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).
