cryptogenic and young stroke
Contents
~25% of ischaemic strokes have no identified cause after standard workup (cryptogenic). In patients <60, PFO is found in ~50% — RoPE score distinguishes pathogenic PFO from incidental. PFO closure reduces recurrence in selected patients (age 18–60, cryptogenic, high-risk PFO features). ESUS-directed empirical anticoagulation does not work. Extended workup targets dissection, thrombophilia, occult AF, vasculitis, and drugs.
- standard stroke labs + ESR, CRP, ANA, lupus anticoagulant, anticardiolipin, anti-β2-glycoprotein I
- fasting lipids, A1C, homocysteine
- toxicology screen if <45 (cocaine, amphetamines)
- CTA head and neck (or MRA) → assess for dissection, vasculopathy
- TTE with agitated saline (bubble study) → if positive or high suspicion and negative, proceed to TEE
- if PFO found → calculate RoPE score → if ≥7 and age 18–60 → refer for PFO closure discussion
- prolonged cardiac monitoring ≥14 days (implantable loop recorder if initial monitoring negative and no cause found)
- if vasculitis suspected (multiterritory infarcts, young, systemic features): vessel wall MRI, complement, ANCA, extractable nuclear antigens
- thrombophilia screen (≥2 wk post-event, off anticoagulation): protein C/S, antithrombin, factor V Leiden, prothrombin gene
- consider LP if CNS vasculitis, infection, or malignancy suspected
when to suspect
- age <60 with ischaemic stroke and no conventional risk factors (HTN, AF, DM, significant atherosclerosis)
- cortical infarct pattern on imaging (embolic distribution)
- standard workup (ECG, telemetry, carotid imaging, TTE) non-diagnostic
- recurrent stroke without identified mechanism
young stroke aetiology
| category | examples |
|---|---|
| cardioembolism | PFO ± atrial septal aneurysm, occult AF, valvular disease, endocarditis |
| arterial dissection | carotid or vertebral — trauma, connective tissue disorder, spontaneous |
| thrombophilia | antiphospholipid syndrome, protein C/S deficiency, factor V Leiden |
| vasculopathy | moyamoya, fibromuscular dysplasia, CNS vasculitis, reversible cerebral vasoconstriction syndrome |
| haematological | sickle cell, polycythaemia vera, PNH, TTP |
| drugs | cocaine, amphetamines, oral contraceptives + smoking |
| other | migraine with aura (diagnosis of exclusion), CADASIL, mitochondrial disease |
Arterial dissection is the most common cause in patients <45. Antiphospholipid syndrome requires confirmation at ≥12 weeks.
bubble study and PFO assessment
Agitated saline TTE — first-line screening for right-to-left shunt. Microbubbles appearing in left atrium within 3 cardiac cycles = intracardiac shunt (PFO); >3 cycles suggests pulmonary AVM.
- perform at rest and with Valsalva release (opens PFO flap)
- grade: small (<10 microbubbles), moderate (10–30), large (>30)
- if TTE negative but clinical suspicion high → TEE with bubble (sensitivity ~95% vs ~50% for TTE)
High-risk PFO features (predict pathogenicity and identify closure candidates):
- large shunt (>20 microbubbles or curtain pattern)
- atrial septal aneurysm (septal excursion >10 mm)
- hypermobile interatrial septum
- prominent Eustachian valve
RoPE score (risk of paradoxical embolism)
Estimates probability that a PFO found in cryptogenic stroke is pathogenic rather than incidental.
| variable | points |
|---|---|
| no hypertension | +1 |
| no diabetes | +1 |
| no prior stroke or TIA | +1 |
| non-smoker | +1 |
| cortical infarct on imaging | +1 |
| age 18–29 | +5 |
| age 30–39 | +4 |
| age 40–49 | +3 |
| age 50–59 | +2 |
| age 60–69 | +1 |
| age ≥70 | +0 |
Interpretation: score ≥7 → PFO likely causative (~85% attributable fraction); score ≤3 → PFO likely incidental. Higher scores also predict lower stroke recurrence (the PFO was the mechanism, and it can be fixed).
PFO closure — who qualifies
CSBPR and AHA/ASA recommend device closure when all criteria met:
- age 18–60
- cryptogenic ischaemic stroke (standard and extended workup excludes other causes)
- PFO with high-risk features (large shunt or atrial septal aneurysm)
Based on CLOSE (2017), RESPECT Extended (2017), and GORE-REDUCE (2017) — all showed significant reduction in recurrent stroke with closure vs antiplatelet therapy alone.
Post-closure: DAPT (ASA + clopidogrel) × 3–6 months → ASA monotherapy. New-onset AF occurs in ~5% post-procedure (usually transient).
All trials used antiplatelets post-closure. Closure alone without ongoing antiplatelet therapy is not supported.
If closure not pursued or not eligible → antiplatelet therapy (ASA or clopidogrel). Anticoagulation over antiplatelets for PFO-stroke is not established outside of concurrent AF or thrombophilia.
ESUS — embolic stroke of undetermined source
Defined as non-lacunar infarct without cardioembolic source, ipsilateral stenosis >50%, or other identified cause. ~17% of ischaemic strokes.
Empirical anticoagulation for ESUS does not work:
- NAVIGATE ESUS (2018): rivaroxaban vs ASA → no benefit, more bleeding → trial stopped early
- RE-SPECT ESUS (2019): dabigatran vs ASA → no benefit
ESUS is a heterogeneous category — the mechanism matters. Management depends on what the extended workup reveals:
- occult AF found → anticoagulate
- PFO found → closure if criteria met
- atherosclerotic source identified → statin + antiplatelet ± revascularisation
- none found → antiplatelet monotherapy + prolonged cardiac monitoring
traps
- PFO prevalence is ~25% in the general population — finding one does not mean it caused the stroke. Use RoPE score
- do not anticoagulate ESUS empirically — two large RCTs showed no benefit
- hypercoagulability testing during acute illness or on anticoagulation gives unreliable results — defer ≥2 weeks, off anticoagulation
- antiphospholipid antibodies require confirmation at ≥12 weeks to diagnose APS
- dissection can be missed on CTA — if suspicion high and CTA negative, MRA with fat-sat sequences is more sensitive for intramural haematoma
- implantable loop recorder detects more AF than 14-day Holter (~30% vs ~16% at 12 months) — consider if initial monitoring negative and no cause found
- do not forget oral contraceptives + smoking as a modifiable cause in young women — counsel and stop