The study included a total of 520 patients with ischemic stroke who were admitted to the stroke units between 2016 and 2019. After excluding patients with identifiable causes of stroke and patients who were lost during the investigational procedures, a total number of 63 patients with cryptogenic stroke were eligible for further work up (Fig. 1).
Patients with cryptogenic cerebrovascular stroke included 36 males (57.1%) and 27 females (42.8%). Their age ranged from 20 to 59 years with mean age of 36.1 ± 9.3 years.
Twenty-four patients had a previous history of one or more stroke or transient ischemic attack (TIA) (38.09%).
Seven patients tested positive for lupus anticoagulants (11.1%), and 3 patients tested positive for anticardiolipin antibodies (4.7%). Eight patients had protein C deficiency (12.6%), 9 patients had protein S deficiency (14.2), 4 patients had antithrombin III deficiency (6.3%), one patient was diagnosed with Takayasu arteritis, and one patient had systemic lupus erythematosus (SLE). We had one patient with concomitant deep venous thrombosis, pulmonary embolism, and stroke.
Site of cerebrovascular stroke on neuroimaging studies
Fifty-one ischemic strokes were located anterior, i.e., in the distribution of anterior cerebral artery or middle cerebral artery (80.9%), and 12 ischemic strokes were located posterior in the distribution of the vertebral, basilar, or posterior cerebral artery (19.1%).
Cardiac imaging studies in patients with cryptogenic stroke
Four patients had intracardiac thrombi (6.3%), 5 patients had descending aorta plaques (7.9%) only one of them had complex aortic plaque (which is defined as increased echo density and thickening of the intima > 5 mm with shaggy overlying echogenic material and marked irregularities in the intimal wall), and 2 patients had filamentous mass in relation to aortic valve (Lamble’s excrescence) (3.1%).
Assessment of the interatrial septum
Twenty-six patients had patent foramen ovale PFO (41.2%) by trans-esophageal echocardiography, 13 of them had associated atrial septal aneurysm (ASA), 5 had associated fenestration, and 1 patient had secundum atrial septal defect.
Twenty-four patients had positive shunting on bubble study on TTE and/or TEE (using agitated saline, Valsalva maneuver, and/or abdominal compression). The degree of shunting by TEE was mild in 5 patients, moderate in 13 patients, and severe in 6 patients.
Contrast transcranial Doppler
We had 5 patients with severe degree of shunt on TCD at rest, 16 patients with grades II and III shunts, and 4 patients with grade I shunt.
One patient with PFO showed evidence of right to left shunt on c-TCD only, and one patient did not reveal any evidence of right to left shunt on both TEE and c-TCD.
Management
We included the 25 patients with PFO and evidence of right to left shunt in active team discussion to determine the best management plan.
Surgical repair
Three female patients were referred for surgical repair of the interatrial septum due to multiple fenestrations occupying the whole septum; two of them had a very large, highly mobile ASA that was deemed not to be suitable for transcatheter closure (video 1).
Additional file 1: Video 1. 2 D trans-esophageal echocardiography in mid esophageal four chambers view showing patent foramen ovale (PFO) with very large highly mobile Atrial septal aneurysm (ASA).
Medical management
Four patients refused transcatheter closure and opt to medical treatment. They were kept on dual antiplatelet therapy (DAPT) therapy including acetylsalicylic acid and clopidogrel. One patient had recurrence TIA within the first 2 months of medical treatment, and he was crossed over to the transcatheter closure arm.
Transcatheter closure
Nineteen patients underwent transcatheter PFO closure. The procedure was done under general anesthesia and trans-esophageal echocardiography guidance in all patients.
Right femoral vein access was used in all patients. Intravenous dose of 100 IU/Kg heparin was given after securing the vascular access; activated clotting time (ACT) was monitored in all the patients with a target level more than 250 s; additional heparin doses were given if needed according to the ACT. All sheaths and catheters were routinely flushed with heparinized saline (1 IU/ml); manual compression was used in all patients after sheath removal.
We used balloon interrogation and sizing of the PFO tunnel in 15 patients (78.9%).
Five patients had PFO device (one 18-mm device and four 25-mm devices); 5 patients had atrial septal occluder device (ASO)—this was done in patients with large sized and/or long tunneled PFO—(two 14-mm devices, one 15-mm device, one 16-mm device, and one 12-mm device); 8 patients had cribriform device (five 25 mm, two 30 mm, and one 35 mm). We failed to cross the PFO in only one patient (Figs. 2a, b, 3a, b, 4a, b, c).
Incidence of complications
The procedure was successful in 18 patients (94.7%). None of the patients had major procedure-related complications; we did not experience any cases of device embolization or device erosion.
We encountered one case of atrial fibrillation that occurred during catheter manipulation within the left atrium while device deployment; it was successfully cardioverted using single synchronized DC shock. Cardiac monitoring of this patient at follow-up did not show any recurrent paroxysmal attacks.
We had one patient with device-related thrombosis on the left side disc (Fig. 5a). It was discovered 1 week after the procedure and was managed successfully by triple therapy (DAPT and oral anticoagulation) with no embolic events, and complete resolution of the thrombus at the follow-up as evidenced by trans-esophageal echocardiography study.
One patient had a TIA within the first 3 months after PFO device closure; this was managed by addition of anticoagulation to the patient’s medical treatment during the first 6 month after the procedure, with no recurrent events thereafter.
Follow-up after device closure
Clinical follow-up every month for the first 6 months was done for all patients.
Transthoracic echocardiography was done the day next to the procedure, at 1 week, at 1 month, 3 months, and at 6 months.
TTE and/or TEE with bubble study was done to all patients at 6 months (Fig. 5b). c-TCD was done in patients with equivocal or positive bubble study results.
Absence of shunt was successfully achieved in 15 patients (83.3%) at 6 months as evidenced by bubble study and/or c-TCD.
Three patients showed significant reduction of the amount of shunt without complete abolishment. Those three patients had severe (grade III-curtain) right to left shunt at rest by c-TCD during their baseline assessment. They were all managed conservatively with extended DPAT without new clinical events.
All the patients were kept on DAPT therapy for 6 months, then single antiplatelet therapy for another 6 months. Patients were followed up regularly to estimate their bleeding and thrombotic risks; continuous evaluation by the stroke team members was done to determine the best anti-thrombotic therapy.