Cause Of Cryptogenic Stroke Research Articles

Detection of Vulnerable Plaque in Patients with Cryptogenic Stroke.

In up to 40% of ischemic stroke cases the etiology remains unknown. A substantial proportion of these patients has non- or only mildly stenosing carotid artery plaques not fulfilling common criteria for large artery stroke, but beeing suspicious for arterio-arteriell embolism. Several imaging techniques allow the non-invasive analysis of plaque features. Nevertheless, carotid MRI might be best suited to assess the key features of vulnerable plaques. This review article discusses potential causes of cryptogenic stroke, the role of plaque imaging in non-stenosing plaques and the association of vulnerable plaques and specific plaque features with stroke risk and stroke recurrence.

Ischaemic stroke of undetermined cause

The definition of cryptogenic stroke or stroke of undetermined origin is affected by the current knowledge of the cause and pathogenesis of stroke and by the availability, comprehensiveness, quality, and timeliness of the ancillary investigations undertaken to discover the cause of the stroke. In The Lancet Neurology, Linxin Li and colleagues report findings from a populationbased study of the burden, outcome, risk factors, and long-term prognosis of cryptogenic stroke in patients with a first transient ischaemic attack (TIA) or ischaemic stroke. They found that of 2555 first ischaemic events, 812 (32%) were cryptogenic. The study shows that the prognosis of cryptogenic stroke and the risk of recurrence are similar to those of large artery disease and small vessel disease. For example, death or dependency at 6 months was similar after cryptogenic stroke compared with large artery and small vessel subtypes combined (23% vs 27%; p=0·26), as was the 10-year risk of recurrence (32% vs 27%; p=0·91). Secondary stroke prevention must be similarly aggressive and appropriate in stroke with and without identified cause. The findings from this Article question the role of paroxysmal atrial fibrillation as the major cause of cryptogenic stroke, which contrasts with the present enthusiasm for the use of technology to detect paroxysmal atrial fibrillation and for the possibility to prevent recurrent cryptogenic stroke with anticoagulants.

Interventional closure of atrial septal defects, patent oval foramen and ventricular septal defects

Percutaneous transcatheter closure techniques and devices for congenital intracardiac shunts have considerably improved; therefore, catheter closure is now the treatment of choice for atrial septal defects (ASD). This is technically feasible in more than 80% of patients with a secundum ASD and the success rate is higher than 99%. General anesthesia is as a rule unnecessary and the hospital stay is very short. A patent oval foramen (POF) is a potential cause of cryptogenic stroke and peripheral embolisms. The catheter occlusion has many advantages in comparison to lifelong anticoagulation therapy and for some patients it is the only therapeutic option. Randomized trials have shown that interventional closure leads to results which are comparable to drug therapy and for some occlusion systems even evidence of significant advantages compared to drug therapy was found. Even ventricular septal defects (VSD), including perimembraneous and post-myocardial infarction VSDs can be closed by catheter techniques with a high success rate.

D-dimer for prediction of long-term outcome in cryptogenic stroke patients with patent foramen ovale.

Patent foramen ovale (PFO) is a potential cause of cryptogenic stroke, given the possibility of paradoxical embolism from venous to systemic circulation. D-dimer level is used to screen venous thrombosis. We investigated the risk of embolism and mortality according to the presence of PFO and D-dimer levels in cryptogenic stroke patients. A total of 570 first-ever cryptogenic stroke patients who underwent transesophageal echocardiography were included in this study. D-dimer was assessed using latex agglutination assay during admission. The association of long-term outcomes with the presence of PFO and D-dimer levels was investigated. PFO was detected in 241 patients (42.3 %). During a mean 34.0 ± 22.8 months of follow-up, all-cause death occurred in 58 (10.2 %) patients, ischaemic stroke in 33 (5.8 %), and pulmonary thromboembolism in 6 (1.1 %). Multivariate Cox regression analysis showed that a D-dimer level of > 1,000 ng/ml was an independent predictor for recurrent ischaemic stroke in patients with PFO (hazard ratio 5.341, 95 % confidence interval 1.648-17.309, p=0.005), but not in those without PFO. However, in patients without PFO, a D-dimer level of > 1,000 ng/ml was independently related with all-cause mortality. The risk of pulmonary thromboembolism tended to be high in patients with high D-dimer levels, regardless of PFO. Elevated D-dimer levels in cryptogenic stroke were predictive of the long-term outcome, which differed according to the presence of PFO. The coexistence of PFO and a high D-dimer level increased the risk of recurrent ischaemic stroke. The D-dimer test in cryptogenic stroke patients may be useful for predicting outcomes and deciding treatment strategy.

