A new theory of cryptogenic stroke and its relationship to patent foramen ovale; or, the puzzle of the missing extra risk

SummaryCryptogenic stroke (or stroke of undetermined cause) is a common cause of stroke and is statistically associated with patent foramen ovale (PFO). The largest study of cryptogenic stroke is the Homma study, which is a sub-study of the WARSS trial; it produced the following data: cryptogenic stroke patients with and without PFO, when treated with either aspirin or warfarin, all had identical recurrence rates. This is puzzling because it seems as though there ought to have been some extra risk in one of the two groups under one of the two treatments. How could everything come out the same?A review of the epidemiology of cryptogenic stroke shows that, compared to patients with stroke of determined cause, cryptogenic stroke patients are a little younger and have lower doses of the usual risk factors (hypertension and diabetes mellitus) but more PFO. Cryptogenic strokes appear to be embolic strokes from an unknown source.A previously published article setting forth a hypothetical theory of stress-induced stroke was used to analyze these data. It is suggested that stress can induce episodic systemic platelet activation and hypercoagulability, which causes transient thrombus formation and subsequent embolization on both the arterial and venous sides of the circulation; the latter requires a PFO to cause a stroke (paradoxical embolism). The sum of these two mechanisms explains cryptogenic stroke. The PFO subset of cryptogenic stroke includes patients with both early and late stage disease who have an aggregate risk approximately equal to that of patients without PFO. Cryptogenic stroke is part of the disease of stress-induced cerebrovascular disease. Aspirin and warfarin have already been shown to be equally effective in secondary prevention of ischemic stroke.