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Towards an epidemiology of the known unknowns in cryptogenic stroke
  1. Issa J Dahabreh1,
  2. David M Kent2
  1. 1Center for Clinical Evidence Synthesis, Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, Boston, Massachusetts, USA
  2. 2Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, Boston, Massachusetts, USA
  1. 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; dkent1{at}

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[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 …

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  • Funding This study was partially funded by grants UL1 RR025752 and R01 NS062153, both from the National Institutes of Health. The funder had no role in the preparation, review or approval of the manuscript. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

  • Competing interests None.

  • Provenance and peer review Commissioned; internally peer reviewed.

  • i Given the case-control design of the study, we focus on results presented in the OR scale, despite the advantages of the risk difference scale for causal inference. Risk difference calculations are not possible from case-control data without making additional assumptions, or relying on external information on the source population.