Provoked right-to-left shunt in patent foramen ovale associates with ischemic stroke in posterior circulation.

Right-to-left shunt (RLS) via the patent foramen ovale is an important cause of cryptogenic stroke. The Valsalva maneuver provokes or enhances RLS, but RLS can also occur during normal respiration. This study examined whether the ischemic lesion pattern differs depending on the character of RLS. All consecutive patients with a patent foramen ovale (diagnosed by transesophageal echocardiography) who had a cryptogenic stroke and underwent transcranial Doppler-patent foramen ovale test (monitoring of microbubbles in the right middle cerebral artery by transcranial Doppler after hand-agitated saline injection) were divided according to whether RLS was constant (microbubbles detected both at baseline and after the Valsalva maneuver) or provoked (microbubbles detected only after the Valsalva maneuver). The groups were compared in terms of clinical and imaging characteristics. Seventy-six patients met the eligibility criteria: 50 had constant RLS and 26 had provoked RLS. Provoked RLS patients were significantly younger. The ischemic lesions in provoked RLS patients were located predominantly in the vertebro-basilar circulation (73.1% versus 28.0%; P=0.002), whereas constant RLS patients were more likely to have multicirculatory lesions (16.0% versus 0.0%; P=0.045). After adjusting for confounders, provoked RLS associated independently with a vertebro-basilar lesion location (OR=3.306; P=0.03). The predominance of posterior-circulatory infarction in provoked RLS patients suggests that the Valsalva maneuver may promote RLS and paradoxical embolization to the posterior circulation.

Stroke : Highlights of Selected Articles

<i>Stroke</i> : Highlights of Selected Articles

Patent foramen ovale and the risk of cryptogenic stroke.

COMMENTARY JONATHAN TOBIS. MD* Clinical Professor of Medicine, Director of In- terventional Cardiology Research, and Director, Interventional Cardiology Fellowship Program, University of California, Los Angeles Patent foramen ovale and the risk of cryptogenic stroke HE ARTICLE BY ROTH AND ALL1 in this issue describes Tin depth more than 10 years of research that address— es the question, Should we close a patent foramen ovale (PFO) to prevent recurrent cryptogenic stroke? See related article, page 417 There is no longer any doubt that PFO can be the pathway for thrombus from the venous circulation to go from the right atrium to the left atrium, bypassing the pulmonary capillary filtration bed, and entering the arterial side to produce a stroke, myocardial in— farction, or peripheral embolus. Two questions remain: What should we do to prevent another episode? And is percutaneous closure of a PFO with the current de- vices preferable to medical therapy? How much do we know about the risks and benefits of closure of PFO? I maintain that we know a great deal about interatrial shunt and paradoxical embolism as a cause of cryptogenic stroke. Prospective random- ized clinical trials now give us data with which we can provide appropriate direction to our patients. Percu— taneous closure is no longer an “experimental proce- dure,” as insurance companies claim. The experiment has been done, and the only issue is how one inter- prets the data from the randomized clinical trials. The review by Roth and Alli comprehensively de— scribes the observational studies, as well as the three randomized clinical trials done to determine whether PFO closure is preferable to medical therapy to pre— vent recurrent stroke in patients who have already had one cryptogenic stroke. If we understand some of the subtleties and differences between the trials, we can reach an appropriate conclusion as to what to recom— mend to our patients. *Dr. Tobis is one of the principal investigators of the PREMIUM Trial, which is assessing the benefit and safety of the Amplatzer PFO closure device to treat patients with debilitat- ing migraine headache. doi:1 0.3949/ccjm.8&#39;| a.1 4066 CLEVELAND CLINIC JOURNAL OF MEDICINE A review of 10 reports of transcatheter closure of PFC vs six reports of medical therapy for cryptogenic stroke showed a range of rates of recurrent stroke at 1 year—between 0% and 4.9% for transcatheter clo— sure, and between 3.8% and 12% for medical therapy.1 These numbers are important because they were used to estimate the number of patients that would be necessary to study in a randomized clinical trial to demonstrate a benefit of PFC closure vs medical therapy. Unlike most studies of new devices, the PFC closure trials were done in an environment in which patients could get their PFO closed with other devices that were already approved by the US Food and Drug Administration (FDA) for closure of an atrial septal defect. This ability of patients to obtain PFO closure outside of the trial with an off—label device meant that the patients who agreed to be randomized tended to have lower risk for recurrence than patients studied in the observational populations. From a practical standpoint, this meant that the event rate in the pa- tients who participated in the randomized clinical tri~ als (1.7% per year) was lower than predicted from the observational studies.“ Another way of saying this is that the randomized clinical trials were underpowered to answer the ques— tion. A common way of dealing with this problem is to combine the results of different studies in a meta— analysis. This makes sense if the studies are assessing the same thing. This is not the case with the PFO clo— sure trials. Although the topic of percutaneous PFO closure vs medical therapy was the same, the devices used were different. In the CLOSURE trial (Evaluation of the STARFlex Septal Closure System in Patients With a Stroke and/or Transient lschemic Attack Due to Pre- sumed Paradoxical Embolism Through a Patent Fo- ramen Ovale),3 the device used was the STARFlex, which is no longer produced—and for good reasons. It is not as effective as the Amplatzer or Helex devices in VOLUME 81 0 NUMBER 7 JULY 2014

