BACKGROUND: In industrialized countries a considerable and increasing proportion of strokes occur at younger ages. Stroke at young age causes marked disability at worst and thus long-standing socioeconomic consequences and exposes survivors for 4-fold risk of premature death compared with background population. Up to 50% of young patients with ischemic stroke remain without definitive etiology for their disease despite extensive modern diagnostic work-up (i.e. cryptogenic stroke). The group of cryptogenic strokes includes those with patent foramen ovale (PFO) or other abnormalities in the atrial septum in the heart as the only or concomitant finding. Population prevalence of PFO is high, 25%, and the mechanisms how PFO would be associated causally with ischemic stroke remain to be clarified. Moreover, there are only scarce data on clinical outcome, long-term risk of new vascular events, and prevention of such events in these patients.

DESIGN: Searching for Explanations for Cryptogenic Stroke in the Young: Revealing the Etiology, Triggers, and Outcome (SECRETO) is an international prospective multicenter case-control study of young adults (age 18-49) presenting with an imaging-positive first-ever ischemic stroke of undetermined etiology (aim N=2000). Patients are included after standardized diagnostic procedures (brain MRI, imaging of intracranial and extracranial vessels, cardiac imaging, and screening for coagulopathies) and age- and sex-matched to healthy controls in a 1:1 fashion. Up to 45 study sites worldwide will be needed to recruit the planned participant population during a 3-year period. Neurovascular imaging and echocardiography studies, and ECGs will be read centrally.

AIMS: SECRETO involves five principal fields of investigation: (1) Stroke triggers and clinical risk factors; (2) Long-term prognosis (new vascular events, functional and psychosocial outcomes); (3) Abnormalities of thrombosis and hemostasis; (4) Biomarkers of e.g. inflammation, atherogenesis, endothelial function, thrombosis, platelet activation, and hemodynamic stress to characterize postulated cryptogenic stroke mechanisms; and (5) genetic study, including genome-wide association and candidate gene studies as well as next-generation sequencing approach. All analyses consider cardiac functional and interatrial structural properties as a possible mediator. Furthermore, SECRETO Family Study (substudy) aims at collecting extensive family history of thrombotic events from informative patients being screened for SECRETO main study and collect genetic samples from all consenting family members for whole-genome sequencing.

SIGNIFICANCE: SECRETO will provide novel information on clinical and subclinical risk factors, both transient and chronic, predisposing to cryptogenic ischemic stroke in young adults. This study also reveals long-term prognosis of this understudied patient population and may discover new genetic background underlying the disease mechanism and provide potential targets for drug development.

PATIENTS:

Inclusion Criteria:

1. Age 18 to 49 at stroke onset
2. Patient hospitalized due to first-ever imaging-positive ischemic stroke of undetermined etiology after complete timely diagnostic testing.

Exclusion Criteria:

1. Baseline mandatory tests not obtained in the first week following stroke onset, including:

   • Brain MRI
   • Routine blood tests, including complete blood count, CRP, fasting glucose, creatinine, aPTT, INR, total cholesterol, LDL-cholesterol, HDL-cholesterol, HbA1C, hemoglobin electrophoresis in individuals of African origin

2. Other baseline mandatory tests not obtained within the first two weeks following stroke onset, including:

   • Imaging of cervicocephalic arteries by CTA, MRA, or DSA
   • Transesophageal (highly recommended) or transthoracic echocardiography
   • 24-hour Holter monitoring or continuous in-hospital ECG monitoring with automated arrhythmia detection for at least 24 hours
   • Screening for thrombophilia, including antiphospholipid antibodies and other coagulopathies (any abnormal finding must be retested at mandatory 3-month follow-up visit >12 weeks from initial testing or >4 weeks after cessation of anticoagulation at any later time point); mandatory tests include anticardiolipin antibodies, lupus anticoagulant, anti-β2-glycoprotein antibodies, factor V mutation (or aPC resistency ruled out), factor II mutation, homocysteine, antithrombin III, protein C, and protein S

3. No evidence of current brain ischemia

4. Current stroke due to cerebral venous thrombosis or as a complication of subarachnoid hemorrhage, angiography, or cardiac surgery

5. Patient otherwise not eligible for the study or adherent for follow-up (eg nonresident) or has concurrent disease affecting outcome (eg multiple sclerosis, cancer)

6. Informed consent not obtained from the patient or a proxy.

CONTROL SUBJECTS:

Inclusion Criteria:

1. Age 18 to 49 years
2. Absence of prior ischemic stroke as ascertained using the Questionnaire for Verifying Stroke-Free Status

Exclusion Criterion:

1. Informed consent not obtained

1. Patients aged 18 to 49 hospitalized due to first-ever imaging-positive ischemic stroke of undetermined etiology;
2. Age-, gender- and race-ethnicity-matched stroke-free control subjects