Here, only an overview of the main subtypes of ischemic stroke in the young will be provided, as rarer etiologies have been covered comprehensively in recent review papers.18 Stroke subtype distribution can be categorized using the Trial of Org 10172 in Acute Stroke Treatment (TOAST)
criteria.19 These criteria were first presented in 1993 by Adams et al. and remain the most commonly applied classification for ischemic stroke in research as well as in clinical practice. Table 1 shows the largest studies on early-onset ischemic stroke published within the last 20 years and subtypes of stroke according to the TOAST criteria.
The most common single established etiology in young adults is cervicocephalic arterial dissection (up to 25% of cases), included in the other determined group of the TOAST. Other common TOAST subgroups comprise stroke of undetermined etiology, i.e. cryptogenic strokes (UE, 19-40%), cardioembolism from high-risk source (CE, 134%), and large-artery atherosclerosis (LAA, 7-26%).1,2,20-27 The variability of etiologies between studies largely depends on the completeness of the diagnostic work-up and whether e.g. low-risk or uncertain sources of cardioembolism (mainly PFO) are classified as UE or CE. Moreover, the proportion of UE differs significantly between studies since according to the TOAST criteria this subgroup includes all three of the following categories: (1) patients with no evident cause despite extensive evaluation, considered as true cryptogenic strokes, TOAST 5b, (2) patients with incomplete diagnostic evaluation, TOAST 5c, and (3) patients with two or more potential etiologies, TOAST 5a. LAA accounts for approximately 10-25% of early-onset ischemic strokes, but has an even greater proportion in certain ethnic groups such as Asians. In younger stroke patients, the proportion of UE is larger.1,28 Sporadic small-vessel disease (SVD) accounts for 5-17% of early-onset strokes.
In 2009, Amarenco et al. proposed a new approach to stroke subtyping, the Atherosclerosis-Small-vessel disease-Cardiac pathology-Other causes (A-S-C-O) phenotyping of ischemic stroke,29 which takes multiple simultaneous etiologies better into consideration and grades the level of evidence of diagnostic evaluation.30 Using this classification, however, may leave a larger proportion of definite causes of stroke unidentified.31 In 2013, the same authors further highlighted the high frequency of dissection in young stroke patients by adding “D” to the A-S-C-O acronym, producing A-S-C-O-D.32 In the same publication, they also suggested that the cut-off for atherosclerotic stenosis of the significant vessel (either carotid or intracranial) should be as high as 70% instead of the earlier 50%.
Furthermore, in 2005 the Causative Classification System (CCS) was designed to improve the classification of stroke subtypes based on TOAST, with high interrater reliability between multiple investigators.33 Finally, Subtypes of Ischemic Stroke Classification System (SPARKLE) seems to provide a further advantage in assessing the carotid plaque burden in ischemic stroke etiological classification.34
In summary, several classifications can be used to describe the etiological subgroups, but TOAST remains the most commonly used in both clinical practice and research.
2.2.1 Cryptogenic stroke
The entity of cryptogenic ischemic stroke was probably first introduced in 1988 as “infarction, unknown cause” within the National Institute of Neurological and Communicative Disorders35 Several criteria have since then been proposed for the minimum diagnostic work-up for cryptogenic ischemic stroke such as the ones from the guidelines of the American Heart Association/American Stroke Association.36 According to these guidelines, the minimum baseline evaluation should consist of non-contrast brain and carotid artery computed tomography (CT) or magnetic resonance imaging (MRI), complete blood count, electrocardiogram (ECG), markers of cardiac ischemia, and serum electrolytes.