The Search for Cryptogenic Stroke, A Case of Marantic Endocarditis

Nonbacterial thrombotic endocarditis (NBTE) is rare and undoubtedly an under-recognized cause of cryptogenic stroke. Its diagnosis relies on a high index of clinical suspicion, particularly in patients with previous malignancy. We present a case of a young woman, with three neurologic events occurring in rapid succession over three weeks, ultimately resulting in her death. The echo imaging findings here appear relatively benign compared to the catastrophic consequences, and speaks of the aggressive fibrin and platelet deposition that can embolize widely in this condition, confirmed on the postmortem examination. We discuss the details of NBTE aiming to increase awareness while assessing patients with undetermined systemic embolization.

Patent foramen ovale.

Patent foramen ovale.

Stroke Literature Synopses: Clinical Science

Paradoxical embolism via a patent foramen ovale (PFO) is a common cause of cryptogenic stroke. Because PFO is a common anatomic variant seen in 25% of the general population, clinicians are faced with the dilemma of whether a PFO is an incidental finding or stroke related. Recent clinical trials of PFO closure failed to show a benefit of closure compared with medical therapy in reducing composite primary end points. Yet, these trials may have enrolled individuals with incidental PFO. To derive a prediction instrument to stratify patients by attributable fraction (probability that the index event was related to PFO), Kent et al performed a patient-level meta-analysis of observational cohorts of patients with cryptogenic stroke investigated for PFO by transesophageal echocardiogram or transcranial Doppler (n=3023). The patients with cryptogenic stroke with PFO were younger, less likely to have conventional risk factors or a history of transient ischemic stroke (TIA)/stroke and more likely to have large superficial infarcts than those without PFO. Multivariable logistic regression revealed that the odds of PFO presence was lower …

Imaging Characteristics of Ischemic Strokes Related to Patent Foramen Ovale

Subclinical atrial fibrillation (AF) and patent foramen ovale (PFO) are the major causes of cryptogenic stroke, and neuroimaging may help distinguish the cause. We compared the imaging characteristics of ischemic stroke caused by PFO (PFO-stroke) and AF (AF-stroke). We recruited 117 patients with PFO-stroke and 358 patients with AF-stroke after excluding other causes. The lesion patterns were classified according to number, location, size, and pertinent vascular territory and were compared between the 2 groups. Occlusion of the corresponding artery and its recanalization rate were also investigated. The lesion pattern of a PFO-stroke was more frequently observed as a single cortical infarction (34.2% versus 3.1%; P<0.001) or multiple small (<15 mm) scattered lesions (23.1% versus 5.9%; P<0.001) and in the vertebrobasilar artery territory (44.4% versus 22.9%; P<0.001). By contrast, AF-stroke was more frequently observed as a large cortico-subcortical infarction or confluent lesion (>15 mm) with additional lesions in multicirculatory territories. For a PFO-stroke, occlusion of the corresponding vessel on angiography was less frequent (34.2% versus 71.5%; P<0.001), and the neurological deficit evaluated by the National Institutes of Health Stroke Scale was mild (3.48±4.16 versus 9.15±7.35; P<0.001). The recanalization rate was also lower (57.1% versus 78.3%; P=0.007). A PFO-stroke usually appears as a single cortical or multiple small ischemic lesions in the vertebrobasilar circulation without any visible vessel occlusion on angiography. The recanalization rate is significantly lower than in AF-stroke. These imaging characteristics of PFO-stroke may help to diagnose the mechanism and determine the treatment strategy.

