ISCHEMIC STROKE / CLASSIFICATION AND ETIOPATHOGENESIS

Stroke in young adults

David Goldemund M.D.
Updated on 12/01/2024, published on 17/12/2021

young adults stroke = stroke in persons aged 18 to 55 years
- some authors specify an upper age limit of 45 or 49 years
young adults comprise 10%–15% of all stroke patients, with a significant increase after the age of 40 [Smajlović, 2015]
compared to the older population, where arteriolopathy, atherothrombosis, and cardioembolism due to AFib predominate, the spectrum of risk factors and possible causes in the younger population is distributed differently and are more diverse [Schöberl, 2017]
- 25% – cardioembolic stroke (valvular defects, cardiac tumors, PFO)
- 20% – arterial dissection
- 10% – rare causes (vasculitis, vasculopathies, thrombophilia, genetic diseases, etc. )
- 25-50% – cryptogenic stroke (of which 20-30% meet ESUS criteria)
- ?% – stroke in pregnancy and puerperium
approximately after the age of 40, the proportion of vascular risk factors increases, together with the proportion of large and small vessel disease (TOAST 1 and 3)
a thorough etiologic diagnostic evaluation and individualized secondary prevention are essential
the acute treatment is the same for patients of all ages (including recanalization therapy if eligible)

Etiology and risk factors

the identification of rare causes of juvenile stroke requires significant diagnostic effort
the most common etiology of stroke in young adults is cryptogenic stroke (20-40%) and cardioembolic stroke [Smajlović, 2015]
- TOAST classification may overestimate patients with stroke of undetermined etiology (TOAST 5), mainly because patients with two or more potential etiologies are categorized into this group
in young patients with carotid artery occlusion or stenosis, exclude dissection and vasculitis

modifiable vascular risk factors are similar for younger and older patients
- hypertension, heart disease (including atrial fibrillation), dyslipidemia, and diabetes mellitus are the most common risk factors among the elderly
- in young stroke patients, the most common vascular risk factors are dyslipidemia, smoking, and hypertension [Putaala, 2012]
- patients without documented risk factors have less frequent recurrent ischemic strokes and non-cerebrovascular arterial events

