Stroke in the young usually results from a variety of conditions that, although individually uncommon, collectively account for approximately 40% of all strokes. Ischemic strokes can be caused by atherosclerotic cerebrovascular disease, nonatherosclerotic abnormalities, cardiac emboli, hematologic or coagulation disorders, substance abuse, migraines, oral contraceptive use, inflammatory disorders, and many other conditions. The spectrum of etiologies may differ by geographic region (Ghandehari and Moud 2006), with traditional stroke etiologies reportedly higher in eastern countries (Razzaq et al 2002; Mehndiratta et al 2004). The etiology and risk factors of ischemic stroke after the age of 40 is similar to those seen in older patients (Putaala 2009). The frequency of etiologies of cerebral infarct in the young may differ according to the classification system used. Thus, based on the widely used TOAST classification system, the main etiologies in a series of 104 patients aged 18 to 45 were cardiac embolism (21%) and “other causes” (19%), whereas large atherothrombotic arteriopathy and small vessel disease each accounted for 10% of etiologies. In this cohort, the etiology of 40% of the cerebral infarcts could not be determined (Chatzikonstantinou et al 2012). More recently, in a large cohort of 3331 patients between the ages of 15 and 50 with a first-ever cerebral infarct assessed according to TOAST criteria at 15 European stroke centers, stroke of other determined etiology was the most common subgroup (22%), followed by cardioembolism, found in 17% of the patients (Yesilot Barlas et al 2013). In the subgroup of other determined etiology, cervical artery dissection (13%) was the main cause, followed by genetic thrombophilia and systemic vasculitis. In the cardioembolism subgroup, atrial fibrillation or flutter was the most common high-risk source of embolism, whereas patent foramen ovale was the most frequent low-risk source of embolism. Small-vessel occlusion and large-artery disease were found less frequently, accounting for 12% and 9% of etiologies, respectively. Etiology of ischemic stroke could not be determined in 40% of the patients (Yesilot Barlas et al 2013). Compared by gender, the most common TOAST subgroup in females was “other determined etiology” (24%), mostly involving cervical artery dissection (13%) and nonatherosclerotic inflammatory arteriopathies (systemic vasculitis), whereas small-vessel occlusion (15%) and nonatherosclerotic, noninflammatory arteriopathies (mainly cervical artery dissection) were the most common TOAST etiological subgroups in males. The proportion of strokes of undetermined etiology was larger in females (43%) than in males (37%) (Yesilot Barlas et al 2013).
In a cohort of 511 patients between 18 and 49 years of age (mean age of 39.8), most of whom were being seen for a first-ever stroke, no significant differences were found between females and males as to the proportion of small- and large-vessel disease, prothrombotic states, cervical arterial dissection, and stroke of undetermined etiology, although cardioembolism and substance abuse predominated in men as compared with women (Nakagawa and Hoffmann 2013). Moreover, 44% of young stroke patients (and almost 60% of the women) had nontraditional etiologies for stroke, including prothrombotic states, migraine-related conditions, substance abuse, cervical artery dissection, cerebral venous thrombosis, inflammatory and miscellaneous vasculopathy, and pathological conditions occurring either exclusively (related to pregnancy and postpartum) or more frequently in women (fibromuscular dysplasia and Moyamoya syndrome) (Nakagawa and Hoffmann 2013).
On the other hand, using the recent ASCO system, which introduces a complete stroke phenotype classification (stroke etiology and the presence of all underlying diseases, divided by grade of severity), the proportion of small vessel disease in the same cohort was no different in comparison to the TOAST system, whereas the frequencies of large vessel disease, embolism from a cardiac source, and other etiologies were lower compared to the TOAST criteria, with 8.7%, 10.6%, and 13.5%, respectively. The rate of stroke of undetermined cause (“cryptogenic strokes”) using the corresponding score in the ASCO system (A0S0C0O0) was half that of the TOAST system (19%) (Chatzikonstantinou et al 2012). Jaffre and coworkers identified a definite cause of stroke based on the ASCO classification system (grade 1) in half of 400 patients aged 16 to 54 (mean age 44.5; 39% under 44) with a first cerebral infarct. Atherosclerosis and other definite causes (mainly carotid and vertebral arterial dissections) accounted for 18% and 16% of cases, respectively; cardioembolism (9%) and small vessel disease (7%) were less common etiologies (Jaffre et al 2014).
Hemorrhagic strokes may be caused by underlying vascular structural abnormalities, abnormal composition of blood vessels, effects of chronic arterial hypertension, trauma, or effects of acute hypertension and vasoconstriction, such as in the setting of sympathomimetic or illicit drug use. The cause of up to one third of hemorrhages may remain unknown even after an exhaustive evaluation (Awada et al 1996; Lai et al 2005; Koivunen et al 2015). A notable genetic study found that polymorphisms in the glutathione peroxidase (Gpx-3) gene, perhaps via interactions with conventional vascular risk factors, increase the risk for ischemic stroke in children and young adults (Voetsch et al 2007). Such polymorphisms affect the gene's transcriptional activity and thereby compromise plasma antioxidant and antithrombotic activities. Arterial hypertension and arteriovenous malformations were the leading causes in 69 patients with a first-ever intracerebral hemorrhage included in a prospective study aimed at assessing the consequences of stroke in the young. Etiology could not be determined in nearly 20% of these patients and 18% had an incomplete evaluation, mainly because of early death (Rutten-Jacobs et al 2013). In 1 study, arterial hypertension and vascular malformations (mainly cavernous angiomas) were found to be the leading etiologies – each accounting for 25% of cases – in a large retrospective cohort of nontraumatic intracerebral hemorrhage. Cerebral vein thrombosis and illicit drug use were the most common etiologies in patients younger than 30, whereas structural lesions (arteriovenous malformations and cavernous angiomas) and hypertensive microangiopathy were the main etiologies in the over-30 group. The cause of intracerebral hemorrhage remained undetermined in one third of patients, especially in those aged 40 to 49 years (Koivunen et al 2015).