Paroxysmal Atrial Fibrillation in Cryptogenic Stroke: A Case–Control Study

It is unclear if brief episodes of paroxysmal atrial fibrillation (PAF) detected by prolonged cardiac monitoring are an occult of cause of cryptogenic strokes (CS). We compared the incidence of PAF in patients with CS and patients with stroke of known cause (SKC) using prolonged ambulatory cardiac monitoring. We prospectively enrolled patients within 3 months of ischemic stroke to undergo noninvasive cardiac monitoring for 3 weeks. Primary end point was PAF detection independently confirmed by 2 blinded cardiologists. The study consisted of 132 patients, 66 had CS and 66 had SKC. Episodes of PAF were detected in 16 of 64 (25%) patients with CS and 9 of 64 (14%) patients with SKC (P=.12). Duration and number of PAF episodes, PAF burden, and time of first PAF detection did not differ significantly between the 2 groups (P>.05 for all). In patients younger than 65 years, PAF was more common in the CS group (22% versus 3%; P=.07), whereas in patients 65 years or older, the rates of detection were similar (27% in CS versus 25% in SKC; P=.9). Among patients younger than 65 years with embolic imaging pattern, PAF was only observed in the CS group (21% versus 0%; P=.03). Very short episodes of PAF are common in patients with CS and with SKC, but their pathogenic significance is unclear. Predominance of PAF in younger patients with CS and embolic infarct pattern suggests a causative role in these cases. More research is needed before prolonged cardiac rhythm monitoring can be recommended to guide anticoagulation in CS patients.

PFO Closure for Cryptogenic Stroke: Review of New Data and Results

Observational studies over 20years have suggested that a patent foramen ovale (PFO) is an important cause of cryptogenic stroke in young individuals; case series and registries suggest that PFO closure confers superior protection from recurrent transient ischemic attack (TIA) and stroke. Recently completed randomized clinical trials did not confirm this hypothesis, but have provided reassurance that the risk of recurrent stroke is low at 1.5%/yr. A target subset that may benefit are those with ischemic stroke, a large right-to-left shunt, and an atrial septal aneurysm. Further study is needed to determine the optimum strategy to reduce the long-term stroke risk in a lifetime of varying situational risk factors and temporary interruptions of medical therapies.

Double Atrial Septum with Interatrial Chamber Formation and Recurrent Paradoxical Embolism

Paradoxical embolism is a common cause of cryptogenic stroke. Cardiogenic origin is often the real culprit of unexplained stroke. We report a rare case of double atrial septum with an interatrial chamber and stenosis of the inferior vena cava orifice, which lead to recurrent paradoxical embolism, and then highlight the clinical importance of this rare type of congenital heart disease.

Abstract TP348: Crytogenic Stroke and Paroxysmal Atrial Fibrillation: Criteria for Long Term Cardiac Monitoring

