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Keywords:

  • aortic arch atheroma;
  • cryptogenic stroke;
  • patent foramen ovale

Abstract

  1. Top of page
  2. Abstract
  3. What makes a stroke cryptogenic?
  4. Conclusions
  5. Search strategy and selection criteria
  6. Disclosure of Conflict of Interests
  7. References

Summary.  Strokes that remain without a definite cause even after extensive work-up are classified as cryptogenic. These constitute about 30–40% of all strokes. Stroke aetiology may remain undetermined for the following reasons: (i) the cause of stroke is transitory or reversible and the diagnostic work-out is not therefore performed at the appropriate time; (ii) all known causes of stroke are not fully investigated; (iii) some causes of stroke remain unknown. Recent studies have challenged the previous view that cryptogenic stroke is a relatively benign cerebrovascular event, and have shown that cryptogenic stroke is associated with a higher rate of recurrence and adverse outcome at long-term follow-up. The determination of stroke aetiology is a valuable procedure to avoid the risk of stroke recurrence, especially in young patients. In this review, we discuss new evidence on the aetiology of cryptogenic stroke, specifically focusing on patients with patent foramen ovale and atheroma of the aortic arch.

Strokes of indefinite cause, even after an extensive work-up, are classified as cryptogenic [1,2]. Cryptogenic strokes account for about 30–40% of all strokes [1–3]. Up until the last decade, a cryptogenic stroke was seen as a relatively benign event, and patients with a stroke of unknown cause were considered to have a lower risk of recurrence than those with other types of stroke. However, the rate of recurrence after a cryptogenic stroke was recently reported to be about 30% during the first year after the index event [1]. This is in stark contrast with previous studies that found a 10–20% rate of stroke recurrence after 2 years [4,5].

What makes a stroke cryptogenic?

  1. Top of page
  2. Abstract
  3. What makes a stroke cryptogenic?
  4. Conclusions
  5. Search strategy and selection criteria
  6. Disclosure of Conflict of Interests
  7. References

1. The cause of a stroke may be transitory or reversible, and so diagnostic work-out might not be undertaken at the appropriate time.

(a) An example of a transitory or reversible cause is atrial fibrillation (AF), which accounts for about 10% of all strokes and 50% of the cardioembolic strokes [6,7]. Unfortunately, AF often remains underdiagnosed as it is frequently asymptomatic: up to 30% of AF patients are unaware of their arrhythmia [8], and about 25% of patients presenting with AF-associated stroke have had no prior diagnosis of AF [9,10]. Moreover, AF is intermittent in ∼30% of patients with stroke, and might not therefore be seen in a single ECG recording [11]. It was examined whether seven-day ambulatory ECG monitoring allowed further detection of AF in patients admitted with an acute stroke or transient ischemic attack (TIA) in whom standard ECG and 24-Holter show normal results [12]. AF was detected in 22 of 149 patients (14.8%) with an acute stroke or TIA by event-loop recording (ELR), a device designed to monitor the heart rhythm for one week or longer in ambulatory patients. Standard ECG identified such arrhythmia in 6.7% of patients. In about half of the cases, AF was identified at admission and in the remaining cases within the first five days. 24-Holter found AF in an additional 5% of the patients presenting with a normal standard ECG. Finally, ELR allowed further detection of arrhythmia in 5.7% of the patients. In all cases, the diagnosis of AF modified the therapeutic options.

(b) Vasospasm can be both reversible and transitory. An example of this is migraine infarct. Consequently, when the cerebral ischemia presents, the vasospasm has often already been resolved [13].

(c) Embolic artery occlusion can also be transient as the embolus can disappear without any residual evidence when detected by computed tomography, magnetic resonance imaging (MRI) or angiography.

