Searching for Explanations for Cryptogenic Stroke in the
Young: Revealing the Etiology, Triggers, and Outcome

In 60% of all strokes in young adults the cause remains unknown and are called
cryptogenic.
To prevent, treat and prescribe secundary preventive medication or give advice,
it is essential that the cause (etiology) is known.
An underdiagnosed but possibly relevant finding in young adults is an open
foramen ovale between the two heart atria. This can be detected with
transcranial Doppler of the heart in combination with transthoracal
echocardiography. If and how this plays a role in causing strokes is not known.
With this study we look for new etiologies by looking at risk factors and
triggers and we closely investigate the heart by more structured and extensive
echo cardiography.

Area of interest (study setting): Specific aims:
Transient triggers and chronic risk
factors (case-crossover and casecontrol)
(1) To investigate frequency and strength of association between transient
physical and
psychological triggers and early-onset CIS.
(2) To look for frequency and characteristics of preceding infections, their
potential
hazard periods, and impact on the risk for early-onset CIS.
(3) To estimate the strength of association of well-documented chronic vascular
risk
factors and anthropometric measures and early-onset CIS, and
(4) Similarly analyze measurable less well-documented risk factors (eg migraine
with
aura, stress, short or long sleep duration, snoring).

Advanced cardiac imaging (case-only (1) To develop a step-by-step performance
protocol for standardization of transthoracic
and case-control) and transesophageal echocardiography for better accuracy in
the evaluation of
potential cardiac sources of embolism.
(2) To identify high-risk cardiac features (case-control study) focusing on
patent foramen
ovale (PFO) characteristics, and left atrial and left atrial appendage
dimensions, as
well as their functional parameters.

Thrombosis/hemostasis, biomarkers
(case-control); see Appendices I and II.
(1) To investigate the role of modestly and often transiently elevated
antiphospholipid
antibodies in early-onset CIS. Blood samples outside of the acute/subacute
period
after index stroke are essential for this analysis.
(4) To study whether activation of intrinsic coagulation factors and thrombosis
initiator
activity (eg high vWF or low ADAMTS13) is associated with early-onset CIS.
(5) To explore whether plasma biomarkers of inflammation, atherogenesis,
endothelial
function, thrombosis, platelet activation, hemodynamic stress, and renal
dysfunction
may hint of underlying mechanisms of early-onset CIS.

Genetics (case-control)
(1) To assess to what extent routinely tested genetic thrombophilia with
uncertain
causality (factor V and II mutations, deficiency of antithrombin, protein C or
protein S)
increase the risk of early-onset CIS.
(2) To test association of potentially relevant candidate genes, e.g. genes
encoding
endothelial function, platelet glycoprotein receptors, thrombosis activation and
regulation, inflammatory response regulation (however, the decision whether to
study
candidate genes may be dependent on the results of more sophisticated genetic
approaches).
(3) To find new genetic loci and ultimately susceptibility genes for
young-onset ischemic
stroke using genome-wide association study (GWAS) and next generation
sequencing techniques (whole exome or whole genome sequencing, depending on
funding opportunities). For GWAS, this cohort will be meta-analyzed with
existing
young-onset stroke cohorts to increase power to detect significant loci.

Prognosis (follow-up of patients)
(1) To describe long-term risks of recurrent ischemic cerebrovascular events
(primary
outcome), composite of noncerebrovascular arterial or venous thrombotic events,
or
cerebral venous thrombosis, death from any cause, and new-onset atrial
fibrillation
(secondary outcomes).
(2) To assess functional neurological, neuropsychosocial, and vocational
outcomes.
(3) To find predictors of outcomes based on patient phenotype*e.g. considering
PFO
status, neuroimaging subtype, thrombosis/hemostasis or biomarker profile*and
genotype established in previous studies.
(4) To define use of secondary preventive measures in this patient population,
evaluate
compliance to medication and its effectiveness with propensity score matching
method.
(5) To describe the change in the patient phenotype and risk factor profile
during followup
and assess whether the causal stroke etiology will be revealed at the time of
recurrence.

Case-control

Very low risk.