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    1 Comment for this article
    Consider Hyperhomocysteinemia and B12 deficiency
    J David Spence, M.D. | Stroke Prevention & Atherosclerosis Research Centre, Robarts Research Institute, Western University, London, Canada
    The observation that the risk of stroke with patent foramen ovale is higher in older patients (1) accords with my experience. However, I disagree with the conclusion that this finding “warrants trials of patent foramen ovale closure in older patients.”

    I suspect that the finding is related largely to a high prevalence of hyperhomocysteinemia in old patients, often due to deficiency of vitamin B12. Homocysteine is a clotting factor that markedly increases the risk of stroke in patients with atrial fibrillation [2]. The prevalence of hyperhomocysteinemia among patients attending my secondary stroke prevention clinic before 2009 was
    very high: at age >80, 40% of patients had a plasma total homocysteine (tHcy) > 14 µmol/L.[3]

    After that observation I began requesting of referring physicians that they measure serum B12 in their patients at the time of referral. Perhaps as a result, the prevalence of vitamin B12 supplements being taken at the time of referral increased markedly, and the prevalence of biochemical B12 deficiency (a serum B12 below the reference range) declined from 10.9% to 5.4% of referrals [4]. However metabolic B12 deficiency (a serum B12 below the median with tHcy >14 µmol/L) remained quite prevalent: among patients age >80 years metabolic B12 deficiency was present in 18.1% and hyperhomocysteinemia in 35%.

    Old patients with a PFO have had it all their life, but perhaps it only became a problem when they developed hypercoagulability late in life. A paradoxical embolus is essentially a pulmonary embolus that went left through the PFO instead of going right into the pulmonary artery. Percutaneous closure may prevent strokes, but not pulmonary emboli.

    In some patients with PFO it may be more prudent to prescribe anticoagulation [5], and in all patients with stroke, serum B12 and homocysteine should be measured. Metabolic B12 deficiency is very common, has serious consequences and is easily treated [6].


    1. Mazzucco S, Li L, Rothwell PM. Prognosis of Cryptogenic Stroke With Patent Foramen Ovale at Older Ages and Implications for Trials: A Population-Based Study and Systematic Review. JAMA Neurol. 2020.
    2. Poli D, Antonucci E, Cecchi E, Marcucci R, Liotta AA, Cellai AP, et al. Culprit factors for the failure of well-conducted warfarin therapy to prevent ischemic events in patients with atrial fibrillation: the role of homocysteine. Stroke. 2005;36(10):2159-63.
    3. Spence D. Mechanisms of thrombogenesis in atrial fibrillation. Lancet. 2009;373(9668):1006-7.
    4. Ahmed S, Bogiatzi C, Hackam DG, Rutledge AC, Sposato LA, Khaw A, et al. Vitamin B 12 deficiency and hyperhomocysteinaemia in outpatients with stroke or transient ischaemic attack: a cohort study at an academic medical centre. BMJ Open. 2019;9(1):e026564.
    5. Spence JD. Anticoagulation in patients with Embolic Stroke of Unknown Source. Int J Stroke. 2019;14(4):334-6.
    6. Spence JD. Metabolic vitamin B12 deficiency: a missed opportunity to prevent dementia and stroke. Nutr Res. 2016;36(2):109-16.
    CONFLICT OF INTEREST: I am a consultant to Orphan Technologies Inc., which is testing a truncated form of cystathionine beta synthase for treatment of homocystinuria.
    Views 3,508
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    Original Investigation
    July 6, 2020

    Prognosis of Cryptogenic Stroke With Patent Foramen Ovale at Older Ages and Implications for Trials: A Population-Based Study and Systematic Review

    Author Affiliations
    • 1Wolfson Centre for Prevention of Stroke and Dementia, University of Oxford, Oxford, United Kingdom
    JAMA Neurol. Published online July 6, 2020. doi:10.1001/jamaneurol.2020.1948
    Key Points

    Question  Is the prognosis of cryptogenic transient ischemic attack and stroke in patients receiving medical treatment alone associated with the presence of patent foramen ovale and age?

    Findings  In this population-based study, risk of recurrent ischemic stroke (2.05 per 100 patient-years) was consistent with the pooled estimate from a systematic review and meta-analysis (2 per 100 patient-years). Risk increased with mean cohort age, and only in patients with cryptogenic transient ischemic attack and stroke aged 65 years or older was patent foramen ovale vs no patent foramen ovale associated with a higher risk of recurrent ischemic stroke.

    Meaning  The findings of this study suggest that a higher risk of stroke recurrence at older ages in patients with patent foramen ovale warrants trials of patent foramen ovale closure in older patients.


    Importance  Patent foramen ovale (PFO) closure may prevent recurrent stroke after cryptogenic transient ischemic attack (TIA) or stroke (TIA/stroke) in patients aged 60 years or younger. Patent foramen ovale is associated with cryptogenic stroke in the older population, but risk of recurrence is unknown. Data on prognosis of patients receiving medical treatment at older ages (≥60 years) are essential to justify trials of PFO closure.

    Objective  To examine the age-specific risk of recurrence in patients with cryptogenic TIA/stroke with PFO.

    Design, Setting, and Participants  A prospective study was nested in the population-based Oxford Vascular Study between September 1, 2014, and March 31, 2019, with face-to-face follow-up for 5 years. A total of 416 consecutive patients with a diagnosis of cryptogenic TIA or nondisabling stroke, screened for PFO at a rapid-access TIA/stroke clinic, were included. A systematic review and meta-analysis of cohort studies reporting on ischemic stroke recurrence after cryptogenic TIA/stroke in patients with PFO who were receiving medical therapy alone, or with PFO vs no-PFO was conducted. Sample size calculation for future trials on PFO closure was performed for patients aged 60 years or older.

    Exposures  Patent foramen ovale and age as modifiers of risk of recurrent stroke after cryptogenic TIA/stroke in patients receiving only medical therapy.

    Main Outcomes and Measures  Risk of ischemic stroke recurrence in patients with cryptogenic TIA/stroke and PFO receiving medical therapy only, and in patients with vs without PFO, stratified by age (<65 vs ≥65 years), as well as sample-size calculation for future trials of PFO closure in patients aged 60 years or older.

    Results  Among the 153 Oxford Vascular Study patients with PFO (mean [SD] age, 66.7 [13.7] years; 80 [52.3%] men), recurrent ischemic stroke risk (2.05 per 100 patient-years) was similar to the pooled estimate from a systematic review of 23 other studies (9 trials and 14 observational studies) (2.00 per 100 patient-years; 95% CI, 1.55-2.58). However, there was heterogeneity between studies (P < .001 for heterogeneity), owing mainly to risk increasing with mean cohort age (meta-regression: R2 = 0.31; P = .003). In the pooled analysis of 4 studies including patients with or without PFO, increased risk of stroke recurrence with PFO was seen only at age 65 years or older (odds ratio, 2.5; 95% CI, 1.4-4.2; P = .001 for difference; P = .39 for heterogeneity). The pooled ischemic stroke risk was 3.27 per 100 patient-years (95% CI, 2.59-4.13) in 4 cohorts with mean age 60 years or older. Assuming the more conservative 2.0 per 100 patient-years ischemic stroke risk in the PFO nonclosure arms of future trials in patients aged 60 years or older, projected sample sizes were 1080 per arm for 80% power to detect a 33% relative risk reduction.

    Conclusions and Relevance  The findings of this study suggest that age is a determinant of risk of ischemic stroke after cryptogenic TIA/stroke in patients with PFO, such that trials of PFO closure at older ages are justified; however, projected sample sizes are large.