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Patent foramen ovale (PFO) is a common finding in the general population and is present in approximately one quarter of adults. The potential role of PFO in the pathogenesis of ischaemic brain infarction of unknown aetiology in young adults has been investigated during the past 15 years, and associations with other diseases have been proposed. The most plausible mechanism of stroke associated with PFO is paradoxical embolism, but there is uncertainty about this because a venous source of emboli is seldom identified. If the theory of venous emboli is relevant, prothrombotic states should be associated with PFO and ischaemic stroke. Relatively little is known about the risk factors of cryptogenic brain infarction, although this subgroup of stroke is relatively common. As the present diagnostic methods for detecting PFO have certain limitations, new non-invasive, simple and reliable methods would be useful. Two new methods examined here, the dye dilution method and ear oximetry, were both found to be feasible and to be highly specific and sensitive in relation to the present gold standard, contrast transoesophageal echocardiography. A case-control study among adult patients with PFO and cryptogenic brain infarction showed the presence of a prothrombotic state, particularly factor V Leiden and prothrombin G2021OA gene mutation, to be associated with an increased risk of stroke, and migraine was also identified as a risk factor. Associations with the classical risk factors for venous thrombosis and Valsalva manoeuvre-like activities at the onset of stroke were also observed. The results lend support to the theory that paradoxical embolism is one of the pathogenic mechanisms behind cryptogenic brain infarction with associated PFO. In another case-control study among adult patients with cryptogenic brain infarction but without associated PFO, prothrombotic states were not identified as risk factors, except that an association was found between elevated factor VIII activity and stroke. The major independent risk factors for such cryptogenic strokes were current cigarette smoking, hypertension and a low level of high density lipoprotein cholesterol.