This article discusses cryptogenic stroke and the results of recent randomized trials that can inform its evaluation and management. Most cryptogenic strokes appear embolic, leading to the term embolic stroke of undetermined source. It was previously thought that embolic stroke of undetermined source was a single, therapeutically relevant entity, the underlying sources of which would respond to anticoagulant therapy; however, two large randomized trials found no benefit with anticoagulation compared to antiplatelet therapy for secondary stroke prevention after embolic stroke of undetermined source. A single antiplatelet drug remains the recommended long-term antithrombotic treatment for secondary stroke prevention in embolic stroke of undetermined source. However, three caveats should be considered with regard to cryptogenic stroke. First, those with minor stroke symptoms presenting early after onset should receive 3 weeks of dual antiplatelet therapy. Second, all patients with cryptogenic stroke should be monitored for atrial fibrillation. Third, patients 60 years of age or younger with a patent foramen ovale (PFO) should be carefully evaluated to determine whether the PFO may have caused the stroke and whether they might benefit from PFO closure. More personalized strategies may soon be available to guide treatment of cryptogenic stroke. In the meantime, it is hoped that the application of recent findings from clinical trials will reduce stroke recurrence in this important population.
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