However, it is evident that the proportion of cryptogenic stroke diminishes if timely additional examinations are done.18 These should include e.g. prolonged ECG monitoring, also intracranial artery imaging, both transthoracic echocardiography (TTE) and transesophageal echocardiography (TEE), and extended laboratory measurements to reveal any prothrombotic states. For example, if imaging of carotid vessels is delayed, an etiology such as dissection might be missed and optimal secondary prevention misdirected. This could also lead to other futile etiologic examinations.18 More extensive diagnostic work-up may also reveal occult atrial fibrillation (AF), valve vegetations, atrial myxomas, and aortic arch atheromas. Also occult cancer and other diseases causing hypercoagulability, heredity prothrombotic disorders, and vasculitis should be sought.18,37-39 For instance, in approximately one-third of patients with reversible cerebral vasoconstriction syndrome (RCVS), computed tomography angiography (CTA) or MRA may have to be repeated since these might not confirm the diagnosis during the first week. RCVS usually manifests as a bilateral pattern of “string of beads” that should resolve within 12 weeks. Furthermore, in some cases, digital subtraction angiography might be necessary, and it remains the reference imaging for depicting RCVS.40,41 Cerebrospinal fluid analysis can further help to differentiate RCVS from central nervous system vasculitis. These ancillary diagnostic studies might decrease the proportion of ischemic strokes initially considered as cryptogenic. However, a systematic review by McMahon and colleagues with 16 clinical practice guidelines and 7 consensus statements concluded that there is little agreement on more advanced or specialized investigations for rarer causes of acute ischemic stroke.42 This might lead to inappropriate use of costly and specialized resources and skills, as well as a lack or delays in a more specific etiological diagnosis.
Table 1. Frequencies of the main subtypes of ischemic stroke according to Trial of Org 10172 in Acute Stroke Treatment classification in a large patient series, including young patients, published within the last 20 years.
LAA, large-artery atherosclerosis; CE, cardioembolism; SVD, small-vessel disease; OTH, other determined etiology;
UE, undetermined etiology. *Includes patients with transient ischemic attack.
2.2.2 Embolic stroke of undetermined source
Criteria to define embolic stroke of undetermined source (ESUS) was proposed in 2014 to characterize a subgroup of cryptogenic ischemic strokes.43 Before the publication of ESUS criteria, it was already shown that patients with undetermined strokes with an embolic pattern were younger and had more favorable risk factor profile, but still had a high risk of stroke recurrence.44 The diagnostic criteria for ESUS are shown in Table 2.
Table 2. Diagnostic criteria for embolic stroke of undetermined cause.43 Non-lacunar stroke detected by CT or MRI
Absence of extracranial or intracranial atherosclerosis causing ≥50% luminal stenosis in arteries supplying the area of ischemia
No major-risk cardioembolic source of embolism
No other specific cause of stroke identified (e.g. arteritis, dissection, migraine/vasospasm, drug misuse)
CT, computed tomography; MRI, magnetic resonance imaging
Specifically regarding young patients, a preliminary report including just 100 young patients with a mean age of 45 years suggested that up to 4/5 cryptogenic ischemic strokes in the young fulfill the ESUS criteria.45 This report also showed that minor embolic sources, including frequent supraventricular extrasystoles, atrial dilatation, or PFO, do not seem to be more prevalent in young ESUS patients than in stroke of determined cause. However, large-scale comparisons between characteristics of ESUS and other defined stroke subtypes in young patients as well as data on their long-term outcome were lacking at that time.
Regarding age-inclusive studies, Ntaios et al. applied ESUS criteria to the Athens Stroke Registry, including more than 2700 stroke patients, and classified approximately 10% of them as ESUS, with a median age of 68 years.46 The risk factor profile in ESUS was shown to be similar to the general stroke population, including hypertension (65%) and dyslipidemia (51%). This study also revealed that the most frequently affected arterial territory in ESUS was the entire middle cerebral artery and that the symptoms were maximal at onset. ESUS were of moderate severity (median National Institution of Health Stroke Scale, NIHSS 5) compared with cardioembolic strokes (median NIHSS
13). Moreover, in the Global ESUS Registry with more than 2100 patients, ESUS patients (16%) were significantly younger than non-ESUS patients and they had a relatively high prevalence of hypertension (64%), diabetes (24%), and prior stroke (17%). The most frequent secondary prevention with ESUS patients was antiplatelet therapy (90% of patients), while only 7% received anticoagulation.47
Ntaios et al. showed that the long-term mortality in all-aged ESUS was lower than in cardioembolic strokes, although the frequency of recurrence and composite cardiovascular endpoints were similar.
Moreover, the risk of recurrent strokes in ESUS was higher than in non-cardioembolic strokes.48 They also showed that the risk of recurrent ischemic stroke/transient ischemic attack and death in ESUS was reliably stratified by CHA2DS2-VASc score (Congestive heart failure, Hypertension, Age 75 years or older (2 points), Diabetes mellitus, Stroke or transient ischemic attack (2 points), Vascular disease, Age 65 to 74 years, Sex category). The high-risk CHA2DS2-VASc group had approximately a 13-fold risk of ischemic stroke/transient ischemic attack and death relative to the low-risk group.49