Background: Cryptogenic stroke represents 30% of all ischemic strokes. Undetected atrial fibrillation may be a cause of cryptogenic stroke and may lead to ineffective secondary stroke prevention. Long term cardiac monitoring assists in identifying atrial fibrillation. The purpose of this performance improvement project was to develop a protocol for long term cardiac monitoring for patients with cryptogenic stroke. Methods: Stroke faculty, cardiology and stroke nurses developed a protocol for long term cardiac monitoring. A 14 day “event monitor” is placed electronically on day of discharge. Inclusion and exclusion criteria were identified. Inclusion: diagnosis stroke/TIA; EKG has not shown atrial fibrillation/flutter; vascular imaging of the extracranial and intracranial circulation excludes significant large vessel occlusive disease; evidence of abdominal or pelvic embolic on CT scan; echocardiography excludes thrombus or structural heart disease. Exclusion: documented atrial fibrillation/flutter; etiological diagnosis for the qualifying stroke/TIA event has been determined, i.e. probable small-vessel disease, probable large vessel disease, arterial dissection, venous sinus thrombosis, hypercoagulable states; echocardiography reveals indication for long-term anticoagulation; absolute indication for oral anticoagulation therapy; contraindications to oral anticoagulation therapy. Results: This protocol was effective in providing patients with long term cardiac monitoring. Patients are scheduled in the stroke discharge clinic for diagnostic review. Conclusions: This protocol assists in identifying patients who have paroxysmal atrial fibrillation and need anticoagulation for secondary prevention. The following process improvements are needed: 1) process for follow up, 2) improve communication with PMD, 3) improve transition of care when patients are transferred to rehabilitation, 4) costs can be prohibitive and, 5) 14 days may not be effective in detecting atrial fibrillation.

Abstract WP220: Determinants for Cryptogenic Stroke: Clinico-radiologic Findings

Background: Cryptogenic stroke accounts for 30-40% of all strokes. Aortic arch atheroma(AAA), patent foramen ovale(PFO) and paroxysmal atrial fibrillation(PAF) are common causes which require different treatment strategies. However not all patients could undergo extensive work-ups. We investigated clinico-radiological characteristics of these 3 common causes of cryptogenic stroke to find a model helping decision-making. Method: We enrolled 194 patients with cryptogenic stroke at the time of admission. After performing extensive work-ups including electrocardiography, transthoracic or transesophageal echocardiography, transcranial right-to-left shunt test, coronary computed tomography angiography or cardiac telemetry, patients were allocated into 3 groups; (1) AAA(n=25), (2) PFO(n=94), and (3) PAF(n=75). Vascular risk factors and findings on diffusion-weighted image were analyzed. Results: Clinico-radiologic features were different. Patients with PFO were younger (mean, 56.1[PFO] vs. 73.9[AAA] vs. 70.6[PAF] years; p &lt;0.001) and hypertension was less common ( p &lt;0.001). Smoking was more common in AAA group ( p =0.018). PAF-related strokes had higher NIHSS ( p &lt;0.001) and a larger lesion (≥20mm, 81.1%[A-fib] vs. 16.0%[AAA] vs. 46.2%[PFO]; p &lt;0.001). By contrast, AAA-related strokes showed small but multiple lesions scattered in multiple vascular territories ( p &lt;0.001). Patients with PFO had subcortical lesions ( p =0.029) in posterior circulation ( p =0.004). Multivariate regression analysis revealed that age, NIHSS, hypertension, multiple(≥3) lesions and involvement of multiple vascular territories could differentiate 3 groups (R 2 =0.6581). We calculated probability for 3 groups and performed external validation. Conclusion: Patients with cryptogenic stroke showed distinct features which may provide clues for stroke mechanisms. Our data suggested that etiologic work-ups for cryptogenic stroke could be guided by these features.

Prediction of Cardioembolic, Arterial, and Lacunar Causes of Cryptogenic Stroke by Gene Expression and Infarct Location

The cause of ischemic stroke remains unclear, or cryptogenic, in as many as 35% of patients with stroke. Not knowing the cause of stroke restricts optimal implementation of prevention therapy and limits stroke research. We demonstrate how gene expression profiles in blood can be used in conjunction with a measure of infarct location on neuroimaging to predict a probable cause in cryptogenic stroke. The cause of cryptogenic stroke was predicted using previously described profiles of differentially expressed genes characteristic of patients with cardioembolic, arterial, and lacunar stroke. RNA was isolated from peripheral blood of 131 cryptogenic strokes and compared with profiles derived from 149 strokes of known cause. Each sample was run on Affymetrix U133 Plus 2.0 microarrays. Cause of cryptogenic stroke was predicted using gene expression in blood and infarct location. Cryptogenic strokes were predicted to be 58% cardioembolic, 18% arterial, 12% lacunar, and 12% unclear etiology. Cryptogenic stroke of predicted cardioembolic etiology had more prior myocardial infarction and higher CHA(2)DS(2)-VASc scores compared with stroke of predicted arterial etiology. Predicted lacunar strokes had higher systolic and diastolic blood pressures and lower National Institutes of Health Stroke Scale compared with predicted arterial and cardioembolic strokes. Cryptogenic strokes of unclear predicted etiology were less likely to have a prior transient ischemic attack or ischemic stroke. Gene expression in conjunction with a measure of infarct location can predict a probable cause in cryptogenic strokes. Predicted groups require further evaluation to determine whether relevant clinical, imaging, or therapeutic differences exist for each group.

