What's the Take Home?

A Young Normotensive Woman Who Has Sustained a Cryptogenic Stroke

Ronald N. Rubin, MD—Series Editor

Rubin RN. A young normotensive woman who has sustained a cryptogenic stroke. Consultant. 2018;58(4):140-147.


A 33-year-old woman presented with a history of a sudden neurologic event. She had been in her usual excellent state of health when she noted an episode of difficulty in articulating words accurately, along with weakness of the right hand. The episode had lasted several hours then had slowly abated and had nearly normalized. There had been no aura or headache.

Her history was significant for having delivered her second child 10 weeks ago without problems and having initiated oral contraceptives the week prior to the event. She was taking no other medications.

Physical examination findings were within normal limits, including blood pressure and cardiac findings. Her lower extremities appeared normal, with no redness or edema. Neurologic evaluation demonstrated subtle residual speech impairment and hand weakness (grade of 1 of 5).

Results of a basic metabolic panel and a complete blood cell count (CBC), as well as the glucose level and cholesterol levels, were normal, as were 12-lead electrocardiography (ECG) findings. Magnetic resonance imaging (MRI) of the brain revealed a very small but definite area of ischemia in the left cerebral cortex, a finding consistent with a small ischemic stroke in the distribution of the middle cerebral artery.

She underwent more-detailed studies as follows: A 24-hour Holter monitoring study was negative for rhythm abnormalities. A spiral computed tomography (CT) scan was negative for pulmonary embolism (PE), and venous and pelvic Doppler ultrasonography scans were negative for deep-vein thrombosis (DVT). D-dimer results were within normal limits. Doppler transthoracic echocardiography (TTE) was negative for structural heart disease, but transesophageal echocardiography (TEE) using agitated saline contrast (bubble study) revealed the presence of a patent foramen ovale (PFO).




Answer: C is the correct statement

Cryptogenic strokes are ischemic strokes that remain without obvious probable cause after a complete traditional diagnostic evaluation, which by current standards includes stroke topography (brain MRI and CT), vessel evaluation (MRI of the head and neck and carotid and transcranial Doppler ultrasonography), cardiac structure evaluation (TTE and TEE), cardiac rhythm evaluation (ECG and 24-hour Holter monitoring), and hematology/metabolic core evaluation (CBC, blood glucose).1 Depending on study source and patient age, up to 40% of ischemic strokes will be cryptogenic, although as time goes on and advanced studies become more routine, that number has been progressively lowering into the 25% range.1 Another factor lowering the incidence is the unfortunate US epidemic of obesity and metabolic syndrome such that traditional large-vessel atherosclerotic, small-vessel hypertensive, and metabolic causes of stroke are now much more common in the 31- to 60-year-old group, which often launches an evaluation for unusual cause. Thus, Answer A is not a correct statement in that incidence of cryptogenic stroke is not nearly that high, especially when patients aged 31 to 60 years are included.

Conversely, the correct statement is Answer C. That is, once the standard evaluation has been performed and the results are negative, the next line of studies includes more-detailed testing for low-burden and/or occult episodes of AF (eg, prolonged outpatient cardiac monitoring)—an especially common etiology in older patients; more-detailed cardiac and great-vessel studies (eg, endovascular Doppler ultrasonography for ulcerating lesions, bubble studies for PFO), and coagulation studies (eg, antiphospholipid antibody tests) and venous hypercoagulability tests for paradoxical embolism (DVT, PE, blood testing).1,2 Essentially, all of the above result in small or larger embolic material finding its way into the neck and cerebral arterial circulation, causing an embolic-type ischemic stroke—Answer C. As mentioned above, AF is one of the more common findings in alleged cryptogenic stroke, with approximately 15% being new diagnoses of AF, making Answer D also not correct.