2. Inadequate investigation into known causes.

(a) Bang et al. [1] demonstrated that in those patients with cryptogenic stroke in whom specific causes were suspected but not proven (i.e. significant stenosis, >50%, of a non-relevant artery or mild stenosis, 30–50%, of a relevant artery), the recurrence rate was significantly higher than in those without such findings. In that study, the recurrence rate and the overall outcome of patients with cryptogenic stroke were compared with those of patients with other types of stroke. The rate of recurrence in patients with stroke of undetermined cause was 30%, higher than in those patients with documented causes of stroke. Bang et al. [1] hypothesized that patients with a stroke of undetermined cause may have a variation of large artery disease (LAD), because more than half of these patients had recurrent strokes that were classified as LAD. The recurrence rate in patients with mild stenosis of a relevant artery or significant stenosis of a non-relevant artery was significantly higher than in those without documented cerebrovascular stenosis. Serial angiographic studies showed that the progression of the lesion occurred as frequently as it did in 60% of the patients with intracranial atherosclerosis, and was particularly common in medium-sized arteries. The risk factors in the undetermined cause group were similar to those of the LAD group.

(b) In 1992, Amarenco et al. [14] showed that atheromas of the aortic arch (AAAs) that were more than 4 mm in thickness were associated with a significantly increased risk of ischemic stroke, particularly in patients with a stroke of presumed undetermined cause. Afterwards, the embolic potential of AAAs was documented by pathological examinations [15], while transesophageal echocardiography (TEE) was used to define the role of AAAs as a risk factor for cerebral and peripheral embolism in vivo [16]. TEE provides an accurate imaging of the proximal portion of the aorta.

In 2000, Kallikazaros et al. [17] showed a close relationship between atherosclerosis of the carotid arteries and that of the ascending aorta. They found that aortic plaques were present in 82.8% of patients with carotid plaques. Kitagawa [18] recommended aortic arch examination by TEE or MRI in patients with cryptogenic stroke, especially for those with mild stenosis (<50%) in the extracranial and/or intracranial cerebral arteries.

In the French Study of Aortic Plaques in Stroke (FSAPSG) [19], a prospective follow-up of 331 consecutive stroke patients older than 60 years, all patients underwent TEE to assess the presence, size, and thickness of proximal aortic plaques. The rate of stroke recurrence in patients with large plaques (≥4 mm) was higher than in those with small plaques (1–3.9 mm) or in patients with no plaques (11.9% per year vs. 3.5% per year vs. 2.8% per year).

The causative role of AAAs for cerebral embolism is supported by the association of large AAAs with the occurrence of high-intensity transient signal (HITS) at intracranial Doppler [20]. HITS were seen in 56% of patients with AAAs, and in 20% of patients without AAAs [odds ratio (OR) 5.0, 95% confidence interval (95% CI) 0.98–26.9, = 0.064]. Complex AAAs were associated with a higher frequency of HITS than non-complex AAAs (OR 2.6, 95% CI 1.7–3.9, = 0.005).

There is no consensus on optimal secondary prevention in patients with a stroke associated with AAAs (Table 1). In the FSAPSG study [19], there was no significant difference in the event rate between patients with plaques more than 4 mm in thickness treated with warfarin or aspirin. However, later studies showed that warfarin was more efficacious than antiplatelet agents in preventing stroke in patients presenting with systemic emboli and mobile aortic arch atheromas [21,22]. One retrospective study [23] suggested that the use of statins could reduce the risk of stroke or vascular event by as much as 60%. The Aortic Arch Related Cerebral Hazard (ARCH) study [24] is an ongoing international, randomized controlled trial comparing the efficacy of warfarin with that of aspirin plus clopidogrel in patients with arch atheroma and stroke or peripheral embolism.

Table 1.   Recommendations for secondary prevention in patients with stroke and patent foramen ovale (PFO) or aortic atheroma [55]
Grade of recommendationMethodological quality of supporting evidence
  1. In patients with cryptogenic ischemic stroke and a PFO, antiplatelet therapy over no therapy (grade 1C+) and antiplatelet therapy over warfarin is suggested (grade 2A). (Note that for patients with evidence of deep vein thrombosis and PFO, anticoagulation is recommended.) In patients with stroke associated with aortic atheroma, antiplatelet therapy is recommended over no therapy (grade 1C+). For patients with cryptogenic stroke associated with mobile aortic arch thrombi, either oral anticoagulation or antiplatelet agents are recommended (grade 2C).

