Identification Of Risk Factors For Pseudotumor Cerebri

特发性颅内高压(IIH)，又称大脑假瘤(PTC)，是一种在缺乏临床、实验室或放射学证据的情况下，以孤立的颅内高压为特征的综合征，会对视觉系统造成灾难性的影响。临床表现是由脑脊液(CSF)压力升高引起的，然而，其发病机制尚不清楚。最普遍的假设是，脑脊液压力增加是由于蛛网膜绒毛对脑脊液的吸收减少所致。虽然大多数病例是非家族性的，但家族性PTC的报道提出了遗传易感因素的可能存在，这导致了暴露于沉淀剂后的临床表现。因此，我们假设IIH是多因素的，潜在的遗传血栓危险因素使患者容易出现局部血栓衬里蛛网膜绒毛，这反过来导致颅内压升高，而常规成像技术没有显示出脑静脉血栓形成。这种基因变异可能发生在凝血因子V中。 凝血因子V是一种在止血中起关键作用的酶辅因子。在因子V基因的25个外显子中已经发现了几个多态性/突变。突变因子V活性改变是最常见的易发生血栓形成的遗传性凝血障碍。凝血因子V基因的多个突变/多态，包括V-Hong Kong(Arg306Gly)、V-Cambridge(Arg306Thr)、Arg485Lys、V-Leiden(Arg506Gln)和R2等位基因(Arg-1299)位于第7、10和13外显子。我们扫描了51例IIH患者和68名对照的这三个外显子的多态性。与对照组相比，IIH患者FV血栓形成相关的3个基因(F V Leiden、1628G to A替换和R2等位基因)的患病率显著升高(优势比2.1[95%可信区间0.97~4.56]，p=0.044)。相关血栓前状态的发生率在我们的患者群体中也很高(67%)。对血栓形成的易感性可能是一个重要的遗传修饰物，当它与其他因素一起存在时，允许发生IIH。我们的研究是首次报道与IIH风险增加相关的基因多态。 鉴于这些发现，我们已经制定了一项临床方案来研究血栓易感性在肾病性膀胱癌患者PTC发生中的作用。对发生PTC和无PTC的肾病患者进行血栓易感性筛查，包括PT、APTT、活化蛋白C抵抗、血清蛋白C、蛋白S、抗凝血酶III、纤维蛋白原、第VIII因子、第IX因子、第XI因子和总同型半胱氨酸、抗磷脂抗体(ACA和狼疮AC)，筛查Fv Leiden突变、Fv G1628A多态、Fv R2等位基因、凝血酶原20210突变和5，10-亚甲基四氢叶酸还原酶基因C677T多态性。

Idiopathic Intracranial Hypertension (IIH), also known as Pseudotumor cerebri (PTC) is a syndrome characterized by symptoms and signs of isolated intracranial hypertension leading to catastrophic effects on the visual system in the absence of clinical, laboratory, or radiological evidence of a space-occupying lesion or hydrocephalus. The clinical picture is caused by increased cerebrospinal fluid (CSF) pressure; however, its pathogenesis is not well understood. The most prevalent hypothesis is that the increased CSF pressure is attributable to reduced CSF absorption through the arachnoid villi. Although the majority of cases are non-familial, reports of familial PTC raise the possible existence of genetic predisposition factor which leads to clinical manifestations following exposure to a precipitating agent. Thus, we hypothesize that IIH is multifactorial and that an underlying genetic thrombotic risk factor predisposes the patients to develop local thrombi lining arachnoid villi, which in turn leads to increased intracranial pressure without demonstrable cerebral venous thrombosis by conventional imaging techniques. Such a genetic variation might occur in coagulation factor V. Coagulation Factor V is an enzyme cofactor with pivotal functions in hemostasis. Several polymorphisms/mutations have been identified among the 25 exons of the Factor V gene. Altered activity of mutated Factor V is the most common hereditary blood coagulation disorder predisposing to thrombosis. A number of mutations/polymorphisms of the Factor V gene, including V-Hong Kong (Arg306Gly), V-Cambridge (Arg306Thr), Arg485Lys, V-Leiden (Arg506Gln), and the R2 allele (Arg-1299), all known to be associated with thrombotic risk, are located in exons 7, 10, and 13. We scanned these three exons for polymorphisms in 51 IIH patients and 68 controls. The prevalence of three FV thrombosis associated polymorphisms (Factor V Leiden, 1628 G to A substitution and R2 allele) in IIH patients was found to be significantly higher compared to the controls (odds ratio 2.1 [95% confidence interval 0.97-4.56], p=0.044). The incidence of associated prothrombotic states was also documented to be high in our patient population (67 %). Susceptibility to thrombosis may be an important genetic modifier which, when present in combination with the other factors, is permissive for development of IIH. Our study is the first report of a genetic polymorphism related to an increased risk to IIH. In view of these findings, we have developed a clinical protocol to study the role of thrombosis susceptibility in the development of PTC in nephropathic cystinosis patients. Nephropathic cystinosis patients who developed PTC and control nephropathic cystinosis patients without PTC are being screened based upon a thrombosis susceptibility screening panel, including PT, APTT, Activated Protein C resistance, serum levels of protein C, protein S, antithrombin III, fibrinogen, Factor VIII, Factor IX, Factor XI and total homocysteine, antiphospholipid antibodies (ACA and Lupus AC) and screening for FV Leiden mutation, FV G1628A polymorphism, FV R2 allele, Prothrombin 20210 mutation and 5,10-methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphism in patients with severe homocysteinemia (bigger or equal to 100 ?Ymol/l).