Specific therapeutics for cryptogenic stroke depend on which of the unusual etiologies discussed above is discovered, whether inflammatory (eg, vasculitic), anatomic (eg, patent ductus arteriosus), or arrhythmic (eg, AF). Our case appears to be related to a PFO, so the discussion of therapy will focus on that entity.

The approach to PFO can be framed as being surgical, medical, or both. The largest and longest study of cryptogenic stroke among adults with PFO shows a low recurrence after 4 years when aspirin alone is used.3 This is much lower and better than the prognosis associated with general stroke, where the typical etiologies of large- or small-vessel disease are found.3 When a PFO is found on bubble study, the accepted first-line therapy is daily aspirin in the 300 mg/day range, with observed recurrence being very low. Warfarin seems equivalent to aspirin in meta-analyses. As for the newer DOACs, theoretically they too should be effective, but not enough data are available yet to suggest their use, especially given the good data on the very low recurrence rates and safety of the use of aspirin or warfarin.1,2 Thus, at this this time, Answer B is not correct. It must be noted, however, that when a PFO is discovered in the setting of a positive hypercoagulable evaluation with an associated venous thrombotic event (eg, DVT, PE), then anticoagulation with warfarin is preferred to aspirin.2

As for surgical repair of PFO, which can now be performed with endovascular methods, a series of new available data shows significantly lower recurrence of ischemic stroke compared with medical therapy.4-7 Newer surgical techniques using PFO closure devices show particular promise.8,9

Cryptogenic strokes

Patient Follow-Up

The patient’s neurologic deficits quickly improved over the ensuing weeks, and she was neurologically normal at 1 month’s follow-up. Aspirin was started initially as a preventive therapy but was changed to warfarin after the hypercoagulable state evaluation revealed the presence of factor V Leiden. No decision has been made about whether to surgically close the foramen ovale. 

Ronald N. Rubin, MD, is a professor of medicine at the Lewis Katz School of Medicine at Temple University and is chief of clinical hematology in the Department of Medicine at Temple University Hospital in Philadelphia, Pennsylvania.


  1. Saver JL. Cryptogenic stroke. N Engl J Med. 2016;374(21):2065-2074.
  2. Schwamm LH, Jaff MR, Dyer KS, Gonzalez RG, Huck AE. Case 13-2016—a 49-year-old woman with sudden hemiplegia and aphasia during a transatlantic flight. N Engl J Med. 2016;374(17):1671-1680.
  3. Mas J-L, Arquizan C, Lamy C, et al; Patent Foramen Ovale and Atrial Septal Aneurysm Study Group. Recurrent cerebrovascular events associated with patent foramen ovale, atrial septal aneurysm, or both. N Engl J Med. 2001;​345(24):1740-1746.
  4. Søndergaard L, Kasner SE, Rhodes JF, et al; Gore REDUCE Clinical Study Investigators. Patent foramen ovale closure or antiplatelet therapy for cryptogenic stroke. N Engl J Med. 2017;377(11):1033-1042.
  5. Saver JL, Carrol JD, Thaler DE, et al; RESPECT Investigators. Long-term outcomes of patent foramen ovale closure or medical therapy after stroke. N Engl J Med. 2017;377(11):1022-1032.
  6. Mas J-L, Derumeaux G, Guillon B, et al; CLOSE Investigators. Patent foramen ovale closure or anticoagulation vs. antiplatelets after stroke. N Engl J Med. 2017;377(11):1011-1021.
  7. Ropper AH. Tipping point for patent foramen ovale closure. N Engl J Med. 2017;377(11):1093-1095.
  8. Furlan AJ, Reisman M, Massaro J, et al; CLOSURE I Investigators. Closure or medical therapy for cryptogenic stroke with patent foramen ovale. N Engl J Med. 2012;366(11):991-999.
  9. Carroll JD, Saver JL, Thaler DE, et al; RESPECT Investigators. Closure of patent foramen ovale versus medical therapy after cryptogenic stroke. N Engl J Med. 2013;368(12):1092-1100.