Strong recommendation High-quality evidence 1AConsistent evidence from randomized controlled trials without important limitations or exceptionally strong evidence from observational studies
Strong recommendation Moderate-quality evidence 1B Evidence from randomized, controlled trials with important limitations (inconsistent results, methodological flaws, indirect or imprecise), or very strong evidence from observational studies.
Strong recommendation Low- or very low-quality evidence 1CEvidence for at least one critical outcome from observational studies, case series, or from randomized, controlled trials with serious flaws or indirect evidence
Weak recommendation High-quality evidence 2AConsistent evidence from randomized controlled trials without important limitations or exceptionally strong evidence from observational studies
Weak recommendation Moderate-quality evidence 2B Evidence from randomized, controlled trials with important limitations (inconsistent results, methodological flaws, indirect or imprecise), or very strong evidence from observational studies
Weak recommendation Low- or very low-quality evidence 2CEvidence for at least one critical outcome from observational studies, case series, or from randomized, controlled trials with serious flaws or indirect evidence

3. Some causes of stroke are still unknown and/or may only be hypothesized through epidemiological studies (e.g. patent foramen ovale).

Prevalence of patent foramen ovale

In the general population, patent foramen ovale (PFO) is a relatively common anatomical abnormality. A pooled analysis of autopsy studies [25] showed an average prevalence of PFO of 26% (range 17–35%), while echocardiographic studies showed a prevalence ranging from 3.2% to 18% [26]. A meta-analysis of case–control studies confirmed an increased prevalence of PFO in patients with cryptogenic stroke aged 55 years or younger in comparison with controls (OR 5.01, 95% CI 3.24–7.75) but not in patients aged 55 years or older (OR 1.20, 95% CI 0.56–2.56) [27].

Pathogenesis of ischemic stroke in patients with PFO

Over the last decade, PFO has been identified as an independent risk factor for stroke, particularly in young adults with an otherwise unexplained cerebrovascular event. However, the pathophysiological process linking this anatomical abnormality to stroke remains elusive in most cases. Paradoxical embolism from the peripheral venous system, embolization from thrombi formed within the atrial septum and thrombus formation as a result of transient atrial arrhythmias have all been advocated [28,29].

Paradoxical embolism, which is perhaps the more plausible cause of stroke, requires a favorable pressure gradient for right-to-left shunting. However, such a gradient only occurs transiently and during conditions such as pulmonary hypertension or during the Valsalva maneuver [30]. Moreover, the evaluation of patients with cryptogenic stroke and PFO does not always reveal a venous source of emboli. By performing venography of the lower limbs, Stollemberg et al. [31] found a deep vein thrombosis in 24 out of 42 patients with arterial embolism and PFO; venous thrombosis was located exclusively in the calf veins in 13 of the patients. In the PELVIS study [32], patients 18–60 years old underwent a MRI venography of the pelvis within 72 h from the onset of a stroke. A thrombus was found in 20% of cryptogenic stroke patients with PFO.

Available reports on thrombophilic states in stroke patients with PFO are limited and mostly anecdotal. Pezzini et al. [33] showed in a case–control study that the prothrombin G20210A mutation and, to a lesser extent, the factor V G1691A mutation may represent risk factors for PFO-related stroke. This is of interest, given that Hankey et al. [34] reported no association between inherited thrombophilia and ischemic strokes overall. Testing for thrombophilic disorders is not recommended for all patients with cryptogenic stroke but only for young patients with previous venous thrombosis and a positive familial history for thromboembolic events.

