Towards an epidemiology of the known unknowns in cryptogenic stroke
- 1Center for Clinical Evidence Synthesis, Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, Boston, Massachusetts, USA
- 2Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, Boston, Massachusetts, USA
- Correspondence to Dr David Kent, Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, 800 Washington Street, Box 63, Boston, MA 02111, USA;
Contributors IJD and DMK discussed the manuscript by Pezzini et al. and jointly developed the ideas presented in this editorial. IJD wrote the first draft of the paper and DMK critically revised it for important intellectual content. Both authors read and approved the final version for publication.
- Cryptogenic stroke
- patent foramen ovale
- paradoxical embolism
- risk factors
- coronary artery disease
- gene association
- risk stratification
[T]here are known knowns; there are things we know we know. We also know there are known unknowns; that is to say we know there are some things we do not know. But there are also unknown unknowns — the ones we don't know we don't know.
US Secretary of Defense Donald Rumsfeld
Ischaemic stroke is a heterogeneous disorder, with many potential causes. According to the TOAST (Trial of Org 10172 in Acute Stroke Treatment) classification, a stroke may be due to large vessel, small vessel or cardioembolic disease, or may have some other determined cause.1 Different stroke mechanisms can point to different strategies for secondary prevention. Yet, even after an extensive work-up, about 30% of ischaemic strokes cannot be classified into any of these four categories and are instead classified as ‘cryptogenic’.
Although one might expect secondary prevention of cryptogenic stroke to be relatively standardised, because the underlying mechanism is unknown in all patients, it is true that cryptogenic stroke is itself a heterogeneous entity. Possible disease mechanisms include atheroembolic (eg, in patients with aortic arch atheromas), cardioembolic (such as in patients with occult paroxysmal atrial fibrillation), and lacunar disease. For patients with cryptogenic stroke found to have a patent foramen ovale (PFO), the possible mechanisms underlying the ischaemic event would include all of the above plus paradoxical embolism, that is, a stroke caused when an embolus formed in the venous circulation gains access to the systemic arterial circulation through a right-to-left shunt (RLS). Does the fact that the cause …