’innervation permettent de distinguer deux compartiments anatomiques distincts au niveau du pénis : une partie proximale (les 2/3 du pénis) autonome dont les artères et les nerfs proviennent du plexus hypogastrique inférieur (supra-lévatorien), et le tiers distal somatique dont les artères et les nerfs proviennent des artères et nerfs dorsaux du pénis (infra-lévatorien).Les communications entre les systèmes autonomes et somatiques (entre le plexus hypogastrique inférieur supra-lévatorien et le nerf pudendal infra-lévatorien) existent donc à quatre niveaux : proximal, intermédiaire, à la racine du pénis et intracaverneuses. Les communications intracaverneuses sont responsables des marquages autonomes observés dans les nerfs dorsaux du pénis. Elles confèrent également aux corps caverneux une sensibilité à peu près semblable à celui du gland au cours de l’acte sexuel.Conclusion: Nos résultats montrent de très nombreuses anastomoses vasculaires et nerveuses dans les corps caverneux entre les systèmes supra et infra-lévatoriens avec 2 régions anatomiques distinctes : les 2/3 proximaux érectiles et le 1/3 distal sensitif. Ces anastomoses permettent d’espérer une certaine plasticité dans la vascularisation et l’innervation du pénis en cas de dysérection. / Introduction: The innervation and the vascularization of the corpora cavernosa of the penis are very difficult searchable by the classical anatomic dissections. Therefore, they remain not very well known. The computer-assisted anatomic dissection (CAAD), combining immunohistochemical methods and three-dimensional reconstruction is a unique tool for the microscopic analysis of the arteries and nerves in the corpora cavernosa.The objectives of this study were therefore to investigate the microscopic innervation and vascularization of the corpora cavernosa by the CAAD.Materials and methods: Serial histological sections of penis were performed in eight adult male cadavers and one piece after penectomy for cancer in the hospital of Kremlin Bicetre. The sections were processed by histological methods (hematoxylin-eosin and Masson trichrome) and immunohistochemistry to detect nerve fibers (anti-S100), somatic fibers (anti-PMP22), adrenergic fibers (anti-TH), cholinergic fibers (anti-VAChT) and nitrergic fibers (anti-nNOS). The slides were then scanned by a high resolution scanner and two-dimensional images were reconstructed in three dimensions using WinSurf software.Results: Three-dimensional reconstruction of immunolabeled histological sections allowed describing the innervation and vascularization of the corpora cavernosa of the penis. The arteries and nerves of the penis are widely anastomosed.The anastomoses between the cavernous arteries and urethral arteries are outside the tunica albuginea of the corpus spongiosum hence the term "cavernous urethral shunts".The innervation of the penis distinguishs two distinct anatomical portions: a proximal portion (2/3 of the penis) is autonomic whose arteries and nerves come from the inferior hypogastric plexus (supralevator), and the third including somatic distal nerves from the dorsal nerves of the penis (infralevator).The communications between autonomic and somatic systems (between the inferior hypogastric plexus and the pudendal nerve) exist in four levels: proximal, middle, crura of penis and intra-cavernous. The intra-cavernous communications are responsible for autonomic fibers observed in the dorsal nerves of the penis.Conclusion: Our results show a large number of vascular and nerve anastomoses in the corpora cavernosa between supra and infralevator sustems with two distinct anatomical regions: the 2/3 proximal erectile portion and 1/3 distal sensorial portion. These anastomoses provide a hope for the plasticity in the vascularization and innervation of the penis in cases of erectile dysfunction.

<p>Cerebral cavernous malformations (CCMs) are multicavernous vascular lesions affecting the central nervous system. Affected individuals have a lifetime risk of recurrent headaches, focal neurological deficits, seizures, and intracerebral hemorrhage leading to stroke. Patients tend to fall into two classes: familial cases with a known family history and multiple lesions, and; sporadic cases with no family history and single lesions. This epidemiological pattern suggests a two-hit mutational mechanism for CCM. While somatic mutations have been identified in lesions from familial patients, it is unknown if sporadic cases follow the same genetic mechanism. Using a next-generation sequencing strategy, I have identified somatic mutations from sporadic CCM lesions in the three known CCM genes, including one lesion bearing two independent mutations in CCM1. These data support a two-hit mutation mechanism in CCM for sporadic patients.</p><p>The mechanism of CCM pathogenesis (how mutations in one of the three CCM genes causes lesions to form and develop) is currently unknown. We developed mouse models that recapitulate the human disease. We have further shown that inhibition of Rho Kinase decreases the number of late-stage, multicavernous lesions. This is the first potential therapeutic strategy to specifically treat CCM, and suggests that the RhoA pathway is a central player in CCM pathogenesis.</p> / Dissertation

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.

The distinction between cavernous haemangiomas of the liver (which are the second most common hepatic mass lesions) from malignant lesions, is often difficult. An incorrect diagnosis of cavernous haemangioma, in a patient with malignancy, may adversely influence the outcome of subsequent treatment in these patients, due to delay in therapy. Although previous studies have suggested that ⁹⁹ᵐTc erythrocyte blood pool scintigraphy is both highly sensitive and specific for haemangiomas, a basic flaw in all previous studies has been the small number of control patients studied. Bayesian analysis clearly shows that specificity for a test is dependant on the pre-test probability of the lesion being present. Thus all the studies done to date, may reflect an inappropriately high specificity for ⁹⁹ᵐTc scintigraphy, in diagnosing cavernous haemangiomas, because they have mainly studied patients with haemangiomas and relatively few patients with other lesions. This study was thus undertaken to clarify the true accuracy of this technique, in distinguishing haemangiomas from other hepatic mass lesions, by studying a large number of patients with haemangiomas and other hepatic mass lesions.

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

Objective: While cavernous carotid aneurysms can cause neurological symptoms, their often-uneventful natural course and the increasing options of intravascular aneurysm closure call for educated decision-making. However, evidence-based guidelines are missing. Here, we report 64 patients with cavernous carotid aneurysms, their respective therapeutic strategies, and follow-up. Methods: We included all patients with cavernous carotid aneurysms who presented to our clinic between 2014 and 2020 and recorded comorbidities (elevated blood pressure, diabetes mellitus, and nicotine consumption), PHASES score, aneurysm site, size and shape, therapeutic strategy, neurological deficits, and clinical follow-up. Results: The mean age of the 64 patients (86% female) was 53 years, the mean follow-up time was 3.8 years. A total of 22 patients suffered from cranial nerve deficit. Of these patients, 50% showed a relief of symptoms regardless of the therapy regime. We found no significant correlations between aneurysm size or PHASES score and the occurrence of neurological symptoms. Conclusion: If aneurysm specific symptoms persist over a longer period of time, relief is difficult to achieve despite aneurysm treatment. Patients should be advised by experts in neurovascular centers, weighing the possibility of an uneventful course against the risks of treatment. In this regard, more detailed prospective data is needed to improve individual patient counseling.