Anatomical abnormalities associated with PFO

The increased risk of stroke in patients with PFO could be explained by the high prevalence (50–90%) of anatomic abnormalities associated with PFO, such as atrial septal aneurysm (ASA) [35], prominent Eustachian valves or Chiari networks or atrial septal defect. The Stroke Prevention Assessment of Risk in a Community (SPARC) study [36] suggested that, after adjusting for age and co-morbidity, PFO is not an independent risk factor for cerebrovascular events. Interestingly, the risk of stroke in subjects with PFO associated with ASA was shown to be nearly four times higher than in those without ASA [hazard ratio (HR) 3.72, 95% CI 0.88–15.71, = 0.074]. In the general population, the prevalence of ASA screened by trans-thoracic echocardiography (TTE) is 1.9%, if ASA is defined as a septal excursion of ≥10 mm [37], with a base diameter of ≥15 mm. A greater prevalence of ASA in patients with stroke (7.9%) than in population-based controls (2.2%) was shown by using TEE [38].

Diagnosis of PFO

Over the last decade trans-cranial Doppler (TCD) sonography and echocardiography, both with infusion of agitated-saline as an echo-contrast, have been introduced for the diagnosis of PFO. In one of the studies [39], TEE, considered as the gold standard, showed a prevalence of PFO of 39%. TTE showed a PFO in 18% of the patients, and TCD in 27% of the patients. Six PFOs that could not be detected by TCD were less than 2 mm in size at TEE, implying that TCD misses small defects. Another study [40] compared the sensitivity of TCD vs. TEE for detecting cardiac PFO, and confirmed that TCD is a sensitive non-invasive method for detecting right-to-left cardiac shunts. Despite its sensitivity, TCD is limited by its inability to provide information about the morphological features of the atrial septum or other cardiac structures. So, it is the first diagnostic step in patients with cryptogenic stroke, but a subsequent TEE is mandatory when TCD is positive for right-to-left shunt.

Prognosis of PFO

Population-wide figures [41] suggest that the yearly risk of cryptogenic stroke in healthy persons with PFO may be as low 0.1%, suggesting that additional factors may be necessary to increase the risk of stroke. The features include a large anatomical separation between the primum and secundum septum (4 mm or more) or the association of right-to-left shunting at rest and high membrane mobility [42]. In an observational study, De Castro et al. [43] found that PFO patients with acute stroke or TIA presented significantly more frequently a right-to-left shunt at rest and higher membrane mobility (> 6.5mm), when compared with asymptomatic PFO carriers. The cumulative risk of recurrence of cerebrovascular event at 3 years was 4.3% (95% CI 0–10.2%) for ‘low-risk’ PFO (PFO at rest or during the Valsalva maneuver, and a membrane mobility ≤ 6.5 mm or membrane mobility > 6.5 mm with patency during the Valsalva maneuver only) and 12.5% (95% CI 0–26.1%) for ‘high-risk’ PFO patients (PFO at rest and membrane mobility > 6.5 mm). Anzola et al. [44] found an increased risk of stroke recurrence in patients with severe right-to-left shunt (more than 10 bubbles at TCD), compared to patients with ‘low-risk’ PFO (less than 10 bubbles; 8.2% and 0.6% per year, respectively; OR 17.1%, 95% CI 2.1–72.2, = 0.0012).

Management strategy in patients with PFO

Available data suggest that primary preventive interventions are unlikely to have a favorable risk-to-benefit ratio for patients with PFO [45]. Currently, there is no consensus on the optimal management strategy of patients with PFO and stroke (Table 1). Treatment options include: treatment with antiplatelet agents or vitamin K antagonists (VKAs), percutaneous device closure and surgical closure.