Percutaneous Closure of Patent Foramen Ovale

For patients with cryptogenic stroke found to have a patent foramen ovale (PFO), the rationale for mechanical closure can seem deeply compelling. PFO appears to be a common cause of cryptogenic stroke,1 most likely through a “paradoxical” (venous to arterial) embolism. Since this conduit can be eliminated with a minimally invasive percutaneous procedure, why wait around for a second, possibly disabling, event? Indeed, the logic of closure also has strong support from a wealth of observational studies. Our recent review uncovered 57 studies, describing mostly single-arm case series, but also 7 comparative studies of closure versus medical treatment.2 All together, this observational evidence included 8916 patients: 1903 medically treated, 7013 undergoing closure. The summary incidence rate (IR) of recurrent neurological events (stroke or transient ischemic attack) in closure studies was extremely low (0.8 [0.6–1.2] per 100 person-years). Notably, of 49 studies investigating closure-treated patients, more than half had absolutely no stroke recurrences on follow-up. In contrast, the IR of recurrent events among medically treated patients was considerably …

Abstract 2922: Patent Foramen Ovale Is A Cause Of Ischemic Stroke In Patients With Antiphospholipid Syndrome

Background: The antiphospholipid syndrome (APS) is a systemic autoimmune disorder characterized by a combination of arterial and/or venous thrombosis and recurrent fetal loss, and can be an independent risk factor for a first-ever ischemic stroke especially in young female patients. Patent foramen ovale (PFO) has been established as a cause of cryptogenic stroke. Atrial septal aneurysm (ASA) is associated with PFO. Until recently, the precise pathophysiology of APS as causing ischemic stroke has been essentially unknown. In the present study, we investigated the relationship between APS and potential embolic sources including PFO and ASA using transesophageal echocardiography (TEE). Methods: This study was a retrospective case series design. From July 2006 to June 2008, 120 patients with ischemic stroke who admitted to Juntendo University Hospital underwent TEE. In this study period, consecutive ischemic stoke patients diagnosed as APS based on the modified Sapporo criteria were enrolled and classified into APS group. Controls were selected among age- and gender-matched stroke patients without APS who also underwent TEE. We assessed clinical characteristics and presence of embolic sources including PFO and atrial septal aneurysm (ASA) between APS and Control groups. Results: Nine of ischemic stroke patients with APS and 41 controls were included. Primary APS was present in one patient (11.1%) of the APS group, and APS with SLE were found in eight patients (88.9%). There is no significant difference in age, risk factors for ischemic stroke, and MRI findings between two groups. The prevalence of PFO and ASA were significantly higher in APS group compared to Control group (89% vs 41%, P=0.027; 67% vs 20%, P=0.015, respectively). C reactive protein was relatively higher in APS group. Multiple logistic regression analysis showed that PFO (OR: 13.71; 95% CI: 1.01 to 185.62; P=0.049) and ASA (OR: 8.06; 95% CI: 1.17 to 55.59; P=0.034) were independently associated with the APS group. Conclusion: Atrial septal abnormalities including PFO and ASA are strongly associated with APS group, and could be potential embolic sources in ischemic stroke patients with APS.

RNA Expression Profiles From Blood for the Diagnosis of Stroke and Its Causes

A blood test to detect stroke and its causes would be particularly useful in babies, young children, and patients in intensive care units and for emergencies when imaging is difficult to obtain or is unavailable. Whole genome microarrays were used to show specific gene expression profiles in rats 24 hours after ischemic and hemorrhagic stroke, hypoxia, and hypoglycemia. These proof-of-principle studies revealed that groups of genes (called gene profiles) can distinguish ischemic stroke patients from controls within 3 to 24 hours after the strokes. In addition, gene expression profiles have been developed that distinguish stroke due to large-vessel atherosclerosis from cardioembolic stroke. These profiles will be useful for predicting the causes of cryptogenic stroke. The results in adults suggest that similar diagnostic tools could be developed for children.