Etiology and Risk Factors for Ischemic Stroke

Cryptogenic stroke represents a diagnostic challenge. Several conditions have been found to be more frequent in patients with cryptogenic stroke. Aortic arch atheroma (AAA) and patent foramen ovale (PFO) have been shown to be highly prevalent in the adult population, especially in patients with ischemic cerebrovascular events, particularly cryptogenic strokes. In both conditions, clinical relevance and stroke risk are related to age, with AAA being more frequent and severer in patients 1 55 years, and the relationship between stroke and PFO being stronger in those ! 55 years of age. This review is focused on the prevalence, risk of stroke and therapeutic strategies in patients with cryptogenic stroke related to AAA or PFO. Copyright © 2007 S. Karger AG, Basel Stroke is the leading cause of death and disability in most developed countries. Unlike acute myocardial infarction, the underlying mechanism of stroke is heterogeneous. The tremendous progress and widespread availability of imaging modalities have prompted a rapid and Published online: November 1, 2007 Carlos A. Molina, MD, PhD Neurovascular Unit, Department of Neurology, Magnetic Resonance Unit Hospital Universitari Vall d’Hebron, Universitat Autonoma de Barcelona Passeig Vall d’Hebron 119-129, ES–08035 Barcelona (Spain) Tel. +34 932 746 235, Fax +34 932 746 255, E-Mail cmolina@vhebron.net © 2007 S. Karger AG, Basel 1015–9770/07/0247–0084$23.50/0 Accessible online at: www.karger. com/ced Cryptogenic Stroke Cerebrovasc Dis 2007;24(suppl 1):84–88 85 AAA: Source of Cerebral Embolism or Marker of Increased Atherosclerosis Load? Postmortem, case series and community-based studies have demonstrated that AAA is a relatively frequent finding, and that its incidence and severity increase markedly with age [2] . Several factors have been identified to be associated with an increased risk of AAA, including hypertension, cigarette smoking, diabetes mellitus, hypercholesterolemia and peripheral vascular disease. Natural history studies using transesophageal echocardiography (TEE) have established that aortic plaques tend to be stable (90%) or are slowly progressive over the years after the first diagnosis [3, 4] . These studies, however, are limited by the relative short follow-up period ( ! 28 months) and the lack of information regarding the proportion of patients treated with drugs that may potentially alter the course of the disease (i.e. statins). Therefore, long-term follow-up studies balanced by potential confounders are needed. Whether AAA is a source of emboli or simply represents a marker of an increased atherosclerotic load is a matter for discussion. The association between AAA and carotid atherosclerosis has been demonstrated in some studies. Moreover, Kazui et al. [5] observed a prevalence of 20% of severe AAA ( 1 5 mm) in a cohort of patients with lacunar stroke, compared with 4% in controls. Recently, an association was described between AAA and the presence and extent of intracranial atherosclerotic stenosis. Together with the strong epidemiologic link between peripheral vascular disease and AAA [6] , these studies may indicate that AAA reflects an increased atheroma load. On the other hand, in most studies AAA is associated with cryptogenic stroke and particularly with embolic events [7–9] . In fact, it has been reported that atheromas located in the midto distal arch tend to be associated with ischemic events in the left carotid artery territory. Moreover, the embolic potential of AAA has been consistently demonstrated in case-control studies using transcranial Doppler monitoring, showing an increased number of microembolic signals in both middle cerebral arteries in patients with AAA compared with those without [10, 11] . Rundek et al. [10] used an automated high-intensity transient-signal detection system and found embolic signals in 14 of 18 patients with severe arch atheroma, but in only 8 of 28 patients without. Castellanos et al. [11] used manual signal detection, and found embolic signals in 3 of 10 patients with severe arch atheroma, but in none of 39 without, and Viguier et al. [12] similarly found embolic signals in 2 of 14 patients with severe atheroma, but in none of 30 without. There is pathologic evidence supporting the embolic potential of AAA. Postmortem studies described cases of recurrent stroke with ulcerated AAA covered by fresh and soft thrombi, and multiple cholesterol emboli associated with severe AAA. The risk of recurrent stroke in patients with AAA is closely correlated with atheroma size and with the presence of ulcerations and mobile components. The extensive use of TEE for the diagnosis and follow-up of AAA provided valuable information, not only on its natural history, but also on its capability to stratify patients at high risk of recurrence, based on the sonographic characteristics of the AAA. Two case-control studies have clearly demonstrated the relationship between AAA size and risk of recurrent stroke. Using TEE, Amarenco et al. [7] prospectively studied 250 stroke patients 1 60 years and 250 controls 1 60 years. Atheromas of 4 mm or more were found in 14.4% of stroke patients and in only 2% of controls. The hazard ratio for ischemic stroke increased progressively with plaque thickness, from 3.3 for AAA of 1–2 mm to 13.8 for AAA of 4 mm or more. In this study, severe AAA was significantly more frequent in stroke of undetermined origin (28%) than in patients with an identifiable cause of stroke (8%). On the other hand, Jones et al. [13] demonstrated in a community-based case-control study a strong association between plaque appearance on TEE and the risk of recurrent stroke. In those patients with recurrent stroke, the adjusted hazard ratio for patients with an atheroma ! 5 mm was 2.3, rising to 7.1 in patients with complicated severe plaques 6 5 mm with ulcerations and mobile components. A recent meta-analysis [6] , comparing all reported studies including postmortem studies, case series, casecontrol studies and a substudy of the Stroke Prevention in Atrial Fibrillation (SPAF) Echo trial, estimated the odds of stroke in patients with severe AAA to be 3.76 (95% CI: 2.58–5.48), providing robust and firm evidence of the role of AAA in stroke risk. Since severe AAA is associated with a higher risk of recurrent embolism, anticoagulation represented the first attempt to prevent further embolic events caused by severe AAA atheroma. Two small retrospective nonrandomized studies [8, 14] showed that treatment with warfarin was associated with a reduced incidence of vascular events in these patients. For patients with mobile thrombi, there was a significant reduction in motility and a trend towards fewer embolic events in those patients on anticoagulation. The SPAF Investigators Committee on Echocardiography [15] randomized patients with high-