After the observational Lausanne study [46] and French PFO/ASA study [47], the PICCS study [48], a study nested in the Warfarin-Aspirin Recurrent Stroke Study (WARSS) [49], compared aspirin and warfarin in the prevention of recurrence in patients with non-cardio-embolic stroke. Within 30 days of a non-cardio-embolic stroke, patients were randomly assigned to receive warfarin [International Normalized Ratio (INR) 1.4–2.8] or aspirin 325 mg for 2 years. In the PICSS study [48], 630 patients underwent TEE for the detection of PFO. Of these, 265 patients had cryptogenic stroke while 365 had a stroke of a known subtype. In agreement with previous studies, 98 of 250 (39.2%) with cryptogenic stroke had a PFO compared to 28.9% (105/365) with a known cause of stroke (< 0.02). A larger PFO was significantly more common in patients with cryptogenic stroke (20% vs. 9.7%). However, during the 2-year follow-up, no significant differences were seen in rates of recurrent stroke or death in patients with PFO compared to those with no PFO. Event rates among the cryptogenic stroke patients with PFO treated with aspirin (17.9%, = 56) and warfarin (9.5%, = 42) were not statistically significant (HR 0.52, 95% CI 0.16–1.67, = 0.28) and were similar to patients with cryptogenic stroke without PFO (HR 0.50, 95% CI 0.19–1.31, = 0.16). The authors concluded that on medical therapy the presence of PFO in stroke patients did not increase the chance of adverse events, regardless of PFO size or the presence of atrial septal aneurysm [48,49]. The rate of severe bleeding was similar between patients receiving warfarin and those receiving aspirin, but the rate of minor bleeding was significantly higher in the warfarin group. Among patients who suffered a cryptogenic stroke and were treated medically, PFO alone was not associated with a meaningfully increased risk of subsequent stroke or death. However, a small increase or decrease in risk cannot be excluded from these data. The data are inadequate to make any conclusion about isolated ASA and the results regarding patients with PFO and ASA are rather weak. The French PFO/ASA study [47] indicated that cryptogenic stroke patients with both PFO and ASA carry an increased risk of stroke recurrence when treated pharmacologically. In contrast, in the PICSS study [48] no association between PFO and ASA with recurrent stroke or death was found.

Closure of PFO

Technology related to the percutaneous PFO closure has improved remarkably in recent years, so that surgery is rarely used to treat the abnormalities of the atrial septum [50]. The Amplatzer® (AGAMedical, Golden Valley, MN, USA) device seems to be safer than the CardioSEAL® device [51]. A systematic review including 1355 patients who underwent percutaneous PFO closure showed a rate of recurrent ischemic events varying from 0 to 4.9% at 1 year after the procedure [52]. Windecker et al. [53] compared the risk of recurrence in 308 patients with cryptogenic stroke and PFO, treated either medically (158 patients) or by percutaneous PFO closure (150 patients). Patients treated with percutaneous PFO closure had larger PFO and had more previous cerebrovascular events than patients treated medically. After 4 years of follow-up, percutaneous PFO closure appeared at least as effective as medical treatment for the prevention of recurrent cerebrovascular events. PFO closure was more effective than medical treatment in patients who achieved a complete closure or had more than one previous cerebrovascular event. In patients with PFO and ASA, the long-term risk of recurrent ischemic events after transcatheter treatment for atrial septal abnormality is comparable to that of patients with PFO alone. Serious complications related to percutaneous PFO closure (major hemorrhage, cardiac tamponade, need for surgery, pulmonary embolism, and death) were reported in 1.5% of patients and minor complications (arrhythmia, device fracture, air embolization, and femoral hematoma) in 7.9%. The devices currently used to close PFO achieve a complete PFO closure in more than 95% of cases and are associated with complications in less than 1% of cases [54].

As for the treatment of patients with a cerebrovascular event and PFO, North American guidelines [55] have been published based on weak evidence: case reports, observational studies, and case–control studies or prospective studies with reduced simple sizes. The International Guidelines do not recommend antithrombotic therapy as primary prophylaxis in subjects with PFO. After a first cerebrovascular event, the risk of recurrence can be stratified based on the anatomical features of the defect of the atrial septum and presence of a thrombophilic state. In patients with cryptogenic stroke/TIA and ‘low-risk’ PFO, antiplatelet therapy (aspirin 100–300 mg daily or clopidogrel 75 mg daily) is recommended to prevent recurrent events. In patients with cryptogenic stroke/TIA and PFO with deep vein thrombosis and/or thrombophilic state (hereditary or acquired persistent thrombophilia), VKAs (INR target 2.5) for an indefinite period are recommended.