DDx in young stroke patients using the TOAST classification
*Large-Artery Atherosclerosis (TOAST 1)*
in young adults, large-artery pathologies are primarily attributed to vasculitis or non-inflammatory vasculopathies (classified as TOAST 4) premature atherosclerosis in large vessels is rare (more likely occurring after the age of 40
Cardioembolism (TOAST 2) → Cardioembolic stroke
valvular heart disease patent foramen ovale (PFO) intracardiac tumors (myxoma, fibroelastoma) endocarditis septal defects cardiomyopathy myocarditis atrial fibrillation (rare in young people)
Small artery disease (TOAST 3)
typical arteriolopathy presenting with a lacunar syndrome is uncommon in younger patients hereditary cerebral microangiopathies are included in TOAST 4 (CADASIL, CARASIL, CARASAL, etc.)
Stroke of other determined etiology (TOAST 4)
Vasculitis < 5% of stroke patients < 50 years of age mainly PACNS and Takayasu arteritis occur at a younger age giant cell (temporal) arteritis occurs in elderly patients (> 50 years of age) *→ vasculitis overview* Non-inflammatory vasculopathies arterial dissection vasospasm primary (idiopathic) secondary (due to complicated migraine, SAH-related vasospasm, VSP provoked during angiography or by drugs, etc.) *reversible vasoconstriction syndrome (RCVS)* moya-moya angiopathy multiple etiologies (e.g., idiopathic, Grange syndrome, ACTA2 mutations, vasculitis, etc.) metabolic diseases *Fabry disease* homocystinuria *MELAS* cerebral amyloid angiopathy (CAA) embolization from (pseudo) aneurysm (extra-/intracranial) migraine (probably due to prolonged vasospasm) heritable connective tissue disorders (HCTDs) Marfan syndrome Ehlers-Danlos syndrome fibromuscular dysplasia (FMD) Sneddon syndrome non-inflammatory thrombotic angiopathy affecting small to medium-sized arteries; presenting as stroke + livedo racemosa carotid artery web *Grange syndrome* dolichoectasia (usually involving the basilar artery) bone disorders and stroke (bony stroke) rare bone or cartilage anomalies affecting arteries supplying the brain may be considered in patients with recurrent ischemic stroke of unknown cause in the same vascular territory in addition to conventional vascular imaging, the dynamic imaging modalities with the patient’s head rotated or reclined may confirm the diagnosis (e.g., Bow hunter´s syndrome) Eagle’s syndrome is a condition associated with the elongation of the styloid process or calcification of the stylohyoid ligament, clinically characterized by throat and neck pain radiating into the ear; rarely, it may cause carotid dissection (Ogura, 2015) (Saccomanno, 2018) Genetically linked microangiopathies CADASIL CARASIL CARASAL *Fabry disease* COL4 disorders *RVCL-S (Retinal Vasculopathy with Cerebral Leukoencephalopathy and Systemic manifestations)* → overview of genetic cerebral small vessel diseases Other microangiopathies Susac syndrome (retino-cochleo-cerebral vasculopathy) rare microangiopathy of the cochlea, retina, and brain of unknown etiology (probably vasculitic in origin) Parainfectious etiology COVID-19 often in younger patients, in up to 1/3 of cases asymptomatic) [Shahjouei, 2021] [Fridman, 2020] 36% in age <55 yrs, 46% < 65 y [Shahjouei, 2021] predominantly embolic mechanism with large artery occlusion (LVO) due to a hypercoagulable state [Shahjouei, 2021] [Yaghi, 2020] more severe course compared to non-COVID patients ↑ D-dimers Hematologic disorders hypercoagulable states primary – most often antiphospholipid syndrome and APC resistance secondary oncohematologic diseases (e.g., leukemia, polycythemia vera) thrombotic thrombocytopenic purpura (TTP) non-specific intestinal inflammation nephrotic syndrome hemoglobinopathies (typically sickle cell disease) hematological malignancies hyperviscosity syndrome (HVS) Paradoxical embolization intracardiac shunt (PFO, ASD, etc.) – usually classified as TOAST 2 extracardiac shunt pulmonary AV malformations (PAVM) patent ductus arteriosus (PDA) (Panagopoulos, 2019) persistent left superior vena cava (PLSVC) (Hutyra, 2010) (Azizova, 2020) → Paradoxical embolism and stroke Iatrogenic insults angiography (including cardiac catheterization) → complications of endovascular procedures carotid revascularization (CEA, CAS) Extra Corporeal Circulation (ECC) related complications air and fat embolism (see below) Fat, air and tumor embolism fat embolism typically occurs after trauma (long bone fractures) and surgery (including plastic surgery with fat removal) air embolism (microscopic x macroscopic) a consequence of the incorrect insertion of a venous catheter into an artery [Riebau, 2004] improper extraction of the central venous catheter (CVC) [Brockmeyer, 2009] repeated IV applications in combination with pulmonary AV shunt or PFO during catheterization embolization of cholesterol particles from plaques should be assessed as TOAST 1 → Cholesterol Embolization Syndrome (CES) spontaneous x iatrogenic Systemic hypoperfusion diffuse lesions or border zone (watershed) infarcts etiology systemic hypotension cardiac failure extracorporeal circulation (ECC) surgery hypoperfusion in carotid occlusion/stenosis (⇒ TOAST 1! ) Medication, drugs various mechanisms ( e.g., vasospasm, cardioembolism in endocarditis) oral contraceptives (usually in combination with a hypercoagulable state and/or smoking) cocaine, crack, amphetamines, LSD, and heroin (drugs often cause IC bleeding) sympathomimetics, ergotamine, sumatriptan Pregnancy-related stroke various mechanisms (most usually due to a hypercoagulable state or cardioembolism) specific causes of stroke in pregnancy: preeclampsia/eclampsia amniotic fluid embolization (AFE) choriocarcinoma postpartum cerebral angiopathy postpartum/peripartum cardiomyopathy (PPCM)
Cryptogenic stroke (TOAST 5) → see here
In addition to the TOAST classification, it’s important to consider stroke during pregnancy and puerperium which may have various etiopathogeneses