PFO closure may be considered for patients with recurrent cryptogenic stroke despite optimal medical therapy. Moreover, PFO closure may be recommended for patients with ‘high-risk’ PFO at [PFO at rest and membrane mobility >6.5 mm or PFO with severe right to-left shunt (>10 bubbles), or in the presence of ASA]. The treatment with 100–300 mg aspirin daily should be continued for an indefinite period of time.

Conclusions

  1. Top of page
  2. Abstract
  3. What makes a stroke cryptogenic?
  4. Conclusions
  5. Search strategy and selection criteria
  6. Disclosure of Conflict of Interests
  7. References

In clinical practice, stroke aetiology can be identified in more than half of patients by using routine diagnostic procedures. The determination of stroke aetiology is a valuable procedure to avoid the risk of stroke recurrence, especially in young patients. To reduce the proportion of strokes of undetermined aetiology, the following examinations as part of the assessment of a cryptogenic stroke should be performed (Table 2).

Table 2.   Diagnostic stroke work-up
First level investigations (50–55%)*
  1. *The rates represent the probability to find the aetiology of stroke with each level of investigation.

Medical history Risk factors Neurological assessment Laboratory assessment (include ESR, CRP) Electrocardiogram (ECG) Duplex imaging of extracranial artery Computerized tomography (CT) scan
Second level investigations (10–15% more)*
Trans-thoracic echocardiography (TTE) Contrast trans-cranial Doppler (TCD) Compressive ultra-sonography (CUS) Trans-esophageal echocardiography (TEE) ECG Holter or ELR Brain and cerebral vessel MRI
Third level investigations (3–4% more)*
Coagulation and autoimmune assessment (antinuclear antibodies, anti-dsDNA, anti-SM, antiphospholipid, lupus anticoagulant activity, deficiencies of protein C, protein S and antithrombin) Intra-arterial angiography Cerebrospinal fluid analysis Genetic study (factor V G1691A mutation, prothrombin G20210A variant, CADASIL, MELAS; Fabry disease and collagen vascular disease) Dermal and skeletal muscle biopsy
  • 1
    ECG Holter or ELR (seven-day ambulatory ECG monitoring): detection of AF influences the therapeutic options in patients without contraindication to oral anticoagulants, allowing for optimal secondary prevention.
  • 2
    TCD is mandatory in patients with suspected PFO. If positive, TEE to confirm and characterize the atrial septal anatomy should be performed. Lower limb compression ultrasonography showing a deep vein thrombosis reinforces the relationship between PFO and stroke.
  • 3
    TEE is able to detect aortic thrombi and plaques greater than 4 mm that require an appropriate antithrombotic treatment.

Search strategy and selection criteria

  1. Top of page
  2. Abstract
  3. What makes a stroke cryptogenic?
  4. Conclusions
  5. Search strategy and selection criteria
  6. Disclosure of Conflict of Interests
  7. References

Data for this review were identified by searching in PubMed for single or combined terms including: ‘cryptogenic stroke’, ‘unknown aetiology stroke’, ‘unexplained stroke’, ‘aortic arch atheromas’, ‘patent foramen ovale’, ‘atrial septal defect’, ‘paradoxical embolism’, ‘treatment’, ‘thrombophilia’, ‘transcranial Doppler’, ‘trans-thoracic echocardiography’, ‘trans-esophageal echocardiography’, and ‘recurrent stroke’. Original research papers, clinical series, case reports, and reviews were included. Our research covered all relevant data to 1 October 2007.

References

  1. Top of page
  2. Abstract
  3. What makes a stroke cryptogenic?
  4. Conclusions
  5. Search strategy and selection criteria
  6. Disclosure of Conflict of Interests
  7. References
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